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H Greim

Publications and source records attributed to H Greim.

At least 37 records · Page 2Linked to original sources
PubMed1998

Changes in the classification of carcinogenic chemicals in the work area. (Section III of the German List of MAK and BAT values).

Carcinogenic chemicals in the work area were previously classified into three categories in section III of the German List of MAK and BAT values (the list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification was based on qualitative criteria and reflected essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. In the new classification scheme the former sections IIIA1, IIIA2, and IIIB are retained as categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to the risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by non-genotoxic mechanisms, and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose/response relationships and toxicokinetics and for which risk at low doses can be assessed are classified in category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for category 4 (1,4-dioxane) and category 5 (styrene) are presented.

Animals↗
PubMed1998

Toxicity of aliphatic amines: structure-activity relationship.

SARs may enable the evaluation of the toxic potential of chemicals by drawing conclusions from available data on structurally-related chemicals, thus reducing the need for further testing. The Advisory Committee on Existing Chemicals of Environmental Relevance (BUA) [1,2] of the German Chemical Society (Gesellschaft Deutscher Chemiker [GDCh]) has compiled data on the toxicity and ecological impact for several groups of chemicals [3, 4]. In the present review, some common toxicological properties for aliphatic amines were revealed after evaluation and comparison of the toxicity data.

Administration, Oral↗
PubMed1998

Stable expression of human cytochrome P450 1B1 in V79 Chinese hamster cells and metabolically catalyzed DNA adduct formation of dibenzo[a,l]pyrene.

Chinese hamster V79 cell lines were constructed for stable expression of human cytochrome P450 1B1 (P450 1B1) in order to study its role in the metabolic activation of chemicals and toxicological consequences. The new V79 cell lines were applied to studies on DNA adduct formation of the polycyclic aromatic hydrocarbon (PAH) dibenzo[a,l]pyrene (DB[a,l]P). This compound has been found to be an environmental pollutant, and in rodent bioassays it is the most carcinogenic PAH yet discovered. Activation of DB[a,l]P in various metabolizing systems occurs via fjord region DB[a,l]P-11, 12-dihydrodiol 13,14-epoxides (DB[a,l]PDE): we found that DB[a,l]P is stereoselectively metabolized in human mammary carcinoma MCF-7 cells to the (-)-anti- and (+)-syn-DB[a,l]PDE which both bind extensively to cellular DNA. To follow up this study and to relate specific DNA adducts to activation by individual P450 isoforms, the newly established V79 cells stably expressing human P450 1B1 were compared with those expressing human P450 1A1. DNA adduct formation in both V79 cell lines differed distinctively after incubation with DB[a,l]P or its enantiomeric 11,12-dihydrodiols. Human P450 1A1 catalyzed the formation of DB[a,l]PDE-DNA adducts as well as several highly polar DNA adducts as yet unidentified. The proportion of these highly polar adducts to DB[a,l]PDE adducts was dependent upon both the concentration of DB[a,l]P and the time of exposure. In contrast, V79 cells stably expressing human P450 1B1 generated exclusively DB[a,l]PDE-DNA adducts. Differences in the total level of DNA binding were also observed. Exposure to 0.1 microM DB[a,l]P for 6 h caused a significantly higher level of DNA adducts in V79 cells stably expressing human P450 1B1 (370 pmol/mg of DNA) compared to those with human P450 1A1 (35 pmol/mg of DNA). A 4-fold higher extent of DNA binding was catalyzed by human P450 1B1 (506 pmol/mg of DNA) compared to human P450 1A1 (130 pmol/mg of DNA) 6 h after treatment with 0.05 microM (-)-(11R,12R)-dihydrodiol. In cells stably expressing human P450 1B1 the DNA adducts were derived exclusively from the (-)-anti-DB[a,l]PDE. These results indicate that human P450 1B1 and P450 1A1 differ in their regio- and stereochemical selectivity of activation of DB[a,l]P with P450 1B1 forming a higher proportion of the highly carcinogenic (-)-anti-(11R, 12S,13S,14R)-DB[a,l]PDE metabolite.

Animals↗
PubMed1998

Biokinetic studies in humans with stable isotopes as tracers. Part 2: Uptake of molybdenum from aqueous solutions and labelled foodstuffs.

