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621 results on '"van Ravenzwaay, Bennard"'

5. New approach methodologies in human regulatory toxicology – Not if, but how and when!

Author

Schmeisser, Sebastian, Miccoli, Andrea, von Bergen, Martin, Berggren, Elisabet, Braeuning, Albert, Busch, Wibke, Desaintes, Christian, Gourmelon, Anne, Grafström, Roland, Harrill, Joshua, Hartung, Thomas, Herzler, Matthias, Kass, George E.N., Kleinstreuer, Nicole, Leist, Marcel, Luijten, Mirjam, Marx-Stoelting, Philip, Poetz, Oliver, van Ravenzwaay, Bennard, Roggeband, Rob, Rogiers, Vera, Roth, Adrian, Sanders, Pascal, Thomas, Russell S., Marie Vinggaard, Anne, Vinken, Mathieu, van de Water, Bob, Luch, Andreas, and Tralau, Tewes

Published
2023
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25. The short-term toxicity and metabolome of dicyclopentadiene.

Author

van Ravenzwaay, Bennard, Kocabas, Neslihan Aygun, Faulhammer, Frank, Flick, Burkhard, Giri, Varun, Sperber, Saskia, Penman, Michael G., Higgins, Larry G., Kamp, Hennicke, and Rooseboom, Martijn

Subjects
*DICYCLOPENTADIENE, *ADRENAL glands, *IN vivo toxicity testing, *WEIGHT gain, *PATHOLOGICAL physiology, *HEPATOTOXICOLOGY, *METABOLOMICS
Abstract

Dicyclopentadiene (DCPD) was investigated in a 14-day oral rat toxicity study based on the OECD 407 guideline in combination with plasma metabolomics. Wistar rats received the compound daily via gavage at dose levels of 0, 50 and 150 mg/kg bw. The high dose induced transient clinical signs of toxicity and in males only reduced body weight gain. High dose liver changes were characterized by altered clinical chemistry parameters in both sexes and pathological changes in females. In high dose males an accumulation of alpha-2 u-globulin in the kidney was noted. Comparing the DCPD metabolome with previously established specific metabolome patterns in the MetaMap® Tox data base suggested that the high dose would result in liver enzyme induction leading to increased breakdown of thyroid hormones for males and females. An indication for liver toxicity in males was also noted. Metabolomics also suggested an effect on the functionality of the adrenals in high dose males, which together with published data, is suggestive of a stress related effect in this organ. The results of the present 14-day combined toxicity and metabolome investigations were qualitatively in line with literature data from subchronic oral studies in rats with DCPD. Importantly no other types of organ toxicity, or hormone dysregulation beyond the ones associated with liver enzyme induction and stress were indicated, again in line with results of published 90-day studies. It is therefore suggested that short term "smart" studies, combining classical toxicity with 'omics technologies, could be a 2 R (refine and reduce) new approach method allowing for the reduction of in vivo toxicity testing. • Dicyclopentadiene 14-day toxicity in rats target organs: liver and kidney. • Metabolomics correctly predicts subchronic DCPD toxicity. • "smart" in vivo studies are a NAM that can reduce the need for subchronic in vivo testing. [ABSTRACT FROM AUTHOR]

Published
2024
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29. Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny – Part IV: the ECETOC and CLE Proposal for a Thyroid Function-Related Neurodevelopmental Toxicity Testing and Assessment Scheme (Thyroid-NDT-TAS)

Author

Melching-Kollmuss, Stephanie, primary, Bothe, Kathrin, additional, Charlton, Alex, additional, Gangadharan, Babunilayam, additional, Ghaffari, Rashin, additional, Jacobi, Sylvia, additional, Marty, Sue, additional, Marxfeld, Heike-Antje, additional, McInnes, Elizabeth F., additional, Sauer, Ursula G., additional, Sheets, Larry P., additional, Strupp, Christian, additional, Tinwell, Helen, additional, Wiemann, Christiane, additional, Botham, Philip A., additional, and van Ravenzwaay, Bennard, additional

