Biological effects of ionizing radiation. Radiation protection.

Physico-chemical effects of ionizing radiation
In §1.6 "Ionizing radiation" we dealt in detail with the properties of different types of radiation and its interactions with the substance environment; however, it was mainly from the point of view of radiation physics, ie the influence of the material environment on the propagation of radiation, its absorption, scattering or conversion to other types of radiation. Here we will deal with radiation interactions from the point of view of the substance itself exposed to radiation, ie the effects of radiation on the physical and chemical properties of the substance. Special attention will be paid to the effects of radiation on living tissue.
The very name "ionizing radiation" (see definition in §1.6) suggests that the basic physical effect of this radiation on every substance is ionization - negative electrons are ejected from the originally electrically neutral atoms, which turns these atoms into positively charged ions. The resulting effect of this ionization on the irradiated substance decisively depends on its atomic composition :

Basic quantities of dosimetry
Dosimetry of ionizing radiation is a field of radiation physics, which deals with the effects of radiation on substances in relation to the types and properties of radiation interaction with matter and the amount of radiation absorbed in matter (absorbed energy - "dose"). The studied substance is mainly living tissue, model measurements of doses and dose rates are performed in water, air and special dosimetric phantoms. It builds on the physical mechanisms of interaction of radiation with substances, discussed in detail in §1.6 "Ionizing radiation".
Absorbed radiation dose
The degre of physico-chemical effects of radiation on a substance - as well as the induced biological effects, if the irradiated substance is living tissue - it is proportional to the concentration of ions formed in a given volume of the substance. And this concentration of ions, in turn, is proportional to the energy that has been transferred to the substance in the given volume by radiation.
This default dosimetric quantity, called transmitted or communicated energy E, represents the energy [J, eV] which the ionizing radiation has transmitted to the substance in a certain volume. It is generally given by three components: E = SE_in - SE_out + SE_nucl . Here SE_in is the sum of the energies of all ionizing particles that have entered the given volume, SE_out is the sum of the energies of all particles that have left the given volume. SE_nucl is the sum of all possible changes in the rest energies of nuclei and particles that occurred in the considered volume during the event. nuclear transformations caused by the effects of radiation (in practice, this third component is usually zero, with the exception of high-energy radiation of about 10 MeV and higher). This quantities has only a "school" meaning and is not used in dosimetric practice...
The basic dosimetric quantity, which characterizes the physico-chemical and later even biological effects of radiation on the substance, is the absorbed radiation dose :

The size of the dose or dose rate depends on the intensity of radiation at the irradiated site (it is directly proportional to the fluention of radiation), the type and energy of quantum of ionizing radiation, as well as the properties of interaction and absorption of this radiation in the substance. Although the radiation dose is a physical quantity that is basically applicable to various substances and materials, in radiation dosimetry it is used mainly in biological applications - it is mainly determined for soft tissues or water. And so it is for all the dosimetric quantities listed below.
Note:The quantity of radiation dose is introduced to express the degree of usual (obvious, macroscopic, atomic) effects of radiation on matter - ie absorbed energy, which is manifested by physico-chemical changes at the level of electron shells, or by increasing the kinetic energy of the movements of atoms and molecules in matter. In rare cases, however, the energy of the radiation can be absorbed by the atomic nucleus in a way that is not directly reflected at the atomic level. This is especially the case with neutron radiation, where some neutrons can be absorbed by the nuclei of the irradiated substance to form a heavier isotope. This does not affect the normal physicochemical properties of the substance, but only the increase in the mass of some atoms. It is debatable whether this part of the absorbed energy should be included in the radiation dose. The situation is even more complicated here: nuclei that have absorbed neutrons are often radioactive (activation occurs) and during their radioactive transformations considerable energy is subsequently released, causing a radiation load - sometimes for a longer time after primary irradiation...

Exposure, kerma, Terma
When evaluating the effect of indirectly ionizing radiation on the substance, we can still encouter the quanties of exposure and kerma, especially in the older literature :
¨ Kerma (abbreviation of kinetic energy released in material)
is very similar to the definition of K = DE/Dm and the same unit [Gy] as the absorbed dose, but for DE takes the sum of initial kinetic energies of the charged particles released as a result of interaction of the particles of the primary radiation in the considered volume of the substance of mass Dm. Kerma is introduced because the basic definition of dosages comprising only released directly ionizing particles gave no information on what occurs in the vicinity of the monitored volume of the substance, especially in the case of secondary indirect ionizing radiation. For charged primary particles, there is no difference between the kerma and the dose (for radiation generated by charged particles, the kerma is not even introduced). Even for indirectly ionizing radiation in the equilibrium state *), when the secondary radiation is absorbed, K = D applies; only in non-equilibrium processes, near the surface of the substance or at high energies, when part of the radiation can escape, will K ¹D, while the differences are not large in practice. The relationship D = K.(1- g) applies between the dose and the kerma, where g is the fraction of the energy of the released charged particles that is lost during the radiation processes in the material. For X-rays and gamma rays with an energy less than 3MeV, the values of both quantities (kerma and dose) practically coincide, the value of g is only fractions of a percentage.
*)Electron equilibrium is a state where the energy released by the primary radiation in a given elementary volume of matter is as great as the energy transmitted there by the secondary electrons. This balance is disturbed at the surface of the substance and around the interface of two different environments. Upon penetration of the primary indirectly ionizing quantum (photon) into the environment, the released energy is carried away by secondary electrons and can be absorbed at a greater depth. At low energies (X-rays), the outreach of the secondary electrons is very small and the energy is absorbed almost immediately at the point of release from the interaction of the primary particle - the electron equilibrium is met and the dose value is numerically the same as kerma. In the high-energy g-radiation carries the secondary electrons to the released energy to a greater depth - the dose shows an initial rise and only at a greater depth does the electron equilibrium occur and the dose follows the kerma with its value.
In the case of indirectly ionizing radiation (photons g , neutrons), the kerma characterizes the energy transferred to the charged particles in matter (electrons and protons), especially during the first collision. Kerma depends only on the interactions of the primary radiation in the material of the mass element Dm, while the absorbed dose also depends on the secondary particles that were formed around the analyzed volume element and entered this mass element Dm (in which they have been partially or completely absorbed). For kerma, it is necessary to specify to which substance it relates (eg kerma in air or kerma in tissue).
Kerma through interactions with the medium rather expresses the properties of the radiation beam, while dose expresses the effect on the irradiated environment. If kerma is determined in the same given material environment, mostly in air, it can be used to quantify the "intensity, abundance" of radiation sources, the kerma power is proportional to the fluence of the radiation.
In recent literature occurs, although rarely quantity Terma :
¨ TERMA (Total Energy Released per unit MAss of material) has practically the same definition of T = DE/Dm and the same unit [Gy] as the absorbed dose. It is a multiple of the mass attenuation coefficient (m/r) and the primary fluence [MeV/cm²] of the radiation energy at a given location.
If the balance of charged particles is reached during the interaction of the radiation beam, there is no difference between the quantities of therma and dose (or their relationship is linear). However, differences may occur at the interface of different substances or at the edges of the bundle.
¨ Exposure
is defined as the ratio of the absolute value DQ of the total electric charge of one sign ions, which have been released by the interaction of photons (X or gamma) in a mass element of air of mass Dm, with complete braking of all electrons and positrons formed: DQ/Dm, to relate on the unit mass of this air. The unit of exposure in the SI system is the coulomb per kilogram [C.kg^-1] *). Only the charge of ions released by the interaction of primary photons and the interaction of secondary electrons released from air atoms is included in this total electric charge DQ, not including another charge which may arise from the absorption of braking radiation emitted by electrons (or characteristic X-rays). For high energy photons g (higher than 2-3MeV), where the additional ionization caused by the braking radiation cannot be neglected, the magnitude of the exposure no longer objectively captures the effect of such radiation.
*) Rentgen R
The former unit of exposure in the system of CGS units (Centimeter- Gram- Second) was rentgen R : It is the amount of radiation at which 1 electrostatic unit (1 esu » 3.3.10^-10 C) of charge is released by ionization in 1cm ³ of dry air (under normal conditions of temperature and pressure). The conversion relationship is 1R = 0.258 C.kg^-1.
From the exposure value cannot be determined completly objectively the exact dose of radiation absorbed by a substance other than air, because the absorbed radiation dose depends on the properties of the material and on the type and energy of the radiation. For gamma and X rays with normal energies of tens to hundreds of keV, a dose of approximately 0.01 Gray (1 Rad) is absorbed upon exposure to 1 rentgen in human tissue. In simple terms, the conversion relationship applies: 1 rentgen » 10 mSv. In the various radiation tables, the conversion factor between X-rays and Sieverts is given in the range 1 R = (0.0087-0.0096) Sv.
As with the radiation dose, even at kerma and exposure are defined the kerm power and exposure power, as the increment of kerma or exposure per unit time (1 second); the word "speed" was previously used instead of the word "power".
Both of these quantities, exposure and kerma, are mostly abandoned in dosimetric practice, they are still used marginally in the primary standardization of radiation beams (eg in radiotherapy, radiodiagnostics). However, in the literature in the field of radiodiagnostics and radiotherapy, terminology often persists. For monitoring X-rays in X-ray diagnostics, eg "input kerm power in air" is used.
Terminological note:
We use the word "exposure" in our materials from nuclear and radiation physics in its general natural-scientific meaning: lighting - the degree of irradiation of an object or material, exposure (or exposure time) during a photograph or other radiation imaging. It has almost nothing to do with the above-mentioned older abandoned dosimetric quantity!

Radiation dose from radioactivity
Radionuclides are often used sources of ionizing radiation in practice (§1.2 "Radioactivity"). Due to the irradiated object, the radioactive substance can be located either outside - an external radionuclide emitter, or it can be contained directly inside the investigated object - internal distribution of radioactivity.
External radionuclide source
External radionuclide sources are most often made in the form of encapsulated closed radioactive emitters. However, sources of radiation can also be nearby situated radioactive preparations in vials or test tubes, as well as a patient with applied activity for radionuclide diagnosis or therapy. The radioactive emitter emits its radiation (given by the type of radioactive transformations and activity) essentially isotropically in all directions, up to a full spatial angle of 4p. With the distance r from the source, the radiation "dilutes", it is distributed on an imaginary sphere with an area S = 4p r². Radiation intensity I (fluence of quanta) emitted by a radioactive source is therefore directly proportional to the activity of preparation A and indirectly proportional to the square of the distance r from the source (this is exactly true for a spot emitter, approximately in situations where the distance is significantly greater than the dimensions of the source) :
I = G . ^A / ₄_p_r 2 ,
where G is the number of quanta emitted by the radionuclide per decay.

The same applies to the energy fluence determining the radiation dose. The amount of energy W[J/s] emitted by a radioactive emitter per unit time (1s.) is given by the product of activity A[Bq] and mean energy <E> [eV] of quantum emitted per 1 decay: W = G.A. <E> .1.6.10^-19 (coefficient 1,6.10^-19 is the conversion factor between energy units [eV] and [J] ). The radiation dose obtained at time t , at a distance r from the radioactive source, will therefore be :
D = G. ^{(A. <E> .1,6.10}^{^-19}⁾ / ₍₄_p_r 2 ₎ . t ,
which is usually expressed in abbreviated form D = G . ^A/_r 2 .t, using the constant G = <E>.1,6.10^-19/4p (for a given radionuclide).
The radiation dose D from the external radioactive source of radiation is given by a simple relation *)
D = G . ^A/_r2 . t ,
where A is the activity of the source, r is the distance from the source, t is the exposure time. The coefficient G is the so-called dose constant (gamma-constant), indicating the dose rate [Gy.s^-1] at a distance of 1 m from a radioactive source with an activity of 1Bq.
*)We mean photon radiation (gamma) here and spot (or small enough) emitter, placed in vacuum (or in air), without shielding materials. It is problematic to use this relationship for radiation a and b, because part of such radiation is already absorbed in the source itself and further absorption occurs in air or another environment lying between the source and the measured location. We do not consider the half-life of a radionuclide source here - we mean a situation where the exposure time t is short compared to the half-life (otherwise time integration would be necessary, similar to the following paragraph for distributed radioactivity).
The G- constant has the base unit [Gy.m².Bq^-1.s^-1], but in practice it is most often used [mGy.m².GBq^-1.h^-1] - dose rate [mGy/hour] at a distance of 1m from a radioactive source with an activity of 1 GBq. The dose G constant includes the properties of the radionuclide - the number of photons emitted for decay and their energy, in relation to the absorption in the irradiated substance (in water or soft tissue); has different individual values for each radionuclide. In commonly used units [mGy.m²/GBq.hour], the dose gamma-constant for some of the most frequently used radionuclides has the values :

Radionuclide:	positron radionuclides ¹⁸ F, ¹⁵ O, ¹¹ C	⁶⁰ Co	^99m Tc	¹³¹ I	¹³⁷ Cs	¹⁹² Ir	²²⁶ Ra	²⁴¹ Am
G -constant: [mGy.m² .GBq^-1 .h^-1]	0.138	0.308	0.016	0.052	0.077	0.109	0.201	3.8.10^-3

In practice, in order to determine the dose from radionuclide emitters, it is necessary to take into account the effects of radiation absorption in the source itself or its packaging, as well as in the environment between the source and the measured site - the resulting dose will be lower : I = G. ^A/₄_p_r2 . e^-m^.^r, where m is the linear absorption coefficient of the medium.
Photon radiation energy ® radiation dose
The energy of incident gamma or X photons is decisive for the ways of interaction with a substance (§1.6, part "Interaction of gamma radiation and X") and thus also for the received radiation dose, which is caused mainly by the absorbed energy of the secondary electrons. Photon radiation of higher energies has a lower absorption coefficient (linear attenuation coefficient), but if absorption occurs, the transmitted energy - dose - is higher. The overall trend is: higher photon energy leads to a higher radiation dose. This also applies to the resulting radiobiological effect. The first ejected electrons may be high energy, but more and more electron interactions grow into a spray of ultimately low energy electrons. Thus, harder gamma radiation also produces a larger number of low-energy electrons, which have a higher LET and "more time" for the formation of radicals ® higher radiobiological efficiency.
Internal distribution of radioactivity
To some extent, the opposite situation to an external "spot" sealed radioactive source, is a radioactive substance dispersed (distributed) in the analyzed or irradiated material, eg in a tissue or organ. This situation (apart from internal contamination - see below §5.5, passage "Internal contamination") occurs especially during diagnostic and therapeutic applications of radioactively labeled substances - radiopharmaceuticals - into the body, where these radioactive substances are then taken up in individual tissues and organs, according to their pharmacokinetics; is discussed in detail in §4.8 "Radionuclides and radiopharmaceuticals for scintigraphy" and §3.6, section "Biologically targeted radioisotope therapy with open beta and alpha radionuclides").
In this case, the quantum of ionizing radiation interact immediately with the substance, instantly after its emission from a radioactive atom. In principle, all emitted quantum and particles (with the exception of neutrinos) participate here in the radiation dose - electrons and positrons, Auger electrons, gamma and X photons, alpha particles, or even reflected daughter nuclei (§1.2, passage "Nucleus recoil ").
The charged particles, a or b, have a short range and give off all their energy near the place of their emission. In the case of uniform distribution of the radionuclide in the substance with specific (mass) activity A'[Bq/kg], the dose rate D' in [Gy/s] from short-range radiation
                       D' = A'. <E> .1,6.10^-19 ,
where <E> is the mean energy of the emitted particles in [electronVolts] per decay (coefficient 1,6.10^-19 is the conversion factor between energy units [eV] and [J]).
E.g. for the most frequently used therapeutic radionuclide ¹³¹I (for thyroid therapy), the dose from uptake activity in the lesion weighs g grams is D = 0.109 Gy. g /MBq .h .
Therefore, if we have homogeneously distributed radioactivity with a time course A(t)_[Bq] in a given area of a substance of mass m, this will result in a total radiation dose D_0-T
[Gy] in this area in time T :
            D_0-T = ₀n^{^T}A(t) dt . <E>. 6.10^-19/m   , or   D_0-T = A^S_0-T. <E> .6.10^-19/m   ,
where A^S_0-T is the total so-called cumulative activity (introduced in §5.5, "Internal contamination") in the examined volume at time 0 - T. These relations are important especially for determining radiation doses in the body and in tumor lesions during radionuclide therapy (§ 3.6, passage "Planning, monitoring and dosimetry of radionuclide therapy", Fig.3.6.11).
Assuming a time decrease of the activity of the distributed radionuclide according to the usual exponential law A(t) = A₀ .e^-^(ln2/T1/2^{^ef}^{) .t} with an effective half-life T_1/2^ef[s] *), the dose rate will decrease with the time according to this dependence: D'(t) = A₀ .e^-^(ln2/T1/2^{^ef}^{) .t}. <E>.1,6.10^-19. The total radiation dose D [Gy], caused by the radionuclide distributed in the substance, will then be given by the time integral from 0 to ¥: D = _₀ò^{^¥}[A₀ .e^-^{(ln2 /T}1/2 ^{^ef}^{) .t}. <E>.1,6.10^-19] dt, which gives the result :
                        D = A₀ . (T_1/2^ef / ln2). <E>. 1,6.10^-19 .
*) The effective half-life T_1/2^efof the activity of a radioactive substance is given by the physical half-life T_1/2^physicalof the relevant radionuclide and in the case of the organism also by the biological half-life T_1/2^biol excretion of the radioactive substance from the given tissue: T_1/2^ef = T_1/2^phys.T_1/2^biol) / (T_1/2^phys + T_1/2^biol). For the kinetics of radionuclides in tissues and organs, the biological half-life of excretion is usually dominant, which is usually significantly shorter than the half-life of the radionuclide used.
If the radioactive substance also emits high-energy penetrating gamma radiation escaping from the analyzed volume with distributed radioactivity, as well as in the case of uneven distribution of the radioactive substance or its irregular time dynamics, the situation is more complicated and radiation doses are determined by MIRD (§5.5, part "Internal contamination").
Determination of the radiation dose from radionuclides distributed in the organism, tissues and organs is important both for determining the radiation exposure from diagnostic applications of radiopharmaceuticals in scintigraphy, especially in therapeutic applications of open radionuclides (§3.6, section "Radioisotope therapy").

Radiobiological efficiency of radiation. Dose equivalent, effective dose
The basic dosimetric quantity - the absorbed dose - does not include the immediate local distribution of energy transferred to the substance, which can significantly affect the specific processes of physical, chemical and especially biological effects of ionizing radiation. Therefore, another quantity is introduced which describes the rate of energy loss along the path of the particle in the substance, and thus also the rate of braking of the particle and the density of ions formed along the path :

In terms of the biological effects of ionizing radiation on the irradiated substance (described below), the radiation is divided according to the density of ionization, which it induces in the substance during its passage :
¨ Sparsely ionizing radiation - X, gamma, beta radiation. For beta particles with typical energies of hundreds of keV, LET is about 0.2 keV/micrometer. When passed through water or tissue, it forms about 100 ion pairs /1 micrometer.
¨ Densely ionizing radiation - alpha radiation, neutron radiation, proton radiation *). For alpha particles with energies of 4-8 MeV, the LET in the tissue is about 100 keV/micrometer, at the end of the path in the Bragg maximum it can locally increase up to 300 keV/mm. It forms up to 2000 ion pairs /1 micrometer of tissue. Densely ionizing radiation of slower particled has "more time" to form radicals - higher radiobiological efficiency.
*) This applies to low-energy radiation, up to about tens of MeV. However, high energy (about 100MeV) proton radiation and alpha or heavy ions, however, it is sparsely ionizing in substances for most of its path. Only at the end of the path, in the region of the Bragg peak, the ionization density is high - see Fig.1.6.1 in §1.6 "Ionizing radiation".
As the biological efficiency of different types of radiation can vary considerably (depending on the ionization density), for the purposes of radiobiology and radiation protection, a so-called quality factor Q is introduced for each type of radiation *), which indicates how many times a given type of radiation is more biologically effective than photon radiation - X or gamma (X-ray with an energy of 200keV are taken as the basis).
*) Also called "radiation weighting factor" wR or in radiotherapy "relative biological effectiveness" RBE (Relative Biological Effectivenes).
The value of this empirical quality factor Q depends on the type and energy of radiation. For X, gamma and beta radiation, the quality factor Q = 1, for neutrons Q » 2-5 (slow neutrons with energy up to 10keV, or again for very fast neutrons with energy >20MeV), 10-20 (fast neutrons 100keV-20MeV ), for protons Q » 5 , for alpha radiation is even Q » 20 (as well as for fast heavy nuclei and fission products).
For a more objective assessment of the effect of radiation, a "corrected" dose quantity is introduced with the help of quality factor Q in the field of radiobiology and radiation protection, which already takes into account the different biological efficiency of individual types of radiation :

Different tissues and organs in the body are differently sensitive to radiation and their radiation damage leads to differently serious consequences for the whole organism. Based on statistical analyzes, the own coefficients of risk of radiation damage are empirically introduced for each organ and tissue. Using these coefficients, we can then determine - estimate - the risk of damage to the body resulting from exposure to ionizing radiation. For the purposes of radiation protection, the following quantity is therefore introduced :

Thus, the effective dose D _ef is calculated using the contributions of the equivalent organ doses H_Tof all individual irradiated tissues: during the summation, each organ equivalent dose H_Tis multiplied by its tissue weighting factor w_T, which expresses the contribution of that particular organ or tissue damage to whole body damage caused by the effects of uniform whole body irradiation. With the aid of an effective dose of D_ef, the effects of irradiating any tissue, organ or part of the body can be converted into comparable effects resulting from uniform irradiation of the whole body. The advantage of an effective dose is that it allows to express the radiation exposure by a single number (the unit is again Sievert [Sv]) even in the case of uneven irradiation, or irradiation of only certain organs, as if it were a radiation load in the case of uniform irradiation. This makes it possible to compare the radiation loads of people from various sources - eg from natural radiation, X-ray examinations, or from different types of radiopharmaceuticals in nuclear medicine. All of these assessments relate to the stochastic effects of radiation - and are only very approximate "qualified estimates", often of a hypothetical nature, especially in the low dose range around 0.1Gy (discussed below in the section "Very low dose issues - are harmful or beneficial ?") ...
Effective dose D_efit is therefore a quantity that assesses the degree of health risk that arises for a person from the radiation to which he was exposed. It is an empirical biophysical quantity that is not directly measurable - is obtained from the measured radiation dose of a given type of radiation by taking into account the estimated biological effects of this radiation and the sensitivity of the individual affected tissues and organs. It takes into account the fact that different types of radiation have different biological activities and that different tissues and organs are differently sensitive, and their damage has different health consequences for the organism. However, it should be borne in mind that the concept of an effective dose is only a very rough and simplified averaged estimate of the complex and individually dependent processes of the biological effects of radiation in organisms. It has the character of a "qualified estimate" of radiation doses with a number of uncertainties and inaccuracies of the order of tens of %!
The probability of biological stochastic effects is proportional to the absorbed radiation dose[mGy] and irradiated region size [cm³]. In planar X-ray diagnostics, this is quantified by the quantity DAP (Dose Area Product) [mGy.cm²], which is the product of the absorbed dose D and the area S of the irradiated area: DAP = D. S. In X-ray CT diagnostics, this is quantified by the DLP (Dose Length Product) [mGy.cm], which is the product of the absorbed dose D and the length L of the irradiated area: DLP = D. L. The effective dose D_ef [mSv] for a patient, expressing the effects of radiation on the organism as a whole, is then calculated as the product of: D_ef= E_DAP . DAP, or D_ef = E_DLP . DLP, where the coefficients E_DAP or E_DLP include the averaged tissue (organ) weighting factors w_T for structures in the irradiated area (§5.7 "Radiation load in radiation diagnosis and therapy").
To assess the long-term effects of radiation from internal contamination with a radioactive substance - radiotoxicity - the so-called dose schedule is also introduced, which is the total absorbed dose of ionizing radiation caused by a given radioactive substance in an organism, organ or tissue over a period of 50 years from its uptake into the organism. Radiotoxicity depends not only on the physical parameters of the radionuclide (half-life, type and energy of radiation), but also on the chemical characteristics of the contaminant, which determine the metabolism, distribution to the various organs, biological half-life, route of excretion (see below §5.5, section "Internal contamination") - the residence time of a radioactive substance in tissues and organs.
To assess the exposure of selected groups of people or populations, a collective equivalent or effective dose is sometimes used, which is the sum of the respective doses of all individuals in a given group. These data can be used for demographic radiohygienic analyzes and to optimize radiation protection.

Physical and biophysical dosimetric quantities
It is necessary to draw attention to the different nature of individual dosimetric quantities. Dose, kerma, exposure, linear energy transfer and some others are physical dosimetric quantities that can be (at least in principle) determined on the basis of purely physical measurements. They describe the objective measure of the physical (and possibly induced chemical) effect of radiation on substances. They can be used not only in biological, but also in various other technological applications of radiation, where they determine the degree of required (or undesirable) effects of radiation on a given material or process. The field of biological and medical applications is the dominant field of application of all dosimetric quantities.
Dose equivalent and effective dose (and other quantities derived therefrom) are the biophysical dosimetric quantity intended for radiobiology and radiation protection - from basic physical quantities arise by recalculation using empirical physical-biological factors - quality factor Q and tissue weighting factors w_T. They are not directly measurable. Approximate values of conversion factors were determined by radiobiological experiments and based on the results of randomized clinical trials. It is necessary to further distinguish which quantities relate to stochastic and deterministic radiation effects.

Methods for dosimetric determination of radiation doses
The doses of ionizing radiation are determined by the physical methods described in detail in Chapter 2 "Detection and spectrometry of ionizing radiation". Dosimeters are used, which are simple radiometers - ionization chambers, GM detectors, scintillation detectors, film dosimeters, thermoluminescence and OSL dosimeters - calibrated in dosimetric quantities: radiation dose [mGy] or [mSv], dose rate [mGy/s] or [mSv/s]. Dosimeters are used to perform physical measurements (often using phantoms modeling the tissue environment and geometric configuration of irradiation), monitoring workers and patients ("in vivo" personal dosimetry), radiation monitoring of workplaces and the environment.
Biodosimetry
Sometimes there are situations where radiation exposure occurs (or exposure is suspected), without the relevant persons being dosimetrically monitored - it is irradiation with an unknown dose. When physical dosimetry is lacking, the possibility of retrospective dose determination (or its estimation) arises by monitoring changes in some biological parameters. Biological dosimetry or biodosimetry is a radiobiological method that helps determine the size of the absorbed dose according to the type and intensity of the post- radiation response of the organism (these radiobiological effects are discussed in detail in the following §5.2 "Biological effects of ionizing radiation"). For the reconstruction of doses can be used some biological parameters, such as changes in blood counts, occurrence of chromosomal aberrations or micronuclei in blood cells, observation of somatic mutations in blood cells, DNA or mRNA damage, increase in p53 protein concentration, ATM-kinase, .... As adequate treatment needs to be started as early as 1-2 days after irradiation, it is desirable to use expression biochemical analysis (statim), such as ELISA or RT-PCR ...

5.2. Biological effects of ionizing radiation
As mentioned above, the primary effect of ionizing radiation on matter is the interaction of the quanta (electromagnetic or corpuscular) of this radiation with the electron shell of atoms, occasionally with atomic nuclei. The result is excitation and ionization of atoms, which can lead to physical changes and chemical reactions, and in the case of living tissue to biochemical changes. These secondary effects can then lead to changes and damage to the irradiated organism, or even to its extinction - death. From a biological and medical point of view, the special field of radiobiology deals with the effects of radiation on living tissue and organisms. We cannot deal with the medical details of this field here, they are mostly outside the scope of our physical treatise. We will mention here only those findings that are important from a physical point of view, for applications of radiation in medicine and biology and also from the point of view of radiation protection methods.
The basic building blocks of all living tissues are cells. Therefore, in order to understand the biological effects of ionizing radiation, the mechanisms of radiation action at the cellular and subcellular level are crucial. This is related to the chemical and biochemical effects of ionizing radiation at the molecular level. Therefore, we will analyze these subcellular aspects first, followed by an analysis of radiation effects at the level of tissues, organs and the whole organism.
Note: However, these molecular, cellular and tissue aspects cannot always be strictly separated, so they will sometimes overlap in interpretation.

