Biomedical subjects

H G Neumann

Publications and source records attributed to H G Neumann.

At least 37 records · Page 2Linked to original sources

PubMed1997

[Incidence and outcome of pregnancies with contraception].

In 1992, 1531 women aging 25-45 years from 5 urban and rural regions were interviewed about infertility and subfecundity within the German part of a study by the European community. 1248 of them had a positive reproductive history with 3018 pregnancies. 400 (= 13.25%) occurred during contraception. This affected 296 women (= 19.6% of all women). Smoking seems to have a promotion effect. The risk of ectopic pregnancies seems to be higher in contraceptive users. The highest fetal loss was found in women using an IUD. There were no differences in the course and outcome of pregnancy between users and nonusers of contraceptives. About 40% of the women in the corresponding group reported an irregular application of the contraceptive technique.

Adult↗

PubMed1996

2-Nitrosofluorene and N-hydroxy-2-aminofluorene react with the ubiquinone-reduction center (center N) of the mitochondrial cytochrome bc1 complex.

We determined the sites of artificial electron transfer onto 2-nitrosofluorene (NOF), a metabolite of carcinogenic 2- acetylaminofluorene in mitochondria and isolated cytochrome bc1 complex. NOF-induced O2 consumption in mitochondria was sensitive to antimycin A, but insensitive to myxothiazol. In the isolated cytochrome bc1 complex, NOF induced rapid MOA-stilbene-insensitive reoxidation of cytochrome b, whereas in the presence of antimycin A, reoxidation was very slow. The corresponding hydroxylamine, N-hydroxy-2-aminofluorene (N-OH-AF), reduced cytochrome b specifically through center N of the cytochrome bc1 complex. We conclude that NOF and N-OH-AF bind to center N of the cytochrome bc1 complex and act as electron acceptor and donor, respectively. The N-OH-AF/NOF interconversion is considered to be involved in the cytotoxicity of 2-acetylaminofluorene in vivo.

Animals↗

PubMed1996

Acute and chronic toxicity of aromatic amines studied in the isolated perfused rat liver.

Isolated perfused livers from male Wistar rats were used to study acute and chronic toxic effects of carcinogenic aromatic amines. We investigated the hypothesis that aromatic amines can generate reactive oxygen species as part of their metabolism. Concentrations of 200-400 microM of 2-acetylaminofluorene (AAF), N-hydroxy-AAF, trans-4-acetylaminostilbene (AAS), N-hydroxy-AAS, and N-hydroxy-2-acetylaminophenanthrene in the recirculating perfusate were not toxic in a 2-hr exposure time as assessed by LDH efflux into the perfusate, glutathione excretion into bile, and changes of the beta-hydroxybutyrate/acetoacetate ratio in the perfusate. N-Acetoxy-AAF, however, was severely toxic. Menadione served as a positive control. It is concluded that exposures likely to occur in carcinogenicity studies with these aromatic amines will not be acutely toxic. In additional experiments the isolated perfused liver system was used to demonstrate chronic effects generated by feeding the carcinogenic dose of 0.02% AAF for up to 12 weeks. The following alterations were observed in livers from AAF-fed animals. excretion of glutathione into bile is drastically reduced after 5 or more weeks, increasingly less glucose is released into the perfusate, and oxygen consumption is constantly increased by 20% after 3 and more weeks of AAF feeding. Whereas the total glutathione level increased with time in homogenates of such livers, it decreased in the mitochondrial fraction. The results are interpreted as adaptive responses to chronic toxic effects of AAF which may be related to the promoting properties of this carcinogen.

2-Acetylaminofluorene↗

PubMed1996

Assessment of environmental and occupational exposures to butadiene as a model for risk estimation of petrochemical emissions.

1,3-Butadiene (BD) is an important industrial chemical and environmental contaminant, e.g. in urban air, traffic exhausts and tobacco smoke. It has been shown to be genotoxic in vitro and in vivo and carcinogenic in rodents, mice being more sensitive than rats. The present study confirmed this species difference. Using micronuclei in erythrocytes or bone marrow as a marker, mice responded at an effective level of 50 p.p.m., while the highest ineffective level in rats was 500 p.p.m. (inhalation of BD for 5 days). A dose-dependent increase in N-terminal valine haemoglobin adducts was seen in both rats and mice, but the adduct levels in the latter species were on average five times higher. For the first time, specific N6-alkyldeoxyadenosine adducts were identified in lung and liver DNA of rats exposed to BD by inhalation. No significant difference in DNA adduct level was seen in lung tissue of rats and mice at similar exposure levels. Occupational exposure levels to BD in the European Process industry are variable, but generally < 1 p.p.m. Haemoglobin adduct levels were seen to be increased among the worker groups with higher potential exposure to BD (process work, bomb voiding and repair duties) as compared with adduct levels in less exposed workers in maintenance and the laboratory or control personnel. However, the N-terminal valine haemoglobin adducts measured in the workers were one to two orders of magnitude lower than extrapolated for the same exposure dose in mice. In the same workers no exposure-related effects were seen in the cytogenetic parametres studied, i.e. chromosomal aberrations, sister chromatid exchanges or micronuclei in peripheral blood lymphocytes, or in the Ras oncoprotein levels of plasma samples. The studies so far conducted suggest that human exposure at the levels seen in the present day process industry can be documented at the biological dose level using haemoglobin adduct measurement, but not at the biological effect level using cytogenetic biomarkers. In order to quantitate the human genotoxic risk of BD exposure more work needs to be done on the role of other active BD metabolites than 1,2-epoxy-3-butene and on the genetic polymorphisms controlling the variability of individual responses.

