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  • 1
    ISSN: 1432-0738
    Keywords: Tissue distribution ; Toxicokinetics ; Elimination ; Half-life ; Polychlorinated dibenzo-p-dioxins (PCDDs) ; Polychlorinated dibenzofurans (PCDFs) ; Marmoset monkeys (Callithrix jacchus)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A defined mixture of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) was subcutaneously administered to marmoset monkeys (Callithrix jacchus). Tissue concentrations in hepatic and adipose tissue were measured at different times after treatment (1–28 weeks). One week after application high concentrations could be detected for the 2,3,7,8-substituted congeners only. The percent of the administered dose in whole liver differed for the various 2,3,7,8-substituted congeners, ranging from 24.5±4.5% for 2,3,7,8-TCDD to 74.1±4.9% for 2,3,4,6,7,8-H6CDF. Therefore, the concentration ratio (liver/adipose tissue) was also very different, ranging from about 1 (2,3,7,8-T4CDD or 2,3,7,8-T4CDF) to 〉10 in the case of some higher chlorinated PCDDs and PCDFs. Half-lives of PCDDs and PCDFs were very different for the various 2,3,7,8-substituted congeners. For the most toxic compound (2,3,7,8-T4CDD) a t/2 of about 8 weeks in hepatic tissue and about 11 weeks in adipose tissue was found when calculated from data obtained later than 6 weeks after injection. For 2,3,7,8-T4CDD and 1,2,3,7,8-P5CDD the decreases in hepatic concentrations were much faster during the first 6 weeks after administration (t/2 of 4 weeks). This was apparently due to redistribution phenomena. Half-life increased with increasing degrees of chlorination. In some cases (e.g. OCDD, OCDF) no significant decrease in tissue concentrations could be observed after 28 weeks. The shortest t/2 was determined for 2,3,7,8-T4CDF: shorter than 6 days in hepatic tissue and about 10 days in adipose tissue. Calculation of the body burden of thenon-2,3,7,8-substituted PCDDs/PCDFs 1 week after injection revealed that all groups of isomers were present at less than 5%. Consequences of these findings for the use of TCDD-toxic-equivalency factors are discussed and a change in strategy is suggested.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0738
    Keywords: Tissue distribution ; Toxicokinetics ; Placental transfer ; Mother's milk ; Polychlorinated dibenzo-p-dioxins (PCDDs) ; Polychlorinated dibenzofurans (PCDFs) ; Marmoset monkeys (Callithrix jacchus)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A defined mixture of polychlorinated dibenzop-dioxins and dibenzofurans (PCDDs and PCDFs) was subcutaneously administered to a pregnant marmoset monkey (Callithrix jacchus) 11 weeks prior to delivery. Transfer of PCDDs and PCDFs via placenta and mother's milk was investigated by measurement of concentrations in a newborn 1 day after birth and in an infant of the same litter after a lactation period of 33 days. Furthermore, comparative measurements were performed in different tissues of the mother at the end of the lactation period, and in addition, in two groups of four adult monkeys each 1 and 6 weeks after treatment. Deposition of the PCDDs and PCDFs into fetal liver was very low for most of the 2,3,7,8-substituted congeners. Highest deposition was observed for 2,3,7,8-T4CDD and 1,2,3,7,8-P5CDD. For all other compounds concentrations in the hepatic tissue of newborn shortly after birth were lower than one tenth of corresponding concentrations in adults. Especially for PCDFs, prenatal deposition in fetal liver was extremely low. Fetal liver is apparently largely unable to accumulate PCDDs/PCDFs. In contrast to liver, concentrations of 2,3,7,8-substituted PCDDs/PCDFs in adipose tissue of the newborn were at least one third of the levels in adults. However, concentrations of OCDD and OCDF were about three times higher in the newborn than in adult adipose tissue. Transfer of some of the 2,3,7,8-substituted PCDDs and PCDFs to the off-spring via mother's milk was considerable, leading to hepatic concentrations in the suckled infant at the end of the 33-day nursing period well above corresponding concentrations in the dam. When hepatic concentrations in the infant and dam were compared 2- to 4-fold higher concentrations were found in the infant's liver for 2,3,7,8-T4CDD/F and for 1,2,3,7,8-P5CDD. In the case of the 2,3,7,8-substituted H6CDDs, P5CDFs, and most of the H6CDFs, hepatic concentrations in the infant and dam were in the same range at the end of the suckling period. In contrast to this, less than one tenth the concentration of OCDD was found in the infant's liver when compared with adult liver. A corresponding phenomenon was observed for PCDFs. At the maximum absorption, 1 week after injection, for almost all 2,3,7,8-substituted congeners highest concentrations were measured in hepatic tissue of adult monkeys. This is especially true for those substances with six and more chlorine atoms. Besides adipose tissue, comparatively high levels were found in thymus and also in lung tissue. The limited data available point to a long persistence of some of the 2,3,7,8-substituted congeners in the thymus. Especially low concentrations of all the congeners were measured in the brain and testes.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0738
    Keywords: PCDD mixtures ; Induction of P450IA1 ; 2,3,7,8-Cl4DD equivalents ; Human hepatoma HepG2 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Dose-response curves of the induction of P4501A1-dependent 7-ethoxyresorufin O-deethylase (EROD) were analyzed in human hepatoma HepG2 cells treated with defined mixtures of polychlorinated dibenzop-dioxins (PCDDs) and their 2,3,7,8-substituted constituents, similar to previous studies with rat hepatocytes and H4IIE cells (Schrenk et al. 1991). PCDDs appear to act less potent in human HepG2 cells in comparison with rat cells. For example, EC50 values of 2,3,7,8-Cl4DD were 8-fold and 19-fold higher than in rat H4IIE cells and hepatocytes, respectively. EC50 values of PCDDs were compared with that of 2,3,7,8-Cl4DD and expressed as 2,3,7,8-Cl4DD equivalents (TEs). Although the rank order of PCDD potencies was similar, TEs for some PCDDs (1,2,3,7,8-Cl5 DD; TE=0.75 and 1,2,3,4,7,8-Cl6DD; TE=0.61) were found to be higher than in the rat system. In contrast to rat cells no significant induction of EROD could be detected with Cl8DD in HepG2 cells up to its limit of solubility. Experimentally determined TEs of PCDD mixtures containing 49 constituents were found to be largely due to additive effects of their 2,3,7,8-substituted constituents.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0738
    Keywords: PCDD mixtures ; Induction of P450IA1 ; 2,3,7,8-Cl4DD equivalents ; H4IIE cells ; Primary cultures of rat hepatocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract As a first step to assess biological activities of complex mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), induction of 7-ethoxyresorufin O-deethylase (EROD) by defined mixtures and their constituents has been analysed in vitro. Two cell systems have been compared: primary hepatocyte cultures and hepatoma H4IIE cells. EC50 values of PCDDs were compared with that of the most potent compound, 2,3,7,8-Cl4DD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and expressed as 2,3,7,8-Cl4DD equivalents (TEs). TEs for three defined mixtures containing up to 49 PCDDs could be predicted from the sum of TEs for the 2,3,7,8-substituted congeners. Efficacies (maximal enzyme induction) of less potent PCDDs (1,2,3,4-Cl4DD, Cl8DD and of a mixture containing 86% Cl8DD and of benz(a)anthracene were lower in hepatocytes (by 33%) and in H4IIE cells (by 50%). The results suggest that biological activities of complex PCDD mixtures are largely due to additive effects of their 2,3,7,8-substituted consituents.
    Type of Medium: Electronic Resource
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