TY  - JOUR
AB  - The combustion of traditional fuels in low-income countries, including those in sub-Saharan Africa, leads to extensive indoor particle exposure. Yet, the related health consequences in this context are understudied. This study aimed to evaluate the in vitro toxicity of combustion-derived particles relevant for Sub-Saharan household environments. Particles (< 2.5 µm) were collected using a high-volume sampler during combustion of traditional Ethiopian biomass fuels: cow dung, eucalyptus wood and eucalyptus charcoal. Diesel exhaust particles (DEP, NIST 2975) served as reference particles. The highest levels of particle-bound polycyclic aromatic hydrocarbons (PAHs) were found in wood (3219 ng/mg), followed by dung (618 ng/mg), charcoal (136 ng/mg) and DEP (118 ng/mg) (GC-MS). BEAS-2B bronchial epithelial cells and THP-1 derived macrophages were exposed to particle suspensions (1-150 µg/mL) for 24 h. All particles induced concentration-dependent genotoxicity (comet assay) but no pro-inflammatory cytokine release in epithelial cells, whereas dung and wood particles also induced concentration-dependent cytotoxicity (Alamar Blue). Only wood particles induced concentration-dependent cytotoxicity and genotoxicity in macrophage-like cells, while dung particles were unique at increasing secretion of pro-inflammatory cytokines (IL-6, IL-8, TNF-α). In summary, particles derived from combustion of less energy dense fuels like dung and wood had a higher PAH content and were more cytotoxic in epithelial cells. In addition, the least energy dense and cheapest fuel, dung, also induced pro-inflammatory effects in macrophage-like cells. These findings highlight the influence of fuel type on the toxic profile of the emitted particles and warrant further research to understand and mitigate health effects of indoor air pollution.
AU  - McCarrick, S.*
AU  - Delaval, M.N.
AU  - Dauter, U.M.*
AU  - Krais, A.M.*
AU  - Snigireva, A.*
AU  - Abera, A.*
AU  - Broberg, K.*
AU  - Eriksson, A.C.*
AU  - Isaxon, C.*
AU  - Gliga, A.R.*
C1  - 70094
C2  - 55417
CY  - Tiergartenstrasse 17, D-69121 Heidelberg, Germany
SP  - 1515-1532
TI  - Toxicity of particles derived from combustion of Ethiopian traditional biomass fuels in human bronchial and macrophage-like cells.
JO  - Arch. Toxicol.
VL  - 98
IS  - 5
PB  - Springer Heidelberg
PY  - 2024
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The assessment of persistence (P), bioaccumulation (B), and toxicity (T) of a chemical is a crucial first step at ensuring chemical safety and is a cornerstone of the European Union's chemicals regulation REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals). Existing methods for PBT assessment are overly complex and cumbersome, have produced incorrect conclusions, and rely heavily on animal-intensive testing. We explore how new-approach methodologies (NAMs) can overcome the limitations of current PBT assessment. We propose two innovative hazard indicators, termed cumulative toxicity equivalents (CTE) and persistent toxicity equivalents (PTE). Together they are intended to replace existing PBT indicators and can also accommodate the emerging concept of PMT (where M stands for mobility). The proposed "toxicity equivalents" can be measured with high throughput in vitro bioassays. CTE refers to the toxic effects measured directly in any given sample, including single chemicals, substitution products, or mixtures. PTE is the equivalent measure of cumulative toxicity equivalents measured after simulated environmental degradation of the sample. With an appropriate panel of animal-free or alternative in vitro bioassays, CTE and PTE comprise key environmental and human health hazard indicators. CTE and PTE do not require analytical identification of transformation products and mixture components but instead prompt two key questions: is the chemical or mixture toxic, and is this toxicity persistent or can it be attenuated by environmental degradation? Taken together, the proposed hazard indicators CTE and PTE have the potential to integrate P, B/M and T assessment into one high-throughput experimental workflow that sidesteps the need for analytical measurements and will support the Chemicals Strategy for Sustainability of the European Union.
AU  - Escher, B.I.*
AU  - Altenburger, R.*
AU  - Blüher, M.
AU  - Colbourne, J.K.*
AU  - Ebinghaus, R.*
AU  - Fantke, P.*
AU  - Hein, M.*
AU  - Köck, W.*
AU  - Kümmerer, K.*
AU  - Leipold, S.*
AU  - Li, X.*
AU  - Scheringer, M.*
AU  - Scholz, S.*
AU  - Schloter, M.
AU  - Schweizer, P.J.*
AU  - Tal, T.*
AU  - Tetko, I.V.
AU  - Traidl-Hoffmann, C.
AU  - Wick, L.Y.*
AU  - Fenner, K.*
C1  - 67695
C2  - 54002
CY  - Tiergartenstrasse 17, D-69121 Heidelberg, Germany
SP  - 1267-1283
TI  - Modernizing persistence-bioaccumulation-toxicity (PBT) assessment with high throughput animal-free methods.
JO  - Arch. Toxicol.
VL  - 97
IS  - 5
PB  - Springer Heidelberg
PY  - 2023
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Sustained exposure of the lung to various environmental or occupational toxins may eventually lead to pulmonary fibrosis, a devastating disease with no cure. Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins such as fibronectin and collagens. The peptidase plasmin degrades the ECM, but protein levels of the plasmin activator inhibitor-1 (PAI-1) are increased in fibrotic lung tissue, thereby dampening plasmin activity. Transforming growth factor-β1 (TGF-β1)-induced activation of SMAD transcription factors promotes ECM deposition by enhancing collagen, fibronectin and PAI-1 levels in pulmonary fibroblasts. Hence, counteracting TGF-β1-induced signaling is a promising approach for the therapy of pulmonary fibrosis. Transient receptor potential cation channel subfamily M Member 7 (TRPM7) supports TGF-β1-promoted SMAD signaling in T-lymphocytes and the progression of fibrosis in kidney and heart. Thus, we investigated possible effects of TRPM7 on plasmin activity, ECM levels and TGF-β1 signaling in primary human pulmonary fibroblasts (pHPF). We found that two structurally unrelated TRPM7 blockers enhanced plasmin activity and reduced fibronectin or PAI-1 protein levels in pHPF under basal conditions. Further, TRPM7 blockade strongly inhibited fibronectin and collagen deposition induced by sustained TGF-β1 stimulation. In line with these data, inhibition of TRPM7 activity diminished TGF-β1-triggered phosphorylation of SMAD-2, SMAD-3/4-dependent reporter activation and PAI-1 mRNA levels. Overall, we uncover TRPM7 as a novel supporter of TGF-β1 signaling in pHPF and propose TRPM7 blockers as new candidates to control excessive ECM levels under pathophysiological conditions conducive to pulmonary fibrosis.
AU  - Zeitlmayr, S.*
AU  - Zierler, S.*
AU  - Staab-Weijnitz, C.A.
AU  - Dietrich, A.*
AU  - Geiger, F.*
AU  - Horgen, F.D.*
AU  - Gudermann, T.*
AU  - Breit, A.*
C1  - 65757
C2  - 52900
SP  - 2767-2783
TI  - TRPM7 restrains plasmin activity and promotes transforming growth factor-β1 signaling in primary human lung fibroblasts.
JO  - Arch. Toxicol.
VL  - 96
IS  - 10
PY  - 2022
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through end of lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (in ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display deficient short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, and vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.
AU  - Kozlova, E.V.*
AU  - Valdez, M.C.*
AU  - Denys, M.E.*
AU  - Bishay, A.E.*
AU  - Krum, J.M.*
AU  - Rabbani, K.M.*
AU  - Carrillo, V.*
AU  - Gonzalez, G.M.*
AU  - Lampel, G.*
AU  - Tran, J.D.*
AU  - Vazquez, B.M.*
AU  - Anchondo, L.M.*
AU  - Uddin, S.A.*
AU  - Huffman, N.M.*
AU  - Monarrez, E.*
AU  - Olomi, D.S.*
AU  - Chinthirla, B.D.*
AU  - Hartman, R.E.*
AU  - Kodavanti, P.R.S.*
AU  - Chompre, G.*
AU  - Phillips, A.L.*
AU  - Stapleton, H.M.*
AU  - Henkelmann, B.
AU  - Schramm, K.-W.
AU  - Curras-Collazo, M.C.*
C1  - 63358
C2  - 51489
CY  - Tiergartenstrasse 17, D-69121 Heidelberg, Germany
TI  - Persistent autism-relevant behavioral phenotype and social neuropeptide alterations in female mice offspring induced by maternal transfer of PBDE congeners in the commercial mixture DE-71.
JO  - Arch. Toxicol.
PB  - Springer Heidelberg
PY  - 2021
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (Cmax) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48 h was better than 24 h, with no further improvement of TSI after 7 days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of Cmax were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and Cmax as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and the corresponding oral doses were obtained by reverse modeling. Application of this in vitro/in silico method to the rat hepatotoxicant pulegone resulted in an ADI that was similar to values previously established based on animal experiments. In conclusion, the proposed method links oral doses and blood concentrations of test compounds to the probability of hepatotoxicity.
AU  - Albrecht, W.*
AU  - Kappenberg, F.*
AU  - Brecklinghaus, T.*
AU  - Stoeber, R.*
AU  - Marchan, R.*
AU  - Zhang, M.*
AU  - Ebbert, K.*
AU  - Kirschner, H.*
AU  - Grinberg, M.*
AU  - Leist, M.*
AU  - Moritz, W.*
AU  - Cadenas, C.*
AU  - Ghallab, A.*
AU  - Reinders, J.*
AU  - Vartak, N.*
AU  - van Thriel, C.*
AU  - Golka, K.*
AU  - Tolosa, L.*
AU  - Castell, J.V.*
AU  - Damm, G.*
AU  - Seehofer, D.*
AU  - Lampen, A.*
AU  - Braeuning, A.*
AU  - Buhrke, T.*
AU  - Behr, A.C.*
AU  - Oberemm, A.*
AU  - Gu, X.*
AU  - Kittana, N.*
AU  - van de Water, B.*
AU  - Kreiling, R.*
AU  - Fayyaz, S.*
AU  - van Aerts, L.*
AU  - Smedsrød, B.*
AU  - Ellinger-Ziegelbauer, H.*
AU  - Steger-Hartmann, T.*
AU  - Gundert-Remy, U.*
AU  - Zeigerer, A.
AU  - Ullrich, A.*
AU  - Runge, D.*
AU  - Lee, S.M.L.*
AU  - Schiergens, T.S.*
AU  - Kuepfer, L.*
AU  - Aguayo-Orozco, A.*
AU  - Sachinidis, A.*
AU  - Edlund, K.*
AU  - Gardner, I.*
AU  - Rahnenführer, J.*
AU  - Hengstler, J.G.*
C1  - 56416
C2  - 47055
SP  - 1609-1637
TI  - Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations.
JO  - Arch. Toxicol.
VL  - 93
IS  - 6
PY  - 2019
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Engineered amorphous silica nanoparticles (nanosilica) are widely used in industry yet can induce adverse effects, which might be classified according to the oxidative stress model. However, the underlying mechanisms as well as the potential interactions of the three postulated different tiers of toxicity—i.e. oxidative-, pro-inflammatory- and cytotoxic-stress response—are poorly understood. As macrophages are primary targets of nanoparticles, we used several macrophage models, primarily murine RAW264.7 macrophages, and monitored pro-inflammatory and anti-oxidative reactions as well as cytotoxicity in response to nanosilica at max. 50 µg/mL. Special attention was given to the activation of mitogen-activated protein kinases (MAPKs) as potential regulators of the cellular stress response. Indeed, according to the oxidative stress model, also nanosilica elicits an, albeit modest, anti-oxidative response as well as pronounced pro-inflammatory reactions and cytotoxicity in macrophages. Interestingly however, these three tiers of toxicity seem to operate separately of each other for nanosilica. Specifically, impeding the anti-oxidative response by scavenging of reactive oxygen species does not prevent the pro-inflammatory and cytotoxic response. Furthermore, blocking the pro-inflammatory response by inhibition of MAPKs does not impair cell death. As hazard assessment has been guided by the prevailing assumption of a dose-dependent coupling of sequential tiers of toxicity, identification of critical physico-chemical parameters to assist the safe-by-design concept should be enabled by simply monitoring one of the toxicity read-outs. Our results indicate a more complex scenario in the case of nanosilica, which triggers independent pleiotropic effects possibly also related to different material properties and primary cellular targets.
AU  - Fritsch-Decker, S.*
AU  - Marquardt, C.*
AU  - Stöger, T.
AU  - Diabaté, S.*
AU  - Weiss, C.*
C1  - 53659
C2  - 44783
SP  - 2163-2174
TI  - Revisiting the stress paradigm for silica nanoparticles: Decoupling of the anti-oxidative defense, pro-inflammatory response and cytotoxicity.
JO  - Arch. Toxicol.