Cells - basic units of living organisms
All living organisms are formed by cells *) - small formations or "chambers" bounded by the cell wall (cytoplasmic membrane - lipoprotein with 2 layers of phospholipids) and filled with viscous aqueous colloidal solution of various chemicals, especially complex organic macromolecules of proteins. The field of biology, studying cells, their structure and function, is called cytology (Greek cytos = cavity ).
*)R. Hooke first observed cork cells as early as 1665 using a simple microscope, other cells were more perfectly observed by A. Leeuwenhoek. Name of the cell (lat. Cellula ; cella = chamber) arose from the resemblance to cells in honeycomb. J.E.Purkyne also made a significant contribution to the origin of the science of cells - cytology.
Only the discovery of cells and the gradual recognition of complex biochemical reactions taking place in cells at the molecular level, at the end of the 19th and in the 20th century, transformed biology and medicine from descriptive empirical doctrine (description of species, "counting of petals and stamens", external manifestations of diseases, ..., with many unsubstantiated and erroneous opinions) to real science, enabling to understand the essence and functioning of life on a uniform exact basis, under physiological and pathological situations. Research into complex biochemical processes at the subcellular level will continue for a long time.
Viruses
On the border between living organisms and inanimate nature, there are viruses (Latin virus = poison ) - intracellular parasites of microscopic dimensions of about a hundredth to a tenth of a micrometer. They consist of nucleic acid (DNA or RNA), encased in a protein shell ( capsid ). Although viruses contain nucleic acids that carry genetic information in their sequence, they are unable to grow and produce their own proteins, reproduce, or obtain and store nutrients and energy - they need a "host" cell to do so. When a virus enters a cell, it parasitizes on it, uses its nutrients and can kill it. Or it can copy its genetic information into the cell's DNA (via reverse transcriptase- see below) and force ("reprogram") the host cell to work in favor of the virus. In higher organisms, viral infections are the cause of many diseases.
However, over the course of evolution, some biological species have "learned" to use originally parasitic genetic sequences from viruses for other - beneficial - functions that have given them evolutionary benefits.
Proteins - the basic building and functional substances of cells
In the basic filling of the cell, called the cytoplasm (Greek cytos = cavity, plasma = creation ), more complex structures - organelles - "float". The liquid part of the cytoplasm, which is an aqueous gel of large and small molecules, is called the cytosol. The cytoplasm is composed mainly of a colloidal solution of proteins (Gr. protos = first , they are biological substances primordial importance) - they are polypeptide chains of linear polymers of amino acids.
Amino acids are molecules containing a carboxyl group (-COOH) and a nitrogen amine group (-NH2 ); these groups and other atoms (hydrogen atom and side chain) are attached to a central carbon atom. Amino acids are able to combine with each other by a so-called peptide bond, in which the carboxyl group of one amino acid reacts with the amino group of another amino acid. They can thus form - polymerize - even very long polypeptide chains - proteins. Of the large number of chemically existing amino acids, only 24 species (20 basic, 4 special) occurs in cells :

The carboxyl and amine groups, the hydrogen atom and the side chain are attached asymmetrically (with the exception of glycine) on the central (alpha) carbon - chiral asymmetry, which manifests itself in the ability to twist the plane of polarized light. Depending on the spatial orientation of the attached groups on the alpha-carbon, the amino acids can be leftrotatory "L" or dextrorotatory "D" (from Latin Leavus = left , Dexter = right ). Polypeptide bonds can only occur between amino acids of the same chirality, L or D. In the early stages of prebiotic evolution, the "left-handed" chirality of amino acids randomly prevailed, and this preference then evolved to all biochemical processes. Thus, only leftrotatory alpha-L-amino acids are present in biochemistry; and natural carbohydrates are in turn D-dextrorotatory ...
The primary structure of proteins is given by the sequence of amino acids in the polypeptide chain ( peptide bond represents the CN connection between two amino acids, leading to the presence of the peptide group -CONH-). There are 20 types of amino acids in proteins, both aliphatic (alanine, glycine, leucine, valine, ...) and aromatic (with benzene nucleus - phenylalanine, tyrosine, tryptophan, ...), acidic (aspartic acid, glutamic acid), basic (lysine, histidine, arginine), with bound sulfur (cysteine, methionine) and several others. Individual amino acids have different biochemical properties, so amino acid sequences in the protein it determines the chemical properties of the protein and its spatial structure. Linear polypeptide chains are formed into a spatial (3D) structure due to the formation of hydrogen bonds between the groups of the protein backbone - the secondary structure is either regular repetitive (helical, bending and fiber folding), or irregular and compact, or more complex joining of different fibers and sequences (tertiary structure). Some types of proteins are the basic building blocks of cells, other types of proteins perform specific functions of cells and tissues through their complex chemical reactions (as will be specifically mentioned below in a number of places). The set of proteins that are contained in the cell or that the cell can synthesize, defines its ability to perform various biochemical reactions - processing (decomposition and synthesis) of chemicals, obtaining chemical energy, creating building "materials" of cells and other parts of the organism - it largery detrmines the resulting properties of cells and organisms.
By systematically examining of proteins - their origin, structure, mutual reactions and functions in cells and organisms - deals with a relatively new scientific discipline called proteomics. The functional properties of some proteins are discussed below in the section "Proteins, enzymes, kinases".
Biochemical reactions - the basis of cell life
The chemical reactions taking place in cells are controlled and highly organized, with the basic control role being played by a complex DNA molecule (deoxyribonucleic acid, see below), which encodes the composition of proteins - their primary structure, the sequence of amino acids. Cells have the ability to metabolize, grow, and make their own "copies" by dividing one cell into two (for asymmetric division into stem and effector cells, see below). The simplest forms of life, single-celled organisms, are made up of separate cells. Higher multicellular organisms are formed by a community of a large number of cells, usually differentiated, where different cells perform their different specific functions, coordinated by chemical regulatory mechanisms and "communication systems".
Biochemical reactions usually involve highly complex organic molecules containing large numbers of carbon, hydrogen, oxygen, nitrogen, phosphorus and others. The molecular weight of these macromolecules in biochemistry and molecular biology is expressed in special units called kilodaltons (kDa), which is 1000 Daltons (Da). 1 Dalton corresponds to 1/12 of the mass of a carbon atom, ie roughly the mass of a hydrogen atom, 1Da = 1.66.10^-27 kg (J. Dalton was an English chemist, lived in the years 1766-1844, significantly contributed to the knowledge of the laws of atoms and their chemical merging). Thus carbon has 12Da, methane CH₄ has a mass of 16Da, water has 18Da, glucose C₆ H₁₂ O₆ has 180Da; the p53 protein has a molecular weight of 53 kDa.
The difficulty of understanding the function of living organisms
Despite all the advances in biochemistry and molecular biology, our understanding of how living organisms work at the molecular level is still very limited. The number, complexity, and interconnectedness of the biochemical processes that take place in living cells, still defy our ability to comprehensively analyze and understand the mechanisms of the dynamic behavior of these systems.
In addition to the extent and complexity, stochastic effects are also applied to intracellular systems, caused by random movements of molecules. Some biochemical substances are contained in cells only in very small concentrations, sometimes only units or tens of molecules. With such a small amount, collisions and reactions of these molecules occur relatively rarely, and thus with considerable statistical fluctuations. Such random (stochastic) phenomena can have a significant effect on the dynamics of biochemical processes, which can be reflected in the behavior of the whole cell.
Prokaryotic and eukaryotic cells
Such a complex phenomenon as life has undergone a very long and complicated development, a number of stages of which we do not yet know (for the evolution of life, see the work "Anthropic Principle or Cosmic God", passage "Origin and evolution of life"). In terms of structure and development, cells can be divided into two basic groups :
Prokaryote (Greek: pro = pre; karyon = nucleus , cells without nucleus, "pre-nuclear"),
whose circular DNA is exposed and floats freely in the cytoplasm in a structure called a nucleotide. Prokaryotes are the primitive oldest developmental form of cells, now occurring as bacteria and cyanobacteria. We recognize two groups of bacteria: eubacteria, which occur in large numbers in our environment; archaebacteria, living in an environment inhospitable to other organisms (hot springs, seabed, acidic or alkaline environment). The dimensions of the bacteria range from about 1-10 mm. These evolutionarily very old cell types form single-celled organisms, they do not form any functionally differentiated tissues, they can only associate into colonies.
Eukaryote (Greek eu = normal, correct; karyon = nucleus - ie "true nuclear") ,
whose DNA (linear, spiral shape) is concentrated mainly in the cell nucleus, where it is associated with histones in chromosomes, which are multiple and contain other chromosomal proteins. Respiratory and metabolic enzymes are concentrated in organelles, particularly mitochondria and lysosomes (see below). These cells also have a so-called cytoskeleton - a system of flexible fibers (formed by microfilaments and thin hollow tubes - microtubules) in the protoplasm, providing mechanical support to the cell structures; they also mediate the intracellular transfer of complex molecules between the nucleus and other organelles (during cell division they then form a mitotic spindle). Eukaryotic cells have relatively larger dimensions, about 5-100 mm. In addition to unicellular organisms, they form organized communities of multicellular organisms with cells functionally specialized in tissues and organs, including humans. In the following text, we will consider mainly eukaryotic cells, especially somatic cells incorporated into tissues and organs; prokaryotic cells will be briefly mentioned in several places for comparison. The figure shows only a very simplified scheme of cell structure, with enlarged sections of the cell wall (cytoplasmic membrane), cycloskeleton (microtubule), mitochondria, nucleus (DNA carried by histone) and DNA structure (some nucleotides) :

Eukaryotic cell structure. Details of some structures are schematically drawn in enlarged sections (frames).

From a chemical point of view, life is a very complex system of molecules that can organize itself , metabolize using chemical binding energy, grow , reproduce and also evolve over longer periods of time .

D N A , R N A , proteins
The whole mechanism of cell life organization is based on a cooperating system of nucleic acids DNA (deoxyribonucleic acid), RNA (ribonucleic acid) and proteins: genetic information is stored in DNA, which is transcribed into RNA, which then serves as matrices for protein production - below "Proteosynthesis". Different types of proteins are not only the basic building blocks in cells and tissues, but are also carriers of cell and tissue function (enzymes).
Nucleic compounds - etymology of names:
Latin nucleus = core - here it is a cell nucleus. Nucleotides are therefore compounds found in the cell nucleus. Nucleic acids are then polymeric compounds of nucleotides showing an acidic chemical nature, in practice caused by bound phosphoric acid. Ribonucleic acid RNA is formed by chains of the monosaccharide ribose bound via phosphoric acid, together with nitrogenous heterocyclic molecules cytosine, uracil, thymine, adenine, guanine. Ribose is a 5-carbon pentose sugar; the name comes from Latin ribes = merusalka, currant, or Arabic ribas = rhubarb - in the juice of these plants, in addition to acidic components, ribose sugar is also found. In the cytoplasm of cells there is a large number of small organelles called ribosomes (ribo = containing RNA, soma = body - small bodies containing RNA). In deoxyribonucleic acid DNA, instead of ribose, its derivative deoxyribose is bound, in which one hydroxyl group "OH" is replaced by a hydrogen atom "H".
Note: This etymology refers to eukaryotic cells. Similar compounds, although somewhat simpler, are also found in prokaryotic cells, where they are scattered in the cytoplasm, there being no nucleus.

Deoxyribonucleic acid DNA
A weak acid reaction is caused by phosphoric acid H₃PO₄ linked between nucleotides. It is a very complex long macromolecule, a polymer of repeating sequences of deoxyribonucleotides, which has the shape of a double spiral in eukaryotic cells - Fig. 5.2.2a. DNA contains about 100,000 ¸ 200,000,000 nucleotide pairs, has a molecular weight of about 2 ¸ 100 MDa (megadaltons) (lower limit is for DNA plastids, mitochondria and prokaryotic cells, upper limit for human DNA). The "unwound" DNA would have a linear length of decimetres to meters (in humans about 2m ..!..); in cells, however, it is very compactly coiled in chromosomes only a few micrometers in length (see below).
From a chemical point of view, DNA has a polymeric structure - it consists of a chain of repeating and interconnected similar building blocks called nucleotides, which are formed by phosphate H₃PO₄ (phosphoric acid binding part), deoxyribose (5-carbon sugar, pentose - monosaccharide 2- deoxy- b- D-ribose; hence the name DNA), purine and pyrimidine bases (nitrogen heterocyclic compounds). Nucleotides differ in the representation of 4 various bases: adenine A , guanine (a purine base) G , cytosine C , thymine (pyrimidine base) T . These four types of nucleotides are arranged in DNA in a certain order or sequence. This unique grouping of nucleotides in a strand is the basis of hereditary information stored in the DNA - the genetic code. They form triplets, each encoding one amino acid. DNA thus contains information about the structure of proteins composed of these amino acids.
The section of a DNA molecule that encodes the order of nucleotides in a particular functional RNA and subsequently, through mRNA, also determines the order of amino acids in a particular protein with a specific function, "produced" by a cell, is called a gene (Greek: genos = genus, origin; talent ) *) . Thus, genes provide "instructions" for protein production - see below "Ribonucleic acid - proteosynthesis". Although some genes are transcribed into RNA, it does not go further into proteins; the resulting ribonucleic acids have some regulatory functions. Overall, however, in eukaryotic cells, only a small fraction of DNA sequences encode any (functional) proteins. It is just over 20,000 genes, which represents only about 5% of the human genome. Most DNA sequences are a kind of "genetic garbage" - "waste" or "useless" DNA (junk DNA, noncoding DNA), which is a relic of the intricate (convoluted) path of evolution (fossil sequences - "old junk"). They were often originally "parasitic" genes of viral origin, that were incorporated into DNA of ancient organisms. Some of them have been transformed and functionally involved, most have remained non-functional, others can potentially endanger the organism (perhaps co-operate in the formation of tumors..?..). However, this "unnecessary DNA" is also in many cases transcribed into RNA, which is a (protein)non-coding but has a regulatory function - it determines, for example, the start, stop or intensity of transcription of coding parts of DNA. On detecting function of each genetic sequences, including "unnecessary" (junk) was targeted large-scale project ENCODE (Encyclopedia of DNA Code Elements; "encode") launched in 2003.
*) Genes, genetics Inheritance - the transmission of some properties of living organisms to offspring, between generations, has been observed for a long time. Some biologists (such as J.G.Mendel in the 60s of the 19 centaury, during several years of experiments with the cultivation of peas with different colors of flowers) empirically traced some regularities of this heredity, but its true biological cause remained unknown for a long time. Only the development of cell molecular biochemistry in the middle of the 20th century showed, that the essence of hereditary information is a DNA molecule.
Another structural peculiarity of genes in eukaryotic DNAs is that the functionally coding sequences of deoxyribonucleotides - called exons (Greek exo = out ;outer unit) are interrupted by non-coding sequences, so-called introns (lat. intro = inside; inner unit) without genetic content, whose role, probably regulatory, has not yet been fully clarified. Shortly after transcription into mRNA are intronic sequences "cut" (ie. splicing) and thus excluded from the further process of gene expression; the subsequent joining of the coding sequences (derived from exons) creates a functional mRNA, allowing the continuous synthesis of polypeptide chains of proteins during translation (see below "Ribonucleic acid - proteosynthesis").
To imagine genetic information only linearly as a long line of nucleotides - the "letters" of the genetic code - is simplified and can be misleading; geometric dimensions and relationships also apply. The double helix of DNA is intricately twisted and intertwined, so that parts of DNA that are separated by a long series of nucleotides, can come into close proximity in the nucleus and then influence each other's genetic activity.
The nucleotide sequence of DNA in dividing cells are able to create their own exact copies, which pass on genetic information to future generations. A specific form of a gene for a certain trait or property of an organism is called an allele (Greek: allos = other), eg a gene for flower color. If a given organism has the same alleles in its gene pair, it is called a homozygote, when different alleles then a heterozygote.
The structure of DNA
DNA is made up of two parallel chains (also called strands), connected by hydrogen bonds between the nuclear bases into a kind of "ladder" that twists into a double helix. Both chains are complementary to each other, their bases are precisely paired with hydrogen bonds. The nucleotide sequence on one strand is fully determined by the sequence on the other strand ("positive-negative" pair). These hydrogen bonds between complementary bases make double-stranded DNA a very stable macromolecule, despite its complexity. Only two nucleotide pairs always are associated with each other: C « G , A« T (Watson-Circk pairing); these base pairs form a kind of "ladder step" of DNA.
Revealing the structure of DNA
We cannot directly observe the structure of DNA molecules, due to the very small transverse dimensions and the compactification of the llongitudinal dimensions. Under the microscope, we observe only virtually unstructured chromosomes. The assembly of the DNA structure was aided by X-ray diffraction crystallography (it is described in more detail in §3.3, section "X-ray diffraction analysis of the crystal lattice structure"). It was possible to grow small DNA single crystals, that diffractedly reflected X-rays, which created interference patterns on the photographic medium, which made it possible to determine the distribution of atoms in the molecule. A team of researchers R.Franklin, R.Goling, F.Crick and J.Watson at the MRC Molecular Biology Laboratory in Cambridge in 1953 completed the analysis of DNA structure and Crick and Watson created a model that very successfully explains all cellular genetic processes.
This structure allows replication: for each of the strings it is possible to create a new string, completely identical to the original. During replication, the two strands of DNA move away from each other, and a new second strand is added to each of them, nucleotide by nucleotide. Each of the two newly formed DNA molecules has one strand from the original molecule and the other newly synthesized. During cell division, DNA is thus able to accurately reproduce itself and thereby transmit genetic information to future generations of cells. Replication is a very precise process in which control and correction mechanisms are built. Each time a new nucleotide is added to a new DNA strand, the correct pairing of the previous nucleotide is checked; if the pairing is not correct, the repair enzymes immediately remove the faulty nucleotide and replace it with the correct one. Furthermore, the correct base pairing between the original DNA strand and the newly synthesized strand is checked, with the mismatched nucleotide on the new strand being replaced by the correct one. Thanks to these ongoing fixes, the resulting replication error rate is only ~10^-9! Much more often than replication failures, nucleotides and the genetic sequence of DNA are damaged by external influences - ionizing radiation and reactive chemicals (genotoxic effects discussed in detail below). Cell division and the cell cycle are discussed below in the section "Effect of radiation on cells", section "Radiation effects during the cell cycle".
Telomeres
Both end parts of DNA of eukaryotic cells are provided with so-called telomeres (Greek telos = end, meros = part ) - marginal "termination" complexes of repeating sequences, which protect the ends of chromosomes from unwanted chemical bonds *), as well as from the "false" evaluation of the end part as a DNA break (and the initiation of repair mechanisms or apoptosis - see below). Telomeres have a constant structure of repeating sequences, very similar in different biological species. In human and most other eukaryotic cells, it is a short hexanucleotide sequence [TTAGGG]_n of up to n = 2000 repeats.
*) This can be compared to a metal or plastic reinforcing shoe lace ending that protects them from fraying.
However, in most replications, there is no complete synthesis telomere-containing DNA ends - telomere shortening occurs. The enzyme DNA polymerase, which replicates the DNA sequence, is not able to copy it completely to the end regions. With each mitotic division of the cell, the length of the telomeres is shortened by about 50-150 bases, leading to a gradual reduction in the protection of the DNA ends; eventually this results in a loss of mitotic ability of the cells. With excessive truncation, telomeres no longer adequately protect the ends of chromosomes, which cellular control mechanisms evaluate and arrest the cell cycle (such cells remain in the G1 phase of the cell cycle or undergo apoptosis).
Mitotic shortening of telomeres in DNA is the main mechanism of the process of "aging" of cells, called senescence *) - see also below "Extinction - death - of cells". Telomere shortening acts as a "mitotic counter" - eukaryotic cells can only reach a certain limit in the number of their divisions, the so-called Hayflick limit (about 50-80 cycles); then they lose the ability to divide, replicative aging (senescence) of cells occurs. However, prokaryotic cells that have circularly ordered DNA without telomeres, can divide indefinitely.
*)Cell aging is probably a multifactorial process involving both intracellular "program" molecular mechanisms and time-accumulating exogenous detrimental factors affecting cell viability. Progressive damage to cells by reactive forms of oxygen and nitrogen (radicals) during metabolism and tissue life is applied, with the ever-decreasing capacity of antioxidant mechanisms.
Note: Occasionally there is speculation about evolutionary significance of shortening of telomeres, replicative aging and extinction of organisms: that this process prevents the overfilling of limited living space by long-lived organisms, which would slow down evolution. However, this hypothesis is somewhat debatable for two reasons. 1. First, replication truncation of telomeres is only one of the mechanisms of senescence. 2. But most importantly, the environment has been (and still is) filled with a huge number of prokaryotic organisms with circularly ordered DNA without telomeres, where this effect does not apply; and yet the evolution of eukaryotes has continued successfully... In interspecies competition and evolution of eukaryotes, however, it may have some significance..?..
However, there is a special enzyme called telomerase (it is a complex composed of RNA and proteins: RNA matrix serves as a template for sequence synthesis of telomere sequences in DNA, reverse transcriptase transcribes from RNA to DNA), which is able to synthesize the terminal sequences of telomeres and thus prevent their shortening during cell division. For the successful functioning of telomerase, the enzyme tankyrase is required *), which causes inhibition of the telomere-bound protein TRF1 ("synergistic" action of telomerase and tankyrase). Such cells are then capable of unrestricted division (immortilization - "immortality" of cells), which physiologically takes place only in the early stages of development of the organism in dividing embryonic cells and then only in undifferentiated stem cells; pathologically applied in cancer cells(§3.6 "Radiotherapy", passage "Carcinogenesis").
*) A complex nucleonprotein system with a specific function is bound to telomeres. One of the studied proteins of this kind is TRF1 (Telomeric Repeat-binding Factor 1), which binds to the ends of the telomere and prevents telomerase (see below) in its activity to synthesize the shortening ends of the telomere. However, there is the enzyme tankyrase, which removes the TRF1 protein and thus helps telomerase to work...
However, some new experiments show that telomerase is not the only mechanism for DNA telomere recovery. An alternative method of "treating" telomeres may be telomerase-independent inter-telomeric homologous recombination (see "Reparation Processes" below), which may lead to elongation of telomere segments, sometimes several-fold. This method is observed in some plants and is possibly evolutionarily older than telomerase. Closed structures, a kind of "telomere loop" at the ends of the DNA, which can replicate or elongate (mechanisms of a kind of "rolling circle") have also been observed. However, somatic effector cells, performing specialized activity in tissues and organs, lose the ability to divide indefinitely and no longer divide after reaching the Hayflick limit.
Note:Mitotic telomere shortening occurs only in eukaryotic cells with linearly ordered DNA, where the polymerase is unable to ensure complete replication of the terminal portions. For prokaryotic cells (bacteria) with circularly arranged DNA without telomeres, the limit on the number of divisions does not apply.
Chromosomes
There are two types of DNA in eukaryotic cells: nuclear and mitochondrial (this is mentioned below in the section on mitochondria). Nuclear DNA is located in the cell nucleus in chromosomes (Greek chromos = color, soma = body) - specific structures about 2-5 mm long, after staining (with classical Giemsa-Romanowski dyes or fluorescent dyes) observed in an optical microscope. Chromosomes are composed of protein carriers, so-called histones (they are small basic nucleoproteins with a high content of positively charged amino acids, forming complexes with DNA), around which the DNA molecule is "wrapped". The chromosomes in cells are arranged in sets , with the number of chromosomes in one set (so-called monoploid number x) being normally the same for each cell in a given organism; in humans it is x = 23 chromosomes. The number of homologous sets of chromosomes in a cell, called ploidy, is different for different species of organisms. In humans, most cells are diploid (2 sets of chromosomes, 23 from the mother and 23 from the father), but germ cells are haploid (only one set of 23 chromosomes). A higher number of chromosome sets than 2 is referred to as polyploidy (triploidy-3, tetraploidy-4, hexaploidy-6, ...); often found in plants, probably played an important role in evolution. Another anomaly is the so-called aneuploidy , when a particular chromosome can be multiplied 3 × or 4 ×, or reduced - 1 ×, or completely lost. Anomalies in the number or structure of chromosomes, so-called chromosome aberrations, arise as a result of disorders in mitosis and DNA damage (see below).
Ribonucleic acid RNAAnother important "informational" macromolecule in cells is ribonucleic acid RNA. It is somewhat simpler than DNA, with which it is similar in many respects: RNA consist of a single sugar-phosphate polynucleotide strand, which, however, contains the monosaccharide ribose instead of deoxyribose. RNA further differs from DNA in that the pyrimidine base uracyl U occurs instead of thymidine T. (similar to thymine, uracyl forms a complementary pair U-A with adenine). The other bases adenine, guanine, cytosine, are the same in both nucleic acids.
The "World of RNA"
In terms of genetic information in current cells, RNA plays a "helper" role, although necessary (see below). However, evolutionary biology concluded that early life was probably based on RNA (the "RNA world "), the first simpler molecules of which could have arisen spontaneously from prebiotic molecules. The original precursors of the present cells - protocells - were probably just "clumps" of ribose molecules, polymerized into short stretches of RNA, coated with water into a simple phospholipid membrane. Under appropriate conditions, RNA molecules are able to make copies of themselves and thus "multiply". Peptides ("RNA-peptide world ") may have aided these processes . Suitable combinations of peptides can produce enzymes, that catalyze RNA copying. Replicating RNA molecules encoded properties that were "genetically" passed on to the next generation. Mutations that occurred by chance during "copying" led to changes, of which the "positive" ones allowed these early cells to adapt better to the environment and thus compete with each other by natural selection (Darwinian evolution ). It was only later that a suitable combination of RNA molecules developed DNA, which, thanks to its greater chemical stability, took on the role of primary genetic molecule for long-term storage of genetic information throughout the organism and for transmission to future generations. RNA began to function as a "bridge" between DNA and proteins (see below "Information transfer - proteosynthesis"). Figuratively speaking, RNA passed the "scepter" of storing genetic information to its duplicate "sister" DNA and for themselves retained the role of "mediator" (mRNA). Thus, prokaryotic cells (without nucleus and without organelles) with cyclically arranged DNA were first formed; later, more complex eukaryotic cells developed with a linearly arranged DNA in the form of a double helix located in the nucleus and with a number of organelles performing specific functions of cell metabolism.
From the point of view of evolutionary biology, the questions of the origin of life, its evolution and desertification, are discussed in the "Emergence and Evolution of Life" section of the work "Anthropic Principle or Cosmic God".
Information transmission - proteosynthesis
The basic process by which the information contained in DNA is translated into a specific structure or function is protein synthesis or proteosynthesis. So-called gene expression, in which the information stored in the DNA gene is converted and realized on a specific cellular structure or function, takes place in two stages. First, transcription occurs (transcription, copy), when an information or mediator RNA (mRNA - messenger RNA) is created , the strand of which is a copy of the base sequence of one of the strands of the DNA double helix. The transcription of DNA into RNA is catalyzed by an enzyme called DNA-dependent RNA polymerase. The single-stranded linear mRNA molecule separates upon transcription and travels to the cytoplasm. The mRNA is then translated (transcribed) into a protein, whose amino acid sequence is encoded by the mRNA as a matrix or template; this second stage - protein synthesis - takes place in ribosomes (see below "Ribosomes - protein factories"). The information is thus translated from the "language" of DNA nucleic acids into the "language" of the amino acids from which the proteins are assembled. The proteins formed can be used by the cell itself, or they can travel to other cells, tissues or organs.

RNA splicing
As mentioned above in the DNA section, only a small part of the DNA sequences encode some (functional) proteins. The coding regions of the exon represent only small "islands", which are surrounded by a "sea" of unnecessary intron sequences.- "genetic jung" which makes up about 9/10 of the sequences present. Short sections of DNA that encode proteins are interrupted by long sequences that do not encode anything and should be removed before proteosynthesis. The removal of non-coding regions cannot take place in DNA (whose structure must be maintained as the genetic information for the next cell generation), but it does so only at the RNA level by a process called splicing of RNA. The information contained in the DNA is first transcribed into a precursor mRNA molecule ( pre-mRNA), which is an exact copy of a single strand of DNA; it therefore contains many non-coding sections. During pre-mRNA splicing, the boundaries between coding and non-coding regions are recognized by small nuclear RNAs by base pairing. The non-coding portions are then removed and the protein coding sequences are recombined into the resulting mRNA , which enters the cytoplasm (ribosomes) for proteosynthesis.
New research (the ENCODE project) has shown that non-coding RNA derived from "genetic litter", "unnecessary DNA", is often used to regulate the expression of coding genes.
The so-called transfer RNA participates in the translation process(tRNA), whose function is to transfer amino acids to the ribosome. The three nucleotides in the mRNA that determine the inclusion of one amino acid in a protein is called a codon. In tRNA, it corresponds to a trio of nucleotides that bind to a codon - the so-called anticodon, which is specific to each type of tRNA. The transfer tRNA carries in its acceptor part on the one hand the corresponding amino acids, on the other hand it has a triple nucleotide (anticodon) which can pair with the codon of the mRNA. Its molecular mechanism ensures that the correct amino acids are included in the protein according to the given sequence of the genetic code. In this two-step proteosynthesis the resulting proteins then realize the appropriate structure or function in the cell or organism. It can be said that genetic information in a cell or organism is expressed in the form of proteins: the genome (a set of hereditary information) is transformed into a proteome (a set of all the proteins in a given organism).
Note:There is also a reverse process, so-called reverse transcription , in which an RNA molecule is able to store its gene sequence in DNA through the enzyme reverse transcriptase. This occurs when cells are infected by certain viruses , whose RNA can thus enter the DNA of eukaryotic cells and alter their genetic sequence. In a way, the above-mentioned synthesis of DNA telomeres by telomerase also belongs to this category of reverse transcription.
After the synthesis of proteins in ribosomes, their post-translational modifications can occur - additional chemical modifications that can give proteins new properties and regulate their functions. Such a typical modification is phosphorylation and dephosphorylation (attachment or detachment of the phosphate group PO₄ to a protein), acting as a "switch" between the active and inactive forms of the protein.
Thus, most genes encode a protein, and these proteins perform almost all functions in the body. Furthermore, through proteins, individual genes can interact indirectly with each other: one gene produces a protein that has (in addition to possibly other functions)the ability to alter, for example, the rate of transcription of another gene. This creates a kind of gene regulatory network with very complex behavior.
Direction of genetic information transfer
Genetic information contained in nucleotide sequences in DNA/RNA and transformed into amino acid sequences in proteins is transferred in cells only in precisely defined directions :
1. Transfer - copying - from one DNA to another DNA. This occurs during replication - cell division.
2. Transfer from DNA to RNA - transcription to mRNA - as the first stage of protein synthesis.
3. Transfer from mRNA to protein - translation - as the completion of protein synthesis.
4. Reverse transcription from RNA to DNA, in which insertion (transcription) occurs in the opposite direction. This is observed when cells are attacked by retroviruses, which use reverse transcriptase to "sneak" certain sections of their RNA into the DNA of the attacked cell, thereby forcing it to create proteins for its own needs. .....
  Reverse transfer from protein to RNA or DNA, as well as transfer from protein to protein, is not possible. Evolution has not created any mechanisms for these reverse transfers. This universal observation for all life here on Earth is sometimes called the "Central Dogma of Molecular Biology"..?..
  The impossibility of these reverse transfers of genetic sequences is the biomolecular reason why the inheritance of traits and changes acquired during the life of a particular organism does not apply (this individual inheritance was assumed by J.B. Lamarck).
Proteins, enzymes, kinases
Proteins (Greek protos = first; biological substances of primary importance) - are the basic material of life. They are the building material of various structures in cells and tissues and the carrier or "executor" of many biochemical functions. These biopolymers consist of amino acids ( 22 basic types of amino acids) linked by chemical bonds into long chains as "beads on a string" (as discussed in more detail above in the introductory section on cells). For proper function of proteins is important not only the amino acid sequence - the primary structure, but also the geometric spatial structure (3D) - the secondary and tertiary structure into which the amino acid chains are folded or "packed". The specific (and relatively unchanged, rigid) three-dimensional structure largely determines the function of proteins by the "key and lock" method: in order for a protein to bind to a specific target molecule or structure, as when a key fits into a lock. The primary structure, given the amino acid sequence, does not necessarily determine the geometric arrangement of the protein. The assembly of proteins into the correct spatial arrangement is aided by special protein molecules called chaperones (French chaperon = guard lady) - they are "guardians" who ensure the correct spatial structure of proteins, prevent incorrect binding (some chaperones event. incorrectly packed structures again "unwrap").
Some proteins, however, are not fixedly arranged spatially shaped, they are unstructured, flexible - whether as a whole or containing parts with a fixed structure as well as flexible parts, or they consist of a three-dimensional shape "as needed". Such flexible proteins can bind to various types of molecules (they are "promiscuous"); examples are p21 and p27 proteins. The known p53 protein also contains unstructured sections.
Proteins that control or catalyze biochemical reactions or processes are called enzymes (the name comes from the Greek zyme = ferment, yeast ). Each enzyme is "specialized" for a particular function; enzyme + substrate ® product + enzyme. The biochemical names of enzymes are usually formed by a base related to the function and the suffix "-ase": e.g. lipase (enzyme that breaks down fats into simpler substances), proteinase (breaks down proteins into smaller parts, peptides), amylase (digestive enzyme that breaks down long molecules of starch (Greek amylon = starch ) into simpler carbohydrates), phosphatase (an enzyme that releases a phosphate group from its binding to another compound).
   Important enzymes are the so-called kinases (Greek kineo = move), which are able to activate certain processes and transfer phosphates to other compounds, acceptors that have OH groups; a phosphoester of the acceptor molecule is formed. The transfer and binding of the phosphate group PO₄ (the source of which is most often adenosine triphosphate ATP, see "mitochondria" below) - phosphorylation - to a certain site of a protein activates the specific reactivity, for which the phosphate group supplies energy. Protein kinases, proteinases, and molecules that regulate their activity, link the various signaling pathways in the cell. MAPK (mitogen-activated protein kinases) is a group of cellular kinases that gradually phosphorylate with each other to form a network or cascade leading and amplifying the signal; at the end of the pathway are substances sensitive to phosphorylation. The pathways usually end in the nucleus, where they phosphorylate certain transcription factors.
  The biochemical names of some kinases are formed in a similar way to other enzymes. Tyrosine kinase is an enzyme that transfers phosphate to the hydroxyl group of the cyclic amino acid tyrosine bound in the protein. This affects the function and activity of the protein - it participates in the regulation of cell growth and division, the transmission of signals to cells; increased tyrosine kinase activity (e.g., the epidermal growth factor receptor EGFR) can lead to tumor growth. For many kinases, the names originated in a more complex way based on the diseases they were discovered in reseach. The so-called ATM kinase (Ataxia Telangiectasia Mutated) is particularly important for our area of biological effects of radiation, which phosphorylates and increases the expression of the p53 protein, which acts as a transcription factor and is essential for cell cycle regulation and induction of apoptosis (are discussed in more detail below "Mechanisms of Cell Death", "Apoptosis"). It is also the anti-apoptotic protein Bcl-2 (B cell lymphoma leukemia-2) and, conversely, the proaptotic Bax (Bcl-2 associated X protein).
Cyclins are proteins that are present in the cell mainly in a certain part of the cell cycle; during the cell cycle, there are cyclic changes in their concentration (hence their name) - expression and degradation, which plays an important role in cell cycle regulation. Cyclins contain homologous chains of about 100 amino acids in size.They bind to their partners - cyclin-dependent kinases CDK. At low cyclin concentrations, most CDKs are in an inactive free state. As the concentration increases, cyclins may bind to certain CDK regulatory sites, causing an increase in their activity - active CDKs can phosphorylate a number of other enzymes, causing their activation and deactivation, which can significantly affect cell cycle dynamics. Due to the complicated regulatory mechanisms in eukaryotic cells, several species of cyclins and their respective CDKs are present, regulating different phases of the cell cycle: cyclins D (regulating the passage of the control node in the late G1 phase), cyclins E (affecting G1 to S phase transition), cyclins A (controlling the course of the S phase), cyclins B (controlling the onset of mitosis and some processes of its course).
The simpler substances of a proteinaceous nature are the so-called peptides (Greek pepto = boil, digest; they are formed, among other things, by digesting of proteins). They also consist of amino acid chains, but in smaller numbers, about a few dozen (peptides were mentioned at the beginning of our discussion of cells). They are used for cell communication, eg in the immune and nervous systems, and include a number of hormones. This group of substances of proteinaceous nature includes cytokines (Greek: kytos = cavity, cell; kineo = moving, transmitting ) produced by cells and used for their interaction and transmission of information. These include, for example, interferon (lat. inter = between; fero = to carry) and interleukins (the interaction of white blood cells).
DNA Modification and Damage
Some chemicals can penetrate the cell nucleus, interact with DNA, and modify it in such a way that it cannot successfully transmit genetic information during cell division. Such substances can slow down or stop cell division - they are called cytostatics. Such affected cells eventually undergo mitotic death, mainly in the form of apoptosis. Ionizing radiation (and the chemical radicals induced by it) have a similar effect, which will be discussed in detail below. Both of these mechanisms are used to kill tumor cells during chemotherapy and radiotherapy (§3.6 "Radiotherapy").
A number of chemicals entering cells from the outside and emerging inside during metabolism or ionizing radiation, can react with nucleotides and alter DNA sequences - causing genotoxicity. RNA from viruses can also enter the DNA of eukaryotic cells (by the action of so-called reverse transcriptase) and change its genetic information; so-called oncoviruses may be the trigging mechanism of mutations, that can lead to tumor transformation of cells.

