ONCOGENOUS SUBSTANCES (Greek onkos the weight, a tumor + gennao to create, make; synonym: blastomogenic substances, carcinogens, carcinogenic substances) — the substances of various chemical nature capable in pure form to cause development in an organism of tumors.
In 1775 P. Pott described cancer of chimney sweeps resulting from long pollution of skin products of fuel burning. At the end of 19 century A. N. Hanau unsuccessfully tried to cause cancer by greasing of leather of rats and dogs coal tar. In 1906 Fischer (V. of Fischer) established that introduction under skin of an ear of a rabbit of dye sharlakhrot in luccu oil can cause atipichesky growth of an epithelium in an injection site. According to a number of researchers, it is caused by chemical influence of the entered substance, according to others, e.g. V. G. Garshin, caused by inflammatory reaction. Though in these cases development of cancer was never observed, the possibility of induction of proliferation of an epithelium as a result of influence of certain chemical substances was established. In 1912 Bayonne (H. P. G. Vauop) reported about emergence of atipichesky growths of an epithelium after introduction under skin of an ear of a rabbit of coal tar. In 1914 — 1916 Yamagiva and Itikava (To. Yamagiwa, To. Ichikawa) received in nek-ry experiences atipichesky growths of an epithelium after introduction under skin of an ear of rabbits of dye sharlakhrot, drawings in these sites of small injuries and greasings by coal tar. Further in sites of atipichesky growths of an epithelium there were papillomas passing in some cases into plo-skzkletochny keratosic cancer, so-called tar cancer. G. V. Blinders and S. M. Dam-berg, H. N. Petrov and N. A. Krotkina in the 20th 20 century got cancer practically at all experimental animals at long greasing of skin coal tar. At the same time in some cases, in addition to a carcinoma cutaneum, there were tumors of lungs, mammary glands, etc. that began to be explained with a systemic effect of O. of century on an organism. At the beginning of the 30th 20 century I. Hieger noticed that nek-ry Oncogenous pitches and mineral oils fluoresce in an ultraviolet light that is characteristic of the polycyclic aromatic hydrocarbons (PAH). E. Kenneuey, I. Hieger and J. W. Cook with sotr. (1932) selected on this sign a number of PAU and among them 1,2,5,6 dibenzanthracene (DBA). Long greasing of leather of mice the DBA benzene solution was resulted at first by papillomas, and then cancer; at hypodermic administration of DBA solution sarcomas developed. In 1933 J. W. Cook and sotr. allocated from coal tar benzpyrene (see), and G. Wiland and to Dana (A. E. of Dane) synthesized metilkholantrep (see). In 1938 B. M. Mikhaylov and H. T. Chernova, Fizer and Newman (L. Fieser, M. of Newman) independently from each other synthesized 7,12 dimethylbenzanthracene (see. Dimetilbenzantratsen ).
The following stage in O.'s studying century mice and rats had a receiving experimental tumors by means of amino-azo compounds — orthoaminoazotoluene and paraaminoazobenzene. Oncogenous effect of these substances differed from action of PAU in the fact that they did not cause development of tumors on site of introduction, and induced tumors of a liver and sometimes adenoma of lungs.
Observations over professional cancer of a bladder induced to experimental studying of nek-ry cyclic amines — 2 naphthylamine, benzidine and their derivatives which are used at production of dyes. In 1938 Hyuper (W. Page of Hueper) with sotr. during the feeding to dogs 2 naphthylamines caused in them development of cancer of bladder., experimental cancer of a bladder by means of benzidine was got further. In 1941 Wilson, De Eds, Cox (R. N. Wilson, E. De Eds, And. J. Dried) revealed that 2 acetoaminofluorene — the representative of group of fluorenes — induces multiple tumors of a liver, kidneys, a bladder and other bodies at rats. In 1956. Magicians, Barnes (R. of N. Magee, J. M of Barnes) reported that nitroso compound dimethylnitrosamine causes development of tumors of a liver in rats. A large amount of nitroso compounds was described, to-rye can cause various tumors more than in 12 animal species; one of them cause tumors of a bladder, others — a gullet, a prestomach, a ferruterous stomach, a large intestine, etc. Oncogenous activity of nek-ry other chemical substances, napr, urethane, vinyl chloride, aflatoxins, etc. is shown. Urethane, e.g., causes adenomas of lungs and a tumor of a liver in mice of nek-ry closed lines.