VL  - 92
IS  - 7
PY  - 2018
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Genotoxic carcinogens pose great hazard to human health. Uncertainty of current risk assessment strategies and long latency periods between first carcinogen exposure and diagnosis of tumors have raised interest in predictive biomarkers. Initial DNA adduct formation is a necessary step for genotoxin induced carcinogenesis. However, as DNA adducts not always translate into tumorigenesis, their predictive value is limited. Here we hypothesize that the combined analysis of pro-mutagenic DNA adducts along with time-matched gene expression changes could serve as a superior prediction tool for genotoxic carcinogenesis. Eker rats, heterozygous for the tuberous sclerosis (Tsc2) tumor suppressor gene and thus highly susceptible towards genotoxic renal carcinogens, were continuously treated with the DNA alkylating carcinogen methylazoxymethanol acetate (MAMAc). Two weeks of MAMAc treatment resulted in a time-dependent increase of O(6)-methylguanine and N7-methylguanine adducts in the kidney cortex, which was however not reflected by significant expression changes of cyto-protective genes involved in DNA repair, cell cycle arrest or apoptosis. Instead, we found a transcriptional regulation of genes involved in the tumor-related MAPK, FoxO and TGF-beta pathways. Continuous MAMAc treatment for up to 6 months resulted in a mild but significant increase of cancerous lesions. In summary, the combined analysis of DNA adducts and early gene expression changes could serve as a suitable predictive tool for genotoxicant-induced carcinogenesis.
AU  - Klaus, V.
AU  - Bastek, H.*
AU  - Damme, K.*
AU  - Collins, L.B.*
AU  - Frötschl, R.*
AU  - Benda, N.*
AU  - Lutter, D.
AU  - Ellinger-Ziegelbauer, H.*
AU  - Swenberg, J.A.*
AU  - Dietrich, D.R.*
AU  - Stemmer, K.
C1  - 50827
C2  - 42894
CY  - Heidelberg
SP  - 3427–3438
TI  - Time-matched analysis of DNA adduct formationand early gene expression as predictive tool for renal carcinogenesis in methylazoxymethanol acetate treated Eker rats.
JO  - Arch. Toxicol.
VL  - 91
IS  - 10
PB  - Springer Heidelberg
PY  - 2017
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Gold nanoparticles (AuNPs) have been extensively explored in biomedical applications, for example as drug carriers, contrast agents, or therapeutics. However, AuNP can exhibit cytotoxic profile, when the size is below 2 nm (ultrasmall AuNP; usAuNP) and when the stabilizing ligands allow for access to the gold surface either for the direct interaction with biomolecules or for catalytic activity of the unshielded gold surface. Furthermore, usAuNP exhibits significantly different biodistribution and enhanced circulation times compared to larger AuNP. This review gives an overview about the synthesis and the physico-chemical properties of usAuNP and, thereby, focusses on 1.4 nm sized AuNP, which are derived from the compound Au55(PPh3)12Cl6 and which are the most intensively studied usAuNP in the field. This part is followed by a summary of the toxic properties of usAuNP, which include in vitro cytotoxicity tests on different cell lines, electrophysiological tests following FDA guidelines as well as studies on antibacterial effects. Finally, the biodistribution and pharmacokinetics of ultrasmall AuNP are discussed and compared to the properties of more biocompatible, larger AuNP.
AU  - Schmid, G.*
AU  - Kreyling, W.G.
AU  - Simon, U.*
C1  - 51526
C2  - 43279
CY  - Heidelberg
SP  - 3011–3037
TI  - Toxic effects and biodistribution of ultrasmall gold nanoparticles.
JO  - Arch. Toxicol.
VL  - 91
IS  - 9
PB  - Springer Heidelberg
PY  - 2017
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Indoor air pollution is associated with increased morbidity and mortality. Specifically, the health impact of emissions from domestic burning of biomass and coal is most relevant and is estimated to contribute to over 4 million premature deaths per year worldwide. Wood is the main fuel source for biomass combustion and the shift towards renewable energy sources will further increase emissions from wood combustion even in developed countries. However, little is known about the constituents of wood smoke and biological mechanisms that are responsible for adverse health effects. We exposed A549 lung epithelial cells to collected wood smoke particles and found an increase in cellular reactive oxygen species as well as a response to bioavailable polycyclic aromatic hydrocarbons. In contrast, cell vitality and regulation of the pro-inflammatory cytokine interleukin-8 were not affected. Using a candidate approach, we could recapitulate WSP toxicity by the combined actions of its constituents soot, metals and PAHs. The soot fraction and metals were found to be the most important factors for ROS formation, whereas the PAH response can be mimicked by the model PAH benzo[a]pyrene. Strikingly, PAHs adsorbed to WSPs were even more potent in activating target gene expression than B[a]P individually applied in suspension. As PAHs initiate multiple adverse outcome pathways and are prominent carcinogens, their role as key pollutants in wood smoke and its health effects warrants further investigation. The presented results suggest that each of the investigated constituents soot, metals and PAHs are major contributors to WSP toxicity. Mitigation strategies to prevent adverse health effects of wood combustion should therefore not only aim at reducing the emitted soot and PAHs but also the metal content, through the use of more efficient combustion appliances, and particle precipitation techniques, respectively.
AU  - Dilger, M.*
AU  - Orasche, J.
AU  - Zimmermann, R.
AU  - Paur, H.R.*
AU  - Diabaté, S.*
AU  - Weiss, C.*
C1  - 47826
C2  - 39516
CY  - Heidelberg
SP  - 3029-3044
TI  - Toxicity of wood smoke particles in human A549 lung epithelial cells: The role of PAHs, soot and zinc.
JO  - Arch. Toxicol.
VL  - 90
IS  - 12
PB  - Springer Heidelberg
PY  - 2016
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Dietrich, D.*
AU  - von Aulock, S.*
AU  - Marquardt, H.W.J.*
AU  - Blaauboer, B.J.*
AU  - Dekant, W.*
AU  - Kehrer, J.*
AU  - Hengstler, J.G.*
AU  - Collier, A.C.*
AU  - Gori, G.B.*
AU  - Pelkonen, O.*
AU  - Lang, F.*
AU  - Nijkamp, F.P.*
AU  - Stemmer, K.
AU  - Li, A.*
AU  - Savolainen, K.*
AU  - Hayes, A.W.*
AU  - Gooderham, N.*
AU  - Harvey, A.*
C1  - 27315
C2  - 32639
SP  - 1739-1741
TI  - Open letter to the European commission: Scientifically unfounded precaution drives European commission's recommendations on EDC regulation, while defying common sense, well-established science, and risk assessment principles.
JO  - Arch. Toxicol.
VL  - 87
IS  - 9
PB  - Springer
PY  - 2013
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - We present in this article an outline of some cyclotron-based irradiation techniques that can be used to directly radiolabel industrially manufactured nanoparticles, as well as two techniques for synthesis of labelled nanoparticles using cyclotron-generated radioactive precursor materials. These radiolabelled nanoparticles are suitable for a range of different in vitro and in vivo tracing studies of relevance to the field of nanotoxicology. A basic overview is given of the relevant physics of nuclear reactions regarding both ion-beam and neutron production of radioisotopes. The various issues that determine the practicality and usefulness of the different methods are discussed, including radioisotope yield, nuclear reaction kinetics, radiation and thermal damage, and radiolabel stability. Experimental details are presented regarding several techniques applied in our laboratories, including direct light-ion activation of dry nanoparticle samples, neutron activation of nanoparticles and suspensions using an ion-beam driven activator, spark-ignition generation of nanoparticle aerosols using activated electrode materials, and radiochemical synthesis of nanoparticles using cyclotron-produced isotopes. The application of these techniques is illustrated through short descriptions of some selected results thus far achieved. It is shown that these cyclotron-based methods offer a very useful range of options for nanoparticle radiolabelling despite some experimental difficulties associated with their application. For direct nanoparticle radiolabelling, if care is taken in choosing the experimental conditions applied, useful activity levels can be achieved in a wide range of nanoparticle types, without causing substantial thermal or radiation damage to the nanoparticle structure. Nanoparticle synthesis using radioactive precursors presents a different set of issues and offers a complementary and equally valid approach when laboratory generation of the nanoparticles is acceptable for the proposed studies, and where an appropriate radiolabel can be incorporated into the nanoparticles during synthesis.
AU  - Gibson, N.*
AU  - Holzwarth, U.*
AU  - Abbas, K.*
AU  - Simonelli, F.*
AU  - Kozempel, J.*
AU  - Cydzik, I.*
AU  - Cotogno, G.*
AU  - Bulgheroni, A.*
AU  - Gilliland, D.*
AU  - Ponti, J.*
AU  - Franchini, F.*
AU  - Marmorato, P.*
AU  - Stamm, H.*
AU  - Kreyling, W.G.
AU  - Wenk, A.
AU  - Semmler-Behnke, M.
AU  - Buono, S.*
AU  - Maciocco, L.*
AU  - Burgio, N.
C1  - 3946
C2  - 28684
SP  - 751-773
TI  - Radiolabelling of engineered nanoparticles for in vitro and in vivo tracing applications using cyclotron accelerators.
JO  - Arch. Toxicol.
VL  - 85
IS  - 7
PB  - Springer
PY  - 2011
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - A urinary trichloroacetic acid (TCA) concentration of 100 mg/l at the end of the last work shift (8 h/day, 5 days/week) of the week has been established in workers as exposure equivalent for the carcinogenic substance trichloroethene (EKA for TRI) at an exposure concentration of 50 ppm TRI. Due to the continuous reduction of atmospheric TRI concentrations during the last years, the quantitative relation given by the EKA for TRI is revised for exposures to low TRI concentrations. A physiological two-compartment model is presented by which the urinary TCA concentrations are calculated that result from inhaled TRI in humans. The model contains one compartment for trichloroethanol (TCE) and one for TCA. Inhaled TRI is metabolized to TCA and to TCE. The latter is in part further oxidized to TCA. Urinary elimination of TCA is modeled to obey first order kinetics. All required model parameters were taken form the literature. In order to evaluate the model performance on the urinary TCA excretion at low exposure concentrations, predicted urinary TCA concentrations were compared with data obtained in two volunteer studies and in one field study. The model was evaluated at exposure concentrations as low as 12.5 ppm TRI. It is demonstrated that the correlation described by the hitherto used EKA for TRI is also valid at low TRI concentrations. For TRI exposure concentrations of 0.6 and 6 ppm, the resulting urinary TCA concentrations at the end of the last work shift of a week are predicted to be 1.2 and 12 mg/l, respectively.
AU  - Csanády, G.A.
AU  - Göen, T.*
AU  - Klein, D.
AU  - Drexler, H.*
AU  - Filser, J.G.
C1  - 5239
C2  - 27575
SP  - 897-902
TI  - Trichloroacetic acid in urine as biological exposure equivalent for low exposure concentrations of trichloroethene.
JO  - Arch. Toxicol.
VL  - 84
IS  - 11
PB  - Springer
PY  - 2010
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Slama, R.*
AU  - Cyrys, J.
AU  - Herbarth, O.*
AU  - Wichmann, H.-E.
AU  - Heinrich, J.
C1  - 1074
C2  - 26144
SP  - 293-295
TI  - A further plea for rigorous science and explicit disclosure of potential conflicts of interest.
JO  - Arch. Toxicol.
VL  - 83
IS  - 4
PB  - Springer
PY  - 2009
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Two male volunteers (A and B) inhaled 1.43 and 1.34 mmol, respectively, of vaporous 13C-labeled ethylene glycol (13C2-EG) over 4 h. In plasma, 13C2-EG and its metabolite 13C2-glycolic acid (13C2-GA) were determined together with the natural burden from background GA using a gas chromatograph equipped with a mass selective detector. Maximum plasma concentrations of 13C2-EG were 11.0 and 15.8 µmol/l, and of 13C2-GA were 0.9 and 1.8 µmol/l, for volunteers A and B, respectively. Corresponding plasma half-lives were 2.1 and 2.6 h for 13C2-EG, and 2.9 and 2.6 h for 13C2-GA. Background GA concentrations were 25.8 and 28.3 µmol/l plasma. Unlabeled background EG, GA and oxalic acid (OA) were detected in urine in which the corresponding 13C-labeled compounds were also quantified. Within 28 h after the start of the exposures, 6.4% and 9.3% 13C2-EG, 0.70% and 0.92% 13C2-GA, as well as 0.08% and 0.28% 13C2-OA of the inhaled amounts of 13C2-EG, were excreted in urine by volunteers A and B, respectively. The amounts of 13C2-GA represented 3.7% and 14.2% of background urinary GA excreted over 24 h (274 and 88 µmol). The amounts of 13C2-OA were 0.5% and 2.1% of background urinary OA excreted over 24 h (215 and 177 µmol). From the findings obtained in plasma and urine and from a toxicokinetic analysis of these data, it is highly unlikely that workplace EG exposure according to the German exposure limit (MAK-value 10 ppm EG, 8 h) could lead to adverse effects from the metabolically formed GA and OA.
AU  - Carstens, J.
AU  - Csanády, G.A.
AU  - Faller, T.H.
AU  - Filser, J.G.
C1  - 8980
C2  - 21145
SP  - 425-432
TI  - Human inhalation exposure to ethylene glycol.
JO  - Arch. Toxicol.