Cell wall
protects the cells, separates cells from the surrounding environment and from other cells, separates the processes taking place inside the cell, and mediates the regulation of cellular functions by acting as a selective barrier - membrane. In eukaryotic cells, the cell wall is formed by a bilayer phospholipid membrane. Cells receive chemical "signals" from their surroundings (and possibly from other cells) and respond to them. For simple bacteria, this is limited to the perception of increased nutrient concentrations, but for multicellular organisms work more complex and advanced forms of communication with the environment, including intercellular communication. Intercellular communication involves the whole chain: excretion of a signaling molecule (eg hormone) from the transmitting cell ® transport of the signaling molecule to the surface of the target cell ® registration of the molecule by a receptor on the cell surface ® transmission of the signal to the inside the target cell ® cell response - induction of biochemical or biophysical changes in the target cell. Small hydrophobic molecules similar to amino acids (such as acetylcholine, dopamine, histamine, ...) can penetrate the cell directly by diffusion through the phospholipid bilayer of the plasma membrane - passive transport. To exchange some ions between the cell and the environment serves transmembrane proteins, which form so-called ion channels.
Receptors
On the surface of cells (cell walls) there are so-called receptors (Latin receptor = receiver of stimulus) - specific molecules that are able to recognize other specific molecules in the environment, chemically bind them and transport them to the inside the cell, or by ion channel affect the flow of ions through the plasma membrane. A substance (molecule) that is able to selectively bind to a cellular receptor is called a ligand (lat. ligo = bind ). The ligand binds to the receptor and specific signaling to the inside the cell is triggered. In terms of structure, the transmembrane receptor consists of three basic parts (domains) :
- The extracellular domain , formed by the amino-terminal end of the receptor protein, has a ligand binding site;
- A transmembrane domain that anchors the molecule in the cell membrane;
- The intracellular domain , formed by the carboxy-terminal C- termination of the macromolecule, after its activation triggers signal transmission - it activates other molecules of the signaling cascade in the cytoplasm, possibly up to the nucleus.
Receptor activation occurs by kinases and phosphorylation, as mentioned above in the section "Proteins, enzymes, kinases". After ligand binding and phosphorylation of the receptor, the conformation (spatial arrangement, rotation - other isomerism) of this molecule changes and the binding site for specific intracellular signaling molecules is revealed on the inner domain; with the help of kinases, the activation of other molecules of the signaling cascade follows. If the chemical signal is transmitted to the nucleus, transcription factors are phosphorylated, which in this way induce transcription (or repression) of specific genes, which then produce the relevant effector proteins (lat. facio = do, efficio = power).
Cytoskeleton - skeleton and the tanspoter of cell functions
Cytoskeleton - "cell skeleton" (cellular "grid" or matrix) - is a system of mechanical support and "reinforcement" of eukaryotic cells. It consists of a complex mesh of fibrous protein structures in the cytoplasm. These structures are of three types :
- Microfilaments (lat. filamentum = thread, fiber) are the thinnest fibrous structures (thickness approx. 5-7 nm), which by their contractility move the cells as a whole, using the energy obtained by ATP cleavage (see below). Microfilaments are contained to an increased extend, for example, in specialized muscle fiber cells.
- Intermediate filaments are formed by slightly thicker protein fibers (approx. 10-15nm) and ensure the mechanical stability of cells and tissues against mechanical stress.
- Microtubules (lat. tubulus = tube, pipe) are the thickest and most complex structures of the cycloskeleton (diameter about 20-30nm). They are thin hollow tubes composed of a protein called tubulin, arranged in long chains of dimeric units in which alpha- and beta-tubulin molecules alternate. These fibers are helically twisted (13 dimers of alpha and beta tubulin form one complete thread) and the individual threads are "laterally" bound to the tube. Tubulin molecules contain binding sites for guanosine triphosphate (GTP). Tubulin polymerization, associated with microtubule elongation, occurs by sequential attachment to that end of the microtubule ("+" end) that contains beta-tubulin with bound GTP. Hydrolysis of GTP produces GDP (guanosine diphosphate) and further fiber growth is stopped. The opposite process to polymerization - dissociation, consisting in the separation of tubulin dimers from the end of the fiber containing alpha-tubulin ("-" end), leads to the gradual depolymerization and shortening of microtubules. The assembly and degradation of microtubules is controlled by proteins called MAP (Microtubule Associated Proteins). Microtubules with their ends ("-") are "anchored" in the central part of the cell in the so-called centrosome, bodies in close proximity to the nuclear membrane, which plays an important role in cell division.
Intracellular movement and transpost
is one of the essential properties of cells, which is necessary for carrying out basic biological processes. Targeted intracellular movement is mediated by the cytoskeleton, to which a number of special proteins can bind. Along the microtubules, a number of important molecules are transported in the cell. It is through special substances called kinesins that have binding sites for different molecules. Kinesins as "molecular machines" move - "walk, step" - along the hollow fibers of microtubules (by means of dinein "molecular motor" bonds, which contact the microtubules with rod-shaped protrusions) as along a "cable car" and thus transfers temporarily bound molecules. To drive each step, an adenosine triphosphate (ATP) molecule is used, which alternates with the kinesin terminals, hydrolyzing the adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and cleaving the phosphate. The released chemical energy is converted by electrical polarization into a mechanical force, causing movements and transport of molecules. In one such step, the kinesin is shifted by a distance of two tubulin dimers, about 10 nm. In one second, a kinesin molecule can perform about 80 steps.
Unlike the usual concept of a skeleton (human skeleton, skeleton of a building), the cytoskeleton is not a fixed and rigid structure, but a highly flexible and dynamic system that is constantly adjusted according to the needs of the cell. The changes in the structure and size of cytoskeleton units are caused by polymerization and depolymerization (decomposition, dissociation) of proteins into chains and fibers (with a helical spatial structure - in the case of microtubules). There is a constant supply of cytoskeletal proteins (tubulin, actin) in the cell; these monomers then polymerize into cytoskeletal structures or, conversely, disintegrate back into monomers. The cytoskeleton transforms chemical energy into mechanical energy - it is responsible for all types of cellular movements, intracellular (organelle movement, cell division) and extracellular (movement of cells, flagella, cilia ...). Furthermore, the cytoskeleton interconnects individual cell structures. And not just mechanically. Along the cytoskeleton fibers, especially microtubules, various proteins interact and transmit chemical signals, necessary for the regulation of cellular processes. It mediates the intracellular transfer of complex molecules between the nucleus and other organelles, it also participates in cell division (during cell division it creates mitotic spindle).
In somatic cells, which are part of tissues and organs, on the cytoskeleton follows up outside the cell the so-called extracellular matrix: a system of protein fibrin and collagen fibers (Lat. fibra = fiber , Greek kolla = glue ), connecting the cells and holding them together in tissues and organs. It ensures the connection between cells, maintains the integrity and shape of tissues, transmits movement. The intercellular space itself is filled with a fluid of gel consistency (interstitial fluid, "tissue fluid"), which serves to transfer nutrients and oxygen to the cells and to remove-drainage of metabolic waste products.

Eukaryotic cell structure. Details of some structures are schematically drawn in enlarged sections (frames).
(this picture is shown here again for better clarity)

Cellular organelles
Mitochondria - chemical "power stations" of the cell
Important organelles in the eukaryotic cell are mitochondria (Greek mitos = fiber; chondros = grain) - are important organelles in a eukaryotic cell. They have a diverse shape from elongated fibers to compact grains, about 0.2-5 micrometers in size. The number of mitochondria depends on the metabolic activity of the cell: in average cells there are several hundred of them, cells with higher energy consumption requirements can contain several thousand mitochondria, in metabolically exposed cardiomyocytes there are up to 100,000 of them and they occupy more than 30% of the cell volume.
They have two membranes, inner and outer :
- The inner membrane is irregular, many times bent (depressions into the interior are sometimes called krists). It is selectively permeable only to molecules involved in the respiratory chain and oxidative phosphorylation. Multiprotein complexes are located on the inner membrane, which mediate cellular respiration by proton and electron transport; cytochrome c is particularly important for our interpretation (see "Apoptosis" below).
- The outer membrane resembles a cell wall and is permeable to most small molecules, but not to more complex protein molecules (such as cytochrome c). It developed during the phylogenetic development of the plasma membrane of aerobic bacteria after their endocytosis (see below).
The main function of mitochondria is the production of chemical energy in the form of molecules ATP (adenosine triphosphate) C₁₀H₈N₄O₂NH₂(OH)₂(PO₃H)₃H. ATP molecules, which are "energy transporters" in cells, are formed in mitochondria by oxidation of citrates and fatty acids (Krebs cycle, hydrogen oxidation, oxidative phosphorylation). At the site of need, ATP is then oxidized to ADP (adenosine diphosphate + P) or AMP (adenosine monophosphate + 2P) to release considerable energy (approximately 57 J/g). Mitochondria are sometimes referred to as "power stations" of cells in which the oxidation of nutrients occurs, especially glucose, to form carbon dioxide, water and output ATP, whose energy is used in cells for endothermic processes - macromolecule synthesis, transport of molecules against the gradient, cell movement (including muscle contraction), formation of electrical potentials in membranes, heat production. Mitochondria are formed (multiply) in cells by continuous binary division ("budding", similar to bacteria) independent of the cell cycle; inside the inner membrane they contain their own mitochondrial DNA, completely different from nuclear DNA.
Evolutionary origin of mitochondria
Mitochondria have an interesting evolutionary origin. Ancient eukaryotic cells, when developed from prokaryotes, had no mitochondria. They ate, among other things, the various prokaryotic cells they fed on. About 1.5-2 billion years ago, the original eukaryotic cells sometimes phagocytosed some species of ancient aerobic bacteria (similar to protobacteria of the order Rickettsiales), which, however, did not decompose and digest, but left them intact - they established endosymbiosis with them *). The host cell obtained oxygen and nutrients from the environment, which they passed on to these bacteria - future mitochondria - which metabolized them into energy molecules for their own needs as well as the needs of the whole cell. Such a symbiosis has proven to be mutually beneficial. Over the millions of years, the host cell has completely "domesticated" its bacteria, the endosymbiot has given up most of its independence and become a mere organelle. Circular DNA, similar to prokaryotic nucleotides, is still present in mitochondria and ensures their partial genetic autonomy. In plant eukaryotic cells, chloroplasts (a kind of photochemical "battery") occur instead of mitochondria, whose similar evolutionary origin is derived from endosymbiosis with cyanobacteria.
*)Trace phylogenetic "evolutionary tree" of eukaryotes to the "root" is very difficult. In addition to the primary endosymbiosis somewhere in the beginning, several other secondary or tertiary endosymbiosis occurred during evolution. Comparative analysis of morphological characters are often misleading. A more reliable method is now molecular phylogenetics, which has developed procedures for reconstructing phylogeny according to the similarity of genes and proteins. By comparing gene sequences (most often genes for RNA small ribosome unit, SSU rRNA, which are present in all cells) in different organisms, certain similarities can be traced, which may be indications for their phylogenetic relatedness. The problem is that during evolution, gene fusions of originally separate genes very often took place and, conversely, gene splits into two new parts. Therefore, it is necessary to perform phylogenetic studies on multiple genes and proteins - multigene or phylogenomic analyzes using sequencing of genomes and mediator mRNA molecules, followed by statistical analysis of similarities.
Lysosomes
Other organelles in the cell are lysosomes ("decomposition bodies" - "digestive vesicles"). Digestion is the enzymatic breakdown of ingested nutrients into basic biological building blocks, which are amino acids, monosaccharides and fatty acids. In lysosomes the chemical decomposition - hydrolysis - of various more complex organic substances (sugars, fats, nucleic acids, proteins) takes place in an acidic environment with many different enzymes. The products of this decomposition can then be processed in mitochondria to form ATP energy molecules, that "distribute" the binding chemical energy needed to synthesize complex substances and for other cell functions. And in ribosomes for the creation of specific cellular proteins. Lysosomes are about 0.1-1 micrometer in diameter, and there are several hundred of them in cells; a larger number are found in the gastrointestinal tract - liver and pancreatic cells.
Ribosomes - "factories" for proteins
Ribosomes (ribonucleon-protein particles) are small organelles found in large numbers in the cytoplasm of cells and also on the surface of the endoplastic reticulum. They are about 20-30 nanometers in size. The number of ribosomes in cells is highly variable, proportional to the growth rate of the cell. In most cells, there are on the order of 10,000 - 100,000 ribosomes, but in some cases in eukaryotic mammalian cells there can be up to 10 million. Ribosomes have only a temporary existence in cells, a relatively short one. After the production of a specific protein is completed, the two subunits separate and usually decompose. In eukaryotic cells, new ribosomes are formed in the nucleolus, where RNA synthesis and ribosome biogenesis take place. In prokaryotic cells, this process takes place in the cytoplasm, where RNA molecules travel.
Ribosomes are composed of RNA and proteins, structured into two subunits. The small subunit of the ribosome has a molecular weight of about 800 kDa and consists of 20 proteins and an RNA molecule of about 1600 nucleotides in length (16S RNA). The large ribosome subunit is about 1500 kiloDaltons in size and consists of 33 proteins and two RNA molecules (23S RNA of 2900 nucleotides in length and 5S RNA of 120 nucleotides in length). In ribosomes, proteins are synthesized from the mRNA strand by translation - decoding information from the mRNA according to which the resulting amino acid sequence is assembled; tRNA molecules are used for "reading", which carry an amino acid on the one hand and a triple nucleotide (anticodon) on the other hand, which can be paired with an mRNA codon (as described above). Specific nucleotides of 16S RNA from the small subunit of the ribosome form hydrogen bonds with codon and anticodon nucleotides only when properly paired and geometrically oriented. The actual peptide covalent bond, which connects two amino acids, is formed in a large subunit of the ribosome, where the so-called peptidyl-transferase center containing 23S RNA and ribosomal proteins is located. Ribosomes are a kind of cellular "construction lines" or "factory" for protein production: nuclear DNA ("design office") supplies informational mRNA ("technical drawing"), which in ribosomes translates into the amino acid sequence of proteins (using a transfer tRNA for each amino acid) - runs its own "production" of a specific protein molecule. It was discussed in more detail above "Information transfer - proteosynthesis".
Other organelles
A relatively large formation in the cell's is the endoplasmic reticulum (in the microscope it appears as a kind of "clot" in the cytoplasm) in the shape of a coiled membrane sheet. It consists of two types: a rough (granular) reticulum whose surface is dotted with ribosomes (these granules cause "roughness") and a smooth endoplasmic reticulum with a network of channels connected to the rough reticulum. These units play a central role in the synthesis of proteins, lipids, steroids and other substances in the cell. Golgi complex is endomembrane system vesicles in the vicinity of the endoplasmic reticulum, used to transport and modification of proteins.

Cell specialization
Multicellular organisms consist of cells of different species that have different shapes and different activities - they are "specialized" to create various differentiated tissues and organs with a specific function, or to mechanically build, for example, a supporting or locomotor system. These specialized cells, performing a certain function, are called effector cells (Latin effector = executor). There are about 230 species of various specialized cells in the human body. These are, on the one hand, body cells - somatic (Greek sóma = body ) - these are practically all cells in the body, and sexual cells - gametic (Greek gameté = woman, wife)) - in mammals they are eggs and sperm.
To ensure growth and regeneration, stem cells (maternal, clonogenic) are also present in the tissues and organs. Stem cells are capable of unrestricted division, being able to produce both identical stem and daughter cells, bearing the characteristics of a given differentiated tissue - asymmetric division into two different cells, an identical stem and a different daughter cell *). Asymmetric division ensures the process of differentiation, in which the emerging cells by their structure and function adapt to the specific role they are to play in the organism. All cells in the organism are provided with the same genetic equipment, but as a result of this process, only a certain part of genetic information is realized in a particular cell (due to specific transcription factors, only certain genes are transcribed in the cell, others are not applied). Daughter effector cells usually enter the quiescent G0 phase of the cell cycle.
*) Cell division and cell cycle are discussed below in the section "Effects of radiation on cells", section "Radiation effects during the cell cycle".
New research has shown that specialized effector cells can, under certain circumstances (eg due to stress from an unfavorable environment, such as a change in the acidity of the environment), lose their specialization and become cells that have all the genetic equipment available. The division of these cells may appear to be involved in the regeneration of damaged tissues; it is also speculated that some cells, after losing specialization due to mutations, may transform into clonogenic tumor cells.
Extinction - death - of cells
Extinction of living organisms
No organisms do not live forever - they are "lethal". The causes of extinction (death) of organisms can be very diverse, but we can roughly divide them into two categories :
1.External causes - mechanical destruction, attack and "eating" by another organism, thermal damage, chemical or radiation damage, adverse change in external conditions, lack of nutrients.
2.Internal factors - physiological disorders and diseases, "wear and tear" of organs and degeneration of vital functions, aging - senescence.
External and internal factors are often closely related. Infections, radiation or chemical pollutants, even if the organism successfully copes with them in the acute phase, can initiate latent processes of internal degradation, which can eventually cause the extinction of the organism ...
Aging of organisms
Aging - senescence - of a living organism is a complex irreversible process by gradually reducing the efficiency of vital functions and decaying the body's structures. It is an integral part of the life of all multicellular organisms and will eventually result in their extinction. The rate of senescence is a fundamental limiting factor for the life span of organisms. This maximum life span is very different for each species of organism.
The longest living organisms are some conifers - Sequoia sempervirans or Pinus aristata, reaching 3000-5000 years. Examples of animals are long-lived turtles such as Chelonoidis nigra (approximately 200 years) or bivalves Arctica islandica (500 years). Most animals have a life span of years or decades, in insects they are usually months, the shortest is in mayflies (max. 3 days).
Aging is a multifactorial process involving various mechanisms, of which three are probably the most important :
- > Reactive free radicals, especially oxygen, formed during many metabolic processes in the body. The main source of free radicals in cells are mitochondria, in which cellular respiration and the production of chemical energy take place. Although antioxidant enzymes are present in organisms, the ability to produce them decreases with age. Free radicals then begin to accumulate more and can damage cells and tissues (especially causing DNA strand damage, as described in the following section).
- > Accumulation of DNA defects arising spontaneously and accidentally during life due to replication errors, oxygen radical reactions, or mutagenic reactions (which usually enter cells from the environment with food). Some of these more serious defects in important genetically coding parts of DNA are not repaired, they accumulate in the organism, disorders of proper function of cells in tissues can occur. It is observed that the number of spontaneous chromosomal aberrations in somatic cells increases with age.
- > Telomere shortening during mitotic cell division (described above in the section "DNA, RNA, proteins, chromosomes, telomeres", passage "Telomeres"). After exceeding a certain critical length, the telomeres lose their protective function of the terminal parts of the DNA and the cell can no longer divide; usually programmed cell death - apoptosis - occurs. The regular shortening of telomeres during each division means that somatic cells can perform only a limited number of divisions during their lifetime - about 50-80. This number of divisions is called the Hayflick limit (Hayflick and Moorhead found out in 1951) . Therefore, the cells capable of dividing are becoming less and less in the organism over time, the functional capacity of the tissues decreases and therefore the organism ages - replicative aging.
Note:The aging process - senescence - is sometimes related to the 2nd law of thermodynamics - growth entropy (disorder) of closed systems. However, this 2nd law of thermodynamics is only a hidden physical framework lying deep in the molecular background. However, the real explicit mechanisms here are the biochemical processes of free radicals, DNA defects and telomere shortening during cell division.
Mechanisms of cell death
At the cellular level, we encounter four basic types - mechanisms - extinction and inactivation: apoptosis, autophagy, necrosis and senescence of cells. "Mitotic catastrophe" is sometimes mentioned as a special category. Under physiological circumstances, eukaryotic cell death is one of the mechanisms for maintaining tissue homeostasis balance in the production of new cells and the extinction of old, redundant, damaged cells. It can also serve as protection against mutated cells, which can be dangerous for the body.
Cell apoptosis
The basic way of controlled (programmed) death of damaged, dysfunctional or otherwise redundant cells in multicellular organisms is called apoptosis (Greek apoptosis = falling - the name comes from the fall of leaves caused by the death of cells in the petioles) - a kind of cellular "suicide". It is a complex chain of processes influenced by a number of factors and controlled by many complex biochemical molecules, especially proteins and enzymes. Apoptosis can be induced by two types of stimuli :
¨ Internal (intracellular) activation of apoptosis - irreparable DNA damage, toxic substances in the cell (eg oxidation products), lack of nutrients. Apoptosis triggered by internal mechanisms acts as a protection against the survival and proliferation of defective cells, especially mutated cells with damaged DNA.
¨ External (extracellular) activation of apoptosis - binding of certain substances (ligands of "death"), transmitted by regulatory mechanisms of tissues and the organism, on the relevant receptors of the cytoplasmic membrane. Properly functioning apoptosis, triggered by external regulatory mechanisms from the tissue, helps maintain tissue homeostasis and provides effective protection against excessive cell proliferation.

Above: Internal and external signaling pathways of apoptosis activation. Bottom: Morphological changes of the cell during apoptosis.

