TY - JOUR A1 - Lutz, Werner K. A1 - Jaggi, W. A1 - Schlatter, C. T1 - Covalent binding of diethylstilbestrol to DNA in rat and hamster liver and kidney [Short Communication] N2 - No abstract available KW - Toxikologie KW - Carcinogenesis KW - Covalent binding index - Diethylstilbestrol KW - DNA binching KW - Estrogen KW - Hormone Y1 - 1982 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61066 ER - TY - JOUR A1 - Däniken, A. von A1 - Friederich, U. A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Tests for mutagenicity in Salmonella and covalent binding to DNA and protein in the rat of the riot control agent o-chlorobenzylidene malononitrile (CS) N2 - The aim of this study was to determine whether o-chlorobenzylidene malononitrile ( CS) exhibits any genotoxic activity towards Salmonella or mammalian DNA in vivo. CS was synthesized with a [\(^{14}\)C]-label at the benzylic carbon atom. It was administered i. p. at a dose level of 13 mg/kg (1 mCi/kg) to young adult male rats. Liverand kidney DNA was isolated after 8, 25, and 75 h. The radioactivity was at (liver, 8 and 75 h) or below (all other samples) the limit of detection of 3 dpm. Therefore, a possible binding of CS to DNA is at least 10\(^5\) times lower than that of the strong hepatocarcinogen aflatoxin B1, and 4,000 times lower than that of vinyl chloride. In contrast to this lack of DNA binding, but in agreement with the chemical reactivity of CS, a binding to nuclear proteins could be detected with specific activities ranging between 50 and 121 dpm/mg for liver and between 3 and 41 dpm/mg for kidney. Protein binding could well be responsible for its pronounced cytotoxic effects. Cs was also tested in the Ames Salmonella/microsome assay. Strains TA 1535, TA 1537, TA 1538, TA 98, and TA 100 were used with or without pre-incubation. Only with strain TA 100 and only without pre-incubation, a doubling of the number of revertants was detectable at the highest dose Ievels used, 1,000 and 2,000 !lg CS per plate. With pre-incubation of TA 100 with CS, a slight increase of the number of revertants was seen at 100 and 500 !lg per plate, and a subsequent fall below control values at 1,000 J.tg. A check for the number of surviving bacteria revealed a strong bacteriotoxicity of the higher doses of es so that the calculated mutation frequencies, i.e., the oumber of revertants per number of surviving bacteria, increased with doses up to 500 !J.g. This toxicity could be counteracted in part by the addition of increasing amounts of rat liver microsomes. In the view of these results, and taking into account the rare and low exposure of man, it is concluded that CS will not create a risk for the induction of point mutations or of carcinogenic processes mediated by DNA binding. KW - Toxikologie KW - o-Chlorobenzylidene malononitrile KW - Riot control agents KW - DNA Binding KW - Salmonella/microsome assay KW - Carcinogens KW - Mutagens Y1 - 1981 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61073 ER - TY - JOUR A1 - Däniken, A. von A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Lack of covalent binding to rat liver DNA of the hypolipidemic drugs clofibrate and fenofibrate N2 - \(^{14}\)C-Labelled clofibric acid and fenofibric acid were administered p.o. to 200 g male and female rats. After 10 h, liver nuclear DNA and protein were isolated and the radioactivity was determined. Binding to protein was clearly measurable whereas no binding to DNA could be detected from any drug. A comparison of the Iimit of detection of such DNA binding with well-known chemical carcinogens revealed that the known hepatocarcinogenicity of clofibrate cannot be based upon an initiating, DNA damaging, mode of action but must be due to other, nongenotoxic, mechanisms such as peroxisome proliferation, hepatomegaly, or cytotoxicity due to protein binding. The risk assessment in man and the interpretation of the carcinogenicity data for rodents are discussed. KW - Toxikologie Y1 - 1981 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61087 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Jaggi, W. A1 - Lüthy, J. A1 - Sagelsdorff, P. A1 - Schlatter, C. T1 - In vivo covalent binding of aflatoxin B\(_1\) and aflatoxin M\(_1\) to liver DNA of rat, mouse and pig N2 - [\(^{14}\)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. KW - Toxikologie Y1 - 1980 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61097 ER - TY - JOUR A1 - Jaggi, W. A1 - Lutz, Werner K. A1 - Lüthy, J. A1 - Zweifel, U. A1 - Schlatter, C. T1 - In vivo covalent binding of aflatoxin metabolites isolated from