Published
2023
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34. Intra- and inter-laboratory reproducibility and accuracy of the LuSens assay: A reporter gene-cell line to detect keratinocyte activation by skin sensitizers

Author

Ramirez, Tzutzuy, Stein, Nadine, Aumann, Alexandra, Remus, Tina, Edwards, Amber, Norman, Kimberly G., Ryan, Cindy, Bader, Jackie E., Fehr, Markus, Burleson, Florence, Foertsch, Leslie, Wang, Xiaohong, Gerberick, Frank, Beilstein, Paul, Hoffmann, Sebastian, Mehling, Annette, van Ravenzwaay, Bennard, and Landsiedel, Robert

Published
2016
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37. Predicting acute paraquat toxicity using physiologically based kinetic modelling incorporating in vitro active renal excretion via the OCT2 transporter

Author

Noorlander, Annelies, Wesseling, Sebastiaan, Rietjens, Ivonne M.C.M., van Ravenzwaay, Bennard, Noorlander, Annelies, Wesseling, Sebastiaan, Rietjens, Ivonne M.C.M., and van Ravenzwaay, Bennard

Abstract

Including active renal excretion in physiologically based kinetic (PBK) models can improve their use in quantitative in vitro- in vivo extrapolation (QIVIVE) as a new approach methodology (NAM) for predicting the acute toxicity of organic cation transporter 2 (OCT2) substrates like paraquat (PQ). To realise this NAM, kinetic parameters Vmax and Km for in vitro OCT2 transport of PQ were obtained from the literature. Appropriate scaling factors were applied to translate the in vitro Vmax to an in vivo Vmax. in vitro cytotoxicity data were defined in the rat RLE-6TN and L2 cell lines and the human A549 cell line. The developed PQ PBK model was used to apply reverse dosimetry for QIVIVE translating the in vitro cytotoxicity concentration-response curves to predicted in vivo toxicity dose-response curves after which the lower and upper bound benchmark dose (BMD) for 50% lethality (BMDL50 and BMDU50) were derived by applying BMD analysis. Comparing the predictions to the in vivo reported LD50 values resulted in a conservative prediction for rat and a comparable prediction for human showing proof of principle on the inclusion of active renal excretion and prediction of PQ acute toxicity for the developed NAM.

Published
2023

38. Gut Microbiota as Well as Metabolomes of Wistar Rats Recover within Two Weeks after Doripenem Antibiotic Treatment

Author

Murali, Aishwarya, Zickgraf, Franziska Maria, Ternes, Philipp, Giri, Varun, Cameron, Hunter James, Sperber, Saskia, Haake, Volker, Driemert, Peter, Kamp, Hennicke, Weyer, Dorothee Funk, Sturla, Shana J., Rietjens, Ivonne M.G.M., van Ravenzwaay, Bennard, Murali, Aishwarya, Zickgraf, Franziska Maria, Ternes, Philipp, Giri, Varun, Cameron, Hunter James, Sperber, Saskia, Haake, Volker, Driemert, Peter, Kamp, Hennicke, Weyer, Dorothee Funk, Sturla, Shana J., Rietjens, Ivonne M.G.M., and van Ravenzwaay, Bennard

Abstract

An understanding of the changes in gut microbiome composition and its associated metabolic functions is important to assess the potential implications thereof on host health. Thus, to elucidate the connection between the gut microbiome and the fecal and plasma metabolomes, two poorly bioavailable carbapenem antibiotics (doripenem and meropenem), were administered in a 28-day oral study to male and female Wistar rats. Additionally, the recovery of the gut microbiome and metabolomes in doripenem-exposed rats were studied one and two weeks after antibiotic treatment (i.e., doripenem-recovery groups). The 16S bacterial community analysis revealed an altered microbial population in all antibiotic treatments and a recovery of bacterial diversity in the doripenem-recovery groups. A similar pattern was observed in the fecal metabolomes of treated animals. In the recovery group, particularly after one week, an over-compensation was observed in fecal metabolites, as they were significantly changed in the opposite direction compared to previously changed metabolites upon 28 days of antibiotic exposure. Key plasma metabolites known to be diagnostic of antibiotic-induced microbial shifts, including indole derivatives, hippuric acid, and bile acids were also affected by the two carbapenems. Moreover, a unique increase in the levels of indole-3-acetic acid in plasma following meropenem treatment was observed. As was observed for the fecal metabolome, an overcompensation of plasma metabolites was observed in the recovery group. The data from this study provides insights into the connectivity of the microbiome and fecal and plasma metabolomes and demonstrates restoration post-antibiotic treatment not only for the microbiome but also for the metabolomes. The importance of overcompensation reactions for health needs further studies.

