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Fragki, S. (author), Piersma, A.H. (author), Westerhout, J. (author), Kienhuis, A. (author), Kramer, N.I. (author), Zeilmaker, M.J. (author)Toxicology is moving away from animal testing towards in vitro tools to assess chemical safety. This new testing framework requires a quantitative method, i.e. kinetic modelling, which extrapolates effective concentrations in vitro to a bioequivalent human dose in vivo and which can be applied on “high throughput screening” of a wide variety of...article 2022
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Sewell, F. (author), Strupp, C. (author), van der Laan, J.W. (author), Wolf, D.C. (author), Wolterink, G. (author), Woutersen, R. (author), Zvonar, Z. (author), Heusinkveld, H. (author), Braakhuis, H. (author)Currently the only methods for non-genotoxic carcinogenic hazard assessment accepted by most regulatory authorities are lifetime carcinogenicity studies. However, these involve the use of large numbers of animals and the relevance of their predictive power and results has been scientifically challenged. With increased availability of innovative...article 2020
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Oerlemans, A. (author), Verscheijden, L.F.M. (author), Mol, J.G.J. (author), Vermeulen, R.C.H. (author), Westerhout, J. (author), Roeleveld, N. (author), Russel, F.G.M. (author), Scheepers, P.T.J. (author)Tebuconazole (TEB) is a widely used triazole fungicide, but the toxicokinetics of its human metabolites are not fully described. For proper interpretation of biological monitoring data, knowledge on the metabolism and elimination of the compound is required. A human volunteer study was performed with the aim to describe the time courses of...article 2019
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Wambaugh, J.F. (author), Hughes, M.F. (author), Ring, C.L. (author), MacMillan, D.K. (author), Ford, J. (author), Fennell, T.R. (author), Black, S.R. (author), Snyder, R.W. (author), Sipes, N.S. (author), Wetmore, B.A. (author), Westerhout, J. (author), Setzer, R.W. (author), Pearce, R.G. (author), Simmons, J.E. (author), Thomas, R.S. (author)Prioritizing the risk posed by thousands of chemicals potentially present in the environment requires exposure, toxicity, and toxicokinetic (TK) data, which are often unavailable. Relatively high throughput, in vitro TK (HTTK) assays and in vitro-to-in vivo extrapolation (IVIVE) methods have been developed to predict TK, but most of the in vivo...article 2018
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Leist, M. (author), Ghallab, A. (author), Graepel, R. (author), Marchan, R. (author), Hassan, R. (author), Bennekou, S.H. (author), Limonciel, A. (author), Vinken, M. (author), Schildknecht, S. (author), Waldmann, T. (author), Danen, E. (author), van Ravenzwaay, B. (author), Kamp, H. (author), Gardner, I. (author), Godoy, P. (author), Bois, F.Y. (author), Braeuning, A. (author), Reif, R. (author), Oesch, F. (author), Drasdo, D. (author), Höhme, S. (author), Schwarz, M. (author), Hartung, T. (author), Braunbeck, T. (author), Beltman, J. (author), Vrieling, H. (author), Sanz, F. (author), Forsby, A. (author), Gadaleta, D. (author), Fisher, C. (author), Kelm, J. (author), Fluri, D. (author), Ecker, G. (author), Zdrazil, B. (author), Terron, A. (author), Jennings, P. (author), van der Burg, B. (author), Dooley, S. (author), Meijer, A.H. (author), Willighagen, E. (author), Martens, M. (author), Evelo, C. (author), Mombelli, E. (author), Taboureau, O. (author), Mantovani, A. (author), Hardy, B. (author), Koch, B. (author), Escher, S. (author), van Thriel, C. (author), Cadenas, C. (author), Kroese, D. (author), van de Water, B. (author), Hengstler, J.G. (author)Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event...article 2017
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Langenberg, J.P. (author), van der Schans, M.J. (author), Noort, D. (author)In this chapter an overview is presented on the state of knowledge concerning the toxicokinetics of sulfur mustard. The procedures to analyze intact sulfur mustard in the blood and tissues of laboratory animals at toxicologically relevant levels are discussed. In view of the fact that the reviewed toxicokinetic studies were performed one to...bookPart 2016