Internal signaling pathway of apoptosis
An important role in apoptosis, especially in the process of internal activation of apoptosis, plays the p53 protein (having a molecular weight of 53 kilodaltons and a length of 393 amino acids). Under normal circumstances, its level in the cell is low (maintained by the mdm2 protein ), which is sufficient to maintain cell cycle regulation. DNA damage activates ATM kinase, which triggers the production of DNA repair proteins and (via mdm2) activates and phosphorylates the p53 protein, which acts as a transcription factor. In the early stages, p53 can activate DNA repair (via GADD45 proteins ) and slow down the cell cycle (via p21 proteinen coded by the WAF/CIP1 gene) so that repair can occur over time. The p21 protein inhibits cyclin-dependent CDK kinases and arrests the cell cycle in the G1 phase; in the case of proper function of p53, the cell cycle is restored only after the elimination of errors in DNA. If p53 detects DNA damage beyond repair options, its expression is increased, thereby inducing the synthesis of Bax and other mitochondrial-binding proteins; at the same time, the anti-apoptotic Bcl2 protein (mentioned below) is inhibited. Mitochondrial membranes lose potential and become permeable; cytochrome c *) is released from mitochondria, DIABLO protein (direct IAP binding protein with low pI) , AIP (Apoptosis-Inducing Protein) and the caspase chain is started (see below).
*)Cytochrome c , if it is inside the mitochondria - located on the inner membrane (through which it mediates electron transport), is important for cellular respiration (there is cytochrome-c-reductase and cytochrome-c-oxidase). However, if released from the mitochondria, it becomes a proteolytic cell poison that can lead to cell death.
Thus, the p53 protein (discovered in 1979 in the British Cancer Research) has the function of a cell cycle regulator and a kind of "guardian of the genome" :
-It can activate DNA repair, while temporarily pausing the cell cycle to allow time for repair mechanisms;
-If it turns out that the cell's DNA is so severely damaged that its repair is no longer possible, it can trigger apoptosis, which programmatically leads the cell to "safe" extinction.
In this way, the organism is protected from potentially dangerous cells with a damaged genome, ie also against tumor cells. Hence the name tumor-suppressor gene TP53 for the corresponding DNA sequence (located at 17p13.1), which encodes as a product (transcription factor) the p53 protein. Mutations in the TP53 gene can lead to tumor growth (along with other factors, see §3.6 " Radiotherapy ", section "Carcenogenesis"). Several other genes (cooperating and competing) are also involved in the function of TP53.
External signaling pathway of apoptosis
External activation of apoptosis is initiated by the arrival of a "deadly" ligand that binds to the appropriate "deadly" receptor located on the cell surface. One such ligand is the so-called TRAIL gene (the name comes from the field of oncology: tumor necrosis factor-related apoptosis-inducing ligand ). Below the cell surface, pro-caspases are then activated (8 and 2), the process branches to the inhibition of the mitochondrial membrane (and the release of cytochrome c as in the above-mentioned internal activation) and to the direct activation of effector caspases (-3,6,7).
Caspase chain
The actual phase of irreversible apoptosis is caused by the activation of proteins from a group of cysteine proteases called caspases *) (abbreviation caspase = cysteinyl aspartate-specific protease), which break down intracellular proteins (proteolytic degradation), including the cytoskeleton and cell matrix; this then leads to the morphological changes of the cell mentioned below. They also attack the nucleus and cleave DNA.
*)So far, 14 species of caspases are known, of which about half are involved in apoptosis. Some of them, so-called pro-caspases (-2,8,9,10) in inactive form, commonly occur in the cytoplasm. By reacting these "signaling" caspases with cytochrome c, or association with receptors, effector caspases (-3,6,7) are expressed, which break down proteins and other macromolecules in the cell.
After starting the apoptotic process the DNA cleaves into smaller sections, hydrolysis of cellular proteins, degradation of cycloskeletal structures and organelle membranes takes place. Furthermore, there is a membrane depolarization of the cell wall, the exposing of phospholipids on the cell surface, increased permeability of the plasma membrane, and later the violation of the integrity of the cell wall. In the final phase, the cell shrinks and breaks down into several smaller fragments (apoptotic bodies), on the surface of which molecules get from the inner wall (eg phosphatidylserine - PS) stimulate their phagocytosis - "ingestion" by surrounding cells, phagocytes or immune cells (macrophages - increased exposure of PS on the cell surface is an attractive signal for macrophages: "eat me! "). Thus, in contrast to necrosis, there is also a regulated and gentle "clearance" of cell death products.
Apoptosis is the main mechanism of biological action - cell death - when irradiated with low and medium doses, tenths to units of Gy. In the induction of apoptosis by ionizing radiation (internal signaling pathway), the mechanism of its occurrence and time dependence differ significantly in different cell types. Rapidly dividing radiosensitive cells can enter apoptosis from different points in the cell cycle, less radiosensitive cells show varying lengths of "blockage" at some stage of the cell cycle, mostly in the G2 phase. At this time, the cells do not divide and are given time to repair the damage. If the damage is irreversible, apoptosis is initiated. The total time that cells have available to repair DNA damage before eventual entry into apoptosis is an important factor in the radiosensitivity of these cells at lower doses (2-5Gy). At higher doses (approximately 20 Gy), ionizing radiation-induced apoptosis occurs independently of cell blockage at a certain stage of the cycle, and the time that apoptosis occurs after irradiation depends on the radiation dose received.
An interesting effect accompanying the apoptosis of specific irreversibly damaged cells is the so-called bystander effect (discussed below), leading to apoptosis or genetic changes in some surrounding cells, which were not originally damaged.
Inhibition of apoptosis
Antiapoptotic mechanisms may also be involved in cells and tissues. Some mutations in the TP53 gene (deletion or point mutation) can cause inhibition of apoptosis. Apoptosis can also be blocked at the mitochondrial level. The antiapoptotic gene Bcl-2 (B cell lymphoma / leukemia protein 2 - was isolated from tumor cells of lymphoma B), which is found in mitochondria and whose increased concentration protects mitochondrial membranes - prevents the penetration of cytochrome c and the triggering of the caspase chain of proteolytic degradation in the cytoplasm (blocks the effect of p53 protein). Bcl-2 is intensively expressed by its BCL-2 gene during embryonic development; in adulthood it occurs only in stem cells (and in tumor cells).
  Both Bcl-2 and BAX are transcriptional targets for an important regulatory protein p53. Expression of the pro-apoptotic Bax protein can be induced by ionizing radiation, cytotoxic agents (such as chemotherapeutics), or other genotoxic stress.
Cell autophagy
This is a kind of "self-ingestion" of a cell (from the Greek auto = himself ; fago = eat, devour ). During complete autophagy (macroautophagy) of cells, autophagocytosis, the walls of lysosomes are disrupted and the cell content is subsequently degraded (decomposed, "digested"). Autophagic vacuoles form in the cell, latter the process of autophagy can affect the whole cell. Autophagy can be induced by cytotoxic substances or radiation, under physiological conditions it acts as an adaptation mechanism to a lack of nutrients or oxygen. Partial autophagy- a controlled process of self-cleavage and digestion - occurs when a cell tries to survive adverse conditions by digesting part of the cell cytoplasm or its less important organelles. Autophagic vesicles are transported to lysosomes, in whose acidic environment complex biological molecules decompose, recycling energy and necessary substances. This maintains protein homeostasis during adverse conditions; after their subsided, the cell can continue to function and divide.
Cell necrosis
The direct death (extinction) of cells, which is practically not controlled by cellular mechanisms, is called necrosis (Greek nekros = dead ). It arises as a result of severe irreversible damage to cells - mechanical damage, chemical damage, strong overheating or hypothermia, hypoxia, strong radiation. Oxidative phosphorylation is stopped, ions accumulate in the cell, cell edema (enlargement) occurs, organelle membranes rupture and proteolytic enzymes are released into the cytoplasm. Protein and DNA are broken down, the cell wall is broken, and the degraded cell contents spill into the extracellular space, which is accompanied by an inflammatory reaction in the tissue. Necrosis can affect entire groups of adjacent cells (tissue necrosis).
  When irradiated with ionizing radiation, cells necrosis occurs only at very high doses of tens to hundreds of Gy.
Cell senescence
Cell aging , called senescence , is a long-term multifactorial process involving both intracellular "program" molecular mechanisms and time-accumulating exogenous detrimental factors affecting cell viability. Progressive damage to cells by reactive oxygen and nitrogen during the life of tissues is applied, with the ever-decreasing capacity of antioxidant mechanisms. Cells can only reach a certain limit in the number of their divisions, the so-called Hayflick limit (about 40-60 cycles); then the cells lose their ability to divide. The limited replication potential of cells is mainly due to the shortening of the so-called telomere - they are marginal complexes in DNA that protect the ends of chromosomes from adverse reactions and binding and from their evaluation by cellular mechanisms such as DNA breaks. During DNA replication, there is no complete synthesis of the DNA ends, so at each cell division, the marginal ends - telomeres - are shortened in the daughter DNA. With excessive truncation, telomeres no longer adequately protect the ends of chromosomes, which evaluate cell control mechanisms and stop the cell cycle. Telomere shortening thus functions as a "mitotic counter". After reaching the Hayflick limit, cells age, replication senescence occurs (cf. also the passage "Extinction - death - cells" above) .
However, there is a special enzyme called telomerase (it is a complex composed of RNA and proteins, containing sequences serving as a template for the synthesis of DNA telomere sequences - reverse transcriptase), which is able to re-synthesize the terminal sequences of telomeres and thus prevent their shortening during cell division. Such cells are then capable of unrestricted division (immortilization - "immortality" of cells), which physiologically takes place only in dividing embryonic and stem cells, while pathologically it is applied in tumor cells (§3.6 "Radiotherapy", passage "Carcinogenesis").
Senescence can be accelerated by some harmful chemical factors, as well as exposure to ionizing radiation (aging of skin cells accelerates excessive sun exposure) - premature stress-induced senescence (a regulatory pathway of senescence, independent of telomere shortening leads through the p16 protein).
Entosis of cells
Entosis of cells (from the Greek. entos = inside ) is a phenomenon where two cells connected to each other and will merge in one cell, temporarily or permanently - one cell is "internalized" inside another, a "cell within a cell" is formed. In laboratory cell colonies, it is occasionally observed under a microscope that two cells gradually approach each other, "entering" each other, occur "drawing" one living cell into the cytoplasm of another cell. In many cases, it is "cannibalism", where one cell absorbs another, which disappears due to lysosomal enzymes - this could be classified as cell death (as is the case with phagocytes). However, sometimes endosymbiosis occurs, when the absorbed cell survives, it may even divide inside the "host" cell, or it may leave it again without damage.
  Entosis occurs in cells that have separated from binding in the extracellular matrix. As such a released cell approaches close to another cell, adhesion forces to the cytoskeleton of a neighboring cell begin to act on it, which can push it inward. So far, the question is whether entosis is a phenomenon that actually occurs in the body (where cells are fixed in the tissues in the extracellular matrix) or only in free cell cultures..?.. Entosis could play a role in cancer. It is not yet clear whether positive (another type of cell death that can help reduce tumor cells) or negative (tumor cells can "hide" in other cells from immune mechanisms or chemotherapeutics and then relax again and begin to multiply)..?..
Mitotic catastrophe
This is sometimes referred to as a more complex combined mechanism that may (but may not) result in cell death. It occurs as a consequence of erroneous mitosis when a cell attempts to divide without proper repair of damaged DNA (as in Figure 5.2.2c), due to failure in the G2/M control node and premature activation of CDK1. In a mitotic catastrophe, a larger number of multipolar dividing spindles and decondensed chromosomes appear, nuclear fragmentation or loss of the nuclear membrane occurs, two or more nuclei may be present (multinucleation) caused by an inaccurate distribution during cytokinesis. This situation can lead to "secondary" mitotic cell death, mainly by the mechanism of apoptosis or autophagy. However, if the process of apoptosis is inhibited, asymmetric multipolar division may occur, resulting in aneuploid cells with gene mutations or chromosomal instability.
Note:Faulty mitosis can also occur due to the action of certain chemicals that attach to the microtubules and prevent them from polymerizing or depolymerizing. Depolymerization of cytoplasmic microtubules and polymerization of new microtubules (astral, polar, kinetochore) around centrosomes at the nuclear membrane, forming a dividing spindle, is one of the key articles in cell mitosis. The respective anti-tubulin substances (microtubule inhibitors) are therefore referred to as mitotic poisons. Of the natural plant substances, it is, for example, colchicine (an alkaloid contained in ocun), which causes inhibition of microtubule polymerization, or taxol (the alkaloid paclitaxel contained in yew), which causes inhibition of depolymerization. However, the targeted intervention of microtubular inhibitors in cell division can be used to stop the growth of tumor cells (§3.6 "Radiotherapy", passage "Chemotherapy").
Immune death of cells
In multicellular prokaryotic organisms, complex interactions of various specialized cells occur. During evolution, the immune system evolved, whose task is to protect the body from foreign cells - especially infection by external intruders, but also from its own damaged or mutated cells. ... The main biochemical molecules mediating immune protection are proteins from the group of immunoglobulins . .
Although immunoglobulins can also induce apoptosis, the main mechanism of immune killing of unwanted or "suspicious" cells is the activation of complements - membrane glycoproteins C1-C9, which by their proteolytic effects attack cytoplasmic cell membranes and they cause their penetration. The cell dies and released chemicals cause an inflammatory reaction with leukocyte accumulation. Unlike apoptosis, this is the external proteolytic destruction of the cell. Another mechanism of immune cytocides is the induction of phagocytosis - the fixed Fc region of bound antibody specifically binds to the Fc receptor of some types of leukocytes, especially macrophages, which then recognize and subsequently phagocytose tumor cells. ...
These cell killing mechanisms are used in biologically targeted therapy of cancer using monoclonal antibodies (§3.6 "Radiotherapy", passage "Monoclonal antibodies") .
Further details of the structure of cells and their chemical and biological functions lie beyond the scope of this physically focused treatise. We will therefore turn to our main topic - the biological effects of ionizing radiation :

Mechanisms of the effect of radiation on living matter
Free radicals
One of the basic chemical phenomena in the irradiation of substances with ionizing radiation, especially substances containing water and more complex compounds, is the formation of free radicals. Free radicals are those atoms and molecules, that have one or more unpaired electrons in the last orbit of the electron shell. Such an atom or molecule is then highly unstable and reactive *). It tries to reach an equilibrium state by obtaining another electron "into a pair" from the surrounding molecules. In this reaction, a molecule that has lost an electron can become a new radical. Free reactive radicals, due to their oxidative and reducing effects, are able to cleave various types of internal molecular bonds in biomolecules and degrade thus their chemical structure, necessary for the respective biological functions.
*)In addition to free radicals, some other substances whose molecules do not have unpaired electrons show similar properties of high reactivity. It is, for example, hydrogen peroxide H₂O₂, hypochlorous acid or atomic oxygen O₁. These substances are also formed during irradiation and contribute to biological effects (especially in the increased presence of oxygen - see "oxygen effect" below).
Free radicals enter into many reactions in the biological environment. It is, for example, lipoperoxidation of fats (with the formation of aldehydes), oxidation of proteins, glycation proteins with glucose, changes in RNA and DNA strands, that can lead to cell death or to mutations (see below).
  Over millions of years of evolution, organisms have partially "learned" to use free radicals even to their advantage. Examples are white blood cells containing precursors and enzymes that are capable of generating free radicals; they then participate in the elimination of bacteria in the phagocytes. In terms of the biological effects of radiation, however, we will deal mainly with such reactions of free radicals, that lead to cell damage.
  Certain "opponents" of free radicals are antioxidants. These substances either prevent the formation of free radicals, or the free radical preferentially oxidizes this substance, which counteracts the oxidation inside the cell. The best known antioxidants are ascorbic acid (vitamin C), uric acid (prevents the formation of hydroxyl radicals in the blood plasma), cysteine, folic acid ; elements such as selenium, magnesium, zinc, chromium, ...
Effect of irradiation on cells
If we want to outline the effects of ionizing radiation on cells, it is necessary to consider two basic situations separately :
× Strong irradiation (with a dose of hundreds of Gy) => decomposition of biochemical molecules, denaturation of proteins in the cytoplasm and organelles, cessation of all vital functions, immediate cell death (in interphase) - cell necrosis.
× Weaker irradiation (tenths to units of Gy) => negligible effect on cytoplasm and organelles, radiobiological effect on DNA can result in mitotic death of cell - apoptosis, or change in genetic information - mutations. Or, thanks to repair mechanisms, there will be no effect.
In our treatise, we will deal with radiobiological processes especially in common situations of small and medium radiation doses of tenths, units or tens of Gy. We begin with the effects of individual radiation quanta.

"Cell.gif" image
So what happens when an incoming quantum of ionizing radiation enters into the cell ? According to the "Cell.gif" image (which we have shown here again for clarity), a eukaryotic cell has a complex structure, so it depends on which specific part of the cell is affected by the quantum of radiation :
-->If the quantum of radiation hits the cytoplasm and damages some protein in the cytosol, this molecule is soon removed in the lysosome and nothing happens. There are a large number of protein molecules in the cytoplasm and they are constantly supplemented by proteosynthesis in ribosomes.
-->When the quantum of radiation hits a some cellular organelle - lysosome, mitochondria, microtubulus, this structure is soon replaced by a newly formed one and essentially nothing happens again.
-->However, if the quantum of radiation hits the cell nucleus and the deoxyribonucleic acid DNA in it, a number of serious biological effects can occur, discussed in detail below :
Dominant effect of radiation on DNA, genotoxicity
As mentioned above, ionizing radiation causes chemical and biochemical changes in living tissue, which can generally damage all parts of cells, cytoplasm, individual organelles. However, the response of cells to radiation is determined primarily by the behavior of DNA. Nuclear deoxyribonucleic acid (DNA) is the most biochemically important macromolecule in a cell - it contains basic information about the structure and function of a cell. Intervention in the biochemical structure of DNA can cause a cell to stop producing the necessary protein, or it can produce altered "foreign" proteins that do not fulfill their function (sometimes they can even be toxic).
DNA macromolecules are the dominant "targets" for the biological effects of ionizing radiation - there may be mainly breaks in the sugar-phosphate chain and base changes. E.g. oxidation on an amino group such as adenine produces an OH group to which cytosine binds instead of thymine - an error occurs in sorting the amino acid into an string. On the DNA double helix, the radiation can cause a number of damages (see Fig.5.2.2b), the main ones being two types of interruptions or "breaks" :
×Single strand break (SSB) ,
damaging only one strand (string) of DNA. These breaks are usually easily repaired by the cell using the enzyme DNA ligase.
×Double strand break (DSB) ,
affecting both strands (strings) of DNA. Here, repair is much more difficult and often unsuccessful. A double break in the structure of DNA often leads to the death of a cell - to its lethal damage, it usually disappears by apoptosis (it was described in detail above in the section "Mechanisms of cell death").
Mechanisms for repairing DNA damage will be discussed below - section "Repair processes".
The DNA fragments, micronuclei
When the double stranded DNA breaks occur, these breaks often fail to repair. A large DNA fragment may then separate from the original DNA double helix, which remains in the cytoplasm and during cell division may enter the cytoplasm of one of the daughter cells. Micronuclei are fragments of chromosomes, encased in a nuclear membrane. They tend to be about 1/10 the size of a cell nucleus and are well visible under a microscope after chromatin staining.
During radiation exposure, other biochemical molecules in the cytoplasm, cytoskeleton or organelles - lipids, carbohydrates, proteins and others - are also damaged in the cells. However, a large number of these molecules are contained in the cells (and they are continuously supplemented by the synthesis of other molecules) and a more pronounced effect of radiation would occur only when a larger percentage of these molecules were damaged; this occurs only at relatively high doses of tens and hundreds of Gy. However, significant DNA damage occurs even at lower doses (tenths to units of Gy), when the effect on other biochemical molecules is still small. Therefore, in explaining the mechanisms of the effects of ionizing radiation on cells, we focus primarily on the effects on DNA.
Note:Some new radiobiological studies using very thin "micro-bundles" of charged particles (mainly alpha and protons, but it was also proven on X-rays) have shown, that in some cases the direct DNA damage is not necessary to trigger intracellular damage mechanisms. Even in the case of cytoplasm irradiation, a kind of "remotely induced" response (bystander response) can sometimes occur, leading to radiation damage to cells - apoptosis or genetic changes (cf. the "Bystander effect" discussed below).
Since DNA damage leads to disruption or change of genetic information in the cell, we talk about the genotoxic effects *) of ionizing radiation and the chemicals induced by it in cells. Overall, ionizing radiation acts as a cytostatic (cell damage, cell division arrest) and mutagen (damage or alteration of genetic information). For the harmful effects of ionizing radiation on the organism, individual tissues and organs, the collective name radiotoxicity is used.
*)Genotoxicity is also shown by a number of chemicals, that enter cells from the outside (through the body's metabolic pathway) or are formed inside the cells (during internal metabolism of cells or at ionizing radiation). These substances enter the cell nucleus, react with DNA and cause deterministic (mitotic cell death - cytostatics, stronger irradiation) or stochastic effects.(mutations, tumor formation - long-term effects of carcinogens or weaker radiation); see "Dose-biological effect relationship" below. Also some viruses (retroviruses, oncoviruses) have a high genotoxicity: the RNA of these viruses is able, by the action of reverse transcriptase, to enter the DNA of eukaryotic cells and change their gene sequence.
No specific genetic changes or mutations are known, that can be attributed only to the effects of ionizing radiation and distinguish them from changes caused by chemical action (external or internal). The genetic effects of radiation are manifested only by an increased frequency of spontaneously occurring mutations and genetic changes.

Basic stages of the effect of ionizing radiation on the organism
First, we in a overview analyze the radiation effects from the global point of view of the whole organism (in the next explanation, we will return again to the inductive procedure: intracellular mechanisms ® cells ® tissues ® organs ® organism). The process of the effect of ionizing radiation on living tissue takes place in four significant stages, differing in their speed and mainly in the type of ongoing processes; the relevant processes are schematically shown in Fig.5.2.1 :

Fig.5.2.1. Schematic diagram of significant processes and their time sequence in the effects of ionizing radiation on living tissue.
Note: The scale on the time axis is basically logarithmic, but in some sections it is slightly modified so that it is possible to clearly draw individual events.

Only the physical and chemical stage depends on the physical parameters of the radiation, while the subsequent radiobiological response of the cells is determined only by the biological properties of the specific cell types. It can be seen from Fig.5.2.1, among other things, that in most cases the interaction of quantum ionizing radiation with living tissue has no effect. It is when :
J Occurs recombination of free radicals before they just react with biologically important substances;
J Repair mechanisms at cell level successfully repair DNA or other substance damage;
J Cells killed by radiation are quickly replaced by the division of healthy cells - compensatory cell proliferation;
J The body's immune mechanisms recognize and destroy genetically mutated cells.
The radiation effects on the organism occurs mainly under two circumstances :
N When an organism is irradiated with a high dose of radiation, and too many cells is destroyed, which the organism is unable to timely replace;
N When the repair mechanisms at the cell level do not successfully and correctly repair all the damage and the body's immune system does not recognize and eliminate the mutated cells timely, which are then further divided.
All of these situations, which may or may not result in biological effects, will be discussed in more detail below.
Only a small part of the absorbed energy of radiation is converted into dissociation and binding energies of chemical reactions, the vast majority of energy is ultimately converted into heat. However, at doses used in biological applications, this radiation heating is negligible.

Hit and radicals mechanism of radiation effect on cells
Let us now return to the intracellular processes of the radiation effect, the influence on DNA. Damage to the structure of DNA occurs through two basic mechanisms :

Fig.5.2.2. Radiobiological effects at the subcellular level.
a) Interventional and radicals mechanism of the effect of radiation on cell. a) Above: When radiation enters the DNA macromolecule, ionization and a direct destructive effect occur. Bottom: Ionizing radiation interacts with the water molecule, radiolysising of water occurs: H ₂ O ® H ⁺ + OH ^- - formation of free radicals . Highly reactive H ⁺ and OH ^- radicals attack complex organic molecules and chemically change them . DNA is disrupted in the nuclei of cells.
b) Different types of DNA damage due to radiation and chemical influences (rough schematic drawing). c) Radiation effects during the cell cycle.

Representation of intervention and radicals effect
In organisms, complex biochemical molecules are dispersed mainly in water. In the aqueous medium (solution, suspension), the proportion of direct and indirect effect depends on the concentration of molecules of biologically important substances. When irradiating dried samples, the direct effect is mainly observed; in the case of aqueous solutions, the share of the indirect effect is usually dominant and the higher the lower the concentration. Inside the cells there is an aqueous environment with a medium-high concentration of biologically important molecules - the indirect mechanism is dominant here, but it is necessary to take into account also the direct effect. The proportion of direct and indirect effect also depends on whether it is sparsely or densely ionizing radiation. The radical mechanism of the indirect effect predominates in sparsely ionizing radiation. Densely ionizing radiation produces such a high concentration of radicals, that they often recombine before these radicals can react with biologically important molecules - somewhat increased importance can therefore have a direct effect.
Note: In the development of radiobiological ideas, the effort to explain the effects of ionizing radiation on living tissue led to the expression of two basic theories - older interventional and newer radicals theories. Their role and contribution to radiation effects were later specified and improved by the mechanism of dual radiation action and the linear-quadratic model, discussed below.
Oxygen factor
The effect of ionizing radiation also depends on the presence of oxygen - the so-called oxygen effect. In the presence of oxygen, the radiolysis of water produces strongly oxidizing peroxide radicals, which react irreversibly with the atoms in the DNA. Thus, the presence of oxygen increases the radiation effects, especially in sparsely ionizing radiation. In densely ionizing radiation, where there is an increased proportion of the direct intervention mechanism (and also increased radical recombination), the oxygen effect is less significant. In some cases, the oxygen effect can be significantly applied in radiotherapy (§3.6, section "Physical and radiobiological factors of radiotherapy").

Mechanism of dual radiation action, molecular-biological process
Radical theory was later further improved and refined on the basis of knowledge of molecular biology. Not only the total energy (dose) transferred to the tissue is important for the resulting biological effect, but also the spatial distribution of this energy in elementary volumes, as well as the time distribution of the dose. Microdosimetric analysis of the radiation dose distribution and monitoring of chromosomal aberrations revealed that the radiation damage of the cell depends on the ionization density at the critical site. It turned out that to damage the cell it is necessary to reach a certain critical value of local energy density at a given place and time (demonstrated in 1972 by H.H.Rossi and A.M.Keller). Cell damage occurs through a combination of two primary events *) taking place on the double strands of nucleic acid DNA in the cell nucleus - dual radiation action, while the probability of damage depends on the number of fractures and the action of repair processes - it is a complex molecular-biological process.
*)Disruption of only one strand (chain) of DNA can usually be easily repaired by the repair mechanisms of the cell (see below) - this is sublethal ("potentially lethal") damage. Simultaneous damage to both strands of DNA at nearby sites usually leads to a lethal effect on the cell. Cellular DNA repair processes do not take place immediately, but have a certain duration (approximately tens of minutes). Therefore, at higher intensity (dose rate) even sparsely ionizing radiation, increases the likelihood that also a break in the second strand of DNA will occur before the first strand is repaired, which usually results in lethal cell damage - individual sublethal damage accumulates in the lethal. The biological effect then depends not only on the total radiation dose, but also on its time schedule - the so-called dose rate effect (discussed below in the LQmodel section ); at higher dose rates, a greater radiobiological effect occurs.

Schematic comparison of the effects of beta and alpha radiation on DNA.
Above:
Beta electrons with a low ionization density cause mostly simple breaks in DNA that the cell can repair.
Bottom:
Alpha particles with a high ionization density cause double breaks in DNA, which usually result in cell death by apoptosis.

Particles of "sparsely" ionizing radiation, ie beta and gamma, usually form only one primary disruption (fracture) during their passage through the critical site, so that the final occurrence of damage requires the passage of two individual particles through the site in rapid succession (so-called b - process) - the number of these damages then depends mainly on the square of the dose, for smaller doses the damage is significantly lower. Particles "dense" ionizing radiation (alpha, neutrons, protons), are capable of a single pass through the critical point cause two or more primary failures (ie. a -Processes) which is sufficient to create real damage, so the number of lesions, i.e. radiation effect, it is directly proportional to the dose radiation; damage occurs more easily here, these types of radiation have a higher biological efficiency, which reflects the above-mentioned quality factor Q. The mathematical analysis of these processes (a- and b- processes, as well as processes of cell repair and repopulation) is the so-called linear-quadratic LQ model of dose-response of the radiation effect; is derived and discussed in detail below - the section "Dose - Radiation Effect Relationship", part of LQmodel.

Chromosome aberrations
Because DNA macromolecules are bound in chromosomes, DNA damage can manifest itself in changes in the shape, arrangement and structure of chromosomes - so-called chromosomal aberrations, which can be observed under a microscope. A number of different chromosome abnormalities have been observed, which can be divided into two basic groups :
× Numerical aberrations consisting of an abnormal number of chromosomes whose intrinsic structure is intact. They arise during cell division, which can lead to errors in the separation of chromosomes into daughter cells. This can lead to polyploidy (multiplication of the whole chromosome set 3 x or 4 × ) or aneuploidy(numerical deviation of only a certain specific chromosome, which can be multiplied 3 × or 4 ×, or reduced - 1 ×, or completely lost).
× Structural aberrations , where the structure of a chromosome is disrupted due to chromosome breaks (caused by double-stranded DNA breaks) and subsequent rearrangements. Structural aberrations are divided into balanced (where the amount of original genetic information is quantitatively preserved) and unbalanced (where part of the genetic information is missing or in excess). Several types of changes in chromosome structure are observed: deletions (part of the chromosome is missing - either terminal at one end or interstitial in the middle); duplication of a section of a chromosome; inversion (two breaks on one chromosome, rewinding a segment between breaks and rejoining - the order of genetic information changes); translocation (exchange of two cleaved segments of two chromosomes); fragmentation (a chromosome splits into two or more smaller parts); annular chromosome (deletion of the ends of both arms followed by twisting and joining of the broken ends); - and several others.
Chromosomal aberrations are most prominently applied until in cell division, where they can either prevent division or cause uneven distribution of genetic information into daughter cells. Some chromosomal aberrations are insignificant and practically harmless, others lead to cell death, some cause mutations and malformations. Severe and multiple chromosomal aberrations are observed in tumor cells. Microscopic (cytogenetic) monitoring of chromosomal aberrations is also of great importance in the study of the biological effects of ionizing radiation and in the radiation protection of exposed persons.

Effects of radiation on cells
The above-mentioned mechanisms of radiation effects at the subcellular level result in effects on the basic building blocks of all living tissues - on cells. When irradiating a cell with an appropriate dose of radiation, there are basically two significant types of damage (Fig.5.2.1 on the right) :

Thus, irradiation of cells leads to a number of harmful changes (radiotoxicity), many of which may be corrected by the body's repair mechanisms, but some may lead to cell destruction and some changes (eg in the DNA code) may be permanent or reproducible. Tissues with intensive cell division, such as hematopoietic or tumorous, mucous membranes, developing fetuses (especially in the early stages of development) are particularly sensitive to the effects of ionizing radiation.

Radiation effects during the cell cycle
The effect of radiation on cells depends, in addition to the physicochemical factors mentioned, on the type of cells and on the time phase in the cell cycle when the irradiation occurred.
Cell division - the cell cycle
The cell cycle is a sequence of time-ordered processes that a cell goes through in the period between its divisions - it is the period from the formation of a cell to the previous division of the mother cell into two daughters until the stage when it divides again into two daughter cells (only very schematically shown in Fig.5.2.2c). Cycle duration (so-called generation time) is different for various cell types: for rapidly dividing cells it is only 20-24 hours, for others it divides only 2 times a year (eg hepatocytes), some do not divide at all (neurons, eye lens cells). The basic division of the cell cycle is the "resting" period of interphase G (gap) between two divisions and phase M of the cell division itself, mitosis (Greek mitos = thread, fiber). In more detail, the cell cycle of eukaryotic cells is divided into several phases (Fig.5.2.2c) :
¨ G1 phase - postmitotic - after the end of previous division, there is a period of cells growth (G), synthesis of RNA, proteins. Physiological processes take place in a cell, given the type of a particular cell and its function in the organism. It takes about 10-12 hours.
¨ G0 phase - rest . During the G1 phase, the cell can leave this phase (and the whole cell cycle) and enter the resting so-called G0 phase, where it no longer divides. This is especially true for fully differentiated cells such as neurons. Some cells are able to leave the G0 state, go into the G1 phase and start dividing again if necessary (eg hepatocytes), while the neurons remain in the G0 state permanently and no longer divide.
¨ S phase - synthetic - DNA replicates to double the number (duplication of genetic material). Duration is about 6-10 hours.
¨ G2 phase - premitotic - duplicates organelles and forms the structures needed for cell division. It takes about 2-4 hours.
¨ M phase - mitotic - there is nuclear division (karyokinesis) and then the division of the whole cell (cytokinesis). The mitotic phase, which lasts about 1-2 hours, is divided into 5 consecutive stages :
× Prophase - a preparatory phase of karyogenesis, during which the nuclear membrane dissolves and chromosomes unfold (chromosomes are doubled after the S-phase, but are still connected in the centromere ). Cytoplasmic microtubules depolymerize and the released tubulin is used to polymerize three types of new microtubules in the nucleus: - astral microtubules, diverging radially from both centrosomes; - polar microtubules , forming a dividing spindle between the centrosomes ; - kinetochore microtubules , involved in the pull of split chromosomes to the poles of the spindle.
× Metaphase - chromosomes line up in the equatorial plane of the spindle, there is a pull on opposite sides to the poles of the spindle.
× Anaphase - chromosomes rupture into two equal parts by shortening the microtubules of the dividing spindle.
× Telophase - the dividing spindle disappears, chromosomes are concentrated in two new nuclei, around which a nuclear membrane is formed. This completes karyogenesis.
× Cytokinesis - a cytoplasmic barrier is formed between the two parts. This occurs either by strangulation due to the contractile ring (in animal cells); in yeast it is budding, in plant cells a compartment between the cells grows from the center to the edge.
The mother cell is thus divided into two identical daughter cells *), which enter the G1 phase; ® cycle repeats - if is not stopped by the check nodes (described below), physiologically mainly restriction G1-checkpoint, when the cell is put into the "service" G0 phase, it is not further divided and performs its differentiated function.
Considerably simpler manner undergoing division prokaryotic cells (bacteria): it is binary division, in which the cell first elongates into an elongated shape, replicates its DNA, begins to form a septum in the middle, whereby the mother cell then splits into two identical daughter cells.
*)Stem and effector cells
In multicellular organisms with different differentiated tissues, the mechanism of division is more complex. Here, the tissues consist of stem cells (maternal, clonogenic) and daughter, effector cells. Stem cells are capable of unlimited division, while they are able to produce both identical stem cells and daughter cells, bearing the properties of a given differentiated tissue - asymmetric division to two different cells, an identical stem cell and a different daughter cell. Due to their division, clonogenic stem cells are more radiation-sensitive than daughter effector cells (which, in addition, are continuously replenished by stem cell division).
Asymmetric division ensures the process of differentiation, in which cells, by their structure and function, adapt to the specific role they are to play in the organism. All cells in the body are equipped with the same genetic equipment, but as a result of this process, only a certain part of the genetic information is realized in a particular cell (due to specific transcription factors only certain genes are transcribed in the cell, others are not applied). Daughter effector cells usually enter the quiescent G0 phase of the cell cycle.
Cell cycle check nodes
The complex process of cell division is controlled by several stages of regulation. The key points of the cell cycle are certain "check nodes" or points (Check Point), in which the state of the cell in a given phase and its ability to continue the cycle is "evaluated" (Fig.5.2.2c). In the check nodes, it is verified whether all events taking place in the respective phase of the cell cycle have been successfully completed - before the cell proceeds to the next stage of its cycle. The main role of check points is to "supervise" the correctness or damage of DNA, to ensure proper cell division with maximum flawless transmission of genetic information. Certain control mechanisms probably work continuously at every moment of the cell cycle, but their activity results in several significant milestones of individual stages :
Y First checkpoint G1 (G1-checkpoint) or G1/S is at the end of the G1 phase. Here it is decided whether the cell will continue the division cycle or go into the resting G0 phase. Control node G1 is sometimes also called start (only from this point a new cell cycle can continue) or restriction - it forms a kind of "barrier" to the continuation of the cycle, which is overcome by the expression of cyclin D induced by growth factors; otherwise, the cell remains in the G0 resting phase.
YThe second check node is in S-phase and controls DNA transcription; suspends the cell cycle until, it is completely replicated DNA.
YThird G2/M check point, located at the end of phase G2 (G2-checkpoint) controls a number of factors that determine whether a cell is ready to successfully enter mitosis. It oversees the integrity of DNA, examines whether DNA is damaged and whether its synthesis has been completed, delays the onset of mitosis, and stops the cell cycle in the event of DNA damage.
YThe last control node M (M-checkpoint) comes into play only during mitosis in anaphase and checks the correct course and termination of mitosis. The signaling pathway of the mitotic control node M checks, among other things, the correct connection of the chromosome kinetochore to the dividing spindle.
If the control mechanisms find an inconsistency in one of the control nodes, the cell cycle is interrupted: either repair processes are started, or in the case of more severe irreparable damage (such as a double DNA break), apoptosis may be initiated (Fig.5.2.2c in the middle) - "programmed" cell death described in more detail above in section "Cell death".
Radiosensitivity of cells and tissues
The greatest radiosensitivity is manifested when the cell is affected in the late G1 and premitotic G2 phase, when checkpoint mechanisms can stop the cell cycle. Slightly lower sensitivity is in the M phase and in the transition between the G1 and S phases, the lowest sensitivity for cells in the G0 phase.
Living tissue is made up of a mixture of cells at various stages of the cell cycle. The average time that cells are in certain phases depends on the type of tissue. Tissues growing rapidly with a short cell cycle have a higher time proportion of G2 and M cell phases, so they are more sensitive to radiation. Slow-growing well-differentiated tissues (such as nerve, muscle, ligament) are relatively radioresistant, as most cells remain in the G1 phase for a relatively long time and some are even in the G0 resting phase. Different radiation sensitivities of individual tissue types are important from the point of view of radiation protection and play a key role in the radiation treatment (§3.6 "Radiotherapy" ), where fractional irradiation and sometimes a combination of chemotherapy and radiotherapy are used, among other things to achieve some synchronization of the cell cycle with irradiation cycle.

