@article{StopperZimmermannNeil1988,
  author    = {Stopper, Helga and Zimmermann, U. and Neil, G. A.},
  title     = {Increased efficiency of transfection of murine hybridoma cells with DNA by electropermeabilization},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63488},
  year      = {1988},
  abstract  = {Dispase-treated murine hybridoma cells (SP2/0-Ag14) were transfected with the G418 resistance gene bearing plasmid pSV2-neo by electropermeabilization with a high degree of efficiency. The cells were subjected to intermittent multiple high-voltage short duration (5 p.s) DC pulses at intervals of 1 min in a weakly conducting medium followed by selection in G418-containing medium. The transfection medium, temperature, pulse duration, and voltage were empirically determined by preliminary electropermeabilization experiments. Increasing the number of pulses resulted in a higher percentage of transfected cells, but a decrease in the number of viable cells, with the optimal transfectant yield resulting when five pulses of 10 kV jcm were administered. This method allows the rapid and efficient injection of DNA into mammalian cells, and permits the rapid production of stable, drug resistant hybridoma celllines for use in subsequent fusion experiments.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperPechanSchiffmann1992,
  author    = {Stopper, Helga and Pechan, R. and Schiffmann, D.},
  title     = {5-azacytidine induces micronuclei in and morphological transformation of Syrian hamster embryo fibroblasts in the absence of unscheduled DNA synthesis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63443},
  year      = {1992},
  abstract  = {lt is known that 5-azacytidine (5-AC) induces tumors in several organs of rats and mice. The mechanisms of these effects are still poorly understood although it is known that 5-AC can be incorporated into DNA. Furthermore, it can inhibit DNA methylation. The known data on its clastogenic andjor gene mutation-inducing potential are still controversial. Therefore, we have investigated the kinds of genotoxic effects caused by 5-AC in Syrian hamster embryo (SHE) fibroblasts. Three different endp6ints (micronucleus formation, unscheduled DNA synthesis (UDS) and cell transforrnation) were assayed under similar conditions of metabolism and dose at target in this cell system. 5-AC induces morphological transformation of SHE cells, but not UDS. Therefore, 5-AC does not seem to cause repairable DNA lesions. Furthermore, our studies revealed that 5-AC is a potent inducer of mkronuclei in the SHE system. Immunocytochemical analysis revealed that a certain percentage of these contain kinetochores indicating that 5-AC may induce both clastogenic events and numerical chromosome changes.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperMetzler1991,
  author    = {Stopper, Helga and Metzler, M.},
  title     = {Carcinogenic oestrogens induce respiration deficiency mutation in yeast},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63466},
  year      = {1991},
  abstract  = {In addition to hormonal activity, genetic darnage has been proposed as an important factor in oestrogen-mediated carcinogenesis. However, as short-term tests for oestrogens usually fail to show DNA mutations, lesions other than dassie nuclear DNA mutation have to be considered. Oestrogeninduced mitochondrial darnage was studied in the yeast Saccharomyces cerevisiae. Stilbene-type, but not steroidal, oestrogens were found to induce respiration-dcficient petite mutation. The effect was inversely correlated with cytotoxicity and required aromatic hydroxyl groups at the stilbene molecule. It only occurred under growth conditions and apparently was not due to the A TPase inhibitory qualities of stilbene oestrogens. Other studies have shown that petite mutation clones, which can be induced by a variety of substances, contain altered mitochondrial DNA. The mechanism of petite mutation induction might be important in tumorigenesis by also acting on nuclear DNA or facilitating carcinogenesis by disturbance of mitochondrial function.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperKuehnelPodschun1994,
  author    = {Stopper, Helga and K{\"u}hnel, A. and Podschun, B.},
  title     = {Combination of the chemotherapeutic agent 5-fluorouracil with an inhibitor of its catabolism results in increased micronucleus induction},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63383},
  year      = {1994},
  abstract  = {The rate limiting step in 5-fluorouracil catabolism is catalyzed by the enzyme dihydropyrimidine dehydrogenase. Since degradation of 5-fluorouracil decreases its efficacy in chemotherapy, the inhibition of its catabolism is a promising tool. We investigated the formation of micronuclei in vitro in mouse L5178Y cells. 5-fluorouracil induced an increase in micronucleus frequency, which could significantly be enhanced by the concurrent application of 2,6-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase. The 5-fluorouracil concentration necessary to reach maximal genotoxic effects could be reduced to half in the presence of inhibitor. 2,6-Dihydroxypyridine alone and the naturally occuring enzyme substrate uracil did not induce micronucleus formation. Combined application of the chemotherapeutic agent 5-fluorouracil and an inhibitor of its could reduce side-effects by lowering the effective dose of the active drug. With this study we provide further support for the usefulness of this concept.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperKoerberSpenceretal.1993,
  author    = {Stopper, Helga and K{\"o}rber, C. and Spencer, D. L. and Kirchner, S. and Caspary, W.J. and Schiffmann, D.},
  title     = {An investigation of micronucleus and mutation induction by oxazepam in mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63404},
  year      = {1993},
  abstract  = {Tbe benzodiazepines are a class of d.rugs that are widely used in the treatment of various psychiatric disorders. One member of um ~' oxazepam, is also a common metabolite of sevmd other benzod.iazepines. Since the evidence for the genetic toxicity and carcinogenic properties of these compounds is incol:lsb1ent, we investigated the oxazepam-induced fonnation of micronuclei in Syrian Hamster embryo fibroblast (SHE) cells, human amniotic fluid fibroblast-like (AFFL) cells and LS178Y mouse cells. A dose-dependent increase in micronucleus fractions was found in all tbree ceU llnes. The time course of micronucleus induction in L5178Y cells showed a maximum at 5 h after treatment, suggesting that the micronuclei were fonned in the first mitosis after treatment. Kinetochore staining (CREST -antiserum) revealed the presence of kinetochores in -SO\% of the micronuclei in aU tbree ceU types. ThJs resu1t was further confinned by in situ bybridization in LS178Y cells and indicates tbe presence of wbole Chromosomes or centric fragments as weU as acentric fragments in the oxazepam-induced micronuclei. The LS178Y cells did not show a mutagenic response to oxazepam at any of the doses or expression times used.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperKoerberSchiffmannetal.1993,
  author    = {Stopper, Helga and K{\"o}rber, C. and Schiffmann, D. and Caspary, W. J.},
  title     = {Cell-cycle dependent micronucleus formation and mitotic disturbances induced by 5-azacytidine in mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63411},
  year      = {1993},
  abstract  = {5-Azacytidine was originally developed to treat human myelogenous leukemia. However, interest in this compound has expanded because of reports of its ability to affect cell differentiation and to alter eukaryotic gene expression. In an ongoing attempt to understand the biochemical effects of this compound, we examined the effects of 5-azacytidine on mitosis and on micronucleus formation in mammalian cells. In L5178Y mouse cells, 5-azacytidine induced micronuclei at concentrations at which we and others have already reported its mutagenicity at the tk locus. Using CREST staining and C-banding studies, we showed that the induced micronuclei contained mostly chromosomal fragments although some may have contained whole chromosomes. By incorporating BrdU into the DNA of SHE cells, we determined that micronuclei were induced only when the compound was added while the cells were in S phase. Microscopically visible effects due to 5-azacytidine treatment were not observed until anaphase of the mitosis following treatment or thereafter. 5-Azacytidine did not induce micronuclei via interference with formation of the metaphase chromosome arrangement in mitosis, a common mechanism leading to aneuploidy. SupravitalUV microscopy revealed that chromatid bridges were observed in anaphase and, in some cases, were sustained into interphase. In the first mitosis after 5-azacytidine treatment we observed that many cells were unable to perform anaphase separation. All of these observations indicate that 5-azacytidine is predominantly a clastogen through its incorporation into DNA.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperKirchnerSchiffmannetal.1994,
