Toxicity manifests itself and can be studied only in the process of interaction between a chemical substance and a biological system (cell, isolated organ, organism, population).

The formation and development of reactions of a biosystem to the action of a toxicant, leading to its damage (i.e., violation of its functions, viability) or death, is called a toxic process.

The mechanisms of formation and development of the toxic process, its qualitative and quantitative characteristics, are primarily determined by the structure of the substance and its effective dose (Fig. 1).

Rice. 1. Main characteristics of toxic action

However, the forms in which the toxic process manifests itself undoubtedly also depend on the type of biological object and its properties.

External signs called manifestations toxic process. In a number of the definitions of toxicology mentioned above, there is a view that the only form of manifestation of the toxic process is intoxication (poisoning). Intoxication is indeed the main and most studied, but far from the only form.

Manifestations of a toxic process are primarily determined by the level of organization of a biological object, on which the toxicity of a substance (or the consequences of its toxic action) is studied:

§ cellular;

§ organ;

§ organismic;

§ population.

If the toxic effect is studied at the cell level(usually in in vitro experiments), then the cytotoxicity of the substance is judged. Cytotoxicity is detected by the direct action of the compound on the structural elements of the cell.

The toxic process at the cellular level is manifested:

Reversible structural and functional changes in the cell (change in shape, affinity for dyes, number of organelles, etc.);

premature cell death (necrosis, apoptosis);

mutations (genotoxicity).

If, in the process of studying the toxic properties of substances, their damaging effect is investigated on individual organs and systems, a judgment is made on the organ toxicity of the compounds. As a result of such studies, manifestations of hepatotoxicity, hematotoxicity, nephrotoxicity, etc. are recorded, that is, the ability of a substance, acting on the body, to cause damage to one or another organ (system). Organotoxicity is evaluated and investigated, first of all, in the process of studying the properties (biological activity, harmful effects) of new chemicals; in the process of diagnosing diseases caused by chemicals.

The toxic process on the part of an organ or system manifests itself:

functional reactions (miosis, spasm of the larynx, shortness of breath, short-term drop in blood pressure, increased heart rate, neutrophilic leukocytosis, etc.);

organ diseases;

neoplastic processes.

Toxic effect of substances registered on the population level, can be labeled as ecotoxic. Ecotoxic effects are usually investigated by prophylactic physicians either as routine routine surveillance or as part of predetermined studies.

Ecotoxicity at the population level manifests itself:

· an increase in morbidity, mortality, the number of congenital developmental defects, a decrease in the birth rate;

· Violation of the demographic characteristics of the population (correlation of ages, sexes, etc.);

· the fall in the average life expectancy of the members of the population, their cultural degradation.

Of particular interest to the doctor are the forms of the toxic process that are detected at the level of the whole organism. They are also multiple, and can be classified as follows:

Ø intoxication - diseases of chemical etiology;

Ø Transient toxic reactions - quickly passing, not threatening health conditions, accompanied by a temporary disability (for example, irritation of the mucous membranes);

Ø Allobiotic states - coming on impact chemical factor change in the body's sensitivity to infectious, chemical, radiation, other physical effects and psychogenic stress (immunosuppression, allergization, tolerance to a substance, asthenia, etc.);

Ø Special toxic processes - non-threshold processes with a long latent period that develop in a part of the exposed population under the action of chemicals, as a rule, in combination with additional factors (for example, carcinogenesis).

Intoxication (poisoning)

Of all the manifestations of the toxic process, the most studied and significant for the doctor is intoxication. The mechanisms of formation and features of the course of intoxications depend on the structure of poisons, their doses, conditions of interaction with the body, etc. However, there are some General characteristics this form of toxic process.

1. Depending on the duration of the interaction chemical and body intoxication can be acute, subacute and chronic.

acute called intoxication, which develops as a result of a single or repeated action of substances for a limited period of time (usually up to several days).

Subacute called intoxication, which develops as a result of continuous or intermittent (intermittent) action of a toxicant lasting up to 90 days.

Chronic called intoxication, which develops as a result of prolonged (sometimes years) action of a toxicant.

The concept of acute, subacute, chronic intoxication should not be confused with the acute, subacute, chronic course of a disease that has developed as a result of contact with a substance. Acute intoxication with certain substances (mustard gas, lewisite, dioxins, halogenated benzofurans, paraquat, etc.) may be accompanied by the development of a long-term (chronic) pathological process.

2. periods of intoxication.

As a rule, during any intoxication, four main periods can be distinguished: the period of contact with the substance, the latent period, the peak period of the disease, and the recovery period. Sometimes the period of complications is especially distinguished. The severity and duration of each of the periods depends on the type and properties of the substance that caused intoxication, its dose and the conditions of interaction with the body.

3. Depending from localization pathological process manifestations of intoxication can be local and general.

Local called manifestations in which the pathological process develops directly at the site of application of the poison. Possible local damage to the eyes, skin, respiratory tract and lungs, various areas of the gastrointestinal tract. Local action can be manifested by tissue alteration (the formation of inflammatory-necrotic changes - the action of acids and alkalis on the skin and mucous membranes; mustard gas, lewisite on the eyes, skin, mucous membranes of the gastrointestinal tract, lungs, etc.) and functional reactions (pupil constriction under the action of organophosphorus compounds on the organ of vision).

General manifestations are called manifestations in which many organs and systems of the body are involved in the pathological process, including those remote from the place of application of the toxicant. The causes of general intoxication, as a rule, are: resorption of the toxicant into the internal environment, resorption of the decay products of the affected integumentary tissues, reflex mechanisms.

If any organ or system has a low threshold of sensitivity to a toxicant, in comparison with other organs, then under certain dose effects, selective damage to this particular organ or system is possible. Substances to which the sensitivity threshold of a particular organ or system is significantly lower than other organs are sometimes referred to as selectively acting. In this regard, such terms are used as: neurotoxicants, nephrotoxicants, hapatotoxicants, pulmonotoxicants, etc.

