Crooked dose – effect. Dose-effect relationship Duration of effect depending on dose and time of day

Dose-effect curve (or concentration-effect) This means changing the infusion of a given ligand onto a biological object depending on the concentration of that ligand. Such a curve can be observed both for individual cells or organisms (if small doses or concentrations produce a weak effect, and large doses produce a strong effect: a graduated curve) or for a population (in this case it is necessary to protect, in which hundreds of individuals have the same effect) concentration or dose of ligand influences effect: corpuscular curve ).

Varying the dose-effect ratio and the use of similar models is the main element for determining the interval of therapeutic and safe doses and/or the concentration of drugs and other chemical substances with which humans and other biologists come into contact. The original object.

The main parameters that are measured in each model are the maximum possible effect (Emax) and the dose (concentration) that produces the maximum effect (ED 50 and EC 50, similarly).

When carrying out this type of investigation, the mother needs to take into account that the dose-effect relationship is required to remain from the time of exposure of the biological object until the end of the investigation (inhalation, ingestion, ingestion on the Iru Toscho); Therefore, a broad assessment of the effect at different times of exposure and different ways of receiving the ligand in the body will often lead to different results. Also, in experimental research, these parameters may be unified.

Power is crooked

Kryva Dose-Estabulum is a darling graph, a show of the venue of the bioologic O'Ct. According to the investigator, it is possible to rely on physiological and biochemical processes and to determine the level of mortality; Nowadays, individual deaths can include a number of individuals (at different mortality rates), ordered descriptive categories (for example, stage of decline), or physical and chemical units (the amount of blood pressure, enzyme activity). Depending on the clinical investigation, a number of effects are observed at various organizational levels of the object of investigation (clinical, tissue, organismal, population).

For everyday use, the dose of the administered drug or its concentration (calculate in milligrams or grams per kilogram of body weight, or milligrams per cubic meter of volume when administered by inhalation) is reported. It is along the abscis axis, and the magnitude of the effect is along the ordinate axis. In certain situations (which means that there is a large gap in doses between the minimum effect that can be recorded and the maximum possible effect), a logarithmic scale is displayed on the ordinate axis (this option is called a “superlogarithm” original coordinates"). Most often, the dose-effect curve has a sigmoid shape and is described by the Hill level. , especially evident in sublogarithmic coordinates.

Statistical analysis of the curve is calculated using statistical regression methods, such as probit analysis, logit analysis or the Spearman-Kerber method. In this case, models in which nonlinear approximation is used are likely to give superiority on par with linear or linearized ones, as the empirical occurrence appears linear compared to the observed Intervals: this is due to the fact that in the absolute majority of dose-effect relationships, the mechanisms of development of the effect are non-linear, otherwise Experimental data may appear linear over certain specific conditions and/or at certain dose intervals.

Zagalni respect

The spectrum of manifestations of the toxic process is indicated by the toxicant. However, the severity of the effect that develops is a function of the strength of the active agent.
To determine the number of words that apply to a biological object, we use the concept of dose. For example, the introduction of a toxicant in the amount of 500 mg into the shell of a gar with 250 g and a rabbit with 2000 g means that the animals are given doses of the same 2 and 0.25 mg/kg (the concept of “dose” will not be considered in the report). hot).
The “dose-effect” relationship can be traced to all levels of organization of living matter: from the molecular to the population level. In this case, in most of the episodes of the registry, there is a secret pattern: with higher doses, the level of damage to the system increases; The process ends up with more storage elements.
Regardless of the current dose, any kind of speech for singing minds can be harmful for the body. This is true for toxicants that act locally (Table 1) and after resorption from the internal media (Table 2).

Table 1. Relationship between the concentration of formaldehyde in air that is inhaled and the severity of the toxic process

(P.M. Misiak, J.N. Miceli, 1986)

Table 2. Deposition between the concentration of ethanol in the blood and the severity of the toxic process

(T.G. Tong, D. Pharm, 1982)

In the manifestation of the “dose-effect” relationship, the internal and interspecies diversity of organisms flows in. Indeed, individuals that belong to the same species are actually differentiated from one another by biochemical, physiological, and morphological characteristics. This is due to the importance of their genetic characteristics. Even more pronounced, due to the same genetic characteristics, interspecies diversity. In connection with this, the dose of a particular substance, in which it affects the deterioration of organisms of the same and, moreover, different species, can sometimes vary greatly. Also, the “dose-effect” relationship influences the authorities on both the toxicant and the organism, which is different. In reality, this means that a broad assessment of toxicity, based on the studied “dose-effect” relationship, should be carried out in experiments on various biological objects, and must necessarily go into statistical methods of analysis. ki danikh, scho otrimutsya.

The “dose-effect” relationship between the surrounding cells and organs

2.1. Respect in advance

The simplest object required for registration of a biological toxicant is cellin. With the development of toxic mechanisms, these provisions are often omitted, concentrating attention on the assessment of the characteristics of the interaction of the chemical substance with target molecules (more amazing). Such a simplistic approach, justified at the initial stages of work, is not at all acceptable when moving on to the understanding of the basic regularity of toxicology - the “dose-effect” relationship. At this stage, it is necessary to take into account the clear and clear characteristics of the reaction of each effector apparatus of the bioobject to doses of toxicant that are growing, and compare them with the laws of action of the xenobiotic on molecular comparison.

2.2. Basic concepts

The receptor concept of the action of toxicants on the cell or organ transmits, which is based on the reaction of the tongue with a biological structure - the receptor (divisional section "Mechanism of action"). The most profound findings developed during studies on models of interaction of xenobiotics with selective receptors of endogenous bioregulators (neurotransmitters, hormones, etc.). In such studies, basic regularities have been established that underlie the “dose-effect” relationship. It is known that the interaction of the speech complex with the receptor is subject to the law of active masses. However, in hypothetical cases there is no evidence that allows one to understand the specific characteristics of the primary reaction and the severity of the effect on the side of the entire biological system. For the hem of folds, it is customary to see two toxicometric characteristics of the xenobiotic:
1. Affinity – reflects the level of affinity of a toxicant to a receptor of this type;
2. Efficiency – characterizes the production of speech and the singing effect after interaction with the receptor. In this case, xenobiotics that act as an endogenous bioregulator are called agonists. The compounds that block the action of agonists are called antagonists.

2.3. Affinity

Varying the affinity of the toxicant to the receptor, in essence, is due to the experimental treatment of the concentration between the quantity of the substance that is added to the incubation medium, and the quantity that is created as a result of the interaction toxicant-receptor complex. The primary methodical technique is radioligand research (wonderful thing).
According to the ancient law of active masses, the importance of affinity must be ensured, so that the investigator is aware of the large characteristics of the place in the media less than the participants in the process - the toxicant [P]. The number of [R]T receptors that take part in the reaction is not yet known. There is a methodical approach that allows you to refine this complexity during the course of the experiment and at the stage of analysis of processing the results.

2.3.1. The description of the “toxicant-receptor” interaction is consistent with the law of active substances

In the simplest way to describe the process of strengthening the speech receptor complex, the kinetic characteristics of the reaction are of a different order.