Radiation damage => poisoning of the organism with chemical poison
From the above description of the mechanism of the harmful effect of ionizing radiation on living tissue, it follows that the radiation effects are not any "mysterious" unusual phenomena caused by invisible radiation. The final effect is chemical or chemical-biological: the radiation only supplies energy to the tissue (in a specific form of ionization), which ultimately leads to the production of "poison" (free radicals) and internal chemical "poisoning" of cells - overal we talk about radiotoxicity. After all, it is similar to diffusingly applying, for example, hydrogen peroxide or another highly reactive chemical to a tissue, having denaturing or genotoxic effects. There are three characteristic differences between chemical poisoning and radiotoxicity :
1.Chemical poison molecules are delivered to the tissue from the outside, they penetrate the metabolic pathway (blood, lymphatic), they accumulate inhomogeneously in certain cell types. Ionizing radiation supplies only energy and toxic substances are generated inside cells and tissues, while they are distributed practically homogeneously in the entire volume of irradiated tissue, inside all cells.
The situation is more complicated at internal contamination with a radioactive substance, when its distribution is inhomogeneous - in the target tissues and organs, depending on the chemical composition. And also for short-range radiation in the tissue (a, b), when only the immediate vicinity of the interaction site is irradiated.
2.Difference in the nature of the dose-response effect. When lower concentrations of chemical toxicants are applied, almost all cells survive, and only when a certain threshold concentration is exceeded will practically all cells in the population die. When exposed to ionizing radiation, even small doses can result in the destruction of a small percentage of cells, but even after receiving very high doses, a certain part of the cell population survives (see "LQ model" below). The radiobiological effect has a statistical probabilistic character, it is governed Poisson distribution *) of probability. After irradiation of a set of N₀ cells, N cells survive, whereas N/N₀ ~ e ^-^{(number of lethal lesions)}. This dependence is mathematically realized in a linear-quadratic model, derived below.
*)The Poisson distribution generally models random events in a set of a large number of elements in a situation where the probability of a given process is relatively small with respect to the total number of elements. If we have a set of elements (atoms, cells) with instantaneous number N , in which the given stochastic process (nuclear decay, cell damage) is caused by the control factor f (time, dose) with probability l, then the element of the factor Df causes the loss of the members of the set by DN = - l . Df elements. This leads to a differential equation for the dependence of the number of remaining elements N on the acting factor f : dN / df = - l , the solution of which under the boundary initial conditions N(f = 0) = N_o is an exponential function N = N_o .e ^-^l^.
f. It is derived and discussed in more detail in §1.2, part "General laws of atomic nucleus transformation" for the case of radioactive decay.
3. Another difference in DNA damage caused by common factors (such as oxidants from metabolism) and ionizing radiation is that after ionizing irradiation there is a increased ossurence of clusters of DNA damage (especially in densely ionizing radiation); for common non-radiation damage, this distribution is more even.

Repair processes
Cells are not completely defenseless against radiation damage; when irradiating living tissue, there are not only one-way and irreversible changes leading to damage to cellular structures and their functions. In the biological stage of the radiation effect, there are also opposing processes - processes of repair and regeneration, which lead to the restoration of the ability of cell division and function of tissues and organs. Thus, radiation changes in living tissues may be reversible.
In the early stages of evolution, cells lived under the influence of shortwave radiation, especially ultraviolet radiation. During evolution, mechanisms have had to evolve that maintain the integrity of DNA (relative stability of genetic information). Enzymatic repair systems, which are able to eliminate DNA damage (radiation or chemically induced), have been a positive evolutionary factor for cells and have mostly been preserved in cells. It is also worth mentioning the fact that repair systems are not closely specific to only one harmful substance.
There are basically two types of repair processes at two different levels :

Probability of biological effect
After a specific "radiation action" (cell intervention by a quantum of ionizing radiation), the probability of a biological effect depends mainly on two circumstances :
1. Type of DNA damage (Fig.5.2.2b). 2. The phase of the cell cycle in which the damage occurred (Fig.5.2.2c).
Simple breaks of DNA strands the repair mechanisms can usually repair flawlessly (if they have "enough time" to do so). Double DNA breaks, if they occur in the G1 and G2 phases, are recognized in the "check points" and usually lead to cell death (Fig.5.2.2c in the middle). However, DNA damage that occurs after the "checkpoints" stage may not be recognized by cellular regulatory mechanisms and mitosis may occur with this error - there is an increased risk of dividing cells with altered genomes, which may result in mutations (stochastic effects) - Fig.5.2.2c at the bottom. During the practical irradiation of the organism, the individual cells in the tissues are in various phases of their cell cycle and at the same time DNA of various kinds is damaged. Therefore, individual microscopic events are averaged into the resulting radiobiological effect - deterministic or stochastic.
Much depends also on the speed of the cell cycle. Cells that divide rapidly have, on average, less time to repair damage to their DNA, so they will suffer more from the consequences of unrepaired or incorrectly repaired damage. This leads to an important general conclusion: rapidly dividing cells are more radiosensitive.
The repair and regeneration processes lead, inter alia, that the radiation dose dividing into smaller sub-doses at sufficient time intervals, cause to smaller biological effects, compared to the same dose absorbed at once. Respectively, at the same total absorbed dose, the biological effect reduces if it was achieved at a lower dose rate (which of course corresponds to a longer exposure time) - see "LQ model" below - dose rate effect.

Effects of radiation at the tissue level
The effects of radiation at the subcellular and cellular levels discussed above are the basic starting point for understanding the effects at higher levels of the organization - in tissues, organs, the whole body. However, they are not a completely sufficient starting point! There is a well-known general experience, that a system is not just a simple sum of its elements (or "an organized whole is more than the sum of its parts"). Some radiation effects in living tissue are caused not only by basic cellular mechanisms, but also by the interaction of various tissue factors, such as intracellular communication trought biochemical signaling pathways, movement of molecules and ions through the intercellular space, cell division and tissue regeneration. At the level of organs and the whole organism, complex biological relationships between different types of cells and tissues in the activity of organs and functional relationships between individual organs in the body approach this.
Biochemical interactions of cells. Extra-target remote-induced radiation effects - bystander effect, abscopic effect
The view of classical radiobiology is largely mechanistic: damage occurs only in cells that are directly affected by ionizing radiation or a chemical agent, which damages the DNA or other important structure of the cell. This is indeed the case when irradiating a set of isolated cells (such as bacterial colonies). However, in higher organisms, cells are incorporated into tissues in which cells biochemically interact with each other through a number of complex processes (especially regulatory ones). Some of these processes (repopulation, redistribution, reoxygenation) are mentioned below in connection with the dependence of biological effects on the radiation dose and its time course. Due to these cell interactions, it can be expected that other surrounding cells in the tissue may react to (radiation) damage to one particular cell in a certain way.
This process has actually been observed in experiments with very narrow sharply collimated beams (micro-beam) radiation a which irradiated cells in tissue culture. It was found that after irradiation of the target cells, some surrounding cells showed signs of damage, even though they were not irradiated themselves. Experiments in which a sample of irradiated cells was transferred to a colony of unirradiated cells led to similar results. This remarkable effect could be due to the mentioned biochemical interactions of cells in the tissue. The exact mechanism of this phenomenon is not yet known. The surrounding cells could be affected in basically three ways :
× Through the intercellular environment
Cells affected by radiation can produce certain diffusible substances that are able to affect other neighboring cells. Primary irradiated and lethally damaged cells can "send chemical signals" to their surroundings (extracellular matrix) - release biochemical molecules involved in apoptosis of irreversibly damaged irradiated cells (p53 protein or TRAIL ligand is considered, as mentioned in the passage above "Apoptosis"), or molecules of toxic, oxygen or nitrogen radicals. These substances can diffuse and enter surrounding cells (or bind to appropriate receptors on the surface, activate external apoptosis signaling pathways), in which they can cause a similar response to that of a directly affected cell.
× Over intercellular junction
Intercellular communication (gap junction) they are carried out by membrane channels, called connexons, with a diameter of about 1.5-2 namometers, through which molecules up to 2 kDa can pass. When one cell is damaged, the canal usually closes quickly, preventing damage to neighboring cells. However, if this pathway is not inhibited in time, damage can be transmitted to surrounding cells.
× Macrophages
Finally, the activity of macrophages could contribute to the apoptosis of the surrounding unaffected cells. In addition to the apoptotic cell itself, the attracted activated macrophages could attack and eat even some neighboring cells.

For this phenomenon of radiation effects induced in neighboring cells, is used the name bystander effect (Eng. Bystander = viewer, bystanders, gaper) - "effect of the non-participating spectator": the surrounding directly unaffected cells are not a "neutral observers" radiation damage of irradiated cells, but are also "drawn" into this process. The bystander effect thus slightly increases the total number of radiation-damaged cells in the irradiated tissue (Fig.5.2.4b). The bystander effect can cause apoptosis, chromosomal aberrations and mutations in surrounding cells.
Note:The bystander effect was observed not only in radiation-damaged cells, but also in local chemical cytotoxic damage.
Abscopal effect
The phenomenon of biological changes in the non-irradiated part of the biological system as a result of the reaction of the irradiated part is generally referred to as a side, extra-target or abscopic effect (lat. Ab = outside, away; scopium = target, aim, angle of view). Post-radiation changes usually occur in cells and tissues closely adjacent to irradiated areas - such as the aforementioned bystander effect. However, "long-distance" abscopic effects were also observed. In radiotherapy with local irradiation of a single tumor lesion sometimes (unfortunately rarely) an immunoeffect - immunogenic cell death - is also induced against other metastases of the same tumor (see also §3.6, section "Immunotherapy"). The exact mechanism of the aboscopic immunoefect is not yet known, but it is probably due to massive apoptosis or necrotic death of tumor cells irradiated with a high radiation dose. This elicits a local inflammatory immune response in which T cells form within the irradiated tumor, which can be specifically activated by the uptake of antigens from tumor cells. These specifically activated effector T cells then migrate to unirradiated secondary tumors, where they initiate a targeted "destructive" immune response against tumor cells of given type, that have the same antigens (involving monocytes transforming into macrophages).
In addition to this highly desirable effect, an adverse abscopal effect in normal healthy tissues that could induce genomic instability, cell death, or oncogenic cell transformation is sometimes discussed. However, such a mechanism has not been demonstrated, the causes of the side effects of radiation on healthy tissue are probably different (§3.6, section "Side effects of radiotherapy - radiotoxicity, secondary malignancy"). It would be unlikely if the radiation-mutated cells merely migrated and established a distant tumor site without such a site forming near the irradiated site.
However, a situation could arise where the irradiation causes a decrease in the body's immunity, as a result of which a still "dormant" clone of mutated cells may initiate tumor growth at some point. Such a complex process, however, probably not be considered as a radiation abscopic effect ..?..
Various radiosensitivity of cells and tissues
The organism is a functional complex of tissues and organs, that do not have the same sensitivity to irradiation (radiosensitivity). At the same absorbed dose, different biological effects are seen in different tissues. In analyzing the effects of radiation on cells, we found that rapidly dividing cells are more sensitive to radiation damage. This basic finding is also manifested at the tissue level and is sometimes expressed by the rule: "the radiosensitivity of the tissue is directly proportional to the reproductive activity and indirectly proportional to the degree of differentiation" *). This rule is only approximate, for specific tissues and organs they are affected by specific biological influences (see below "Local tissue and organ radiation effects"). Tissues and organs have different sensitivities not only to damage by cell death, but also different susceptibility to application of cytogenetic effects, the risk of tumor formation.
*)The direct and inverse proportionality there cannot be taken mathematically, but only as an expression of the increasing or decreasing trend. It is sometimes called the Bergonia-Tribondeau rule, according to the first authors who came to him empirically.

Relationship between radiation dose and biological effect
It is obvious, that the biological effect of radiation is primarily dependent on the size of the absorbed dose - increases with dose. In terms of dose-effect relationship, we distinguish between two basic types of radiobiological effects :

For stochastic effects, the severity of the disability and the course of the resulting disease do not depend on the dose; only the probability of occurence the tumor or genetic damage depends on the absorbed dose. These are disease states which, even without the influence of radiation, occur "spontaneously", without an obvious cause *), in the population. In individual cases, it is not possible to distinguish radiation-induced tumors and genetic changes from spontaneous cases, their clinical picture is the same (there are no symptoms specific for tumors caused by ionizing radiation). Ionizing radiation only increases the likelihood of these diseases, the corresponding risk is additional to other risks. The average risk factor for radiation-induced malignancy is estimated at 0.055 Sv^-1, or 5.5% per 1Sv (ie if 1000 people receive an effective dose of 1Sv, 55 of them can be expected to cause fatal tumor).
*)As discussed above, this is probably due to the genotoxicity of some chemicals, which either enter the cells from the outside (through the body's metabolic pathway) or are formed inside the cells (during the internal metabolism of the cells). These substances enter the nucleus, react with DNA and cause disorders of its gene sequence, which may not be successfully repaired ...
Dependence of stochastic effects on age
At the same radiation dose, the probability of stochastic effects is inversely related to the age of the irradiated individual. This is due to two circumstances :
¨ Time factor - stochastic radiation effects have a long latency, the probability of their manifestation increases with time since irradiation. When the body is irradiated at a younger age, there is probably more time available for late stochastic effects to occur. When irradiated in old age, stochastic effects are often not enough to apply until the end of life.
¨ In children, due to growth, there is a more intense cell division, which leads to higher radiosensitivity.
Linear-quadratic dose dependence of stochastic effects
According to the theory of dual radiation action, the probability of radiation damage to the cell - and thus the probability of unsuccessful DNA repair ® the probability of mutations and the occurrence of stochastic effects, especially malignant transformations, depends on the ionization density at a given site. Similar to deterministic effects (where radiation cell killing has a linear-quadratic dose dependence - see the " LQ model " for derivation below ), so for stochastic effects, the probability distribution of malignant transformations at an effective dose is linear-quadratic. At low doses up to about 1Sv, the curve is linear the shape is directly proportional to the frequency of malignancies at the dose (black line in Fig.5.2.3a), at higher doses the occurrence of radiation-induced malignancies is proportional to the square of the effective dose - quadratic dependence. However, the theoretically expected quadratic dependence of stochastic effects for higher doses is difficult to demonstrate, given that at high doses almost all cells in the population die rapidly with deterministic effects.
Linear threshold-free dependence of stochastic effects (?)
Thus, at low doses, for stochastic effects, it is usually assumed that the degree of effect, ie the probability of radiation-induced damage (tumor or genetic) is linearly dose-dependent (black line in Fig.5.2.3a) and that the stochastic effects are non-threshold - they can be caused even by very small doses, even at the level of the natural radiation background, although with a slight probability. In classical radiobiology, it is hypothetically assumed that each mutation of an individual cell (whether generated by radiation or biochemically) can be the first step to carcinogenesis (it is discussed in §3.6 "Radiotherapy"). Even if this were, however, the mutagenic effects of very low radiation doses may be questionable..?.. - will be discussed below.
Note:In the interest of scientific objectivity, it would perhaps be appropriate to point out at this point that in the area of very low doses <0.2 Gy, the generally accepted linear threshold-free dependence is only a hypothesis, resulting from the direct extrapolation of proven effects from higher dose areas (> 0.5Gy) towards zero, to the low dose range, where these effects have never been directly demonstrated (discussed in more detail below in the section "Small doses of radiation: - are harmful or beneficial?").
The "conservative approach" to radiation protection is based on this assumption, the so-called linear threshold-free dependence of stochastic effects, which is reflected in a number of standards and regulations for working with ionizing radiation. However, recent radiobiological studies indicate that the dose-response of stochastic effects is not linear, but that at very low doses the effects are probably lower than would correspond to the linear dependence *) - blue curve in Fig.5.2.3a.
*)This behavior could be related to radiation-induced repair and also to the so-called hyper-radiosensitivity to low doses (see below "Deviations from the LQ model"), when irradiated cells (with the risk of altered genome) with increased more likelyhood disappear. The views of radiobiologists differ here, and the relatively increased probability of low-dose stochastic effects is sometimes discussed, eg in connection with the afore mentioned bystander effect ..?..
In addition, if some alternative views are confirmed (mentioned below "Small doses of radiation: - are they harmful or beneficial?"), the curve of the dependence of stochastic effects on the radiation dose could in fact be in the form of a green curve in Fig.5.2.3a - even for stochastic effects could be exist a threshold (!) (similar to deterministic effects), but many times lower. And at the lowest doses, the so-called radiation hormesis could manifest itself - a section of the green curve of the curve below the horizontal axis..?.. Radiobiological results will certainly be refined, but for small doses of radiation, comparable to the natural level to which our organisms are "adapted", at present there is no direct evidence that low levels of radiation are harmful to health (see the discussion below in the section "Small doses of radiation: - are they harmful or beneficial?").

Fig.5.2.3. Dependence of biological effect on the size of absorbed radiation dose.
a) Probability of occurrence for stochastic effects. b) Severity of damage for deterministic effects.
c) Dose dependences of the surviving fraction of N/N₀ cells according to a linear-quadratic model.

Deterministic effects become clinically manifest until after a certain threshold dose is reached, while with increasing dose increases, the probability of damage (i.e. when irradiated group of people, the number of individuals who show damage increases; at higher doses the effects are seen in everyone) and mainly the severity of the damage increases with the idividual's dose. The dependence of the radiation effect on the absorbed dose for deterministic effects is shown in Fig.5.2.3 in the middle. The basic pathogenic mechanism is a reduction in the number of cells (cells depletion) in the irradiated tissue. Toxic substances also contribute to the harmful effect, arising from the extinction and decomposition of a large number of cells. The sigmoidal shape of the curve, beginning from a certain dose threshold, is a reflection of the fact that there is a certain functional reserve, usually quite large, in the irradiated tissue (cell population). Therefore, a decrease in the number of cells with increasing dose does not initially cause any functional problems in the irradiated tissue, only at higher doses does the deficit of cells lead to somatic manifestations. The value of the threshold dose for humans around 1Gy according to Fig.5.2.3 b is only average (whole body) and indicative. Each tissue generally has a different threshold dose of deterministic effects, depending on cell radiosensitivity and functional reserve in the tissue - eg approximately: skin 3Gy, lungs 5Gy, sperm 0.3Gy, eye lens 1.5Gy, developing embryo in utero 0.1Gy, .....
Pathologically increased radiosensitivity
occurs in individuals with genetic disorder of chromosomal instability, where the ability of repair mechanisms at the cellular level is reduced (impairment of stability and reparability of DNA by homologous recombination - hypersensitivity to genotoxic effects), as well as reduction of immune processes (immunosuppression) at the organism level *). If both dominant genes are in order in a heterozygous cell, radiation or other damage to one of them may not impair cell function. However, if one gene is OK and the other is disrupted, damage to one gene can lead to total cell dysfunction. In homozygotes with such a reparability disorder, the consequences of the damage are even more pronounced, they are fully applied. In these individuals, the threshold dose is reduced for deterministic effects, and even diagnostic irradiation (eg more demanding X-ray examination of CT or angio, dose approx. 40-60 mSv) can cause slight deterministic effects in them. During radiotherapy is manifest a increased radiotoxicity to healthy tissues, in chemotherapy increased sensitivity to cytostatics. Also, the risk of stochastic effects, even from the natural radiation background or other pollutants (chemical, including metabolic products), is significantly higher - more frequent occurrence of tumors (especially lymphomas).
*)One of such disorders is the so-called Nijmegen breakage syndrome (NBS, the name is derived from a city in the Netherlands, where the disorder was first identified in 1981 and where there is a central registry of these patients) - autosomal inherited syndrome of chromosomal instability. It is caused by a mutation in a gene called NBS1 or NBN, which encodes the protein nibrin, which has an important function in repairing chromosomal breaks caused by ionizing radiation or other genotoxic agents. Genetic chromosomal instability also occurs in Ataxia telangiectasia syndromes, Bloom's syndrome, Fanconi anemia, Xeroderma pigmentosum, Li-Fraumeni syndrome mutated TP53 gene encoding p53, or the very rare Werner premature aging syndrome. A number of pathological clinical manifestations result from cell cycle disorders. In addition to increased radiosensitivity and more frequent occurrence of cancer, there are also growth disorders, neurological and skin manifestations, and infectious diseases often occur due to reduced immunity. Fortunately, these congenital inherited disorders, which are not causally treatable (only their specific clinical manifestations can be treated), occur very rarely, the total incidence of all mentioned species is about 0.02% of the population. However, heterozygous carriers is significantly more, about 0.5%.
Note: Please, do not confuse this pathologically increased overall radiosensitivity with physiologicalhyper-radiosensitivity (relative) in the area of low radiation doses, which is inherent in all cells - is discussed below in the section "Hyperradiosensitivity to low doses. Model of induced repair".
Deterministic + stochastic effects
The stochastic and deterministic effects of radiation have basic intracellular mechanisms and some external aspects in common and cannot always be strictly separated from each other. The basis of deterministic effects lies in the mechanism of radiation killing of cells, which has a probabilistic (ie "stochastic") character at the cellular level, is governed by Poisson statistics (see below "LQ model"). At medium and higher doses, however, the number of killed cells is so large, that statistical fluctuations are practically do not manifested, the resulting dependence is deterministic. Even at low doses (below the threshold of deterministic effects), for which only stochastic effects are usually discussed, a small number of cells are "covertly" killed; externally, this does not manifest itself simply because the remaining intact cells are sufficient to provide a functional need for tissue or organ, and are replaced in time by the division of these intact cells. The LQ model not only describes deterministic radiobiological effects, but also implicitly lies in the foundations of probability of stochastic effects.
It should also be borne in mind that, along with the early deterministic effects are may latently apply even late stochastic effects, if the organism survives the deterministic effects. This is observed with radiotherapy based on deterministic effects on tumor tissue, where in addition to acute radiotoxicity, secondary post -radiation malignancies may occur over time, due to the stochastic effects of the part of the radiation absorbed outside the primary target tumor (including scattered radiation) and irradiated even the other tissues and organs (§3.6 "Radiotherapy", part "Physical and radiobiological factors of radiotherapy").
Terminological note:
In our text, we often use the term "deterministic radiation effect" in a somewhat weaker and more general sense than in radiation protection - in the sense of lethal damage and cell death, without the need for manifestation of somatic effects for the whole organism. Thus, "deterministic effects at the cellular and local tissue and organ level" (eg in radiotherapy).

Properties:	Deterministic effects	Stochastic effects
Pathogenesis:	Cell death - reducing their number	Change of cytogenetic information - mutations
Specificity:	Specific clinical picture, typical for the effects of ionizing radiation	Non-specific image, indistinguishable from spontaneous cases
Dose dependence:	The effect only becomes apparent from a certain threshold dose, then increases with dose	The probability of occurrence increases with dose from zero (threshold-free dependence)
Time dependence:	Mostly relatively fast onset	Late effects, long latency

Radiobiological modeling
The radiobiological effects of radiation on cells and tissues generally depend mainly on the absorbed dose, on the type of radiation, the type of cells in the tissue and also on time factors. These generally complex dependencies have been measured in a number of radiobiological experiments and verified in clinical studies, especially in radiotherapy. There was a natural attempt to describe these empirical laws using mathematical models and functions, that would express the dependence of the radiobiological response on dose D , its time distribution and the properties of irradiated tissue. Models that would allow to compare and analyze different radiobiological data and predict cell survival based on physical aspects (type and energy of quantum radiation) and biological properties of cells and tissues (radiosensitivity, repair capabilities of normal and tumor cell lines).
It is mainly a functional expression of the surviving number of N cells from the originally irradiated number N₀, resp. dose dependence of the surviving cell fraction [N/N₀] (D). Until to the 70s, this modeling consisted in the construction of empirical mathematical functions containing appropriate powers of dose D , irradiation time T and number of fractions n (powers were mostly non-integer, eg T^0.33 or T^0.11, n^0.24 etc. - so did eg. M.Standquist in 1946, or F.Ellis in 1969); these functions were interleaved (fit) from empirically determined dependencies.
A major advance in radiobiological modeling occurred in the 1980s, when a so-called linear-quadratic (LQ) model was formulated on the basis of more detailed microdosimetric measurements and evaluation of chromosomal aberrations - see below. This approach is no longer purely empirical, but is based on an analysis of the mechanisms of the process of damage and killing of cells by ionizing radiation at the subcellular and molecular level. The parameters of this model (coefficients a, b and time factors) can be derived from the measured data (experimental and clinical), which allows within one model distinguish the behavior and responses of different tissue types. The LQ model is used primarily for deterministic radiation effects, but implicitly also lies in the basis of stochastic effects. We will analyze the LQ model in more detail here, then briefly list some other modified models below.

Linear-quadratic (LQ) model of radiobiological effect
The deterministic radiation effect, consisting in the destruction of a larger number of cells, is caused mainly breakage of both strands of DNA in the nuclei of cells. As discussed above (see "Intervention and Radicals Theory of Radiation Effect"), according to the theory of dual radiation action, radiation damage to a cell depends on the ionization density at a critical site. To determine the functional expression of the surviving number of N cells (from the originally irradiated number of N₀ cells) on the received dose D , the LQ model uses three initial assumptions :
× The break of a single strand of DNA can be easily repaired - sublethal damage ® cell survival.
× The break of both chains (strands) of DNA is difficult to repair - lethal damage ® usually cell death (apoptosis).
× It is probabilistic events with Poisson statistics: after irradiation of a set of N₀ cells, N cells survive, given by the exponential regularity N = N₀ .e^-^{<probability of lethal cell damage>}.