Molybdenum (Mo) has been identified as an essential trace mental for humans. The present study was aimed at the assessment of data on intestinal Mo absorption from aqueous solutions and from foodstuffs in humans applying the methodology for intrinsic labelling described in Part 1. The intestinal absorption of Mo was investigated by means of a double tracer method in 3 healthy volunteers on a total of 15 occasions. When administered as aqueous solution, almost complete uptake of Mo was observed up to doses of 1 mg and only a slight decrease for higher doses. But addition of black tea reduces the absorbed fraction by about a factor of ten. Studying Mo absorption from food, intrinsically labelled cress showed a reduced uptake as compared to extrinsically labelled cress and aqueous solutions. Even less Mo was absorbed from an extrinsically labelled composite meal. The data obtained demonstrate a pattern of intestinal Mo absorption which is different from that of other essential trace metals, e.g., Fe or Co.

Food↗
PubMed1998

Maximum workplace concentration values and carcinogenicity classification for mixtures.

In Germany, the Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) generally sets maximum workplace concentration values (i.e., a proposed occupational exposure level [OEL]) for single substances, not for mixtures. For mixtures containing substances with a genotoxic and carcinogenic potential, the commission considered it scientifically inappropriate to establish a safe threshold. This approach is currently under discussion. Carcinogenic mixtures are categorized according to either the carcinogenicity of the mixture or the classification of the carcinogenic substances included. In regulating exposure to mixtures, an approach similar to that used by the American Conference of Governmental Hygienists is proposed: For components with the same target organ and mode of action or interfering metabolism, synergistic effects must be expected and the respective OELs must be lowered. However, if there is proof that the components act independently, the OELs of the individual compounds are not considered to be modified. In the view of the commission, calculating OELs for solvent mixtures according to their liquid phase composition is not justified, and the setting of scientifically based OELs for complex mixtures is not possible.

Carcinogens↗
PubMed1997

The toxicity of brominated and mixed-halogenated dibenzo-p-dioxins and dibenzofurans: an overview.

Brominated dibenzo-p-dioxins and dibenzofurans can be formed under laboratory conditions by pyrolysis of flame retardants based on polybrominated biphenyls and biphenyl ethers. Their occurrence in the environment, however, is due to combustion processes such as municipal waste incineration and internal combustion engines. As these processes generally take place in the presence of an excess of chlorine, predominantly mixed brominated and chlorinated compounds have been identified so far in environmental samples. Brominated dibenzo-p-dioxins or dibenzofurans bind to the cytosolic Ah receptor about as avidly as their chlorinated congeners and induce hepatic microsomal enzymes with comparable potency. The same holds true for mixed brominated-chlorinated compounds. Gross pathologic symptoms-hypothyroidism, thymic atrophy, wasting of body mass, lethality-also occur at doses that, on a molar concentration basis, are virtually identical to those seen with the chlorinated compounds. Their potency to induce malformations in mice following prenatal exposure is equivalent to that of chlorinated dibenzo-p-dioxins and dibenzofurans. Possible activities as (co)carcinogens and endocrine disrupters have not been evaluated, but are likely to exist. Considering the overall similarity in action of chlorinated and brominated dibenzo-p-dioxins and dibenzofurans, environmental and health assessments should be based on molar body burdens without discrimination for the nature of the halogen.

Animals↗
PubMed1997

Considerations on genetic and environmental factors that contribute to resistance or sensitivity of mammals including humans to toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Part 1: Genetic factors affecting the toxicity of TCDD.

