I Zwirner-Baier

University of Wuerzburg, Würzburg, Bavaria, Germany

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Publications (14)59.4 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Early indicators of aniline hydrochloride (AH) toxicity were investigated in male Fisher 344 rats for 1 or 4 weeks at dietary dose levels of 10, 30 or 100 mg/kg body weight (bw)/day (actual intake at least 6, 17 and 57 mg/kg). The doses were based on earlier studies that had shown spleen toxicity and carcinogenicity in male rats at 100 mg/kg/day but not at 10 mg/kg/day. In the present study a dose-related formation of haemoglobin adducts and Heinz bodies was found from 10 and 30 mg/kg bw/ day, respectively, onwards. Signs of anaemia (decreased red blood cell counts and increased reticulocytes) were recorded from 30 mg/kg onwards. At 100 mg/kg, an overt haemolytic anaemia was associated with increases in serum transferrin concentration and total iron binding capacity in the blood reflecting major perturbations in iron metabolism. At this dose there was an increase in peripheral neutrophil leucocytosis in the blood, indicating an inflammatory process in the spleen. Histopathologic evaluation showed a focal perisplenitis and haemosiderin deposition in sinusoidal Kupffer cells of the liver at 100 mg/kg. These results corroborate the contention that carcinogenic doses of aniline cause early effects on haematological parameters, inflammatory reaction in the spleen and perturbations in iron metabolism as a result of haemolytic anaemia. Accordingly, the carcinogenicity of aniline may be linked to definable threshold-related processes.
    Human &amp Experimental Toxicology 09/2004; 23(8):379-89. · 1.45 Impact Factor
  • I Zwirner-Baier, K Deckart, R Jäckh, H-G Neumann
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    ABSTRACT: The assessment of the carcinogenic properties of aniline is still controversial. Aniline has, if at all, genotoxic properties but is also acutely toxic and it has been proposed that the hematotoxic effects are responsible for the formation of hemangiosarcomas and fibrosarcomas in the spleen of male rats. As part of a bigger project in which the pathology of male Fischer F344 rats was studied after feeding 10, 30, or 100 mg/kg body weight aniline hydrochloride for 1 and 4 weeks in the diet, the aniline-hemoglobin (Hb) adducts were determined as a biochemical effect marker during those periods. An improved method for the work-up procedure and the adduct analysis was developed for this purpose. The Hb adduct levels increased proportionately with dose after 1 week, which indicates that metabolic activation was not saturated. After 4 weeks of feeding, the adduct levels increased less than proportionately, which suggests that a saturation process is involved. Since it is unlikely that metabolic activation was saturated, the results could be explained by a more rapid clearance of stressed erythrocytes at the carcinogenic dose level. The latter interpretation is supported by other observations which indicate that erythrocytes are damaged dose dependently. A no-observed-effect level (NOEL) has not been reached but could be close to the low dose of 10 mg/kg body weight per day. The Hb adduct formation at the low dose, however, indicates that this should not be considered a no-effect level (NEL). The results support the conclusion that hemolytic anemia is an essential prerequisite for aniline toxicity and tumor development, but they do not fully explain the tissue specificity.
    Archive für Toxikologie 01/2004; 77(12):672-7. · 5.22 Impact Factor
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    ABSTRACT: Methods for the assessment of exposures to diesel exhaust were evaluated, including various biomarkers of internal exposure and early biological effects. The impact of possible biomarkers of susceptibility was also explored. Underground workers (drivers of diesel-powered excavators) at an oil shale mine in Estonia were compared with surface workers. Personal exposures to particle-associated 1-nitropyrene (NP) were some eight times higher underground than on the surface. Underground miners were also occupationally exposed to benzene and polycyclic aromatic hydrocarbons, as indicated by excretion of urinary metabolites of benzene and pyrene. In addition, increased O(6)-alkylguanine DNA adducts were detected in the white blood cells of underground workers, suggesting higher exposure to nitroso-compounds. However, no differences between underground and surface workers were observed in the levels of other bulky DNA adducts determined by 32P-postlabelling, or in DNA damage. The study indicated that smoking, diet and residential indoor air pollution are important non-occupational factors to consider when interpreting biomonitoring results.