animal tissue to rat-liver DNA N2 - Ring-labelled [\(^{14}\)C)aflatoxin B\(_1\) (AFB\(_1\)), prepared by biosynthesis. or generally labelled [\(^3\)H]AFB\(_1\) was administered by oral gavage to young adult male rats. After 6 hr. the liver was removed and two fractions were isolated, namely macromolecules, which contamed about 3 % of the initial dose of AFB\(_1\) radioactivity. and water-soluble, low-molecular aftatoxin conjugates containing about0·2% of the administered radioactivity. These two fractions were administered orally to other rats in order to determine the potential of radioactive aftatoxin residues for covalent binding to DNA. Such binding can be used as an indicator for carcinogenic potency. Liver DNA was isolated 9-12 hr after admmistration of the aflatoxin derivatives and in no case was any radioactivity detected on the DNA. It can be deduced on the basis of the limit of detection of radioactivity on the DNA, that macromolecule bound AFB\(_1\) derivatives are at least 4000 times less active than AFB\(_1\) with respect to covalent binding to rat-liver DNA. and that the water-soluble conjugates are at least 100 times less potent than AFB, itself. It is concluded that the carcinogenic risk for humans who consume liver or meat. containing such aflatoxin residues is negligible when compared with the risk from intake of aftatoxins in other food items. KW - Toxikologie Y1 - 1980 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61101 ER - TY - JOUR A1 - Viviani, A. A1 - Däniken, A. von A1 - Schlatter, C. A1 - Lutz, Werner K. T1 - Effect of selected induction of microsomal and nuclear aryl hydrocarbon monooxygenase and epoxide hydrolase as well as cytoplasmic glutathione S-epoxide transferase on the covalent binding of the carcinogen benzo(a)pyrene to rat liver DNA in vivo N2 - Groups of four adult male rats [ZUR:SIV -Z] were pretreated with corn oil (control; 2 ml/kg/day i. p. for 3 days), trans-stilbene-oxide (SO; 200 mg/kg/day i. p. for 2 days), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 \(\mu\)g/kg i. p. once, 4 days before killing), phenobarbital (PB; 1 gjliter in the drinking water for 8 days), and dieldrin (20 mg/kg/day i. p. for 3 or 9 days). They received an injection of [G-\(^3\)H]benzo(a)pyrene (BaP, 31 \(\mu\)g/kg, 7.4. 10\(^9\) dpm/kg; i. v.) 16 h before killing. In the liver of each rat, five enzymatic activities and the covalent binding of BaP to DNA have been determined. The rnicrosomal aryl hydrocarbon monooxygenase activity (AHM) ranged frorn 75% of control (SO) to 356% (TCDD), the nuclear AHM from 63% (SO) to 333% (TCDD). Microsomal epoxide hydrolase activity (EH) was induced up to 238% (PB), nuclear EH ranged from 86% (TCDD) to 218% (PB). A different extent of induction was observed in the two compartments. Highest induction of glutathione S-epoxide transferase activity (GST) was found with PB (202%). The DNA binding of BaP was modulated within 79% (dieldrin, 9 days) and 238% of control (TCDD). An enzyme digest of control DNA was analysed by Sephadex LH-20 chromatography. Multiple linear regression analysis with all data expressedas o/o of control yielded the following equation: DNA Binding = 1.49 · Microsomal AHM- 1.07 · Nuclear AHM+ 0.33 · Microsomal EH- 0.52 · N uclear EH+ 0.11 · Cytoplasmic GST + 58.2. From this analysis it is concluded that (1) AHM located in the endoplasmic reticulum is most important in the formation of DNA-binding metabolites, (2) EH in the same compar.tment is not determinative in thls respect nor has it a protective effect, (3) both membrane-bound enzyme activities located in the nucleus may inactivate potential ultimate carcinogens, and ( 4) cytoplasmic GST probably cannot reduce DNA binding due to its subcellular localization. KW - Toxikologie KW - Carcinogen KW - Benzo(a)pyrene-DNA binding KW - Enzyme induction KW - Aryl hydrocarbon rnonooxygenase KW - Epoxide hydrolase KW - Glutathione Stransferase Y1 - 1980 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61114 ER - TY - JOUR A1 - Jaggi, W. A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Comparative studies on the covalent binding of the carcinogen benzo(a)pyrene to DNA in various model systems N2 - The covalent binding of tritiated benzo(a)pyrene (BP) to DNA has been determined in rat liver in vivo, in rat liver perfused in situ, after incubation of BP with liver single cells, with liver homogenate, with liver microsomes and DNA, with fibroblasts from a rat granulorna pouch, and with · 2 cell lines. Li ver single cells were found to be a valuable compromise between the rnost sensitive