@article{BaertschLutzSchlatter1991,
  author    = {Baertsch, A. and Lutz, Werner K. and Schlatter, C.},
  title     = {Effect of inhalation exposure regimen on DNA binding potency of 1,2-dichloroethane in the rat},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60743},
  year      = {1991},
  abstract  = {1 ,2-Dichloroethane (DCE) was reported to be carcinogenic in rats in a long-tenn bioassay using gavage in com oil (24 and 48 mg/kg/day), but not by inhalation (up to 150-250 ppm, 7 h/day, 5 days/week). The daily dose metabolized was similar in the two experiments. In order to address this discrepancy, the genotoxicity of DCE was investigated in vivo under different exposure conditions. Fernale F-344 rats (183-188 g) were exposed to [1,2-14C]DCE in a closed inhalation chamber to either a low, constant concentration (0.3 mg/l = 80 ppm for 4 h) or to a peak concentration (up to 18 mg/1 = 4400 ppm) for a few minutes. After 12 h in the chamber, the dose metabolized under the two conditions was 34 mg/kg and 140 mg/k:g. DNA was isolated from liver and lung and was purified to constant specific radioactivity. DNA was enzymaticaBy hydrolyzed to the 3' -nucleotides which were separated by reverse phase HPLC. Most radioactivity eluted without detectable or with little optical density' indicating that the major part of the DNA radioactivity was due to covalent binding of the test compound. The Ievel of DNA adducts was expressed in the dose-nonnalized units ofthe Covalent Binding Index, CBI = f.Lmol adduct per mol DNA nucleotide/ mmol DCE per kg body wt. In liver DNA, the different exposure regimens resulted in markedly different CBI values of 1.8 and 69, for "constant-low" and ''peak" DCE exposure Ievels. In the Jung, the respective values were 0.9 and 31. It is concluded that the DNA darnage by DCE depends upon the concentration-time profile and that the carcinogenic potency determined in the gavage study should not be used for low-Ievel inhalation exposure.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{HegiUlrichSagelsdorffetal.1990,
  author    = {Hegi, M. E. and Ulrich, D. and Sagelsdorff, P. and Richter, C. and Lutz, Werner K.},
  title     = {No measurable increase in thymidine glycol or 8-hydroxydeoxyguanosine in liver DNA of rats treated with nafenopin or choline-devoid low-methionine diet},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60790},
  year      = {1990},
  abstract  = {Male rats were treated for 2 months with 1000 ppm nafenopin in the diet or for 4 or 7 days with a choline-devoid low-methionine diet. DNA was isolated from the livers and analyzed for the presence of cis-thymidine glycol-3'-phosphate (cis-dTGp) by 32P-postlabeling and for the Ievel of 8-hydroxy-deoxyguanosine (8-0H-dG) by electrochemical detection (ECD). In no DNA sample was the Ievel of cis-dTGp above the Iimit of detection of 1 modified thymidine per 106 nucleotides. With 8-0H-dG, a background Ievel of this modification of 20 8-0H-dG per 106 nucleosides was found in liver DNA of control rats, which was not affected by either treatment. It is postulated for thymidine glycol that a potential increase was below the Iimit of detection or was rapidly repaired in vivo and that the steady-state Ievel of endogenous 8-hydroxydeoxyguanosine appears not tobe influenced by the treatments chosen.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{MarinovichLutz1985,
  author    = {Marinovich, M. and Lutz, Werner K.},
  title     = {Covalent binding of aflatoxin B\(_1\) to liver DNA in rats pretreated with ethanol},
  series = {Experientia},
  volume    = {41},
  journal   = {Experientia},
  number    = {10},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-55237},
  pages     = {1338 -- 1340},
  year      = {1985},
  abstract  = {Male Fischer F-344 rats were given ethanol in the drinking water and/or by single oral administration. Following this, the animals received p.o. 100 ng/kg of the hepatocarcinogen eHJaflatoxin BI (AFBI)' 24 h later, the level of DNA-bound AFBI was determined in the liver and was found not to be affected by any type of ethanol pretreatment. A cocarcinogenic effect of ethanol in the liver is therefore unlikely to be due to an effect on the metabolic activation and inactivation processes governing the formation of DNA-binding AFBI metabolites.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{CaviezelAeschbachLutzetal.1984,
  author    = {Caviezel, M. and Aeschbach, A. P. and Lutz, Werner K. and Schlatter, C.},
  title     = {Reduction of covalent binding of aflatoxin B1 to rabbit liver DNA after immunization against this carcinogen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80116},
  year      = {1984},
  abstract  = {The covalent binding of [3H]aflatoxin B1 (AF) to liver DNA was determined, 6 h after oral administration to male rabbits. A Covalent Binding Index, CBI (flmol AF/mol DNA-P)/(mmol AF/kg b. w.) = 8,500 was found. Pretreatment of rabbits with AF coupled to bovine serum albumin in Freund's adjuvant led to the production of AF-directed antibodies. Administration of [3H]AF to such immunized rabbits resulted in a CJH of only 2,500, i.e., the iiDJ{.lUnization provided a protection by a factor of more than 3. Although this is encouraging evidence for the potential of active immunization against genotoxic carcinogens, a nurober of pointswill have to be clarified, such as the time course for the DNA binding and the question of a possible shift to other target cells.},