The marked species differences in short-term toxicity (30-day LD50) of ca. 10,000 (LD50: guinea pigs ca. 1 microgram/kg body wt and Han/Wistar Kuopio rats more than 9600 micrograms/kg body wt) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the central issues of the controversies that have developed on the validity of risk assessment strategies for TCDD and related compounds. One of the most challenging issues that toxicologists face today is the identification of genes that contribute to or are responsible for increased resistance or sensitivity to TCDD and related compounds. It is assumed that most, if not all, toxic effects of TCDD are mediated more or less through the binding affinity to the Ah receptor. This hypothesis was extended and tries to explain the differences in sensitivity/resistance of animals including humans to TCDD by their total fat (lipid) content. In this respect the gene or genes which is or are responsible for obesity of mammals including humans are of great interest. An obvious linear positive logarithmic relationship between the oral 30-day LD50 (microgram/kg) of TCDD in different species and strains of mammals and their total body fat content (TBF%) was found: log LD50 = 5.30 x log (TBF)-3.22, or LD50 = 0.000603 x (TBF)5.30. By means of this regression the toxicity of TCDD in mammals including humans of different age and/or body weight can be predicted if their total body fat content is known. Examples of single-gene and polygenic disease models in different mammals, such as nonobese diabetic, diabetic, viable yellow, obese, and fat mice, as well as transgenic mice, and other suitable animal models, such as fatty Zucker rats, Han/Wistar (Kuopio) rats, and minipigs, are discussed, and predicted LD50 values of TCDD in these animals and humans are presented.

Animals↗
PubMed1997

Proposed changes in the classification of carcinogenic chemicals in the work area.

Carcinogenic chemicals in the work area are currently classified into three categories in Section III of the German List of MAK and BAT Values. This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these Categories--IIIA1, IIIA2, and IIIB--be retained as Categories 1, 2, and 3, to conform with EU regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, it is now proposed that these three categories be supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not convey a significant risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. It is proposed that chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures be classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics and for which risk at low doses can be assessed will be classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented. The proposed changes in classifying carcinogenic chemicals in the work area are presented for further discussion.

Animals↗
PubMed1997

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition.

Contents of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and of 16 further congeners--polychlorinated dibenzodioxins and dibenzofuranes (PCDD/PCDF)--were determined in lipids of adipose tissue and of livers of 3 stillborns and of 17 infants (0.43-44 weeks old) who died from sudden infant death syndrome. International toxic equivalents (I-TEq) calculated for the sum of TCDD together with all of the 16 congeners (1.55-29.63 ng/kg lipids of adipose tissue, n = 20; 2.05-57.73 ng/kg liver lipids, n = 19) were within the range of or lower than the values published for adults. TCDD concentrations in lipids of breast-fed infants were higher (0.38-4.1 ng/kg lipids of adipose tissue, n = 9; 0.49-3.9 ng/kg liver lipids, n = 8) compared to non breast-fed subjects (0.16-0.76 ng/kg lipids of adipose tissue, n = 8; 0.29-0.71 ng/kg liver lipids, n = 7). Neither I-TEq values nor TCDD concentrations exceeded values published for adults. Since even in stillborns PCDD/PCPF were found (I-TEq, 9.70-10.83 ng/kg lipids of adipose tissue, 6.17-8.83 ng/kg liver lipids; TCDD, 1.3-2.1 ng/kg lipids of adipose tissue, 0.76-1.5 ng/kg liver lipids; n = 3), transplacental exposure has to be deduced. All of the findings concerning TCDD concentrations in the organism become intelligible on the basis of a physiological toxicokinetic model which was developed to describe the body burden of TCDD for the entire human lifetime in dependence of TCDD uptake from contaminated nutrition. The model reflects sex and age dependent changes in the following parameters: body weight, volumes of liver, adipose and muscle tissue, food consumption, and excretion of faeces. TCDD is supposed to be taken up orally, to be distributed freely in lipids of the organism and to be eliminated unchanged by excretion in lipids of faeces as well as by metabolism in the liver. The model was used to predict the half-life of elimination of TCDD (4 months in newborns increasing to approximately 5 years in adults) and concentrations of this compound in lipids of adipose tissue, blood, liver and faeces at different ages. Furthermore, the influence of breast-feeding on the TCDD burden of a mother, her milk and her child was simulated. The model was validated by means of own data gained in adipose tissue and livers of infants and also using a series of values measured by other authors in mother's milk and in tissues and faeces of infants and adults. Predictions as well as experimental findings demonstrate a distinct increase in the TCDD body burden of breast-fed infants. Generally, it can be concluded for the excretion of unchanged, non-volatile, non protein bound highly lipophilic compounds that their half-life is short in infants (approximately 5 months) and increases to approximately 10 years reached between 40 and 60 years of age.

Adipose Tissue↗
PubMed1997

Compartmental transfer of mercury released from amalgam.