Air Pollutants↗

PubMed1995

Early initiating and promoting effects in 2-AAF-induced rat liver carcinogenesis: an immunohistochemical study.

2-Acetylaminofluorene (2-AAF) is a complete carcinogen in rat liver. To investigate the specific properties, that distinguish 2-AAF from incomplete carcinogens, rats were fed 0.02% AAF in the diet for 6, 12, 16 weeks and some indicators of genotoxic and chronic toxic effects were studied immunohistochemically. GST-P, a marker for single initiated cells and preneoplastic foci, was induced in response to 2-AAF exposure. The effects were slight after 6 weeks of feeding, after 12 weeks GST-P-positive preneoplastic foci were present. The proto-oncogenes c-fos and c-jun are induced by several tumor promoters. In the present study c-FOS protein levels were increased in all 2-AAF treated animals at early stages not only in preneoplastic foci. However, all GST-P-positive foci were also c-FOS-positive. Surprisingly c-JUN was not enhanced in GST-P positive foci. It was comparatively expressed in hepatocytes and bile duct cells in all animals. We did not observe any immunolabeling for p53, either in preneoplastic foci or in hepatocytes from treated animals. A significant increase of apoptoses was noted in the whole liver lobule but also gathered in groups in the periportal area. The results support our proposal that oxidative stress and energy impairment in the mitochondria of periportal hepatocytes trigger morphological alterations in the rat liver.

2-Acetylaminofluorene↗

PubMed1995

Cytotoxicity of aromatic amines in rat liver and oxidative stress.

A possible role of oxidative stress in producing acute toxicity in rat liver by aromatic amines and nitroarenes was tested. Oxidative stress was assessed by measuring the excretion of oxidized glutathione (GSSG) into the bile in isolated perfused livers and in female Wistar rats with cannulated bile ducts. The liver perfusion system was calibrated with t-butylhydroperoxide (t-BH) and menadione. The minimal concentration in the perfusate of t-BH necessary to observe a significant effect was 18 microM for 5 min. It was calculated that rat liver is able to cope with an extra production of about 70 nmol GSSG per min and g liver before GSSG is excreted into bile. No effect was observed when 2-aminofluorene, 2-acetylaminofluorene (AAF), trans-4-aminostilbene, and trans-4-acetylaminostilbene were added to the perfusate at 50 microM for 20 min. Moreover, 2-aminofluorene, trans-4-aminostilbene, 2-nitrofluorene and trans-4-nitrostilbene did not increase GSSG excretion when administered simultaneously with effective concentrations of t-BH. AAF was not acutely toxic, blood transaminases and lipid peroxidation were not increased with AAF doses as high as 1 mmol/kg. Since the dose rate of aromatic amines, like AAF, in feeding studies for tumor formation is about 100 times below that examined in the isolated perfused livers, it is highly unlikely that oxidative stress is generated by metabolites able to undergo redox cycling and that reactive oxygen contributes to acute toxic effects.

2-Acetylaminofluorene↗

PubMed1995

A metabolite of carcinogenic 2-acetylaminofluorene, 2-nitrosofluorene, induces redox cycling in mitochondria.

The present study was designed to confirm the recent proposal that 2-nitrosofluorene (2-NOF) as well as N-hydroxy-2-aminofluorene (N-OH-AF) induce a redox-cycle in rat liver mitochondria as part of the chronic toxic effects of the carcinogen 2-acetylaminofluorene (2-AAF). The formation of O2.- was demonstrated in submitochondrial particles by the formation of adrenochrome with NADH and succinate as respiratory substrates. 2-NOF was as effective as paraquat, a known redox-cycler, the lowest effective concentration being 0.4 nmol 2-NOF/mg protein. Experiments with isolated mitochondria showed that 2-NOF, in contrast to N-OH-AF, induces cyanide-resistant O2 consumption only in the presence of respiratory substrates, indicating that the reduction, but not the reoxidation, depends on a continuous flow of electrons through the respiratory chain of the mitochondrial membrane. Lipid peroxidation was estimated by the formation of thiobarbituric-acid-reactive substances. In comparison to the well-known prooxidant tert-butylhydroperoxide, 2-NOF was not significantly active. The results support the notion that 2-NOF induces oxidative stress by mitochondrial redox-cycling in vivo. Effects other than lipid peroxidation seem to be important for the chronic toxicity of 2-AAF.

