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  1. Artikel: Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.

    Bull, R J

    Environmental health perspectives

    2000  Band 108 Suppl 2, Seite(n) 241–259

    Abstract: Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute--chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH and TCA appear capable of only inducing liver tumors in mice, but ... ...

    Abstract Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute--chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH and TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concentrations of TCA in blood required to induce liver cancer approach the mM range. Concentrations of DCA in blood associated with carcinogenesis are in the sub-microM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA and/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPAR-alpha that are observed in rodents. This may be attributed to lower levels of expressed PPAR-alpha in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA and TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis.
    Mesh-Begriff(e) Animals ; Carcinogens, Environmental/adverse effects ; Dichloroacetic Acid/adverse effects ; Dose-Response Relationship, Drug ; Humans ; Liver Neoplasms/chemically induced ; Liver Neoplasms, Experimental/chemically induced ; Mutagens/adverse effects ; Risk Assessment ; Trichloroacetic Acid/adverse effects ; Trichloroethylene/adverse effects
    Chemische Substanzen Carcinogens, Environmental ; Mutagens ; Trichloroethylene (290YE8AR51) ; Trichloroacetic Acid (5V2JDO056X) ; Dichloroacetic Acid (9LSH52S3LQ)
    Sprache Englisch
    Erscheinungsdatum 2000-05
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 195189-0
    ISSN 1552-9924 ; 0091-6765 ; 1078-0475
    ISSN (online) 1552-9924
    ISSN 0091-6765 ; 1078-0475
    DOI 10.1289/ehp.00108s2241
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: In vitro toxicity and genotoxicity assessment of disinfection by-products, organic N-chloramines.

    Laingam, S / Froscio, S M / Bull, R J / Humpage, A R

    Environmental and molecular mutagenesis

    2012  Band 53, Heft 2, Seite(n) 83–93

    Abstract: Disinfection by-products (DBPs) are of concern to both water industries and health authorities. Although several classes of DBPs have been studied, and there are regulated safe levels in disinfected water for some, a large portion of DBPs are not ... ...

    Abstract Disinfection by-products (DBPs) are of concern to both water industries and health authorities. Although several classes of DBPs have been studied, and there are regulated safe levels in disinfected water for some, a large portion of DBPs are not characterized, and need further investigation. Organic N-chloramines are a group of DBPs, which can be formed during common disinfection processes such as chlorination and chloramination, but little is known in terms of their toxicological significance if consumed in drinking water. Only a few in vitro studies using bacterial assays have reported some genotoxic potential of organic N-chloramines, largely in the context of inflammatory processes in the body rather than exposure through drinking water. In this study, we investigated 16 organic N-chloramines produced by chlorination of model amino acids and amines. It was found that within the drinking water-relevant micromolar concentration range, four compounds were both cytotoxic and genotoxic to mammalian cells. A small reduction of cellular GSH was also observed in the treatment with these four compounds, but not of a magnitude to account for the cytotoxicity and genotoxicity. The results presented in this study demonstrate that some organic N-chloramines, at low concentrations that might be present in disinfected water, can be harmful to mammalian cells.
    Mesh-Begriff(e) Cell Line ; Cell Survival/drug effects ; Cells, Cultured ; Chloramines/toxicity ; DNA Damage/drug effects ; Disinfectants/toxicity ; Disinfection ; Drinking Water ; Glutathione/analysis ; Humans ; Micronuclei, Chromosome-Defective/chemically induced ; Micronucleus Tests ; Mutagens/toxicity ; Oxidative Stress/drug effects
    Chemische Substanzen Chloramines ; Disinfectants ; Drinking Water ; Mutagens ; Glutathione (GAN16C9B8O)
    Sprache Englisch
    Erscheinungsdatum 2012-02-23
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639145-x
    ISSN 1098-2280 ; 0893-6692
    ISSN (online) 1098-2280
    ISSN 0893-6692
    DOI 10.1002/em.20684
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: Cancer risk assessment: importance of identifying mechanisms of action.

    Bull, R J

    Journal - American Water Works Association

    1990  Band 82, Heft 10, Seite(n) 57–60

    Abstract: The process by which regulatory standards are established for drinking water contaminants is based on extrapolating animal toxicity data to humans using a standard mathematical model. The assumptions and judgments involved introduce a relatively high ... ...