In most cases, poisonings are of a mixed nature, and are accompanied by signs of both local and general plan.

4. Depending on impact intensity toxicant (a characteristic determined by the dose-time features of the action), intoxication can be severe, moderate and mild.

Severe intoxication- a life-threatening condition. The extreme form of severe intoxication is fatal poisoning.

Moderate intoxication- a disease in which a long course is possible, the development of complications, irreversible damage to organs and systems, leading to disability or disfigurement of the victim.

Light intoxication- ends with a complete recovery within a few days.

Concentration of toxicants in biota components, due to its analytical accessibility and the possibility of a simple quantitative expression of the effect, it is often considered as an ecotoxicological response to environmental pollution. However, the fate of a biological system is ultimately determined not by the levels of its contamination, but by how pronounced the deviations of the main population and biocenotic characteristics are due to the toxic load.

Despite the fact that until now a single concept " population"does not exist, we will adhere to the opinion that as such a stable group of individuals united territorially, having a single life cycle, and in relation to organisms with cross fertilization - a single gene pool, to some extent reproductively isolated from other similar groups and having the ability to homeostasis in changing environmental conditions. As an ecotoxicological reaction of systems at the population level, we consider the effects of direct toxic effects and effects mediated (modified) by population mechanisms and the natural environment.

Direct toxic effects. It is obvious that the signs of damage caused by the accumulation of toxicants in mammalian organisms and considered in detail within the framework of toxicology should occur not only in mammals from natural populations, but also with certain specificity in other objects of the biota. To the greatest extent, such effects of direct toxic effects can be distinguished at the molecular and cellular-tissue levels of functioning. biological systems. This is due to the fact that in the presence of powerful endogenous homeostatic mechanisms, suborganismal indicators are the least affected by changing living conditions. It is also important that at present there are well-developed quantitative methods for diagnosing such deviations.

One of the clearest indicators direct toxic effect are biochemical changes that are most specific to the effects of specific toxicants. It is known from toxicology that the intake of many xenobiotics into the organisms of warm-blooded animals stimulates the generation of reactive oxygen species. In violation or overload of the molecular mechanisms of inactivation of these radicals, it is possible to enhance the processes of free radical oxidation and the accumulation of products of lipid peroxidation.

The blocking of these processes is carried out due to endogenous antioxidants- vitamins A and E. The accumulation of products of lipid peroxidation by warm-blooded animals under conditions of toxic environmental pollution is associated with this depletion of endogenous protector resources. The consequence of this is a violation of the structure of biomembranes and enzymatic systems of xenobiotic metabolism, i.e. manifestation of signs of intoxication. Most clearly, biochemical disorders can be diagnosed in animals that constantly live in conditions of toxic exposure.

It has been shown, for example, that in the liver of great tit chicks in the contaminated zones, the intensity lipid peroxidation almost twice as high as in clean areas. A similar picture is in the pied flycatcher. The noted levels correlate well with the accumulation of lead, zinc, copper in the skeleton of the chicks. For the same species, a significant, almost twofold decrease in the levels of vitamins E and A in the liver of chicks in contaminated areas was noted. The latter indicators also correlate with the content of heavy metals in organisms.

Evaluating such direct toxic effects, it must be borne in mind that the discussed indicators are recorded in organisms living in natural conditions. This means that individual individuals with the maximum manifestation of signs of intoxication, which for this reason do not meet the stringent requirements of the environment, can be eliminated from the population. In contrast to laboratory or vivarium experiments, the analyzed samples in this case reflect the result of selection determined both by intrapopulation mechanisms and by the quality of the habitat. In this regard, the cited data are most successful for nestlings, since the mentioned selection factors in the nesting period in birds are expressed to the least extent.

There are numerous information obtained, among other things, on other objects, according to which it is possible to diagnose a wide variety of signs of damage (biochemical, physiological, functional, etc.) caused by direct toxic effects. However, in any case, the natural environment acts as a kind of filter that corrects these indicators. That is why, in contrast to laboratory experiments in natural conditions, at equal levels of toxic load with laboratory levels, determined by the content of toxic substances in objects environment, it is often not possible to diagnose the presence of specific direct toxic signs in animals.

Let's take another example illustrating what has been said. It is known that most pollutants of the natural environment lead to the manifestation in animals of clearly expressed signs of damage to both the peripheral and the central nervous system. Neurotoxic manifestations are observed, as a rule, at low levels of exposure, preceding other clinical signs. Certain neuropsychic shifts that manifest themselves in this case, expressed in a change in the rate of reaction to an external stimulus and in the behavior of animals, lead not only to a change in the zoosocial status of the animal, but also to an inadequate reaction of animals to danger. This was shown in deer hamsters, when animals poisoned with dieldrin sharply reduced their reaction to the appearing shadow of a predator. For this reason, such animals should be predominantly eliminated from the population.

Despite the obvious in these cases direct conditionality of toxic effects the intake of pollutants into animal organisms, the discussed indicators cannot be considered as effects of the supraorganismal level, i.e. strictly speaking, ecotoxicological effects. Rather different. The ecotoxicological response of the system will be determined not so much by the severity of biochemical or other deviations, but by the changes in the structure of the population caused by them due, for example, to a decrease in the number of groups of organisms most sensitive to toxicants.

The toxicity of substances from the group depends on their chemical composition, the amount affecting the body, the route of entry, the mechanisms and duration of action, environmental conditions, sensitivity, the initial state of the body and a number of other factors.

Types of toxicity

Separate acute and chronic toxicity of substances, thus determining their effect on the body and the danger to humans. In plant protection, they are mainly used with acute toxicity, which provides quick effect against harmful organisms. In special cases where the use of large quantities poses a risk to beneficial organisms and humans, use their chronic toxicity by introducing small amounts of poisonous substances into the baits and updating these baits every day for a week (for example, the use of blood anticoagulants -).

