7089
1987
eng
bookpart
1
2013-08-20
--
--
Model risk analysis of nitrosatable compounds in the diet as precursors of potential endogenous carcinogens
The potential health risk posed by the endogenous formation of N-nitroso compounds (NOC) from nitrosation of dietary ureas, guanidines, amides, amino acids and amanes (primary, secondary and aromatic) was estimated according to the model:
Risk = ( daily intake of precursor] X (gastric concentration of nitrite ]n X [nitrosatability rate constant] X [cilrcinogenicity of derivative].
The daily intakes ofthese compound classes span five orders ofmagnitude (100 g/day amides, top; 1-10 mg/day secondary amines, ureas, bottom); the nitrosation rate constants span seven orders of magnitude (aryl amines, ureas, top; amides, secondary amines, bottom); and the carcinogenicity estimates span a 10 000-fold range from 'very strong' to 'virtually noncarcinogenic'. The resulting risk estimates likewise span an enormous range (nine orders of magnitude ): dietary ureas and aromatic amines combined with high nitrite concentration could pose as great a risk as the intake of preformed N-nitrosodimethylamine in the diet. In contrast, the risk posed by the in-vivo nitrosation of primary and secondary amines is probably negligible. The risk contributed by amides (including protein), guanidines and primary amino acids is intermediate between these two extremes.
8008
urn:nbn:de:bvb:20-opus-86188
In: Relevance of N-nitroso compounds to human cancer / ed. H. Bartsch. - Lyon: IARC, 1987. - S. 328-332. - (Centre International de Recherche sur le Cancer <Lyon>: IARC scientific publications ; 84). - ISBN 92-832-1184-7
Deutsches Urheberrecht
S. E. Shephard
C. Schlatter
Werner K. Lutz
deu
swd
Risikoanalyse
deu
swd
Carcinogen
deu
swd
Ernährung
Medizin und Gesundheit
open_access
Institut für Pharmakologie und Toxikologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/7089/Lutz_7089.pdf
6818
1979
eng
conferenceobject
1
2013-10-21
--
--
Modulation of the in vivo covalent binding of the carcinogen benzo(a)pyrene to rat liver DNA by selective induction of microsomal and nuclear aryl hydrocarbon hydroxylase activity
The influence of microsomal (mAHH) and nuclear (nAHH) aryl hydrocarbon hydroxylase activity on the covalent binding of t:titiated benzo(a)pyrene to rat liver DNA was evaluated in vivo. Induction ofmAHH was obtained after phenobarbitone treatment (180% of control), which increased DNA binding to 210%, but left the nAHH unchanged. mAHH and nAHH were slightly indilced with dieldrin (130% and 120%), but the binding remairred unchanged. The increasing effect of mAHlt as weil as the possibly decreasing effect of nAHH induction on the binding became obvious when the data of 11 individual rats were used to solve the equation Binding = aX(mAHH) + bX(nAHH) + c. Multiple linear regression analysis resulted in positive values for a and c, a negative value for b, and a multiple correlation coefficient R = 0.82. An influence of other enzymes involved in the metabolism of benzo(a)pyrene cannot be excluded. The Study shows clearly that the binding of a foreign compound to DNA in vivo is not only dependent on microsomal enzyme activities but also on nuclear activities even if the latter are considerably lower than those of mic'rosomes.
urn:nbn:de:bvb:20-opus-80132
8013
In: Mechanism of toxic action on some target organs : drugs and other substances ; proc. of the Europ. Soc. of Toxicology ; meeting held in Berlin (West), june 25 - 28, 1978 / Chambers, Philip L. - Berlin: Springer, 1979. - [Archives of toxicology / Supplement] ; 2; ISBN: 3-540-09305-2, p. 285-8.
Deutsches Urheberrecht
A. Viviani
Werner K. Lutz
deu
swd
DNA
eng
uncontrolled
Benzo(a)pyrene
eng
uncontrolled
DNA-Binding
eng
uncontrolled
Carcinogen
eng
uncontrolled
Enzyme
eng
uncontrolled
Induction
eng
uncontrolled
Aryl Hydrocarbon Hydroxylase
eng
uncontrolled
Rats
eng
uncontrolled
Phenobarbitone
eng
uncontrolled
Dieldrin
Medizin und Gesundheit
open_access
Institut für Anatomie und Zellbiologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6818/Lutz70.pdf
6814
1979
deu
article
1
2013-10-17
--
--
In vivo covalent binding of chemicals to DNA as a short-term test for carcinogenicity
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.
urn:nbn:de:bvb:20-opus-80127
8012
In: Mechanism of toxic action on some target organs : drugs and other substances ; proc. of the Europ. Soc. of Toxicology ; meeting held in Berlin (West), june 25 - 28, 1978. - Berlin: Springer, 1979. - [Archives of toxicology / Supplement] ; 2, ISBN: 3-540-09305-2, p. 411-415.
