[The use of the aquarium fishes Danio rerio and Poecilia reticulata as highly sensitive species for testing the carcinogenicity of chemical compounds]. / Ispol'zovanie akvariumnykh ryb Danio-rerio i Poecilia reticulata kak vysokochuvstvitel'nykh ob''ektov pri vyiavlenii kantserogennosti khimicheskikh soedinenii.

Aquarium fishes Danio rerio and Poecilia reticulata are recommended as test-objects for testing carcinogenic chemical agents. 30 compounds were tested for their action on these objects. The analysis of the incidence of induced tumors, period of their appearance and Iball index shows high sensitivity of the aquarium fishes to the carcinogenic action. Data are presented on the dynamics of experimental carcinogenesis, morphology of induced tumours, as well as on modifications of carcinogenesis (the role of environmental temperature, age, dose, exposition, etc.). Advantages and limitations of the "fish model" are compared with those found in the experiments carried on mammals.

[Metabolic activation systems used in short-term tests for the detection of environmental carcinogens]. / Sistemy metabolicheskoi aktivatsii, primeniaemye v kratko-srochnykh testakh dlia vyiavleniia kantserogenov okruzhaiushchei sredy.

The recent data on metabolic activation of carcinogens are presented. Molecular mechanisms of activation, induction methods for systems providing biotransformation of xenobiotics as well as the comparative analysis of these systems (host, cell and cell free) are characterized from the standpoint of their use in short-term tests. The prospects of application of various metabolic activation systems are shown.

[Modifying effect of environmental chemical factors on the metabolic activation of carcinogens]. / Modifitsiruiushchee vliianie khimicheskikh faktorov okruzhaiushchei sredy na metabolicheskuiu aktivatsiiu kantserogenov.

Current investigations of modifications of metabolic activation of carcinogens by the environmental chemical factors which are able to induce or inhibit the metabolic activation are reviewed. From the standpoint of ecological oncology the most promising are the following trends: 1) modelling under experimental conditions of integral ecosystems including the complex of living organisms, environmental carcinogens, and factors which modify their biotransformation; 2) study of the imprinting effectors of metabolism modifiers; 3) detection in the environment of modifiers of metabolic activation of carcinogens. The comprehensive oncological-ecological studies of chemicals which influence different pathways of carcinogen metabolism are very important for both primary prevention of cancer and the environmental protection.

[Terminology of carcinogenesis in light of the current concepts of the mechanisms of action of chemical carcinogens]. / Terminologiia jantserogeneza v svete sovremennykh predstavlenii o mekhanizmakh deistviia khimicheskikh kantserogenov.

The approaches to prepare a uniform and unified scientific terminology of chemical carcinogenesis are presented. The main definitions proposed (carcinogen, initiation, promotion, mutagen, multistage carcinogenesis, anti-carcinogen, cocarcinogen, carcinogenic risk, etc.) are based on the current state of comprehending mechanisms of the action of chemical carcinogens.

[Correlation of the mutagenic and carcinogenic activity of various aromatic amines]. / Korreliatsiia mutagennoi i kantserogennoi aktivnosti nekotorykh aromaticheskikh aminov.

Six aromatic amines were studied for their mutagenic activity using Salmonella typhimurium TA 100 and TA 98. 3,3'-dichlorobenzidine, ortho-tolidine, benzidine, 2-naphthylamine proved to be mutagenic, while aminotobias acid and 2,2',4,4'-tetraaminodiphenyl did not show mutagenic activity. Chronic experiments on mice and rats using these compounds revealed a close correlation between carcinogenicity and mutagenicity.

[Imprinting effect of aroclor 1254 in the metabolic activation of benz[a]pyrene by rat liver tissue]. / Imprintingovyi éffekt aroklora 1254 pri metabolicheskoi aktivatsii benz[a]pirena tkan'iu pecheni krys.