The number of amalgam-covered surfaces and the occlusal area of the fillings, the concentrations of total mercury in plasma, erythrocytes and urine, the urinary excretion rate, and the absorbed daily doses estimated by two separate methods from intra-oral Hg emission were determined in 29 volunteers with a low amalgam load. The transfer of Hg from the fillings via the oral cavity and blood to urinary excretion was evaluated by multiple correlations between these variables. In addition, the combination of variables most representative of the entire compartmental transfer of amalgam Hg was determined. Urinary excretion (1), Hg concentration in plasma (2) and absorbed dose (3) were most closely correlated to each other, followed by correlations with the variables of the fillings (4). Correlation coefficients were 0.75 for variables 1 vs 2 and 2 vs 3, and 0.49 for variables 3 vs 4. It was concluded that variables 1-3 best reflected the transfer of mercury from amalgam fillings throughout the organism and that they were relatively insensitive to dietary mercury. The determination of total mercury in plasma and of its urinary excretion rate appears, under practical aspects, most suitable for the investigation of Hg uptake from amalgam.

Adult↗
PubMed1997

[Not Available].

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Europe↗
PubMed1996

Stable expression of human inducible nitric oxide synthase in V79 Chinese hamster cells.

A recombinant expression vector containing the full-length cDNA for human inducible nitric oxide (NO) synthase was constructed for constitutive expression in V79 Chinese hamster cells. Expression was followed by Western analyses using three different NO synthase antisera. Activity remained stable during 4 months of continued cultivation. Activities were 25 pmol min-1 mg-1 cytosolic protein with L-arginine and 47 pmol min-1 mg-1 cytosolic protein with NG-hydroxy-L-arginine as substrates. Activity was concentration-dependently inhibited by inhibitors such as NG-methyl-L-arginine, NG-nitro-L-arginine, NG-nitro-L-arginine methyl ester, aminoguanidine, and S-methyl-isothiourea. The rank order of inhibitor potencies was different from published results obtained with rodent inducible NOS. Parental V79 cells do not express and cannot be induced for NO synthase activity. Therefore, the genetically engineered V79 cell line is defined for the cDNA-encoded human inducible NO synthase. The new cell line may serve as a useful tool to study human inducible NO synthase.

Animals↗
PubMed1996

Stable expression of human cytochrome P450 3A4 in conjunction with human NADPH-cytochrome P450 oxidoreductase in V79 Chinese hamster cells.

V79 Chinese hamster cells were constructed for stable expression of human cytochrome P450 3A4 with and without coexpression of human NADPH-cytochrome P450 oxidoreductase. Expression of the cDNAs was shown by Northern and Western analyses. Activity was tested by 6 beta-hydroxylation of testosterone for cytochrome P450 3A4 and by cytochrome c reduction for NADPH-cytochrome P450 reductase. Five V79 cell lines were obtained expressing cytochrome P450 3A4, human NADPH-cytochrome P450 oxidoreductase, and both. Cytochrome P450 3A4 activity depended highly on cytochrome P450 reductase activity, with lowest activity when only the parental Chinese hamster cytochrome P450 reductase was present, 5- and 10-fold higher when coexpressed with the human NADPH-cytochrome P450 reductase. Correspondingly, cytotoxic and genotoxic potency of aflatoxin B1 was increased by orders of magnitudes when human cytochrome P450 3A4 was coexpressed with the human NADPH-cytochrome P450 reductase. The effect of NADPH-cytochrome P450 reductase coexpression on cytochrome P450 3A4 activity was also tested by nifedipine oxidation and midazolam hydroxylation. Nifedipine oxidation was increased about 10-fold, 1-hydroxylation of midazolam and 4-hydroxylation of midazolam were increased 15-fold.

Aflatoxin B1↗
PubMed1996

The German toxicology curriculum: establishing a postgraduate training program for experts in toxicology.