Deutsches Urheberrecht
Werner K. Lutz
C. Schlatter
deu
swd
DNA
eng
uncontrolled
DNA-Binding
eng
uncontrolled
Carcinogen
eng
uncontrolled
Short-term Carcinogenicity Test
eng
uncontrolled
Aflatoxin
eng
uncontrolled
Toluene
eng
uncontrolled
Tritiated Water
Medizin und Gesundheit
open_access
Institut für Pharmakologie und Toxikologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6814/Lutz69.pdf
6813
1984
eng
article
1
2013-10-17
--
--
Reduction of covalent binding of aflatoxin B1 to rabbit liver DNA after immunization against this carcinogen
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.
urn:nbn:de:bvb:20-opus-80116
8011
In: Disease, metabolism and reproduction in the toxic response to drugs and other chemicals : proc. of the Europ. Soc. of Toxicology meeting held in Rome, March 28 - 30, 1983. - Mitarb.: Chambers, Philip L. - Berlin: Springer, 1984 [Archives of toxicology / Supplement] ; 7, p. 249-252.
Deutsches Urheberrecht
M. Caviezel
A. P. Aeschbach
Werner K. Lutz
C. Schlatter
deu
swd
Krebs
deu
swd
DNA
eng
uncontrolled
Aflatoxin
eng
uncontrolled
Cancer prevention
eng
uncontrolled
Carcinogen
eng
uncontrolled
Covalent binding
eng
uncontrolled
DNA
eng
uncontrolled
Immunization
Medizin und Gesundheit
open_access
Institut für Pharmakologie und Toxikologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6813/Lutz55.pdf
5497
1980
eng
article
1
2012-01-27
--
--
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
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.
urn:nbn:de:bvb:20-opus-61114
6111
Journal of Cancer Research and Clinical Oncology (1980) 98, 2, 139-52.
Deutsches Urheberrecht
A. Viviani
A. von Däniken
C. Schlatter
Werner K. Lutz
deu
swd
Toxikologie
eng
uncontrolled
Carcinogen
eng
uncontrolled
Benzo(a)pyrene-DNA binding
eng
uncontrolled
Enzyme induction
eng
uncontrolled
Aryl hydrocarbon rnonooxygenase
eng
uncontrolled
Epoxide hydrolase
eng
uncontrolled
Glutathione Stransferase
Medizin und Gesundheit
open_access
Institut für Pharmakologie und Toxikologie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/5497/Lutz66.pdf
2452
2008
deu
doctoralthesis
1
2008-08-19
--
2008-08-07
Kombinationswirkungen nicht linearer Dosis-Wirkungsbeziehungen
Mixture analysis with nonlinear dose response
Um realistische Risikoabschätzungen von karzinogenen und genotoxischen Expositionen besser bewerten zu können, bedarf es Untersuchungen von Kombinationen welche sich von der Einzellstoffbetrachtung loslöst. Die Zielsetzung der vorliegenden Arbeit bestand darin, herauszufinden, ob die Gentoxizität einer Kombination in ihrer Stärke vom erwarteten Effekt der normalen Additivität abweicht, wenn die Kurven der Dosis – Wirkungsbeziehung der Einzelkomponenten nicht lineare Verläufe zeigen. Dabei muss zwischen Dosisaddition und Wirkaddition der Kombinationen unterschieden werden, das heißt ob die Einzelkomponenten einen untereinander ähnlichen oder unabhängigen Wirkmechanismus verfolgen. Für nicht lineare Dosis – Wirkungsbeziehungen differieren also die Kurvenverläufe zwischen Dosisaddition und Wirkaddition und bilden einen möglichen Bereich der Additivität zwischen ihnen (auch: „Hülle der Additivität“). Nur Reaktionen welche außerhalb dieses Bereiches ablaufen, dürfen als synergistische oder antagonistische Effekte bezeichnet werden. Diese Überlegungen wurden überprüft mit der Analysierung von Mikrokernen, induziert in L5178Y Maus – Lymphom – Zellen durch die methylierenden Substanzen Methylmethansulfonat (MMS) und Methyl-Nitroso-Urea (MNU), sowie dem Topoisomerase II Inhibitor Genistein (GEN). Alle drei Chemikalien erzeugen reproduzierbare sublineare Dosis – Wirkungsbeziehungen. Für die Analyse der Kombinationseffekte wurden diese Substanzen in drei binären Mixturen miteinander gemischt. Für MMS + MNU war der Effekt vereinbar mit Dosisaddition und lag signifikant höher als der vorkalkulierte Effekt der Netto – Wirkung. Für MMS + GEN lag der gemessene Effekt