In accordance with the law of the ranks:

K D – dissociation constant for the “toxicant-receptor” complex.
1/K D is the constant of the associative process, i.e. the degree of affinity of the toxicant to the receptor.
The fragments of the number of receptors in the system that undergoes interaction (culture of cells, isolated organ, etc.) is the sum of strong [R] and entered into interaction with the speech receptors, then:

[R]T = + [R] (3)

Z urakhuvannyam rіvnyan (2) and (3), maєmo

/[R] T = y = [P]/([P] + K D) (4)

The stage of saturation of the receptor with the toxicant “y” is the development of the receptor, which is associated with speech, to the final number of receptors. The amount of fragments of the complex that, once established, can be determined experimentally shows the possibility of expanding the value of K D to the same level (4). The graphical representation of the saturation of the receptor depending on the concentration of the toxicant in the media may have the appearance of hyperpain, which can also be used to determine the value of the dissociation constant.

2.3.2. Larger models of toxicant-receptor interactions

Experimentally, the curves associated with the toxicant on the receptors are often steep or gentle, but they can be observed in accordance with the law of active mass. Sometimes the degree of saturation of the receptor with a toxicant depending on its concentration is revealed. Please explain this in three ways:
1. The reaction between the molecule and the receptor is not bimolecular. In which case a different form of assignment is required, the following is presented to the ranks (4):

Y = [P] n /([P] n + K D) (5)

De n (Heal constant) – formally represents the number of molecules of a toxicant that participate in the formation of one “toxicant-receptor” complex.
2. The population of the receptor with which the toxicant interacts is heterogeneous. Thus, if in a biological object two receptor subtypes are located in equal numbers, which are separated by 3 times the value of the association constant of the “toxicant-receptor” complex, then the total value of the Heal constant is determined by the dependence and more expensive 0.94. At high values, the value of the association constants and their integral value increases even more to 1.0.
3. A significant influence on the process of establishment of the “toxicant-receptor” complex may include such phenomena as changes in the conformation of the receptor, the cooperativity of its adjacent subunits, and various allosteric effects. Thus, the curve connecting a toxicant to a receptor often has an S-like appearance. It is important to note the mutual influx of vascular compartments associated with the toxicant and the macromolecule (for example, the creation of a complex with one subunit of the receptor leads to a change in its relationship with other strong subunits). A similar effect is avoided by binding acetylcholine with a preparation of tissue membranes to target the cholinergic receptor. The increased concentration of free [3H]-acetylcholine in the incubation medium is accompanied by an increase in the affinity of the speech to receptor proteins (Figure 1). The local anesthetic, when added to the incubation medium, disrupts the cooperativeness of the receptors and thereby increases the affinity of acetylcholine for them. As a result, a change in the shape of the curve of the “connection - concentration of the toxicant” is observed and it transforms from S-like to initially hyperbolic.

Malyunok 1. Injecting prilocaine into the process of binding acetylcholine to the cholinergic receptor (J.B. Cohen et al., 1974)

2.4. Efficiency

Numerical studies have shown that between the production of speech, the formation of a complex with the song receptor and the severity of the biological effect that occurs with it (for example, shortening of smooth ulcer fibers of the intestinal wall, change in heart rate, vision secret, etc.) is far from First of all, the coldness will be straightened out. To describe the results of experimental studies, which have been studied, it is based on a low theory.
As stated earlier, all toxicants that interact with the receptor mentally can be divided into agonists and antagonists. At which lower, at a given concentration of the toxicant, the following symbols appear: [A] - concentration of the agonist; [B] – antagonist concentration.

2.4.1. Occupation theories

The foremost of these theories was that of Clarke (1926), who assumed that the expression of the effect that is to be avoided is linearly related to the number of receptors covered by the toxicant (/[R]).
How it flows from the river (4)

/[R] T = [A]/([A] + K A) = E A /EM (6)

De E A – intensity of the effect due to the action of the agonist at a stagnant concentration;
E M - the maximum possible effect from the side of the studied biological system;
K A is the dissociation constant for the agonist-receptor complex.
Consistent with Clark's theory, 50% of the magnitude of the effect develops for such a dose of agonist that occupies 50% of the receptors ([A] 50). This dose of speech is called moderately effective (OD 50).
Similarly, in accordance with the law of action, there is interaction between the receptor and the antagonist, without causing any effect

Up to B = [B][R]/[BR] (8)

De K V is the dissociation constant for the receptor-antagonist complex.
If the agonist and antagonist act on the receptor simultaneously, then, naturally, the number of receptors that bind to the agonist decreases. The number of receptors in a biological object can be designated as

[R] T = [R] + + (9)

Consistent with the analyzed theory, a toxicant can be either an agonist or an antagonist. However, the results of numerical studies indicate that such a classification of speeches is insufficient to describe the effects that are being guarded against. It has been established that the maximum effect produced by different agonists acting on the same receptor system is not the same.
For this purpose, Stephenson (1956) proposed three subsumptions:
- the maximum effect can be achieved by the agonist in those cases in which only a small part of the receptors are occupied;
- the effect that develops is not linearly related to the number of receptors;
- Toxicants may have different effectiveness (probably arousing activity), then. This produces an effect that interacts with the receptor. However, words with varying effectiveness in order to achieve the same effect, must cover the different number of receptors.
It is evident that the strength of the effect lies not only in the number of occupied receptors, but in the magnitude of any stimulus “S” that is formed when the “toxicant-receptor” complex is created:

E A /E M = (S) = (e/[R] T) = (ey A) (10)

Where e is a dimensionless value that characterizes the effectiveness of the agonist. According to Stephenson, throughout the world, a toxicant has an effect when it interacts with the receptor complex. Kilkisno Stephenson significant e = 1, for the reason that the maximum effect of speech on the biosystem becomes 50% of the theoretically possible reaction of the reaction of the biosystem to an awakening stimulus.
Furchgott (1964) assumed that the value of “e” directly lies in the background concentration of receptors in the biological system [R] T, and in the century the additional concept of “internal effectiveness” of speech (), the value of which is expressed as a proportional concentration atsion of receptors in the system

E/[R] T (11)

How it flows from the river (10)

E A / E M = ([R] T y A) (12)

Substitution of virazu (6) equalization (12) bring to

E A / E M = (e [A] / ([A] + K)) (13)

Since the concentration of receptors ready to interact with the receptor agonist changes by q times (with irreversible blockade of the receptor antagonist), then the real effectiveness of monitoring the speech becomes equal to q, and also q nanny (13) comes into sight

E A * / E M * = (qe / (+ K)) (14)

This pattern is graphically represented by baby 2.

Figure 2. Effect of histamine on a preparation of the small intestine of a guinea pig in the brain of long-lasting blockade of receptors with dibenamine (OD 50 = 0.24 μM; K A = 10 μM; e = 21) (R.F. Furchgott, 1966)

Another concept that allows us to describe the relationship between the current concentration of speech and the severity of the effect that develops is proposed by Arians (1954). The author proposes to characterize the finished speech by the value that is designated as “internal activity” (E)

(E) = E A.MAX /EM (15)

However, the theoretically possible maximum effect can be measured experimentally only with the addition of a strong agonist, the value of E for most speech lies in the interval 0< Е <1. Для полного агониста Е = 1, Е антагониста равна 0.
Thus, the most possible biological effect can develop when the toxicant occupies part of the receptors. In this case, the irreversible connection with the number of receptors is likely to lead to a shift of the “dose-effect” curve to the right, without reducing the magnitude of the maximum effect. Only after the transition between the receptors binding to the antagonist and the magnitude of the maximum effect begins to decrease.
In the course of research, the dose-effect relationship with the position of occupational theories for the characterization of toxicants is determined by the following parameters:
1. K A - association constant with the agonist-receptor complex (pK A = -lgK A). So, the value of the value is often assessed by an indirect method (that is, not by the amount of the “toxicant-receptor” complex created, but by the magnitude of the effect that develops when a small amount of the toxicant is added to the medium) on the basis of the concept of “stimuli” ", in short, talk about "getting ready" association constants.
2. EC 50 or OD 50 - such concentrations or doses of the toxicant, in which a reaction is formed in a biological object, is equal to the intensity of 50% of the maximum possible (pD 2 = -lgED 5 0).
3. Do - dissociation constant to the receptor-antagonist complex. The strength of action of a competitive antagonist can be expressed only by one parameter – affinity to the receptor. This parameter is assessed when the agonist is added before the incubation medium.