A well-known inductor of a system of multifunctional monooxygenases, the arochlor 1254, being applied to one-day rats produced an imprinting effect which was expressed in a strong and long-term increase in the metabolic activation of benzo(a)pyrene by the liver S9-fraction in the Salmonella/microsome test, as well as in the arylhydrocarbonhydroxylase activity. The imprinting was not revealed when the inductor was applied on the 9th day as well as it was not revealed for 2-acetylaminofluorene in the liver, or benzo(a)pyrene and 2-acetylaminofluorene in the kidneys, independently of the period of application.

[Sovol as an inducer of procarcinogen activating microsomal enzymes]. / Sovol kak induktor mikrosomnykh fermentov, aktiviruiushchikh prokartsinogeny.

The commercial mixture of polychlorinated biphenyls (Sovol) studied by biochemical and immunochemical methods was found to be an inducer of a wide range of cytochrome P-450 isoenzymes. The induced enzymes activated in the Ames test a series of procarcinogens differing both in structure and in target organs: benz(a)pyrene, 3-methylcholanthrene, nitrosomorpholine, dimethylnitrosamine, aflatoxin B1, orthoaminoazotoluene, 2-acetylaminofluorene, cyclophosphamide and benzidine. According to the parameters the studied Sovol is similar to Aroclor 1254 and may be recommended to be used as an inducer of microsomal enzymes in routine tests for carcinogen screening.

[The modifications of mutagenesis and anticarcinogenesis]. / Modifikatsii mutageneza i antikantserogenez.

The problems of anticarcinogenesis are discussed in the context of mechanistic approaches and the well-known mechanisms of multistage carcinogenesis. Various events at extra- and intracellular levels are involved in mutagenesis and carcinogenesis. The most promising candidates for suppression of chemical carcinogenesis are some nitrosation modifiers, dietary sorbents, metabolic activation modulators, reactive metabolite trappers, repair inducers, gene expression inhibitors, etc. Short-term tests for mutagenicity are more preferable for screening potential anticarcinogenic agents. The bioassays for anticarcinogenesis should be assessed for sensitivity, specificity and predictability and the genetic profiles of the antimutagenic activity of the modifiers analysed.

[Molecular mechanisms of initiation and promotion of multistage chemical carcinogenesis]. / Molekuliarnye mekhanizmy initsiatsii i promotsii mnogostadiinogo khimicheskogo kantserogeneza.

Multistage carcinogenesis is the process of development of neoplastic changes, including the successive stages of initiation and promotion which occur in a strict order. This process is subject to the application of a similarly strict sequence of exo-and/or endogenous carcinogenic factors, either of which alone is incapable of tumor induction. Initiation includes the phases of metabolic activation, interaction of reactive metabolites with DNA and fixation of induced lesion. It is the stage of development of such primary mutation lesions of genotype of target-cells as the irreversible transition of these cells to an "initiated" status (predisposition to transformation). Promotion is the stage of quantitative and quantitative-qualitative changes including secondary epigenomic reversible lesions of the phenotype (gene expression) of initiated cells. This process culminates in irreversible transformation of cells.

[Use of the bacterial flocculation test for assessing the mutagenic properties of carcinogenic nitrosamines and nitramines]. / Ispol'zovanie bakterial'nogo floktuatsionnogo testa dlia otsenki mutagennykh svoistv kantserogennykh nitrozaminov i nitraminov.

Fluctuation test developed by Green allows to detect the mutagenicity of trace and non-toxic chemical concentrations. Mutagenic activity of both carcinogenic nitramines--nitrodimethylamine, nitrodiethylamine and nitromorpholine (0.1--10 mM) and their nitrosamine analogues-nitrosodimethylamine, nitrosodiethylamine and nitrosomorpholine (0.01--0.1 mM) was detected in fluctuation test with Salmonella typhimurium TA 98 and TA 1530 as indicator organism in the presence of postmitochondrial supernatant from liver of rats treated with Aroclor 1254. Nearly all compounds appeared to be mutagenic even in the absence of co-factors of microsomal oxygenation.

[Role of age in N-nitrosodimethylamine- and N-dimethylnitramine-induced carcinogenesis in Rana temporaria L. amphibians]. / Rol' vozrasta v kantserogeneze, indutsirovannom N-nitrozodimetilaminom i N-dimetilnitraminom u amfibii Rana temporaria (L).