2-Acetylaminofluorene↗

PubMed1995

The implications for risk assessment of measuring the relative contribution to exposure from occupation, environment and lifestyle: hemoglobin adducts from amino- and nitro-arenes.

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).

Carcinogens, Environmental↗

PubMed1995

Macromolecular adducts caused by environmental chemicals.

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.

Biomarkers↗

PubMed1994

Biomonitoring of aromatic amines. IV: Use of hemoglobin adducts to demonstrate the bioavailability of cleavage products from diarylide azo pigments in vivo.

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.

3,3'-Dichlorobenzidine↗

PubMed1994

Synergistic effects of trans-4-acetylaminostilbene and 2-acetylaminofluorene at the level of tumor initiation.

The synergism of two carcinogenic aromatic amines with different tissue specificities was studied at the level of initiation in Wistar rats. Gamma-glutamyl transpeptidase and glutathione S-transferase P were used as markers for preneoplastic foci in liver. 2-Acetylaminofluorene (AAF) is a complete rat liver carcinogen, whereas trans-4-acetylaminostilbene (AAS) produces ear duct tumors quite selectively, but also acts as a strong initiator in rat liver. When these carcinogens were administered sequentially as two doses of each or simultaneously as four doses of a mixture to neonate animals, which then were treated with phenobarbital in the drinking water for promotion, the initiating activity was additive. When these chemicals were given to young adult animals within 4 weeks in two series of four doses, followed by partial hepatectomy and phenobarbital in the drinking water, the number of preneoplastic foci was greater in groups which had received AAS in both series or in the second series after AAF than in those groups which had received only AAF or AAF in the second series. The average size of foci depended clearly on the sequence in which the two carcinogens were administered. The foci were larger when AAF was given after AAS. The results support the notion that AAS is a strong initiator in rat liver, and that AAF, which is a complete liver carcinogen, has promoting properties under certain circumstances in addition to its initiating properties. The two carcinogens seem to produce the initiating lesions independently but the extent of initiation is additive in this model situation. The simplified neonatal rat liver model appears to be particularly suitable for investigating initiating properties and is proposed for studies of synergistic effects of genotoxic chemicals on the initiation stage, independent of organotropism. It avoids a number of complicating factors related to treatment schedule, forced proliferation rate and toxicity in other models.

2-Acetylaminofluorene↗

PubMed1994

The role of nongenotoxic mechanisms in arylamine carcinogenesis.

The growth of preneoplastic nodules during the feeding of a carcinogenic 2-acetylaminofluorene (2-AAF) regimen is preceded by several alterations in the physiologic homeostasis. Many of these alterations can be considered adaptive responses to the drug exposure. One property of AAF could be identified that clearly distinguishes this complete rat liver carcinogen from at least two other, incomplete rat liver carcinogens. Highly specific redox cycling in mitochondria was demonstrated in vitro, and this observation could well contribute an explanation of the morphologic and histochemical observations in vivo. It is emphasized that nongenotoxic effects may play an important role in the generation of tumors by genotoxic carcinogens.

2-Acetylaminofluorene↗

PubMed1994

Hydrolyzable hemoglobin adducts of polyfunctional monocyclic N-substituted arenes as dosimeters of exposure and markers of metabolism.

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.

Animals↗

PubMed1994

[The impact of reproductive loss for human fertility. Results of the German part of a European study of the epidemiology of infertility and subfertility].

Within the German part of an European Community study of the epidemiology of infertility and subfecundity we analysed the fetal loss (i.e. spontaneous abortions, artificial abortions, ectopic pregnancies, stillbirth, early neonatal death and all babies who died after the 7th day within the first year of life). For this investigation women from 5 urban and rural regions in Germany in the age group 25-45 years were selected in five districts from random samples of the local registers. 1531 interviews were conducted in 1992 by trained female interviewers in the same way as in the other participating European countries. 1248 of the women had a positive reproductive anamnesis with 3018 pregnancies. 565 (= 45.3% of women who were pregnant at any time) had fetal loss. In East Germany as well as in West Germany we found a positive age and pregnancy association. The main loss we observed in the age group under 20 and over 35 years. In all groups artificial abortion was the most important part of fetal loss (rural region of East Germany: 15.5% and West Germany: 13.1% of all registered pregnancies). The time to pregnancy (TTP) was prolonged in women over 30 years of age. Here we also found an increasing rate of spontaneous abortions. Smokers are more prevalent in women with ectopic pregnancies, spontaneous abortions and live born babies who died within the first 7 days after delivery.(ABSTRACT TRUNCATED AT 250 WORDS)

Abortion, Spontaneous↗

PubMed1994

[Accident in the Hoechst AG company 22 February 1993. 2. Public health evaluation].