VL  - 77
IS  - 8
PY  - 2003
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The Long-Evans cinnamon (LEC) rat, an authentic model for Wilson disease, is characterized by a mutation in the Atp7b gene leading to a defective copper excretion and, as a consequence, to an accumulation of the metal in the liver and copper-associated hepatotoxicity. In the present communication expression profiles of genes in the liver from wild-type Long-Evans agouti (LEA) and LEC rats at different stages of copper accumulation and liver disease were investigated. Disease states were defined according to serum aspartate aminotransferase activity and bilirubin levels in serum and from histopathology of the liver. Gene expression was determined with the Affymetrix RTU34 oligonucleotide array covering 1031 genes. Compared to the LEA rat, the nondiseased LEC rat with already increased hepatic copper level showed an enhanced expression of genes, particularly related to oxidative stress and DNA damage. During the progression of the liver disease, in particular genes related to oxidative stress, DNA damage, apoptosis and inflammation with acute-phase reaction were upregulated.
AU  - Klein, D.*
AU  - Lichtmannegger, J.
AU  - Finckh, M.
AU  - Summer, K.H.
C1  - 22378
C2  - 21292
SP  - 568-575
TI  - Gene expression in the liver of Long-Evans cinnemon rats during the development of hepatitis.
JO  - Arch. Toxicol.
VL  - 77
IS  - 10
PY  - 2003
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Physiological toxicokinetic (PT) models are used to simulate tissue burdens by chemicals in animals and humans. A prerequisite for a PT model is the knowledge of the chemical's distribution among tissues. This depends on the blood flow and also on the free fraction of the substance and its tissue:blood partition coefficients. In the present study we determined partition Coefficients in human tissues at 37degreesC for the two selected xenoestrogens bisphenol A (BA) and daidzein (DA), and their unspecific binding to human serum proteins. Partition coefficients were obtained by incubating blood containing BA or DA with each of the following tissues: brain, liver, kidney, muscle, fat, placenta, mammary gland, and adrenal gland. Blood samples were analysed by HPLC. For BA and DA, all partition coefficients in non-adipose tissues were similar (average values: BA 1.4, DA 1.2). However, the lipophilic properties of both compounds diverge distinctly. Fat:blood partition coefficients were 3.3 (BA) and 0.3 (DA). These values indicate that with the exception of fat both compounds are distributed almost equally among tissues. In dialysis experiments, the unspecific binding of BA and DA with human serum proteins was measured by HPLC. For BA, the total concentration of binding sites and the apparent dissociation constant were calculated as 2000 and 100 nmol/ml, respectively. Because of the limited solubility of DA, only the ratio of the bound to the free DA concentration could be determined and was found to be 7.2. These values indicate that at low concentrations only small percentages of about 5% (BA) and 12% (DA) are as unbound free fractions in plasma. Since only the unbound fraction can bind to the estrogen receptor, binding to serum proteins represents a mechanism that limits the biological response in target tissues
AU  - Csanády, G.A.
AU  - Oberste-Frielinghaus, H.R.
AU  - Semder, B.
AU  - Baur, C.*
AU  - Schneider, K.T.*
AU  - Filser, J.G.
C1  - 8981
C2  - 20382
SP  - 299-305
TI  - Distribution and unspecific protein binding of the xenoestrogens bisphenol A and daidzein.
JO  - Arch. Toxicol.
VL  - 76
IS  - 5
PB  - Springer
PY  - 2002
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Inhalation is the most important route of absorption for many volatile substances. The inhaled chemical is distributed via the bloodstream into the organs and tissues. It is eliminated mainly unchanged by exhalation and also via metabolism. The blood concentration can be considered as a surrogate for the body burden of the chemical. It depends on the rate of uptake and on the rate of elimination. The rate of uptake by inhalation is determined by the blood:air partition coefficient of the gaseous compound, the actual concentration of the chemical already in the blood entering the lungs, the blood flow through the lungs, and the alveolar ventilation. The latter is greatly influenced by physical activity, which thus has a crucial impact on the rate of uptake. Consequently, the blood concentration of an inhaled chemical and the resulting alveolar retention, representing the rate of metabolism at steady-state, are dependent on the intensity of physical work. Both parameters can be calculated for steady-state conditions using simple algebraic equations, if one assumes that the rate of metabolic elimination is limited by the blood flow through the metabolizing organs. This assumption is valid for many rapidly metabolized inhaled gases and vapours at low concentrations present under workplace conditions. The derived equations give the theoretical background for the observations presented from a series of experimental studies which demonstrate that physical activity can be a major determinant of the toxicokinetics of inhaled compounds. Practical examples illustrate the procedure. We conclude that workplace-related physical activity should be taken into account for compounds with blood:air partition coefficients above 6 in the determination of occupational limit concentrations in air.
AU  - Csanády, G.A.
AU  - Filser, J.G.
C1  - 23907
C2  - 31391
SP  - 663-672
TI  - The relevance of physical activity for the kinetics of inhaled gaseous substances.
JO  - Arch. Toxicol.
VL  - 74
IS  - 11
PB  - Springer
PY  - 2001
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - We measured the background levels of di(2-ethylhexyl) phthalate (DEHP) and its hydrolytic metabolite mono(2-ethylhexyl) phthalate (MEHP) in blood from naive female Sprague-Dawley rats and in de-ionized charcoal-purified water using an analytical procedure that is based on sample treatment with acetonitrile, n-hexane extraction and analysis by gas chromatography. In blood, blank values of 91.3 +/- 34.7 micrograms DEHP/l (n = 31) and 30.1 +/- 13.1 micrograms MEHP/l (n = 20) were obtained, and in water, values of 91.6 +/- 44.2 micrograms DEHP/l (n = 26) and 26.7 +/- 10.4 micrograms MEHP/l (n = 15) were found. Since there is no difference between the background valves obtained from blood of naive rats and water, we conclude that DEHP and MEHP result from contamination during the analytical procedure.
AU  - Kessler, W.
AU  - Phokha, W.
AU  - Csanády, G.A.*
AU  - Filser, J.G.
C1  - 23902
C2  - 31392
SP  - 62-64
TI  - No background concentrations of di(2-ethylhexyl) phthalate and mono(2-ethylhexyl) phthalate in blood of rats.
JO  - Arch. Toxicol.
VL  - 75
IS  - 1
PB  - Springer
PY  - 2001
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - We developed a new two-chamber system for the coculture of hepatocytes and fecal microflora under aerobic and anaerobic conditions, respectively, to investigate the sequential metabolism of chemicals by the liver and microflora in vitro. The culture device consisted of two chambers separated by a permeable polycarbonate membrane. In the aerobic compartment, hepatocytes were cultivated as a monolayer on the membrane and in the anaerobic compartment fecal microflora as a suspension. To characterize the metabolic capacity of the microflora and hepatocytes, various marker enzymes were studied. Azoreductase, nitroductase, beta-glucuronidase, beta-glucosidase and sulphatase were tested in the microflora of the feces from three volunteers who had had significantly different eating habits for years (daily meat, mixed diet, vegetarian). The microflora exhibited significant activities and the various enzymes differed only moderately in the samples from the three volunteers. For rat hepatocytes the activities of various cytochrome P450 forms and conjugating enzymes served as markers. The enzyme activities were tested in the coculture system during a 4-h culture period intended for the test protocol. Deethylation of ethoxycoumarin and 2alpha-, 6beta- and 16alpha-hydroxylation of testosterone decreased by about 30%, 25%, 40% and 20%, respectively, while there was no loss of glucuronidation and sulphonation of 3-OH-benzo(a)pyrene nor of glutathione conjugation of 1-chloro-2,4-dinitrobenzene during the 4-h culture period. The activities of the tested hepatic phase I and II enzymes were not changed after coculture of the hepatocytes with the microflora for 4 h. The applicability of the in vitro system for studying the metabolic interaction of liver and microflora was demonstrated using 7-ethoxycoumarin and the developmental drug EMD 57033, a thiadiazinon derivative from Merck KGaA, as model compounds. Both compounds were oxidized and conjugated by liver cells. In the coculture of hepatocytes and fecal microflora the resulting glucuronides and sulphoconjugates were split by hydrolytic enzymes of the intestinal microflora.
AU  - Laube, B.
AU  - Winkler, S.
AU  - Ladstetter, B.*
AU  - Scheller, T.*
AU  - Schwarz, L.R.
C1  - 23967
C2  - 31414
SP  - 379-387
TI  - Establishment of a novel in vitro system for studying the interaction of xenobiotic metabolism of liver and intestinal microflora.
JO  - Arch. Toxicol.
VL  - 74
IS  - 7
PB  - Springer
PY  - 2000
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzymes in liver, together with feed refusal, has been suggested to play an important role in 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced lethality in rats. This study was carried out to further analyse the toxicological significance of reduced gluconeogenesis by comparing dose-responses and time-courses of effects of TCDD on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver, liver glycogen concentration as well as plasma concentrations of glucose and amino acids in both genders of TCDD-sensitive Long-Evans (L-E) rats and TCDD-resistant Han/Wistar (H/W) rats. A dose-dependent decrease in PEPCK activity was observed in H/W rats, but in L-E rats the activity was not decreased. However, TCDD impaired the strong increase in liver PEPCK activity observed in pair-fed controls of the L-E strain. Liver glycogen concentrations were severely decreased in L-E rats and moderately in H/W rats. This effect seems to be secondary to reduced feed intake, since a similar decrease was seen in pair-fed controls. Decreases in plasma glucose concentrations were also more profound in L-E rats than in H/W rats, but pair-fed controls were generally less affected. Circulating concentrations of amino acids were markedly increased in TCDD-treated L-E rats, which is likely to reflect increased mobilization of amino acids and their decreased metabolism in liver. Reduction of liver PEPCK activity cannot account for the sensitivity difference of these two strains of rats in terms of mortality. Nevertheless, the response of both strains of TCDD-treated rats regarding gluconeogenesis is different from that seen in pair-fed controls and suggesting that impairment of this pathway contributes to the development of the wasting syndrome.
AU  - Viluksela, M.*
AU  - Unkila, M.*
AU  - Pohjanvirta, R.*
AU  - Tuomisto, J.T.*
AU  - Stahl, B.U.
AU  - Rozman, K.K.
AU  - Tuomisto, J.*
C1  - 24098
C2  - 31440
SP  - 323-336
TI  - Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on liver phosphoenolpyruvate carboxykinase (PEPCK) activity, glucose homeostasis and plasma amino acid concentrations in the most TCDD-susceptible and the most TCDD-resistant rat strains.
JO  - Arch. Toxicol.
VL  - 73
IS  - 6
PB  - Springer
PY  - 1999
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Summer, K.H.
AU  - Klein, D.*
AU  - Lichtmannegger, J.
AU  - Wolff, T.
C1  - 20751
C2  - 17559
SP  - 127-129
TI  - 2-Chloro-acetophenone is an effective glutathione depletor in isolated rat hepatocytes.
JO  - Arch. Toxicol.
VL  - 71
PY  - 1996
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Csanády, G.A.
AU  - Filser, J.G.
AU  - Becka, M.
C1  - 40445
C2  - 37977
SP  - 227-230
TI  - Statistical analysis of toxicokinetic data by nonlinear regression [1].
JO  - Arch. Toxicol.
VL  - 67
IS  - 3
PY  - 1993
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The pharmacokinetics of styrene were investigated in male Sprague-Dawley rats and male B6C3F1 mice using the closed chamber technique. Animals were exposed to styrene vapors of initial concentrations ranging from 550 to 5000 ppm, or received intraperitoneal (i.p.) doses of styrene from 20 to 340 mg/kg or oral (p.o.) doses of styrene in olive oil from 100 to 350 mg/kg. Concentration-time courses of styrene in the chamber atmosphere were monitored and analyzed by a pharmacokinetic two-compartment model. In both species, the rate of metabolism of inhaled styrene was concentration dependent. At steady state it increased linearly with exposure concentration up to about 300 ppm; more than 95% of inhaled styrene was metabolized and only small amounts were exhaled unchanged. At these low concentrations transport to the metabolizing enzymes and not their metabolic capacity was the rate limiting step for metabolism. Pharmacokinetic behaviour of styrene was strongly influenced by physiological parameters such as blood flow and especially the alveolar ventilation rate. At exposure concentrations of styrene above 300 ppm the rate of metabolism at steady state was progressively limited by biochemical parameters of the metabolizing enzymes. Saturation of metabolism (Vmax) was reached at atmospheric concentrations of about 700 ppm in rats and 800 ppm in mice, Vmax being 224 μmol/(h·kg) and 625 μmol/(h·kg), respectively. The atmospheric concentrations at Vmax/2 were 190 ppm in rats and 270 ppm in mice. Styrene accumulates preferentially in the fatty tissue as can be deduced from its partition coefficients in olive oil:air and water:air which have been determined in vitro at 37°C to be 5600 and 15. In rats and mice exposed to styrene vapors below 300 ppm, there was little accumulation since the uptake was rate limiting. The bioaccumulation factor body:air at steady state (K′st*) was rather low in comparison to the thermodynamic partition coefficient body:air (Keq) which was determined to be 420. K′st* increased from 2.7 at 10 ppm to 13 at 310 ppm in the rat and from 5.9 at 20 ppm to 13 at 310 ppm in the mouse. Above 300 ppm, K′st* increased considerably with increasing concentration since metabolism became saturated in both species. At levels above 2000 ppm K′st* reached its maximum of 420 being equivalent to Keq. Pretreatment with diethyldithiocarbamate, administered intraperitoneally (200 mg/kg in rats, 400 mg/kg in mice) 15 min prior to exposure of styrene vapours, resulted in effective inhibition of styrene metabolism, indicating that most of the styrene is metabolized by cytochrome P450-dependent monooxygenases. In order to simulate chronic exposure rats and mice were exposed to 150 and 500 ppm styrene on 5 consecutive days (6 h/day). On day 6, inhalation kinetics were studied. No change in the rate of styrene metabolism was detected compared to non-pretreated controls. Intraperitoneal administration of styrene to rats and mice led to concentration-time courses in the atmosphere of the closed chamber with agreed with those predicted by the applied pharmacokinetic model. After p.o. administration of styrene to rats and mice concentration time-courses showed considerable inter-animal variability. The pharmacokinetic model was extended by a first order absorption from the gastrointestinal tract with half-lives of 0.87 h (rat) and 0.41 h (mouse) to obtain reasonable fits through the measured data. The pharmacokinetic parameters of inhaled styrene were extrapolated allometrically from rat to mouse and from rat and mouse to man. A good agreement was obtained with experimentally determined values indicating similar pharmacokinetic behaviour of styrene in these species.