  author    = {Stopper, Helga and Kirchner, S. and Schiffmann, D. and Poot, M.},
  title     = {Cell cycle disturbance in relation to micronucleus formation induced by the carcinogenic estrogen diethylstilbestrol},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-82250},
  year      = {1994},
  abstract  = {In addition to its tumor-promoting activity in honnone-receptive tissue, the carcinogenic estrogen diethylstilbestrol (DES) has been found to induce cell transformation, aneuploidy and micronucleus formation in mammalian cells. The majority of these micronuclei contained whole chromosomes and were fonned during mitosis. Here a possible relationship between a disturbance in cell cycle progression and micronucleus fonnation is investigated by exposing Syrian hamster embryo (SHE) cells to DES. Continuous bromodeoxyuridine labeling followed by bivariate Hoechst 33258/ethidium bromide flow cytometry was employed for analysis of cell cycle transit and related to the time course of micronucleus formation. Treatment of SHE cells with DES resulted in delayed and impaired cell activation (exit from the GO/G 1 phase), impaired S-phase transit and, mainly, G2-phase traverse. Cells forming micronuclei, on the other hand, were predominantly in G2 phase during DES treatment. These results suggest that impairment of Sand G2 transit may involve a process ultimately leading to micronucleus formation.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperJonesZimmermann1987,
  author    = {Stopper, Helga and Jones, H. and Zimmermann, U.},
  title     = {Large scale transfection of mouse L-cells by electropermeabilization},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63497},
  year      = {1987},
  abstract  = {Mouse L-cells were transfected by electropenneabilization using the selectable plasmid pSV2-neo which confers resistance to G-418 (Geneticin). 1be DNA concentration used was 1 l'gfml, the field strength was 10 kV fcm, the duration of the pulse was S ~s. Transfeetion yield was optimal at a temperature of 4°C when using a time in between consecutive pulses of 1 minute compared to shorter (of the order of seoonds) or Ionger (3 minutes) time intervals. A more detailed study of the relationship between the number of pulses applied (up to 10) and transfection yield showed it to be almost linear in this range at 4 o C. The yield of transfectants in response to 10 pulses was up to 1000 per 106 cells (using 3.3 pg DNA per cell). The inßuence of the growth phase of the cells on the transfection yield and I or the subpopulation of the mouse L--ceU line used was shown. Furthennore the clone yield depended on the DNA per ceU ratio within a very small range.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperEckertSchiffmannetal.1994,
  author    = {Stopper, Helga and Eckert, I. and Schiffmann, D. and Spencer, D. L. and Caspary, W. J.},
  title     = {Is micronucleus induction by aneugens an early event leading to mutagenesis?},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63390},
  year      = {1994},
  abstract  = {This study was designed to investigate a previously unidentified potential mechanism for mutation induction as well as to clarify a biological comequence of micronucleus formation. We compared the induction of micronuclei with mutation inductioo as measured by trißuorothymidine (TFI') resistance in mouse L5178Y cells using four aneugens: colcemid, diethylstilbestrol, griseofulvin and vioblastine. AU four compounds induced micronuclei which appeared in the first cell cycle after treatment. More than 85\% of the micronuclei induced by each compound stained positive for the presence of kinetochores implying that the micronuclei contained wbole cbromosomes. However, these same compounds were unable to induce TFf resistance under tbree different treatment regimes. We concluded that tbese compounds, under conditions where tbey induce primarily kinetochore positive micronuclel, were not able to induce mutations. Thus, the induction of micronuclei containing wbole chromosomes barborlog a select.able gene is not an early event leadlog to mutations in these cells.},
  subject      = {Toxikologie},
  language  = {en}
}
@phdthesis{Sieber2009,
  author    = {Sieber, Maximilian},
  title     = {Evaluation of 1H-NMR and GC/MS-based metabonomics for the assessment of liver and kidney toxicity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-43052},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {For the assessment of metabonomics techniques for the early, non-invasive detection of toxicity, the nephrotoxins gentamicin (s.c. administration of 0, 60 and 120 mg/kg bw 2x daily for 8 days), ochratoxin A (p.o. administration of 0, 21, 70 and 210 µg/kg bw 5 days/week for 90 days) and aristolochic acid (p.o. administration of 0, 0.1, 1.0 and 10 mg/kg bw for 12 days) were administered to rats and urine samples were analyzed with 1H-NMR and GC/MS. Urine samples from the InnoMed PredTox project were analyzed as well, thereby focusing on 1H-NMR analysis and bile duct necrosis as histopathological endpoint. 1H-NMR analysis used water supression with the following protocol: 1 M phosphate buffer, D2O as shift lock reagent, D4-trimethylsilyl­propionic acid as chemical shift reference, noesygppr1d pulse sequence (Bruker). For multivariate data analysis, spectral intensity was binned into 0.04 ppm wide bins. GC/MS analysis of urine was carried out after protein precipitation with methanol, drying, derivatization with methoxyamine hydrochloride in pyridine and with methyl(trimethylsilyl)­trifluoroacetamide on a DB5-MS column using EI ionization. The chromatograms were prepared for multivariate data analysis using the R-program based peak picking and alignment software XCMS version 2.4.0. Principal component analysis (PCA) to detect and visualize time-point and dose-dependent differences between treated animals and controls and orthogonal projection to latent structures discriminant analysis (OPLS-DA) for identification of potential molecular markers of toxicity was carried out using SIMCA P+ 11.5 1H-NMR-based markers were identified and quantified with the Chenomx NMR Suite, GC/MS based markers were identified using the NIST Mass Spectral Database and by co-elution with authentic reference standards. PCA of urinary metabolite profiles was able to differentiate treated animals from controls at the same time as histopathology. An advantage over classical clinical chemistry parameters regarding sensitivity could be observed in some cases. Metabonomic analysis with GC/MS and 1H-NMR revealed alterations in the urinary profile of treated animals 1 day after start of treatment with gentamicin, correlating with changes in clinical chemistry parameters and histopathology. Decreased urinary excretion of citrate, 2-oxoglutarate, hippurate, trigonelline and 3-indoxylsulfate increased excretion of 5-oxoproline, lactate, alanine and glucose were observed. Ochratoxin A treatment caused decreased excretion of citrate, 2-oxoglutarate and hippurate and and increased excretion of glucose, myo-inositol, N,N-dimethylglycine, glycine, alanine and lactate as early as 2 weeks after start of treatment with 210µg OTA/kg bw, correlating with changes in clinical chemistry parameters and histopathology. Integration of histopathology scores increased confidence in the molecular markers discovered. Aristolochic acid treatment resulted in decreased urinary excretion of citrate, 2-oxoglutarate, hippurate and creatinine as well as increased excretion of 5-oxoproline, N,N-dimethylglycine, pseudouridine and uric acid. No alterations in clinical chemistry parameters or histopathology were noted.Decreased excretion of hippurate indicates alterations in the gut microflora, an effect that is expected as pharmacological action of the aminoglycoside antibiotic gentamicin and that can also be explained by the p.o. administration of xenobiotica. Decreased Krebs cycle intermediates (citrate and 2-oxoglutarate) and increased lactate is associated with altered energy metabolism. Increased pseudouridine excretion is associated with cell proliferation and was observed with aristolochic acid and ochratoxin A, for which proliferative processes were observed with histopathology. 