Factors affecting toxicity

For various organisms, a measure of toxicity is a dose - the amount of a poisonous substance per unit of measurement of an object that causes a certain effect. It is expressed in units of mass relative to the unit mass of the treated object (µg/g, mg/kg), volume (concentration in µg/ml, mg/l) or per object (µg/individual). When assessing the toxicity of a particular substance, the general biological law of the development of living beings is always taken into account: the viability of a species is determined by the degree of heterogeneity of its population. Based on this, the assessment is carried out using a certain number of organisms and according to some average indicator. The most commonly used dose is 50% effect (inhibition of some vital process) or 50% death of experimental organisms. In the first case, such a dose is referred to as an effective dose of ED 50, in the second it is called lethal, or SD 50 or 50. These indicators are also used to determine the degree of population resistance to and selectivity of action on certain types of organisms.

In accordance with modern ideas about poisons, any chemical agent, after entering the body, must interact with a certain chemical receptor, which is responsible for the passage of a vital biochemical reaction. Such a receptor is called a "site of action". The toxicity of a substance for the body will depend on how much poison has reached the site of action, how strongly and for how long the biochemical reaction is blocked, and also what is the significance of this reaction for the life of the organism. For this reason, any factor that affects the processes of entry of a substance into the body, its "behavior" in it and interaction with the receptor causes a change in toxicity.

Also, the toxicity of a substance to a living organism depends on the dose of the toxicant and the duration of exposure. In a certain range, with increasing dose and exposure, the effect increases proportionally.

The duration of exposure to the greatest extent depends on the chemical, thermal stability and photostability, as well as on the volatility of the substance. Chemically resistant and low-volatile substances remain on plants and in the soil for a long time. The effectiveness and duration of action of synthetic pyrethroids is largely determined by their photostability.

Of the environmental conditions, the greatest influence on toxicity is exerted by temperature. Under its influence, it is possible to change the activity of both the substance itself and the reaction of the body. With increasing temperature, losses from the treated surface increase, but its toxicity can simultaneously increase, for example, with the formation of more toxic substances (transition of thione isomers to thiol ones). At the same time, under conditions of optimal temperature, the body becomes more sensitive to a toxic substance due to increased metabolic processes.

All soil factors that affect soil retention will have an impact on drug toxicity. With increasing content organic matter and silty particles in the soil, the sorption by the soil complex sharply increases. As a result, the amount of the substance in the soil solution decreases, its efficiency decreases and, as a result, the consumption rate has to be increased.

The toxicity of the poison also depends on the rate of active or passive diffusion of substances through various tissues. The higher the penetration rate, the greater the toxicity of the compound, since the opportunities for it and deposition are reduced. Many organisms also have internal structural barriers that prevent toxic substances from reaching vital centers.

The toxicity of a poison that has penetrated to the site of action depends on the degree of similarity between the toxin molecule and the receptor molecule. The need for such a similarity of molecules is confirmed by the fact that the toxicity of many substances depends on the structure of the molecule and the spatial arrangement of atoms. The insecticidal activity of synthetic pyrethroids depends on the amount of active stereoisomers in the preparation. Such a dependence was noted for fungicides from the group of triazoles (metalaxyl), y-derivatives of aryloxyphenoxypropionic acid, etc.

Toxicity indicators

As already mentioned, a universal measure of toxicity for harmful organisms is the dose of a poisonous substance - the amount of a drug that causes a certain effect. It is usually expressed in units of mass relative to the mass unit of the harmful organism (in milligrams per kilogram).

Toxicity indicators are indicated by letter symbols indicating the magnitude of the effect:

• DM (lethal dose) = (

Pathological(from Greek patos - pain, sickness) a condition that develops as a result of the interaction of a harmful substance (poison) with the body is called intoxication or poisoning.

Intoxication (toxicosis)- a pathological condition associated with a violation of chemical homeostasis due to the interaction of various biochemical structures of the body with toxic substances of exogenous or endogenous (formed inside the body) origin.

The term "intoxication" refers to the entire process of development of toxicosis from its very initial symptoms to the full clinical picture of the disease, the content of which depends on the physiological role of the main toxicity receptors, i.e. certain biochemical structures with which this toxicant (poison) selectively interacts.

In accordance with the terminology adopted in Russia, exogenous intoxications caused by xenobiotics are usually called poisoning, in contrast to endogenous intoxications associated with the accumulation in the body of toxic substances of its own metabolism (autointoxication).

Toxicity - property of a substance that causes a violation of biochemical processes and physiological functions of the body.

Toxicity is characterized by the amount of a substance that causes a damaging effect, and the nature of the toxic effect on the human or animal body. The nature of the toxic action means:

• 1. The mechanism of toxic action.
• 2. The nature of pathophysiological processes and the main symptoms of the lesion that arose after the defeat of the biotarget.
• 3. Dynamics of development of toxic action in time.
• 4. Other aspects of the toxic effect of the substance on the body.

There are three concepts of toxic dose:

• 1. Therapeutic therapeutic dose - the dose of a substance that produces a specific therapeutic effect.
• 2. Toxic dose - a dose of a substance that causes pathological changes in the body that do not lead to death.
• 3. Lethal (lethal) dose - the dose of a substance that causes the death of an organism.

Toxicity is characterized by the dose of a substance that causes a certain degree of poisoning. If a person of mass G(kg) inhales air with a concentration of C (mg / l) in it of a harmful substance (poison) over time t(min) at the intensity of breathing V(l / min), then the specific absorbed dose of a harmful substance (the amount of a harmful substance that has entered the body), Dya(mg/kg), will be equal to

The German chemist F. Gaber proposed to simplify this expression. He made the assumption that for people or a particular species of animals that are in the same conditions, the ratio V/G constantly, thus it can be excluded when characterizing the inhalation toxicity of a substance, and received the expression T=Ct(mgh min/l).

Work Ct Gaber called the indicator (coefficient) of toxicity and took it for constant value(see ch. 3.7).

For inhalation poisoning, the dose D = ct, where C is the concentration of vapor or aerosol in mg / m 3, t- inhalation time in min.