system (microsomal incubation of BP with DNA) and the biologically most relevant system (in vivo ). KW - Toxikologie Y1 - 1979 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61131 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Deuber, R. A1 - Caviezel, M. A1 - Sagelsdorff, P. A1 - Friederich, U. A1 - Schlatter, C. T1 - Trenbolone growth promotant: covalent DNA binding in rat liver and in Salmonella typhimurium, and mutagenicity in the Ames test N2 - 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. KW - Toxikologie KW - Trenbolone KW - Anabolieagent KW - DNA binding KW - Genotoxicity KW - Ames test KW - Salmonella typhimurium Y1 - 1988 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60897 ER - TY - JOUR A1 - Bösch, R. A1 - Friederich, U. A1 - Lutz, Werner K. A1 - Brocker, E. A1 - Bachmann, M. A1 - Schlatter, C. T1 - Investigations on DNA binding in rat liver and in Salmonella and on mutagenicity in the Ames test by emodin, a natural anthraquinone N2 - Emodin (1,6,8-trihydroxy-3-methylanthraquinone), an important aglycone found in natural anthraquinone glycosides frequently used in Iaxative drugs, was mutagenic in the Salmonellajmammalian microsome assay (Ames test) with a specificity for strain TA1537. The mutagenic activity was activationdependent with an optimal amount of S9 from Aroclor 1254-treated male Sprague-Dawley rats of 20% in the S9 mix (v jv) for 10 p.g emodin per plate. Heat inactivation of the S9 for 30 min at 60 ° C prevented mutagenicity. The addition of the cytochrome P-448 inhibitor 7,8-benzoflavone (18.5 nmoles per plate) reduced the mutagenic activity of 5.0 p.g emodin per plate to about one third, whereas the P-450 inhibitor metyrapone (up to 1850 nmoles per plate) was without effect. To test whether a metabolite" binds covalently to Salmonella DNA, [10-\(^{14}\)C]emodin was radiosynthesized, large batches of bacteria were incubated with [10-\(^{14}\)C]emodin and DNA was isolated. [G- \(^{3}\)H]Aflatoxin B1 (AFB1) was used as a positive control mutagen known to act via DNA binding. DNA obtained after aflatoxin treatment could be purified to constant specific activity. With emodin, the specific activity of DNA did not remain constant after repeated precipitations so that it is unlikely that the mutagenicity of emodin is due to covalent interaction of a metabolite with DNA. The antioxidants vitamin C and E or glutathione did not reduce the mutagenicity. Emodin was also negative with strain TA102. Thus, oxygen radicals are probably not involved. When emodin was incubated with S9 alone for up to 50 h before heat-inactivation of the enzymes and addition of bacteria, the mutagenic activity did not decrease. It is concluded that the mutagenicity of emodin is due to a chemically stable, oxidized metabolite forming physico-chemical associations with DNA, possibly of the intercalative type. In order to check whether an intact mammalian organism might be able to activate emodin to a DNA-binding metabolite, radiolabelled emodin was administered by oral gavage to male SD rats and liver DNA was isolated after 72 h. Very little radioactivity was associated with the DNA. Considering that DNA radioactivity could also be due to sources other than covalent interactions, an upper limit for the · covalent binding index, CBI = (p.moles chemical bound per moles DNA nucleotides)/(mmoles chemical administered per kg body weight) of 0.5 is deduced. This is 104 times below the CBI of AFB1. The demonstration of a lack of covalent interaction with DNA bothin Salmonellaandin rat liver is discussed in terms of a reduced hazard posed by emodin as a mutagenic drug in use in humans. KW - Toxikologie KW - DNA binding KW - (Rat liver) KW - (Salmonella) KW - Ames test KW - Emodin KW - Anthraquinone glycosides KW - natural Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60913 ER - TY - JOUR A1 - Shephard, S. E. A1 - Schlatter, C. A1 - Lutz, Werner K. T1 - Assessment of the risk of formation of carcinogenic N-nitroso compounds from dietary precursors in the stomach N2 - 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. KW - Toxikologie Y1 - 1987 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60925 ER - TY - JOUR A1 - Jaggi, W. A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Covalent binding of ethinylestradiol and estrone to rat liver DNA in vivo N2 - Thecovalent bindingof [6,7-\(^3\)H]ethinylestradiol (EE)and [6,7-\(^3\)H]estrone (E) to liver DNA of 200 g female ratswas measured 8 h after the administration of 80 \(\mu\)g (9.2 mCi) estrogen by gavage. The binding is 1.5 for EE and 1.1 for