    Toxicology Letters 09/2002; 134(1-3):305-17. · 3.15 Impact Factor
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    ABSTRACT: Hemoglobin adducts were determined as biomarkers of 1,3-butadiene (BD) in 30 workers and 10 controls from an Italian BD plant and in 14 diesel-exposed miners. N-(2,3,4-trihydroxybutyl)valine (THBVal), an N-terminal valine globin adduct of reactive butadiene metabolites, was analyzed by gas chromatography/high resolution mass spectrometry after a modified Edman degradation and further acetylation. The BD exposure for the plant workers was 31 microg/m(3) (personal sampling). Whereas there was no detectable difference in hemoglobin adduct levels (range 17.7-61.4 pmol/g globin) between the total group of exposed and controls, slight but significant differences could be found between two subgroups of workers from different production units as well as one subgroup and controls (P<0.05), between smoking (n=13) and non-smoking exposed workers (n=17; P=0.066) as well as between smoking exposed workers and controls (P=0.055). Adduct levels of the miners (all non-smokers) were in the same range as those of the Italian BD-workers and controls. The internal exposure and strain measured by THBVal levels resulting from a very low occupational BD exposure was in the range of the contribution of moderate smoking.
    Chemico-Biological Interactions 06/2001; 135-136:675-8. · 2.97 Impact Factor
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    ABSTRACT: The genotoxic effects of 2-acetylaminofluorene (AAF) alone cannot explain the formation of rat liver tumors. It has been proposed that mitochondrial effects are associated with its tumor-promoting properties. These mitochondrial effects are thought to trigger apoptosis and regenerative proliferation, which alters the liver lobule in a cirrhosis-like manner. A situation is generated which favors the growth of initiated cells. To test this sequence of events, the dose dependence of early effects with time was studied. Male Wistar rats received 50, 100, 200, 400, or 800 ppm AAF in the diet and the following endpoints were analyzed at 2, 4, 8, and 16 weeks of feeding: apoptotic cell death, cell proliferation, GST-P-positive foci (placental form of glutathione S-transferase), and morphological alterations. Hydrolyzable hemoglobin adducts were used as a dosimeter for metabolic activation after 2 weeks of feeding. The hemoglobin adduct levels increased linearly with dose. With the conventional carcinogenic concentration of 200-ppm AAF in the diet, the number of apoptoses increased first, predominantly in the periportal area (2 weeks). Cell proliferation followed with some delay (4 weeks). This reflects regenerative tissue response and not the growth of initiated cells, because the number of enzyme-altered foci was still extremely low at that time. Foci developed only later when the morphology had changed. With 50 ppm AAF in the diet, a no-effect level had not been reached for any of the endpoints, but foci developed much more gradually than with higher doses. Unexpectedly, the proliferative response stabilized at 8 weeks with a labeling index of 12-17, with all AAF concentrations. The observed sequence of events supports the hypothesis. It is concluded that (1) The proliferation of initiated cells-defined as promotable cells-is largely determined by the cellular environment, such as morphologically altered liver. (2) The morphological alterations in rat liver result from imperfect regeneration from toxic effects. (3) Imperfect regeneration results from limitations in the possibilities to adapt to chemical stress. (4) If these limits are overwhelmed and morphology has changed to a certain extent, preneoplastic foci develop; this occurs much faster, at least, than without these changes.
    Toxicological Sciences 06/2000; 55(1):44-51. · 4.33 Impact Factor
  • I Zwirner-Baier, H G Neumann
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    ABSTRACT: Diesel exhaust contains numerous genotoxic carcinogens. It is essentially unknown to which extent this source contributes to the total load of these chemicals in humans. One possible approach to the problem is to find suitable biomarkers. To this end five polycyclic mononitroarenes (nitro-PAH) were selected and methods developed to determine the sulfinic acid-type hemoglobin adducts they form in vivo. The nitro-PAHs are: 1-nitropyrene, 2-nitrofluorene, 3-nitrofluoranthene, 9-nitrophenanthrene, and 6-nitrochrysene. Hydrolysis of the hemoglobin adducts yields the respective arylamines which were analyzed by gas chromatography/mass spectrometry. The detection limit was 0.01-0.08 pmol/g Hb. Blood samples were analyzed from 29 bus garage workers, occupationally exposed to diesel exhaust, and from 20 urban hospital workers and 14 rural council workers as controls. Hb adducts above the detection limit were found in most blood samples. The most abundant cleavage products were 1-aminopyrene and 2-aminofluorene with levels ranging from 0.01 to 0.68 pmol/g Hb. However, there was no significant difference between the groups for 1-nitropyrene and 2-nitrofluorene supporting the conclusion that both are widespread environmental contaminants resulting in significant background exposures. A significant difference on a group from individuals from urban and rural areas was found only if all five adducts were added, this may indicate an additional exposure from traffic. The new specific nitro-PAH Hb adducts are proposed to be used as biomarkers to trace the sources and to identify above-background exposures.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 05/1999; 441(1):135-44. · 3.90 Impact Factor