Double DNA break can be caused by two types of processes :
¨a -process - intervention of one ionizing particle, which breaks both strands-chains of DNA at the same time (manifests itself mainly in densely ionizing radiation, but also in sparse ionizing radiation secondary electrons can damage both branches of DNA). The number of irreversibly damaged cells is directly proportional to the dose - a linear dependence on the dose D. If the initial number of cells is N₀, then after irradiation the number of surviving cells can be expressed by the exponential relationship N = N₀ .e ^-a^.D, where a is average probability of a-damage per unit dose (derivation from Poisson's statistical distribution is analogous to the exponential law of radioactive decay - see §2.2, section "General laws of atomic nucleus transformation", instead of time t would be dose D ). Coefficient values a range from about 0.1 ¸ 0.8 Gy^-1.
¨b -process - time-close interventions of two independent ionizing quanta, in which each of them breaks one strand of DNA (breaking one strand of DNA allows repair - sublethal damage, damage to both strands is usually lethal). The number of radiation-damaged cells here is proportional to the square of the dose - quadratic dependence on dose D. The relevant exponential law of cell number decrease in this case will be N = N₀ .e ^-b^.D^², where b is the average probability of b-damage per square unit dose. The dependence is initially gradual, almost linear (possibility of cell repair after sublethal damage), then turns into a steeper exponential course, caused by the accumulation of sublethal effects in lethal. The coefficient b acquires values of about 0.01 ¸ 0.1 Gy^-2 for human cells.
The total probability of cell survival when applying both processes will then be given by the product of individual probabilities, which leads to the resulting exponential law: N = N₀ .e^-⁽^a^.D
+^b^.D^²⁾. The dose dependence of cell survival is often expressed by the curve of the surviving fraction of cells N/N₀ on a (semi) logarithmic scale :
            - ln (N/N₀) = a .D + b .D² - linear-quadratic dependence, Fig.5.2.3c above.
For densely ionizing radiation (high LET, mainly a-process) this curve has an almost linear shape, for sparsely ionizing radiation (low LET, b-process predominates) the graph has the shape of a parabola.
In applications of LQ model, an a/b ratio [Gy] is often introduced to express the dose, at which the damage by the a-mechanism is the same as the b-mechanism (the linear and quadratic components are biologically equivalent in terms of the resulting lethal effect for cells). Graphically, the value of the ratio a/b characterizes the curvature of the graph of the dependence of the surviving fraction of cells ln(N/N₀) on the dose according to Fig.5.2.3c. Values a/b they depend on the relative representation of the individual phases of the cell cycle. For rapidly dividing cells (eg tumor cells) the values of the ratio are a/b » 10 Gy, for normal (late-reacting) tissues is a/b » 2 ¸ 4 Gy. The a/b ratio appears in the derived biophysical dose quantity, which is the so-called biologically effective dose (biological equivalent of dose) BED = -ln(N/N₀)/a = D.[1 + D/(a/b)]. BED is important in radiotherapy in assessiment the effect of fractionation of the total radiation dose D on n sub fractions d , when BED = D.[1 + d/(a/b)] (see §3.6 "Radiotherapy", section "Physical and radiobiological factors of radiotherapy") .
Time factor
Such simple dependences apply in the case of a single exposure. In the case of time-prolonged irradiation - continuous or repeated (fractionated), in addition to the mentioned mechanisms, time factors of cell repair (especially in the case of b-damage) and repopulation of cells by division in tissue, also apply. When irradiated with dose D during the irradiation time T in the LQ model, two additional quantities are introduced into the initial linear-quadratic dependence - factors of cell regeneration RG and repopulation RP :
1. Reparation
For each elementary time interval Dt, during which the cells receive a dose DD = D. Dt /T and the N. b. DD² cells are damaged, at the same time it is also enough to regenerate the N. l. Dt cells, where the parameter l is the rate of cell repair (l = ln2 /T_1/2, where T_1/2 is the half-life of repair). Integration from 0 to T gives a modified exponential law N = N₀ .e^-^RG.^b^.D, in which in the quadratic exponent appears an additional regeneration time coefficient, the so-called Lea-Catchesid factor *) RG = 2[(1- e ^-^l^.T). (1-1/l.T)] / l.T, which is a function of the rate of cell repair l and irradiation time T. The rate coefficient of repair l ranges from about 0.4 hours^-1 for normal tissues to about 1.5 hours^-1 for rapidly dividing tissues (e.g. tumor).
*) Lea-Catcheside dose-time integral :
In the general case, continuous irradiation of a set of N(t) cells with a time-varying dose D(t) with an instantaneous dose rate R(t) = DD(t)/Dt can be considered. Then, for each elementary time interval Dt during which the cells receive a dose DD = R (t).Dt and N(t). b. DD² cells is damaged (sublethal), at the same time it is enough to regenerate N (t). l. Dt of cells, where parameter l is the rate of cell repair. By integrating the relevant differential equation from t = 0 to the continuous time t , under boundary conditions at t = 0 N(0) = N₀, we obtain a solution for the time dependence of the number of cells N(t), which can also be written in the original (quadratically) exponential form N(t) = N₀ .e ^-^RG(t).^b^{.D (t)}^², where the modifying quantity
          RG(t,l) = [2/D(t)²]. ₀n^{^t}R(t).dt . ₀n^{^t'}R(t').e^-^l^.(t-t')dt'
is the so-called generalized Lea-Catchesid function (simplified function of this kind in the years 1942 to 1945 have found empirically D.E.Lea and D.G.Catcheside when examining the cell aberrations on Drosophile ), expressing the "balance" between cell damage by dose rate R(t) and their continuous repair with a rate coefficient of l. The RG function depends on the time course of the dose rate R(t) during the entire exposure. In extreme cases of short exposure time T << 1/l is RG ® 1 (repair does not apply during irradiation), in the opposite case of long irradiation time T >> 1/l with low dose rate is RG ® 0 (almost all potentially lethal damage can be repaired).
b -process, in co-production with cell repair, thus causes the so-called dose rate effect: that the biological effect of ionizing radiation depends not only on the total absorbed dose, but also on the dose rate *), as is schematically shown in the lower part of Fig.5.2.3c. For low dose rate (LDR), the number of reparations is high and the curve of the surviving fraction of cells is relatively flat - less biological effect (blue curve). The higher the dose rate, the more likely it is that a break in the second strand of DNA will occur before the first strand is repaired, usually causing lethal damage to the cells. For high dose rate (HDR), therefore, the curve of the surviving fraction is steeper - a larger biological effect, significantly increasing with dose (red curve in Fig.5.2.3c below).
*) In the exponential law for b -process N = N_o .e ^-^RG.^b^.D^² the dose rate is output explicitly, when a quadrate dose D² = D.D a single dose quantity D we transfer to Lea-Catcheside factor RG: RG .D = 2. [(1-e ^-^l^.T .) (1-1/l.T)]. D /L.T and realize that the D/T is the dose rate R . In the general Lea-Catchesid integral, the dose rate R appears directly.
2. Repopulation
In addition to the exponential decrease in the number of cells due to radiation damage, there is a continuous replacement of extinct cells by dividing the surviving cells. Over the time interval Dt, the number N of existing cells increases by N.n.Dt, where n is the rate of cell repopulation; the doubling time T_2r = ln2 /n of the number of cells by repopulation is often used. Integration yields an exponential law of cell number growth by repopulating N = N₀ .e ⁿ^.T. In logarithmic form, this leads to another additive term RP = ln2. T/T_2r, expressing the ratio of irradiation time T and time T_2r doubling of cell number by repopulation. Cell repopulation further enhances the above dose rate effect.
Including these time effects, the linear-quadratic dependence takes the final form (on a semi-logarithmic scale) :
             - ln (N / N₀ ) = a .D + { 2. [(1-e ^-^l^.T ). (1-1 / l .T)] / l .T } . b .D² - ln2.T / T_2r   .
These relationships between the biological effect and the radiation dose, including its time course (irradiation time T), play an important role, especially in radiotherapy, where fractionation of irradiation doses is used in order to optimize the resulting radiation response of tumor tissue with respect to healthy tissue - see §3.6 "Radiotherapy".
An interesting consequence of the above dependences of the LQ model may be the absence of a deterministic effect even at relatively high total radiation doses (significantly higher than the thresholds for single irradiation according to Fig.5.2.3b), if irradiation is long-term with dose rate lower than cell repair and repopulation. In this case, only stochastic effects can occur.
Deviations from the LQ model. Alternative models and dependencies.
Althout the linear-quadratic model is very well supported by theoretical analyzes and number of experimental results, it is a somewhat simplified mechanistic description of complex processes taking place during ionizing irradiation of tissues and cell populations. In practice, from the standard (idealized) LQ model some deviations occurs.
Higher exponents of the dose
A double DNA break is usually considered unrepairable, leading to inactivation and mitotic cell death. However, later experiments have shown that even such damage can sometimes be repaired by the cell, albeit with less probability. In addition to the first and second powers, it is sometimes appropriate to include smaller corrections containing higher powers (exponents) of the dose in the dose dependence of the radiobiological effect (Fig.5.2.4a). They could partly have their origins in multiple interactions (simultaneous or rapidly consecutive) of quantum ionizing radiation, resp. their chemical radicals, with cell nuclei that are more difficult to repair. In reality, however, many different influences apply here. This is especially evident in densely ionizing radiation (with a high value of linear LET energy transfer), where, in addition, the transmitted energy is distributed unevenly (especially in the region of the Bragg maximum for radiation a, protons and other heavy charged particles). Dependence [ln (N/N₀)](D) can then develop into a Taylor series by the various powers of the dose D .
Tissue biological influences
Even more significant are some individual biological influences. Each tissue is in fact a heterogeneous cell population, containing cells at different stages of the cell cycle and cells with different radiosensitivity - with different coefficients a, b: the resulting survival curve [ln (N/N₀)](D) is then a superposition of several different LQ curves. In addition, during the actual exposure, so-called cell redistribution may occur (change in the relative proportion of cells with different radiosensitivity: a decrease in the proportion of G1 and G2 cells and total clonogenic cells, while M and S cells and effector daughter cells will have a relatively higher proportion) during irradiation, or reoxygenation (change in oxygen content - the above-mentioned "oxygen effect"). The oxygen effect is significant especially when using sparsely ionizing radiation (photon radiation g or X is most often used), where the indirect radicals mechanism of the radiation effect predominates. In densely ionizing radiation, where there is an increased proportion of the direct intervention mechanism (and also increased radicals recombination), the effect of oxygen (oxygenation) on the radiobiological effects is less significant. These biological processes can result in changes in the radiation sensitivity of cells and tissues during exposure, leading to further deviations from the LQ model dependencies.
Bystander effect
The so-called bystander effect of remote induction of radiation effects in tissue is also discussed (described above in the section "Effects of radiation at the tissue level"), which may slightly increase the number of damaged cells (Fig.5.2.4b). The influence of the bystander effect can be included in the LQ model by inserting a new empirical coefficient B> 1, indicating the average number of damaged cells when one cell is hit: N/N₀ = e ^-^{B (}^a^{.D +}^b^.D^²⁾. However, this is equivalent to a standard LQ model with slightly higher values of the parameters a' = B.a, b' = B.b. Due to the bystander effect, the resulting radiosensitivity coefficients a', b´ for the tissue are therefore slightly higher than the coefficients a, b for individual cells. Factor B is different for different tissues. In practical radiobiological experiments, however, radiosensitivity is determined for tissue (or tissue cultures), where the influence of the bystander effect is already implicitly contained: a®a´, b®b´. The LQ model for practical use therefore remains unchanged. The bystander effect does not change the basic principles and dependencies of the LQ model, it only causes differences in radiosensitivity between the cell and tissue levels.

Fig.5.2.4. Some deviations of the dependence of the biological effect on the dose from the LQ model.
a) Multiple radiation interaction with the cells resulted in the presence of members of the higher power of the dose D . b) The bystander effect slightly increases the total number of damaged cells (decreases the fraction of surviving cells). c) In the area of low doses, a relatively increased cell sensitivity - hyperradiosensitivity - is observed on the graph of the surviving fraction of cells.

Hyper-radiosensitivity to low doses. Induced repair model
The higher the absorbed dose of ionizing radiation, the greater the amount of free radicals generated - the greater the damage to cells in the tissue or cell population. And the higher the percentage of cells killed: the dose dependence of the N/N₀ of the surviving fraction of cells should be monotonically decreasing. However, some radiobiological experiments have shown that in the area of very low doses (approx. 0.1-0.5 Gy), the otherwise gradually decreasing, almost linear dependence of N/N₀ of the surviving fraction of cells (according to Fig.5.2.3c) has a significant "valley", showing a relatively increased sensitivity of cells than would correspond to these low doses (Fig.5.2.4c) - the so-called hyper-radiosensitivity to low doses for deterministic effects. The cells start to repair only after a certain dose ...
Thedetailed mechanism of this paradoxical behavior is not yet known. It may be related to the kinetics of enzymes in the G2 phase of the cell cycle during reparations by homologous recombination (see the "Nitrocellular Repairs" section above), where the concentration of enzymes increases with increasing dose, inducing an increased rate of reparations. Thus, at the cellular level, it appears that cells may need some low level of damage to initiate the production of repair enzymes by feedback processes. If at low doses this level is not reached, the reparations would not work and in the check-point would be next mitosis stopped ® inactivation of cell ® higher sensitivity to low doses. At a higher dose (and thus greater DNA damage), the production of repair enzymes would already take place ® more efficient repair ® relatively lower sensitivity - the dependence returns to the standard curve of the LQ model. This phenomenon is sometimes referred to as induced repair.
Note1: Some "physiological defense mechanism" against the mutagenic effects of radiation in the area of increased probability of survival of cells with partially impaired genetic information is also being considered vaguely; these cells die due to hypersensitivity (in the spirit of the above-mentioned motto for damaged cells "dead cell = good cell") and do not endanger the organism with later stochastic effects.
Note2: The mechanism of radiation-induced repair could contribute to radiation hormesis discussed below in the section "Low doses of radiation: - are they harmful or beneficial?".
Note3: A kind of "prototype" low dose hyperradiosenzitivity perhaps could be called Petkau effect ( phenomenon), who in 1972 described the Canadian radiobiologist A.Petkau. It was allegedly an increased destruction of cell membranes during long-term irradiation with very low doses of radiation. He explained the mechanism of action of negative oxygen ions, which at lower concentrations damage the membranes more, while at higher concentrations they have greater recombination and less effect. This explanation is not very convincing and the Patkau phenomenon itself was not confirmed by later radiobiological studies (it was observed at a time when technical means and radiobiological knowledge did not yet allow to reliably demonstrate such a phenomenon or reveal its mechanism; it could be a chemical effect of carriers of used radionuclide ²²Na, or similar side effects). In light of current radiobiological findings, the primary effect of a low dose should be on DNA whose uncorrected damage induces cell apoptosis with secondary cell membrane damage (as discussed in the "Mechanisms of Cell Death" section above). Not much was known about cell apoptosis at that time.
Within the LQ model with standard parameters a, b hyperradiosensitivity can be included by inserting an initial component a with a higher parameter value a_hyper > a - assuming a dose dependence of the parameter a: a(D) = a + (a_hyper - a) .e ^-^D/D^hyper, where a_hyper is the initial higher value describing slope [ln (N/N₀)](D) for low doses, a the default value for the higher dose, D_hyper (» 0.2 Gy) is a boundary area hyperradiosenzitivity expression. The LQ model N/N₀= e ^-^[^a^{(D)
.D +}^b^.D^²^] with such a dose-dependent parameter a(D) then captures the experimental data well. For high doses D >> D_hyper turns into a standard LQ model with the usual parameters a, b, for low doses D << D_hyper behaves as an LQ model with parameters a_hyper, b. It is thus a combination of two LQ models with different a -sensitivities (two different directives in Fig.5.2.4c), combined into one equation; it is sometimes called the IndRep model (induced repair).
Notice: Please do not confuse this physiological (relative) low-dose hyper-radiosensitivity, inherent in all cells, with pathologically increased overall radiosensitivity due to genetic disorders of chromosomal instability - mentioned above in the section "Dose-biological relationship".
(multi) Target model
This simple and largely phenomenological model is the predecessor of the LQ model. It is based on the assumption that there are one or more radiation- sensitive targets in the cell. If one of these targets is hit (by radiation or radicals), it leads to cell inactivation and death. If one such a target is present, then by an analogous application of Poison's statistical distribution of the probabilities of intervention, which we used above for the a - process in the LQ model, we get the dependence of the surviving fraction of cells N/N₀ on the dose D: N/N₀ = e ^-^D/D^o, where D_o is the dose that leads on average to one hit of the target. If n targets are present, then the multi-target model of single-intervention inactivation gives the dependence: N/N₀ = 1 - (1 - e^-^D/D^o)ⁿ. To obtain better agreement with experimental values in the low dose range, sometimes the n-target dependence is combined with the 1-target dependence (each with a different value of the empirical constant D_o).
Kinetic models of DNA breaks - LPL and RMR model
Models based on the analysis of the kinetics of such DNA breaks, which may (but may not) result in the killing of cells, come from the 1980s. Models lethal and potentially lethal effect (LPL, S.B.Curtis 1989), and corrected/uncorected damage (repair/misrepair model - RMR, C.A.Tobias 1985), sometimes unite into so-called model of two lesions TLK (two-lesion kinetic) are for the usual doses (units up to tens of Gy) practically identical to the LQ model.
The local effect model
Local Effect Model (LEM ) takes into account the local dose distribution along the path of ionizing radiation, in relation to the dimensions and density of the distribution of cell nuclei in the irradiated tissue. It is based on a simple general relationship N/N₀ = e ^-^N(D), where N(D) is the average number of lethal lesions per cell at dose D (only the a-process is taken into account). It then introduces the local volume density of lethal lesions s(D) = N(D)/V, (where V is the average volume of cell nuclei), which relates to the local density of the dose distribution along the path of the particles for different types of radiation. Through this analysis model better describes the biological effects of densely ionizing radiation (proton, a particles, radiation of heavy ions).
Two-stage stochastic model
This further improvement in the modeling of the radiobiological effect was developed by Czechoslovak experts (P.Kundrát, M.Lokajíèek, H.Hromèíková). As in the classical LQ model, it is based on the analysis of cell damage by lethal a- process and less severe damage by b- process, which is in principle repairable, but a combination of two b-damage is lethal. Using Poisson statistics, the probability of the cell (cell nucleus) hitting a certain number of particles depending on the dose, LET and size of the nucleus is analyzed, as well as the probability of cell survival after repair processes. In this analysis, it is assumed that the condition for the survival of the cell after a given number of interventions by the ionizing particle is no damage by the a- process and a maximum of one damage by the b- process, as well as its successful repair. The model is elaborated especially for proton and ion radiation.
High-dose modifications of the LQ model - LQL, gLQ, USC, KN, PLQ
When irradiated with high doses of radiation (d > 5, 10 or more Gy/fraction), which allow advanced conformal techniques of stereotactic radiotherapy and HDR brachytherapy (§3.5, section "Stereotactic radiotherapy SBRT"), showed some discrepancy between expected and observed effects: the classical LQ model in these at higher doses per fraction somewhat overestimates the biological effect of radiotherapy, predicting higher damage to normal tissue NTCP. As if the curves of the surviving fraction of cells -ln (N/N_o) (on a log-linear scale) at higher doses actually showed an increased proportion of the linear component than the quadratic. To capture this clinical knowledge, some empirical modifications of the LQ model are sometimes used that better capture the radiobiological effects in at higher doses :
× LQL model (linear-quadratic-linear) for higher doses/fraction (higher than 2.a/b, in practice >approx. 6Gy) adds an additional linear component increasing the surviving fraction of cells.
× Generalized gLQ model (generalized LQ). The standard (conventional) LQ model assumes that the velocity lrepair of radiation-induced sublethal damage remains constant over time, leading to an exponential repair pattern in the Lea-Cathesid term RG. However, some experimental studies suggest that the repair rate of sublethal lesions slows over time. The generalization in the gLQ model consists in introducing a reparation term with a reciprocal time of 1/T into the Lea-Cathesid term RG.
× Universal Survival Curve (USC), which is compiled for the high dose area based on a combination of the LQ model (which gives a good description for small and medium doses) and the multi-target MT model (better describing the effect at higher doses - dependence in this area it is based more as a straight line).
×The KN ( Kavahagh-Newman ) model introduces another dose-dependent factor into the b- member in the LQ model: ln(N/N₀) = -a.D - b.D².[1 + (b/g).D]^-1.
× PLQ (Pade Linear Quadratic) model introduces an additional dose-dependent factor into the overall expression for the probability of cell survival in the LQ model: ln(N/N₀) = (-a.D - b.D²).(1 + g.D)^-1
(the name comes from the fact that the expression can be modeled as a Padé-approximation of the ratio of two polynomials).
Phenomenological character of the LQ model ?
All the above-mentioned complex processes at the level of cells, cell populations and tissues (whose mechanisms are often not yet examined in detail) cause in practice, that the coefficients a, b in the LQ model sometimes lose their unambiguous physical or radiobiological significance and take on the character of empirical constants. In the area of radiation doses used in biological applications (units up to tens of Gy), they good model the real dependence of the N/N₀ of the surviving fraction of cells on the dose, but the LQ model itself becomes rather summary phenomenological description of the biological effect of radiation. Nevertheless, this model, based on a precise analysis of the relevant mechanisms, remains the best and most sophisticated model of dose dependence of the radiobiological effect, even for practical use..!..

Small doses of radiation: - are they harmful, or can they be beneficial ?
or
Will the basic paradigm of radiation protection change ?
" Any irradiation of healthy living tissue with ionizing radiation, even at a very small dose, can be potentially dangerous to the body due to its late stochastic effects. Therefore, it is necessary to reduce radiation doses to a minimum by all available means. "
In the extreme case, even a single quantum of ionizing radiation that enters the body, can damage the DNA in some cell and eventually lead to tumor disease ..?!..

This is the basic starting point of the current radiation protection, "canonized" in all standards and regulations for working with ionizing radiation. In this section, we will try to question this basic paradigm of radiation protection a bit "heretically" - we will discuss some alternative views on the risks of low-dose exposure.
On what factual data is this starting point of radiation protection based? In addition to experiments on small animals (rats), criminal abuses of nuclear forces in Hiroshima and Nagasaki, as well as a number of radiation accidents, have become a source of data on the biological effects of radiation. During these tragic events, many people were irradiated with various doses of radiation, including very high and lethal doses. Radiobiology and radiation medicine thus gained a fairly good idea of the deterministic effects of radiation, the course of radiation sickness and the possibilities of its treatment. Long-term follow-up of a number of people, who received lower doses than corresponded to acute radiation sickness, also provided important information about stochastic effects of radiation and their dose-dependence. Further data on deterministic and stochastic effects of radiation were obtained by monitoring large groups of patients irradiated in medical therapeutic and diagnostic applications (radiotoxicity, secondary post-radiation malignancies).
"Linear threshold-free theory" is only an unsubstantiated hypothesis
A common feature of most studies on the biological effects of ionizing radiation is that these are medium, higher, and high doses (from a few tenths of Sv to many tens of Sv). For these values it is possible to construct a fairly objective relationship between the dose value and biological effects (Fig.5.2.3). As for the lowest doses (at the level of units and tens of mSv), it must be admitted that it is a "terra incognita", where reliable data are lacking *); it is not surprising, because the label "stochastic effects" itself says, that it is difficult to find any causal regularities here ...
*) For medium and higher doses (in the area above about 400mGy) the relationship between dose and effect is proven and statistically significant. However, towards lower doses, the results are blurred due to statistical fluctuations and uncertainties; for the lowest doses, the biological effect is no longer statistically detectable. Given the assumed roughly linear dose-effect relationship, the number of individuals required to demonstrate the statistical significance of a stochastic effect increases with the inverted square of the average dose required to produce the effect. If the effect at doses around 1 Gy is demonstrable in a statistical group of several thousand people, then the demonstration of the effect conditioned by a dose of 0.1 Gy requires a hundred thousand group. For the lowest doses close to zero, the existence of a natural radiation background completely makes it impossible to analyze the relationship between dose and radiation effect. Furthermore, a number of disturbing side "masking" factors can manifest themselves here, completely distorting the observed results!
Conservative radiobiologists and radiation protection experts will therefore take the point [0,0] as a starting point (zero dose = zero effect), interpolate the linear dependence from zero to the actually proven values and replace the missing values in the lowest dose range with extrapolated hypothetical values (straight line on Fig.5.2.3 left). And right here arise a claim about the harmful stochastic effects even the lowest doses of radiation, or the thresholdlessness of stochastic effects. Statement often repeated (and therefore generally accepted), but unproven ! Linear threshold-free theory is not a radiobiological hypothesis, but is the result of processing and straightforward approximation of available data.
Careful analysis of the data collected on dose-response relationships shows that the dose-response is probably not linear. The effects in the area of low doses are probably smaller than would correspond to the previously assumed linear dependence (a blue or green curve in Fig.5.2.3 on the left is possible closer to reality). The assumption of linear dependence and thresholdlessness of stochastic effects, on which the current concept of radiation protection is built, represents a conservative approach, overestimating the risks in the area of small doses.
Let's turn around to an argument from another direction - the development of life on Earth and the role of repair processes in cell nuclei. The basic mechanism of genetic transmission of information in primitive cells evolved hundreds of millions of years ago, when the level of natural ionizing radiation was much higher than today (higher natural radioactivity, lower shielding ability of the atmosphere against cosmic radiation). This high level of radiation background was both an important driving force in the evolution of life (mutations + natural selection ® development of new species), and forced cells to develop sufficiently effective repair mechanisms against radiation damage. And they probably retained these mechanisms its effectiveness to this day. Even now, due to natural radioactivity and cosmic radiation, our organism is irradiated with several thousand quanta of ionizing ^{radiation every second.}A large amount of reactive radicals and oxidants are formed as products of normal metabolism in the body; there are even many more than when irradiated with low or medium doses of ionizing radiation (it is estimated at hundreds of thousands of DNA nucleotide damage in each cell per day). It can therefore be expected that harmful radicals caused by a small dose of ionizing radiation will be lost "like a drop in the sea" of a large amount of harmful products of normal metabolism.
Note: This roughly applies to "sparsely" ionizing radiation. "Densely" ionizing radiation causes double DNA breaks that are less repairable, leading to higher radiobiological efficacy, including a higher risk of stochastic effects.
Radiation hormesis and adaptive response
In addition, some radiologists believe that a reasonable number of disorders caused by a small dose of radiation (especially sparse ionizing radiation) can initiate and stimulate chromosome-level repair mechanisms in the organism, which repair not only these radiation disorders, but can also repair even many other defects caused by metabolim, that might otherwise remain uncorrected. This radiation hormesis *), or adaptive response or radiation-induced repair at low irradiation of cells and organisms, is a kind of "immunization" in the organism.
*)Hormesis
The word hormesis comes from Greek "hormaein" = "arouse, excite, strengthen". This is an experience-based phenomenon in which low doses of some toxic substances not only do not damage the organism, but even improve its physiological functions. Hormesis probably arose during evolution as one of the ability of organisms to respond to adverse environmental conditions - cold, heat, lack of food, toxic substances -- factors that disrupt the functioning of the organism. For this stress factors the organisms often respond by adaptation. Exposure to small amounts of toxic substances, that damage biological molecules, triggers a stress response and can lead to hormesis; the organism then better tolerates higher doses of the given toxic substance. One of these factors stimulating hormesis, could be also ionizing radiation ...

Fig.5.2.3. Dependence of biological effect on the size of absorbed radiation dose
a) Probability of occurrence for stochastic effects. b) Severity of damage for deterministic effects.
c) Dose dependences of the surviving fraction of N/N₀ cells according to a linear-quadratic model.
This image we have shown here again for clarity; these are mainly fig.a) on the left - very low doses.

According to these opinions (but also not yet reliably proven), small doses of radiation could even be beneficial for the organism! A low dose of radiation triggers the "signal" emitted by the damaged DNA, and the subsequent repair process corrects any errors found (and removes those nucleotides that cannot be repaired), not just those caused by the radiation. If the amount of damage caused by the radiation is less than the "capacity" of the repair system, even other errors will be corrected; after irradiation with a small dose, there are fewer errors in the DNA than before - there is a positive effect (the section of the green curve below the horizontal axis in Fig.5.2.3a). At a higher dose, when the extent of radiation damage exceeds the "repair capacity", the effect of irradiation is already negative (the rest of the green curve in positive values).
Several mechanisms can act in the radiation adaptive response :
¨ Time - slowing down the cell cycle, so that by the beginning of the next mitosis, some damages can be repaired;
¨ Chemical - neutralization and thus detoxification of reactive radicals;
¨ Biochemical - activation of enzymes involved in intracellular repair - the above-mentioned radiation-induced repair ;
¨ Immune - stimulation of defense mechanisms at the level of the whole organism, which could help eliminate cells changed not only by radiation.
A certain small "preparatory" or "preventive" dose of radiation can thus protect the cells against damage caused by a subsequent much higher dose. A small dose activatesenzymes in the cell, designed to repair genetic information, making it easier for the cell to deal with the possible consequences of stronger irradiation. Regarding the effect of radiation on complex multicellular organisms, there is also the opinion that a small dose of radiation or some toxins deprives the organism of cells that have weakened repair mechanisms and which would be in danger of succumbing to malignancy in the future.
These (so far) non-conforming opinions were also verified experimentally. Of course, it would be ethically unacceptable to perform such experiments on humans, and not even on higher animals. However, interesting experiments were performed on bacteria. The bacterial culture was divided into two parts, one of which was placed in a well-shielded box, where the level of radiation background was lower than in nature. The second group of bacteria was exposed to a weak field of ionizing radiation under the same other conditions (temperature, pressure, humidity, nutrients). A surprising result was found: bacteria exposed to radiation prospered somewhat better than bacteria from the second group shielded from radiation! However, it was a question of monitoring the entire culture of bacteria (the reproduction of which could show selective effects), not of monitoring individual effects on individual bacteria.
It is clear that these experimental results and speculative considerations cannot be straightforward transferred to the biological effects of radiation for humans. Bacteria are prokaryotic organisms which, due to their unicellularity, cannot, of course, develop tumors. We are eukaryotes with a large number of cells of different species, interconnected by a number of complex signaling pathways; it is this circumstance that enables the development of tumors due to cytogenetic mutations, including the action of ionizing radiation. However, much here may depend on the function and extent of radiation-induced repair.
Only further research in the field of molecular biochemistry and cytology, as well as more extensive epidemiological studies, will hopefully help to clarify the question of the effect of small doses of radiation. Until this is reliably clarified, it is in view reliability of radiation protection, it is necessary to apply in practice a linear threshold-free theory, which in the area of small doses is associated with a slight overestimation of risk and a low probability of possible underestimation.
However, if the above conclusions are demonstrated in further experiments and subsequently in clinical studies, a change in the conservative paradigm of current radiation protection in the field of low radiation doses can be expected in the future and subsequently a revision of relevant standards and regulations. However, radiophobia, which is deeply rooted in Western society due to the mass media, will probably persists for a very long time...

Time course and types of biological effects of radiation
In terms of the time of boarding and time course of the effects of radiation on the organism, or its tissues and organs, we distinguish two groups - early and late :

× Early effects of irradiation
develop within a relatively short time (days to weeks) after a one-time irradiation with a larger dose of radiation. They are caused by the extinction of a significant part of the cells of irradiated tissue, especially stem cells, in rapidly proliferating tissues, in which there is a need for continuous rapid renewal of daughter effector cells that have a short life cycle. Stem cell depletion soon results in a loss of effector cells, which is reflected in deterioration of irradiated tissue function. These tissues (eg hematopoietic tissue or mucosal cells) have a high radiosensitivity and a rapid response to irradiation. These are acute deterministic effects and the rule is that the higher the dose, the earlier the effects start and the more severe they are. If too many stem cells are not damaged, after overcoming these early effects, there is also a relatively rapid recovery of the tissue by cell repopulation (accelerated stem cell division, or a temporary loss of division asymmetry in favor of effector cells) and its return to normal function. However, late radiation effects (deterministic and stochastic), discussed below, may occur over a longer period of time.
Very early radiotoxic effects
When exposed to a high dose of radiation all over the body, very early symptoms of the body's stress response, such as fatigue, nausea, and dry mouth, may appear very quickly, within a few hours. These manifestations of very early radiotoxicity they are not caused by the mechanisms of radiation killing of cells - although a larger number of cells are damaged, but this damage will appear later, only during the mitosis of these cells. Very early radiotoxicity is caused by irritation of the body's regulatory centers (nervous and humoral) by direct exposure to released ions, radicals and other products of radiolysis. At very high doses (hundreds of Gy one-time), very rapid and fatal radiotoxic effects can occur due to denaturation of the cell contents (rapid necrotic cell death) and the intercellular environment.
The early effects of radiation - early radiotoxicity - include :

× Late effects of irradiation
can manifest themselves after several months, years to decades of latency from irradiation. They arise either as deterministic effects after intense irradiation, long-term or repeated exposure to smaller doses of radiation (non-tumor late damage - late radiotoxicity), or as stochastic effects (cancer and genetic disorders). Late deterministic effects are caused by tissue damage with slow effector cell regeneration and thus low stem cell proliferative activity. Damage to stem cells by irradiation will only become apparent when their mitosis is needed to replenish effector cells, which is usually several months apart. Only then do damaged stem cells die and the tissue begins to show a lack of effector cells. Tissues of this type (such as connective tissue, muscle tissue, kidney) with slow cell division have low radiosensitivity and slow response to irradiation. However, the effects persist for a long time, sometimes even permanently.
Combination of early and late radiation effects
Individual organs are often made up of different types of functionally connected tissues - reacting quickly and late, within one organ. Therefore, early acute radiotoxicity occurs during irradiation, after its disappearance, subsequent (consequential) late radiotoxicity may manifest over time. E.g. at irradiation of the lungs, after the acute radiation pneumonitis, late lung fibrosis may gradually develop.
The late effects of radiation include the following types of radiation damage (the first two are deterministic, the second two are stochastic) :

Local tissue and organ radiation effects
Biological effects of radiation, we first analyzed at the molecular-cellular and tissue level in general (see above "Effects of radiation on cells", "Radiation effects during the cell cycle"). We have shown different sensitivity of cells in individual phases of the cell cycle and the resulting difference in radiosensitivity for stem and effector cells, as well as for different tissues and organs. We further analyzed the dependence of biological effects on the size of the absorbed dose and its time course ("Linear-quadratic model of deterministic radiation effect"). Then we focused on the radiation effects on the organism, especially in whole body irradiation.
However, a frequent case of radiation exposure is the dominant exposure of only a certain part of the body, a certain organ or tissue. Especially in the case of radiotherapeutic use of ionizing radiation (§3.6 "Radiotherapy"), a carefully selected part is exposed - the tumor lesion (target volume), while the surrounding healthy tissues and organs also receive certain doses. In these cases, specific aspects of radiation sensitivity and the response of different tissue and organ types to different spatio-temporal dose distributions are very important. From the point of view of the nature of sensitivity to the spatial distribution of the radiation dose in tissues and organs, it is important "organizational structure" and the size of individual functional parts. In general, organisms are composed of cells, grouping into tissues and functional units - organs. Organs consist of smaller groups of cells that provide function in individual parts of the organ - the so-called functional subunits. Functional subunits have different sizes and are differently interconnected and organized within a given organ, event. its links to other tissues and organs. According to the arrangement of functional subunits, biological organs can be divided into two basic types :
¨ A serial organ
is made up of a number of linearly arranged cellular structures (functional subunits), which are functionally arranged one behind the other - in series. The specialized activity of the cells of one section functionally follows the activity of the cells of the previous section. Local damage to even a relatively small place (section) can lead to a "outage" of the function of the entire subsequent rest of the organ. Examples of serial organs are spinal cord, optic nerve, esophagus, ureter, intestine and the like.
¨ A parallel organ
consists of many cellular structures (functional subunits) of roughly the same function, which occupy a larger space and are arranged side by side (in parallel ), working "together". Local damage to a smaller volume of such tissue is not significantly reflected in the activity of the whole organ, the remaining cells are enough to functionally cover its activity for the organism - these organs have a significant functional reserve. Examples of parallel organs are the liver, lungs, kidneys, thyroid gland, spleen, etc.