AU  - Filser, J.G.
AU  - Schwegler, U.
AU  - Csanády, G.A.
AU  - Greim, H.A.
AU  - Kreuzer, P.E.
AU  - Kessler, W.
C1  - 40333
C2  - 38004
SP  - 517-530
TI  - Species-specific pharmacokinetics of styrene in rat and mouse.
JO  - Arch. Toxicol.
VL  - 67
IS  - 8
PY  - 1993
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The gas 1,3-butadiene (BU) is an important industrial chemical and an environmental air pollutant. BU has been shown to be a weak carcinogen in the rat but a potent carcinogen in the B6C3F1 mouse. This species difference makes risk extrapolation to humans difficult and the underlying mechanism should be clarified before meaningful risk extrapolation to humans can be made. One possible explanation for the species differences in cancer response is that there are quantitative species differences in the formation of genotoxic epoxides. To investigate this possibility a physiologically based pharmacokinetic (pbpk) model for BU together with its first reactive metabolite 1,2-epoxybutene-3 (butadiene monoxide, BMO) was developed. Previously reported values on hepatic glutathione (GSH) turnover, depletion of hepatic GSH in rodents exposed to BU, and in vitro metabolic data of BU and BMO were included in the model, which incorporates intrahepatic first-pass hydrolysis of BMO and the ordered sequential, ping-pong mechanism to describe the enzyme kinetics of BMO-GSH conjugation. In vitro studies were carried out to obtain tissue: air partition coefficients of BU and BMO in rat tissue homogenates. The simulated pharmacokinetics of BU, BMO, and GSH agreed with previously published experimental observations in rat and mouse obtained in closed and open chamber experiments. According to the model, the internal dose of BMO (expressed either as the concentration in mixed venous blood or as the area under the concentration-time curve) is approximately 1.6 times higher in the mouse than in the rat for exposure to BU below 1000 ppm. At higher exposure levels, GSH depletion occurs in the mouse, but not in the rat, after about 6-9 h. This GSH depletion results in up to 2-3 times higher internal doses in the mouse than in the rat. The clear but relatively small species difference in body burdens of BMO indicated from our model can only partly explain the marked species difference in cancer response between mice and rats exposed to BU.
AU  - Johanson, G.A.
AU  - Filser, J.G.
C1  - 40246
C2  - 40014
SP  - 151-163
TI  - A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation.
JO  - Arch. Toxicol.
VL  - 67
IS  - 3
PY  - 1993
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The "closed chamber technique" (CCT) is presented. It allows investigation of pharmacokinetics of volatile substances in vivo in animals and in man and in vitro using tissue fractions. During the exposure period only the atmospheric concentrations of the substance are measured. The concentration-time data obtained are pharmacokinetically analyzed by a two compartment model describing uptake, endogenous production and excretion of the unchanged substance and its metabolic elimination. Using this model, pharmacokinetics of ethylene have been determined in rats and man. For both species, the results compared well with an estimation based on an allometric species scaling. Furthermore, the applicability of CCT is demonstrated in vivo on several other gases and vapors of solvents, e.g. trichloroethylene and 1,1,1-trichloroethane, and in vitro on 1,2-epoxybutene-3.
AU  - Filser, J.G.
C1  - 19242
C2  - 12313
SP  - 1-10
TI  - The closed chamber technique--uptake, endogenous production, excretion, steady-state kinetics and rates of metabolism of gases and vapors.
JO  - Arch. Toxicol.
VL  - 66
IS  - 1
PY  - 1992
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The inhalation pharmacokinetics and the endogenous production of ethylene has been determined in healthy volunteers with respect to the formation of the carcinogen ethylene oxide. Ethylene showed a low degree of accumulation in the body determined in six subjects, the thermodynamic partition coefficient “body/air” being 0.53±0.23 (mean ± SD) and the accumulation factor “body/air” at steady-state being 0.33±0.13 (mean ± SD). The rate of metabolism was directly proportional to the exposure concentration. Only 2% of ethylene inhaled was metabolized to ethylene oxide, whereas 98% of ethylene was exhaled unchanged. The rate of the endogenous production of ethylene was 32±12 nmol/h (mean ± SD), as calculated from exhalation data from 14 subjects. The resulting body burden was 0.44±0.19 nmol/kg (mean ± SD). By analyzing published data on ethylene oxide in man its half-life was estimated to be 42 min. Using the pharmacokinetic parameters of ethylene and ethylene oxide, the body burden of ethylene oxide due to the sum of the exposure to environmental ethylene of about 15 ppb and to endogenous ethylene exposure of 0.44 nmol/kg was predicted to be 0.25 nmol/kg. In the blood of five nonsmokers and one smoker the hemoglobin adduct resulting from the reaction of ethylene oxide with the N-terminal valine, N-(2-hydroxyethyl)valine, was quantified by gas chromatography/mass spectrometry. The value of 20±5 pmol/g Hb (mean ± SD) found in the non-smokers corroborated the steady-state level of 18±3 pmol/g Hb (mean ± SD) calculated from the pharmacokinetic approach.
AU  - Filser, J.G.
AU  - Denk, B.
AU  - Törnqvist, M.
AU  - Kessler, W.
AU  - Ehrenberg, L.
C1  - 19248
C2  - 12319
SP  - 157-163
TI  - Pharmacokinetics of Ehtylene in Man; Body Burden with Ethylene Oxide and Hydroxyethylation of Hemoglobin due to Endogenous and Environmental Ethylene.
JO  - Arch. Toxicol.
VL  - 66
IS  - 3
PY  - 1992
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The inhalation pharmacokinetics and the endogenous production of ethylene has been determined in healthy volunteers with respect to the formation of the carcinogen ethylene oxide. Ethylene showed a low degree of accumulation in the body determined in six subjects, the thermodynamic partition coefficient 'body/air' being 0.53 ± 0.23 (mean ± SD) and the accumulation factor 'body/air' at steady-state being 0.33 ± 0.13 (mean ± SD). The rate of metabolism was directly proportional to the exposure concentration. Only 2% of ethylene inhaled was metabolized to ethylene oxide, whereas 98% of ethylene was exhaled unchanged. The rate of the endogenous production of ethylene was 32 ± 12 nmol/h (mean ± SD), as calculated from exhalation data from 14 subjects. The resulting body burden was 0.44 ± 0.19 nmol/kg (mean ± SD). By analyzing published data on ethylene oxide in man its half-life was estimated to be 42 min. Using the pharmacokinetic parameters of ethylene and ethylene oxide, the body burden of ethylene oxide due to the sum of the exposure to environmental ethylene of about 15 ppb and to endogenous ethylene exposure of 0.44 nmol/kg was predicted to be 0.25 nmol/kg. In the blood of five nonsmokers and one smoker the hemoglobin adduct resulting from the reaction of ethylene oxide with the N-terminal valine, N-(2-hydroxyethyl)valine, was quantified by gas chromatography/mass spectrometry. The value of 20 ± 5 pmol/g Hb (mean ± SD) found in the non-smokers corroborated the steady-state level of l8 ± 3 pmol/g Hb (mean ± SD) calculated from the pharmacokinetic approach.
AU  - Filser, J.G.
AU  - Denk, B.
AU  - Törnqvist, M.A.
AU  - Kessler, W.
AU  - Ehrenberg, L.G.
C1  - 40663
C2  - 12319
SP  - 157-163
TI  - Pharmacokinetics of ethylene in man; body burden with ethylene oxide and hydroxyethylation of hemoglobin due to endogenous and environmental ethylene.
JO  - Arch. Toxicol.
VL  - 66
IS  - 3
PY  - 1992
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Gas uptake studies were carried out to evaluate kinetic interactions between 1,3-butadiene and styrene in Sprague-Dawley rats. The animals were co-exposed by inhalation to a mixture of 1.3-butadiene between 20 and 6000 ppm (v/v) and styrene between 0 and 500 ppm. The data demonstrate that metabolism of 1,3-butadiene was partially inhibited by styrene. The inhibition was competitive at atmospheric concentrations of styrene up to 90 ppm. Higher concentrations of styrene resulted in a small additional inhibition only. The apparent Michaelis-Menten constant for 1,3-butadiene, related to the average concentration in the organism of the animals, was K(mapp) = 1.17 ± 0.37 (μmol/l of tissue) and the corresponding atmospheric concentration at steady state was 560 ppm. The inhibition constant of styrene was found to be K(i) = 0.23 ± 0.30 (μmol/l of tissue). The maximal metabolic rate for 1,3-butadiene was 230 ± 10 (μ/kg/h).
AU  - Laib, R.J.
AU  - Tucholski, M.
AU  - Filser, J.G.
AU  - Csanády, G.A.
C1  - 40534
C2  - 38024
SP  - 310-314
TI  - Pharmacokinetic interaction between 1,3-butadiene and styrene in Sprague-Dawley rats.
JO  - Arch. Toxicol.
VL  - 66
IS  - 5
PY  - 1992
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Benzo[a]pyrene (BaP) has been reported to exert a differential effect on murine hematopoiesis that is mouse strain specific. Interpretation of these results based solely on experimental data is restricted and leaves important questions unanswered. Therefore, a mathematical model of murine hematopoiesis was applied in order to: (1) identify the targets of BaP, (2) quantify the damage to target cells and (3) based on these results, interpret differences in strain susceptibility. Model analysis of the hematopoietic response of D2 and BDF1 mice to a daily oral administration of 125 mg/kg BaP showed that proliferating hematopoietic cells are the targets of BaP. Within this group it was found that: (a) erythropoietic cells were the most susceptible to BaP, (b) granulopoietic cells showed a susceptibility half that of erythropoietic cells and (c) the susceptibility of stem cells ranged between that of erythropoietic and granulopoietic cells. This damage pattern was the same for both strains, indicating that the difference between the strains was quantitative. As cell destruction rates were about 3-fold higher for D2 than BDF1 mice, it was concluded that D2 mice were about three times as susceptible to BaP as BDF1 mice. The study showed that the mathematical model, in addition to experimental methods, provided an efficient tool for the analysis of BaP hematotoxicity.
AU  - Scheding, S.*
AU  - Loeffler, M.*
AU  - Anselstetter, V.*
AU  - Wichmann, H.-E.
C1  - 40528
C2  - 38786
SP  - 546-550
TI  - A mathematical approach to benzo[a]pyrene-induced hematotoxicity.
JO  - Arch. Toxicol.
VL  - 66
IS  - 8
PY  - 1992
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - There is presently no scientifically proven method to assess the toxicity of environmental samples containing complex mixtures of chlorinated dibenzo-p-dioxins (CDDs) of known composition. Their risk assessment is currently based on the interim concept of toxicity equivalency factors (TEFs), with the unproven assumption that all interactions of CDDs are additive. To address this problem we conducted acute toxicity studies with four different CDDs, viz 2,3,7,8-tetrachlorodibenzo-p-dioxin (tetra-CDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (penta-CDD), 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (hexa-CDD) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (hepta-CDD), all containing chlorine substituents in the crucial 2,3,7,8-positions. The homologues, dissolved in corn oil/acetone, were administered to groups of five male Sprague Dawley rats at several doses (at least three) by gastric intubation. The obtained mortality data were employed to calculate the LD20,50 and 80 for each homologue. These data were subsequently used to prepare equipotent doses (expected mortality of 20, 50 and 80%) of a mixture containing all four homologues, each of them contributing one fourth of the toxicity, under the assumption of additive toxicity. The obtained LD50 value and (TEF) was for tetra-CDD 43 micrograms/kg (1), penta-CDD 206 micrograms/kg (0.2) hexa-CDD 887 micrograms/kg (0.05) and hepta-CDD 6325 micrograms/kg (0.007), respectively. The dose-response to the mixture confirmed the hypothesis of strict additivity in the acute toxicity of the four CDD homologues.