  • I Zwirner-Baier, H G Neumann
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    ABSTRACT: Aromatic amines are metabolically activated by N-oxidation of either the amine or the acetamide as a first step and esterification of the resulting N-hydroxyl derivatives as a second step. Both pathways may lead to DNA-adducts and subsequently to DNA lesions and mutations. Since the accumulation of non-acetylated adducts has been associated with tumour initiating properties, the balance between acetylation and deacetylation may greatly influence the biological effect. Hydrolysable haemoglobin adducts representing the bioavailability of N-hydroxylamines and the corresponding nitroso-derivatives were analysed following oral administration to female Wistar rats of two arylamine-acetamide couples: 4-aminobiphenyl and 2-aminofluorene, and two arylamine-acetamide-diacetamide triples: benzidine and 3,3'-dichlorobenzidine. The results show that the monoacetamides are readily deacetylated in vivo whereas the diacetamides are not. A dynamic equilibrium is indicated to exist between acetylation and deacetylation, which depends on substrate specificity, and the role of deacetylation is emphasised. In addition, acetylation polymorphism was studied with 4-chloroaniline and 3,3'-dichlorobenzidine in slow acetylating A/J and rapid acetylating C57BL/6J mice. The slow acetylator genotype was associated with significantly higher haemoglobin-adduct levels for both arylamines. The results provide additional support for the use of haemoglobin adducts in biomonitoring as a dosimeter for the biologically active dose of arylamines/arylacetamides. Moreover, biomonitoring of haemoglobin adducts may provide information about an individual's susceptibility to the toxic and carcinogenic effects of these chemicals.
    Archive für Toxikologie 07/1998; 72(8):499-504. · 5.22 Impact Factor
  • H G Neumann, I Zwirner-Baier, C van Dorp
    Archives of toxicology. Supplement. = Archiv für Toxikologie. Supplement 02/1998; 20:179-87.
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    H G Neumann, O Albrecht, C van Dorp, I Zwirner-Baier
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    ABSTRACT: We describe three biomonitoring studies in which hemoglobin (Hb) adducts were used as biochemical markers to assess indirectly the target dose of genotoxic chemicals. We monitored the exposure to 1,3-butadiene in occupationally exposed workers and in two control groups by analyzing the adducts formed by the reaction of the first activation product, butadiene monoepoxide, with the terminal valine of Hb; we also measured hydrolyzable adducts formed by the reaction of metabolically formed nitroso derivatives with Hb from five selected nitropolycyclic aromatic hydrocarbons (1-nitropyrene; 2-nitrofluorene, 3-nitrofluoranthrene, 6-nitrochrysene, and 9-nitrophenanthrene) in coke oven workers of different job categories and control workers of the same geographical area. We detected hydrolyzable adducts from monocyclic nitroarenes in blood from individuals living in a contaminated area where explosives had been produced and from controls. The contaminants considered were 2,4,6-trinitrotoluene; 2,4- and 2,6-dinitrotoluene; and 1,3-dinitrobenzene. Differences between groups were significant, but interindividual variation was great and back-ground exposures must be considered.
    Clinical Chemistry 01/1996; 41(12 Pt 2):1835-40. · 7.15 Impact Factor
  • H G Neumann, C van Dorp, I Zwirner-Baier
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    ABSTRACT: Recent progress in biomonitoring allows measurement of internal exposure of individuals ranging from occupational and life style exposures to environmental levels. Ten specific hemoglobin adducts generated by polycyclic and monocyclic nitro-arenes were measured in coke oven workers and residents living on ground contaminated with explosive wastes, respectively. Consistently, adducts were found in most 'exposed' as well as control individuals, interindividual variation being great. Adduct levels in the majority of exposed individuals were within the range of reference values (95 percentile). Although hemoglobin adduct levels do not directly reflect genotoxic potential and potency of the parent compounds, they correlate with the biologically active dose. On the basis of such target doses, the contribution of specific exposures relative to 'background' and to related chemicals can be assessed. The impact of 'relative risk' on risk perception and risk management is to provide a rationale for the application of the ALARA principle (As Low As Reasonably Achievable).