If affected by other routes (through the gastrointestinal tract, skin, intravenously, intramuscularly, etc.), the dose D is estimated by the amount of substance in mg per 1 kg of live weight (in case of skin damage - in mg / cm 2).

Distinguish toxicity parameters:

• 1. Average lethal (average lethal) doses, causing the death of 50% of experimental animals with a certain method of administration:
  • a) CZ, 5 o (JlK 5 o) - with inhalation poisoning;
  • b) /) 1 5 o (LD 5 o) - with other types of exposure (inside, on the skin, etc., except for inhalation).
• 2. Absolute lethal (lethal) doses, causing the death of 100% of experimental animals:
  • a) CLioo(JIKioo) - in case of inhalation poisoning;
  • b) DGyuoShDyuo) - with other types of exposure.

All those substances in which the LD is low are considered toxic. Yes, at

classic poisons - potassium cyanide and strychnine LD io is 10 and 0.5 mg / kg. Much less LD in chemical warfare agents (sarin, zaman, etc.) and some natural toxins of plant origin (toxins of curare, botulism and diphtheria).

• 3. Threshold doses, causing obvious, but reversible changes in the vital signs of the body:
  • a) RSyu (PKyu) - in case of inhalation poisoning;
  • b) Rdo(PDyu) - for other types of exposure.

The number in the index (0) shows the probability (in%) of the appearance of signs of poisoning. Threshold doses are determined in rabbits (during inhalation), rats (by changing the blood picture) and humans (by smell, effect on the bioelectric activity of the brain). The harmful effects of chemicals on humans always begin at a threshold concentration.

Toxodose- amount of toxic substance. Toxicity \u003d 1 / tox-sodose.

FROM the purpose of quantifying toxicity in toxicology uses certain categories of toxic doses (Table 2.1)

Table 2.1

	Toxodoses for various routes of entry of substances into the body		Toxo effects
	Intravenously through the digestive organs	Through the respiratory organs
1. Median lethal	ld 50		Death of 50% of those affected
2. Absolute lethal	ld 95		Death of 90-100% of those affected
3. Maximum non-lethal	ld 5		Death 0-10% affected
4. Median incapacitating			Disabling 50% of those affected
5. Threshold median			Initial symptoms of damage in 50% of victims
6. Maximum allowable	MPC (prev, allowable number of doses)	MPC (prev. allowable conc.)	No symptoms of injury

To quantify the toxicity of substances, the values ​​are used median effective toxodosis(ED 50), causing certain effects in 50% of experimental animals (affected). AU 50 - first letters of words Effective dose- effective dose. In the case of lethal substances, when the "effect" is estimated by the death of animals, the values ​​are used LD 50 and IC/50 (L from the word letholis- lethal), and when assessing the incapacitation - the magnitude Yu 50 and ICts o (I from the word Incapacitating- disabling), etc. (see Table 2.1).

LD 5 o and LCt 5 o - is the value of the average dose, after which it enters the stomach, abdominal cavity, on the skin within three days, the death of 50% of the experimental animals occurs. Sometimes to determine LD 50 and LCtso experimental animals are observed for not three, but 14 days.

Median Effective doses are statistically more significant compared to other categories of toxodosis ( ED 5 , ED 95, etc.) and in this respect it is more correct to indicate, for example, a dose equal to 2ED 50 , how EDm.

When determining EDso(LDso) the dependences of the effect-dose are studied according to experimental data, which are analyzed using statistical methods usually using probit analysis.

The use of the probit method is based on two assumptions:

• 1. The probabilities of the distribution of bioresponses in toxicological and pharmacological experiments usually follow the law of a log-normal distribution.
• 2. Bioresponse probabilities are estimated using probit values ​​(rather than percentages, as is often done in practical work toxicologists); pierced (from English, probability units) are the probabilistic quantities proposed by Bliss and Gaddem (hence the name: the probit method). The use of probits allows one to analyze the dependences of bioresponses on the logarithms of doses in a linear form:

pierced = a + big D in a wide range of bioresponses from 0.1 to 99.9% (see tables 2.2 and 2.3).

Coefficients of the equation "a" and "b", essentially characterize the sensitivity of animals to a given substance in a given type of application. The probit values ​​for the bioresponses observed in the experiment are found from tables or calculated analytically.

Statistical processing of experimental data is carried out on computers using special programs (Finney and others). In this case, mean square errors are calculated and confidence intervals EDsq(LD 5Q) and other categories of toxodosis. The values ​​of the tangents of the slope angles of the probit lines ( b), in essence, determine the relationship of various categories of toxodosis.

Table 2.2

Converting interest to punched

Table 2.3

Coefficient valuesa, b andP in the fatal injury formula

Substance
Acrolein
acrolonitrite
Carbon monoxide
carbon tetrachloride
Formaldehyde
Hydrochloric acid
Hydrocyanic acid
Hydrofluoric acid
hydrogen sulfide
Methyl bromide
Methyl isocyanate
Nitrogen oxide
propylene oxide
sulphur dioxide

Thus, the values ​​of the tangents of the slopes of the probit lines, which reflect changes in the probability of effects with changes in the values ​​of toxodoses (logarithm of toxodoses), along with median toxodoses, are important in assessing the toxic effect of a substance.

For example, in the event of an accident at a chemically hazardous facility, the degree of damage to people is obtained using a probabilistic approach to determining the damaging factor R then by probit function Rg as

where a, b and P- constants for each specific OHV (Table 2.3.), t - time of exposure to a hazardous chemical, min; C - concentration of OHV at a specific point of the infection zone, ppm, related to the concentration of the substance in mg / l by the ratio

where Сppt, Сmg/l - the concentration of a hazardous chemical, expressed in ppm and mg/l, respectively; t- air temperature, °С; M- molecular weight of the hazardous chemical, kg/kmol; R - air pressure, mm Hg Art.

Toxicity (from the Greek. toxikon - poison) - poisonousness, the property of certain chemical compounds and substances of a biological nature, when they enter a living organism (human, animal and plant) in certain quantities, cause violations of its physiological functions, resulting in symptoms of poisoning (intoxication, disease), and in severe cases, death.