A postgraduate training program in toxicology has been established in Germany. Theoretical training in toxicology is offered on a modular basis to candidates aiming at certification as an "Expert in Toxicology, DGPT." The certificate is awarded by the German Society of Experimental and Clinical Pharmacology and Toxicology [Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (DGPT)]. The precondition for entering the training program is a university degree in medicine, chemistry, biochemistry, biology, or a related subject. To be eligible to take the final examination for Expert in Toxicology, DGPT candidates must have at least 5 years of full-time practical experience in toxicology. They must have gained comprehensive knowledge in at least 1 relevant field, broad knowledge in another 2 fields, and basic knowledge in all 15 relevant fields of toxicology. Candidates must submit at least three independent peer-reviewed papers or professional assessments in toxicology or pharmacology. The course program for providing theoretical training is a joint venture of the German toxicological institutions involved in education. More than a dozen courses, covering the spectrum of fields in toxicology, are held each year at toxicological institutes of universities and research centers throughout Germany specializing in the respective fields. The courses provide candidates with instruction from Germany's leading authorities at research facilities in various fields of toxicology. They provide the best possible education in the spectrum of toxicological subdisciplines.

Accreditation↗
PubMed1996

Chlorinated dibenzodioxins and dibenzofurans (PCDD/F) in blood and human milk of non occupationally exposed persons living in the vicinity of a municipal waste incinerator.

The concentrations of chlorinated dibenzodioxins and dibenzofurans (PCDD/F) in human blood and in milk from non-occupationally exposed persons living in the vicinity of a municipal waste incinerator were determined. As compared to background levels in the general population in Germany the results give no indication of an enhanced body burden of PCDD/F. This is in agreement with earlier investigations in the same area, showing normal background concentrations in soil, fruit and vegetables. In conclusion, no direct health hazard related to PCDD/F-emissions from a local municipal waste incinerator may be expected.

Adolescent↗
PubMed1996

Stable expression and coexpression of human cytochrome P450 oxidoreductase and cytochrome P450 1A2 in V79 Chinese hamster cells: sensitivity to quinones and biotransformation of 7-alkoxyresorufins and triazines.

V79 Chinese hamster cell lines were genetically engineered for the stable expression of human NADPH-cytochrome P450 oxidoreductase (CYPOR) alone or for the combined expression of CYPOR and human cytochrome P450 1A2 (CYP1A2). As determined by immunoblotting, the expression level of CYP1A2 in the latter cell line was found to be the same as in a previously constructed V79 cell line expressing CYP1A2 only. The heterologous expression of CYPOR in V79 cells resulted in increased sensitivity to quinone-type cytotoxins, e.g. duroquinone and menadione, that exert their toxicity primarily through the production of reactive oxygen species during redox cycling. The metabolic properties of the cell line expressing both CYPOR and CYP1A2 were characterized regarding dealkylation and deethylation of 7-alkoxyresorufins and sulfoxidation of the triazine derivatives ametryne and terbutryne, in comparison with the cell line expressing only CYP1A2. Increased CYPOR activity impaired the CYP1A2-dependent fluorometric resorufin assay, presumably by conversion of the 7-alkoxyresorufins and resorufin to their one-electron-reduced semiquinoneimine forms. The CYP1A2-dependent metabolism of the triazine derivatives ametryne and terbutryne was moderately enhanced by increased CYPOR activity. Interestingly, with CYPOR overexpression sulfoxidation was increased 2-3-fold, compared with N-deethylation, with a 1.3-1.9-fold increase. Thus, the level of CYPOR not only had an influence on CYP1A2 activity rates but also affected the relative proportions of metabolites in CYP1A2-specific metabolite profiles.

Animals↗
PubMed1995

Stable expression of human cytochrome P450 2E1 in V79 Chinese hamster cells.

A V79 Chinese hamster cell line was constructed for stable expression of human cytochrome P450 2E1 (CYP2E1) by integration of a SV40 Early promoter recombinant CYP2E1 cDNA into the chromosomal DNA. The cDNA encoded CYP2E1 was effectively expressed and enzymatically active, as shown by hydroxylation of chlorzoxazone and of p-nitrophenol, at rates of about 70 pmol x mg-1 total protein x min-1. CYP2E1 content and activity was increased upon cultivation in the presence of ethanol indicating a substrate mediated stabilization effect. A similar stabilizing effect was also observed for inhibitors of CYP2E1, e.g. imidazole, 4-methylpyrazole, and isoniazid. The feasibility of the newly established cell line V79MZh2E1 for toxicological studies was shown by CYP2E1-mediated activation of N-nitrosodimethylamine and p-nitrophenol and a dose-dependent cytotoxic and mutagenic effect.

Animals↗