  subject      = {Krebs},
  language  = {en}
}
@article{LutzSchlatter1979,
  author    = {Lutz, Werner K. and Schlatter, C.},
  title     = {In vivo covalent binding of chemicals to DNA as a short-term test for carcinogenicity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80127},
  year      = {1979},
  abstract  = {The determination of a covalent binding of radioactive chemieals to DNA in intact mammalian organisms is proposedas a short-term test for carcinogenicity. The effectiveness of covalent binding to rat liver DNA correlates well with the hepatocarcinogenicity known from long-term bioassays. The binding indices range over more than five orders of rriagnitude between the strongest hepatocarcinogen aflatoxin B 1 and the limit of detection of a binding with 100 f-LCi 14C-labelled chemical. The order of magnitude of binding is therefore a surprisingly good quantitative measure for carcinogenicity. The pattern of DNA binding sites is important especially for small alkylating agents where the determination of total binding might indicate a higher carcinogenic potency than is actually observed.},
  subject      = {DNA},
  language  = {de}
}
@inproceedings{VivianiLutz1979,
  author    = {Viviani, A. and Lutz, Werner K.},
  title     = {Modulation of the in vivo covalent binding of the carcinogen benzo(a)pyrene to rat liver DNA by selective induction of microsomal and nuclear aryl hydrocarbon hydroxylase activity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80132},
  year      = {1979},
  abstract  = {The influence of microsomal (mAHH) and nuclear (nAHH) aryl hydrocarbon hydroxylase activity on the covalent binding of t:titiated benzo(a)pyrene to rat liver DNA was evaluated in vivo. Induction ofmAHH was obtained after phenobarbitone treatment (180\% of control), which increased DNA binding to 210\%, but left the nAHH unchanged. mAHH and nAHH were slightly indilced with dieldrin (130\% and 120\%), but the binding remairred unchanged. The increasing effect of mAHlt as weil as the possibly decreasing effect of nAHH induction on the binding became obvious when the data of 11 individual rats were used to solve the equation Binding = aX(mAHH) + bX(nAHH) + c. Multiple linear regression analysis resulted in positive values for a and c, a negative value for b, and a multiple correlation coefficient R = 0.82. An influence of other enzymes involved in the metabolism of benzo(a)pyrene cannot be excluded. The Study shows clearly that the binding of a foreign compound to DNA in vivo is not only dependent on microsomal enzyme activities but also on nuclear activities even if the latter are considerably lower than those of mic'rosomes.},
  subject      = {DNA},
  language  = {en}
}
@incollection{Lutz1991,
  author    = {Lutz, Werner K.},
  title     = {Dose-response relationships in chemical carcinogenesis: from DNA adducts to tumor incidence},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-71625},
  publisher      = {Universit{\"a}t W{\"u}rzburg},
  year      = {1991},
  abstract  = {Mechanistic possibilitles responsible for nonlinear shapes of the dose-response relationship in chemical carcinogenesis are discussed. (i) Induction and saturation of enzymatic activation and detoxification processes and of DNA repair affect the relationship between dose and steady-state DNA adduct Ievel; (ii) The fixation of DNA adducts in the form of mutations is accelerated by stimulation of the cell division, for Jnstance due to regenerative hyperplasia at cytotoxic dose Ievels; (iii) The rate of tumor formation results from a superposition of the rates of the individual steps. It can become exponential with dose if more than one step is accelerated by the DNA damage exerted by the genotoxic carcinogen. The strongly sigmoidal shapes often observed for dose-tumor incidence relationships in animal bioassays supports this analysis. A power of four for the dose in the su~linear part of the curve is the maximum observed (formaldehyde). In contrast to animal experiments, epidemiological data ln humans rarely show a slgnificant deviation from linearity. The discrepancy might be explained by the fact that a I arge nu mber of genes contribute to the overall sensitivity of an individual and to the respective heterogeneity within the human population. Mechanistic nonlinearities are flattened out in the presence of genetic and life-style factors which affect the sensitivity for the development of cancer. For a risk assessment, linear extrapolation from the high-dose lncidence to the spontaneaus rate can therefore be approprlate in a heterogeneous population even if the mechanism of action would result in a nonlinear shape of the dose-response curve in a homogeneaus population.},
  language  = {en}
}