A substance (compound) that has the property of toxicity is called a toxic substance or poison.

Toxicity is a generalized indicator of the body's response to the action of a substance, which is largely determined by the characteristics of the nature of its toxic effect.

The nature of the toxic effect of substances on the body usually means:

• o the mechanism of the toxic action of the substance;
• o the nature of pathophysiological processes and the main symptoms of damage that occur after the defeat of biotargets;
• o dynamics of their development in time;
• o other aspects of the toxic effect of the substance on the body.

Among the factors that determine the toxicity of substances, one of the most important is the mechanism of their toxic action.

The mechanism of toxic action is the interaction of a substance with molecular biochemical targets, which is a trigger in the development of subsequent intoxication processes.

The interaction between toxic substances and a living organism has two phases:

• 1) the effect of toxic substances on the body - the toxicodynamic phase;
• 2) the action of the organism on toxic substances - the toxicokinetic phase.

The toxicokinetic phase, in turn, consists of two types of processes:

• a) distribution processes: absorption, transport, accumulation and release of toxic substances;
• b) metabolic transformations of toxic substances - biotransformation.

The distribution of substances in the human body depends mainly on the physicochemical properties of substances and the structure of the cell as the basic unit of the body, in particular the structure and properties of cell membranes.

An important provision in the action of poisons and toxins is that they have a toxic effect when exposed to the body in small doses. Very low concentrations of toxic substances are created in target tissues, which are commensurate with the concentrations of biotargets. High rates of interaction of poisons and toxins with biotargets are achieved due to the high affinity for the active centers of certain biotargets.

However, before "hitting" the biotarget, the substance penetrates from the place of application into the system of capillaries of blood and lymphatic vessels, then it is carried by the blood throughout the body and enters the target tissues. On the other hand, as soon as the poison enters the blood and tissues of the internal organs, it undergoes certain transformations, which usually lead to detoxification and "expenditure" of the substance for the so-called non-specific ("side") processes.

One of the important factors is the rate of penetration of substances through cell-tissue barriers. On the one hand, this determines the rate of penetration of poisons through tissue barriers separating blood from the external environment, i.e. the rate of entry of substances through certain routes of penetration into the body. On the other hand, this determines the rate of penetration of substances from the blood into the target tissues through the so-called histohematic barriers in the area of ​​the walls of the blood capillaries of the tissues. This, in turn, determines the rate of accumulation of substances in the area of ​​molecular biotargets and the interaction of substances with biotargets.

In some cases, the rate of penetration through cell barriers determines the selectivity in the action of substances on certain tissues and organs. This affects the toxicity and nature of the toxic effect of substances. Thus, charged compounds penetrate poorly into the central nervous system and have a more pronounced peripheral effect.

In general, in the action of poisons on the body, it is customary to distinguish the following main stages.

• 1. The stage of contact with the poison and the penetration of the substance into the blood.
• 2. The stage of transport of a substance from the place of application by blood to target tissues, distribution of the substance throughout the body and metabolism of the substance in the tissues of internal organs - the toxic-kinetic stage.
• 3. The stage of substance penetration through histohematic barriers (capillary walls and other tissue barriers) and accumulation in the area of ​​molecular biotargets.
• 4. The stage of interaction of a substance with biotargets and the occurrence of disturbances in biochemical and biophysical processes at the molecular and subcellular levels - the toxic-dynamic stage.
• 5. The stage of functional disorders of the organism of the development of pathophysiological processes after the "defeat" of molecular biotargets and the onset of symptoms of damage.
• 6. The stage of relief of the main symptoms of intoxication that threaten the life of the affected person, including the use of medical protective equipment, or the stage of outcomes (with fatal toxodoses and untimely use of protective equipment, the death of the affected is possible).

Dose is a measure of the toxicity of a substance. The dose of a substance that causes a certain toxic effect is called the toxic dose (toxodose). For animals and humans, it is determined by the amount of a substance that causes a certain toxic effect. The lower the toxic dose, the higher the toxicity.

Due to the fact that the reaction of each organism to the same toxodose of a particular toxic substance is different (individual), then the severity of poisoning in relation to each of them will not be the same. Some may die, others will be injured in varying degrees of severity or not at all. Therefore, toxodose (D) is considered as random value. It follows from the theoretical and experimental data that the random variable D is distributed according to a logarithmically normal law with the following parameters: D - the median value of toxodose and the dispersion of the logarithm of toxodose - . In this regard, in practice, to characterize toxicity, median values ​​​​of relative, for example, to the mass of the animal, toxodose (hereinafter toxodose) are used.

Poisoning caused by the intake of poison from the human environment is called exogenous, in contrast to endogenous intoxications with toxic metabolites that can form or accumulate in the body in various diseases, often associated with impaired function of internal organs (kidneys, liver, etc.). In the toxigenic (when the toxic agent is in the body at a dose capable of exerting a specific effect) phase of poisoning, two main periods are distinguished: the resorption period, which lasts until the maximum concentration of the poison in the blood is reached, and the elimination period, from the specified moment until the blood is completely cleansed of the poison . The toxic effect may occur before or after the absorption (resorption) of the poison into the blood. In the first case, it is called local, and in the second - resorptive. There is also an indirect reflex effect.

With "exogenous" poisoning, the following main routes of entry of poison into the body are distinguished: oral - through the mouth, inhalation - when toxic substances are inhaled, percutaneous (cutaneous, in military affairs - skin-resorptive) - through unprotected skin, injection - with parenteral administration of poison , for example, with snake and insect bites, cavitary - when poison enters various cavities of the body (rectum, vagina, external auditory canal, etc.).

