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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 56 (1985), S. 151-157 
    ISSN: 1432-0738
    Keywords: Trans-4-dimethylaminostilbene ; Adriamycin ; Acute toxicity ; Tissue specific effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The acute toxicity of the carcinogen trans-4-dimethylaminostilbene was studied in Wistar rats. The animals die after oral administration of 50 mg/kg (LD50) with a latency period of 11 days. Specific lesions of the stomach epithelium together with acute bone marrow incapacity and toxic effects on peripheral blood cells lead to acute anemia, which is considered to be the cause of death. Histological observations indicate that the stomach lesions develop in three phases. Firstly, necroses appear in the proliferative area predominantly in the antrum. This leads, secondly, to cystic transformation of the antrum, cardia, and Brunner's glands and further to peptic erosions and ulcerations. Thirdly, mitotic activity increases. With lethal doses, cell replacement remains incomplete. There ist a correlation between the proliferation rate of different cell types and their susceptibility; but this cannot entirely account for the tissue-specific, systemic effects of trans-4-dimethylaminostilbene. Metabolic activation is also involved, since enzyme induction with methylcholanthrene inhibits toxicity. The study disclosed a new target tissue which may now be used to investigate the mechanism of action of reactive metabolites of an aromatic amine in acute experiments. The same stomach lesions were also observed with adriamycin. With this compound, however, the intestine is also involved.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0738
    Keywords: Key words: Biomonitoring – Azo pigments – Hemoglobin adducts – 3,3′-Dichlorobenzidine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The release and availability of the carcinogenic component of the soluble azo dye Direct Red 46 and the insoluble azo pigment Pigment Yellow 17 were analyzed in Wistar rats using hemoglobin adducts as a dosimeter. The levels of hemoglobin adducts were found to be very low. Intestinal cleavage and release of 3,3′-dichlorobenzidine (3,3′-DCB) from Direct Red 46 and Pigment Yellow 17 was calculated to be 3% and 0.6% of the dose, respectively, in a 4-weeek feeding study. It is proposed to measure blood samples from exposed humans in order to test the applicability of the method and eventually to use it for controlling human exposure to the carcinogenic colorant components.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0738
    Keywords: Key words Biomonitoring ; Haemoglobin adducts ; Aromatic amines ; Acetylation ; Deacetylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aromatic amines are metabolically activated by N-oxidation of either the amine or the acetamide as a first step and esterification of the resulting N-hydroxyl derivatives as a second step. Both pathways may lead to DNA-adducts and subsequently to DNA lesions and mutations. Since the accumulation of non-acetylated adducts has been associated with tumour initiating properties, the balance between acetylation and deacetylation may greatly influence the biological effect. Hydrolysable haemoglobin adducts representing the bioavailability of N-hydroxylamines and the corresponding nitroso-derivatives were analysed following oral administration to female Wistar rats of two arylamine-acetamide couples: 4-aminobiphenyl and 2-aminofluorene, and two arylamine-acetamide-diacetamide triples: benzidine and 3,3′-dichlorobenzidine. The results show that the mono-acetamides are readily deacetylated in vivo whereas the diacetamides are not. A dynamic equilibrium is indicated to exist between acetylation and deacetylation, which depends on substrate specificity, and the role of deacetylation is emphasised. In addition, acetylation polymorphism was studied with 4-chloroaniline and 3,3′-dichlorobenzidine in slow acetylating A/J and rapid acetylating C57BL/6J mice. The slow acetylator genotype was associated with significantly higher haemoglobin-adduct levels for both arylamines. The results provide additional support for the use of haemoglobin adducts in biomonitoring as a dosimeter for the biologically active dose of arylamines/arylacetamides. Moreover, biomonitoring of haemoglobin adducts may provide information about an individual's susceptibility to the toxic and carcinogenic effects of these chemicals.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Journal of cancer research and clinical oncology 79 (1973), S. 60-70 
    ISSN: 1432-1335
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Der Stoffwechsel der ersten Dosen von carcinogenem trans-4-Dimethylaminostilben (trans-DAS) und 4-Dimethylaminobibenzyl (DABB) wurde verglichen mit demjenigen der dreizehnten Dosen, nach sechswöchiger Sondierung weiblicher Ratten, bei 2 Dosen pro Woche. Bei beiden Verbindungen wurden keine auffallenden Veränderungen des Stoffwechsels nach der fortlaufenden Fütterung beobachtet. Lediglich die Harnausscheidung von N-Hydroxy-acetylaminostilbenglucuronid stieg etwas an. Analysiert wurden das Muster der ungebundenen und die Menge der insgesamt gebundenen Metaboliten in Leber und Niere (5 h) sowie die einzelnen in Harn und Faeces nach 48 h ausgeschiedenen Metaboliten. Aus den Ergebnissen wird geschlossen, daß (1) in diesem experimentellen System das Schicksal einer einzelnen Dosis repräsentativ auch für die zur Tumorerzeugung notwendigen nachfolgenden Dosen ist, (2) deutliche Änderungen der Aktivität von Leberenzymen im Verlauf der Tumorerzeugung durch trans-DAS keine Rolle spielen, (3) carcinogene Dosen des Gehörgangtumoren erzeugenden trans-DAS bei der Ratte weniger hepatotoxisch sind als solche des Lebertumoren erzeugenden AAF.