über der Wirkaddition, jedoch unter der Dosisaddition. Für MNU + GEN lag der gemessene Effekt unterhalb der Wirkaddition und deutete damit auf einen echten Antagonismus hin. In Unkenntnis des sublinearen Dosis – Wirkungsverhaltens der Einzelsubstanzen wäre ein synergistischer Effekt von MMS mit beiden Substanzen MNU und GEN fälschlicherweise vorausgesagt worden. Der beobachtete Unterschied zwischen MMS und MNU und deren jeweiligen Kombination mit GEN wäre mit einer stark vereinfachten Interpretation der DNA - Methylierung nicht vorausgesagt worden. Ursachen könnten eine doch zu unterschiedliche Form der DNA – Methylierung und / oder epigentische Faktoren sein. Zusammenfassend kann man sagen, dass Kenntnisse der Nichtlinearität von Dosis – Wirkungskurven der einzelnen Substanzen ausschlaggebend für die Analyse von Synergismus oder Antagonismus in deren Kombinationen ist. Weiterhin ist ein Vorwissen über tiefere mechanistische Vorgänge hilfreich für eine Vorhersage von ähnlichen oder unabhängigen Wirkprozessen.
Distinction between dose addition and response addition for the analysis of the toxicity of mixtures may allow differentiation of the components regarding similar versus independent mode of action. For nonlinear dose responses for the components, curves of dose addition and response addition differ and embrace an "envelope of additivity." Synergistic or antagonistic interaction may then be postulated only if the mixture effect is outside this surface. This situation was analyzed for the induction of micronuclei in L5178Y mouse lymphoma cells by the two methylating agents methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU) and the topoisomerase-II inhibitor genistein (GEN). All three chemicals reproducibly generated sublinear (upward convex) dose-response relationships. For the analysis of mixture effects, these genotoxic agents were investigated in the three binary combinations. Statistical testing for dose addition along parallel exponential dose responses was performed by linear regression with interaction based on the logarithm of the number of cells that contain micronuclei. For MMS+MNU, the mixture effect was compatible with dose addition (i.e., significantly larger than calculated for the addition of net responses). For MMS+GEN, the measured effect was larger than for response addition but smaller than for dose addition. For MNU+GEN, the measured effect was below response addition, indicative of true antagonism. In the absence of knowledge on the sublinear dose-response relationships for the individual components, a synergistic effect of MMS on both MNU and GEN would have been postulated erroneously. The observed difference between MMS and MNU when combined with GEN would not have been predicted on the basis of a simplistic interpretation of DNA methylation as the mode of action and may be due to differences in the profile of DNA methylations and/or epigenetic effects. We conclude that knowledge of nonlinearities of the dose-response curves of individual components of a mixture can be crucial to analyze for synergism or antagonism and that an in-depth mechanistic knowledge is useful for a prediction of similarity or independence of action.
urn:nbn:de:bvb:20-opus-28522
2852
Oliver Tiedge
deu
swd
Kleinkern
deu
swd
Kombination
deu
swd
Dosis-Wirkungs-Beziehung
deu
swd
Synergie
deu
swd
Addition
deu
swd
Gegensatz
deu
swd
Risikoanalyse
deu
swd
Genanalyse
deu
swd
Genmutation
deu
swd
Carcinogen
deu
uncontrolled
Mikrokern
deu
uncontrolled
sublinear
deu
uncontrolled
Mauslymphomzellen
deu
uncontrolled
genotoxisch
eng
uncontrolled
alkylating agents
eng
uncontrolled
genotoxicity
eng
uncontrolled
cell culture
eng
uncontrolled
dose response
eng
uncontrolled
mixture models
Medizin und Gesundheit
open_access
Institut für Pharmakologie und Toxikologie
Universität Würzburg
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/2452/tiedgediss.pdf.pdf