According to L. M. Shabada and sotr. (1937), a nek-swarm similarity of chemical structure of PAU and sterols, synthesis of a metilkholantren proceeding from deoxycholic to - you, hormonal dependence of tumors of a mammary gland, prostate and nek-ry other bodies can testify to a possibility of endogenous emergence in an organism of the chemical substances having oncogenous activity. Such endogenous O.' existence was proved as a result of introduction to mice of benzene extracts of a liver onkol, the patients causing tumors in the field of introduction and in other bodies century. Substances from a class of sterols were the operating oncogenous beginning in these experiences. Oncogenous action derivatives of tryptophane (3 oxykynurenine, 3-oksiantrani-Lowai can possess to - that and other orthoaminophenols), to-rye find in blood, e.g., not less than at 50% of patients with cancer of a bladder. M. O. Raushenbakh et al. (1974) found Oncogenous derivatives of tryptophane in blood of patients with leukoses. They showed also that oncogenous action a number of metabolites of tyrosine, napr, couple-oksifon:shmolechnaya to - that possesses, the raised excretion a cut with urine is observed at all patients with leukoses and a reticulosarcoma.
The established possibility of synthesis in an organism of oncogenous nitroso compounds from nitrites, nitrates and secondary amino is important, Krom is promoted by a bacterial flora and acid reaction of the environment.
Distribution of oncogenous substances in the environment
O. century in the Wednesday surrounding the person can have a natural and artificial origin. O. for century of a natural origin such as, e.g., waste products of nek-ry fungi — mycotoxins, in particular aflatoxins, fuzariotoksina, and also pirolizidinovy alkaloids of a groundsel are known. The possibility of formation of benzpyrene as a result of volcanic activity was shown and its presence at a lava, ashes, volcanic dirt, and also tests of the soil, water and vegetation at a zone of volcanoes of Kamchatka, Sakhalin and Kuril islands is revealed. Benzpyrene is found also in deep layers of earth in a zone of permafrost. Synthesis of PAU, in particular benzpyrene, plants, napr, at germination of seeds in the conditions of addition to a medium of substances, carbonic (acetate or phosphate) can be other source of O. of century of a natural origin.
The main sources of O. of century of an artificial origin in the environment are emissions of the industrial enterprises (hl. obr. oil and uglepererabatyvayushchy, coke-chemical, metallurgical industry), heating systems and exhaust gases of internal combustion engines. The indicator of presence in the environment of PAU consider benzpyrene, to-ry it is found in a significant amount in pitches, pitches, smokes, exhaust gases and together with them in firm parts or droplets of aerosols comes to the atmosphere. Its partial destruction happens under the influence of ultraviolet rays and ozone, a part dissipates, a part settles on the earth. In the soil, especially industrial districts, find considerable concentration of PAU. At the same time in districts of old building or long ago they are higher than the existing industrial enterprises that testifies to a possibility of accumulation of O. of century in the environment. Benzpyrene in the soil passes into sublayers, at the same time the quantity it gradually decreases. Under the influence of nonspecific oxidases of soil bacteria O.'s destruction is observed century that leads to self-cleaning of the soil. At considerable pollution of the soil of PAU their quantity increases in vegetables, potatoes, cabbage, etc.
As a result of sedimentation from the atmosphere, transition from the soil and with drain waters of the enterprises, storm drains of the cities and exit gases of the PAU motorized vessels and other O. century get to reservoirs. The seas and the rivers become soiled also the oil and products of its processing containing O. century. Oncogenous substances collect in the form of a peculiar film in a surface layer, and also in organisms of fishes and mollusks, plankton, are transferred to a long distance and as well as in the soil, can collapse under the influence of physical. - chemical factors and microorganisms.
century divide O. according to their chemical structure into polycyclic aromatic hydrocarbons (see), nek-ry amines (see), azo compounds (see), nitroso compounds (see. Nitrozoamina, nitrozoamida ), carbamates (see. Carbamic connections ) and some other.