5-oxoproline and N,N-dimethylglycine can be associated with oxidative stress. Glucose, a marker of renal damage in clinical chemistry, was observed for all three nephrotoxins studied. Single study analysis with PCA of GC/MS chromatograms and 1H-NMR spectra of urine from 3 studies conducted within the InnoMed PredTox project showing bile duct necrosis revealed alterations in urinary profiles with the onset of changes in clinical chemistry and histopathology. Alterations were mainly decreased Krebs cycle intermediates and changes in the aromatic gut flora metabolites, an effect that may result as a secondary effect from altered bile flow. In conclusion, metabonomics techniques are able to detect toxic lesions at the same time as histopathology and clinical chemistry. The metabolites found to be altered are common to most toxicities and are not organ-specific. A mechanistic link to the observed toxicity has to be established in order to avoid confounders such as body weight loss, pharmacological effects etc. For pattern recognition purposes, large databases are necessary.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{ShephardSengstagLutzetal.1993,
  author    = {Shephard, S. E. and Sengstag, C. and Lutz, Werner K. and Schlatter, C.},
  title     = {Mutations in liver DNA of lacI transgenic mice (Big Blue) following subchronic exposure to 2-acetylaminofluorene},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60683},
  year      = {1993},
  abstract  = {2-Acetylaminofluorene (2-AAF) was administered at Ievels of 0, 300 and 600 ppm in the diet for 28 days to female transgenic micc bearing the lacl genein a Iambda vector (Big Blue® mice). The Iambda vector was excised from liver DNA and packaged in vitro into bacteriophage particles which were allowed to infect E. coli bacteria, forming plaques on agar plates. Approximately 10\(^5\) plaques wcre screened per animal for the appearance of a bluc colour, indicative of mutations in the lac/ gcnc which had resulted in an inactive gene product. Background mutation rate was 2.7 x 10\(^{-5}\) (pooled results of two animals, 8 mutant plaques/289 530 plaques). At 300 ppm in the diet, the rate of 3.5 X 10\(^{-5}\)(8/236 300) was not significantly increased over background. At 600 ppm in the dict, the rate increased approximately 3 fold to 7.7 x 10\(^{-5}\) (17 /221240). In comparison to the usual single or 5-day carcinogen exposure regimes, the 4-week exposure protocol allowed the use of much lower dose Ievels 00-1000 fold lower). Overt toxicity could thus be avoided. The daily doses used were somewhat higher than those required in 2-year carcinogenicity studies with 2·AAF.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{ShephardSchlatterLutz1987,
  author    = {Shephard, S. E. and Schlatter, C. and Lutz, Werner K.},
  title     = {Assessment of the risk of formation of carcinogenic N-nitroso compounds from dietary precursors in the stomach},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60925},
  year      = {1987},
  abstract  = {A literature review has shown that the daily intakes of various N -nitroso-precursor classes in a typical European diet span five orders of magnitude. Amides in the form of protein, and guanidines in the form of creatine and creatinine, are the nitrosatable groups found most abundantly in the diet, approaching Ievels of 100 g/day and 1 gjday, respectively. Approximately 100 mg of primary amines and amino acids are consumed daily, whereas aryl amines, secondary amines and ureas appear to lie in the 1-10 mg range. The ease of nitrosation of each precursor was estimated, the reactivities being found to span seven orders of magnitude, with ureas at the top and amines at the bottom of the scale. From this infonnation and an assessment of the carcinogenicity of the resulting N-nitroso derivatives, the potential health risk due to gastric in vivo nitrosation was calculated. The combined effects of these risk variables were analysed using a simple mathematical model: Risk = [daily intake of precursor] x [gastric concentration of nitrite]\(^n\) x [nitrosatability rate constant} x [carcinogenicity of derivative]. The risk estimates for the various dietary components spanned nine orders of magnitude. Dietary ureas and aromatic amines combined with a high nitrite burden could pose as great a risk as the intake of preformed dimethylnitrosamine in the diet. In contrast, the risk posed by the in vivo nitrosation of primary and secondary amines is probably negligib1y small. The risk contribution by amides (including protein), guanidines and primary amino acids is intermediate between these two extremes. Thus three priorities for future work are a comprehensive study of the sources and Ievels of arylamines and ureas in the diet, determination of the carcinogenic potencies of key nitrosated products to replace the necessarily vague categories used so far, and the development of short-term in situ tests for studying the alkylating power or genotoxicity of N-nitroso compounds too unstable for inclusion in long-term studies.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{ShephardLutzSchlatter1994,
  author    = {Shephard, S. E. and Lutz, Werner K. and Schlatter, C.},
  title     = {The lacI transgenic mouse mutagenicity assay: quantitative evaluation in comparison to tests for carcinogenicity and cytogenetic damage in vivo},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60638},
  year      = {1994},
  abstract  = {The detection Iimit of the lacl transgenic mouse mutagenicity assay lies, in practice, at approximately a 50-100\% increase in mutant frequency in treated animals over controls. The sensitivity of this assay in detecting genotoxins can be markedly improved by subchronic rather than acute application of the test compound. The lac/ transgenic mouse mutagenicity assay was compared quantitatively to rodent carcinogenicity tests and to presently used in vivo mutagenicity assays. With the genotoxic carcinogens tested thus far, a rough correlation between mutagenic potency and carcinogenic potency was observed: on average, to obtain a doubling in lacl mutant frequency the mice bad to be treated with a total dose equal to 50 times the TD50 daily dose Ievel. This total dose could be administered eilher at a high dose rate within a few days or, preferably, at a low dose rate over several weeks. This analysis also indicated that a lacl experiment using a 250-day exposure period would give a detection Iimit approximately equal to that of a long-term carcinogenicity study. In comparison to the micronucleus test or the chromosome aberration assay, acute sturlies with the presently available lacl system offered no increase in sensitivity. However, subchronic lacl sturlies (3-4-month exposure) resulted in an increase in sensitivity over the established tests by 1-2 orders of magnitude (shown with 2-acetylaminofluorene, N-nitrosomethylamine, N-nitrosomethylurea and urethane). 1t is concluded that a positive result in the lacl test can be highly predictive of carcinogenicity butthat a negative result does not provide a large margin of safety.},
  subject      = {Toxikologie},
  language  = {en}
}
@misc{SchlatterLutz1990,
  author    = {Schlatter, J. and Lutz, Werner K.},
  title     = {The carcinogenic potential of ethyl carbamate (urethane): risk assessment at human dietary exposure levels},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60826},
  year      = {1990},