Table values ​​of toxodoses (except for inhalation and injection routes of penetration) are valid for an infinitely large exposure, i.e. for the case when extraneous methods do not stop the contact of a toxic substance with the body. In reality, for the manifestation of one or another toxic effect of the poison, there must be more than those given in the toxicity tables. This amount and the time during which the poison must be, for example, on the skin surface during resorption, in addition to toxicity, is largely due to the rate of absorption of the poison through the skin. So, according to US military experts, the chemical warfare agent Vigas (VX) is characterized by a skin-resorptive toxodose of 6-7 mg per person. For this dose to enter the body, 200 mg VX liquid drip must be in contact with the skin for about 1 hour, or approximately 10 mg for 8 hours.

It is more difficult to calculate toxodoses for toxic substances that contaminate the atmosphere with steam or fine aerosol, for example, in case of accidents at chemically hazardous facilities with the release of emergency chemically hazardous substances (AHOV - according to GOST R 22.0.05-95), which cause damage to humans and animals through the respiratory system .

First of all, they make the assumption that the inhalation toxodose is directly proportional to the concentration of hazardous chemicals in the inhaled air and the breathing time. In addition, it is necessary to take into account the intensity of breathing, which depends on the physical activity and the condition of the person or animal. In a calm state, a person takes about 16 breaths per minute and, therefore, on average absorbs 8-10 l / min of air. With moderate physical activity (accelerated walking, march) air consumption increases to 20-30 l/min, and with heavy physical activity (running, excavation) it is about 60 l/min.

Thus, if a person of mass G (kg) inhales air with a concentration of C (mg / l) in it of AHOV during time τ (min) at a breathing rate of V (l / min), then the specific absorbed dose of AHOV (the amount of AHOV that got into into the body) D(mg/kg) will be equal to

The German chemist F. Gaber proposed to simplify this expression. He made the assumption that for humans or a particular species of animals under the same conditions, the ratio V/G is constant, thus it can be excluded when characterizing the inhalation toxicity of a substance, and received the expression K=Cτ (mg min/l). Haber called the product Cτ the toxicity coefficient and took it as a constant value. This work, although not a toxodose in the strict sense of the word, makes it possible to compare various toxic substances by inhalation toxicity. The smaller it is, the more toxic the substance during inhalation action. However, this approach does not take into account a number of processes (exhalation of a part of the substance back, neutralization in the body, etc.), but nevertheless, the Cτ product is still used to assess inhalation toxicity (especially in military affairs and civil defense when calculating possible losses troops and the population under the influence of chemical warfare agents and hazardous chemicals). Often this work is even incorrectly called toxodose. The name of relative toxicity by inhalation seems to be more correct. In clinical toxicology, to characterize inhalation toxicity, preference is given to the parameter in the form of a concentration of a substance in the air, which causes a given toxic effect in experimental animals under conditions of inhalation exposure at a certain exposure.

The relative toxicity of OM during inhalation depends on the physical load on the person. For people engaged in heavy physical work, it will be much less than for people who are at rest. With an increase in the intensity of respiration, the speed of the OF will also increase. For example, for Sarin with pulmonary ventilation of 10 L/min and 40 L/min, the LCτ 50 values ​​are about 0.07 mg·min/L and 0.025 mg·min/L, respectively. If for the phosgene substance the product Cτ of 3.2 mg min/l at a respiratory rate of 10 l/min is moderately lethal, then with pulmonary ventilation of 40 l/min it is absolutely lethal.

It should be noted that the tabular values ​​of the constant Сτ are valid for short exposures, at which Сτ = const. When inhaling contaminated air with low concentrations of a toxic substance in it, but for a sufficiently long period of time, the value of Сτ increases due to the partial decomposition of the toxic substance in the body and incomplete absorption by the lungs. For example, for hydrocyanic acid, the relative toxicity during inhalation of LCτ 50 ranges from 1 mg · min / l for its high concentrations in the air to 4 mg · min / l when the concentrations of the substance are low. The relative toxicity of substances during inhalation also depends on the physical load on the person and his age. For adults, it will decrease with increasing physical activity, and for children - with decreasing age.

Thus, the toxic dose that causes damage equal in severity depends on the properties of the substance, the route of its penetration into the body, the type of organism and the conditions for using the substance.

For substances penetrating the body in a liquid or aerosol state through the skin, gastrointestinal tract, or through wounds, the damaging effect for each specific type of organism under stationary conditions depends only on the amount of poison that has penetrated, which can be expressed in any mass units. In toxicology, the amount of poison is usually expressed in milligrams.

The toxic properties of poisons are determined experimentally on various laboratory animals, therefore, the concept of specific toxodose is often used - a dose related to a unit of animal live weight and expressed in milligrams per kilogram.

The toxicity of the same substance, even when it enters the body in one way, is different for different animal species, and for a particular animal it differs markedly depending on the method of entry into the body. Therefore, after the numerical value of the toxodose, it is customary to indicate in brackets the type of animal for which this dose is determined, and the method of administration of the agent or poison. For example, the entry: "sarin D death 0.017 mg/kg (rabbits, intravenous)" means that a dose of the substance sarin 0.017 mg/kg injected into a rabbit's vein causes death in him.

It is customary to subdivide toxodoses and concentrations of toxic substances depending on the severity of the biological effect they cause.

The main indicators of toxicity in the toxicometry of industrial poisons and in emergency situations are:

Lim ir - the threshold of irritating action on the mucous membranes of the upper respiratory tract and eyes. It is expressed by the amount of a substance that is contained in one volume of air (for example, mg / m 3).

A lethal or lethal dose is the amount of a substance that causes death with a certain probability when it enters the body. Usually they use the concepts of absolutely lethal toxodosis, causing the death of the body with a probability of 100% (or the death of 100% of those affected), and medium-lethal (slow-fatal) or conditionally fatal toxodosis, the lethal outcome from the introduction of which occurs in 50% of the affected. For example:

LD 50 (LD 100) - (L from lat. letalis - lethal) medium lethal (lethal) dose that causes the death of 50% (100%) of experimental animals when the substance is injected into the stomach, into the abdominal cavity, onto the skin (except for inhalation) under certain conditions of administration and a specific follow-up period (usually 2 weeks). It is expressed as the amount of a substance per unit body mass of the animal (usually mg/kg);

LC 50 (LC 100) - average lethal (lethal) concentration in the air, causing the death of 50% (100%) of experimental animals upon inhalation exposure to a substance at a certain exposure (standard 2-4 hours) and a certain follow-up period. As a rule, the exposure time is specified additionally. Dimension as for Lim ir

The incapacitating dose is the amount of a substance that, when ingested, causes the failure of a certain percentage of those affected, both temporarily and fatally. It is designated ID 100 or ID 50 (from the English incapacitate - disable).