Published
2023

39. Connecting Gut Microbial Diversity with Plasma Metabolome and Fecal Bile Acid Changes Induced by the Antibiotics Tobramycin and Colistin Sulfate

Author

Murali, Aishwarya, Giri, Varun, Zickgraf, Franziska Maria, Ternes, Philipp, Cameron, Hunter James, Sperber, Saskia, Haake, Volker, Driemert, Peter, Kamp, Hennicke, Funk-Weyer, Dorothee, Sturla, Shana J., Rietjens, Ivonne M.C.M., van Ravenzwaay, Bennard, Murali, Aishwarya, Giri, Varun, Zickgraf, Franziska Maria, Ternes, Philipp, Cameron, Hunter James, Sperber, Saskia, Haake, Volker, Driemert, Peter, Kamp, Hennicke, Funk-Weyer, Dorothee, Sturla, Shana J., Rietjens, Ivonne M.C.M., and van Ravenzwaay, Bennard

Abstract

The diversity of microbial species in the gut has a strong influence on health and development of the host. Further, there are indications that the variation in expression of gut bacterial metabolic enzymes is less diverse than the taxonomic profile, underlying the importance of microbiome functionality, particularly from a toxicological perspective. To address these relationships, the gut bacterial composition of Wistar rats was altered by a 28 day oral treatment with the antibiotics tobramycin or colistin sulfate. On the basis of 16S marker gene sequencing data, tobramycin was found to cause a strong reduction in the diversity and relative abundance of the microbiome, whereas colistin sulfate had only a marginal impact. Associated plasma and fecal metabolomes were characterized by targeted mass spectrometry-based profiling. The fecal metabolome of tobramycin-treated animals had a high number of significant alterations in metabolite levels compared to controls, particularly in amino acids, lipids, bile acids (BAs), carbohydrates, and energy metabolites. The accumulation of primary BAs and significant reduction of secondary BAs in the feces indicated that the microbial alterations induced by tobramycin inhibit bacterial deconjugation reactions. The plasma metabolome showed less, but still many alterations in the same metabolite groups, including reductions in indole derivatives and hippuric acid, and furthermore, despite marginal effects of colistin sulfate treatment, there were nonetheless systemic alterations also in BAs. Aside from these treatment-based differences, we also uncovered interindividual differences particularly centering on the loss of Verrucomicrobiaceae in the microbiome, but with no apparent associated metabolite alterations. Finally, by comparing the data set from this study with metabolome alterations in the MetaMapTox database, key metabolite alterations were identified as plasma biomarkers indicative of altered gut microbiomes resulting from a

Published
2023

46. Gut Microbiota as Well as Metabolomes of Wistar Rats Recover within Two Weeks after Doripenem Antibiotic Treatment

Author

Murali, Aishwarya, primary, Zickgraf, Franziska Maria, additional, Ternes, Philipp, additional, Giri, Varun, additional, Cameron, Hunter James, additional, Sperber, Saskia, additional, Haake, Volker, additional, Driemert, Peter, additional, Kamp, Hennicke, additional, Weyer, Dorothee Funk, additional, Sturla, Shana J., additional, Rietjens, Ivonne M. G. M., additional, and van Ravenzwaay, Bennard, additional

Published
2023
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