    Abstract The process by which regulatory standards are established for drinking water contaminants is based on extrapolating animal toxicity data to humans using a standard mathematical model. The assumptions and judgments involved introduce a relatively high degree of uncertainty and conservativeness into both the qualitative and quantitative aspects of the process. Setting standards based on knowledge of specific mechanisms of carcinogenicity would decrease the uncertainty involved in risk assessment. Understanding these mechanisms is necessary for arriving at the most appropriate mathematical construct for calculating more rational standards.
    Mesh-Begriff(e) Carcinogenicity Tests ; Carcinogens, Environmental/standards ; Carcinogens, Environmental/toxicity ; Humans ; Models, Theoretical ; Neoplasms/chemically induced ; Risk Assessment ; Toxicology/methods ; Toxicology/standards ; United States ; United States Environmental Protection Agency/standards ; Water Pollutants, Chemical/standards ; Water Pollutants, Chemical/toxicity ; Water Supply/standards
    Chemische Substanzen Carcinogens, Environmental ; Water Pollutants, Chemical
    Sprache Englisch
    Erscheinungsdatum 1990-10
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Review
    ZDB-ID 241726-1
    ISSN 0003-150X
    ISSN 0003-150X
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel: Carcinogenic and mutagenic properties of chemicals in drinking water.

    Bull, R J

    The Science of the total environment

    1985  Band 47, Seite(n) 385–413

    Abstract: Isolated cases of careless handling of industrial and domestic waste has lead to a wide variety of dangerous chemicals being inadvertently introduced into drinking water. However, chemicals with established carcinogenic and mutagenic properties that ... ...

    Abstract Isolated cases of careless handling of industrial and domestic waste has lead to a wide variety of dangerous chemicals being inadvertently introduced into drinking water. However, chemicals with established carcinogenic and mutagenic properties that occur with a high frequency and in multiple locations are limited in number. To date, the chief offenders have been chemicals of relatively low carcinogenic potency. Some of the more common chemicals are formed as by-products of disinfection. The latter process is generally regarded as essential to the production of a "microbiologically safe" drinking water. Consequently, any reductions in what may be a relatively small carcinogenic risk must be balanced against a potential for a higher frequency of waterborne infectious disease. The results of recent toxicological investigations will be reviewed to place the potential carcinogenic and mutagenic hazards frequently associated with drinking water into perspective. First, evidence for the carcinogenicity of certain volatile organic compounds such as trichloroethylene, tetrachloroethylene and carbon tetrachloride is considered. Second, the carcinogenic activity that can be ascribed to various by-products of chlorination is reviewed in some detail. Finally, recent evidence that other chemicals derived from the treatment and distribution of drinking water is highlighted as an area requiring move systematic attention.
    Mesh-Begriff(e) Acetonitriles/toxicity ; Aldehydes/toxicity ; Animals ; Carbon Tetrachloride/toxicity ; Carcinogens ; Chlorine ; Chloroform/toxicity ; Chlorophenols/toxicity ; Disinfection/adverse effects ; Humans ; Ketones/toxicity ; Mutagens ; Polyvinyl Chloride/adverse effects ; Tetrachloroethylene/toxicity ; Trichloroethylene/toxicity ; Water Pollutants/toxicity ; Water Pollutants, Chemical/toxicity ; Water Supply/adverse effects ; Water Supply/analysis
    Chemische Substanzen Acetonitriles ; Aldehydes ; Carcinogens ; Chlorophenols ; Ketones ; Mutagens ; Water Pollutants ; Water Pollutants, Chemical ; Trichloroethylene (290YE8AR51) ; Chlorine (4R7X1O2820) ; Chloroform (7V31YC746X) ; Polyvinyl Chloride (9002-86-2) ; Carbon Tetrachloride (CL2T97X0V0) ; Tetrachloroethylene (TJ904HH8SN)
    Sprache Englisch
    Erscheinungsdatum 1985-12
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article ; Review
    ZDB-ID 121506-1
    ISSN 1879-1026 ; 0048-9697
    ISSN (online) 1879-1026
    ISSN 0048-9697
    DOI 10.1016/0048-9697(85)90344-4
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel: Differences in phenotype and cell replicative behavior of hepatic tumors induced by dichloroacetate (DCA) and trichloroacetate (TCA).