2.4.2. The theory of "mutual fluidity"

To clarify the data that emerge in the process of study of the dose-effect relationship, which cannot be understood from the position of the occupation theory, Peton (1961) proposed the theory of “reciprocal fluidity”.
Let us assume that the severity of the reaction of a biological system to a given speech is determined not only by the number of receptors that occupy it, but also by the speed with which the speech interacts with the receptor, and then leaves There seems to be something new. The author has come up with the following explanation: the receptor, not the organ key, is where you press the more, the sound is drawn in, and the piano key is where the sound is pulled at the moment of impact, and then, as you press the keyboard for a long time Yes, the sound still fades away .
Consistent with Peton's theory, strong agonists are substances that often absorb and often deprive the receptor; Antagonisms are things that permanently bind a receptor.

2.4.3. Theories of conformational changes in the receptor

For many reasons, the “dose-effect” curve appears to be hyperbolic in its functional relevance. The Heal coefficient of these curves is not greater than 1 (wonderful). As has already been noted, these features, as well as the S-like nature of the dose-effect curves of the inode, can be explained by the phenomenon of cooperative interaction of receptor proteins. It has also been shown that numerous chemical receptor modifiers (for example, dithiothreitol - a descendant of sulfhydryl groups), non-reversible cholinergic receptor blockers (for example, haloalkylamines), and other anticholinergic drugs (atropics) n), competitive muscle relaxants, local anesthetics and many other substances. for agonists that convert from S-like to hyperbolic.

To explain these and other phenomena that are important to interpret from the position of occupation theories (sensitization and desensitization of receptors during the action of agonists), Katz and Teslef back in 1957 Thus, in the application of muscle relaxants, a cyclic (conformational) model of interaction was observed.
The model is based on the phenomenon that the receptor [R] is a receptor, so the “toxicant-receptor” complex can be active (RA, RP A) and inactive (RI, RP I). This is schematically represented by baby 3.

Malyunok 3. The scheme of interaction between a toxicant and a receptor is consistent with the Katz-Teslef model.

This model allows us to explain the effect of agonists and competitive antagonists on the receptor.
An agonist, such as acetylcholine, interacts with R A , so that the RP A complex has a higher affinity to R A than before R I . The difference between RP A and RP I is linked to the side of RP A, the fragments of R I have low affinity to the agonist, and the RP I complex dissociates from the effects of the free R I. The coil of the effect is formed at the stage of conformational transformation RP A RP I. The intensity of the stimulus that occurs in the biological system lies in the number of such transformations in one hour. Competitive antagonists, for example, d-tubocurarine, may be more compatible with R A and reduce the agonist effect, including some receptors in the process of interaction with the rest.
Based on this model, it is practically impossible to experimentally determine the values of the conversion constants or the internal activity of the agonists. Therefore, until now, in experiments, as before, occupation models have been widely used.

The dose-effect relationship is equal to the body

3.1. Respect in advance

Biological systems, which are used in toxicology to study the “dose-effect” relationship, include tissues, organs, and the whole organism. The sensitivity of various organs and systems of the body to toxicants is not the same. Therefore, this stage is necessary for the investigation of the developed toxicity characteristics of the traced substance.
The transplantation of isolated organs from artificial brains, which model the natural environment, may be of great importance for understanding the mechanisms of interaction between the toxicant and the organism. The description of the theory of the receptor action of toxicants is formulated importantly on the basis of data obtained from the studies themselves on the isolated organs. It is not surprising that research on these objects plays an important role in toxicology.

3.2. Dose-effect curve

In general terms, it can be assumed that the “dose-effect” curve of the agonist in sublogarithmic coordinates (logarithm of dose - intensity of effect) takes an S-like shape regardless of a number of different and different features functions that are being assessed. The method, in addition to which depends on the storiness, whether the toxicant is continuously added to the incubator, or the one-time application of the substance to the biological object at growing concentrations, does not have a significant impact on the result, since the effect is not assessed in absolute terms, but in is expressed in hundreds as the maximum possible ( 100%). The determination of the relevant values is absolutely necessary because any biological preparation, when carefully prepared, is unique in all its aspects, including sensitivity to chemical substances. In addition, as the experiment progresses, the reactivity of the drug decreases. These facilities transfer the obligatory standardization of the object before further investigation. A graphical presentation of the dose-effect curve of a toxicant P, aligned with the curve for any standard speech, provides all the necessary information about the action of P, including its toxicometric characteristics.
The fragments of the constant leveling of the curves, obtained during the experiment, are technically difficult to perform, and the most important parameters of the curves are more often adjusted.

3.2.1. Average effective dose (OD 50)

p align="justify"> The main parameter of the “dose-effect” relationship for a toxicant and biological object is the value of the average effective dose (OD 50), then. such a dose of speech, when applied to an object, an effect develops that is more than 50% of the maximum possible. When working on isolated organs, calculate the vicor value EC 50 (the average effective concentration of speech in the sample). Effective doses are based on units of toxicant mass per unit mass of biological object (for example, mg/kg); effective concentration - in units of mass of toxicant per unit volume of the medium (for example, g/liter; m/liter). Replace the value of OD 50 with a negative logarithm: -log ED 50 = pD 2 (Table 3).

Table 3. pH 2 values for active toxicants isolated in an experiment on an isolated organ (the effect that is being assessed is the shortening of meat fibers to the drug) (J.M. Van Rossumm, 1966)

3.2.2. Vibrant activity

Another parameter of the “dose-effect” relationship is the relative activity of the toxicant, the value that is defined as the effect that the toxicant produces at a given dose, up to the maximum possible effect that develops when acting on the biosystem . This characteristic is signified, as it was generally signified, by the amount of internal speech activity (E).
In a narrow meaning of the word, this concept describes the phenomenon of the dominance of the powers of agonists, with clear explanations of the manifestations about the mechanism of their toxic action. However, at this time, it is often interpreted in the broader sense as a sign of the equal activity of speeches that swell the songs of power, without harmonizing the mechanisms, in addition to which stink initiates the effect that is being guarded against. In baby 4, the “dose-effect” curves of a series of expressions are presented, which vary with the values of E and, apparently, OD 50, which is the parasympathetic branch of the autonomic nervous system.