  abstract  = {Ethyl carbamate is found in fermented foods: bread contains 3-15 ng/g, stone-fruit brandies 200-20,000 ngfg, and about one-third of table-wine samples analysed contained more than 10 ng/g. In animals, ethyl carbamate is degraded to C02, H20 and NH3, with intermediate formation ofethanol. This degradation has been shown tobe inhibited (postponed) in the mouse by ethanol concentrations in the blood of about 0.15\% and higher. A quantitatively minor pathway involves a two-step oxidation of the ethyl group to vinyl carbamate and epoxyethyl carbamate, the postulated electrophilic moiety that reacts with DNA. This reaction is probably the mode of the mutagenic action observed in many cellular and animal systems. The fact that only vinyl carbamate, but not ethyl carbamate, is mutagenic in a standard Ames test is probably because there is insufficient production of the intermediate oxidation product in the standard test. Consistent with this metabolism is the carcinogenic activity of ethyl carbamate in various animal species and in different organs; this activity can be seen even after a single high dose in early life. Quantitative analysis of the total tumour incidences after chronic exposure of rats and mice to 0.1-12.5 mg ethyl carbamate/kg body weightjday in the drinking-water showed a dose-related increase. The main target organs were the mammary gland (female rats and mice having similar susceptibilities) and the Jung (mice only). On the basis of sex- and organ-specific tumour data and with a linear extrapolation to a negligible increase of the lifetime tumour incidence by 0.0001\% ( one additional tumour in one mil{\"u}on individuals exposed for life), a "virtually safe dose .. of 20 to 80 ng/kg body weight/day was estimated. The daily burden reached under normal dietary habits without alcoholic beverages is in the range of about 20 ng/kg body weightfday. Regular table-wine consumption would increase the risk by a factor of up to five. Regular drinking of 20 to 40 ml stone-fruit brandy per day could raise the calculated lifetime tumour risk to near 0.01\%.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{SagelsdorffLutzSchlatter1983,
  author    = {Sagelsdorff, P. and Lutz, Werner K. and Schlatter, C.},
  title     = {The relevance of covalent binding to mouse liver DNA to the carcinogenic action of hexachlorocyclohexane isomers},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61039},
  year      = {1983},
  abstract  = {[\(^3\)H]Hexachlorocyclohexane (HCH) was synthesized by chlorination of [\(^3\)H]benzene prepared by catalytic tritiation of benzene with tritiated water. The isomers of HCH were separated by adsorption chromatography on silica gel. In order to determine the covalent binding to DNA, [\(^3\)H]HCH was administered to male mice by oral gavage, and liver DNA was isolated via cbromatin. The specific radioactivity of the DNA was nonnalized by the dose administered and expressed in the molar units of the Covalent binding index, CBI = DNA damage/dose = (\(\mu\)mol bound HCH/mol DNA nucleotide)/(mmol HCH administered/kg body weight). CBI values of - 0.2 were found 10 h after the administration of alpha- and gamma-HCH. Enzymatic digestion of the DNA to the nucleosides and h.p.l.c. analysis revealed that - 40\% of the radioactivity co-migrated with the natural nucleosides. At elution volumes known to contain the more lipophilic carcinogen-nucleoside adducts, - 10\% of the radioactivity could be detected. The remaining 50\% of th,e radioactivity eluted with the front, representing a mixture of oligonucleotide- HCH adducts and/or hydrophilic degradation products which were strongly bot not covalently associated with intact DNA. Therefore, a true CBI of 0.02-0.1 must be expected both for alpha- and gamma-HCH. This CBI is by a factor of 10\(^5\) -10\(^6\) below the value found with the strongest DNAbinding carcinogens like aflatoxin B1 or dimethylnitrosamine and is unlikely to be decisive for the liver tumor induction in mice because of the foUowing additional findings: (i) both isomers gave rise to similar Ievels of DNA darnage although the alpha-isomer is a much morepotent tumor inducer. This similarity was seen not only at the time of m{\"a}ximum binding but up to 10 days after oral administration; (ii) three mouse strains with apparently different susceptibility to tumor induction by gamma-HCH could not be distinguished with respect to DNA binding; (iii) the level of DNA binding of alpha-HCH (CBI = 0.02-0.1) is more than three orders of magnitude lower than would be expected if the mechanism of tumor induction was by genotoxicity mediated by DNAbinding. For a preliminary investigation on a potential stimulatory effect on liver DN A replication and ceU division, [\(^{14}\)]thymidine was admlnistered i.p. 3.5 h before sacrifice of the [\(^3\)H]HCH-treated mice. The alpha-isomer was found to be more potent than the gamma-isomer in this respect. Taken together, our data allow the conclusion that the non- mutational processes must be more important for the carcinogenicity of HCH.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{SagelsdorffLutzSchlatter1988,
  author    = {Sagelsdorff, P. and Lutz, Werner K. and Schlatter, C.},
  title     = {DNA methylation in rat liver by daminozide, 1,1-dimethylhydrazine, and dimethylnitrosamine},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60875},
  year      = {1988},
  abstract  = {DNA Methylation in Rat Li ver by Daminozide, 1, 1-Dimethylhydrazine, and Dimethylnitrosamine. SAGELSDORFF, P., LUTZ, W. K., AND ScHLAITER C. (1988). Fundam. Appl. Toxico/. 11, 723-730. [methyP4C]Daminozide (succinic acid 2',2'-dimethylhydrazide; 37 mgjkg), l,l( 14C]dimethylhydrazine (UDMH; 19 mgtkg), and (14C]dimethylnitrosamine (DMNA; 0.1 mg/ kg) were administered by oral gavage to male Sprague-Dawley rats. After 24 hr, the animals were killed and DNA was purified from the livers to constant specific radioactivity. After enzymatic degradation of the DNA to the 3'-deoxynucleotides the Ievel of DNA methylation was determined by HPLC analysis. Radiolabeled 7-methylguanine (7mG) was identified by cochromatography with unlabeled 7mG added as standard after acidic depurination of DNA and HPLC analysis ofpurines and apurinic acid. All three compounds were found to methylate DNA. The relative potencies were 1:47:4900 for daminozide:UDMH:DMNA. With [methyPH]UDMH, the formation of7mG was investigated as a function of dose administered, at 20, 2, and 0.2 mgj kg. The methylation ofDNA was strictly proportional to the dose. The data were used to compare the Ievel of DNA alkylation derived from residues of daminozide and UDMH in treated apple with the genotoxicity of the intake of N-nitroso compounds in Germany and Japan. It is estimated that these residues could Iead to a DNA methylation in the Ii ver of about 6\% of an average exposure to DMNA},
  subject      = {Toxikologie},
  language  = {en}
}
@inproceedings{SagelsdorffLutz1987,
  author    = {Sagelsdorff, P. and Lutz, Werner K.},
  title     = {Sensitivity of DNA and nucleotides to oxidation by permanganate and hydrogen peroxide},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80062},
  year      = {1987},
  abstract  = {no abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{ReddingtonKlotzLohseetal.1989,
  author    = {Reddington, M. and Klotz, Karl-Norbert and Lohse, M. J. and Hietel, B.},
  title     = {Radiation inactivation analysis of the A\(_1\) adenosine receptor: decrease in radiation inactivation size in the presence of guanine nucleotide},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60318},
  year      = {1989},
  abstract  = {Radiation inactivation analysis of the binding of the A1 adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine to rat brain membranes yielded a radiation inactivation size of 58 kDa. In the presence of GTPyS this was reduced to 33 kDa, in good agreement with the size of the ligand-binding subunit detected after photoaffinity labelling. The data indicate that the structural association of A\(_1\) adenosine receptors with G-protein components is altered in situ in the presence of guanine nucleotides.},
  subject      = {Toxikologie},
  language  = {en}
}
@misc{ParodiLutzColaccietal.1989,
  author    = {Parodi, S. and Lutz, Werner K. and Colacci, A. and Mazzullo, M. and Taningher, M. and Grilli, S.},
  title     = {Results of animal studies suggest a nonlinear dose-response relationship for benzene effects},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60843},
  year      = {1989},
  abstract  = {Considering the very large industrial usage of benzene, studies in risk assessment aimed at the evaluation of carcinogenic risk at low Ievels of exposure are important. Animal data can offer indications about what could happen in humans and provide more diverse information than epidemiological data with respect to doseresponse consideration. We have considered experiments investigating metabolism, short·term genotoxicity tests, DNA adduct formation, and carcinogenicity long-term tests. According to the different experiments, a Saturation of benzene metabolism and benzene effects in terms of genotoxicity seems evident above 30 to 100 ppm. Below 30 to 60 ppm the initiating effect ofbenzene seems tobe linear fora large intervaJ ofdosages, at least judging from DNA adduct formation. Potentiallack of a promoting effect of benzene (below 10 ppm) could generate a sublinear response at nontox.ic levels of ex.posure. This possibility was suggested by epidemiological data in humans and is not confirmed or excluded by our observations with animals.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{OhgakiLudekeMeieretal.1991,