    Stauber, A J / Bull, R J

    Toxicology and applied pharmacology

    1997  Band 144, Heft 2, Seite(n) 235–246

    Abstract: Dichloroacetate (DCA) and trichloroacetate (TCA) are two hepatocarcinogenic by-products of water chlorination. To compare the effects of DCA and TCA on cell replication in the nodules and tumors they induce, male B6C3F1 mice were administered 2.0 g/L DCA ...

    Abstract Dichloroacetate (DCA) and trichloroacetate (TCA) are two hepatocarcinogenic by-products of water chlorination. To compare the effects of DCA and TCA on cell replication in the nodules and tumors they induce, male B6C3F1 mice were administered 2.0 g/L DCA or TCA in their drinking water for 38 or 50 weeks, respectively. The pretreated mice were then given water containing 0, 0.02, 0.5, 1.0, or 2.0 g/L DCA or TCA for two additional weeks to determine whether cell proliferation in the normal liver or tumors that had been induced by DCA or TCA was dependent on continued treatment. Prior to sacrifice the mice were subcutaneously implanted with mini-osmotic pumps to label DNA in dividing cells with 5-bromo-2'-deoxyuridine (BrdU). Serial sections of nodules/tumors and normal liver were stained immunohistochemically for BrdU, the oncoproteins c-Jun and c-Fos, and hematoxylin and eosin (H & E); or with Periodic acid-Schiff (PAS) stain, BrdU, and H & E, respectively. DCA and TCA transiently stimulated the division of normal hepatocytes relative to rates observed in the livers of control mice. However, at 40 and 52 weeks of treatment, replication of normal hepatocytes was substantially inhibited by DCA and TCA, respectively. Cell division within DCA-induced lesions that were identified macroscopically was significantly higher with increasing dose of DCA administered in the last 2 weeks of the experiment. DCA-induced lesions were found to display immunoreactivity to anti-c-Jun and anti-c-Fos antibodies, were predominantly basophilic, and contained very little glycogen relative to surrounding hepatocytes. In contrast, rates of cell division within TCA-induced altered hepatic foci and tumors were very high and appeared to be independent of continued treatment. TCA-induced lesions did not display immunoreactivity to either c-Jun or c-Fos antibodies. Results from this study suggest that the mechanisms by which DCA and TCA induce hepatocarcinogenesis in the male B6C3F1 mouse differ.
    Mesh-Begriff(e) Administration, Oral ; Animals ; Cell Count ; Cell Division/drug effects ; Dichloroacetic Acid/administration & dosage ; Dichloroacetic Acid/toxicity ; Drinking ; Immunohistochemistry ; Liver/chemistry ; Liver/drug effects ; Liver/pathology ; Liver Neoplasms/chemically induced ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Male ; Mice ; Phenotype ; Precancerous Conditions/chemically induced ; Precancerous Conditions/chemistry ; Trichloroacetic Acid/administration & dosage ; Trichloroacetic Acid/toxicity
    Chemische Substanzen Trichloroacetic Acid (5V2JDO056X) ; Dichloroacetic Acid (9LSH52S3LQ)
    Sprache Englisch
    Erscheinungsdatum 1997-06
    Erscheinungsland United States
    Dokumenttyp Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 204477-8
    ISSN 1096-0333 ; 0041-008X
    ISSN (online) 1096-0333
    ISSN 0041-008X
    DOI 10.1006/taap.1997.8159
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel: Effect of pretreatment with dichloroacetate or trichloroacetate on the metabolism of bromodichloroacetate.

    Austin, E W / Bull, R J

    Journal of toxicology and environmental health

    1997  Band 52, Heft 4, Seite(n) 367–383

    Abstract: Haloacetates are a common class of water chlorination by-products. Depending on the amount of bromide in the source water, varying amounts of chlorinated, brominated, and mixed bromochloro haloacetates are produced. When administered to rodents, ... ...

