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  • 1
    Electronic Resource
    Electronic Resource
    Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens (1986)
    Springer
    Journal of cancer research and clinical oncology 112 (1986), S. 85-91 
    Details
    ISSN: 1432-1335
    Keywords: Chemical carcinogenesis ; Mechanism of action ; Quantitative risk assessment ; Genotoxicity ; Dose-response relationship ; Aflatoxin B1 ; Formaldehyde ; Vinyl chloride
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Investigation of covalent DNA binding in vivo provided evidence for whether a test substance can be activated to metabolites able to reach and react with DNA in an intact organism. For a comparison of DNA binding potencies of various compounds tested under different conditions, a normalization of the DNA lesion with respect to the dose is useful. A covalent binding index, CBI=(μmol chemical bound per mol DNA nucleotide)/(mmol chemical administered per kg body weight) can be determined for each compound. Whether covalent DNA binding results in tumor formation is dependent upon additional factors specific to the cell type. Thus far, all compounds which bind covalently to liver DNA in vivo have also proven to be carcinogenic in a long-term study, although the liver was not necessarily the target organ for tumor growth. With appropriate techniques, DNA binding can be determined in a dose range which may be many orders of magnitude below the dose levels required for significant tumor induction in a long-term bioassay. Rat liver DNA binding was proportional to the dose of aflatoxin B1 after oral administration of a dose between 100 μg/kg and 1 ng/kg. The lowest dose was in the range of general human daily exposures. Demonstration of a lack of liver DNA binding (CBI〈0.1) in vivo for a carcinogenic, nonmutagenic compound is a strong indication for an indirect mechanism of carcinogenic action. Carcinogens of this class do not directly produce a change in gene structure or function but disturb a critical biochemical control mechanism, such as protection from oxygen radicals, control of cell division, etc. Ultimately, genetic changes are produced indirectly or accumulate from endogenous genotoxic agents. The question of why compounds which act via indirect mechanisms are more likely to exhibit a nonlinear range in the dose-response curve as opposed to the directly genotoxic agents or processes is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00404387
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  • 2
    Electronic Resource
    Electronic Resource
    Possible implications from results of animal studies in human risk estimations for benzene: nonlinear dose-response relationship due to saturation of metabolism (1987)
    Springer
    Journal of cancer research and clinical oncology 113 (1987), S. 349-358 
    Details
    ISSN: 1432-1335
    Keywords: Benzene ; Risk estimation ; Carcinogenicity ; Genotoxicity ; Metabolism saturation ; Dose-response relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To date, all risk assessment studies on benzene have been based almost exclusively on epidemiological data. We have attempted a more integrated and quantitative evaluation of carcinogenic risk for humans, trying to utilize, in addition to the epidemiological data, all data available, specifically data on metabolism, genotoxicity, and carcinogenicity in small rodents. An integrated evaluation of the globality of the available data seems to suggest a progressive saturation of metabolic capacity both for man and rodents between 10 and 100 ppm. The most susceptible target cells seem to be different in humans (predominant induction of myelogenous leukemia) and small rodents (induction of a wide variety of tumors). Nevertheless, both epidemiological and experimental carcinogenicity data tend to indicate a flattening of the response for the highest dosages, again suggesting a general saturation of mechanisms of metabolic activation, extended to different target tissues. From a quantitative point of view, the data suggest a carcinogenic potency at 10 ppm two to three times higher than that computable by a linear extrapolation from data in the 100 ppm range. These observations are in accord with the recent proposal of the European Economic Community of reducing benzene time-weighted average occupational levels from 10 to 5 ppm.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00397718
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    Paper (German National Licenses)
    Fulltext
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