On value for the person O. of century divide into four groups. In the first group carry apprx. twenty O. century, oncogenous action to-rykh on the person is proved. Among them there is a benzidine, 2 naphthylamine, a 4-amino-diphenyl causing at hit in an organism in the doses exceeding marginal, cancer of a bladder. Various tumors also cause vinyl chloride, compounds of arsenic, chrome, nickel, nek-ry types of asbestos, etc. The second group includes the century, potentially Oncogenous for the person O., causing in big percent of cases at different ways of introduction of a tumor in several types a lab. animals. Carry many substances to them preferential from groups of nitroso compounds, polycyclic aromatic hydrocarbons, azo compounds and fluo ren. The third group is made by many hundreds of substances which showed rather weak oncogenous activity in experiments on a lab. the animal, i.e. caused tumors in small percent cases (to 30%) and in later terms. The fourth group includes substances, oncogenous action to-rykh raises doubts in connection with insufficient or contradictory experimental data.
A general characteristic of action
Oncogenous properties O. possess century of various chemical structure. Enough rather minor changes in a chemical structure of O. of century to eliminate their oncogenous action or to change its force and an orientation. So, oxidation of many PAU weakens their oncogenous activity, change of a derivative of benzidine can turn the substance causing cancer of a bladder into the substance inducing tumors of a liver, etc. The same oncogenous substance can cause development of tumors of various look and localization. E.g., benzpyrene and other PAU at hypodermic introduction cause sarcomas, and after drawing on skin — a carcinoma cutaneum and tumors of other bodies. On the other hand, the same type of a tumor can be caused by various O. century. So, primary tumor of a liver can be got in an experiment as a result of effect of aminoazo compounds (And the EXPERT), derivatives of benzidine and nek-ry nitroso compounds (NANOSECONDS) that testifies to relative specificity of action of O. of century.
In operation various O. century there is a number of common features. So, malignant tumors arise not right after the beginning of action of O. of century, and only through the certain term called by stage of latency. On average it is equal about 1/5 — 1/7 greatest life expectancies of an organism that makes, e.g., for a mouse of 4 — 6 months and 15 — 20 years for the person. At the same time malignant tumors develop, as a rule, gradually against the background of the previous pretumor changes of fabrics.
Important pattern of action of O. of century is dependence of oncogenous effect of a dose and on duration of action of O. of century. The longer and in bigger quantity O. work century, the stage of latency and zlokachestvenny the tumors induced by them is shorter. At a dose decline and time of action of O. of century the number of the arising tumors decreases and they appear later. O.'s accumulation century in fabrics, napr, at their introduction with adsorbents, strengthens oncogenous effect. Lakes of century usually do not cause inflammatory reaction, and sometimes even suppress or pervert the course of inflammatory process.
Process of transformation of O. of century in an organism with formation of active metabolites is called activation. Representatives of all groups O. of century except for only the few substances which are possessing the strong alkylating action and directly operating on cells and fabrics are exposed to activation. In the course of activation all O. century gain the expressed electrophilic properties and ability to interact with the nucleophilic centers of macromolecules of cells. PAU, as a rule, turn into the epoxides of dihydrodiols which are directly contacting proteins, nucleinic to-tami and other macromolecules of a cell. AAS and fluorenes form in the course of metabolism of N - oxycompound, to-rye turn into the karbony-cation contacting certain components of tissue of liver. 2 naphthylamine as a result of metabolism in a liver turn into 2-amino-1-naphthol and, being allocated with urine, turns in a bladder under the influence of enzyme of glucuronidase into O. century.
Distinctions in oncogenous action are explained with features of metabolism of O. of century in an organism. It is known, e.g., that AAS inducing tumors of a liver at rats and mice do not cause them in Guinea pigs or rainbow trouts, and 2 naphthylamine and benzidine causing in the person and a dog of a tumor of a bladder cause tumors of a liver in rats. The given facts show that in implementation of oncogenous effect of O. of century — in carcinogenesis (see) — an important role is played by an organism and features of a metabolism.
Specific oncogenous structure, by the general for all O. century, it is not found. Nek-ry patterns are noted in each group; e.g., introduction to a molecule of A AS group, to-rye give them water solubility, as a rule, deprives these substances of oncogenous activity. Dependence between oncogenous activity and a chemical structure of PAU was connected with positions 5,6 or 9,10 in structure of dibenzanthracene. A. Pullman attached special significance to a zone «K» of this molecule, edges thanks to high electron density can contact components of a cell. Other scientists attach bigger significance to a zone of the so-called gulf — a step in phenanthrene group of the molecule O. of century consisting of three benzene rings. Consider that this part of a molecule O. of century enters communication with DNA of cells of an organism.