E, expressedas binding to DNA/dose, in units of \(\mu\)mol hormonefmol DNA phosphate/mmole honnone/kg body wt. It is in the same order of magnitude as for benzene and about 10 000 tim es below the binding of typical liver carcinogens, such as aflatoxin B\(_1\) or N,N-dimethylnitrosamine. KW - Toxikologie Y1 - 1978 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61162 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Viviant, A. A1 - Schlatter, C. T1 - Nonlinear dose-response relationship for the binding of the carcinogen benzo(a)pyrene to rat liver DNA in vivo N2 - 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. KW - Toxikologie Y1 - 1978 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61179 ER - TY - JOUR A1 - Viviani, A. A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Time course of the induction of aryl hydrocarbon hydroxylase in rat liver nuclei and microsomes by phenobarbital, 3-methylcholanthrene, 2,3,7,8-tetrachloro-dibenzo-p-dioxin, dieldrin and other inducers N2 - Aryl hydrocarbon hydroxylase (AHH) has been measured in male rat Jiver nucJei and microsomes after treatment of adult animals with various inducers for up to 14 days. After daily i.p. injections of 3-methylcholanthrene (MC, 20 mg/kg) the nuclear activity increased to a maximum of 600 per cent of the control activity after 4 days whereas the microsomal activity was 400 per cent of control at the same date. After 12 days, both activities equilibrated at 400 per cent. A similar time course was found after a single i.p. injection of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD, 0.01 mg/kg) with an induction to .500 and 300 per cent for nuclei and microsomes, respectiveJy. after 2 days, and to 400 per cent for both after 12 days. PhenobarbitaJ (PB) was given continuously in the drinking water (I g/1) and induced the microsomal activity to 200 per cent after 8 days and 170 per cent after 14 days. The nuclear activity was only slightly induced to a constant Ievei of 130 per cent between day 8 and 14. Dieldrin did not significantly increase the microsomal activity after daiJy i.p. injections (20 mg/kg), but the nuclear activity raised to 200 per cent after 3 days and levelled down tocontrol valuesafter 12 days. Other inducers tested were benz[a)anthracene (BA), hexachlorobenzene (HCB} and 1,1.1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT). The induction pattern with BA was similar tothat of MC, a modeJ compound for the group of cytochrome P448 inducers. The induction by HCB and DDT resembled that by PB. a typical cytochrome P450 inducer. KW - Toxikologie Y1 - 1978 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61182 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Saccharin does not bind to DNA of liver or bladder in the rat [Short Communication] N2 - No abstract available KW - Toxikologie Y1 - 1977 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61194 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Mechanism of the carcinogenic action of benzene: irreversible binding to rat liver DNA N2 - No abstract available KW - Toxikologie Y1 - 1977 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61208 ER - TY - JOUR A1 - Shephard, S. E. A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - The lacI transgenic mouse mutagenicity assay: quantitative evaluation in comparison to tests for carcinogenicity and cytogenetic damage in vivo N2 - 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. KW - Toxikologie KW - Transgenie mice KW - Mutagenicity assay KW - Sensitivity KW - Chromosome aberration KW - Micronucleus test KW - Carcinogenic potency Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60638 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 - JOUR A1 - Caviezel, M. A1 - Aeschbach, A. P. A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Reduction of covalent binding of aflatoxin B1 to rabbit liver DNA after immunization against this carcinogen N2 - 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. KW - Krebs KW - DNA KW - Aflatoxin KW - Cancer prevention KW - Carcinogen KW - Covalent binding KW - DNA KW - Immunization Y1 - 1984 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80116 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - In vivo covalent binding of chemicals to DNA as a short-term test for carcinogenicity N2 - 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. KW - DNA KW - DNA-Binding KW - Carcinogen KW - Short-term Carcinogenicity Test KW - Aflatoxin KW - Toluene KW - Tritiated Water Y1 - 1979 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80127 ER -