A comparison of the reactions of adult and juvenile amphibians Rana temporaria showed that the host sensitivity (latency and tumour incidence) of both groups of animals to the carcinogenic action of N-nitrosodimethylamine and dimethylnitramine was of the same order. However, a "shift" in organ sensitivity (different organotropic effect) was observed. The predominance of hepatocellular cancer in adult and hemocytoblastosis in young Rana temporaria was significant (P less than 0,01). The mechanisms of these "shifts" are unknown, but a role of the metabolic and reparative processes has been suggested.

[The tumor as an atavistic adaptive reaction in environmental conditions]. / Opukhol' kak atavisticheskaia adaptivnaia reaktsiia na usloviia okruzhaiushchei sredy.

In sponges, coelenterates, bryozoans, and ascidians, blastogenesis associated with the formation of resting buds and resting blastogenetic structures is similar to the oncogenesis. Just as the tumours, such buds and structures: 1) when released from control of the parent organism, developed independently of the latter and cause its destruction; 2) originate due to the action of various external and internal causes; 3) are hardy to anoxia, dehydration, overcooling; 4) consist of little differentiated and de-differentiated cells. These similarities can be explained in the frame of hypothesis which considers tumours an atavistic resting structure.

[Trends and perspectives in environmental oncology]. / Puti razvitiia i perspektivy èkologicheskoi onkologii.

Environmental oncology is a discipline concerned with studies of multi-aspect relationships between environment and living organisms exposed to the modifying influence of carcinogenic agents. It also deals with general biological regularities involved in neoplasm development as well as their prevention in different species including man, animals and plants. Various investigations conducted at the Laboratory and supported with Russian and foreign grants (1991-1996) are briefly discussed. Among them are biotesting environmental carcinogens (aminoanthraquinons, by-products of drinking water chlorination, development of new testing systems and objects of detection involved in identification of genotoxic substances (criteria for formation of short-term test batteries and evaluation of perspectives, methods and results), investigation of xenobiotic metabolic activation (enzyme imprinting in adult animals), search for anticarcinogens (classification of carcinogenesis inhibitors, development of testing systems for modifiers selection), and establishing environment-related regularities of tumor growth. Vistas in environmental oncology development are discussed.

[Cells of rat lymphosarcoma in chambers for intravital microscopy]. / Kletki limfosarkomy krysy v kamerakh dlia prizhiznennoi mikroskopii

In a chamber for intra vital microscopy, implanted subcutaneously in a rat, stained rat lymphosarcoma cells were applied into a preliminary formed connective tissue layer. The process of intracellular transformation of a dye and its elimination from the cytoplasm was observed. Following elimination of the dye a duplication of lymphosarcoma cells would proceed. This is a very intensive process, and after 5-7 days the connective tissue is completely substituted by tumor cells.

[Metabolic activation and the mutagenic properties of carcinogenic N-nitramines in a liquid incubation test]. / Metabolicheskaia aktivatsiia i mutagennye svoistva kantserogennykh N-nitraminov v zhidkostno-inkubatsionnoi probe.

The study established the mutagenicity of carcinogenic dimethylnitramine and nitromorpholine in a liquid-incubation system using Salmonella typhimurium TA 100 and TA 1530 as indicator, in the presence of hepatic postmitochondrial supernatant obtained from 1254 aroclor-treated rats, oxygen and NADP+--generating system. Synthesis of mutagenic metabolites of nitramines was in correlation with the level of N-dimethylase activity. Ascorbic acid and disulfiram efficiently inhibited intramune-induced mutagenesis. Metabolic activation of nitramines involves (a) conversion of nitramines to nitrosoamines due to reduction of a nitro group, (b) hydroxylation by means of multi-function oxydases, and (c) heterolysis resulting in the formation of an end metabolite which is actually responsible for carcinogenicity and mutagenicity.

[Mutagenic activity of carcinogens and other chemical agents in Salmonella typhimurium tests]. / Issledovanie mutagennoi aktivnosti kantserogenov i drugikh khimicheskikh agentov v testakh na Salmonella typhimurium.