  author    = {Ohgaki, H. and Ludeke, B. I. and Meier, I. and Kleihues, P. and Lutz, Werner K. and Schlatter, C.},
  title     = {DNA methylation in the digestive tract of F344 rats during chronic exposure to N-methyl-N-nitrosourea},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60759},
  year      = {1991},
  abstract  = {The formation of \(O^6\)-methyldeoxyguanosine (\(O^6\)-MedGuo) was determined by an immuno-slot-blot assay in DNA of various tissues of F344 rats exposed to N-methyl-N-nitrosourea (MNU) in the drinking waterat 400 ppm for 2 weeks. Although the pyloric region of the glandular stomach is a target organ under these experimental conditions, the extent of DNA methylation was highest in the forestomach (185 \(\mu\)mol \(O^6\)-MedGuojmol guanine). Fundus (91 J.!moljmol guanine) and pylorus (105 J.!moljmol guanine) of the glandular stomach, oesophagus (124 \(\mu\)mol/mol guanine) and duodenum (109 )lmoljmol guanine) showed lower Ievels of \(O^6\) - MedGuo but differed little between each other. Thus, no correlation was observed between target organ specificity and the extent of DNA methylation. This is in contrast to the gastric carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which preferentially alkylates DNA of the pylorus, the main site of induction of gastric carcinomas by this chemical. In contrast to MNU, the nonenzymic decomposition of MNNG is accelerated by thiol compounds (reduced glutathione, L-cysteine), which are present at much higher concentrations in the glandular stomach than in the forestomach and oesophagus. During chronic exposure to MNNG (80 ppm), mucosal cells immunoreactive to 0 6-MedGuo are limited to the luminal surface [Kobori et al. (1988) Carcinogenesis 9:2271-2274]. Although MNU (400 ppm) produced similar Ievels of \(O^6\)-MedGuo in the pylorus, no cells containing methylpurines were detectable by immunohistochemistry, suggesting a more uniform methylation of mucosal cells by MNU than by MNNG. After a single oral dose of MNU (90 mg/kg) cells containing methylpurines were unequivocally identified using antibodies to \(O^6\)-MedGuo and the imidazole-ring-opened product of 7-methyldeoxyguanosine. In the gastric fundus, their distribution was similar to those methylated by exposure to MNNG, whereas the pyloric region contained immunoreactive cells also in the deeper mucosallayers. After a 2-week MNU treatment, the rate of cell proliferation, as determined by bromodeoxyuridine immunoreactivity, was only slightly enhanced in the oesophagus andin the fundus, but markedly in the forestomach and the pyloric region of the glandular stomach. lt is concluded that the overall extent of DNA methylation, the distribution of alkylated cells within the mucosa and the proliferative response all contribute to the organ-specific carcinogenicity of MNU.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{NolteLorenzenLehretal.1992,
  author    = {Nolte, D. and Lorenzen, A. and Lehr, H.-A. and Zimmer, F.-J. and Klotz, Karl-Norbert and Messmer, K.},
  title     = {Reduction of postischemic leukocyte-endothelium interaction by adenosine via A\(_2\) receptor},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60424},
  year      = {1992},
  abstract  = {The adhesion of leukocytes to the endothelium of postcapillary venules hallmarks a key event in ischemia-reperfusion injury. Adenosine has been shown to protect from postischemic reperfusion injury, presumably through inhibition of postischemic leukocyte-endothelial interaction. This study was performed to investigate in vivo by which receptors the effect of adenosine on postischemic leukocyte-endothelium interaction is mediated. The hamster dorsal skinfold model and fluorescence microscopy were used for intravital investigation of red cell velocity, vessel diameter, and leukocyte-endothelium interaction in postcapillary venules of a thin striated skin muscle. leukocytes were stained in vivo with acridine orange (0.5 mg kg\(^{-1}\) min\(^{-1}\) i.v. ). Parameters were assessed prior to induction of 4 h ischemia to the muscle tissue and 0.5 h, 2 h, and 24 h after reperfusion. ·Adenosine, the adenosine A1-selective agonist 2-chloro-N\(^6\) -cyclopentyladenosine (CCPA), the Arselective agonist CGS 21,680, the non-selective adenosine receptor antagonist xanthine amine congener {XAC), and the adenosine uptake blocker S-(p-nitrobenzyl)-6-thioinosine (NBTI) were infused viajugular vein starting 15 min priortorelease of ischemia until 0.5 h after reperfusion. Adenosine and CGS 21,680 significantly reduced postischemic leukocyte-endothelium interaction 0.5 h after reperfusion (p< 0.01), while no inhibitory effect was observed with CCPA. Coadministration of XAC blocked the inhibitory effects of adenosine. Infusion of NBTI alone effectively decreased postischemic leukocyte-endothelium interaction. These findings indicate that adenosine reduces postischemic leukocyte-endothelium interaction via A\(_2\) receptor and suggest a protective role of endogenous adenosine during ischemia-reperfusion.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{MeierBratschiLutzSchlatter1983,
  author    = {Meier-Bratschi, A. and Lutz, Werner K. and Schlatter, C.},
  title     = {Methylation of liver DNA of rat and mouse by N-nitrosodimethylamine formed in vivo from dimethylamine and nitrite},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61052},
  year      = {1983},
  abstract  = {The extent of formation of N-nitrosodimethylaminc {NDMA) in the stomachs of rats and mice after sirnultancous oral administration of [\(^{14}\)C]dimethylamine and potassium nitrite was determined by measuring the methylation of liver DNA. With doses of around 1 mg dimethylamine hydrochloride/ kg body weight and 50 mg potassium nitrite/kg body weight. 0,8 \% of the amine was nitrosated on average. The individual fluctuations ranged from 0.2 to 1.30\% in the rat and from 0.2 to 1.9\% in the mouse. Simultaneous administration of 50 mg sodium ascorbate (vitamin Cl/kg body weight inhibited the nitrosation by ahout 80\% while 50 mg \(\alpha\)-tocopherol acetate [Vitamin E)/kg body weight reduced the nitrosation by about a half. Assuming similar kinctics and conditions of nitrosation in rats and man. a comparison of the formation of NDMA in vivo from dietary dimethylamine and nitrite with the estimated human uptake of preformed N DMA revealed that in vitro formation in the stomach of man is probably negligible.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{MeierShephardLutz1990,
  author    = {Meier, I. and Shephard, S. E. and Lutz, Werner K.},
  title     = {Nitrosation of aspartic acid, aspartame, and glycine ethylester. Alkylation of 4-(p-nitrobenzyl)pyridine (NBP) in vitro and binding to DNA in the rat},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60804},
  year      = {1990},
  abstract  = {In a colorimetric assay using 4-( p-nitrobenzyl)pyridine (NBP) as a nucleophilic scavenger of alkylating agents, the nitrosation and alkylation reactions were investigated for a number of amino acids and derivatives. The alkylating activity increased with the square of the nitrite concentration. The nitrosation rate constants for aspartic acid, aspartame, and glycine ethylester ( = precursors C) were 0.08, 1.4 and ~ 0.2, respectively, expressed in terms of the pH-dependent \(k_2\) rate constant of the equation dNOCjdt = \(k_2\) • (C]· [nitrite]\(^2\) • The rates correlated inversely with the basicity of the amino group. The stability of the alkylating activity was astonishingly high, both in acid and at neutral pH. Half-lives of 500, 200, and 30 min were determined for aspartic acid (pH 3.5), aspartame (pH 2.5), and glycine ethylester (pH 2.5). Values of 60, 15, and 2 min; respectively, were found at pH 7. It is concluded that rearrangement of the primary N-nitroso product to the ultimate alkylating agent could be rate-limiting. The potential of nitrosated a-amino acids to bind to DN A in vivo was investigated by oral gavage of radiolabelled glycine ethylester to rats, followed irnmediately by sodium nitrite. DNA was isolated from stomach and liver and analysed for radioactivity and modified nucleotides. No indication of DNA adduct formation was obtained. Based on an estimation of the dose fraction converted from glycine ethylester to the nitroso product under the given experimental conditions, the maximum possible DNA-binding potency of nitroso glycine ethylester is about one order of magnitude below the methylating potency of N-nitrosomethylurea in rat stomach. The apparent discrepancy to the in vitro data could be due to efficient detoxification processes in mammalian cells.},