AU  - Stahl, B.U.
AU  - Kettrup, A.
AU  - Rozman, K.K.
C1  - 19466
C2  - 12561
SP  - 471-477
TI  - Comparative Toxicity of Four Chlorinated Dibenzo-p-dioxins (CDDs) and their Mixture. Part I: Acute Toxicity and Toxic Equivalency Factors (TEFs).
JO  - Arch. Toxicol.
VL  - 66
IS  - 7
PY  - 1992
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - There is presently no scientifically proven method to assess the toxicity of environmental samples containing complex mixtures of chlorinated dibenzo-p-dioxins (CDDs) of known composition. Their risk assessment is currently based on the interim concept of toxicity equivalency factors (TEFs), with the unproven assumption that all interactions of CDDs are additive. To address this problem we conducted acute toxicity studies with four different CDDs, viz 2,3,7,8-tetrachlorodibenzo-p-dioxin (tetra-CDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (penta-CDD), 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (hexa-CDD) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (hepta-CDD), all containing chlorine substituents in the crucial 2,3,7,8-positions. The homologues, dissolved in corn oil/acetone, were administered to groups of five male Sprague Dawley rats at several doses (at least three) by gastric intubation. The obtained mortality data were employed to calculate the LD20,50 and80 for each homologue. These data were subsequently used to prepare equipotent doses (expected mortality of 20, 50 and 80%) of a mixture containing all four homologues, each of them contributing one fourth of the toxicity, under the assumption of additive toxicity. The obtained LD50 value and (TEF) was for tetra-CDD 43 μg/kg (1), penta-CDD 206 μg/kg (0.2) hexa-CDD 887 μg/kg (0.05) and hepta-CDD 6325 μg/kg (0.007), respectively. The dose-response to the mixture confirmed the hypothesis of strict additivity in the acute toxicity of the four CDD homologues.
AU  - Stahl, B.U.
AU  - Kettrup, A.
AU  - Rozman, K.K.
C1  - 40525
C2  - 38788
SP  - 471-477
TI  - Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture - Part I: Acute toxicity and toxic equivalency factors (TEFs).
JO  - Arch. Toxicol.
VL  - 66
IS  - 7
PY  - 1992
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Male Sprague-Dawley rats were treated with an LD20, LD50 and LD80 respectively, of tetra-, penta-, hexa-,hepta-CDD and a mixture of the four CDDs, all carrying chlorine substituents in the biologically crucial 2, 3, 7, and 8 positions. Specific activities of two key enzymes of gluconeogenesis, viz, phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate carboxylase (PC), as well as the activity of the preneoplastic marker enzyme γ-glutamyl transpeptidase (γ-GT), were determined in livers of CDD-treated and ad libitum-fed control animals. PEPCK activity showed evidence for dose-related inhibition on the second day after dosing; PC activity was slightly reduced, whereas γ-GT activity was dose-dependently inhibited. By 8 days after dosing PEPCK activities were dose-dependently decreased after administration of all four CDDs and their mixture. PC activities were significantly reduced, but no dose-response was evident. The activity of γ-GT was dosedependently inhibited, but only to a value of 25% below control activities. It is concluded that CDDs share a common mechanism of acute toxicity, viz, inhibition of glucocorticoid-dependent enzymes which results in a derailment of intermediary metabolism not compatible with survival of the animals.
AU  - Weber, L.W.D.
AU  - Lebofsky, M.
AU  - Stahl, B.U.
AU  - Kettrup, A.
AU  - Rozman, K.K.
C1  - 19467
C2  - 12562
SP  - 478-483
TI  - Comparative Toxicity of Four Chlorinated Dibenzo-p-dioxins (CDDs) and their Mixture. Part II: Structure-activity Relationships with Inhibition of Hepatic Phosphoenolpyruvate Carbocykinase, Pyruvate Carbocylase, and gamma-glutamyl Transpeptidase Activities.
JO  - Arch. Toxicol.
VL  - 66
IS  - 7
PY  - 1992
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Male Sprague-Dawley rats were treated with an LD20, an LD50, and an LD80 of 2,3,7,8-tetrachlorodibenzo-p-dioxin (tetra-CDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (penta-CDD), 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (hexa-CDD), 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (hepta-CDD), respectively, and a mixture of the four homologues where each CDD was represented at one-fourth its previously established LD20, LD50, and LD80, respectively. Plasma tryptophan levels, liver ethoxyresorufin O-deethylase (EROD) activities, and liver weights were determined at 2 and 8 days after treatment. Plasma tryptophan levels were dose-dependently elevated, particularly at 8 days after treatment, by as much as 75% over control levels. EROD activity in CDD-treated animals was induced 27- to 28-fold, as compared with vehicle-treated controls, but did not show any dose-response. Liver weights were also significantly increased by the CDD treatments, but the increase was not dose related. There was no correlation between plasma tryptophan levels, a biomarker of acute toxicity of CDDs, and EROD activity, a biomarker of arylhydrocarbon (Ah) receptor-mediated enzyme induction. It is concluded that the acute toxicity of CDDs, which correlates and shows perfect structure-activity relationship with reduced activities of key enzymes of intermediary metabolism, and the induction of enzymes by much lower doses of CDDs in the liver, have different mechanisms of action.
AU  - Weber, L.W.D.
AU  - Lebofsky, M.
AU  - Stahl, B.U.
AU  - Kettrup, A.
AU  - Rozman, K.K.
C1  - 19468
C2  - 12563
SP  - 484-488
TI  - Comparative Toxicity of Four Chlorinated Dibenzo-p-dioxins (CDDs) and their Mixture. Part III: Structure-activity Relationship with Increased Plasma Tryptophan Levels, but no Relationship to Hepatic Ethoxyresorufin o-deethylase Activity.
JO  - Arch. Toxicol.
VL  - 66
IS  - 7
PY  - 1992
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The purpose of the present study was to investigate the effect of perfusion with a medium containing 12 or 24 micrograms Cadmium (as CdCl2) per ml on this metal's accumulation, transfer rate and metallothionein (MT) level. The experiments were performed with an isolated lobule of a dually-perfused human term placenta. Placental cell integrity and viability were characterised by their morphology and metabolic function, manifested in the tissue's electron microscopic structure and glucose and oxygen (O2) consumption, respectively. Perfusion with 24 micrograms Cd/ml medium for 5 h resulted in significant elevation in MT. The transfer rate of Cd to the fetal side of the placenta was very slow, and not until 40 min after the addition of Cd into the maternal side was a significant increase in the metal's level observed in the fetal perfusate. Thereafter, the level of the metal increased gradually and reached a steady state about 1 h later, at a level which was less than 1/20th of its concentration in the maternal perfusate. There was a 60-fold increase in Cd level in the cytosolic fraction obtained from the Cd-treated samples. At 12 micrograms Cd/ml no significant changes were noted in morphology, metabolic function and MT content. None of the Cd levels caused a significant change in O2 and glucose consumption, in spite of the fact that with the higher Cd dose the microstructure of the tissue showed some pathological changes. The observed elevation in MT may provide the fetus some protection against the harmful effects of the metal.
AU  - Boadi, W.Y.
AU  - Yannai, S.
AU  - Urbach, J.
AU  - Brandes, J.M.
AU  - Summer, K.H.
C1  - 18698
C2  - 11799
SP  - 18-23
TI  - Transfer and accumulation of cadmium, and the level of metallothionein in perfused human placentae.
JO  - Arch. Toxicol.
VL  - 65
IS  - 4
PY  - 1991
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Metabolism of isobutene (2-methylpropene) in rats (Sprague Dawley) and mice (B6C3F1) follows kinetics according to Michaelis-Menten. The maximal metabolic elimination rates are 340 μmol/kg/h for rats and 560 μmol/kg/h for mice. The atmospheric concentration at which Vmax/2 is reached is 1200 ppm for rats and 1800 ppm for mice. At steady state, below atmospheric concentrations of about 500 ppm the rate of metabolism of isobutene is direct proportional to its concentration. 1,1-Dimethyloxirane is formed as a primary reactive intermediate during metabolism of isobutene in rats and can be detected in the exhaled air of the animals. Under conditions of saturation of isobutene metabolism the concentration of 1,1-dimethyloxirane in the atmosphere of a closed exposure system is only about 1/15 of that observed for ethene oxide and about 1/100 of that observed for 1,2-epoxy-3-butene as intermediates in the metabolism of ethene or 1,3-butadiene.
AU  - Csanády, G.A.
AU  - Freise, D.
AU  - Denk, B.
AU  - Filser, J.G.
AU  - Cornet, M.
AU  - Rogiers, V.
AU  - Laib, R.J.
C1  - 19249
C2  - 12320
SP  - 100-105
TI  - Investigation of Species Differences in Isobutene (2-methylpropene) Metabolism Between Mice and Rats.
JO  - Arch. Toxicol.
VL  - 65
IS  - 2
PY  - 1991
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Filser, J.G.
AU  - Johanson, G.
C1  - 19250
C2  - 12321
TI  - Low Apparent Alveolar Ventilations in Closed Chamber Gas Uptake Experiments.
JO  - Arch. Toxicol.
PY  - 1991
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Kinetics of the metabolism of 1,2-epoxybutene-3 (butadiene monoxide) were investigated in liver fractions of mouse, rat, and man. In these species similar enzyme characteristics were found. In microsomes, no NADPH-dependent metabolism of butadiene monoxide was detectable. Epoxide hydrolase activity was found only in microsomes. The Vmax [nmol butadiene monoxide/(mg protein x min)] was 19 in mouse, 17 in rat, and 14 in man and the apparent Km (mmol butadiene monoxide/l incubate) was 1.5 in mouse, 0.7 in rat, and 0.5 in man. Glutathione S-transferase activity was found in cytosol only, revealing first order kinetics in the measured range. The ratio Vmax/Km [(nmol butadiene monoxide x l)/(mg protein × min × mmol of butadiene monoxide)] was 15 in mouse, 11 in rat, and 8 in man. The data obtained were used to extrapolate on the total rate of butadiene monoxide metabolism for each species in vivo: it was calculated to be 1.3 times higher in mice and 2.3 times lower in man compared to rats, when corrected for body weight.
AU  - Kreuzer, P.E.
AU  - Kessler, W.
AU  - Welter, H.F.*
AU  - Baur, C.M.*
AU  - Filser, J.G.
C1  - 33986
C2  - 40221
SP  - 59-67
TI  - Enzyme specific kinetics of 1,2-epoxybutene-3 in microsomes and cytosol from livers of mouse, rat, and man.
JO  - Arch. Toxicol.
VL  - 65
IS  - 1
PY  - 1991
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The main urinary metabolite of hydrogen cyanamide (syn.: cyanamide) in rat and man is acetylcyanamide (syn.: N-acetylcyanamide). An analytical method was developed to determine acetylcyanamide in the urine with a limit of quantification of <10 μg/l (mean recovery 96.1 % using spikes of 20 μg/l; relative standard deviation <4%). This methodology is based upon ion chromatography using column-switch techniques and UV detection. It could be demonstrated that in rats an average of 45.6% of oral applied cyanamide (10 mg/kg) was excreted in the urine as acetylcyanamide. In male human volunteers a mean of 40% of oral administered cyanamide (mean dose 0.25 mg/kg body weight) was excreted via the urine as acetylcyanamide. The same group of volunteers participated in a skin absorption study with dermal application of the above cyanamide dose onto a skin surface area of 32 cm2. Within an application period of 6 h an average cyanamide quantity of 2.3 mg was available for skin absorption. A mean portion of 7.7% of this quantity was found as acetylcyanamide in the urine of the participants. Findings from literature state that cyanamide is metabolized in vitro to cyanide. According to examinations performed in vivo, however, such a metabolic pathway seems to be irrelevant for man. In comparison with the control values there was no significant increase of both the cyanide concentrations in the blood and the thiocyanate concentrations in the urine of the above volunteers after the described oral cyanamide administration.
AU  - Mertschenk, B.*
AU  - Bornemann, W.*
AU  - Filser, J.G.
AU  - von Meyer, L.*
AU  - Rust, U.*
AU  - Schneider, J.C.*
AU  - Gloxhuber, C.*
C1  - 40743
C2  - 38963
SP  - 268-272
TI  - Urinary excretion of acetylcyanamide in rat and human after oral and dermal application of hydrogen cyanamide (H2NCN).
JO  - Arch. Toxicol.