Drawing of the "dose-effect" curve of a series of parasympathomimetics (0< Е < 1,0), полученные на препарате изолированной тонкой кишки крысы. (J.M. Van Rossumm, 1966)

3.3. Biological abundance

It has already been stated that a number of toxicological experiments can be carried out on the same biological object (in the simplest cases, inject the animal with a dose of speech; add a medium in the incubation to remove solation organ, rechina in growing concentration, etc.). The study of the “dose-effect” relationship for one and more toxicants requires the performance of anonymous experiments that transmit the results of a large number of biological objects. Whose investigator is faced with the phenomenon of biological fatigue. However, with careful selection, we narrow down objects that are both extremely sensitive and insensitive to chemical substances, in order to achieve the desired variability in obtaining results. It is important to be aware that the way this phenomenon is framed during the analysis of experimental data often influences the implications of the follow-up characteristics of toxicants.
The basis of the phenomenon of biological fastness is the method of averaging the data. When the value of OD 50 is set, it is revealed that averaging of doses has been carried out, which determines the effect on several biological objects, and the value of the effects that are eliminated with small doses of the toxicant (Figure 5). If the goal is to reduce the resulting “dose-effect” curve, then the average dose is increased, which will influence the effect of the variable variability on the side of the bioobject. With a different approach (average effects), one avoids a decrease in the steepness of the dose-effect curve, consistent with the output data.

Malyunok 5. An average dose-curve effect based on various data obtained on several biological drugs with varying sensitivity to the traceable toxicant. Using the method of averaging doses, which produces the same effects (A), gives the correct result. The method of averaging the effects (B) results in a “flattened” result curve.

3.4. Potential effect of many toxicants on a biological object

When agonists and antagonists are applied to a bioobject, there may be varying modifications of the dose-effect relationship (not related to various chemical and physical-chemical interactions odes of xenobiotics). The most frequently registered changes are:
- Parallel plot of the “dose-effect” curve;
- Decrease in the maximum values of the dose-effect curve;
- Parallel zsuv with one-hour decrease in maximum values.
At this time, to explain the effects that are feared, it is most often the case that the occupational theory of toxicant-receptor interaction is used.

3.4.1. Parallel plot of the dose-effect curve

Golovne and the most often explained explanation of the parallel curve of the “dose-effect” curve for speech (A) with a one-hour infusion onto the biological product (introduced into the incubation medium) of speech (B) with internal activity E = 0, based on the admixture і, what (В) є Competitive antagonist (A).
When equalized on the basis of the occupation theory, the equally effective concentrations of the agonist in the presence ([A]) and with the added antagonist ([A*]) in the song concentration [B], we can

[A*]/[A] = 1 + [V]/K (16)

The fragments of coordinates in which effects are registered, and a parallel connection is avoided, like a logarithm, with logarithm of both parts equal (16)

Log - log[A] = log(1 + [B]/KB) = S (17)

LogK B = log(/[A] - 1) - log[B] (18)

From the table (17) it is clear that the value of the curve (S) depends only on the concentration [B] and the value of the dissociation constant for the antagonist-receptor KB complex (Figure 6). The relationship between the magnitude of the stimulus that responds to the agonist and the effect on the side of the biosystem does not play the same role. Often, to characterize the affinity of the antagonist to the receptor, the value pA2 = -logK is used.
The equation (16) and (17) is observed when pA 2 is numerically equal to the negative tenth logarithm of the concentration of the competitive antagonist, in which case it is necessary to add the intermediate agonist in order to cancel the effect in the register Eat without an antagonist.

Figure Theoretical dose-effect curve for an agonist based on the presence (A) and presence (A*) in the incubation midpoint of the antagonist at the final concentration [B]. In the induced application, the value S is equal to 13 and is expressed as S = log - log [A]. Based on the fact that S = log(1 + [B]/K D), it can be determined experimentally.

3.4.2. Decrease in the maximum values of the dose-effect curve

In a number of episodes in the presence of a dose-effect relationship for an agonist (A *), in the presence of an antagonist, it is revealed that the maximum effect that is to be avoided is actually weaker, even though it is avoided in both cases or the presence of an antagonist (A). The reduction in the maximum effect that can be assessed in hundreds of units is interpreted as follows from the position of the occupation theory.
The non-competitive antagonist (B*) reacts with the receptor (R*) of the biosystem, but not the R receptor for the agonist (A), with which the complex is released to reduce the effectiveness of the complex. This leads to a slight decrease in the internal activity of the E agonist, which lies in [B *].
The decrease in the maximum value of the dose-effect curve can be explained by the irreversible suppression of the receptor for the agonist by the competitive antagonist (B).
To characterize the activity of a non-competitive antagonist, calculate the negative logarithm of the dissociation constant for the antagonist-receptor complex

LogK B* = pD* 2

To increase this value, it is necessary to experimentally determine the maximum possible reduction in the effect of the agonist in the presence of the current concentration of the antagonist (E AB*M). Todi

PD* 2 = -log - log[(E AB*M - E A)/(E AB* - E A) - 1] (21)

The equation (21) pD2 can be viewed as a negative logarithm of the concentration of a non-competitive antagonist, with which the agonist effect is reduced by half the maximum level. In this case (E AB*M - E A)/(E AB* - E A) = 2. To simplify development, replace the effect of E A with the maximum effects that develop during operation A in different minds: E AM, E AMV, E AMVM.
Since the effect of the agonist can be completely blocked with the help of a non-competitive antagonist, the value of pD*2 can be calculated using a more simple formula

PD* 2 = -log + log(E A /E AB* -1) (22)

3.4.3. Parallel stress from one-hour decreases in maximum values

In practice, it is extremely rare to encounter drugs (antagonists) that result in either a parallel response or a decrease in the maximum value of the “dose-effect” curve for the agonist. As a rule, there are offensive effects. It is reasonable to categorize many xenobiotics into groups of competitive and non-competitive antagonists of low receptors, which may be largely mechanistic in nature. Proteus, there is a need for strong characteristics of the speech.
рD 2 is guaranteed to equal (22), so that instead the value of the effects E A and E AB represents the values of E AM and E AMB (Figure 7).

Theoretical curves of the potency of the agonist efficacy [A] depending on its concentration in the presence of the midstream antagonist [B]. To expand the value of pD 2, follow the vicoristic relationship between the mentally equal effective doses [A] and [A *] after determining the types of E AM and E AMV *. The growth rate continues to be equal to (23), after confirming the fact that the non-competitive antagonist is still present.

3.5. Value of obvious dissociation constants for the agonist-receptor complex

In this case, as there is a direct connection between the values of pA 2 and pD * 2 antagonists on one side and the dissociation constants of the antagonist-receptor complex, we would like to know theoretically, the connection between pD 2 and Agon. one hundred like that, in a strict sense No, the fragments between the stage of formation of the “agonist-receptor” complex and the stage of formation of the effect lie between the intermediate layers of biochemical and physiological reactions, as a rule, far from being modified (more amazingly). This means that it is impossible to determine the affinity of the toxicant to the receptor (that is, the value of the dissociation constant for the “toxicant-receptor” complex) in relation to the “dose-effect” relationship that emerges during the experiment. To understand this complexity, it is necessary to calculate the value of the explicit dissociation constant. The classic method is based on the use of an irrevocable competitive antagonist.
In 1956, Nickerson discovered that alkyl compounds such as haloalkylamines, such as dibenamine and phenoxybenzamine, can interact irreversibly with receptors of various types. Receptors bind to acetylcholine, histamine, serotonin, and -adrenergic receptors. Due to the strong interaction between inhibitors and agonists and biological drugs, it was found that:
- establish the specific nature of the action of haloalkylamines on the agonist-binding receptor site;
- clarify the classification of receptors based on their relationship to endogenous agonists.
Furchgott based the method on equal effective doses of the agonist that are applied to the intact biological drug and the drug, which is previously treated with a receptor inhibitor (change in [R] T by the value q [R] T).
The effect associated with the action of the agonist before blockade of receptors is described by Rivnyan (13), after blockade - by Rivnyan (14). The same effect in minds develops for the same magnitude of stimulus S. Since S = S*, then E A /E M = E A* /E M*, and thus, the combined ratio of 13 and 14 is obvious

1/[A] = 1/q 1/[A] + (1-q)/qK A (23)

Vibuduyuchu deposit at the coordinates 1/[A] and 1/[A*] is taken directly from the cut 1/q and cut on the axis 1/[A], level (1-q)/qK A . For practical purposes, you can use vicoristovati viraz

K A = (nahil - 1)/vidrazok

The process of preparing these presentations for Malyunku 8:

Malyunok The value of the constant of dissociation of agonists, which is generated on the muscarine-sensitive receptor of the late meat of the small intestine of the guinea pig.
A). The dose-effect curve of acetylcholine for the intact drug (q = 1) and the drug doped with 20 chlorine phenokisbenzamine (5 µM) (q = 0.1624).
b). The daily plot of the correlation between equal effective doses for the intact and treated drug in coordinates 1/[A] and 1/[A*] is reduced to a straight line, on the basis of which (as well as level 23) the values of the dissociation constant can be calculated.

Dose-effect relationship in the group

4.1. Dose-effect relationship for one toxicant

With the development of a “dose-effect” relationship in a group that consists of a large number of individuals, it is possible to emerge from the manifestation of disturbances due to the delay on the level of the surrounding organism. An additional factor that influences the result is individual flexibility.
However, although the reaction of some people or animals in a group to a toxicant is not the same, in the world there will be an increase in the effective dose, the reaction will increase and the severity of the effect and the number of individuals (individuals) in which it develops There is an effect that is being assessed. For example, if you apply a substance that excretes an irritant to the skin of the last ones, then in the world an increase in the amount of toxicant that is applied will result in: - an increase in the number of the last ones, Some people will respond to teasing; - The severity of the signs of irritation among those under investigation will increase. It is clear that the values that are obtained in the course of the work are due to the alignment of statistical patterns.
When a toxicant is injected into the body, there are effects that gradually manifest themselves within a given dose (for example, a decrease in arterial pressure) and effects of the “all or nothing” type (falling/surviving). In this case, it is clear that the effects of the first type can almost immediately be converted into a form suitable for assessing the effects of another type. To determine the dose-effect relationship in a group, up to two types of experimental experiments are performed:
- To trace the secrets of subgroups of creatures;
- Without approval of the subgroup.

4.1.1. Dose-effect analysis using subgroup formation method

The greatest expansion of the method of determining the dose-effect relationship in a group lies in the subgroup formed in this group. For animals entering the subgroup, the toxicant is administered in the same dose, and in the skin subgroup the dose increases. The formation of subgroups may involve a series of random selections. With higher doses, there will be an increase in some products in the skin subgroups that have developed the effect that is being assessed. The persistence that is eliminated in this case can be represented by the cumulative frequency curve of the subgroup, where the number of animals with a positive reaction to the toxicant (part of the number of animals in the subgroup) is a function dose (Fig. 9).

The typical dose-effect curve for a group of animals is symmetrical to the midpoint (50% variation). The main values of the group of responses to the toxicant are around the average value.

Most of the curves have an S-like curve to the log-normal distribution, symmetrical to the midpoint. You can see a number of important characteristics of the curve that are important when interpreting the results.
The central point of the curve (value of 50% of the species) or the average effective dose (OD 50) is a simple way to characterize the toxicity of a speech agent. The effect that is being assessed is the lethality of animals in the group, this point is designated as the median lethal dose (div. below). This value is the most accurate individual toxicity characteristic, since the value of the 95% trust interval is minimal.
The sensitivity of most animals in the population is close to the average value. The dose interval, which includes the main part of the curve around the central point, is also designated as the “potency” of the drug.
A small portion of the population on the left side of the dose-effect curve responds to small doses of the toxicant. This is a group of hypersensitive and hyperreactive individuals. The other part of the population on the right side of the curve responds less to large doses of the toxicant. These are insensitive, hyporeactive and resistant individuals.
The depth of the “dose-effect” curve, especially near the middle value, characterizes the distribution of doses that produce an effect. This value indicates how great the change in the population's response to a given toxicant will be with a change in the effective dose. It would be cool to say that the majority of the population will respond to a toxicant at approximately the same rate within a narrow range of doses, just as it would be hard to say that the sensitivity of individuals to a toxicant varies greatly.
The shape of the curve and its extreme points depend on a number of external and internal factors, such as the state of damage repair mechanisms, the reversibility of effects that are triggered, etc. Thus, the toxic process may not develop until the mechanisms of elimination of the active toxicant in the body are exhausted, and the processes of biochemical detoxification begin to intensify. Thus, the very intensification of the processes of elimination of toxic metabolites from the output xenobiotic may be the reason for the “dose-effect” curve to reach a plateau.
An important variant of the “dose-effect” curve is the persistence that occurs in a genetically heterogeneous group. Thus, in a population with a very high number of individuals whose sensitivity to toxicants is genetically fixed, it is possible to register a typical S-like shape in the left part of the curve (Fig. 10).

dose

Malyunok 10. Variant of the cumulative dose-effect curve with a pronounced hyperreactive component

The “dose-effect” curve is often transformed into a linear distribution of chemicals in the coordinates of log-protons (the dose of a toxicant is presented in logarithms, the severity of the reaction in the response is in probits). This transformation allows the investigator to submit the results of mathematical analysis (for example, to expand the confidence interval, the steepness of the top of the curve, etc.) (Fig. 11).

Malyunok 11. Reconstruction of experimental data on the determination of the “DOSE – EFFECT” duration: a) “EFFECT – DOSE” duration; b) storage "EFFECT - log DOSI"; c) storage "PROBIT EFFECT - log DOSI".

Using the method of forming subgroups, it is possible to determine the severity of the effect that is being assessed (for example, the level of arterial pressure, decreased ear activity, etc.) for a given dose of the toxicant. In this case, based on the obtained data, the average magnitude of the effect is determined, which has expanded in the subgroup of those who followed the response to the administered dose, and the correct interval of the indicator in the skin point is determined. Then there will be a graph of the magnitude of the effect of the administered dose by finding the approximation curve through the “dark” point (Figure 12).

Malyunok 12. Dose-effect curve for assessing the neuroleptic effect of the antipsychotic drug pimozide in intracerebral injections. The skin point on the graph is drawn by the way of registering the effects observed in 10 – 20 animals.

4.1.2. Dose-effect analysis without forming subgroups

With the introduction of drugs that quickly dissipate or are completely eliminated from the body, it is possible to ensure their internal administration to laboratory animals until the toxic effect is completely determined (for example, reduction in the frequency of diarrhea by 40%). Thus, it is possible for the skin surrounding the body to obtain a dose of speech that produces an effect. Investigations are carried out on a large group of creatures. If we draw a graph of the number of animals, which may have an effect that develops depending on the magnitude of the varying doses, then we can take away the well-known S-like curve, the analysis of which follows the rules.