  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{LutzWipfSimon1970,
  author    = {Lutz, Werner K. and Wipf, H. K. and Simon, W.},
  title     = {Alkalikationen-Spezifit{\"a}t und Tr{\"a}ger-Eigenschaftender Antibiotica Nigerfein und Monensin},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61233},
  year      = {1970},
  abstract  = {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.},
  subject      = {Toxikologie},
  language  = {de}
}
@article{LutzWinklerDunitz1971,
  author    = {Lutz, Werner K. and Winkler, F. K. and Dunitz, J. D.},
  title     = {Crystal structure of the antibiotic monensin similarities and differences betweeen free acid and metal complex},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61228},
  year      = {1971},
  abstract  = {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.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzViviantSchlatter1978,
  author    = {Lutz, Werner K. and Viviant, A. and Schlatter, C.},
  title     = {Nonlinear dose-response relationship for the binding of the carcinogen benzo(a)pyrene to rat liver DNA in vivo},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61179},
  year      = {1978},
  abstract  = {Wlth radioactive compound of high specific activity, the binding of carcinogene to DNA can be measured wlth doses that are ineffective ln long-term studies. The binding of tritiated benzo(a )pyrene to liver DNA of adult male rats has been determined 50 hr after a singie l.p. injection of doses between 40 1'9/kg and 4 mg/kg. The doseresponse relationship is linear up to 1 mg/kg, shows a step towards 2 mg/kg, and gives a shallow linear slope above that value. The observed binding ranges from 1.7 to 180 nmoles benzo(a)pyrene per mole DNA phosphate. The nonlinearity could be due to an induction of metabolizing enzymes. The microsomal aryl hydrocarbon hydroxylase activity increases significantly 24 hr after a single dose of 4 mg/kg and 48 hr after doses of 2 and 4 mg/kg, but no induction Ia found with 1 mg/kg. The binding from an equimolar dose is 35 times lower than the one found on mouse skin DNA and 300 times lower than that of N,Ndlmethylnitrosamine in rat liver. A good correlatlon exiats to the respective tumor formation in long-term studles.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzSchlatter1992,
  author    = {Lutz, Werner K. and Schlatter, J.},
  title     = {Chemical carcinogens and overnutrition in diet-related cancer [commentary]},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60712},
  year      = {1992},
  abstract  = {The intake of known dietary carclnogens was compiled and the cancer risk was estlmated on the basis of carcinogenic potencies in animals as derived from the Carcinogenic Potency Database by Gold and co-workers. The total cancer risk was compared with the number of cancer cases attributed by epidemiologists to dietary factors (one-third of all cancer cases, i.e. -80 000 per one million Jives). Except for alcohol, the known dietary carcinogens could not account for more than a few bundred cancer cases. Tbis was seen both with tbe DNA-reactive carcinogens (beterocyclic aromatic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, estragole, aflatoxin B., ethyl carbamate, to name the most important factors) as wen as with those carclnogens wbich have not been shown to react with DNA (e.g. caffelc acid and the carcinogeruc metals arsenic and cadmium). Residues and contaminants turned out to be negligible. Among the various pmsibilities to explain the discrepancy we investigated the roJe of ovemutritlon. Dietary restriction in animals is weil known for its strong reducing effect on spontaneous tumor formation. These data can be used to derive a carcinogenic potency for excess macronutrients: tbe tumor incidence seen with the restrlcted animals is taken as a control value and the increased tumor incidence in the animals fed ad libitum is attributed to the additional feed iotake. For excess standard diet in rats, a carcinogenic potency TD50 of 16 glkg/day was deduced from a recent study. Ovemutrition in Switzerland, estimated to be 5.5 kcallkg/day, was converted to excess food (1.9 g/kg/day) and tbe cancer incidence was calculated. The result, 60 000 cancer cases per one million Jives, is provocatively close to the number of cases not explained by the known dietary chemical carcinogens. Mechanistic studies will be required to test our hypothesis and investigate the role of different types of macronutrients in ovemutrition.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzSchlatter1977,
  author    = {Lutz, Werner K. and Schlatter, C.},
  title     = {Saccharin does not bind to DNA of liver or bladder in the rat [Short Communication]},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61194},
  year      = {1977},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzSchlatter1977,
  author    = {Lutz, Werner K. and Schlatter, C.},
  title     = {Mechanism of the carcinogenic action of benzene: irreversible binding to rat liver DNA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61208},
  year      = {1977},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzSchlatter1978,
  author    = {Lutz, Werner K. and Schlatter, C.},
  title     = {A closed inhalation system for pharmacokinetic and metabolism studies of volatile compounds with small laboratory animals},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80145},
  year      = {1978},
  abstract  = {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.},
  subject      = {Toxikologie},
  language  = {en}
}
@inproceedings{LutzSchlatter1978,
  author    = {Lutz, Werner K. and Schlatter, C.},
  title     = {Extrapolation of carcinogenicity data to low doses with a dose-response study of the binding of benzo(a)pyrene to rat liver DNA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80157},
  year      = {1978},
  abstract  = {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.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzPoetzschSchlatteretal.1991,
  author    = {Lutz, Werner K. and Poetzsch, J. and Schlatter, J. and Schlatter, C.},
  title     = {The real role of risk assessment in cancer risk management},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60730},
  year      = {1991},
  abstract  = {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.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzMaier1988,
  author    = {Lutz, Werner K. and Maier, P.},
  title     = {Genotoxic and epigenetic chemical carcinogenesis: one process, different mechanisms},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60884},
  year      = {1988},
  abstract  = {Chemieals that induce cancer in an intact organism are called carcinogens. This term does not differentiale between their various modes of action. In this review, Werner Lutz and Peter Maier make a mechanistic distinction between carcinogens that alter the genetic information and carcinogens that interfere with epigenetic processes. They considercardnogenesis tobe an ongoing, part1y unavoidable process which is based on a succession of mutations, most likely in stem cells, leading to autonomaus cellular growth regulation. Chemical carcinogens either induce such changes through mutations (genotoxic carcinogens) or they aceeierate the accumulation of critica1 spontaneaus mut11tions (epigenetic carcinogens). Examples are given for both classes of carcinogens, and for the processes that act at genoto:tic/nuclear 11nd epigenetic/mitotic Ievels.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzJaggiSchlatter1982,
  author    = {Lutz, Werner K. and Jaggi, W. and Schlatter, C.},
  title     = {Covalent binding of diethylstilbestrol to DNA in rat and hamster liver and kidney [Short Communication]},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61066},
  year      = {1982},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzJaggiLuethyetal.1980,
  author    = {Lutz, Werner K. and Jaggi, W. and L{\"u}thy, J. and Sagelsdorff, P. and Schlatter, C.},
  title     = {In vivo covalent binding of aflatoxin B\(_1\) and aflatoxin M\(_1\) to liver DNA of rat, mouse and pig},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61097},
  year      = {1980},