In a detailed view, the series and parallel arrangement is partially combined - for example, the parts connected in parallel with the local series arrangement of the elementary functional subunits. And organ systems or tracts (GIT, urinary tract) are a complex series-parallel arrangement of many different parts and functional subunits.
Serial and parallel organs have different radiobiological behavior in terms of spatial distribution of radiation dose. Serial organs may relatively well tolerate a dose evenly distributed over its entire volume, or whole body dose, but are very sensitive to high local dose, which can "exclude from the function" them. Parallel organs behave in the opposite way, which tolerate even a very high local dose to a small volume (the elimination of which will reduce the function only insignificantly), but they are damaged by the high total dose to their entire volume, resp. it depends on the total volume of irradiated tissue. This different nature of the radiation sensitivity of serial and parallel organs to the spatial distribution of the dose is of great importance in radiotherapy, where serial organs in particular often act as so-called critical organs, for which the tolerance dose should not be exceeded (see §3.6 "Radiotherapy").

Sources of irradiation with ionizing radiation
Throughout the duration and evolution of life on Earth, all organisms are exposed to ionizing radiation from natural sources - cosmic radiation (§1.5., part "Cosmic radiation") and natural radionuclides (§1.4., part "Natural radionuclides"). The same is true throughout the existence of man. Since the beginning of the 20th century, after the discovery of X-rays and radioactivity, in addition to natural sources, is comming also a number of artificial sources of ionizing radiation, which are increasingly used in many fields of medicine, research and industry.
Depending on their physical and chemical properties, sources of ionizing radiation cause either external or internal irradiation. External irradiation is caused by sources located outside the body, internal irradiation is caused by radiation from radionuclides found inside the human body. The way of the irradiation and specific doses of radiation further depend on the occurrence and movement of individual sources (natural and artificial) in the environment.

N a t u r a l --- A r t i f i c.	Radiation source	Effective dose [mSv / year]	share [%]	88% ----- 12%
	Radon (and its decay products)	2.1	48
	Terrestrial radiation	0.45	17
	Internal irradiation with natural radionuclides in the body	0.25	9
	Cosmic radiation (secondary)	0.4	14
	--------------------------------------------	-------------	----
	Medical irradiation (diagnostics, therapy)	0.3	11
	Occupational exposure	0.002	0.08
	Technical and consumer items	0.005	0.02
	Nuclear energy (excluding accidents)	0.001	0.04
	Radioactive fallout (nuclear weapons and accidents)	0.005	0.02

The average annual dose from irradiation from natural sources for humans is about 3.2 mSv, from artificial sources it is estimated at about 0.3 mSv/year. At present, therefore, on average, about 90% of the radiation exposure is from natural sources and 10% from artificial sources. In any case, overall these are very small doses of radiation.

Natural sources of ionizing radiation
In our environment, we are constantly exposed to ionizing radiation from cosmic radiation and from natural radionuclides in the air, in surrounding objects, in soil and rocks, building materials and in our bodies. Natural sources causing radiation dose in living organisms and humans can be divided into three components according to their nature and significance :

Artificial sources of ionizing radiation
Ionizing radiation from artificial sources can be divided into three categories according to its nature and radiation significance :

Basic goals of radiation protection
Proven harmful deterministic effects of strong radiation *), as well as the risk of harmful stochastic effects of weak radiation (apart from the above-mentioned alternative possibilities of low radiation doses), leads to the need for protection against ionizing radiation. This radiation protection or radiation hygiene represents a system of technical and organizational measures to reduce unwanted exposure of physical organisms (especially persons) and to protect the environment from this radiation.
*) By this we mean, of course, the harmful effects of radiation on healthy tissue, not the targeted deterministic effects on pathological foci in radiotherapy that are beneficial for the organism (see chapter 3.6 "Radiotherapy")!
The basic goal of radiation protection can therefore be formulated as follows :

The risk from ionizing radiation is additive to the other risks (complementary), that we are exposed to during our lives - environmental and food pollutants, smoking, genetic influences, infectious and other diseases, etc.
From a statistical point of view, these risks are sometimes compared against certain nominal risk factors. These nominal risk factors are determined statistically from a certain additional frequency of illness or death depending on the risk factors. However, the accuracy and objectivity of such determinations is uncertain and debatable, there are a number of factors and selection effects, often unknown. Therefore, in our physically focused treatise on the effects of radiation and radiation protection, we do not address these issues.

The specific nature of ionizing irradiation of the organism
Compared to most other pollutants that affect our organisms, ionizing radiation has its distinctive specifics :
¨ Ionizing radiation is not detectable by our senses
If a person is in a place exposed to ionizing radiation, he doesn't feel it at all. And even at high intensities *), when the radiation dose soon exceeds the lethal value! If we do not have a suitable radiometer "on hand", we cannot assess the danger of this situation.
*) At high radiation intensities, ozone, which can be smelled in the air, can be a warning signal.
¨ Initial symptoms of radiation sickness
is virtually indistinguishable from the initial symptoms of common diseases such as the common cold or flu. If radiation is not suspected, radiation sickness may not be detected in time and treated adequately.
¨ Prolonged clinical manifestation of late effects of radiation
at doses up to about 3Gy, and especially stochastic effects, may lead to the fact, that we will not associate any health problems with radiation in the past.
¨ Low level of knowledge
in the fields of nuclear physics, radioactivity and ionizing radiation in the general human population. This leads to an underestimation or overestimation of the risks of radiation and radiation protection, the emergence of various misinformations and false rumors (such as radiophobia and opposition to nuclear energy).

Principles of radiation protection
In general, three basic principles are used to ensure the objectives of radiation hygiene :

These general principles of radiation protection have their specific form in medical applications of ionizing radiation, see §5.7 "Radiation protection in radiation diagnosis and therapy".
Part of radiation protection is also ensuring the physical safety of sources of ionizing radiation, which should be secured so that there can be no uncontrolled irradiation or contamination of the environment - so that the sources are properly stored and registered, so that the source is not lost or stolen, so that sources of radiation are entrusted only to persons and organizations, that are trained and authorized for the relevant activities.

Basic methods of radiation protection
The task of radiation protection is to reduce the absorbed dose of ionizing radiation in the organism to the lowest possible level (reasonably achievable - "ALARA") and thus significantly reduce the risk of adverse deterministic or stochastic effects of radiation. The obtained radiation dose is determined by several basic factors: the intensity, type and energy of the emitted radiation we work with, the exposure time and the geometric conditions (distance, shielding). So there are three basic ways to protect against external ionizing radiation (+ the fourth way when working with open emitters) :

Unjustified radiophobia when working with radiation :

With erudite work with knowledge of the matter and adherence to the principles of radiation protection, it can be achieved that working with ionizing radiation is no more dangerous and harmful than working with any other materials, machines and equipment .

The practical implementation of the above principles of radiation protection can be significantly aided by the use of protective aids in individual work operations with ionizing radiation. On the one hand, they are shielding aids - lead cases, covers, containers for radiators, shielding walls, aprons, glasses, etc. Furthermore, handling aids - tweezers, pipettes, remote manipulators, conveyors, etc. When working with open emitters, they are aids against contamination - rubber gloves, coats, veils, airtight shoes and more.

Radiation dose limits
Any dose of ionizing radiation can be associated with a certain risk of harmful effects (at least according to the linear threshold-free hypothesis...), so care must be taken to keep the doses as low as possible. For the purposes of assessing and controlling radiation exposure, certain dose tresholds *) have been set per year and for 5 years - the so-called limits (maximum permissible doses) for workers with ionizing radiation sources, which are still associated with a very low probability of radiation damage. The current value of the annual limit for workers was set at 50 mSv, the five-year limit at 100 mSv (5 consecutive years). Basic limits for other populations are set at 1 mSv/year .
*) These are additional doses to doses from natural sources. Spontaneous radiation dose from natural sources are not included in the limits for population or for occupational exposure of radiation workers (however, they are included in cases of targeted and professional activities associated with increased exposure from natural sources - such as work in uranium mines or in high-alitude aircraft).

5.4. Radiation monitoring and personal dosimetry
Radiation monitoring is a targeted measurement of quantities characterizing radiation in order to ensure the optimal level of protection of persons and the workplace or environment from the harmful effects of ionizing radiation. Monitoring is performed at workplaces with ionizing radiation and possibly even in the vicinity of more significant sources of ionizing radiation. The basic quantities measured during radiation monitoring are the radiation dose and dose rate. Their direct measurement is performed using so-called dosimeters, which are specially modified radiometers, calibrated in dose units (Gray, Sievert). In addition, derived dose determination methods are used based on other quantities, eg radiation intensity or radionuclide activity.

Reference levels
For the evaluation of measurement results during monitoring, certain significant values are determined, the achievement of which signals a certain anomalous radiation situation and is, if necessary, an instruction to initiate appropriate radiation protection measures. Three types of reference levels are introduced :

Radiation monitoring usually consists of three parts: monitoring of persons, monitoring of the workplace, monitoring of radioactive waste and possibly monitoring of the surroundings of the workplace with ionizing radiation.

Personal monitoring - personal dosimetry
Personal monitoring consists in measuring the personal radiation doses of individual radiation workers, whether it is external exposure, or possibly on internal irradiation from radioactive contamination. Monitoring of external radiation is performed using personal dosimeters, which radiation workers wear during all work with ionizing radiation and staying in the controlled zone. These dosimeters are centrally evaluated at specified time intervals (usually 1 month), the result is dose values (in mSv).
Note:It should be noted that direct measurement of the absorbed dose is very difficult, apart from laboratory methods, generally dosimetric quantities are not directly measurable. Doses are determined indirectly and approximately, based on certain model assumptions. The surface dose and the dose at a certain depth are derived from the data on the dosimeters. The most complex is the dosimetric analysis of internal contamination - it is described in more detail below in the section "Internal contamination".
The following types of personal dosimeters are used :

Radiation monitoring of the workplaces and environment
In order to ensure the optimal level of radiation protection and radiation prevention, it is important to monitor the intensity of ionizing radiation and the possible presence of radioactive contamination in the areas of workplaces, their surroundings and in the environment of the population - the so-called radiation monitoring. Measuring dose and dose rate are performed in laboratories, examination rooms and nuclear medicine departments. A system of workplace monitoring program is established.
.......................

5.5. Open radionuclides. External and internal contamination
Closed and open emitters
In terms of material nature and technical design, sources of ionizing radiation are divided into two groups :

For the classification of emitters according to activity in relation to radiohygienic risks, the so-called acquit level of activity is introduced: it is a value of total activity (or specific mass activity), below which radiation risks and radioactive contamination are considered negligible (compared to natural sources of radiation). Such an emitter is not subject to radiation protection regulations and we could have it without risk, with a bit of exaggeration, even at home in the living room...
According to the severity of radiation risk, sources of ionizing radiation are divided into 5 categories :
Insignificant sources
(eg small closed standards for spectrometric calibration, ionization fire detectors, radioactive substances with activity lower than the acquit level, etc.);
Small sources
(such as stronger closed emitters and low activities open sources);
Simple sources
(eg X-ray diagnostic devices and defectoscopic devices);
Significant sources
(eg closed emitters for radiotherapy, accelerators, highly active open emitters); and finally
Very significant sources
(such as nuclear reactors or radionuclide production facilities).
Laboratory work with open radionuclides and their storage, radioactive waste, application of radionuclides to patients.
Radiation hygiene when using open emitters - protection of workers from external radiation and internal contamination .

Radioactive contamination
When handling open radioactive substances, their leakage and subsequent contamination (pollution) of objects, the working environment and persons with these radioactive substances can occur. Contamination can be surface external and internal.

Surface contamination
Surface contamination of work surfaces, aids, clothing or people is most common. Surface contamination of people can lead to higher doses of radiation, especially on contaminated areas of the skin, but in some cases can also result in subsequent internal contamination, see below. For continuous control of surface contamination during and after work, radiometers with large-area probes are used, which should be located in all exposed workplaces and in hygienic loops.
A sensitive method of contamination control is the method of wiping from a defined possibly contaminated area of the exposed site with a cotton swab soaked in a suitable solvent (alcohol-gasoline) and then measure it in a test tube with a well scintillation detector.

Decontamination
In the event of contamination of the working environment, it is necessary to prevent the spread of contamination, mark a visibly contaminated area, report this incident to a specialist and cooperate in decontamination under his guidance. When decontaminating, it is necessary to first aspirate as much of the active liquid as possible with filter paper or pulp and then wash and wipe the contaminated area with a suitable cleaning or decontamination agent. Generated waste it is necessary to store in plastic bags and contaminated objects decontaminated or store them in plastic bags for decay of radioactivity. Contaminated water must be poured into the waste of decay sumps. The effectiveness of decontamination is continuously checked by measuring with a radiometer. If the radioactivity cannot be completely eliminated, the site should be marked and covered with protective paper or foil; the expert or supervisor will then decide on the further procedure and resumption of operation.
In the event of personal contamination, the worker must remove contaminated clothing or protective equipment, check the contamination of the body surface and, if necessary, clean it by washing or showering. It is also necessary to check whether there has been any internal contamination of the worker. In cases of suspected internal contamination and exceeding the maximum permissible dose of radiation is necessary to take the medical and radiohygienic measures, including the temporary exclusion of the the worker from the environment with ionizing radiation.
Extensive radioactive contamination is already a radiation accident - see the following §5.6.

Internal contamination
When handling higher activities of open emitters, unwanted penetration of radioactive substances into the body can occur - internal contamination and subsequent internal irradiation.
Note:A special case of "internal contamination" is the deliberate application of a radioactive substance - a radioindicator, radiopharmaceutical - to an organism for the purpose of diagnosis or therapy in nuclear medicine ("Scintigraphy", "Radioisotope Therapy"). From a radiohygienic point of view, this is not considered as contamination.
Upon penetration into the body, the radioactive substance enters the metabolism and can be distributed in individual tissues and organs depending on their chemical composition - part accumulates in the so-called target organs, the rest is distributed throughout the body. Most of the radioactivity is then metabolized and after a certain time it leaves the body (mostly in the urine, to a lesser extent in the faeces, sometimes in sweat or exhaled air). However, part of the radioactivity may remain permanently bound (eg iodine in the thyroid gland, strontium or plutonium in the bones, cesium in the muscles, ...) - it is retention (Lat. retineo, retentum = hold back, retain). Due to inhomogeneous distribution of radioactive substances in target tissues and organs, the internal irradiation of the organism may be highly heterogeneous (see below "Determination of the radiation dose from internal contamination. MIRD method").
Radioactive contamination can enter the organism in basically four ways :

When a radioactive substance enters the body through ingestion or inhalation, the substance passes relatively quickly from the digestive tract or lungs to the blood and lymph. Its other behavior - distribution, metabolism, persistence or excretion from the organism - is determined by the chemical properties of the substance and the rate of radioactive conversion of the radionuclide.

Monitoring of internal contamination
Determination of internal contamination with g -radionuclides can be performed by external measurement of gamma radiation using a sensitive scintillation detector above the critical (target) organs. E.g. in ¹³¹I it is a thyroid gland, so in workplaces performing thyroid therapy with radioiodine, it is necessary to periodically measure the ¹³¹I activity of the thyroid gland in all workers involved in these therapies.
A special method of measuring internal contamination is the use of whole-body detectors of radiation, equipped with scintillation or semiconductor detectors, which are installed in some workplaces with high radioactivity (nuclear reactors, production of radionuclides) and risks of internal contamination - category IV. workplaces. These methods of external monitoring are mainly used for internal contamination by radionuclides emitting g radiation, which penetrates through tissues out of the body. For pure emitters b, external monitoring can only be used if, due to the high energy, the electrons b generate harder braking radiation in the tissue (eg ³²P or ⁹⁰Sr- ⁹⁰Y), which penetrates through tissue out of the body. For low energy radiators b it has low intensity and energy braking radiation, it does not penetrate out of the body and external detection cannot be used. External detection is, of course, not applicable to pure alpha emitters.
Another method of monitoring internal contamination is to measure the activity of blood and urine samples.

Determination of radiation dose from internal contamination. MIRD method.
During external irradiation of the organism, the energy of radiation is transferred to the tissues and organs only for the time when the body is exposed to radiation. If the radionuclide enters the body, it remains deposited there and irradiates it for a long time. Irradiation is heterogeneous and changes over time, as the radionuclide moves and distributes in the body, is excreted from it, and how decreases it amount by radioactive decay. It is generally a complex function of time and space.
Accurate determination of radiation doses in individual tissues and organs during internal radioactive contamination is therefore generally a very complex and difficult task. The absorbed dose depends not only on the physical characteristics of radionuclide (types and energies of emitted radiation, half-life), but also on its chemical form (and very significantly!), normal or pathological pharmacokinetics - rates of accumulation and excretion of the substance in organs, on anatomical factors (sizes, distribution and densities of organs and tissues).
A more detailed analysis of dose distribution in tissues and organs will be provided below. In terms of risk for stochastic effects, for approximate and global assessment of the radiation load from internal contamination are use so called conversion factor of radiological contamination h [Sv/Bq]: it is a coefficient indicating the effective dose in the body (ie. cummulative time duration effective dose), caused by the uptake of a unit activity of 1Bq (in practice 1MBq) of a given radioactive substance into the organism. The values of the conversion factor depend not only on the type of radionuclide, but also on the compound in which the radionuclide is present and on the way in which the radionuclide has entered the organism; values for ingestion h_ing and for inhalation h_inh are most often given. Conversion factors are given for the so-called "reference person" with anatomical and physiological characteristics typical of the average population, eg weight 70 kg. More accurate dose values from internal contamination are determined based on the following models of MIRD metrod :
Radiation dose D [Gy] in the organ in which the radioactive substance is contained (assuming an even distribution for simplicity) is given by the product of two quantities
                                            D = S . A ^S   :
¨ The accumulated activity of A^S
indicates the total number of radioactive transformations that take place in the considered organ during the entire presence of the radionuclide (for the whole time). The value of accumulated activity A^S is determined as an integral or area under the curve of time dependence of activity A(t) in the organ from time t=0 of radionuclide entry, to its complete disappearance (theoretically up ¥): A^S = ₀ò^¥A(t) dt (middle part Fig.5.5.1).
  The excretion of a given radioactive substance from the organ (or the whole body) has an approximately exponential time dependence and its rate is characterized by the so-called effective half-life T_1/2^ef. This effective half-life is is given by a combination of the physical half-life T_1/2^phys of a given radionuclide and the so-called biological half life T_1/2^biol, i.e. the time required to eliminate half of the absorbed amount of a given substance by metabolism. The effective half-life is then T_1/2^ef = T_1/2^biol .T_1/2^phys/ (T_1/2^biol+T_1/2^phys). For the kinetics of radionuclides in tissues and organs, the biological half-life of excretion is usually dominant, which is usually significantly shorter than the decay half-life of the radionuclide itself.
¨The dose constant S
represents the dose related to the unit activity of a given radionuclide in the organ [Gy/Bq] (in practice [mGy/MBq]). The constant S includes the influence of all types of radiation emitted by a given radionuclide - particles b and a, radiation g, characteristic and braking X-rays, conversion and Auger electrons.
Alpha and beta particles (as well as conversion and Auger electrons) are completely absorbed in the source organ and contribute only to the dose in this organ, which in this case is D = <E_a,b>. A^S/m, where <E_a,b> is the mean energy of the emitted particles a or b, A^S is the accumulated activity, m is the mass of the organ or tissue (the dose constant is therefore S = <E_a,b>/m in this case). The basic relation for the radiation dose from the homogeneous distribution of radioactivity in the substance was derived above in §5.1, passage "Radiation dose from radioactivity".
Penetrating gamma and X radiation, in addition, can also shine through into the surrounding tissues and organs (Fig.5.5.1 on the left). Its contribution to the constant S depends on the energy of the radiation, the distances, the size and shape of the source and target organs, and partly on the type of tissue between them.
  Dose constant values for individual organs and radionuclides are determined using microdosimetric methods including phantom modeling and simulation; in the simplified version, they are given in the radiation protection tables (these are average values based on a person weighing 70 kg).

Fig.5.5.1. Radiation doses from the distribution of radioactivity inside the organism. Left: Source and target organs in the body. Middle: Time dependence of activity in source organs. Right: Time dependence for determination of doses by MIRD method.
<E> is the mean energy [J] deposited in the tissue of weight m per one decay of the used radionuclide (beta electrons or alpha particles are considered). If this mean energy is given in nuclear units [eV], there a conversion factor of 10^-19 is also used.
The figure roughly simulates the situation after the penetration of radioiodine ¹³¹I into the organism. Radioiodine is rapidly taken up in the thyroid gland, then metabolized and excreted by the kidneys into the bladder, from where it periodically leaves the body during urination.

The tissue or organ in which we need to determine the radiation dose is called the target, other organs and tissues in the body are considered to be the source for it - the left part Fig.5.5.1. The radiation dose D_T in target organ T is the sum of doses from the "own" accumulated activity A^S_T contained in this organ and the dose contributions of penetrating radiation from the activities A^S_i accumulated in the surrounding source organs "i" :
D _T = S_T . A^S_T + _{i = 1}S^N (S_i .A^S_i) ,
where S_i are the dose constants for target organ irradiation from activity A^S_i contained in the surrounding organs "i" (which are the source for target organ T; in general, each organ can be considered as both a target and source for other organs). The constants S_i include, inter alia, the absorption of radiation in tissues and the decrease in radiation intensity with distance. In the first approximation, the proportionality S_i ~ e ^-^m^.d/d² applies, where m(E_g, r) is the linear attenuation factor of tissue density r for radiation of energy E_g, d is the distance of the source organ from the target organ. However, the precise calculation should include integration across the entire space between the source and target organs, as well as across the actual volume of both organs.
This complex method, including the above-mentioned physical and biological factors for the determination of radiation doses in individual organs from the internal distribution of radioactive substances, is called MIRD (Medical Internal Radiation Dose). The basic MIRD method uses some flat-rate data on anatomical conditions in the so-called "standard human" weighing 70 kg. The refinement of these data can be achieved by using volummetry on density images from X-ray CT - the so-called voxel method. And the specification of actual data on the distribution and pharmacokinetics of a given radioactive substance can in principle be obtained by means of quantitative scintigraphy.
Such an improved, so far the most complex and most accurate method of determining radiation doses in organs and tissues in 3D radiopharmaceutical dosimetry, is important in planning and monitoring the course of radionuclide therapy in nuclear medicine - a more detailed analysis is given in the part "Radioisotope therapy" of chapter 3 "Application of ionizing radiation". It should be point out, that due to the significant variability of biological factors in particular, even when the inclusion these complex methods mentioned above, can not achieve a high accuracy determination of radiation doses in organs - the error is about 30% or above..!..
In practice, for the resulting radiation dose in the target organ, the dose from the organ's own accumulated radioactivity is dominant, while the contribution of radiation from other more distant source organs is usually negligible. This is especially true when the radioactive substance is a pure emitter b (or a), or the proportion of penetrating g-radiation is not high. And so it is in the vast majority of cases of radiation-significant internal contamination, including the application of radiopharmaceuticals in nuclear medicine.

5.6. Radiation protection at workplaces with ionizing radiation
(Categories of workplaces, controlled zone, storage and disposal of radioactive waste.)

Organization of workplaces and their categories
The construction, layout and equipment of workplaces must be carried out in such a way as to ensure sufficient radiation protection of workers, other persons and the environment. In the event of an accident, it must be possible to decontaminate people and the workplace as quickly and efficiently as possible.

Workplaces are divided according to whether they are designed to work with closed emitters (such as X-ray or radiotherapy workplaces) or with open emitters. According to the severity of the radiation risk, workplaces are divided into 4 categories, for workplaces with open emitters it is according to the processed radioactivities.
¨ Category I. workplaces
they are for working with low activities of radionuclides with low radiotoxicity (small sources of IR) and in terms of construction and equipment does not differ from conventional chemical laboratories.
¨ Category II workplaces
process medium activities of open radionuclides, they have a controlled zone and are equipped with protective equipment incl. hoods, or there is a separate sewer for radioactive waste.
¨ Category III workplace
is designed for demanding work with strong sealed emitters (accelerators, irradiators in radiotherapy and industry) and with high activities of open radionuclides (eg radioiodine therapy, uranium ore mining and processing, radiochemical plants). Therefore, considerable requirements are placed on its construction and equipment in order to ensure the fastest and most effective cleaning in the event of contamination. There should be 3 types of rooms in the controlled area: for demanding work with high radioactivities ("hot" operations), for routine laboratory work and measuring rooms. In addition, a special room or areas for storage of radionuclides and radioactive wastes. Floors and walls of laboratories must be smooth and washable, floors are further sloped and provided with waste. Intensive ventilation with active air filtration with an outlet above the roof should also be provided. Liquid radioactive waste is led to decay tanks. The workplace must be equipped with suitable shielding, manipulators, fume hoods and devices for protective dosimetry. The controlled zone should be separated from other areas by hygienic loops with a radiometer for checking of contamination and with the washroom.
¨ Category IV workplaces
This most risk category includes nuclear reactor operations, radionuclide production and radioactive waste repositories with high activities and long half - lives. In addition to irradiation and contamination directly at the workplace, there is also a risk of environmental contamination, which implies the need for radiation monitoring of the workplace and its surroudings.

Controlled zone
The radiohygienically controlled zone is called those areas of the workplace, where ionizing radiation (radioactive substances or other sources of ionizing radiation) is handled and where the regime of protection of persons against ionizing radiation must be observed *). Entrances to the controlled area must be marked with warning signs. Only trained radiation workers with protective equipment and personal dosimeters have free access there, other persons only accompanied by radiation workers and their stay is registered.
*) The current radiation protection standards specify: "Controlled zone is defined wherever it is expected that during normal operation or with foreseeable deviations from normal operation, the radiation dose of workers could exceed 3/10 of the limit for radiation workers".
In some workplaces, especially I. category, the so-called monitored zone is being introduced, which is an area where, during normal operation of radiation sources, the radiation dose could exceed the general limits for the population.

Radiation accidents and crashs
In every human activity - in industry, transport, agriculture, health, science and technology, laboratory work, as well as in everyday life, sometimes something "fails", breaks, will spoil - an accident occurs. Of course, this can also happen in workplaces with ionizing radiation.
By radiation accident we mean an unplanned event that will increase the danger of people from ionizing radiation. In workplaces with closed emitters, it is mainly about unwanted exposure of people. In workplaces with open emitters, it is mainly an uncontrolled leakage of radioactive substance into the working environment (eg by spilling, spraying, breaking the bottle with the radioactive solution, etc.) with subsequent contamination of the workplace, environment or workers. Such events can occur when handling open emitters in the process of their preparation, transport, storage, application and disposal.
For radiation accidents (especially minor ones), the name extraordinary event is sometimes used. The extent of a radiation accident or emergency is distinguished by the 1st to 3rd degree of severity :

An international 7-level table is also used to evaluate radiation accidents in nuclear reactors : 1st stage = deviation from normal operation; 2nd degree = fault; 3rd degree = serious disorder; 4th degree = accident with effects in a nuclear installation; 5th degree = accident with effects on the environment; Stage 6 = accident with serious radioactive consequences; Level 7 = major crash with extensive radioactive consequences.
Below we will briefly mention some examples of more serious radiation accidents.

Nuclear accidents and disasters with open emitters
One of the typical situations where a serious radiation accident with open emitters can occur, is careless work with fissile material (especially uranium ²³⁵U or plutonium ²³⁹Pu), especially if it is in higher concentrations - it is the so-called enriched. If a larger amount of such material is available, the critical amount may be exceeded and a chain fission reaction may be triggered, producing a very strong flash of neutron radiation and g radiation, followed by high contamination with fission products. Persons at the scene of an accident receive very high doses of radiation, often lethal. Several accidents of this kind have happened in laboratories and nuclear plants.
   For example, there was an accident at the Tokai-Mura nuclear enrichment plant in Japan on September 30, 1999. Here, 3 workers prepared nuclear material in a solution of uranium oxide (enriched to more than 18% ²³⁵U) and nitric acid. Inadvertently, more uranium solution was added to the reaction vat, resulting in a supercritical amount. A bluish flash signaled the ignition of the chain reaction. Two workers standing closest died, a third worker was being treated for an acute radiation sickness.
    A number of radiation accidents have occurred at nuclear reactors. A moderate accident (level 5) occurred on March 28, 1979 in Three Mile Island nuclear power plant on River Island near Harrisburg, Pennsylvania in the USA. Due to a failure of the secondary cooling circuit pump, the temperature and pressure in the primary circuit increased, the pressure relief valve opened and the reactor was stopped in an emergency. However, the safety valve blocked in the open position, the pressure in the primary circuit dropped, some spare water cooling pumps failed, the remaining heat began to boil the water, and several fuel cells were burst. Radioactive water, steam and gases leaked into the surroundings - a wide area around the power plant was infested, and several thousand people were evacuated. As later in Chernobyl, the perpetrators kept the accident completely hidden for several days; however, unlike Chernobyl, the circles concerned later succeeded in the concealment of real extent of the accident, so that reliable data on the amount of radioactive material leaked are lacking.
Accident at Chernobyl
The most severe radiation accident to date (7th degree) occurred on April 26, 1986 at the Chernobyl nuclear power plant (the principle of operation of nuclear reactors and their safety is discussed in §1.3 "Nuclear reactions", section "Fission of nuclear nuclei"; and the causes of the Chernobyl accident are described in the section "Chernobyl nuclear reactor accident"). During the destruction of the nuclear reactor, there was extensive contamination of the environment with radioactive fission products and the exposure of 232 people with high doses of radiation (units up to tens of Sv), associated with deterministic effects and acute damage to health; in 31 cases there were even lethal effects (of which 2 workers were killed directly when the reactor exploded, but even if this did not happen, they would receive a lethal dose of radiation)! Many hundreds more people received a radiation dose of tens to hundreds of mSv, for which an increased incidence of stochastic effects can be expected (by at least 1%; although it has not yet been confirmed ...).
   Fortunately, despite the seriousness and local tragedy of the Chernobyl accident, its consequences turned out to be significantly smaller than they initially seemed. And, of course, many times smaller (at least 100 times smaller!) than claimed by some propaganda materials, manipulated for political reasons (Cold War - anti-communism, anti-Sovietism), or from the motives of particular interests (fight against nuclear energy, coal lobby, etc.). In any case, the Chernobyl accident has become a milestone in nuclear energy and radiation protection. It led to a substantial tightening of safety regulations and standards of radiation protection not only in nuclear energy, but in the whole area of ionizing radiation applications (this resulted also in excessive bureaucratization of radiation protection - cf. the section "Bureaucratic requirements for radiation protection" in §5.8). An accident as large as in Chernobyl will probably never happen again !
Another recent major nuclear accident in Japan is briefly described in the section "Accidents at the Fukushima Nuclear Power Plant". No one was to blame for this accident, it was caused by a huge natural disaster. It has also been formally rated 7, but this is misleading, as its scope and severity are incomparably smaller than at Chernobyl.
In large radiation accidents with extensive radioactive contamination of the environment, the main health risks and injuries in the majority of the affected population are often caused not so much by radiation, as by stress from evacuation and concerns arising from overestimation of risks, radiophobia ...

