Cloning of the Complete Gene for Carcinoembryonic Antigen

Carcinoembryonic antigen (CEA) is a widely used tumor marker, especially in the surveillance of colonic cancer patients. Although CEA is also present in some normal tissues, it is apparently expressed at higher levels in tumorous tissues than in corresponding normal tissues. As a first step toward analyzing the regulation of expression of CEA at the transcriptional level, we have isolated and characterized a cosmid clone (cosCEA1), which contains the entire coding region of the CEA gene. A close correlation exists between the exon and deduced immunoglobulin-like domain borders. We have determined a cluster of transcriptional starts for CEA and the closely related nonspecific cross-reacting antigen (NCA) gene and have sequenced their putative promoters. Regions of sequence homology are found as far as approximately 500 nucleotides upstream from the translational starts of these genes, but farther upstream they diverge completely. In both cases we were unable to find classic TATA or CAAT boxes at their expected positions. To characterize the CEA and NCA promoters, we carried out transient transfection assays with promoter-indicator gene constructs in the CEA-producing adenocarcinoma cell line SW403, as well as in nonproducing HeLa cells. A CEA gene promoter construct, containing approximately 400 nucleotides upstream from the translational start, showed nine times higher activity in the SW403 than in the HeLa cell line. This indicates that cis-acting sequences which convey cell type-specific expression of the CEA gene are contained within this region

Ueberpruefung der Datenlage im Hinblick auf eine Verbesserung der Dosis-Wirkungsbeziehung als Basis zur Quantifizierung von Sicherheitsfaktoren Endbericht

Extrapolation factors are used to substitute lacking experimental data by plausible assumptions. All substance specific data should be taken into account to avoid the use of uncertainty factors or to modify default assumptions. If default assumptions are used, the size of the factors should be scientifically supported. The usually applied default values of 10 (or a multiple of 10) result in different statistical safety and are not equally suitable for extrapolation purposes: for time extrapolation in average a factor of 2 to 3 should be sufficient to extrapolate from subchronic to chronic exposure time. To derive a 'no adverse effect level' (NAEL) from a 'lowest observed effect level' (LOAEL) default values should be avoided and benchmark procedures should be applied where possible. Interspecies extrapolations may be described best by scaling according to the caloric demand, but deviations from allometric principles may be additionally integrated by an extra factor. Intraspecies variability is sufficiently covered by a factor of 10, if just toxicokinetic variability for healthy adults is to be respected. Further integration of toxicodynamic variations (and maybe special risk groups) calls for additional factors. If 90-percentiles of the distributions have to be integrated to derive the uncertainty factor, larger factors would have to be chosen. Additional investigations will have to be carried out regarding the size of the intraspecies factor, the factor specific for local effects and for the total extrapolation factor. (orig.)SIGLEAvailable from TIB Hannover: RN 8908(97-033) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekUmweltbundesamt, Berlin (Germany); Bundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman

Basisdaten Toxikologie fuer umweltrelevante Stoffe zur Gefahrenbeurteilung bei Altlasten mit Ableitung von toxikologischen Orientierungswerten durch die BMU-AG ''GefA'' Abschlussbericht (Zusammenfassung)

Within the framework of this project, 75 substances or groups of substances of relevance in land pollution were generally evaluated for their toxic effect on human beings. The methodics, for instance as regards the choice of relevant experiments, calculation of body doses, explanations of reference values etc., follows a certain systematy and definitions, which are described and explained in the paper. (orig.)Im Rahmen des oben genannten Forschungsvorhabens war eine zusammenfassende humantoxikologische Bewertung fuer 75 altlastenrelevante Substanzen bzw. Substanzgruppen vorzunehmen. Bei der Vorgehensweise, z.B. in der Auwahl relevanter Versuche, Berechnung von Koerperdosen, Orientierungswertbegruendung etc., wurden eine bestimmte Systematik und Definitionen zugrunde gelegt, die im folgenden vorgestellt und erlaeutert werden. (orig.)SIGLEAvailable from TIB Hannover: RN 8908(92-101) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman

Grundlagen fuer die Bewertung von Kontaminationen des Bodens mit polyzyklischen aromatischen Kohlenwasserstoffen. T. A: Toxikologische Bewertung von PAK