4.1.3. Dose-effect relationship with mortality indicator

4.1.3.1. Zagalni manifestations

A fatal result after exposure to a toxicant is an alternative reaction, which is implemented according to the principle of “all or nothing”, this effect is considered to be the most important for determining the toxicity of substances, which can be used to increase the average lethal dose. (LD 50).
The determination of acute toxicity for the indicator “mortality” is carried out by the method of forming subgroups (miraculous). The toxicant is administered in one of the possible ways (enterally, parenterally) under controlled conditions. In this case, it is necessary to ensure that the method of administration of the substance is directly related to the toxicity value (Table 4).

Table 4. Testing the toxicity of sarin and atropine for laboratory animals

The creatures of the same conditions, age, water, what to fit on a singing diet, for the necessary minds of placement, temperature, moisture, etc., are considered. The research is repeated on several types of laboratory animals. After introducing the test chemical, precautions should be taken to determine the number of dead animals, usually within a period of 14 days. Once the speech is applied to the skin, it is necessary to register the hour of contact, as well as to formulate the application (from a closed or open space to the infusion). Obviously, the level of skin tension and the severity of resorptive action are a function of both the amount of material applied and the severity of contact with the skin. For all methods of infusion, in addition to inhalation, the exposure dose is expressed as the weight of the substance tested per unit body weight (mg/kg; ml/kg).
For inhalation infusion, the exposure dose is expressed as the quantity of the substance being tested present in one volume of exposure: mg/m3 or parts per million (ppm - parts per million). With this method, it is very important to take into account the hour of exposure. The greater the influx, the greater the exposure dose, the greater the potential for unpleasant action. Information about the dose-response relationship for different concentrations of the substance in air that is inhaled has been removed and must be removed at the same time of exposure. The experiment may be carried out differently, and different groups of experimental animals will inhale the resin at the same concentration, but for different hours.
For an approximate assessment of the toxicity of inhaled active substances, which simultaneously increase the concentration of the toxicant at the time of exposure, it is customary to calculate the value of “toxodose”, which is based on the formula proposed by Haber at the beginning ku centenary:

W = C t de

W - toxodose (mg xv/m 3)
C - toxicant concentration (mg/m3)
t - hour of exposure (xv)

It is expected that with normal inhalation of speech, the new effect (death of laboratory animals) will be achieved both with a short exposure of high doses, and with a trivial influx of speech at lower concentrations, at which an additional hour for the concentration of speech The guilt is lost unchanged. The most common cause of toxodosis is speech therapy, which was used to characterize combat poisoning reactions. The toxicity values of active chemical agents are presented in Table 5.

Table 5. Toxodoses of excreted substances (with inhalation infusion)

(M. Kruger, 1991)

The dose-lethality curve is usually similar in shape to the cumulative frequency effect curve for other dose-effect relationships (more amazing). For the purpose of equalizing the data and their statistical processing, transform the curve into the form of linear depth, the vicoristic coordinate system “log D - penetrations”.
Toxicity based on the indicator “lethality” is usually established based on the overall mortality rate of animals in the group. Most often, as a control rhubarb, there is a 50% death rate of animals, which indicates the median of the dose distribution curve, where the most positive reactions in the rhubarb (surprisingly) are symmetrically concentrated. This value is referred to as the average lithal dose (concentration). At higher levels, this dose of chlorine causes the death of half the animal population.
The concept of assigning LD 50 speeches was first formulated by Trevan in 1927. From this moment begins the formation of toxicology as a reference science that operates on numerous characteristics of the observed power (the amount of toxicity).
In contrast to other levels of mortality, which increase the significance, it is possible to measure the value of LD 5 LD 95, which is consistent with the laws of statistics close to the threshold and maximum toxicity and between dose interval, within which, basically, the effect is realized.
Ethical and economical martyrization at the maximum value of LD 50 is carried out using a minimal number of laboratory animals. In the connection with cym, the significance of the shukana value is invariably connected with the factor of insignificance. This insignificance is ensured by finding 95% of the confidence interval of the value that is being calculated. Doses within this range are moderately lethal with a fatality rate of less than 5%. The confidence interval of the LD value of 50 is significantly smaller than the confidence interval of doses of other equal lethality, which is an additional argument for the cost of characterizing the parameters of acute toxicity.
As has already been stated as an important characteristic of any curve “dose-effect” is its steepness. Thus, since the two words have statistically not significant values for LD 50 and, however, the steepness of the toxicity curve “dose-effect” (then statistically not significant values are similar to LD 16 and LD 84), the mortality rate behind the indicator is equitoxics in a wide range of doses (speeches A and B in Fig. 13). However, rivers that have similar values of LD 50 values and the steepness of the toxicity curve are extremely concerned about their toxic powers (river 3 in Fig. 13).

Malyunok 13. The “dose-effect” relationships of toxicants with similar values of LD 50 values and varying degrees of slope

Speech with a flat “dose-effect” relationship becomes very dangerous for individuals with pronounced hypersensitivity to toxicants. Rivers with a high steepness of storage are more unsafe for the population, since they carry a higher dose than the minimum required to produce an effect in the majority of the population.

4.1.3.2. Values of safe doses of toxicants

In a number of cases there is a need to carefully determine the value of the maximum non-active (safe) dose of toxicants.
The methodology of this task was proposed by Goddam. The investigation will be based on the established dose-effect relationship in a group of animals. It is important that the effect that is assessed be sensitive and assessed not in an alternative form (for example, decreased enzyme activity, increased arterial pressure, increased growth, impaired hematopoiesis, etc.). The duration graph will be at the coordinates “logarithm of dose - magnitude of effect”. Curve analysis allows you to evaluate low indicators. The fragments of the curve, as a rule, have an S-like shape, appearing as a plot, within which the deposits are linear in nature. Determine the steepness of the straight line (b). The threshold effect (y S) is calculated using the formula: y S = tS, where t is the Student’s coefficient, which is indicated in the following tables; S is the value of the standard supply, which is calculated from the wholesale data. Threshold dose (DS) - this is the dose in which a substance produces a threshold effect. For safe dose (DI) it is possible

Log D I = log D S - 6(S/b)

Butt for baby 14

Dose-effect curve(Or concentration-effect) describes the change in the infusion of a given ligand onto a biological object depending on the concentration of that ligand. Such a curve can be observed both for individual cells or organisms (if small doses or concentrations produce a weak effect, and large doses produce a strong effect: a graduated curve) or for a population (in this type of population, in some hundreds of individuals, the concentration or dose of the ligand has an effect: corpuscular curve ).

The main parameters that are measured in each model are the maximum possible effect (E max) and the dose (concentration) that produces the maximum effect (ED50 and EC 50 per day).

When carrying out this type of investigation, the mother needs to take into account that the dose-effect relationship is required to remain from the time of exposure of the biological object until the end of the investigation (inhalation, ingestion, ingestion on the Iru then), that is a strong assessment of the effect in different The time of exposure and different ways for the ligand to enter the body often leads to different results. Thus, in the experimental investigation, these parameters may be unified.

Power is crooked

The dose-effect curve is a two-dimensional graph that shows the severity of the reaction of a biological object depending on the magnitude of the stress factor (concentration of a toxic substance or pollutant, temperature, intensity of reaction, etc.). Under the “reaction” the investigator can remember the physiological and biochemical process, and determine the level of mortality; However, individual deaths can include a number of individuals (at different mortality rates), ordered descriptive categories (for example, stage of decline), or physical and chemical units (the amount of blood pressure, enzyme activity). Depending on the clinical investigation, a number of effects are observed at various organizational levels of the object of investigation (clinical, tissue, organismal, population).