Methods of definition
, as a rule, carry out Definition of oncogenous activity of various chemical connections and their mixes in long experiences on a lab. animals. Examinees of substance enter a lab. — apply to animals with various ways on skin, enter under skin, inside, into various bodies, etc. For obtaining reliable results of testing carry out on two and more animal species and use two ways of introduction, napr, greasing of skin and an adulteration to food. In control researches, in particular, come under influence of solvent, ispytuyemy substance is entered into Krom. Sometimes results can be estimated previously — not on adjusted totals of all experience, and on the changes which are naturally preceding development of a malignant tumor. Also separate express methods of a prediction of possible oncogenous properties of chemical connections are developed. The greatest distribution was gained by the method consisting in definition of ability of O. of century to cause mutations in bacterial system. As object of influence use bacteria of certain strains (e.g., Salmonella typhi murium), and also cultures of cells and fabrics, napr, cultures of cells of an epithelium of skin of patients with a pigmental xeroderma. O.'s most possess mutagen action century and, therefore, on this sign it is possible to emit substances, suspicious in the oncogenous relation. As an object for definition of a mutagenicity of chemical substances use a fruit fly a drosophila, in an organism the cut can occur O.'s activation century. However ability to mutagen action not always matches oncogenous activity since there are many strong mutagens, napr, acetic acid, to-rye do not cause tumors. It is possible to judge oncogenous activity of this or that substance finally, having only caused with its help in an animal a malignant tumor.
Told treats definition of oncogenicity of not studied substances or complex mixtures. Otherwise the situation when suspect presence at this or that complex mixture, napr, of pitches, smokes, exhaust gases of internal combustion engines, famous O. century, e.g. PAU or nitrogen-containing substances is. In these cases apply a row physical. - chemical methods for detection of this or that substance. The oncogenous PAU possessing a specific range of fluorescence reveal by means of the spektralnoflyuorestsentny analysis (see. Spectral analysis ), as a rule, precedes Krom chromatography (see). For detection and quantitative determination of oncogenous NANOSECONDS, in particular dimetil-and diethylnitrosamine, use solution chromatography, use the analyzer of thermal energy.
Prevention of action of O. of century consists in complete cessation or considerable reduction of contact with them. In nek-ry cases it is possible to withdraw completely O. century from production, having replaced them with other, not oncogenous substances. E.g., in the USSR production 2 naphthylamine, dioxybenzidine, dichlorbenzidine, orthotolidine, orthoaminoazotoluene, the paradimetilami-noazobenzol which is O. century is forbidden; the process of manufacture of benzidine is pressurized tekhnol. In some cases as a result of change of technology possibilities of contact with O. of century are considerably reduced; e.g., improvement of production of technical 1 naphthylamine lowered in it impurity oncogenous 2 naphthylamines to 0,05% (instead of 5%). In electrolysis workshops of the aluminum plants the self-burning anodes on previously burned are replaced that considerably reduced concentration of benzpyrene in air of workrooms. In nek-ry cases the pretreatment promoting decrease in oncogenous activity of substances, napr, nek-ry pitches is possible. Under production conditions limit and reduce the number of O. coming to the environment of century according to marginal emissions.
A basis for a gigabyte. O.'s limitations dependence of oncogenous effect of a dose and duration of action of O. of century Materialokhm for development of offers is are century: results of observations over O.'s distribution century in the Wednesday surrounding the person; epidemiol, given about the tumors caused by them at the person, including a research of the special contingents, or risk groups (e.g., certain prof. of group); pilot studies on animals. Results of experiments on animals are very essential, the Crimea various doses of the examinee of substance were entered. The purpose of these experiments — establishment of such dose, at a cut does not appear any tumor during life of experimental animals. Such experimental not oncogenous dose is assumed as a basis for extrapolation of the received results, edges presents considerable difficulties since it is necessary to consider various parameters, napr, the weight (weight) of a body and various bodies of animals and the person, and also them fiziol, and biochemical, features. Recommend to use various mathematical methods, to enter a so-called strength factor. For this purpose the offered maximum allowable concentrations levels reduce in a nek-swarm number (usually 10) time.
In the USSR M3 of the USSR are established and approved by maximum allowable concentration of benzpyrene: in air of working zones — 15 mkg / 100 m 3 , in the atmosphere of settlements — 0,1 mkg / 100 m 3 , in water of superficial fresh reservoirs — 0,005 mkg/l and in the soil — 20 mkg/kg. Dependence of oncogenous effect of a dose and time of action of O. of century allows to consider that their reduction will reduce the frequency of tumors and will distance the moment of their emergence.
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