    Abstract Haloacetates are a common class of water chlorination by-products. Depending on the amount of bromide in the source water, varying amounts of chlorinated, brominated, and mixed bromochloro haloacetates are produced. When administered to rodents, haloacetates have been shown to increase formation of thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine levels in the liver. These responses appear to be modified by prior treatment. To examine potential mechanisms that account for these modifications in oxidative stress, the ability of trichloroacetate (TCA) or dichloroacetate (DCA) pretreatment to alter the metabolism of bromodichloroacetate (BDCA) and the disposition of its metabolites was examined in male B6C3F1 mice. Two-week pretreatment with 1 g/L DCA and TCA in the drinking water of mice alters the initial hepatic metabolism of BDCA and the further metabolism of its metabolite DCA. DCA pretreatment inhibits cytosolic metabolism of both 1 mM DCA or BDCA up to 70%. In contrast, DCA pretreatment stimulates hepatic microsomal BDCA metabolism 1.3-fold but has little effect on microsomal metabolism of DCA. Increased microsomal metabolism of BDCA appears to be attributable to the induction of a metabolic pathway that produces CO2 and bromodichloromethane (BDCM) as metabolites. TCA pretreatment inhibits BDCA metabolism up to 70% in the cytosol and 30% in microsomes but has little effect on DCA metabolism. These results indicate that the hepatic metabolism of the haloacetate becomes quite complex at the high doses that have been employed in cancer bioassays. BDCA serves as a good example, because it is metabolized to at least two carcinogenic metabolites that have different modes of action, BDCM and DCA. As doses approach those that induce cancer in mice, the proportion of and amounts of these metabolites as a fraction of the dose administered will change substantially. This article demonstrates that those interactions will occur from mixed treatment with haloacetates as well.
    Mesh-Begriff(e) Acetates/metabolism ; Acetates/urine ; Animals ; Breath Tests ; Carbon Dioxide/metabolism ; Carbon Radioisotopes ; Cytosol/drug effects ; Cytosol/metabolism ; Dichloroacetic Acid/administration & dosage ; Dichloroacetic Acid/metabolism ; Dichloroacetic Acid/pharmacology ; Drug Interactions ; Liver/drug effects ; Liver/enzymology ; Liver/metabolism ; Male ; Mice ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Trichloroacetic Acid/administration & dosage ; Trichloroacetic Acid/pharmacology ; Water Supply/standards
    Chemische Substanzen Acetates ; Carbon Radioisotopes ; Carbon Dioxide (142M471B3J) ; Trichloroacetic Acid (5V2JDO056X) ; Dichloroacetic Acid (9LSH52S3LQ) ; bromodichloroacetic acid (SJ84PTP2HD)
    Sprache Englisch
    Erscheinungsdatum 1997-11
    Erscheinungsland United States
    Dokumenttyp Comparative Study ; Letter ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 197268-6
    ISSN 1087-2620 ; 0098-4108 ; 0040-9014
    ISSN (online) 1087-2620
    ISSN 0098-4108 ; 0040-9014
    DOI 10.1080/00984109708984071
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Buch: Toxicology of drinking water disinfection

    Bull, R. J.

    1992  , Seite(n) 184–230

    Körperschaft USA-Pullman, WA 99164-6510 Pharmacology and Toxicology Graduate Program and College of Pharmacy, Washington State University
    Schlagwörter Trinkwasser ; Desinfektion ; Toxikologie ; Chlorverbindung ; Kwst. halogeniert ; Karzinogen ; Herz- oder Gefaesskrankheit ; Chlor
    Sprache Englisch
    Verlag New York, NY: Van Nostrand Reinhold
    Dokumenttyp Buch
    Datenquelle SOMED (SOzialMEDizin, Gesundheitswissenschaften und Public Health)

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  8. Artikel: Health effects of drinking water disinfectants and disinfectant by-products.

    Bull, R J

    Environmental science & technology

    1982  Band 16, Heft 10, Seite(n) 554A–9A

    Sprache Englisch
    Erscheinungsdatum 1982-10-01
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ISSN 0013-936X
    ISSN 0013-936X
    DOI 10.1021/es00104a719
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  9. Artikel: Cancer risk assessment: Importance of identifying mechanisms of action

    Bull, R. J.