For everyday use, the dose of the administered drug or its concentration (calculate in milligrams or grams per kilogram of body weight, or milligrams per cubic meter of volume when administered by inhalation) is reported. It is along the abscis axis, and the magnitude of the effect is along the ordinate axis. In certain situations (which means that there is a large gap in doses between the minimum effect that can be recorded and the maximum possible effect), a logarithmic scale is displayed on the ordinate axis (this option is called a “superlogarithm” original coordinates"). Most often, the dose-effect curve has a sigmoid shape and is described by Hill's equations, which is especially evident in sublogarithmic coordinates.

Statistical analysis of the curve is calculated using statistical regression methods, such as probit analysis, logit analysis or the Spearman-Kerber method. In this case, models in which nonlinear approximation is used are likely to give superiority on par with linear or linearized ones, as the empirical occurrence appears linear compared to the observed Intervals: should be based on the fact that in the absolute majority of dose-effect mechanisms, the mechanisms of development of the effect are non-linear, experimental The data may appear linear for certain specific conditions and/or dose intervals.

Also, complete the partial analysis of the dose-effect curve and its approximation to Hill’s equations of a significant level of cooperativity in the effect.

The “dose-effect” relationships in the gradient of importance for most of the parameters had a small non-linear appearance and were divided into dose fields in the vicinity of enterprises that needed to function, only “high” “step”, then the level of intensity changes the value of parameters in the high intensity zone. The “step height” in dose deposits changed in hours, and the change in the “step height”, as our research showed, at that hourly interval seemed to be associated with a higher rate of change display none in the area of medium and high intensity on aphids of low virulence changing the parameters of partnerships in the area of low pressure.

Dose-effect relationship. The body's response to infusion is determined by the amount of obstructed speech or dose in the body, the amount of which is determined by the way it enters the body - by inhalation (inhalation), with water or (orally), Either they are absorbed through the skin, or the influx is obtained with the help of external absorption . Inhalation and oral routes provide biochemical methods of infusing pollutants into the body. In general, the human body begins to detoxify pollutants, so it is more effective to deal with it than to take help from inhalation.

“Dose-effect” curves (Fig. 5.8) characterize the distance between the dose and the reaction in the response (effect) of the body. The “dose-effect” relationships for people and animals can be determined on the basis of these epidemiological studies.

PIDHID “DOSE-EFFECT” – the establishment of an interaction between the stages of flow into the ecosystem – the dose – (for example, obstruction) and the resulting effect. Dose-effect analysis makes it possible to determine the interstitial stability of the ecosystem, as well as assess possible environmental damage from the influx.

The dose-effect effect of phototropism is quite complex, but it appears at first glance. Thus, in experiments on etiolated coleoptiles, it was established that with increasing number of vigin subdivisions directly up to the light level increases, but up to the light threshold value (approximately OD J m 2 light energy ii), translocation of any lead until the reaction in the lead decreases to a certain value , if a “positive reaction” can turn into a “negative” one (then [...]

Lesson 3. Assessment of “dose effect” duration. At this stage, extensive information is collected about the relationship between the doses that are administered and the effect on health.

For the minds of linear dose-effect relationships, the values of approximation coefficients have been established, which may physically replace the coefficients of risk.

Curve 4 – non-linear dose-effect relationship with a convexity to the bottom – is also characteristic of the body’s response to a variety of factors. These inodes are called “sublinear” dose-effect relationships. Although curve 4 does not have a clearly defined threshold, the point on the axis, if the effect can be registered, indicates the practical value of the threshold.[...]

Curve 2 - non-linear "dose-effect" relationship with a convexity - represents a "supra-linear" relationship, which prevents small doses from producing disproportionately large effects. The results of monitoring the consequences of the Chernobil accident to the population indicate the presence of such a potential for radiation effects in low-dose galusa.

While it is difficult to use small doses, then to assess the effects in these types of disorders and disorders, which do not claim to be accurate, we also rely on time intervals. This results in a linear dose-effect relationship.

To transfer the frequency of episodes of stochastic effects during radiation levels, it is recommended to vicorize the linear dose-effect relationship with a similar dosimetric value in which case there is an equivalent dose. It is important to note that at high dose levels the potential for non-stochastic effects results in the negligence of the effective equivalent dose. Zocrema, a high dose of administration to the affected organ can cause non-stochastic effects, although non-stochastic effects are not avoided when the same dose is administered to the whole body.

Curve 1 shows that there is a similar B-like longevity of the effect depending on the dose, and daily changes in the metabolism of the human body are not avoided. Curves 2, 3 and 4 are brought to non-threshold levels: they are transferred to reveal effects at any concentration of the pollutant or to any desired small non-chemical infusion. Similar curves represent the class of stochastic health effects. The linear, non-threshold form of the “dose-effect” relationship 3 is the most widely accepted, since the assumptions about the form of the “dose-effect” relationship in the area of small values often go beyond the linear extrapolation in the area of high doses.

Thus, the GDC can be considered as a point in the relationship between “dose and effect”, which divides the zone of the maximum possible dose from the zone of doses that are considered unpleasant or unsafe for people.

To verify the determined allowance and to determine the nature of the “dose-effect” deposits in the case of a clearly unconventional flow into the environment of polluting streams in the surroundings of a thermal power plant (Reftinskaya GRES, Middle Urals; the main components of hydroxides are dioxide oxides, nitrogen oxides and calcium solids) rocks on permanent In the trial plots, an assessment was made of the status of the herbaceous-tegar layer of forest phytocenoses using syntopic registration of the occurrence of polluted rivers. In the vicinity of this enterprise, which has been operating since the 1970s, signs of degradation of forest ecosystems at the beginning were observed mainly due to the stage of defoliation of the crowns of the tree layer and the change in sprouting ecobiomorph in the grass-teagar layer.

It is necessary to moderate the physical and chemical composition of pollutants and the effects of their influx of growth. Some significant concentrations of components by automatic analyzers do not allow us to predict all possible effects from the influx of air pollution, and the use of biomonitors does not allow us to assess the level of air pollution. control the concentration of the skin phytotoxicant. Therefore, it is necessary to combine the assessment method with the type of monitoring. Changes in the concentration of pollutants, changes in the parameters of deposits and dose - the effect of adjusting meteorological parameters can be the date of external manifestations of pollutants.

The development of approaches to a comprehensive analysis of the natural environment must include the study of “dose-effect” and “dose-response response” in various experiments, the study of nutritional thresholds in the infusion of various factors and the influx of rich average errors. Nyuvachev, development of methods for assessing the reaction of foldable ecological systems to changes in the natural environment .[...]

Various methods of development will be based on the identification of disadvantages, which is followed by the establishment of “dose-effect” relationships and insecurities, which at the same time determine the characteristics of the risk. The total assessment of the assigned period of time gives a high level of correlation between the level of insecurity and indicators of health.

Science has developed a number of approaches to the development of these standards. Their main focus is on the dose-effect relationship analysis, which relates anthropogenic input as an input parameter of the ecosystem to its output parameter.

