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 - 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 - Lutz, Werner K. A1 - Schlatter, C. T1 - A closed inhalation system for pharmacokinetic and metabolism studies of volatile compounds with small laboratory animals N2 - In the inhalation system described an animal can be kept in the same atmosphere of a 2-liter desiccator for up to 24 h. The expired carbon dioxide is adsorbed with soda lime and the resulting reduced pressure is balanced by a supply of oxygen also used for the inflow of the chemical to be investigated. Urine and faeces can be collected ~eparately and the system allows a periodical control of the concentration of the chemical by sampling the air with needle and syringe. KW - Toxikologie Y1 - 1978 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80145 ER - TY - CHAP A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - Extrapolation of carcinogenicity data to low doses with a dose-response study of the binding of benzo(a)pyrene to rat liver DNA N2 - The binding of tritiated benzo(a)pyrene (BP) to liver DNA of 25 adult male rats (SIV 50) has been determined 50 h after a single intraperitoneal injection of doses between 40 ug/kg and 4; mg/kg. The dose-response relations~ ip is linear up to i mg/kg, shows a sigmoid step towards 2 mg/kg and a shallow linear. slope above that value. TlJe 0 bserved bin ding ranges from 1.7 to 180 nmoles BP per mole DNA phosphate. The non-linearity between 1 and 2 mg/kg could be explained 0):1 the basis of an induction of metabolizing enzymes. A pure1y mathematical extrapolation of therumour incidence from a carcinogenic dose (1 x 40mg/kg for a 20% hepatoma incidence in newborn mice) to human exposure levels (aboilt 0.1 ug/kg per day) would never have followed a step like the on~ found in our experiments. Our dose-effect study therefore shows how carcinogenitity data could be extrapolated in a biologically founded way to low doses. KW - Toxikologie Y1 - 1978 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80157 ER - TY - JOUR A1 - Lutz, Werner K. A1 - Schlatter, C. T1 - 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 - TY - JOUR A1 - Lutz, Werner K. A1 - Poetzsch, J. A1 - Schlatter, J. A1 - Schlatter, C. T1 - The real role of risk assessment in cancer risk management N2 - Rtgulatory aclio11s Iaken to reduu tht risk of harmfultffects of exposure to chemieals ofltn arenot commensurDtt with the toxicologicDf risk SJsstS&ment. A numbtr of factors relating to psychology, sociology, economics Dntl politics rather than science and medicine afftct tht final decision. Wemer Lutz and colleagues illustratt the situation using tht feuktmia-indudng chtmiCJJI benzene as an examplt. KW - Toxikologie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60730 ER - TY - JOUR A1 - Lutz, Werner K. A1 - 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 - 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 - 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 -