    American Water Works Association J.

    1990  Band 82, Heft 10, Seite(n) 57–60

    Abstract: The process by which regulatory standards are established for drinking water contaminants is based on extrapolating animal toxicity data to humans using a standard mathematical model. The assumptions and judgments involved introduce a relatively high ... ...

    Körperschaft USA-Pullman, WA 99163 Pharmacology and Toxicology Graduate Program, College of Pharmacy, Washington State University
    Abstract The process by which regulatory standards are established for drinking water contaminants is based on extrapolating animal toxicity data to humans using a standard mathematical model. The assumptions and judgments involved introduce a relatively high degree of uncertainty and conservativeness into both the qualitative and quantitative aspects of the process. Setting standards based on knowledge of specific mechanisms of carcinogenicity would decrease the uncertainty involved in risk assessment. Understanding these mechanisms is necessary for arriving at the most appropriate mathematical construct for calculating more rational standards.
    Schlagwörter Trinkwasser ; Verunreinigung ; Karzinom ; Risiko ; Karzinogen ; Beurteilung
    Sprache Englisch
    Dokumenttyp Artikel
    Datenquelle SOMED (SOzialMEDizin, Gesundheitswissenschaften und Public Health)

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  10. Artikel: Effects of dichloroacetate (DCA) on serum insulin levels and insulin-controlled signaling proteins in livers of male B6C3F1 mice.

    Lingohr, M K / Thrall, B D / Bull, R J

    Toxicological sciences : an official journal of the Society of Toxicology

    2001  Band 59, Heft 1, Seite(n) 178–184

    Abstract: DCA is hepatocarcinogenic in rodents. At carcinogenic doses, DCA causes a large accumulation of liver glycogen. Thus, we studied the effects of DCA treatment on insulin levels and expression of insulin-controlled signaling proteins in the liver. DCA ... ...

    Abstract DCA is hepatocarcinogenic in rodents. At carcinogenic doses, DCA causes a large accumulation of liver glycogen. Thus, we studied the effects of DCA treatment on insulin levels and expression of insulin-controlled signaling proteins in the liver. DCA treatment (0.2-2.0 g/l in drinking water for 2 weeks) reduced serum insulin levels. The decrease persisted for at least 8 weeks. In livers of mice treated with DCA for 2-, 10-, and 52-week periods, insulin receptor (IR) protein levels were significantly depressed. Additionally, protein kinase B (PKBalpha) expression decreased significantly with DCA treatment. In normal liver, glycogen levels were increased as early as at 1 week, and this effect preceded changes in insulin and IR and PKBalpha. In contrast to normal liver, IR protein was elevated in DCA-induced liver tumors relative to that in liver tissue of untreated animals and to an even greater extent when compared to adjacent normal liver in the treated animal. Mitogen-activated protein kinase (MAP kinase) phosphorylation was also increased in tumor tissue relative to normal liver tissue and tissue from untreated controls. These data suggest that normal hepatocytes down-regulate insulin-signaling proteins in response to the accumulation of liver glycogen caused by DCA. Furthermore, these results suggest that the initiated cell population, which does not accumulate glycogen and is promoted by DCA treatment, responds differently from normal hepatocytes to the insulin-like effects of this chemical. The differential sensitivity of the 2 cell populations may contribute to the tumorigenic effects of DCA in the liver.
    Mesh-Begriff(e) Animals ; Blotting, Western ; Carcinogens/toxicity ; Dichloroacetic Acid/toxicity ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Insulin/blood ; Liver/drug effects ; Liver/metabolism ; Liver Neoplasms/chemically induced ; Liver Neoplasms/metabolism ; Male ; Mice ; Mice, Inbred Strains ; Mitogen-Activated Protein Kinases/metabolism ; Protein-Serine-Threonine Kinases ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Receptor, Insulin/metabolism ; Signal Transduction
    Chemische Substanzen Carcinogens ; Insulin ; Proto-Oncogene Proteins ; Dichloroacetic Acid (9LSH52S3LQ) ; Receptor, Insulin (EC 2.7.10.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Sprache Englisch
    Erscheinungsdatum 2001-01
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/59.1.178
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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