  abstract  = {[\(^{14}\)C] Aflatoxin B\(_1\) (AFB\(_1\)) was isolated from cultures of Aspergillus parasiticus grown on [1-\(^{114}\)C] sodium acetate. Covalent binding of AFB1 to liver DNA of rat and mouse was determined 6-8 h afteroral administration. The effectiveness of covalent binding, expressedas DNA binding per dose in the units of a 'Covalent Binding Index' (CBI), (\(\mu\)mol aflatoxin/mol DNA nucleotides)/(mmol aflatoxin/kg animal), was found to be 10 400 for rats and 240 for mice. These CBI partly explain the different susceptibility of the two species for the incidence of hepatic tumors. The corresponding values for pig liver DN A, 24 and 48 h after oral administration, were found to be as high as 19 100 and 13 300. DNA-binding has not so far been reported for this species although it could represent an appropriate animal model for studies where a human-like gastrointestinal tract physiology is desirable. Aflatoxin M \(_1\) ( AFM\(_1\)) is a metabolite found in the milk of cows that have been fed AFB\(_1\)-contaminated diet. [\(^{14}\)C] AFM\(_1\) was also found to be produced by cultures of A. parasiticus giving a yield of about 0.3\% of the total aflatoxins. A test for covalent binding to rat liver DN A revealed a CBI of 2100 shoWing that AFM\(_1\) must also be regarded as a strong hepatocarcinogen. It is concluded that AFB\(_1\) contaminations should be avoided in dairy feed.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzFruehSimon1971,
  author    = {Lutz, Werner K. and Fr{\"u}h, P. U. and Simon, W.},
  title     = {Microcalorimetric determination of ΔH0, ΔG0 and ΔS0 for the interaction of the carrier antibiotics nigericin and monensin with sodium and potassium ions},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61218},
  year      = {1971},
  abstract  = {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.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzDeuberCaviezeletal.1988,
  author    = {Lutz, Werner K. and Deuber, R. and Caviezel, M. and Sagelsdorff, P. and Friederich, U. and Schlatter, C.},
  title     = {Trenbolone growth promotant: covalent DNA binding in rat liver and in Salmonella typhimurium, and mutagenicity in the Ames test},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60897},
  year      = {1988},
  abstract  = {DNA binding in vivo: (6,7-\(^3\)H]ß-trenbolone (ß-TBOH) was administered p.o. and i.p. to rats. After 8 or 16 h, DNA was isolated from the livers and purified to constant specific radioactivity. Enzymatic digestion to deoxyribonucleotides and separation by HPLC revealed about 90\% ofthe DNA radioactivity eluting in the form of possible TBOH-nucleotide adducts. The extent of this genotoxicity, expressed in units of the Covalent Binding Index, CBI = (~mol TBOH bound per mol nucleotide)/(mmol TBOH administered per kg body weight) spanned from 8 t~ 17, i. e. was in the range found with weak genotoxic carcmogens. Ames test: low doses of ß-TBOH increased the number of revertants in Salmonella strain TAl 00 reproducibly and m a dose-dependent manner. The mutagenic potency was 0.2 revertants per nmol after preincubation of the bacteria (20 min at 37° C) with doses between 30 and 60 \(\mu\)g per plate (47 and 94 \(\mu\)g/ml preincubation mixture). Above this dose, the number of revertants decreased to control values, accompanied by a reduction in survival. The addition of rat liver S9 inhibited the mutagenicity. DNA binding in vitro: calf thymus DNA was incubated with tritiated ß-TBOH with and without rat liver S9 Highest DNA radioactivities were determined in the absence of the "activation" system. Addition of inactive S9 (without cofactors) reduced the DNA binding by a factor of up to 20. Intermediate results were found with active S9. DNA binding in Salmonella: ß-TBOH was irreversibly bound to DNA isolated from S. typhimurium TA100 after incubation of bacteria with [\(^3\)H]ß-TBOH. Conclusions: Covalent DNA binding appears to be the mechanism of an activation-independent ("direct") mutagenicity of TBOH which is not easily detected because of the bactericidal activity. The genotoxicity risk arising from exposure of humans to trenbolone residues in meat was estimated using the in vivo data and compared to that from the exposure to unavoidable genotoxins aflatoxin B1 and dimethylnitrosamine. It ts concluded that trenbolone residues represent only a low genotoxic risk.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzBuesserSagelsdorff1984,
  author    = {Lutz, Werner K. and B{\"u}sser, M. T. and Sagelsdorff, P.},
  title     = {Potency of carcinogens derived from covalent DNA binding and stimulation of DNA synthesis in rat liver},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61026},
  year      = {1984},
  abstract  = {~n order to investigate the role of the stimu~ation of ceU division for the initiation (and possi:bly promotion) of live·r tumors by chemical carcinogens, the incorporation of radiolabeUed thymidine into liver DNA was dete:rmined in male rats. Single doses of various level!s of af.latoxin 81, benzidine and carbon tetrachloride (aU known to be genotoxic via DNA binding} did not affect cell division, whereas several hepatoca:rcinogens known not to bind to DNA (alphaHCH, dofibrate, and 2,3;7,8-t!etrachlorodiibenzo~p~dioxin) gave rise to a dosedependent stimulation of Ii ver DNA synthesis within 24 h. An equation combining the infl.uences of mitotic stimu:lation, expressed as dose required to double the contro~ Ievei of DNA synthesis, and DNA binding potency, exp:ressed as t.he Covalent Binding Index, correliated weil with the cardnogenk potency for both dasses of hepatocardnogens.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzBraendleZbinden1978,
  author    = {Lutz, Werner K. and Br{\"a}ndle, E. and Zbinden, G.},
  title     = {Effect of gum Arabic on aminopyrine demethylation in rats},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61146},
  year      = {1978},
  abstract  = {Stimulation of aminopyrine demethylation induced in rats by oral or i.p. administration of phenobarbital was partially inhibited in animals receiving daily treatments of 2 x 200 mg/kg gum Arabic p.o.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1991,
  author    = {Lutz, Werner K.},
  title     = {Dose-response relationship for chemical carcinogenesis by genotoxic agents},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60766},
  year      = {1991},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1990,
  author    = {Lutz, Werner K.},
  title     = {Dose-response relationship and low dose extrapolation in chemical carcinogenesis [commentary]},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60789},
  year      = {1990},
  abstract  = {Data supporting various dose-respome relationships in chemical carcinogenesis are summarized. General principles are derived to explain the relationships between exposure dose, JI>NA adduct Ievel, induction of genetic changes, and tumor incidence. Some mechanistic aspects of epigenetic carcinogens (stimulation of ceU division and maldlfl'erentlation) are analyzed in a similar way. In a bomogeneous pnpulation, non-linearities are frequent. They are due to pbenomena of induction or saturation of enzymatic activities and to the multi-step nature of carcinog~: if a carcinogen acce1erates more than one step, the SUperposition of the dose- response curves for the indJvidual steps can result in an exponential relationship. A fourth power of the dose was the maximum seen in animals (fonnaldehyde). At the lowest dose Ievels, a proportionality between dose and tumor induction is postulated independent of the mechanism of action if the carcinogen aceeierotes the endogenous proass responsible for spootaneous tumor formation. Low-dose thresholds are expected only for situations where the carcinogen acts in a way that has no endogenous counterpart. Epidemiologfcal studies in humans show linear dose- response curves in all but two investigations. The difference from the strongly nonlinear slopes ·seen in animal studies could be due to the heterogeneity of the human population: if the individual sensitivity to a carcinogen is governed by a large number of genetic and Iife-style factors, the non-linea.rities will tend to cancel each other out and the dose- response curve becomes 'quasi-linear'.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1990,
  author    = {Lutz, Werner K.},
  title     = {Endogenous genotoxic agents and processes as a basis of spontaneous carcinogenesis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60816},
  year      = {1990},
