@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 Recent, so far unpublished findings with aflatoxin Mh macromolecule- bound aflatoxin Bh ·diethylstilbestrol, and 1,2-epithiobutyronitrile are included.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}
}
@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}
}
@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{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{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{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{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{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{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{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{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{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{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}
}