TY - CHAP A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Extrapolation of carcinogenicity data to low doses with a dose-response study of the binding of benzo(a)pyrene to rat liver DNA N2 - The binding of tritiated benzo(a)pyrene (BP) to liver DNA of 25 adult male rats (SIV 50) has been determined 50 h after a single intraperitoneal injection of doses between 40 ug/kg and 4; mg/kg. The dose-response relations~ ip is linear up to i mg/kg, shows a sigmoid step towards 2 mg/kg and a shallow linear. slope above that value. TlJe 0 bserved bin ding ranges from 1.7 to 180 nmoles BP per mole DNA phosphate. The non-linearity between 1 and 2 mg/kg could be explained 0):1 the basis of an induction of metabolizing enzymes. A pure1y mathematical extrapolation of therumour incidence from a carcinogenic dose (1 x 40mg/kg for a 20% hepatoma incidence in newborn mice) to human exposure levels (aboilt 0.1 ug/kg per day) would never have followed a step like the on~ found in our experiments. Our dose-effect study therefore shows how carcinogenitity data could be extrapolated in a biologically founded way to low doses. KW - Toxikologie Y1 - 1978 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80157 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - A closed inhalation system for pharmacokinetic and metabolism studies of volatile compounds with small laboratory animals N2 - In the inhalation system described an animal can be kept in the same atmosphere of a 2-liter desiccator for up to 24 h. The expired carbon dioxide is adsorbed with soda lime and the resulting reduced pressure is balanced by a supply of oxygen also used for the inflow of the chemical to be investigated. Urine and faeces can be collected ~eparately and the system allows a periodical control of the concentration of the chemical by sampling the air with needle and syringe. KW - Toxikologie Y1 - 1978 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80145 ER - TY - CHAP A1 - Lutz, Werner K. T1 - Structural characteristics of compounds that can be activated to chemically reactive metabolites: use for a prediction of a carcinogenic potential N2 - Many mutagens and carcinogens act via covalent interaction of metabolic intermediates with DNA in the target cell. This report groups those structural elements which are often found to form the basis for a metabolism to such chemically reactive metabolites. ~mpounds which are chemically reactive per se and which do not require metabolic activation form group 1. Group 2 compri~es of olefins and aromatic hydrocarbons where the oxidation via an epoxide can be responsible for the generation of reactive species. Aromatic amines, hydrazines, and nitrosamirres form group 3 requiring an oxidation of a nitrogen atom or of a carbon atom in alpha position to a nitrosated amine. Group 4 compounds are halogenated hydrocarbons which can either give rise to radicals or can form an ·olefin (group 2) upon dehydrohalogenation. Group 5 compounds depend upon some preceding enzymatic activity either not available in the target cell or acting on positions in the molecule which are not directly involved in the subsequent formation of electrophilic atoms. Examples for each group are taken from the "List of Chemieals and Irrdustrial Processes Associated with Cancer in Humans" as compiled by the International Agency for the Research on Cancer, and it is shown that 91% of the organic carcinogens would have been detected on the basis of structural elements characteristic for group 1-5. As opposed to this very high sensitivity, the specificity ( the true negative fraction) of using this approach as a short-term test for carcinogenicity is shown to be bad because detoxification pathways have so far not been taken into account. These competing processes are so complex, however, that either only very extensive knowledge about pharmacokinetics, stability, and reactivity will be required or that in vivo systems have to be used to predict, on a quantitative basis, the darnage expected on the DNA. DNA-binding experiments in vivo are presented with benzene and toluene to demonstrate one possible way for an experimental assessment and it is shown that the detoxification reaction at the methyl group available only in toluene gives rise to a reduction by at least a factor of forty for the binding to rat liver DNA. This quantitative approach available with DNA-binding tests in vivo, also allows evaluation as to whether reactive metabolites and their DNA binding are always the most important single activities contributing to the overall carcinogenicity of a chemical. With the example of the livertumor inducing hexachlorocyclohexane isomers it is shown that situations will be found where reactive metabolites are formed and DNA binding in vivo is measurable but where this activity cannot be the decisive mode of carcinogenic action. It is concluded that the lack of structural elements known to become potentially reactive does not guarantee the lack of a carcinogenic potential. KW - Toxikologie KW - Structureactivity relationship KW - Reactive