A major chemical accident occurred on 22 February 1993 at plant Griesheim of Hoechst AG Frankfurt/Germany during which approximately 11.8 tons of a chemical mixture containing mostly chlorinated nitroarenes were emitted leading to serious contaminations in Schwanheim/Goldheim, a nearby housing area. Numerous inhabitants of the contaminated area complained of irritation of eyes, skin and mucous membranes, headache and nausea, and 92 persons with moderate symptoms were reported to the National Health Department. Urine samples were collected from the inhabitants of the affected area a few days after the accident and analysed for o-nitrophenol as a representative metabolite to assess the actual uptake of pollutants. O-nitrophenol, however, was also detected in the urine of not knowingly exposed control subjects, an observation not hitherto described in literature. The median levels of o-nitrophenol were three times higher in the exposed population than in the controls. Taking into account the data on pollution measured in the environment, the reported intoxication symptoms, the results of biomonitoring, and the published literature on the components of the mixture, the following conclusions were drawn: (1) The exposure was not high enough to cause severe acute toxic effects. (2) Although the emitted mixture contained carcinogenic components according to animal experiments, the transient exposure to these chemicals does not increase the tumour risk to any measurable extent, i.e. demonstrable by epidemiological methods, especially if weighed against the permanent exposure to "normal" urban pollution.

Accidents, Occupational↗

PubMed1993

Tumors in rat kidney generated by initiation with trans-4-acetylaminostilbene and several promoting treatments.

trans-4-Acetylaminostilbene (AAS) is a complete carcinogen in rats and produces quite selectively tumors in Zymbal's glands. On the basis of DNA adduct formation, it has been proposed that this model arylamine initiates neoplastic transformation of cells in many tissues, particularly liver and kidney, which, in the classical sense are considered to be non-target tissues for this chemical. In the present study an initiating treatment with AAS was followed by unilateral nephrectomy and the application of two nephrotoxic substances, gentamycin or beta-cyclodextrin which, among other activities, stimulate cell proliferation specifically in kidney. The initiating dose of AAS, given alone, gave rise to Zymbal's gland and mammary tumors in female Wistar rats within 88 weeks but not to liver or kidney tumors. When the initiation treatment was followed by unilateral nephrectomy, alone or in combination with gentamycin, or by beta-cyclodextrin, four tumors in two out of ten animals, eight tumors in three/ten, and seven tumors in three/ten, respectively, were observed in the kidney. The administered dose of gentamycin was not sufficient to induce tumors on its own. The results support the view that the genotoxic effects of AAS produce promotable lesions in rat kidney. None of the animals that had been treated with AAS, with or without other treatments, developed tumors or the predominant types of preneoplastic lesions in the liver within 88 weeks; this supports the notion that liver, like kidney, is not a target for complete carcinogenesis for this chemical.

Adenoma, Chromophobe↗

PubMed1993

The structure and function of the H-ras proto-oncogene are not altered in rat liver tumors initiated by 2-acetylaminofluorene, 2-acetylaminophenanthrene and trans-4-acetylaminostilbene.

Liver tumors were generated in Wistar rats in an initiation-promotion experiment. 2-Acetylaminofluorene (AAF), 2-acetylaminophenanthrene (AAP), and trans-4-acetylaminostilbene (AAS) were administered to newborn animals as initiators, and phenobarbital as a promoter was added to the drinking water after weaning. Livers were examined after 26, 52, 78, and 104 weeks. Tumors were present in all groups except for at the first time point. The potency of the initiators decreased in the order AAS > AAP > AAF. DNA from tumors of all groups and of control livers was analyzed for mutations in the H-ras gene, but no mutations could be found. The sequence of almost the entire H-ras gene was determined and was compared to other H-ras genes. There are some differences with the sequence in other rat strains, particularly in intron D containing the alternative splicing site. The expression of the H-ras gene has also been studied by various methods in enzyme altered foci and tumors, but no alterations could be found. It is, therefore, concluded that structural of functional alterations of this proto-oncogene are not involved in the generation of liver tumors in Wistar rats by the three genotoxic arylamines.

2-Acetylaminofluorene↗

PubMed1993

Hemoglobin adducts of N-substituted aryl compounds in exposure control and risk assessment.

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.

Amines↗