Thus, research has shown that weakly expressed changes in the parameters of the “dose-effect” relationship may, as a rule, lead to a non-linear appearance. The nonlinearity of the “dose-effect” relationships is due to the varying fluidity of changing parameters in the gradient of pressure, and the level of obstruction determines the time of stabilization of parameters in a given state i. The lowest time of stabilization is characteristic of the area of high importance, so the “dose-effect” relationship has a non-linear appearance, which is especially clearly manifested in the areas of enterprises that function for a long time (the impact zone and the industrial desert zone are clearly visible). Various fluctuations that arise in the species due to the interaction of exogenous and endogenous factors act as a transfer agent from one country to another, as a result of the level of intensity of fluctuations Between different zones of attention, the shape of the “dose-effect” deposits can change over time. When dealing with difficult speeches, you may experience a number of threshold levels and areas of time-dependent stabilization of parameters (cascading effect).

However, it is important to pay close attention to the approach to the concept of a “refined” dose (this is indicated in the work). It is necessary that the transformation processes obey a linear law, and that the “dose-effect” relationship be linear, and the infusion is proportional to the dose and the integral level instead of congestion and the result synergistic effects. It is also necessary to assume that hospitalization will be transferred in hours. A more complex model is indicated for congestion, where there are appropriate gradients in the space in the hour.

It should be noted once again that assessments of long-term risks for people’s health from early pregnancy loss at various stages of fire cycles are not, unfortunately, based on precise “dose-effect” data. In foreign studies, the “dose-effect” relationship between concentration and health risk is taken to be linear. For 0x and fly ash, such occurrences may be significantly less precise and will require further clarification.

In practice, there are few problems with the reliable values of the normative indicators. Stinks, smells, screams of folds in everyday life “dose-effect”, determined by what is permissible between changes in the ecosystem. In the economic norm, the essential complexities of such an assessment and the ambiguity in the choice of parameters that characterize the strength of the flow and vigor of the ecosystem were taken into account.

Key words -, important metals, acidity, forest litter, industrial contamination, biotesting, phytotoxicity, medicinal kulbab, extensive cooking, storage dose-effect, Middle Urals.

So, all research in these robots was carried out in the vicinity of long-term (over 50 years) functional enterprises and the value of parameters in the vicinity of such enterprises in the area of low and high importance varies slightly over time (Pipes ina, 1996; Trubina, Makhnev, 1997), not clear , and the non-linear nature of the “dose-effect” relationships is cleared up with less effort in the middle of obstructive speeches and thus causes the appearance of a non-linear effect.

Apparently, at small values of the factor that prevails, the system is able to extinguish internal fluctuations and external influxes and remain in a state of dynamic equilibrium near the stationary state. It can be assumed that the non-linearity of the “dose-effect” relationships in the vastness arises from the very low speed of change of parameters in the sphere of low importance and the high speed of change in the sphere of high importance , and the role of the remixer (trigger) from one cycle to the next is played by different fluctuations, which results from the interaction of exogenous and endogenous factors.

It is important to note that the gradient of the official has a number of critical points - a cascading effect (Trubina, 2002), and those that “mix” from one state to another are inherited iznorichnyh fluctuations in the parameters of partnerships. In these robots, it was shown that in the area of vantage, which conveys a sharp change in the parameters of the compounds, various fluctuations can have the greatest amplitude. The influx of different fluctuations on the form of deposits “dose-effect” for other functional parameters of the grass-teagrass layer (biomas) will be indicated and with the influx of important metals from the sulfur dioxide-containing sulfur dioxide (Vorobeichik, 2003 ).

The medicinal effect is present in the amount of speech (dose) taken. The effect is daily, since the dose that is administered is very low (subthreshold dosage) and does not reach the minimum therapeutic level. With a larger dose, the severity of the effect increases. To assess the clinical effect, use the dose-effect curve. Thus, the antipyretic effect is assessed by a decrease in body temperature, and the antihypertensive effect is assessed by a decrease in arterial pressure.

p align="justify"> For some people, the duration of the effect depending on the dose is not avoided, but the same effect is achieved with different doses of the drug. This is particularly clearly expressed in the reactions “no effect/no effect”.

As a butt, you can induce the phenomenon of a bent tail in mice (A). White mice react to the administration of morphine with disturbances, which is noticeable due to the unusual formation of the tail and ends. Vaccination with an increasing dose of morphine was carried out in a group of 10 mice. Less sensitive creatures react to a low dose of morphine; with an increased dose, the phenomenon of a bent tail is avoided in most mice; at a very high dose, the entire group responds (B). Thus, there is an interaction between the frequency of the reaction (the number of reacting individuals) and the administered dose: at a dose of 2 mg/kg, 1 animal in 10 reacts, at a dose of 10 mg/kg - 5 in 10.

Spousal dose - the number of responding individuals (reaction frequency) is indicated by the different sensitivity of individuals and follows a normal distribution curve (B, right-handed). Since the dose-response frequency exhibits a logarithmic distribution like an S-like curve (B, left-handed), then the inflection point indicates the dose if half of the group below responds to the drug. The range of doses in which the corresponding dose changes - the frequency of the reaction is indicated by changes in individual sensitivity as an average value.

The appropriate dose - the effect in humans is difficult, the remainder of the effect varies with the individual. Representative data are selected from clinical studies and averaged. Therefore, it is recommended that therapeutic doses be suitable for most patients, symptoms and illnesses may occur.

The difference in sensitivity may be due to (same dose, different blood concentration) or (same blood concentration, different clinical effect) factors.

The branch of clinical pharmacology that deals with the understanding of the reasons for the varied individual reactions of people to drugs is called. Often the basis for this effect lies in differences in the enzymatic set and activity of enzymes. Ethnic characteristics can also be integrated. Before prescribing any treatment, the physician must consider the patient's metabolic status.

Compound concentration – effect

To determine the therapeutic or toxic effect of medicinal speech, consider administering it to the surrounding organs. For example, during the analysis of the flow of blood into the blood circulation system, the reaction of the blood vessels is monitored. Diya likiv vichaet experimental minds. Thus, the vascular-sound effect is monitored on isolated preparations taken from different sections of the vascular bed: the axillary vein of the leg, portal vein, mesenteric, coronary or basilar arteries.

The vitality of rich organs is supported by the development of singing minds: temperature, the presence of veins and sourness. The organ's response to physiologically and pharmacologically active speech is determined with the help of special vibrating devices. For example, the sound of a blood vessel is recorded by changing the position between two arms to stretch the vessel.

Experiments on isolated organs have little success.

More precisely, the concentration of fluids in vessels is determined.
Completeness of the effect.
The number of effects associated with compensatory action in the whole organism. For example, an increase in heart rate soon under the influx of norepinephrine cannot be registered in the whole organism, as a result of a sharp movement of the arterial pressure triggers reversal regulation, which leads to bradycardia.
Possibility of achieving maximum effect. For example, the negative chronotropic effect cannot be applied to the whole organism to the core.

Vaccination of these organs and isolated organs may be limited.

Destruction of fabrics during preparation.
Loss of physiological control over the function of the isolated organ.
Non-physiological dovkilla.

With equal activity of different liquids, some parts of the network are not present.

Cellular cultures, as well as isolated internal cell structures (plasma membrane, endoplasmic reticulum and lysosomes) are often isolated from isolated organs for the transplantation of human cells. The “more granular” the experimental object is, the more difficult it is to further extrapolate experimental data to a whole organism.