intermediates KW - Metabolic activation KW - DNA Binding KW - Covalent binding index KW - Carcinogens KW - Benzene Y1 - 1984 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80105 ER - TY - CHAP A1 - Lutz, Werner K. T1 - Quantitative evaluation of DNA-binding data in vivo for low-dose extrapolations N2 - no abstract available KW - Toxikologie Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80079 ER - TY - CHAP A1 - Sagelsdorff, P. A1 - Lutz, Werner K. T1 - Sensitivity of DNA and nucleotides to oxidation by permanganate and hydrogen peroxide N2 - no abstract available KW - Toxikologie Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80062 ER - TY - JOUR A1 - Lutz, Werner K. T1 - Dosis-Wirkungs-Beziehungen in der chemischen Kanzerogenese T1 - Dose-response relations in chemical carcinogenesis N2 - Ich habe versucht darzulegen, daß mechanistische Überlegungen zur Extrapolation der Dosis-WirkungsBeziehung herangezogen werden können. Ein nichtlinearer Verlauf ist nicht nur bei den epigenetischen Kanzerogenen wahrscheinlich, sondern auch bei den DNA-bindenden. Echte Schwellen sind aber nur in solchen Fällen zu erwarten, wo kein endogenes Korrelat besteht. Immerhin können auch steile Nichtlinearitäten zu einer drastischen Risikoreduktion führen, so daß die Anstrengungen dahin gehen sollten, die Steigung und den Bereich des überproportionalen Abfalls experimentell zu zeigen. In einer heterogenen Population kann die 0 0- sis-Wirkungs-Kurve zusätzliche "Wellen" bekommen und wird dadurch grundsätzlich flacher. Im Extremfall ergibt sich eine lineare Dosis-Wirkungs-Beziehung unabhängig vom Wirkmechanismus des Kanzerogens. Diese Proportionalität zwischen tiefster Dosis und Effekt wird bei genotoxischen Kanzerogenen aus mechanistischen Gründen schon für eine homogene Population postuliert, doch kann dies in einer heterogenen Population auch bei epigenetischen Kanzerogenen in Frage kommen. KW - Toxikologie Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80046 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Poetzsch, J. A1 - Schlatter, J. A1 - Schlatter, C. T1 - The real role of risk assessment in cancer risk management N2 - Rtgulatory aclio11s Iaken to reduu tht risk of harmfultffects of exposure to chemieals ofltn arenot commensurDtt with the toxicologicDf risk SJsstS&ment. A numbtr of factors relating to psychology, sociology, economics Dntl politics rather than science and medicine afftct tht final decision. Wemer Lutz and colleagues illustratt the situation using tht feuktmia-indudng chtmiCJJI benzene as an examplt. KW - Toxikologie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60730 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Wipf, H. K. A1 - Simon, W. T1 - Alkalikationen-Spezifität und Träger-Eigenschaftender Antibiotica Nigerfein und Monensin T1 - Alkali-cation specificity and carrier qualities of the antibiotics nigericin and monensin N2 - It is shown by means of IR. spectroscopic methodsthat nigericin and monensin bave a cyclic conformation similar to that of their silver salts. Camplex fonnation constants with sodium and potassium ions follow the selectivity order determined by EMF. measurements on liquid membranes: nigericin: K\(^+\) >Rb\(^+\)> Na\(^+\)> Cs\(^+\) >Li\(^+\); monensin: Na\(^+\)> K\(^+\) >Li\(^+\)> Rb\(^+\)> Cs\(^+\). Transport experiments show that nigericin and monensin facilitate the diffusion of potassium ions across model membranes, although in electrolytic transport experiments the permeability is not affected. KW - Toxikologie Y1 - 1970 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61233 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Winkler, F. K. A1 - Dunitz, J. D. T1 - Crystal structure of the antibiotic monensin similarities and differences betweeen free acid and metal complex N2 - The structure of monensin, C36H620 11 , has been deterrnined by X-ray analysis of its crystalline monohydrate (orthorhombic, a = 15.15, b = 23.61, c = 10.65 A, Z = 4, space group P212121). Phases were assigned by direct methods, malring use of the 'tangent formula'. Although the conformation of the free acid resembles that of the silver salt in being cyclic, there are differences in the hydrogen bonding pattern. These featurcs are discussed in relation to the cornplexation of metal ions by m.onensin. KW - Toxikologie Y1 - 1971 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61228 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Früh, P. U. A1 - Simon, W. T1 - Microcalorimetric determination of ΔH0, ΔG0 and ΔS0 for the interaction of the carrier antibiotics nigericin and monensin with sodium and potassium ions N2 - The thermodynainic parameters ΔH0, ΔG0 and ΔS0 - and thereby the equilibrium constants - for the complexation of the carrier antibiotics nigericin and monensin with sodium and potassium ions in methanol at 25°C have been determined by microcalorimetry. Tbc results are discussed in terms of the nature of the interaction between ligands and cations. KW - Toxikologie Y1 - 1971 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61218 ER -