Threshold dose - the amount of a substance that causes the initial signs of damage to the body with a certain probability or, what is the same, the initial signs of damage in a certain percentage of people or animals. Threshold doses are designated PD 100 or PD 50 (from English primary - initial).

KVIO - coefficient of possibility of inhalation poisoning, which is the ratio of the maximum achievable concentration of a toxic substance (C max, mg / m 3) in the air at 20 ° C to the average lethal concentration of the substance for mice (KVIO = C max / LC 50). The value is dimensionless;

MPC - maximum allowable concentration of a substance - the maximum amount of a substance per unit volume of air, water, etc., which, with daily exposure to the body for a long time, does not cause pathological changes in it (deviations in the state of health, disease) detected by modern research methods in the process life or remote periods of life of the present and subsequent generations. There are MPC of the working area (MPC r.z, mg / m 3), maximum one-time MPC in the atmospheric air of populated areas (MPC m.r, mg / m 3), average daily MPC in the atmospheric air of populated areas (MPC s.s, mg / m 3), MPC in the water of reservoirs of various water uses (mg / l), MPC (or permissible residual amount) in food (mg / kg), etc .;

OBUV - an approximate safe level of exposure to the maximum allowable content of a toxic substance in the atmospheric air of populated areas, in the air of the working area and in the water of reservoirs for fishery water use. There are additionally TAC - the approximate allowable level of a substance in the water of reservoirs for household water use.

In military toxicometry, the most commonly used indicators are relative median values ​​of average lethal (LCτ 50), medium excretory (ICτ 50), average effective (ECτ 50), average threshold (PCτ 50) inhalation toxicity, usually expressed in mg min / l, as well as median values ​​of skin-resorptive toxodoses similar in toxic effect LD 50 , LD 50 , ED 50 , PD 50 (mg/kg). At the same time, toxicity indicators during inhalation are also used to predict (estimate) the losses of the population and production personnel in case of accidents at chemically hazardous facilities with the release of toxic chemicals widely used in industry.

In relation to plant organisms, instead of the term toxicity, the term activity of a substance is more often used, and as a measure of its toxicity, the value of CK 50 is mainly used - the concentration (for example, mg / l) of a substance in solution that causes the death of 50% of plant organisms. In practice, they use the rate of consumption of the active (active) substance per unit area (mass, volume), usually kg / ha, at which the desired effect is achieved.

By their origin, toxic substances can be synthetic and natural (Tables 4.2, 4.3).

Table 4.2

Toxicity parameters of some synthetic substances

	LC 50 (mg/m 1), biological object, exposure	LCx 50 , mg min/l	PCτ 50 mg min/l		water h.-b. user, mg/m 3
AHOV inhalation action
	7600, rat, 2 h 3800, mouse, 2 h
Methyl bromide	1540, mouse, 2 h 2250, rat, 2 h
Methyl chloride	5300, rat, 4 h
Methyl mercaptan	1700, mouse, 2 h 1200, rat, 2 h
Ethylene oxide	1500, mouse, 4 h 2630, rat, 4 h
hydrogen sulfide	1200, mouse, 2 h			0,008 (m.s.)
carbon disulfide	10,000, mouse, 2 h 25,000, rat, 2 h
Hydrocyanic acid	400-700 (LC 100), people, 2-5 min
	360 (Z, C 100), people, 30 min
	1900(LC 100), dog, 30 min				Absence in water
Warfare agents

Table 4.3

Toxicity of poisons of some animals

	LD 50 , mg/kg (mice)
Sea snake Enhydrina schistosa
Tiger snake Notechis scutatus
Rattlesnake Crotalusdirissus terrificus, viper Vipera russeli and krait Bungarus cferuleus	0.08-0.09 (w/m)
Sea snakes of the genus Hydrophis and earth vipers Atractaspis	0.1-0.2 (w/br)
Cobras, many rattlesnakes
scorpions
Tiryus serrulatus
Leiurus quinquestriatus
Androctonus australis	0.5 (s/c) 0.009 (i/m)
Buthus occitanus
Opistophthalmus spp.
Coelenterates
Sea nettle Chrysaora quinquecirrha
Cornmouth jellyfish Stomolophus meleagris
Jellyfish Cyanea capillata
Anemonia sulcata
Anemone Anthopleura xanthog ram mica	0.008-0.066 (in / in)
Madrepora corals Goniopora sp.

Note. in / in - intravenously, in / m - intramuscularly, in / br - intraperitoneally, s / c - subcutaneously.

Toxins are additionally isolated from toxic substances of natural origin (Table 4.4). Usually, they include high-molecular compounds (proteins, polypeptides, etc.), when they enter the body, antibodies are produced. Sometimes low-molecular substances (for example, tetrodotoxin and other animal poisons) are also called toxins, which are more correctly classified as natural poisons.

Table 4.4

Toxicity of some toxins

Numerous studies on acute toxicity have made it possible to draw important conclusions: 1) each sample of substances with comparable molecular weights corresponds to a certain limit value of minimal toxodoses; 2) for the totality of the most toxic substances of natural and synthetic origin, there is a direct dependence of the toxicity of compounds on their molecular weights (Fig. 4.4). This allows, when carrying out scientific research predict the toxicity of compounds and choose the limits of toxodoses in toxicological experiments.