VL  - 65
IS  - 4
PY  - 1991
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The major cause of TCDD-induced death in rats is a progressive voluntary feed refusal which has been correlated with reduced gluconeogenesis. Since centrally administered TCDD does not cause death or decreased feed intake in rats, the ability of TCDD to suppress appetite via peripheral mechanisms acting on the central nervous system was examined in two experimental models. First, it was found that the feed intake of rats on scheduled feeding cycles was not decreased by blood transfused from rats with TCDD-induced appetite suppression (8 days after a lethal dose of TCDD, i.p.). In contrast, a similar transfusion from normal, satiated rats did reduce feed intake of recipient rats by approximately 40%, suggesting that TCDD-treated rats are not satiated but rather that they are not hungry. In the second study tryptophan (the amino acid precursor of the neurotransmitter serotonin) was measured in the plasma and tryptophan, serotonin, norepinephrine and dopamine in the hypothalamus as well as dopamine and its metabolites in the striatum 4, 8, and 16 days after TCDD dosage (125 μg/kg, i.p.). Progressive time-dependent increases in tryptophan levels in plasma and brain were paralleled by increases in brain serotonin and 5-hydroxyindoleacetic acid (the primary metabolite of serotonin) in TCDD-treated rats. No changes were observed regarding the other biogenic amines. It is suggested based on these data and on substantial evidence from the published literature that a serotonergic mechanism may be involved in TCDD-induced feed intake reduction.
AU  - Rozman, K.K.
AU  - Pfeifer, B.
AU  - Kerecsen, L.
AU  - Alper, R.H.
C1  - 18240
C2  - 11453
SP  - 124-128
TI  - Is a Serotonergic Mechanism Involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced Appetite Suppression in the Sprague-Dawley Rat?.
JO  - Arch. Toxicol.
VL  - 65
IS  - 2
PY  - 1991
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Male Sprague-Dawley rats (240–245 g) were dosed ip with 5, 15, 25, or 125 μg/kg -,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in corn oil. Ad libitumfed and pair-fed controls received vehicle (4 ml/kg) alone. Two or 8 days after dosing five rats of each group were sacrificed, their livers removed and assayed for the activities of three gluconeogenic enzymes [phosphoenol-pyruvate carboxykinase (PEPCK; EC 4.1.1.32), pyruvate carboxylase (PC; EC 6.4.1.1.), and glucose-6-phosphatase (G-6-Pase, EC 3.1.3.9)], and one glycolytic enzyme [pyruvate kinase (PK; EC 2.7.1.40)] by established procedures. The activity of PK was not affected by TCDD at either time point. The activity of G-6-Pase tended to be decreased in TCDD-treated animals, as compared to pair-fed controls, but the decrease was variable without an apparent dose-response. The activity of PEPCK was significantly decreased 2 days after dosing, but a clear dose-response was apparent only at the 8-day time point. Maximum loss of activity at the highest dose was 56% below pair-fed control levels. PC activity was slightly decreased 2 days after TCDD treatment and displayed statistically significant, dose-dependent reduction by 8 days after dosing with a 49% loss of enzyme activity after the highest dose. It is concluded that inhibition of gluconeogenesis by TCDD previously demonstrated in vivo is probably due to decreased activities of PEPCK and PC. The data also support the prevailing view that PEPCK and PC are rate-determining enzymes in gluconeogenesis.
AU  - Weber, L.W.D.
AU  - Lebofsky, M.
AU  - Greim, H.
AU  - Rozman, K.K.
C1  - 18237
C2  - 11450
SP  - 119-123
TI  - Key Enzymes of Gluconeogenesis are Dose-Dependently Reduced in 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)-treated Rats.
JO  - Arch. Toxicol.
VL  - 65
IS  - 2
PY  - 1991
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The in vitro penetration of 3H-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) into human cadaver skin was studied at concentrations of 65 and 6.5 ng TCDD per cm2 of skin surface. Vehicles used were acetone to simulate exposure to TCDD as a dry material, and mineral oil to simulate exposure to TCDD in an oily medium. Penetration was performed for 30, 100, 300, and 1000 min in improved Franz cells. Skin was used either intact, or with stripped horny layer. Skin was sectioned along its natural layers and radioactivity determined in epidermis and dermis. TCDD did not readily penetrate into human skin in vitro. The vehicle of exposure to TCDD played an important role in dermal penetration. The rapidly evaporating acetone allowed TCDD to penetrate deeply into the loose surface lamellae of the horny layer, but then appeared to be poorly available for further penetration. Mineral oil as the vehicle, on the other hand, represented a lipophilic compartment which competed with lipophilic constituents of the stratum corneum for TCDD and hence slowed its penetration even more. The stratum corneum acted as a protective barrier, as its removal increased the amount of TCDD absorbed into layers of the skin. Hourly rates of absorption of TCDD per unit area of skin were calculated in two ways: a worst case scenario where TCDD absorbed into any layer of skin including the stratum corneum was used for regression analysis; and a physiological approach where only that amount of TCDD was considered absorbed which had penetrated beyond the epidermis into the region of dermal vascularization.(ABSTRACT TRUNCATED AT 250 WORDS)
AU  - Weber, L.W.D.
AU  - Zesch, A.
AU  - Rozman, K.K.
C1  - 18238
C2  - 11451
SP  - 421-428
TI  - Penetration, Distribution and Kinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Human Skin in Vitro.
JO  - Arch. Toxicol.
VL  - 65
IS  - 5
PY  - 1991
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Male Sprague-Dawley rats (240-245 g) were dosed ip with 5, 15, 25, or 125 μg/kg -,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in corn oil. Ad libitumfed and pair-fed controls received vehicle (4 ml/kg) alone. Two or 8 days after dosing five rats of each group were sacrificed, their livers removed and assayed for the activities of three gluconeogenic enzymes [phosphoenol-pyruvate carboxykinase (PEPCK; EC 4.1.1.32), pyruvate carboxylase (PC; EC 6.4.1.1.), and glucose-6-phosphatase (G-6-Pase, EC 3.1.3.9)], and one glycolytic enzyme [pyruvate kinase (PK; EC 2.7.1.40)] by established procedures. The activity of PK was not affected by TCDD at either time point. The activity of G-6-Pase tended to be decreased in TCDD-treated animals, as compared to pair-fed controls, but the decrease was variable without an apparent dose-response. The activity of PEPCK was significantly decreased 2 days after dosing, but a clear dose-response was apparent only at the 8-day time point. Maximum loss of activity at the highest dose was 56% below pair-fed control levels. PC activity was slightly decreased 2 days after TCDD treatment and displayed statistically significant, dose-dependent reduction by 8 days after dosing with a 49% loss of enzyme activity after the highest dose. It is concluded that inhibition of gluconeogenesis by TCDD previously demonstrated in vivo is probably due to decreased activities of PEPCK and PC. The data also support the prevailing view that PEPCK and PC are rate-determining enzymes in gluconeogenesis.
AU  - Weber, L.W.D.
AU  - Lebofsky, M.*
AU  - Greim, H.A.
AU  - Rozman, K.K.
C1  - 40705
C2  - 40215
SP  - 119-123
TI  - Key enzymes of gluconeogenesis are dose-dependently reduced in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats.
JO  - Arch. Toxicol.
VL  - 65
IS  - 2
PY  - 1991
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - A rapid and sensitive one-vial procedure to determine metallothionein (MT) containing zinc (Zn) and cadmium (Cd) is described. New features of this Cd-saturation method are: high mnolecular weight Cd-binding proteins are denatured by treatment with acetonitrile (50% final concentration), and excess of Cd is bound to a cation exchange resin (Chelex-100). With this method, MT has been measured, e.g. in liver of control and zinc- or cadmium-treated rats, in human liver and in cultured human fibroblasts down to absolute amounts of 0.1 μg. The Cd-Chelex assay is 10 times more sensitive than the established Cd-heme assay (Dieter et al. 1986) and therefore is particularly suitable to quantify MT in small tissue samples (e.g., liver biopsies of a few milligrams) and in extrahepatic tissues or cell cultures with low MT concentrations.
AU  - Bartsch, R.
AU  - Klein, D.A.
AU  - Summer, K.H.
C1  - 42042
C2  - 40135
SP  - 177-180
TI  - The Cd-Chelex assay: A new sensitive method to determine metallothionein containing zinc and cadmium.
JO  - Arch. Toxicol.
VL  - 64
IS  - 3
PY  - 1990
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Male and female Sprague-Dawley rats, 4-6 days old were exposed for 3 weeks (6 h/day, 5 days/week) to 2-nitropropane vapours of 0, 25, 40, 50, 80 and 125 ppm. One week later polychlorinated biphenyls (Clophen A50, 10 mg/kg body weight) were administered for promotion twice a week for 8 weeks. Thirteen weeks after starting the experiments the logarithms of the numbers of preneoplastic liver foci deficient in adenosine-5′-triphosphatase were found to be linearly related to the exposure concentrations of 2-nitropropane. Male rats exhibited an approximately four times lower foci incidence than females.
AU  - Denk, B.
AU  - Filser, J.G.
AU  - Deml, E.
AU  - Kessler, W.
AU  - Shen, J.
AU  - Oesterle, D.
C1  - 42071
C2  - 40272
SP  - 329-331
TI  - Dose-dependent emergence of preneoplastic foci in rat livers after exposure to 2-nitropropane.
JO  - Arch. Toxicol.
VL  - 64
IS  - 4
PY  - 1990
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The effect of a usually lethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 125 μg/kg) was studied on the conversion of14C-alanine into14C-glucose in male Sprague-Dawley rats by established procedures (determination of plasma alanine and blood glucose by enzymatic assays and isolation of14C-alanine and14C-glucose from whole blood by column chromatography). TCDD-treated rats converted significantly (p < 0.05) less14C-alanine into14C-glucose than did their pair-fed or ad libitum-fed counterparts, indicating reduced gluconeogenesis as a result of TCDD treatment. This finding suggests that reduced gluconeogenesis in TCDD-treated rats contributed to the progressively developing, severe hypoglycemia observed in these animals. Corticosterone, a key hormone in gluconeogenesis, provides partial protection from TCDD-induced toxicity in hypophysectomized rats. Therefore, the conversion of14C-alanine into14C-glucose was also determined in hypophysectomized rats dosed with TCDD (125 μg/kg) and given corticosterone (25 μg/ ml in drinking water). These rats also converted significantly (p <0.05) less14C-alanine into14C-glucose than did their pair-fed counterparts. However, in contrast to non-hypophysectomized TCDD-treated rats, these rats maintained marginal normoglycemia even at 64 days after dosing with TCDD, which suggests that the partial protective effect of corticosterone in hypophysectomized, TCDD-treated rats is unrelated to its effect on gluconeogenesis. The protection provided by corticosterone supplementation in TCDD toxicity is more likely due to reduced peripheral utilization of glucose enabling the animals to maintain marginal normoglycemia.
AU  - Gorski, J.R.
AU  - Weber, L.W.D.
AU  - Rozman, K.K.
C1  - 17432
C2  - 10037
SP  - 66-71
TI  - Reduced Gluconeogenesis in 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD)-treated Rats.
JO  - Arch. Toxicol.
VL  - 64
IS  - 1
PY  - 1990
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Lipophilicity is suggested to modulate the diffusion and the cytotoxic effects of mercury compounds. To investigate this, the positive inotropic effect of four Hg compounds (HgCl2, CH3HgCl, chlormerodrin, bromomercurihydroxypropane) was studied in catecholamine-depleted isolated heart muscle preparations. The rate of development of the positive effect was inversely correlated to the concentration in the case of HgCl2 and chlormerodrin, i.e. the product of concentration (c) and time to half-maximal effect (t50) remained constant. This was in accordance with the assumption of a permeation-controlled rate of action, as was shown earlier for p-chloromercuriphenylsulfonic acid. In addition, the c x t50 values of the individual mercurials decreased hyperbolically with the increase in lipophilicity as measured by the octanol/water partition. The results support the view that the toxicity of mercurials increases with their lipid solubility. In conjunction with the previously reported negative inotropic effect of Hg compounds, a model is proposed allocating thiol groups responsible for the negative inotropic action to lipid compartments within the cell membrane, while SH groups conveying the increase in contraction force are thought to be situated at the internal surface of the sarcolemma.
AU  - Halbach, S.
C1  - 41191
C2  - 36479
SP  - 315-319
TI  - Mercury compounds: Lipophilicity and toxic effects on isolated myocardial tissue.
JO  - Arch. Toxicol.
VL  - 64
IS  - 4
PY  - 1990
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Male Wistar rats exposed to atmospheric n-hexane excreted in their urine substances which gave rise to absorption spectra like those of pyrroles after the reaction with Ehrlich's reagent. A simple spectrophotometric assay was developed to determine these "pyrrole-like substances" in urine. Their excretion kinetics were evaluated by exposing rats for 8 h to atmospheric n-hexane concentrations between 50 and 3000 ppm. The dose-response curve revealed saturation kinetics according to Michaelis-Menten, Vmax being 1.12 [delta E526.ml urine/8 h n-hexane exposure] and "Km", the atmospheric n-hexane concentration at Vmax/2, being 250 ppm. The excretion of pyrrole-like substances closely correlated with that of 2,5-hexanedione measured by Fedtke and Bolt (1987). Pyrrole-like substances were also found in the urine of a male volunteer. When exposing the person for 3 h to atmospheric n-hexane at a concentration of 146 ppm (equivalent to 55 ppm/8 h) the excreted amount was twice the background value. Due to the sensitivity of this assay it is possible to determine pyrrole-like substances in urine according to the present German MAK or US TLV conditions for n-hexane (50 ppm/8 h).
AU  - Kessler, W.
AU  - Heilmaier, H.
AU  - Kreuzer, P.
AU  - Shen, J.H.