  abstract  = {A list ofendogenaus DNA·damaging agents and processes is given. Endogenaus e/ectrophiles are found with the cosubstrates of physiological transfer reactions (S-adenosylrnethionine for methylation, A TP for phosphorylation, NAD\(^+\) for ADP-ribosylation, acetyl CoA for acetylation). Aldehyde groups (glyceraldehyde- 3-phosphate, formaldehyde, open forms of reducing sugars, degradation products of peroxidation) or alkylating degradation products derived from endogenaus nitrose compounds represent additional possibilities. Radical-forming reactions include leakage of the superoxide anion radical from terminal cytochromes and redox cycles, hydroxyl radical formation by the Fenton reaction from endogenaus hydrogen peroxide, and the formation of lipid peroxides. Genetic instability by spontaneaus deaminations and depurinations as well as replicative instability by tautomer errors andin the presence of mutagenic metal ions represent a third important dass of endogenaus genotoxic processes. The postulated endogenaus genotoxicity could form the mechanistic basis for what is called 'spontaneous' tumor incidence and explain the possibility of an increased tumor incidence after treatment of animals with non-genotoxic compounds exhibiting tumor-promoting activity only. Individual differences are expected to be seen also with endogenaus DNA damage. The presence of endogenaus DNA darnage implies that exogenaus DNAcarcinogen adducts give rise to an incremental darnage which is expected to be proportional to the carcinogen dose at lowest Ievels. An increased tumor risk due to exposure to exogenaus genotoxic carcinogens could therefore be assessed in terms of the background DNA damage~ for instance in multiples of the mean Ievel or of the interindividual variability in a population.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1979,
  author    = {Lutz, Werner K.},
  title     = {In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61122},
  year      = {1979},
  abstract  = {The covalent binding of chemical carcinogens to DNA of mammalian organs is expressed per unit dose, and a 'Covalent-Binding Index', CBI, is defined. CBI for various carcinogens span over 6 orders of magnitude. A similar range is observed for the carcinogenic potency in long-term bioassays on carcinogenicity. For the assessment of a risk from exposure to a carcinogen, the total DN A darnage can be estimated if the actual dose is also accounted for. A detailed description is given for planning and performing a DNA-binding assay. A complete literature survey on DNA binding in vivo (83 compounds) is given with a calculation of CBI, where possible, 153 compounds are listed where a covalent binding to any biological macromolecule has been shown in vivo or in vitro. Recent, so far unpublished findings with aflatoxin Mh macromolecule- bound aflatoxin Bh ·diethylstilbestrol, and 1,2-epithiobutyronitrile are included. A comparison of CBI for rat-liver DNA with hepatocarcinogenic potency reveals a surprisingly good quantitative correlation. Refinements for a DN A-binding assay are proposed. Possibilities and Iimitations in the use of D NA binding in chemical carcinogenesis are discussed extensively.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1986,
  author    = {Lutz, Werner K.},
  title     = {Investigation of the potential for binding of di(2-ethylhexyl)phthalate (DEHP) to rat liver DNA in vivo},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60957},
  year      = {1986},
  abstract  = {It was the aim of this investigation to determine whether or not covalent binding of di(2-ethylhexyl) phthalate (DEHP) to rat liver DNA could be a mechanism of action contributing to the observed induction of liver tumors after lifetime feeding of rodents with high doses of DEHP. DEHP radiolabeled in different positionswas administered orally to female F344 rats with or without pretreatment for 4 weeks with 1\% unlabeled DEHP in the diet. Livu DNA was isolated after 16 hr and analyzed for radioattivity. Administration of [\(^{14}\)C]carboxylate unabeled DEHP resulted in no measurable DNA radioactivity. With DEHP [\(^{14}\)C]· and [\(^{3}\)H]. labeled in the alcohol moiety as well as with 2-ethyl[1-\(^{14}\)C]hexanol, radioactivity was clearly measurable in the DNA. HPLC analysis of enzyme-degraded DNA relvealed that the normal nucleosides had incorporated radiolabel whereas no radioactivity was detectable in those fractions where the carcinogen-modified nucleoside adducts are expected. A quantitative evaluation of the negative data in terms of a Iimit of detection for a covalent binding Index (CBJ) indicates that covalent interaction with DNA is highly unlikely to be the mode of tumorigenic action of DEHP in rodents.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1986,
  author    = {Lutz, Werner K.},
  title     = {Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60967},
  year      = {1986},
  abstract  = {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.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1986,
  author    = {Lutz, Werner K.},
  title     = {Endogenous formaldehyde does not produce detectable DNA-protein crosslinks in rat liver},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60972},
  year      = {1986},
  abstract  = {Formaldehydeis an electrophilic molecule able to crosslink DNA and protein. It has been found to induce tumors in the nasal epithelium in rodents. The safety margin between the maximum tolerated FA concentration in the work place and the concentration found to be tumorigenic in animal studies is very small. Because FA is produced endogenously as a result of a variety of oxidative demethylations, the assessment of the tumor risk from exogenaus FA exposure has tobe related quantitatively to the level of DNA-protein crosslinks induced by endogenaus FA generation. It is reported here that the high level of endogenaus FA formed in the liver after a large dose of methanol or of aminopyrine did not lead to any observable increase in DNA-protein crosslinks. Using positive and negative control data from in vitro incubations of liver homogenate with FA or methanol it is estimated that the endogenous level of DNA damage in the liver must be more than three orders of magnitude below the damage observed at tumorigenic concentrations for the rat nose. The fact that FA is formed endogenously cannot, therefore, be used to claim that exogenous FA merely leads to a negligible increase in DNA damage.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1990,
  author    = {Lutz, Werner K.},
  title     = {Dosis-Wirkungs-Beziehungen in der chemischen Kanzerogenese},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80046},
  year      = {1990},
  abstract  = {Ich habe versucht darzulegen, daß mechanistische {\"U}berlegungen zur Extrapolation der Dosis-WirkungsBeziehung herangezogen werden k{\"o}nnen. Ein nichtlinearer Verlauf ist nicht nur bei den epigenetischen Kanzerogenen wahrscheinlich, sondern auch bei den DNA-bindenden. Echte Schwellen sind aber nur in solchen F{\"a}llen zu erwarten, wo kein endogenes Korrelat besteht. Immerhin k{\"o}nnen auch steile Nichtlinearit{\"a}ten zu einer drastischen Risikoreduktion f{\"u}hren, so daß die Anstrengungen dahin gehen sollten, die Steigung und den Bereich des {\"u}berproportionalen Abfalls experimentell zu zeigen. In einer heterogenen Population kann die 0 0- sis-Wirkungs-Kurve zus{\"a}tzliche "Wellen" bekommen und wird dadurch grunds{\"a}tzlich flacher. Im Extremfall ergibt sich eine lineare Dosis-Wirkungs-Beziehung unabh{\"a}ngig vom Wirkmechanismus des Kanzerogens. Diese Proportionalit{\"a}t zwischen tiefster Dosis und Effekt wird bei genotoxischen Kanzerogenen aus mechanistischen Gr{\"u}nden schon f{\"u}r eine homogene Population postuliert, doch kann dies in einer heterogenen Population auch bei epigenetischen Kanzerogenen in Frage kommen.},
  subject      = {Toxikologie},
  language  = {de}
}
@inproceedings{Lutz1987,
  author    = {Lutz, Werner K.},
  title     = {Quantitative evaluation of DNA-binding data in vivo for low-dose extrapolations},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80079},
  year      = {1987},
  abstract  = {no abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@inproceedings{Lutz1984,
  author    = {Lutz, Werner K.},
  title     = {Structural characteristics of compounds that can be activated to chemically reactive metabolites: use for a prediction of a carcinogenic potential},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80105},
  year      = {1984},
  abstract  = {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.},
  subject      = {Toxikologie},
  language  = {en}
}