Rice. 4.4. Dependence of the toxicity of compounds on their molecular weight (M). Black circles show synthetic poisons

When determining the toxicity parameters experimentally in animals, the effect-dose relationship is examined, which is then analyzed using statistical methods (for example, probit analysis). The establishment of the toxic effect of a substance on the basis of animal experience is correct when studied on rats in no more than 35% of cases, and on dogs - in 53%. The exact values ​​of lethal doses and concentrations for humans, of course, have not been established. Therefore, when extrapolating experimental data to humans, the following rules are followed: 1) if lethal doses for the usual four types of laboratory rodents (mice, rats, guinea pigs and rabbits) differ slightly (less than 3 times), then there is a high probability (up to 70% ) that the lethal dose for humans will be the same; 2) the approximate lethal dose for humans can be found by constructing a regression line from several points in the coordinate system: a) the lethal dose for a given animal species; b) the mass of his body.

In the system of labor safety standards (GOST 12.1.007-76), according to the degree of impact on the body, all harmful substances contained in raw materials, products, intermediate products and production waste are divided into four hazard classes: 1st - extremely dangerous substances, 2nd - highly hazardous substances; 3rd - moderately dangerous substances; 4th - low-hazard substances (Table 4.5). The basis of this division is the numerical values ​​of the above indicators of the toxicity of substances.

Table 4.5

Hazard classes of harmful substances

The name of indicators	Norms for the hazard class
Maximum allowable concentration (MAC) of harmful substances in the air of the working area, mg / m 3
Mean lethal dose when injected into the stomach, mg/kg				Over 5,000
Mean lethal dose when applied to the skin, mg/kg				Over 2 500
Average lethal concentration in the air, mg / m 3				Over 50,000
Inhalation Poisoning Possibility Ratio (POI)

Note. The assignment of a harmful substance to the hazard class is carried out according to the indicator, the value of which corresponds to the highest hazard class.

Features of the nature of the toxic effect on the body are the basis for the toxicological (physiological) classification of harmful substances (poisons and toxins).

According to the impact of harmful substances are divided into groups:

• 1) substances with a predominantly asphyxiating effect (chlorine, phosgene, chloropicrin);
• 2) substances of predominantly general poisonous action (carbon monoxide, hydrogen cyanide);
• 3) substances with a suffocating and general poisonous effect (amyl, acrylonitrile, Nitric acid and nitrogen oxides, sulfur dioxide, hydrogen fluoride);
• 4) substances acting on the generation, conduction and transmission of primary impulses - neurotropic poisons (carbon disulfide, tetraethyl lead, organophosphorus compounds);
• 5) substances with asphyxiant and neurotropic effects (ammonia, heptyl, hydrazine);
• 6) metabolic (disrupting metabolism in living organisms) poisons (ethylene oxide, dichloroethane, dioxin, polychlorinated benzofurans).

When harmful substances enter the body, poisoning (intoxication) occurs. Depending on the rate of entry of harmful substances into the body, acute and chronic poisonings are distinguished.

Acute poisoning occurs with the simultaneous intake of harmful substances into the body and is characterized by an acute onset and pronounced specific symptoms. In this case, the symptoms of intoxication usually develop quickly, and the death of the body or severe consequences can occur in a relatively short time (the case of an accident with a chemical release). In some cases, despite the fact that the acute form of poisoning occurs, the symptoms of intoxication may develop slowly (for example, the effect of phosgene).

Chronic poisoning develops with prolonged, often intermittent intake of harmful substances in small doses, when the disease begins with non-specific symptoms (the case of the use of chemicals in the production).

Sometimes subacute forms of intoxication are also distinguished, which occupy, as it were, an intermediate position in terms of the duration of the effect of a substance on the body between acute and chronic lesions, when exposed to substances for hours, tens of hours and days.

In chronic and subacute forms of poisoning, cumulation occurs, i.e. accumulation in the body of either a toxic substance or the effects it causes. Accordingly, a distinction is made between material and functional cumulation, as well as mixed type cumulation.

If the substance is slowly detoxified, ie. is slowly excreted from the body, and therefore gradually accumulates in the body, then this is material cumulation, for example, during intoxication with arsenic, mercury, DDT, dioxin, etc.

The basis of functional cumulation is the summation of toxic effects, and not the substance itself. For example, under the action of phosgene, it is not the substance that accumulates, but the number of destroyed cellular elements of the lung tissue. A well-known and typical example of functional cumulation is the effect of ethyl alcohol on the body with its frequent use, when damage accumulates in the tissues of the central nervous system, liver, gonads and other organs.

Under the action of poisons, there is often a combination of material and functional cumulation - a mixed type of cumulation, for example, in the case of damage by organophosphorus substances in subacute forms of intoxication.

Thus, an important role in the dynamics of the development of intoxication is played by:

• 1. Ways of penetration of a substance into the body and the rate of entry into the blood. So, when inhaled, the symptoms of damage, as a rule, appear quickly, and when acting through the skin, the poison slowly enters the bloodstream, which is the cause of a pronounced latent period.
• 2. Ways and rates of metabolism of substances at the toxic-kinetic stage. Substances that undergo rapid detoxification in the blood and tissues usually do not have a latent period of action that is characteristic of substances that are resistant to detoxification.
• 3. The rate of penetration of substances through histohematic barriers. These speeds, as a rule, are the limiting factor in the toxic effect of macromolecular substances (polypeptides and proteins) when they penetrate from the blood stream into target tissues. This is the main reason for the long latent period in the action of bacterial toxins.
• 4. Rates of interaction of substances with biotargets. Poisons and toxins, as a rule, interact with biotargets at high speeds. The limiting factors are the rates of accumulation of substances in the area of ​​biotargets.
• 5. The functional significance of the affected biotargets and the dynamics of the development of pathological processes after the "defeat" of the biotargets. For neurotropic substances, the rapid development of symptoms of damage is characteristic, and for cytotoxic substances, it is gradual.
• 6. Conditions of exposure to the substance. A more rapid development of the symptoms of the lesion is observed, as a rule, when receiving several fatal toxodoses. In the chronic experience, the symptoms of intoxication develop more slowly than in the acute experience.