AU  - Filser, M.
AU  - Filser, J.G.
C1  - 21886
C2  - 10971
SP  - 242-246
TI  - Spectrophotometric determination of pyrrole-like substances in urine of rat and man: An assay for the evaluation of 2,5-hexanedione formed from n-hexane.
JO  - Arch. Toxicol.
VL  - 64
IS  - 3
PY  - 1990
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - After initiation, preneoplastic cell foci emerge in rat liver. They develop differently dependent on promotion, which favors foci incidence with respect to number and size. The process of promotion is dependent on various factors, e.g. the onset and duration of the promotion period (e.g. Deml et al 1981, for literature see: Oesterle and Deml 1983; Deml and Oesterle 1987). In the present experiments, using the rat liver foci bioassay (Oesterle and Deml 1983), the kinetics of development of foci was studied after the application of three different promoting schemes.
AU  - Deml, E.
AU  - Oesterle, D.
C1  - 18543
C2  - 11131
SP  - 233-236
TI  - Incidence of Preneoplastic Foci in Rat Liver Dependent on Different Promoting Schemes.
JO  - Arch. Toxicol.
VL  - 13
PY  - 1989
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The solvent 2-nitropropane (2-NP) has been reported to produce liver necrosis and hepatocarcinoma in rats, males being much more sensitive than females (Griffin et al 1980). Since this may be caused by sex specific pharmacokinetics of 2-NP inhalation kinetics in male and in female Sprague-Dawley rats were investigated. Furthermore, as specific indicators of parenchymal hepatic injury the response of glutamic oxalacetic transaminase (GOT) and of glutamic pyruvic transaminase (GPT) was studied in serum after application of 2-NP to the animals.
AU  - Denk, B.
AU  - Baumann, M.
AU  - Filser, J.G.
C1  - 42115
C2  - 38065
SP  - 330-332
TI  - Pharmacokinetics and hepatotoxicity of 2-nitropropane in rats.
JO  - Arch. Toxicol.
VL  - 63
PY  - 1989
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The genotoxicity of the sensory irritant 2-chlorobenzylidene malonitrile (CS) to V79 Chinese hamster cells was investigated using the induction of gene mutations, micronuclei and DNA repair synthesis as biological endpoints. CS efficiently induced micronuclei and mutants resistant to 6-thioguanine in these cells, but it did not elicit DNA repair synthesis. Induction of micronuclei and mutants showed very similar courses of concentration dependence, suggesting that both events were caused by the same mechanism. The hydrolysis products of CS, o-chlorobenzaldehyde and malononitrile dit not induce micronuclei and were much less cytotoxic than CS. The observation of heritable genetic changes in cells exposed to CS in the absence of detectable DNA damage suggests that the genetic effects of CS are not caused by an interaction of the compound or its hydrolysis products with DNA. It appears more likely that the mutagenic activity is the consequence of effects of CS on the mitotic apparatus of the cells causing chromosomal aneuploidy.
AU  - Ziegler-Skylakakis, K.
AU  - Summer, K.H.
AU  - Andrae, U.
C1  - 17838
C2  - 10748
SP  - 314-319
TI  - Mutagenicity and cytotoxicity of 2-chlorobenzylidene malonitrile (CS) and metabolites in V79 Chinese hamster cells.
JO  - Arch. Toxicol.
VL  - 63
IS  - 4
PY  - 1989
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The genotoxicity of the sensory irritant 2-chlorobenzylidene malonitrile (CS) to V79 Chinese hamster cells was investigated using the induction of gene mutations, micronuclei and DNA repair synthesis as biological endpoints. CS efficiently induced micronuclei and mutants resistant to 6-thioguanine in these cells, but it did not elicit DNA repair synthesis. Induction of micronuclei and mutants showed very similar courses of concentration dependence, suggesting that both events were caused by the same mechanism. The hydrolysis products of CS, o-chlorobenzaldehyde and malononitrile did not induce micronuclei and were much less cytotoxic than CS. The observation of heritable genetic changes in cells exposed to CS in the absence of detectable DNA damage suggests that the genetic effects of CS are not caused by an interaction of the compounds or its hydrolysis products with DNA. It appears more likely that the mutagenic activity is the consequence of effects of CS on the mitotic apparatus of the cells causing chromosomal aneuploidy.
AU  - Ziegler-Skylakakis, K.
AU  - Summer, K.H.
AU  - Andrae, U.
C1  - 41159
C2  - 36519
SP  - 314-319
TI  - Mutagenicity and cytotoxicity of 2-chlorobenzylidene malonitrile (CS) and metabolites in V79 Chinese hamster cells.
JO  - Arch. Toxicol.
VL  - 63
IS  - 4
PY  - 1989
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Ethane exhalation was increased in male Sprague-Dawley rats following a single intraperitoneal (IP) injection of Aroclor 1254 (500 mg/kg). In the first 2 weeks following Aroclor 1254 treatment, the increase in ethane exhalation was due to an inhibition of metabolism of endogenous ethane rather than to an increase in ethane production. In weeks 3 and 4 following Aroclor 1254 administration, metabolic clearance of ethane returned to and exceeded control levels, while ethane production increased to approximately twice the control rates (day 30). The HPLC determination of in situ hepatic malondialdehyde levels revealed a 2-fold increase in malondialdehyde content on day 30 following the Aroclor 1254 injection. Further, parallel increases in in situ malondialdehyde levels and ethane production rates were also found 30 days following a single IP injection of 3,3′,4,4′-tetrachlorobiphenyl, 2,3,4,4′,5-pentachlorobiphenyl and 2,2′,4,4′,5,5′-hexachlorobiphenyl (300 μmol/kg). These effects were not reflected in increased diene conjugation. Redox state of the liver was largely unaffected, as evidenced by the relative concentrations of reduced and oxidized NADPH. However, minor changes in reduced and oxidized glutathione were noted.
AU  - Filser, J.
AU  - Dogra, S.
AU  - Cojocel, C.
AU  - Greim, H.
AU  - Regel, U.
AU  - Desch, F.
AU  - Robertson, L.W.
C1  - 17420
C2  - 9982
SP  - 369-374
TI  - Long-term Effects of Commercial and Congeneric Polychlorinated Biphenyls on Ethane Production and malone Dialdehyde Levels Indicators of In-vivo lipid Peroxidation.
JO  - Arch. Toxicol.
VL  - 62
IS  - 5
PY  - 1988
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Filser, J.
AU  - Golka, K.
AU  - Peter, H.
AU  - Denk, B.
C1  - 17493
C2  - 10402
TI  - Pharmacokinetics of Propylene and its Reactive Metabolite Propylene Oxide in Sprague-Dawley Rats.
JO  - Arch. Toxicol.
PY  - 1988
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Filser, J.
AU  - Shen, J.
AU  - Kessler, W.
AU  - Denk, B.
C1  - 17501
C2  - 10410
TI  - Metabolism and Endogenous Production of Ethylene in Humans and Rats.
JO  - Arch. Toxicol.
PY  - 1988
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Weber, L.W.D.
AU  - Rozman, K.K.
AU  - Gorski, J.R.
C1  - 17430
C2  - 10016
TI  - Tissue-Specific Alterations of De Novo Fatty Acid Synthesis in 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-treated Rats.
JO  - Arch. Toxicol.
PY  - 1988
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Using the rat liver foci bioassay a dose-response relationship was evaluated for the promoting activity of the ubiquitous and persistent environmental pollutants polychlorinated biphenyls (PCBs) and chloroform. Initiation of liver foci was performed by oral administration of a single dose of 8 mg/kg body wt of diethylnitrosamine to weanling female Sprague-Dawley rats. For polychlorinated biphenyls (PCBs) and chloroform a dose-dependent promoting effect was found. The lowest effective dose of PCBs was 1 mg/kg body wt, given three times a week for 11 consecutive weeks. That of chloroform was 100 mg/kg body wt, administered twice a week for 11 consecutive weeks. The livers were screened for preneoplastic foci 12 weeks after starting the experiments. The amounts of PCBs as well as chloroform normally taken up by humans are greater than a factor of 1000 lower than the effective experimental doses. Thus the risk of human exposure to these chemicals is estimated to be very low. In the case of heavy pollution with PCBs, however, as happened in the Yusho accident (Japan, 1968), the daily intake of PCBs was in the range of the effective doses used in the experiment.
AU  - Deml, E.
AU  - Oesterle, D.
C1  - 41924
C2  - 0
SP  - 209-211
TI  - Dose response of promotion by polychlorinated biphenyls and chloroform in rat liver foci bioassay.
JO  - Arch. Toxicol.
VL  - 60
IS  - 1-3
PY  - 1987
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The pharmacokinetics of inhaled n-hexane in rat and man were compared. In the rat metabolism was saturable. Up to 300 ppm, the metabolic rate was directly proportional to the concentration in the atmosphere, reaching 47 μmol/(h·kg). Only 17% of n-hexane was exhaled unchanged. Above 300 ppm, the amount of n-hexane in the body rose with increasing atmospheric concentrations from 1.6 up to a limiting value of 9.6, which corresponded to the thermodynamic distribution coefficient of n-hexane between the organism and the atmosphere. Up to 3000 ppm, the rate of metabolism increased to 245 μmol/(h·kg); only a low further increase was found up to 7000 ppm (285 μmol/(h·kg)). In man the steady-state concentrations of n-hexane were about 1 ppm. The metabolic clearance was 132 l/h, and n-hexane accumulated to a factor of 2.3 in the organism. The thermodynamic distribution coefficient was calculated to be 12. Twenty per cent of n-hexane in the body was exhaled unchanged. At low concentrations the rate of metabolism of n-hexane is limited in both species by transport to the enzyme system. Under these conditions the rate of metabolism of n-hexane should not be influenced by xenobiotics which induce the n-hexane metabolizing enzyme system.
AU  - Filser, J.G.
AU  - Peter, H.G.
AU  - Bolt, H.M.
AU  - Fedtke, N.
C1  - 41582
C2  - 36244
SP  - 77-80
TI  - Pharmacokinetics of the neurotoxin n-hexane in rat and man.
JO  - Arch. Toxicol.
VL  - 60
IS  - 1-3
PY  - 1987
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Muzi, G.
AU  - Girski, J.R.
AU  - Rozman, K.K.
C1  - 20693
C2  - 13911
SP  - 34-39
TI  - Composition of Diet Modifies Toxicity of 2,3,7,8- tetrachlorodibenzo- p- dioxin (TCDD) in Cold- adapted Rats.
JO  - Arch. Toxicol.
VL  - 61
PY  - 1987
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Polyclonal antibodies raised toward a debrisoquine 4-hydroxylating cytochrome P-450 species purified from rat liver (P-450UTA) were used to determine which monooxygenase reactions are linked to debrisoquine hydroxylation in human liver. Anti P-450UTA did not inhibit the oxidation of dimethylnitrosamine, morphine, diazepam, vinylidene chloride, trichloroethylene, benzo(a)pyrene and its 7.8-dihydrodiol, but was inhibitory for the hydroxylation of debrisoquine, (±)-bufuralol, lasiocarpine and monocrotaline. A model interpreting the substrate specificity of the human liver enzyme is presented. .
AU  - Wolff, T.
AU  - Distlerath, L.M.*
AU  - Worthington, M.T.*
AU  - Guengerich, F.P.*
C1  - 41653
C2  - 36248
SP  - 89-90
TI  - Human liver debrisoquine 4-hydroxylase: Test for specifity toward various monooxygenase substrates and model of the active site.
JO  - Arch. Toxicol.
VL  - 60
IS  - 1-3
PY  - 1987
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The toxicity of 60μg/kg 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD) given IP in corn oil/5% acetone was examined in male Sprague-Dawley rats adapted to 25 °C or 4 °C ambient temperature. Cold exposure significantly reduced mean time to death and tended to increase mortality. Body weight at the time of death was reduced at both ambient temperatures to about the same extent. Thus, the rate of body weight loss was about twice as fast in nonsurvivors at 4°C than at 25 °C. There was a continuous decrease in feed intake of the non-survivors at 25 °C until death. However, no reduction in feed intake occurred in any of the rats at 4 °C ambient temperature. At 14 days after dosing all TCDD-dosed animals were hypothyroid in terms of T4 but essentially euthyroid in terms of T3. Oxygen consumption at 10 days after dosing was reduced to the same extent in all TCDD-dosed rats without regard to survival status. By day 20 after TCDD dosage, survivors increased their oxygen consumption at both ambient temperatures to nearly control levels whereas non-survivors were unable to do so. Body temperature of all animals remained within normal range except for the non-survivors, which showed reduced rectal temperature shortly before death. It is concluded (1) that cold adaptation aggravates the toxicity of TCDD, (2) that reduced feed intake alone cannot explain TCDD-induced wasting syndrome, (3) that reduced oxygen consumption in TCDD-treated rats may be due to reduced feed intake and/or altered thyroid hormone status, and (4) that TCDD is likely to activate metabolic pathways which represent a wasteful utilization of ingested and/or stored energy.
AU  - Rozman, K.K.
AU  - Greim, H.A.
C1  - 33230
C2  - 35403
SP  - 211-215
TI  - Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cold-adapted rats.