    Notes: Summary The metabolic fates of initial doses of the carcinogen trans-4-dimethylaminostilbene (trans-DAS) and the noncarcinogen 4-dimethylaminobibenzyl (DABB) were compared with the metabolism of the thirteenth doses administered after six weeks of twice weekly dosage by stomach tube to female rats. No significant changes were observed after prolonged feeding in either case. A slight increase in the urinary excretion of N-hydroxy-acetylaminostilbene glucuronide was found to occur. The pattern of unbound metabolites (5 h) and the amount of bound metabolites in the liver and kidney as well as urinary and faecal metabolites excreted in 48 h were analysed. The results implicate that (1) in this particular experimental system the fate of a single dose is representative also of subsequent administrations, (2) major changes in enzyme activities in the liver are not involved in the process of tumour induction by trans-DAS, (3) carcinogenic doses of ear duct tumour-inducing trans-DAS appear to be less toxic to the liver than liver tumour-inducing AAF in the rat. This is part VI of the series: The relevance of chemicobiological interactions for the toxic and carcinogenic effects of aromatic amines. For part V, see: Groth and Neumann (1972). Part of the experiments were performed at the Max-Planck-Institut für Biochemie, München. A preliminary account of the results was given at the symposium “The Biological Oxidation of Nitrogen in Organic Molecules” held at the Chelsea College, London, 19th December, 1971 (Neumann, 1972).
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    International archives of occupational and environmental health 60 (1988), S. 151-155 
    ISSN: 1432-1246
    Keywords: Biological monitoring ; Hemoglobin adducts ; Exposure control ; Aromatic amines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Analysis of hemoglobin adducts in blood samples is suitable for the biological monitoring of genotoxic chemicals. The method is specific because the compound to which the individual was exposed is identified. The sensitivity of the method depends on the analytical procedure applied, but is hardly limiting since large amounts of the protein can be obtained. The method provides not only information about the internal exposure to the environmental chemical, but also about the individual's capacity to generate ultimate genotoxic metabolites from it. Since macromolecular damage in blood cells is correlated to that in potential target tissues, this information is relevant to risk assessment, insofar as macromolecular damage produced by a specific chemical can be correlated with the development of tumors.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1246
    Keywords: Key words Chemical carcinogens ; List of MAK and BAT Values ; Cancer risk
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Carcinogenic chemicals in the work area are currently classified into three categories in section III of the German List of MAK and BAT Values (list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these categories – IIIA1, IIIA2, IIIB – be retained as Categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics, and for which risk at low doses can be assessed are classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 32 (1974), S. 27-38 
    ISSN: 1432-0738
    Keywords: Threshold Dose ; Carcinogens ; Metabolic Activation ; Cellular Target ; Irreversible Effects ; Schwellenwert ; Carcinogen ; Stoffwechselaktivierung ; Irreversible Wirkung ; Chronische Toxicität
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Untersuchungen über das Schicksal vieler carcinogener Stoffe bei Versuchstieren haben zu dem Konzept von der Entstehung reaktionsfähiger Metaboliten im Stoffwechsel geführt. Daraus wurde gefolgert, daß der größte Teil der reaktionsfähigen Moleküle unspezifisch und mit nichtkritischen Zellbestandteilen reagiert und dadurch abgefangen wird. Welche Rolle dies bei der Frage nach der Existenz von Schwellenwerten bei Carcinogenen spielt, hängt davon ab, inwieweit es gelingt den Schaden auf molekularer Ebene zu definieren und damit die Wechselwirkung mit kritischen Zellbestandteilen messen zu können. Voraussetzung für die rationale Eingrenzung eines wirkungsfreien Dosisbereichs scheint zu sein, daß sich das Verhältnis von nichtkritischen zu kritischen Reaktionen mit abnehmender Dosis erhöht und/oder daß — vor allem bei irreversiblen Veränderungen — eine tolerierbare Mindestzahl von Ereignissen erkennbar wird.