Radiation accidents with closed emitters
Even with closed emitters, serious radiation accidents can occur if their radiation intensity (dose rate) is appropriately high. Potentially dangerous emitters from this point of view are particularly strong radiotherapeutic irradiators or industrial emitters, eg for defectoscopy or sterilization. Careless handling of such unprotected emitters can result in external exposure of the body to high radiation doses either whole body (Þ radiation sickness - sometimes lethal, increased incidence of stochastic effects) or locally (Þ radiation burns).
   A tragic radiation accident of this kind happened in September 1987 in the city of Goiania in the Goias region of Brazil, where a cesium emitter ¹³⁷Cs with an activity of about 50,000 GBq was unprofessionally and uncontrollably removed from a radiotherapy irradiation intended for disposal. Ignorant workers took it home, dismantled it and then sold it for scrap. The workers of the waste storage warehouse also distributed the radiator and took its individual parts home (they liked the bluish fluorescence!), even children played with them. The result was 5 deaths from radiation sickness, 20 people had local radiation burns (mostly on their hands).
   Other radiation accidents, some with lethal consequences, occurred during the theft of emitters. There are even several known cases of criminal abuse of emitters against persons (murder or attempted murder). The perpetrators and victims of these radiation plots are mostly persons those involved in espionage activities and organized crime.
   Many radiation accidents have become overexposed to patients during radiotherapy due to incorrect calibration of the irradiator or an error in the irradiation plan. A serious accident of this kind happened in December 1990 at the University Hospital in Zaragoza, Spain, where poor calibration of the linear accelerator caused 2-7-fold overexposure of irradiated patients, as a result of which 18 patients died from radiation and another 9 suffered radiation damage.

It should be noted with satisfaction that radiation accidents are relatively rare at present. The field of applications of ionizing radiation is monitored, coordinated and secured as thoroughly (sometimes perhaps overly bureaucratically...), like perhaps no other field of human activity. Mostly professionally founded people work here, well acquainted with the principles of working with radioactivity and ionizing radiation as well as with the principles of radiation protection.

A radioactive contamination ("dirty") bomb
This is the name given to a weapon in which a classic explosive is combined with radioactive materials. Its purpose is to radioactively contaminate the surroundings around the explosion by scattering radioactive substances. It consists of a chemical explosive charge with an admixture (or casing) of radioactive substances. The explosion of a conventional explosive sprays radioactive substances into the surrounding environment. The extent of contamination depends mainly on the strength of the charge and the amount of radioactive material, the place of detonation (height above the ground), the surrounding terrain (including urban development), the speed and direction of the wind. Contamination from a practically feasible "dirty bomb" is usually dispersed only within a few hundred meters or at most a few kilometers from the place of explosion.
It can have biological effects of ionizing radiation on people in the affected area (usually not fatal), but the main intention is to induce mass radiophobic panic. There are also large economic costs for decontamination and losses from interruption of production activity. In the case of this radiation-contaminating terrorist attack, it is necessary to carry out basically similar radiohygiene measures as in radiation accidents of nuclear facilities ("Radiation accidents and crashs", 3rd degree of seriousness of a radiation accident, or 6th degree of a nuclear reactor accident).
Only some radionuclides, with a long enough half-life, they are suitable for the purpose of a radioactive contamination bomb. They are, for example, cesium-137, cobalt-60, iridium-192, strontium-90, plutonium-238, americium-241, californium-252, or polonium-210, radium-226. And, of course, the fission decay mixture of radionuclides in spent fuel from nuclear reactors is highly effective (§1.3, pasage "Fission products"). There is also the question of the availability of a sufficiently large amount (activity) of suitable radionuclides (e.g. americium-241, or californium, is not available in large quantities...).
The military use of the radioactive contamination bomb is practically zero, but there have been concerns that it could become a weapon in the hands of terrorists. Fortunately, it is not too easy for them. Obtaining large quantities of suitable radionuclides is difficult (on the black market, from lost or stolen sources in industry, medicine, research; regular sources are strictly registered). Handling highly radioactive substances is dangerous, requires professional competence, demanding laboratory conditions and radiation protection. Individual terrorists don't stand a chance here, it could perhaps be partially successful with larger terrorist organizations that could pay for a team of nuclear experts. However, the real danger is probably small..?..
Early detection and prevention of illegal transport of radioactive materials and attempts to prepare radiation-contaminating terrorist charges is basically possible by radiometric monitoring using G.M, scintillation or semiconductor detectors of ionizing radiation, especially gamma radiation. These devices are installed at airports and border crossings.

Radioactive waste
Radioactive waste is such an unusable *) material (substance or object) generated during the production and use of radiation sources, that contains radioactive substances. According to the above classification of radioactive emitters, these wastes are open emitters. Radioactive waste can be potentially dangerous for the environment - it can cause unwanted irradiation or contamination.
*) However, this unusability may be relative and conditioned by the current state of technology. With the development of new technologies, initially difficult waste may become a welcome raw material (see, for example, the section "Nuclear waste" in §1.3).

How can radioactivity be destroyed ?
It is known that almost all pollutants can be eliminated by incineration - at high temperatures above about 600 °C chemical bonds break down, oxidation occurs and the substance ceases to be toxic (with some exceptions are heavy metal compounds, which are sometimes difficult to convert to harmless compounds). This does not apply to radioactive substances - the actual radioactivity cannot be destroyed by incineration! - see the passage "Independence of radioactive decay on external conditions" in chap. 1.2 "Radioactivity". By normal incineration we only break down or change the chemical bonds, but the number of radioactive atoms remains exactly the same as before incineration - some of them escape in gaseous form in smoke, some remain in the solid phase in the ash. To destroy radioactive nuclei, we would have to heat the substance to a temperature of several million degrees for nuclear reactions to occur. In this difficult way, we could hopefully destroy the existing radioactive nuclei,, but in nuclear reactions, on the contrary, new radioactive nuclei could be formed from originally inactive nuclei... In §1.3 "Nuclear reactions" the so-called transmutation technologies disposal of radioactive waste by neutron irradiation (ADTT) are discussed, which may be relevant for long-lived and highly active waste from nuclear reactors.

The activity and half-life of the relevant radionuclides, as well as the chemical form, are decisive for the handling and disposal of radioactive waste. Depending on the half-life and radiotoxicity, a so-called release level is set for each radionuclide (or category of radionuclides): it is the value of activity (total or specific weight or volume activity) below which the risk of contamination is negligible and the substance can be released into the environment without special radiohygienic measures. The value of the release level is determined on the basis of the limitation of the possible radiation exposure during internal contamination by a given radionuclide, using the conversion factors of ingestion and inhalation (analyzed above in section "Determination of radiation dose from internal contamination. MIRD method."). ........ add categories of radionuclides ......
Depending on the state, radioactive waste can be solid, liquid or gaseous :

From the point of view of radiation protection, it is therefore necessary to keep radioactive waste under control until its radioactivity drops to a sufficiently low level due to spontaneous decay, so that no threat to the biosphere can occur. This is a difficult problem for highly active wastes containing radionuclides with long half- lives; this category mainly includes spent nuclear fuel from fission nuclear reactors (§1.3, section "Nuclear waste").
Another possibility is the controlled slow long - term release of radioactive substances into the natural environment (eg into the ocean), when two conditions are met :
1. The current release level of radionuclides must not be exceeded in order to avoid the possibility of increased radiation exposure locally at the point of discharge.
2. The total amount of radioactive substances released must not exceed the "volume capacity" of the volume of distribution of the given substances in nature, so as not to increase the natural background radiation in the future.

5.7. Radiation exposure during radiation diagnostics and therapy
Radiation exposure from diagnostic medical examinations is generally low and is almost always justified by the benefit of accurate diagnosis of possible health disorders and pathological conditions. These exposures are usually comparable to the doses we receive continuously from the natural radiation background all around us. There is no direct evidence that these low radiation doses could be harmful *) - despite a hypothetical linear threshold-free dependence and a number of more or less misleading tables in the radiation protection literature (such as comparisons of radiation and smoking). In contrast, the benefits of a medical examination are unquestionable and can be very significant in terms of health !
*) The issues of the radiobiological effect of low doses of radiation are discussed above in §5.2, section "Relationship between dose and biological effect", section "Problems of very low doses - are they harmful or beneficial?".
The therapeutic use of radiation naturally leads to higher exposures, at which it is necessary to consider and optimize the risks of treatment against the possible benefits. However, even here, with proper planning, optimization and strategy, the health benefits tend to be unquestionable.
Despite the predominant health benefits of ionizing radiation applications in medical diagnostics and therapy, issues of radiation protection must be given due attention here as well.
Radiation doses and patient protection during diagnostic and therapeutic procedures
Medical diagnostics and therapy are among the most important applications of ionizing radiation; it also contributes the most to the radiation exposure of the population from all artificially created radiation sources.
The methodology of radiation protection in medical applications of ionizing radiation - in X-ray diagnostics, radiotherapy and nuclear medicine - is generally based on the basic principles of radiation protection mentioned in §5.3 "Objectives and methods of radiation protection", but has its significant specifics. In particular, there are do not introduce binding exposure limits, so as not to limit certain diagnostic and therapeutic procedures necessary to ensure the health or life of patients. The slogan is used with a bit of exaggeration: "Each patient will receive a radiation dose deserves": the dose needed for accurate diagnosis or effective treatment. Instead of limits, certain recommended dose values, so-called guide values - reference levels, are set as a guideline when performing specific diagnostic or therapeutic methods (see below "Principle of optimization").
The principle of justification of medical exposure
Radiation protection of patients comes out from basic the ethical requirement, that the risk of radiation damage during diagnostic or therapeutic procedures were balanced (or better, if possible, prevailed - overcome) by the expected health benefit for the patient. This basic requirement in the medical application of ionizing radiation is called the principle of justification of medical exposure in radiation protection.
Optimization principle
Another important aspect that contributes in practice to the balance of radiation risk and benefit, is the analysis of radiation protection optimization. In X-ray diagnostics, we will use the lowest exposure that will ensure quality and well-evaluable images, not a higher exposure. When diagnosing in nuclear medicine, it is necessary to apply only such a necessary amount - activity - of radioactive substances (required qualities and purity), which guarantees sufficient diagnostic information in the images with the lowest possible radiation exposure of the patient.
To optimize the amount of applied radioactivity of various radiopharmaceuticals for individual examination methods, tables of guideline values, also called diagnostic reference levels, which also allow recalculation of applied activity for individual patients, mostly according to patient weight (even non-standard - eg children, overweight etc.).

Radiation exposure of patients from X-ray examinations
By far the most common exposure to ionizing radiation (from artificial sources) in humans is X-ray diagnostics. In earlier times (around the 60s-70s of the 20th century), when skiagraphy was performed on X-ray films and sciascopy through fluorescent screens (amplifying foils and image intensifiers were not yet widespread, digital flat-panels did not yet exist), the doses from X-rays were often many tens of mSv. After all, at that time they were not even evaluated ...
With the development of amplifying foils, image amplifiers and especially digital display electronic flat-panels (see §3.2, passage "Electronic X-ray imaging") radiation doses from X-ray examinations decreased significantly, in simple images they represent only tenths to units of mSv. Relatively higher doses (up to tens of mSv) arise in CT examinations of larger areas (whole chest, abdomen, whole body), which is, however, balanced by the greater complexity of diagnostic information. High doses also arise during complicated interventional X-ray-guided procedures (here, in addition, the doses are highly variable, depending on the complexity of the procedure and how easy or difficult it is for the given patient to "perform" the procedure).
Absorbed radiation dose D [mGy] in the X-ray examination of a certain area is basically given by the product of the intensity of X-rays (this is given by the X-ray current [mA]), the exposure time [s] and the corresponding coefficients :
            D = G. mA s .
The product of the current I and the exposure time t indicates the electric amount Q - the total charge of the electrons - which flowed through the X-ray tube during the exposure: Q = I. t _{[mA.s] -
[miliCoulomb]} . The electric amount Q determines the total number of X-rays photons emitted by the X-ray tube, and thus the signal strength during X-ray imaging.
Coefficient G it includes a number of factors, such as the efficiency of X-rays production by X-ray tube, its energy given by the voltage [kV] for X-ray tube, filtration, distance, tissue absorption coefficients. It is measured using phantoms, most often water-filled "aquariums" (for planar X-rays), or cylinders with a diameter of 16 cm (head) or 32 cm (chest) for CT, equipped with ionization chambers, thermoluminescence or semiconductor detectors. The probability of biological stochastic effects is proportional to this absorbed radiation dose [mGy] and the size (volume) of the irradiated area [cm³]. This size - volume - is approximately proportional to the irradiated area [cm²] in the planar image, or the length [cm] of the CT scanned area.
In the planar X-ray diagnostics, this is quantified using the quantity area dose DAP (Dose Area Product) [Gy.cm²], which is the product of the input dose of X-rays and the size - area S - of the irradiated field: DAP = D. S. The effective dose D_ef [mSv] for a patient, expressing the stochastic effects of radiation on the organism as a whole, is then calculated as the product :
            D _ef = E_DAP . DAP ,
where the coefficient E_DAP (regionally normalized effective dose) [mSv Gy^-1 cm^-2] includes the averaged tissue (organ) weighting factors w_T for structures in the irradiated area (§5.1 "Basic quantities of dosimetry", passage "Effective dose"). Specific (actual) DAP values during X-ray examinations are measured using thin plane-parallel ionization chambers mounted on the output collimator of the X-ray tube - so-called DAP meters or KAP meters (§3.2, section "Radiation load during X-ray examinations").
Typical exposures for planar X-ray imaging in AP projection are approximately: head 25mAs, DAP = 1Gy.cm²; chest 30mAs, DAP = 0.6Gy.cm²; abdomen 60mAs, DAP = 1,8Gy.cm²; pelvis 60mAs, DAP = 2Gy.cm².
During the CT scan, the X-ray tube circle rotates around the imaging area and irradiates it on all sides with a substantially uniform dose within each section. The examined area can be approximated in terms of dose by a cylindrical shape of a certain diameter and length. For CT, therefore, dose D is measured by an ionization chamber inside an acrylate cylindrical homogeneous phantom with a diameter of 16 cm for the head and 32 cm for the body and is quantified using the dose rate index CTDI (CT Dose Index) [mGy], with event. correction for the pitch factor for spiral instruments. This dose value determined at the center of the cut is considered to be an objective indicator (index) doses in tissue. Here, the probability of biological stochastic effects is again proportional to the absorbed radiation dose [mGy] and the size (volume) of the irradiated area [cm³], proportional to the scan length [cm]. In X-ray CT diagnostics, this is expressed using the resulting linear dose DLP (Dose Length Product) [mGy.cm], which is the product of the absorbed dose D and the length L of irradiated area: DLP = D . L (= CTDI . L). The effective dose D_ef [mSv] for a patient, expressing the stochastic effects of radiation on the organism as a whole, is then calculated as the product of :
            D _ef = E_DLP . DLP ,
where the coefficient E_DLP (length normalized effective dose) [mSv mGy^-1 cm^-1] includes averaged tissue (organ) weighting factors w_T for structures in the irradiated area (§5.1 "Basic quantities of dosimetry", passage "Effective dose").
Typical dose parameters for CT imaging at 120kV and exposure to 200-400mAs are approximately: head CTDI = 45mGy, DLP = 640mGy.cm; chest CTDI = 15mGy, DLP = 400mGy.cm; abdomen, pelvis CTDI = 17mGy, DLP = 700mGy.cm.
Using special body modeling anthropomorphic phantoms, empirical data and computer simulations, the following approximate values of E_DAPand E_DLP coefficients were determined for the basic examined areas of the human body :

Note: The radiation dose in planar X-ray imaging (as opposed to CT) for individual examined areas is significantly dependent on the geometric projection used. In our illustrative table, we have given approximate values of E_DAP for antero-posterior AP projection.
Current computer-controlled X-ray devices (especially CT) determine the DAP, CTDI and DLP values when imaging a particular patient and record them in the result protocol (in DICOM format). The effective dose D_ef [mSv] can then be easily determined by multiplying the value of DAP or DLP by the appropriate E_DAP or E_DLP coefficient; in the case of a multi-area examination, the total dose of D_ef is given by the sum over all parts of the patient's body examined. This simple method of determining the effective dose from an X-ray examination is quite sufficient for the purposes of radiation hygiene - even more complex methods do not provide more valid results. After all, as stated in §5.1, the very concept of effective dose is only an averaged, rough and simplified "qualified estimate" of complex and individually dependent processes of the biological effects of radiation...
From the point of view of radiation protection optimization, guideline values - diagnostic reference levels - of recommended exposures for planar skiagraphic images and CT imaging were determined for X-ray examinations :

Planar skiagraphic images

CT scan

Investigated area

Input dose
[mGy]

DAP
[mGy.cm²]

Head	PA
	LAT

2.8

2.2

700

550

Thorax	PA
	LAT

0.3

1.1

220

550

Cervical spine	PA
	LAT

1.7

1.3

290

280

Thoracic spine	AP
	LAT

4.4

5.7

1100

1200

Lumbar spine	AP
	LAT

6.2

12.0

1700

3100

Abdomen AP

5.2

2900

Pan AP

4.5

2000

Investigated area	CTDI [mGy]	DLP [mGy.cm]
Head	65	1100
Neck	21	500
Thorax	15	500
Spine	32	550
Abdomen	19	750
Pan	25	860

Radiation exposure of patients from radionuclide examinations
is basically determined by applied activity [MBq] radiotracer (direct proportion), half-life of the radionuclide used, type and energy of radiation emitted, and pharmacokinetics of radiotracer - degree of accumulation of the radiopharmaceutical in various tissues and organs, as well as its rate of biological excretion or the residence time of the radiopharmaceutical in the tissue. These dependencies are quite complex and individual, in full complexity the MIRD method discussed above tries to solve them, Fig.5.5.1.
Based on this method, as well as empirical determinations and estimates, tables of recalculating coeficients - conversion factors h [mSv/MBq] for individual radiopharmaceuticals were compiled, which allow by simply multiplying the applied activity A [MBq] to approximately determine the effective dose D_ef [mSv] for patient: D_ef = h. A. The values of conversion factors h (effective doses/1MBq) and guideline values - diagnostic reference levels - recommended applied activities (normalized to the patient's weight of 70 kg) for some more frequently used radiopharmaceuticals in scintigraphy are given in the following table :

Radionuclide

Chemical form

Effective dose
h [mSv/MBq]

Type of examination

Applied
activity [MBq]

^99m Tc

pertechnate TcO 4

phosphates

DMSA

MAG 3

HIDA

macroaggregates

MIBI, tetrofosmin

HMPAO

leukocytes

antibodies

1.2 . 10 ^-2

5.8 . 10 ^-3

8.7 . 10 ^-3

7.3 . 10 ^-3

1.5 . 10 ^-2

1.1 . 10 ^-2

6.9 . 10 ^-3

9.8 . 10 ^-3

thyroid

skeleton

kidneys static

kidneys dynamic

liver dynamic

perfusion of the lungs

myocardial perfusion

brain perfusion

inflammation

tumors

200
800
150
250
250
200
800
800
600
800

¹³¹ I

iodide

thyroid

¹²³ I

iodide

ioflupan, IBZM

MIBG

2.2 . 10 ^-1

5 . 10 ^-2

thyroid

brain receptors

tumors

200

400

¹¹¹ In

leukocytes

antibodies

DTPA

octreotide

3.9 . 10 ^-1

2.2 . 10 ^-1

5.4 . 10 ^-2

inflammation

tumors

cisternography

neuroedocrine tumors .

200

190

⁶⁷ Ga

citrate

inflammation, tumors

300

¹⁸ F

FDG, FLT, FMISO, ...

2.5 . 10 ^-2

tumors

750

Tab.5.7.3. Diagnostic reference levels of recommended applied activity for the most frequent examination of scintigraphic diagnostics and dose conversion factors h for some used radiopharmaceuticals.

Note: There is a significant difference between X-ray diagnostics and nuclear medicine in the laws of radiation exposure. During X-ray examination, the source of ionizing radiation is a device and the radiation dose depends, among other things, on the number of images performed or on the extent of the area scanned during CT. In scintigraphy, the source of radiation is not a diagnostic device, but the patient himself, resp. its investigating organs. Thus, we can take any number of scintigraphic images without changing the radiation exposure of the patient. The radiation exposure of the patient is determined here already during the application of the radiopharmaceutical - its type (radionuclide and chemical form) and mainly the applied activity [MBq].
A certain way to reduce the radiation exposure of patient after administration of the radiopharmaceutical, is to influence their biokinetics - increased hydration with a recommendation for frequent urination (possible administration of a diuretic) for accelerated elimination of radioactive substances from the body or the application of suitable preparations, restrictive binding radiopharmaceutical to a particular organ (eg kalium iodine KI for protection of thyroid glands when administering ¹³¹I or ^99mTc- labeled radiopharmaceuticals).
Typical values of radiation exposure of patients from radiation diagnostics
The average radiation exposure for the most common methods of X-ray diagnostics (left) and radioisotope diagnostics in nuclear medicine (right) is given in the following table 5.7.4 (based on IAEA materials). These are approximate average values, provided that the guideline values of energy, intensity and exposure time for X-ray diagnostics and guideline values of applied radioactivity for nuclear medicine methods are observed (here these methods are mostly radiopharmaceuticals labeled ^99mTc, only the last line of positron emission tomography PET of tumors corresponds to ¹⁸F-FDG) :

X-ray diagnostics

Radioisotope diagnostics

Type of examination	Eff. dose [mSv]
Lung image	0.05
Spine	0.4
Abdomen	13
Urography	2.1
Mammography	0.5
Angiography	3 - 9
CT head	2
CT body (chest, abdomen)	7 - 10

Type of examination	Eff. dose [mSv]
Static scintigraphy of the kidneys	1.5
Dynamic scintigraphy of the kidneys	2.5
Dynamic cholescintigraphy	2.3
Skeleton scintigraphy	3.5
Perfusion scintigraphy of the lungs	1.2
Thyroid scintigraphy	2.2
Myocardial perfusion scintigraphy	5
PET - tumor diagnostics	7

Standard typical values of effective radiation doses in X-ray and radioisotope diagnostics are arranged according to size in the bar graph in Fig.5.7.1 below. The very lowest radiation doses (almost negligible) are in dental X-rays imaging (0.008 mSv for intraoral X-rays and 0.015 mSv for OPG). Similarly, very low doses are in bone orthopedic images of the limbs and X-rays of the lungs (approximately 0.05-0.07 mSv) . These low effective doses are caused by two circumstances :
1. To obtain sufficiently high-quality images, a relatively low exposure (approximately 20mAs) is sufficient, leading to an absorbed dose of fractions of mGy ;
2. There are no highly radiosensitive tissues and organs in the scanned areas (with a high tissue factor w_T), but only relatively radioresistant tissues with w_T <0.1 .
Significantly higher radiation doses are in CT examinations, where the X-ray tube rotates around the examined area and continuously illuminates it; however, the higher radiation dose is balanced here by a much more detailed diagnostic image. The radiation dose depends on the size of the scanned area (for CT head approx. 2mSv, CT of the abdomen up to 10mSv). And the very highest doses, up to tens of mSv, arise in complicated cases of interventional X-ray- guided procedures (the last column on the left in the diagram - here the doses are also considerably variable, depending on the complexity of the procedure and how easily or difficultly it is "successful" for the given patient to perform this procedure...).
All these values of diagnostic radiation doses fall into the area of very low doses according to Fig.5.2.3 on the left, where stochastic effects are not only very small, but also hypothetical (as discussed above in the section "Problems of very low doses - are harmful or beneficial ?") ..?..
Note to the table and diagram: Specific values of radiation doses are in practice highly variable, approx. +- 50%. The table and diagram are averaged rounded values, more or less indicative (therefore the numerical values of effective doses may not exactly match), depending on the devices used and the setting of their parameters, or the values of the applied activity of radiopharmaceuticals. Some workplaces emphasize lower exposures and "save" radiopharmaceuticals (adjust the quality of images by secondary filtration during evaluation), other workplaces use higher exposures and apply more activity of radiopharmaceuticals (for better primary images or shorter examination times)... Overall, it can be said that with the technical development of instrument electronics and computer evaluation procedures, radiation doses are gradually decreasing.

Fig.5.7.1 Diagram of approximate typical values of radiation doses of patients in the most common X-ray and scintigraphic diagnostic examinations. The blue bars represent X-ray diagnostics, the red radionuclide scintigraphic diagnostics in nuclear medicine.

In radiation therapy, the doses in the target tissues are, of course, quite high - tens of Gy, cancero-lethal tumor dose, but also in the surrounding healthy tissues can reach units of Gy - close tolerance dose. However, even here, with proper planning, optimization and strategy, the health benefit is unquestionable (it is discussed in more detail in §3.6 "Radiotherapy", section "Physical and radiobiological factors of radiotherapy").
In therapeutic applications of radionuclides, the optimally determined amount of radioactivity is applied - it is determined either according to verified empirical formulas, or as a lump sum according to the given diagnosis and the required therapeutic effect (for more details §3.6 "Radiotherapy", passage "Radioisotope therapy"). The activity of each radioactive substance administered to a patient (especially therapeutic applications) must be measured on a properly metrologically calibrated activity meter. The value of the applied activity is recorded in the documentation on diagnosis or therapy; it is an important data for assessing the effect of therapy and radiation exposure.
......................
Radiation risk of stochastic effects - distribution of radiopharmaceuticals according to radiation risk. Assessment of the acceptability of radiation risk in the context of other occupational and environmental risks.
Application of radiopharmaceuticals to children - choice of activity, radiation exposure in children compared to adults. Application of radiopharmaceuticals to women of childbearing potential and pregnancy . ....fill in?
In pregnant women, radiation-related radiodiagnostic procedures should be performed only when absolutely necessary, choosing the most gentle methods possible with regard to fetal protection. .......... fill in?

5.8. Organizational provision of radiation protection
Everyone who uses sources of ionizing radiation is obliged, within the limits of his competence, to take all necessary measures to protect the health of himself, his co-workers and other persons.
The general legislative framework for working with ionizing radiation is currently the so-called "Atomic Act" on the peaceful use of nuclear energy and ionizing radiation and related standards and regulations. Each country has developed its own "Atomic Act ", whereas the basic starting points and procedures are in principle the same - they are based on knowledge of nuclear and radiation physics, radiobiology, medicine and related technical fields.
These "Atomic Acts" sets out the most general rules for working with sources of ionizing radiation. Especially important are the objectives of radiation protection - exclusion of deterministic effects and reduction of stochastic effects to a reasonable minimum, principles of working with IR -optimization of radiation activities (risk versus profit), limitation, natural resources, medical exposure .....
Gradual improvement and innovation of radiation protection regulations are carried out mainly on the basis of expert recommendations of the International Commission on Radiological Protection (ICRP).
Central institutes and offices for nuclear safety and radiation protection are established to supervise and coordinate the whole set of measures for the safe use of ionizing radiation sources. In addition to legislative activities, these instituions assesses projects of workplaces with sources of ionizing radiation, issues relevant permits and performs inspection activities at these workplaces.
In addition, a supervisory worker of radiation protection is established at each workplace with ionizing radiation, which deals with radiation protection issues on site and keeps the relevant documentation. At the larger workplaces of nuclear medicine, a technical and physical department has been established, which, together with other physical and technical issues of the workplace, also provides a radiation protection methodology from a professional point of view. In some large medical institutes, a central Department of Medical Radiation Physics and Hygiene has been established, which coordinates all issues of radiation application and radiation protection.
A set of main principles, measures and methodology of measuring procedures to ensure the optimal level of radiation protection at a particular workplace are written in the so-called Monitoring Program of the workplace (what is measured, how often is measured, where is measured, how and what is measured, interpretation of measurement results and their documentation). Part of the monitoring program is also the determination of reference levels - recording, investigation, intervention.
Another related material is the Quality Assurance Program for diagnostic and therapeutic activities of the workplace, which is a set of control and adjustment activities to ensure the proper functioning of devices and the required quality of radiopharmaceuticals; this is a condition for accurate and reliable measurement and examination results. This is related to radiation protection through optimization between the benefits and risks of ionizing radiation application: the more valid the diagnostic results and the better the effects of therapy, the more the health benefits of patients outweigh the risk of ionizing radiation side effects - and vice versa.
The set of measures, including decontamination procedures and control measurements in the event of radiation accidents and other extraordinary events at the workplace, are summarized in the workplace Emergency code. Also the Operating rules of the workplace contain a number of specific principles for correct and safe work with sources of ionizing radiation.
As organizational and legislative issues are far removed from the professional focus of the author (physics), it will be appropriate to refer to the details of, for example, www-materials: https://www.icrp.org.......(Some aspects are briefly mentioned also in the syllabus " Radiation protection ").

Author's personal note: Unnecessary bureaucracy in radiation protection
As mentioned above, currently the field of applications of ionizing radiation in terms of radiation protection is monitored, coordinated and secured as thoroughly as perhaps no other field of human activity. In general, this must certainly be acknowledged very positively. However, as a physicist working for more than 40 years in the field of nuclear and radiation physics, I would like to make a small critical remarks :
It seems to me that this overall very high-quality concept of radiation protection is sometimes implemented and interpreted in recent years, perhaps overly bureaucratically... It is sometimes based on insignificant details, requirements important in the areas of high activities and radiation intensities are mechanically transferred to small workplaces (such as nuclear medicine), where there are virtually no radiation risks. The number of official "papers" and documents and their scope have grown enormously. They emphasize and broadly describe the tasks, powers, signatures of irrelevant persons - various those statutory representatives, directors, deputies and other officials who have nothing to do with radiation activity and often do not even know about its nature and existence ...
Experts in radiation protection are certainly not responsible for this situation (perhaps with the exception of isolated cases of servile efforts to be "more papal than the pope" and busily multiply irrelevant regulations...). This is related to the more general trend towards a hierarchical organization of Western society, the growth of bureaucracy and the replacement of real law by formal justice - the golden rule "the letter kills, the spirit revives" is forgotten.
In the field of radiation applications, as well as radiation protection, almost exclusively professionally well-founded people work, well acquainted with the principles of working with radioactivity and ionizing radiation. These workers eruditely carry out their professional work and implement radiation protection "as is should be", to the best of their knowledge and conscience. They should be given more confidence, without unnecessary "buzzings" and enormous administrative burden ..!..
Incidentally, a similar bureaucratic approach are seen in regulations and requirements for the preparation and filling of radiopharmaceuticals for nuclear medicine (§4.8, part "Radionuclides and radiopharmaceuticals", note "Radiopharmaceuticals - bureaucracy").

Investigated area :	head	neck	thorax	belly	pelvis
E_DAP[mSv Gy^-1 cm^-2] :	0.04	0.07	0.15	0.18	0.20
E_DLP[mSv mGy^-1 cm^-1] :	0.0023	0.0054	0.017	0.017	0.019

Back: Nuclear physics and physics of ionizing radiation
Nuclear and radiation physics	Radiation detection and spectrometry	Radiation applications
With cintigraphy	Computer evaluation of scintigraphy	Radiation protection
Gravity, black holes and space - time physics Anthropic principle or cosmic God
AstroNuclPhysics ® Nuclear Physics - Astrophysics - Cosmology - Philosophy

Tissue (organ)	bone marrow	intestine	lung	stomach	gonads	bladder	liver	esophagus	thyroid	skin	bones	brain	S -other
w _T	0.12	0.12	0.12	0.12	0.077	0.04	0.04	0.04	0.04	0.01	0.01	0.01	0.12

Influence of ionizing radiation on living organisms - risks and use in medicine