Polycyclic aromatic hydrocarbons (PAH) are toxicologically (because of their carcinogenic effects) and quantitatively relevant harmful substances at waste sites. Their risk assessment and the derivation of soil trigger levels causes problems because of two reasons. First, with regard to oral exposure the carcinogenic risk assessment of both PAH and benzo[a]pyrene which is being used as an index substance was so far based on studies of insufficient quality and is therefore subject to the respective uncertainties. Secondly, the assessment of complex mixtures such as PAH causes methodological problems. Within part A of the research project described here a toxicological re-assessment of benzo[a]pyrene and PAH was carried out for oral and dermal exposure. New cancer risk estimates were conducted on the basis of recently published animal studies on the carcinogenic effects of both benzo[a]pyrene and PAH. The relevance for humans of tumors in target organs observed in animal studies and the quantitative uncertainties of the risk estimates were discussed intensively. The examination of genotoxic and carcinogenic effects caused by PAH mixtures resulted in a methodological proposal for the assessment of complex PAH mixtures. The results were put up for discussion to a body of experts within the framework of an expert meeting. Based on these risk estimates soil trigger levels were derived corresponding to the methodology in the ordinance of the German Federal Soil Protection Law in part B of this project. In this connection, the particularities of PAH effects (problems of mixtures, local carcinogenicity) were taken into account. The question, whether PAH mixtures found at typical sites (gasworks sites, coke-oven sites) are comparable in their composition to the PAH mixtures studied experimentally and the application of the risk estimates to the derivation of soil trigger levels is therefore possible, was examined intensively. This question was answered in the affirmative and the limits of the application were discussed. (orig.)Polyzyklische aromatische Kohlenwasserstoffe (PAK) sind toxikologisch (wegen ihrer krebserzeugenden Wirkung) und mengenmaessig bedeutsame Schadstoffe in Altlasten und schaedlichen Bodenveraenderungen. Ihre toxikologische Bewertung und die Ableitung von Pruefwerten bereitet aus zwei Gruenden Probleme. Zum einen basierte die Krebsrisikobewertung der PAK und des als Leitsubstanz verwendeten Benzo[a]pyrens bei oraler Exposition bislang auf Studien unzureichender Qualitaet und ist entsprechend mit Unsicherheiten behaftet. Zum anderen bereitet die Bewertung komplexer Schadstoffgemische wie PAK methodische Probleme. Im hier beschriebenen Forschungsvorhaben erfolgte in Teil A eine toxikologische Neubewertung von Benzo[a]pyren und PAK fuer orale und dermale Exposition. Auf Basis neu publizierter Tierstudien zur kanzerogenen Wirkung von Benzo[a]pyren und PAK wurden neue Krebsrisikoschaetzungen durchgefuehrt. Die Bedeutung der Tumoren von im Tierversuch relevanten Zielorgane fuer den Menschen und die quantitativen Unsicherheiten der Risikoschaetzungen wurden intensiv diskutiert. Aus der Betrachtung der Wirkung von PAK-Gemischen bezueglich gentoxischer und krebserzeugender Effekte resultierte ein methodischer Vorschlag zur Bewertung komplexer PAK-Gemische. Diese Ergebnisse wurden im Rahmen eines Fachgespraechs einem Expertengremium zur Diskussion gestellt. In Teil B des Vorhabens wurden basierend auf diesen Risikoabschaetzungen entsprechend der Methodik der BBodSchV Pruefwerte abgeleitet. Dabei wurde den Besonderheiten der PAK-Wirkung (Gemischproblematik, lokale Kanzerogenese) Rechnung getragen. Breiten Raum nahm dabei die Pruefung der Frage ein, ob an typischen Standorten (Gaswerkstandorte, Kokerei-Altlasten) anzutreffende PAK-Gemische in ihrer Zusammensetzung den experimentell untersuchten PAK-Gemischen vergleichbar sind und entsprechend die Anwendung der Risikoabschaetzungen bei der Pruefwertableitung moeglich ist. Diese Frage wurde bejaht, die Grenzen der Anwendbarkeit wurden diskutiert. (orig.)SIGLEAvailable from TIB Hannover: RN 8908(99-130,1) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman