1,721,061 research outputs found
Carcinogenicity and genotoxicity of ethylene oxide : new aspects and recent advances
No full textLong-term inhalation studies in rodents have presented unequivocal evidence of experimental carcinogenicity of ethylene oxide, based on the formation of malignant tumors at multiple sites. However, despite a considerable body of epidemiological data only limited evidence has been obtained of its carcinogenicity in humans. Ethylene oxide is not only an important exogenous toxicant, but it is also formed from ethylene as a biological precursor. Ethylene is a normal body constituent; its endogenous formation is evidenced by exhalation in rats and in humans. Consequently, ethylene oxide must also be regarded as a physiological compound. The most abundant DNA adduct of ethylene oxide is 7-(2-hydroxyethyl)guanine (HOEtG). Open questions are the nature and role of tissue-specific factors in ethylene oxide carcinogenesis and the physiological and quantitative role of DNA repair mechanisms. The detection of remarkable individual differences in the susceptibility of humans has promoted research into genetic factors that influence the metabolism of ethylene oxide. With this background it appears that current PBPK models for trans-species extrapolation of ethylene oxide toxicity need to be refined further. For a cancer risk assessment at low levels of DNA damage, exposure-related adducts must be discussed in relation to background DNA damage as well as to inter- and intraindividual variability. In rats, subacute ethylene oxide exposures on the order of 1 ppm (1.83 mg/m3) cause DNA adduct levels (HOEtG) of the same magnitude as produced by endogenous ethylene oxide. Based on very recent studies the endogenous background levels of HOEtG in DNA of humans are comparable to those that are produced in rodents by repetitive exogenous ethylene oxide exposures of about 10 ppm (18.3 mg/m3). Experimentally, ethylene oxide has revealed only weak mutagenic effects in vivo, which are confined to higher doses. It has been concluded that long-term human occupational exposure to low airborne concentrations to ethylene oxide, at or below current occupational exposure limits of 1 ppm (1.83 mg/m3), would not produce unacceptable increased genotoxic risks. However, critical questions remain that need further discussions relating to the coherence of animal and human data of experimental data in vitro vs. in vivo and to species-specific dynamics of DNA lesions
Biological monitoring and Biological Limit Values (BLV): The strategy of the European Union
No full textOccupational standards concerning allowable concentrations of chemical compounds in the ambient air of workplaces have been established in several countries worldwide. With the integration of the European Union (EU), there has been a need of establishing harmonised Occupational Exposure Limits (OEL). The European Commission Directive 95/320/EC of 12 July 1995 has given the tasks to a Scientific Committee for Occupational Exposure Limits (SCOEL) to propose, based on scientific data and where appropriate, occupational limit values which may include the 8-h time-weighted average (TWA), short-term limits/excursion limits (STEL) and Biological Limit Values (BLVs). In 2000, the European Union issued a list of 62 chemical substances with Occupational Exposure Limits. Of these, 25 substances received a skin notation, indicating that toxicologically significant amounts may be taken up via the skin. For such substances, monitoring of concentrations in ambient air may not be sufficient, and biological monitoring strategies appear of potential importance in the medical surveillance of exposed workers. Recent progress has been made with respect to formulation of a strategy related to health-based BLVs. (c) 2005 Elsevier Ireland Ltd. All rights reserved
Differential substrate behaviours of ethylene oxide and propylene oxide towards human glutathione transferase theta hGSTT1-1
No full textThe transformation of ethylene oxide (EO), propylene oxide (PO) and 1- butylene oxide (1-BuO) by human glutathione transferase theta (hGSTT1-1) was studied comparatively using 'conjugator' (GSTT1 + individuals) erythrocyte lysates. The relative sequence of velocity of enzymic transformation was PO > EO >> 1-BuO. The faster transformation of PO compared to EO was corroborated in studies with human and rat GSTT1-1 (hGSTT1-1 and rGSTT1-1, respectively) expressed by Salmonella typhimurium TA1535. This sequence of reactivities of homologous epoxides towards GSTT1-1 contrasts to the sequence observed in homologous alkyl halides (methyl bromide, MBr; ethyl bromide, EtBr; n-propyl bromide, PrBr) where the relative sequence MeBr >> EtBr > PrBr is observed. The higher reactivity towards GSTT1-1 of propylene oxide compared to ethylene oxide is consistent with a higher chemical reactivity. This is corroborated by experimental data of acid-catalysed hydrolysis of a number of aliphatic epoxides, including ethylene oxide and propylene oxide and consistent with semi-empirical molecular orbital modelings
Entwicklung und Optimierung von analytischen Methoden zur Bestimmung der Toxikokinetik von Xeno- und Phytoöstrogenen und Einsatz im biologischen Monitoring
Full text linkToxikokinetik von östrogenartig wirkenden Industriechemikalien und Phytoöstrogenen
Full text linkToxikologische Wirkungen sogenannter "Xenoöstrogene" sind Gegenstand intensiver Diskussionen unter Fachleuten der Wissenschaft und in der Öffentlichkeit. Es besteht prinzipiell Einigkeit darüber, daß solche Stoffe in hohen Dosen in endokrine Regelkreise eingreifen können ("Potential"). Kontrovers diskutiert wird jedoch die Frage, welche Gefährdungen unter realistischen Expositionsszenarios von solchen Stoffen ausgehen ("Potenz"). In der in vivo-Situation ist für die relative biologische Wirksamkeit aufgenommener Stoffe neben deren Rezeptoraffinität ihre Toxikokinetik entscheidend. Um grundlegende toxikokinetische Parameter zu generieren, wurden zunächst analytische Verfahren zur Bestimmung der ausgewählten Xenoöstrogene in biologischem Material etabliert bzw. optimiert. In weiblichen DA/Han Ratten wurde nach Einmalgabe i.v. und p.o. die Toxikokinetik von p-tert-Octylphenol, Bisphenol A und Daidzein untersucht. Aus den Konzentrations-Zeit-Verläufen im Blut nach i.v.-Applikation wurden terminale Halbwertszeiten der Stoffe berechnet. Nach oraler Gabe unterschiedlich hoher Dosen wurden für alle Stoffe die Bioverfügbarkeiten bestimmt. Alle Blutspiegelkurven zeigen mehrgipflige Verläufe, die mit einer enterohepatischen Rezirkulation der Substanzen in Verbindung gebracht werden. Die Substanzen unterliegen alle einem ausgeprägten first-pass-Effekt und werden im Zuge des Phase-II-Metabolismus zu Glucuroniden und Sulfaten umgesetzt. Separate Experimente zeigen ferner, daß p-tert-Octylphenol und Daidzein bzw. deren Konjugate in erheblichem Umfang über die Galle ausgeschieden werden.
Zusammenfassend läßt sich sagen, daß ausgehend von den im Rahmen des Verbundprojektes ermittelten toxikokinetischen Befunden und Literaturdaten für keinen der Prüfstoffe eine ausgeprägte Bioakkumulation zu erwarten ist
Glutathione transferase Ti and M1 genotype polymorphism in the normal population of Shanghai
No full textGlutathione transferases are known to be important enzymes in the metabolism of xenobiotics. In humans genetic polymorphisms have been reported for the hGSTM1 and hGSTT1 genes leading to individual differences in susceptibility towards toxic effects, such as cancer. This study describes the distribution of the two polymorphisms of hGSTT1 and hGSTM1 in the normal Chinese population of Shanghai. Out of 219 healthy individuals having been genotyped for GSTTI and GSTMI, 108 (49%) were identified to be homozygously deficient for the GSTT1 gene and 107 (49%) for the GSTM1 gene
Determination of the ethylene oxide adduct S-(2-hydroxyethyl)cysteine by a fluorometric HPLC method in albumin and globin from human blood
No full textA new method has been developed for the quantification of 2-hydroxyethylated cysteine resulting as adduct in blood proteins after human exposure to ethylene oxide, by reversed-phase HPLC with fluorometric detection. The specific adduct is analysed in albumin and in globin. After isolation of albumin and globin from blood, acid hydrolysis of the protein and precolumn derivatisation of the digest with 9-fluorenylmethoxycarbonylchloride, the levels of derivatised S-hydroxyethylcysteine are analysed by RP-HPLC and fluorescence detection, with a detection limit of 8 nmol/g protein. Background levels of S-hydroxyethylcysteine were quantified in both albumin and globin, under special consideration of the glutathione transferase GSTT1 and GSTM1 polymorphisms. GSTT1 polymorphism had a marked influence on the physiological background alkylation of cysteine. While S-hydroxyethylcysteine levels in "non-conjugators" were between 15 and 50 nmol/g albumin, "low conjugators" displayed levels between 8 and 21 nmol/g albumin, and "high conjugators" did not show levels above the detection limit. The human GSTM1 polymorphism had no apparent effect on background levels of blood protein 2-hydroxyethylation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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