    Toxicology Letters 01/1996; 82-83:771-8. · 3.15 Impact Factor
  • Hans-Günter Neumann, Corinne van Dorp, Iris Zwirner-Baier
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    ABSTRACT: Recent progress in biomonitoring allows measurement of internal exposure of individuals ranging from occupational and life style exposures to environmental levels. Ten specific hemoglobin adducts generated by polycyclic and monocyclic nitro-arenes were measured in coke oven workers and residents living on ground contaminated with explosive wastes, respectively. Consistently, adducts were found in most 'exposed' as well as control individuals, interindividual variation being great. Adduct levels in the majority of exposed individuals were within the range of reference values (95 percentile). Although hemoglobin adduct levels do not directly reflect genotoxic potential and potency of the parent compounds, they correlate with the biologically active dose. On the basis of such target doses, the contribution of specific exposures relative to 'background' and to related chemicals can be assessed. The impact of 'relative risk' on risk perception and risk management is to provide a rationale for the application of the ALARA principle (As Low As Reasonably Achievable).
    Toxicology Letters 12/1995; 82-83C:771-778. · 3.15 Impact Factor
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    I Zwirner-Baier, F J Kordowich, H G Neumann
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    ABSTRACT: Hemoglobin adducts of 10 polyfunctional amino- and nitro-substituted benzenes and toluenes were analyzed: 2,4,6-trinitrotoluene, 2,4- and 2,6-dinitrotoluene, 2-amino-4-nitrotoluene, 4-amino-2-nitrotoluene, 2,4- and 2,6-diaminotoluene, 1,3-dinitrobenzene, 1-amino-3-nitrobenzene, and 1,3-diaminobenzene. A single dose (0.5 mmole/kg) of the test compounds was administered to female Wistar rats by gavage, and blood extracted and hemoglobin prepared after 24 hr. One or more cleavage products could be obtained in each case by hydrolyzing hemoglobin (Hb). Hemoglobin binding indices (HBI: binding [mmole/mole Hb]/dose [mmole/kg]) and the ratios of hydrolyzable adducts were determined. The HBI ranged between < 0.02 and 69.0. The results indicate the in vivo formation of several, covalently bound, hydrolyzable hemoglobin adducts. Conclusions on prevailing metabolic pathways can be drawn. Total binding of several compounds seems sufficient for biomonitoring of human blood samples. These chemicals are considered representative for environmental contamination with explosives of this type, and we propose their Hb adducts be used as dosimeters for human exposure to these suspected carcinogens.
    Environmental Health Perspectives 10/1994; 102 Suppl 6:43-5. · 7.26 Impact Factor
  • I Zwirner-Baier, H G Neumann
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    ABSTRACT: The release and availability of the carcinogenic component of the soluble azo dye Direct Red 46 and the insoluble azo pigment Pigment Yellow 17 were analyzed in Wistar rats using hemoglobin adducts as a dosimeter. The levels of hemoglobin adducts were found to be very low. Intestinal cleavage and release of 3,3'-dichlorobenzidine (3,3'-DCB) from Direct Red 46 and Pigment Yellow 17 was calculated to be 3% and 0.6% of the dose, respectively, in a 4-week feeding study. It is proposed to measure blood samples from exposed humans in order to test the applicability of the method and eventually to use it for controlling human exposure to the carcinogenic colorant components.
    Archive für Toxikologie 02/1994; 68(1):8-14. · 5.22 Impact Factor
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    ABSTRACT: Arylamines, nitroarenes, and azo dyes yield a common type of metabolite, the nitroarene, which produces a hydrolyzable adduct with protein and is closely related to the critical, ultimate toxic and genotoxic metabolite. The target dose as measured by hemoglobin adducts in erythrocytes reflects not only the actual uptake from the environment but also an individual's capacity for metabolic activation and is therefore an improved dosimeter for human exposure. The usefulness of hemoglobin adducts in molecular epidemiology is now widely recognized. With regard to risk assessment, many questions need to be answered. The described experiments in rats address some of these questions. The relationship between binding to hemoglobin in erythrocytes and to proteins in plasma has been found to vary considerably for a number of diamines. The fraction of hydrolyzable adducts out of the total protein adducts formed also varies in both compartments. This indicates that the kind of circulating metabolites and their availability in different compartments is compound specific. This has to do with the complex pattern of competing metabolic pathways, and the role of N-acetylation and deacetylation is emphasized. An example of nonlinear dose dependence adds to the complexity. Analysis of hemoglobin adducts reveals interesting insights into prevailing pathways, which not only apply to the chemical, but may also be useful to assess an individual's metabolic properties. In addition, it is demonstrated that the greater part of erythrocytes and benzidine-hemoglobin adducts are eliminated randomly in rats, i.e., following first-order kinetics.
    Environmental Health Perspectives 04/1993; 99:65-9. · 7.26 Impact Factor