One-hundred and six chemical compounds were tested in Ames test with bacteria Salmonella typhimurium. Eight different strains (mainly, TA98 and TA100) were used. Liver S9 from Aroclor-treated rats was employed for metabolic activation. In group I comprising 51 compounds with sufficient evidence of carcinogenicity for animals, 45 were mutagenic while 6 (urethane, 1,2-dimethylhydrazine, DDT, chlorophorm, 1,4-dioxane and carbon tetrachloride) were not. In group 2 (27 noncarcinogenic compounds), 22 agents failed to exhibit mutagenicity whereas 5 (acrolein, styrene-oxide, acridine orange, I-naphthylamine and dichlormethane) revealed such activity. In groups 1 and 2, the sensitivity was 88.2, specificity--81.5 and predictive value--90%. In group 3 consisting of 28 agents used in chemical, pharmaceutical and food industries but not yet tested for mutagenicity and for the carcinogenicity of which no conclusive data are available, seven appeared to be mutagens (1-aminoanthraquinone, 2-aminoanthraquinone, 1-amino-4-chloranthraquinone, based blue, dinitrochlorbenzene, nitrosodiphenylamine and 2,3,5-trinitronaphthalene).

[Identification of trihalomethanes in drinking water and assessment of their toxicity, mutagenicity and carcinogenicity]. / Identifikatsiia v pit'evoi vode nekotorykh trigalometanov i vyiavlenie ikh toksichnosti, mutagennosti i kantserogennosti.

Dichlorobromomethane (DCMB) and dibromochloromethane (DBCM) isolated from chlorinated drinking water were tested for toxicity, mutagenicity and carcinogenicity. Both agents proved mutagenic in a "dessicator" modification of the Ames test using Salmonella typhimurium TA98 and TA100 in the presence of exogenous metabolic activation. In aquarium Danio rerio fish tests, LD50/30 was 250 mg/l for both compounds. Both agents induced hepatocellular carcinoma in fish: DCMB--in 11 out of 29 animals (at 16.5 weeks) and DBCM--in 3 out of 16 (at 26.5 weeks). These data merit further investigation of the agents' carcinogenicity in chronic experiments in rodents.

[Papillomas of the urinary bladder induced by N-nitroso-N-methylurea in rats]. / Papillomy mochevogo puzyria, indutsirovannye N-nitrozo-N-metilmochevinoi u krys

N-nitroso-N-methylurea (a total dosage--6 mg per animal), administered by a catheter in the urinary bladder cavity in female rats, following 9--56 weeks induced in 16 of 23 rats tumors of the vesical mucous membrane (mostly transitional cell papillomas).

[Action of N-dinitrosopiperazine and N-nitrosodiethylamine on aquarium guppies]. / Izuchenie deistviia N-dinitrozopiperazina i N-nitrozodiétilamina na akvariumnykh ryb guppi.

Tumors and precancerous lesions of the gastrointestinal tract were induced in aquarium fish guppy by dinitrosopiperazine and nitrosodiethylamine dissolved in aquarium water. Nitrosodiethylamine appeared to produce a stronger blastogenic effect than dinitrosopiperazine. Since tumors develop several weeks after exposure to carcinogens, this animal species may be used for express testing nitrosocompounds for blastogenicity.

[Possibility of using fish and amphibians for detecting the carcinogenic action of nitrosomorpholine and its chemical precursors]. / Vozmozhnost' ispol'zovaniia ryb i amfibii dlia vyiavleniia kantserogennogo deistviia nitrozomorfolina i ego khimicheskikh predshestvennikov.

When dissolved in water nitrosomorpholine induced in frogs Rana temporaria and aquarium fish adenomas and cancer, hemocytoblastosis, adenomatous polyps and adenocarcinomas of the intestine, mesenchymomas. A combined action of sodium nitrite and morpholine would induce the tumors concerned, but taken separately NN and M produced only a toxic effect. The morpholine nitration appears to proceed both endogenously and directly in water. It seems rational to use animals of the aqueous medium as an indicator of nitrosoamines and their precursors contamination of hydrosphere.