JO  - Arch. Toxicol.
VL  - 59
IS  - 4
PY  - 1986
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Lipophilicity plays an important role in the biological action of mercurials. The distribution of one inorganic and five organic mercury compounds was determined in an n-octanol/water system. Lipophilicity decreased in the order CH3HgCl, bromomercurihydroxypropane, HgCl2, chlormerodrin, p-chloromercuribenzoic acid (PCMB), p-chloromercuriphenylsulfonic acid (PCMBS). The toxicity of mercurials, as reported in the literature, appears to parallel their lipophilicity.
AU  - Halbach, S.
C1  - 41672
C2  - 38271
SP  - 139-141
TI  - The octanol/water distribution of mercury compounds.
JO  - Arch. Toxicol.
VL  - 57
IS  - 2
PY  - 1985
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Thiourea was investigated for its capacity to cause DNA alterations in cultured mammalian cells. The induction of DNA repair in primary rat hepatocyte cultures and of gene mutations in V79 Chinese hamster cells were used as biological endpoints. In hepatocytes, thiourea elicited a linear increase in DNA repair replication in the concentration range tested (5-25 mM). In V79 cells, thiourea (10-40 mM) significantly increased the frequency of 8-azaguanine-resistant mutants. The present results show that thiourea is weakly, but definitely, genotoxic and mutagenic in cultured mammalian cells.
AU  - Ziegler-Skylakakis, K.
AU  - Rossberger, S.
AU  - Andrae, U.
C1  - 42121
C2  - 38382
SP  - 5-9
TI  - Thiourea induces DNA repair synthesis in primary rat hepatocyte cultures and gene mutations in V79 Chinese hamster cells.
JO  - Arch. Toxicol.
VL  - 58
IS  - 1
PY  - 1985
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - In short-term experiments rats received single doses of 50, 100, and 500 μmoles/kg of the cryptating agent A 222. A dose-related increase in the activities of GOT and GPT in the serum was observed 6 h after treatment, reaching values up to 11 and 3 times that of the controls, respectively. However, the enzyme activities returned to the control levels within 3 days. The activity of alkaline phosphatase and the levels of protein and cholesterol in serum were not altered during the observation period of 7 days. Histopathological examinations did not show any changes in the liver, kidney, heart, lung, thymus, spleen, or intestine. The elevations of GOT and GPT seem to be due to a transient liver lesion, since no histopathological alterations of the liver became apparent. These results show that after single applications of A 222 at all doses used, no severe lesions occur in the observed organs.
AU  - Baumann, M.
AU  - Schäffer, E.H.
AU  - Greim, H.A.
C1  - 41277
C2  - 40448
SP  - 427-429
TI  - Short-term studies with the cryptating agent hexaoxa-diaza-bicyclo-hexacosane in rats.
JO  - Arch. Toxicol.
VL  - 55
IS  - SUPPL. 7
PY  - 1984
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The agent 5-azacytidine, which directly affects nucleic acid metabolism, is a potent teratogen in NMRI mice. The establishment of general teratological data revealed clear-cut dose-response relationships after administration of this agent on either day 12 or day 14 of gestation. Inspection of skeletal abnormalities revealed a clear-cut phase specificity of this drug when administered on days 10 or 11 of pregnancy. Additional studies showed that central nervous system anomalies were induced mainly after administration of azacytidine on days 10, 11, 12, or 13 of pregnancy. A most conspicuous finding was the formation of anomalous glioblast islets within the ventricular zone covering the basal ganglia. The latter malformation mainly occurred after treatment on day 11 or 12 of pregnancy. Another important malformation syndrome was the appearance of capillary ectasias and hind paw hematomas, together wih an intense necrotic cardiomyopathy after treatment on either day 11 or 12 of gestation.
AU  - Schmahl, W.G.
AU  - Török, P.
AU  - Kriegel, H.
C1  - 41746
C2  - 38477
SP  - 143-147
TI  - Embryotoxocity of 5-azacytidine in mice. Phase and dose-specificity studies.
JO  - Arch. Toxicol.
VL  - 55
IS  - 2
PY  - 1984
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The biotransformation and disposition of 3-chloro-4-methyl-(4-14C)-7-hydroxycoumarin [(14C) chlorferron] were investigated in rats after single oral administration. Following administration of (14C) chlorferron at 0.5 and 20 mg/kg body weight to male rats, > 90% of the given dose was eliminated in the urine (77-84%) and faeces (7-15%) within 24 h. Low levels of (14C) chlorferron derived residues were detected in different organs of rats 7 days after dosing. Administration of (14C) chlorferron at 20 mg/kg allowed the isolation of three metabolites in the 24-h urine of male and female rats. Compounds tentatively identified were dechlorinated metabolites of chlorferron besides unchanged chlorferron. The majority of the metabolites were excreted in conjugated forms. The pattern of biotransformation of chlorferron was qualitatively similar in male and female rats. Comparative studies on the elimination and biodistribution of (14C) chlorferron and its parent compound (14C) coumaphos in male rats indicated rapid metabolism and faster elimination of chlorferron and its metabolites from the body than that of the parent compound.
AU  - Malik, J.K.
AU  - Lay, J.P.
AU  - Klein, W.
AU  - Korte, F.
C1  - 41244
C2  - 38555
SP  - 51-59
TI  - Biotransformation and disposition of the coumaphos metabolite 3-chloro-4-methyl-(4-14C)-7-hydroxycoumarin in rats.
JO  - Arch. Toxicol.
VL  - 48
IS  - 1
PY  - 1981
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - The mammalian spot test, which was developed for radiation experiments at the Oak Ridge National Laboratory more than two decades ago, has recently been demonstrated to be a promising method for the detection of presumed somatic mutations induced by chemicals. The results reported in this paper are part of our efforts directed towards the validation and standardization of this test system for mutagenicity testing. (T x HT)F1 embryos, heterozygous for the recessive coat color alleles ln, pa, b, c(ch), p, d, and pe were exposed in utero to a single dose of the test compound between day 8 and 11 post conception. To compare the sensitivities of different genotypes of embryos an additional experiment was carried out with (C57BL/6JHan x T)F1 embryos, which are heterozygous for b, c(ch), p, and d. The offspring were screened for the presence of color spots at the age of 12-14 days and at weaning. The chemical mutagens used in the present experiment were mitomycin C (MC), methyl methanesulfonate (MMS), and procarbazine. The lowest doses tested in these experiments which induced coat color spots (presumed somatic mutations) were 1 mg/kg MC, 50 mg/kg MMS, and 50 mg/kg procarbazine, when the females were treated on day 9 of pregnancy. The frequency of white midventral spots (WMVS), which are caused by an inactivation of melanocyte precursor cells, was increased in the higher dose groups of MC and procarbazine. These doses also reduced the average litter size and caused malformations. The type of malformations depended on the day of treatment. The data obtained with 50 mg/kg procarbazine indicate comparable sensitivities of the two genotypes (T x HT)F1 and (C57BL/6JHan x T)F1. The lowest doubling doses calculated for somatic mutations were 0.3 mg/kg MC, 6.6 mg/kg MMS and 11 mg/kg procarbazine. For germinal gene mutations they were 0.6 mg/kg MC, 1.2 mg/kg MMS and 34 mg/kg procarbazine. The comparison between the expected and observed distribution of coat color spots between the head and body of the mice supports randomness of distribution. Further analysis of the data revealed that the scoring of spots only in the dorsal and lateral regions does not alter the sensitivity of the test. Thereby one can avoid any ambiguity arising from the distribution of midventral white gray and light gray spots.
AU  - Neuhaeuser-Klaus, A.
C1  - 41305
C2  - 38553
SP  - 229-243
TI  - An approach towards the standardization of the mammalian spot test.
JO  - Arch. Toxicol.
VL  - 48
IS  - 4
PY  - 1981
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Greim, H.A.
C1  - 41319
C2  - 38149
SP  - 209-210
TI  - Isolated cell systems as a tool in toxicological research.
JO  - Arch. Toxicol.
VL  - 44
IS  - 1-3
PY  - 1980
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - This in vitro mutagenicity test system comprises five different strains of S. typhimurium as target cells with the rat liver S-9 fraction and appropriate co-factors for metabolic activation of the chemical tested. The bacterial tester strains detect both mutations induced by base pair substitutions and intercalation (frame shift mutations). Usually 108-109 cells of an overnight culture or an exponentially growing culture are incubated for 2-3 days with a mixture of S-9, co-factors, soft agar and the chemical on histidine-deficient agar. The S-9 fraction is obtained from the livers of rats pretreated with 500 mg/kg chlorinated biphenyls (Clophen A-50, Aroclor 1254) to obtain high metabolic activity. For reproducibility it is essential to standardize metabolic activity and protein content of the S-9 and to use three different concentrations thereof in the test system. Since solvents inhibit metabolic activation of the chemicals they must not exceed 4% of the final 2.6 ml incubate. Several independent studies have shown that between 85 and 93% of chemical carcinogens are mutagens in the test. Regarding extrapolation to man one has to consider that the test is preferentially adapted for metabolic activation of the chemicals, whereas inactivation processes are absent or are less active than in vivo. Thus, the test provides qualitative rather than quantitative information on mutagenic effects of a chemical.
AU  - Greim, H.A.
AU  - Göggelmann, W.
AU  - Summer, K.H.
AU  - Wolff, T.
C1  - 41865
C2  - 38406
SP  - 31-40
TI  - Mutagenicity testing with Salmonella microsome test.
JO  - Arch. Toxicol.
VL  - 46
IS  - 1-2
PY  - 1980
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - During microsomal metabolism of 14C-bromobenzene, radioactive material was irreversibly bound to microsomal protein. Although primary monooxygenation of aromatic hydrocarbons leads to the formation of reactive epoxides which may bind to protein, our results indicate that reactive intermediates formed via oxidation of the phenolic metabolites substantially contribute to the overall binding. This conclusion is supported by the following observations: 1) The binding of radioactivity continued to increase even though the primary metabolism was terminated; 2) Addition of UDP-glucuronic acid largely reduced the amount of the free phenols in the incubation mixture and simultaneously decreased the binding; and 3) Inhibition of the epoxide hydratase by 1,1,1-trichloro-2-propene oxide (TCPO) completely prevented the formation of the dihydrodiols, but did not significantly affect the binding. Thus, the results are in agreement with our previous observations on the binding of 14C-naphthalene and 14C-dichlorobiphenyl, and suggest that phenols generated from these aromatic hydrocarbons are further metabolized to protein-binding species.
AU  - Hesse, S.
AU  - Wolff, T.
AU  - Mezger, M.
C1  - 41809
C2  - 40359
SP  - 358-362
TI  - Involvement of phenolic metabolites in the irreversible protein-binding of 14C-bromobenzene catalysed by rat liver microsomes.
JO  - Arch. Toxicol.
VL  - 45
IS  - SUPPL.4
PY  - 1980
SN  - 0340-5761
ER  - 

TY  - JOUR
AU  - Greim, H.A.
AU  - Hofmann, A.F.
AU  - Schwenk, M.
C1  - 42190
C2  - 35825
SP  - 199
TI  - Chimpanzees sulfate lithocholate similar to man.
JO  - Arch. Toxicol.
VL  - 1
PY  - 1978
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Methylmercury chloride (MMC) was given to pregnant rats on the 6th, 7th, 8th, and 9th day after conception in doses of 0.05 and 2.0 mg/kg/day. The female offspring of these animals were tested 90 days after birth for learning ability using operant conditioning procedures. The rats were kept at 90% of their normal body weight and trained in a lever-box to press a bar in order to obtain a food pellet. Significant differences in the acquisition speed became apparent when the ratio of bar presses to reward was increased in a classical contingency of differential reinforcement of high rates even at MMC-doses of 4 × 0.05 mg/kg. These differences were not found in the general motility level nor in motor coordination.
AU  - Müsch, H.R.
AU  - Bornhausen, M.
AU  - Kriegel, H.
AU  - Greim, H.A.
C1  - 41473
C2  - 35827
SP  - 103-108
TI  - Methylmercury chloride induces learning deficits in prenatally treated Rats.
JO  - Arch. Toxicol.
VL  - 40
IS  - 2
PY  - 1978
SN  - 0340-5761
ER  - 

TY  - JOUR
AB  - Pregnant mice administered per os during the days 1-3 (plug day = day 0) post conception (p.c.) with 375 mg 2,2'-dichlorobiphenyl/kg/day revealed on day 18 p.c. increased number of resorptions and doses up from 500 mg/kg/day led to a substantial retardation of the prenatal development. Based on the investigations during the early development it is concluded, that retardation of the fetus is caused by a delayed implantation. It is assumed, that increased resorption is due to kyematopathies detected during the periimplantation period.
AU  - Toeroek, P.
C1  - 41880
C2  - 35795
SP  - 249-254
TI  - Verzögerte Implantation und frühembryonale Keimschaden bei der Maus nach Applikation des PCB: 2,2'-Dichlorbiphenyl.
JO  - Arch. Toxicol.
VL  - 40
IS  - 4
PY  - 1978
SN  - 0340-5761
ER  -