TY  - JOUR
A1  - Lutz, Werner K.
T1  - Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens
N2  - 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. Fora 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 = (\(\mu\)mol 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 tobe 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 Ievels required for significant tumor induction in a long-term bioassay. Rat liver DNA bindingwas proportional to the dose of aflatoxin B1 afteroral administration of a dose between 100 \(\mu\)g/kg and 1 ng/kg. The lowest dose was in the range of generat 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 endogenaus genotoxic agents. The question of why compounds which act via indirect mechanisms are more likely to exhibitanonlinear rangein the dose-response curve as opposed to the directly genotoxic agents or processes is discussed.
KW  - Toxikologie
KW  - Chemical carcinogenesis
KW  - Mechanism of action
KW  - Quantitative risk assessment
KW  - Genotoxicity
KW  - Dose-response relationship
KW  - Aflatoxin B1
Y1  - 1986
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60967
ER  - 
TY  - JOUR
A1  - Grilli, S.
A1  - Lutz, Werner K.
A1  - Parodi, S.
T1  - Possible implications from results of animal studies in human risk estimations for benzene: nonlinear dose-response relationship due to saturation of metabolism
N2  - To date, all risk assessment studies on benzene have been based almost exclusively on epiderniological data. Wehave attempted a more integrated and quantitative evaluation of carcinogenic risk for hurnans, 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 tobe 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 ofthe 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 occupationallevels from 10 to 5 ppm.
KW  - Toxikologie
KW  - Benzene
KW  - Risk estimation
KW  - Carcinogenicity
KW  - Genotoxicity
KW  - Metabolism saturation
KW  - Dose-response relationship
Y1  - 1987
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60936
ER  -