    Notes: Abstract From investigations of the metabolism of many carcinogenic compounds emerged the concept of the metabolic activation to reactive metabolites. This led to the conclusion that ultimate reactive forms are trapped to a major extent by unspecific reactions with noncritical cell constituents. To evaluate the consequences with regard to the question of the existence of threshold doses for carcinogens, it appears necessary to define the detrimental effects on the molecular level and to measure interactions with critical cellular targets. A rationale for demonstrating a threshold dose could be derived if the ratio of noncritical to critical interactions increased with lower doses and/or if a tolerable minimum number of events could be determined, particularly with irreversible changes.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Journal of cancer research and clinical oncology 119 (1993), S. 329-334 
    ISSN: 1432-1335
    Keywords: trans-4-Acetylaminostilbene ; Kidney tumors ; Gentamycin ; β-Cyclodextrin ; Initiation ; Promotion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract trans-4-Acetylaminostilbene (AAS) is a complete carcinogen in rats and produces quite selectively tumors in Zymbal's glands. On the basis of DNA adduct formation, it has been proposed that this model arylamine initiates neoplastic transformation of cells in many tissues, particularly liver and kidney, which, in the classical sense are considered to be non-target tissues for this chemical. In the present study an initiating treatment with AAS was followed by unilateral nephrectomy and the application of two nephrotoxic substances, gentamycin or β-cyclodextrin which, among other activities, stimulate cell proliferation specifically in kidney. The initiating dose of AAS, given alone, gave rise to Zymbal's gland and mammary tumors in female Wistar rats within 88 weeks but not to liver or kidney tumors. When the initiation treatment was followed by unilateral nephrectomy, alone or in combination with gentamycin, or by β-cyclodextrin, four tumors in two out of ten animals, eight tumors in three/ten, and seven tumors in three/ten, respectively, were observed in the kidney. The administered dose of gentamycin was not sufficient to induce tumors on its own. The results support the view that the genotoxic effects of AAS produce promotable lesions in rat kidney. None of the animals that had been treated with AAS, with or without other treatments, developed tumors or the predominant types of preneoplastic lesions in the liver within 88 weeks; this supports the notion that liver, like kidney, is not a target for complete carcinogenesis for this chemical.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Journal of cancer research and clinical oncology 112 (1986), S. 100-106 
    ISSN: 1432-1335
    Keywords: DNA adducts ; Aromatic amines ; 2-Naphthylamine ; 4-Aminobiphenyl ; Benzidine ; 2-Acetylaminofluorene ; 4-Acetylaminostilbene ; 2-Acetylaminophenanthrene ; Noncorrelation ; Organotropism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Many findings support the notion that the generation of DNA adducts by aromatic amines is causally related to carcinogenesis. Adducts have been identified in most cases and representative examples are reviewed. However, extent and persistence of DNA adducts (DNA dose) does not correlate satisfactorily with the tumor response of different tissues. Distribution of DNA damage, repair, indirect and secoridary DNA damage are discussed as possible explanations for the observed noncorrelations. In addition, however, it is proposed to pay attention to specific mechanisms such as receptor mediated cellular effects which are not related to the generation of electrophiles. The effects of trans-4-aminostilbene and 2-amino-fluorene derivatives on rat liver are compared. It is concluded that trans-4-acetylamino-stilbene is a strong liver tumor initiator but an incomplete liver carcinogen lacking tumor promoting protperties, and that 2-acetylaminofluorene is a complete liver carcinogen with initiating and promoting properties.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-6822
    Keywords: acetylaminostilbene ; aromatic amines ; deacetylase ; gene mutation assays ; paraoxon ; thioguanine resistance ; V79 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: The N-acetoxy and N-hydroxy derivatives of trans-4-acetylamino-stilbene (AAS) were demonstrated to induce gene mutations at the hgprt locus and to be cytotoxic in V79 cells. These cells deacetylated AAS. Paraoxon inhibited the deacetylation of AAS by more than 99% and reduced the mutagenicicity and cytotoxicity of N-hydroxy-ASS and N-acetoxy-AAS to about one-tenth. Hence, deacetylated metabolites, formed by the target cells, were important for the observed biological effects.
    Type of Medium: Electronic Resource
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