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Nohynek, G.J. (author), Skare, J.A. (author), Meuling, W.J.A. (author), Wehmeyer, K.R. (author), de Bie, A.T.H.J. (author), Vaes, W.H.J. (author), Dufour, E.K. (author), Fautz, R. (author), Steiling, W. (author), Bramante, M. (author), Toutain, H. (author)Systemic exposure was measured in humans after hair dyeing with oxidative hair dyes containing 2.0% (A) or 1.0% (B) [14C]-p-phenylenediamine (PPD). Hair was dyed, rinsed, dried, clipped and shaved; blood and urine samples were collected for 48 hours after application. [14C] was measured in all materials, rinsing water, hair, plasma, urine and...article 2015
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Bosgra, S. (author), Westerhout, J. (author)In the EU collaborative project ChemScreen an alternative, in vitro assay-based test strategy was developed to screen compounds for reproductive toxicity. A toxicokinetic modeling approach was used to allow quantitative comparison between effective concentrations in the in vitro test battery and observations of developmental toxicity in vivo....article 2015
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Wambaugh, J.F. (author), Wetmore, B.A. (author), Pearce, R. (author), Strope, C. (author), Goldsmith, R. (author), Sluka, J.P. (author), Sedykh, A. (author), Tropsha, A. (author), Bosgra, S. (author), Shah, I. (author), Judson, R. (author), Thomas, R.S. (author), Setzer, R.W. (author)Toxicokinetic (TK) models link administered doses to plasma, blood, and tissue concentrations. High-throughput TK (HTTK) performs in vitro to in vivo extrapolation to predict TK from rapid in vitro measurements and chemical structure-based properties. A significant toxicological application of HTTK has been "reverse dosimetry," in which...article 2015
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Kroese, E.D. (author), Bosgra, S. (author), Buist, H.E. (author), Lewin, G. (author), van der Linden, S.C. (author), Man, H.Y. (author), Piersma, A.H. (author), Rorije, E. (author), Schulpen, S.H.W. (author), Schwarz, M. (author), Uibel, F. (author), van Vugt-Lussenburg, B.M.A. (author), Wolterbeek, A.P.M. (author), van der Burg, B. (author)Previously we showed a battery consisting of CALUX transcriptional activation assays, the ReProGlo assay, and the embryonic stem cell test, and zebrafish embryotoxicity assay as 'apical' tests to correctly predict developmental toxicity for 11 out of 12 compounds, and to explain the one false negative [7]. Here we report on applying this battery...article 2015
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Beker van Woudenberg, A. (author), Snel, C. (author), Rijkmans, E. (author), de Groot, D. (author), Bouma, M. (author), Hermsen, S. (author), Piersma, A. (author), Menke, A. (author), Wolterbeek, A. (author)To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid (VPA), carbamazepine (CBZ), ethosuximide (ETH)...article 2014
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Piersma, A.H. (author), Bosgra, S. (author), van Duursen, M.B.M. (author), Hermsen, S.A.B. (author), Jonker, L.R.A. (author), Kroese, E.D. (author), van der Linden, S.C. (author), Man, H. (author), Roelofs, M.J.E. (author), Schulpen, S.H.W. (author), Schwarz, M. (author), Uibel, F. (author), van Vugt-Lussenburg, B.M.A. (author), Westerhout, J. (author), Wolterbeek, A.P.M. (author), van der Burg, B. (author)The application of alternative methods in developmental and reproductive toxicology is challenging in view of the complexity of mechanisms involved. A battery of complementary test systems may provide a better prediction of developmental and reproductive toxicity than single assays. We tested twelve compounds with varying mechanisms of toxic...article 2013
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Langenberg, J.P. (author), Spruit, W.E.T. (author), Kuijpers, W.C. (author), Mars, R.H. (author), van Helden, H.P.M. (author), van der Schans, G.P. (author), Benschop, H.P. (author), TNO Defensie en Veiligheid (author)ln order to provide a quantitative basis for pretreatment and therapy of intoxications with sulfur mustard the toxicokinetics of this agent as well as its major DNA-adducts are being studied in male hairless guinea pigs for the intravenous, respiratory and percutaneous routes. A highly sensitive method for bioanalysis of the intact agent in...bookPart 2009
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Hissink, A.M. (author), Kulig, B.M. (author), Kruse, J. (author), Freidig, A.P. (author), Verwei, M. (author), Muijser, H. (author), Lammers, J.H.C.M. (author), Mckee, R.H. (author), Owen, D.E. (author), Sweeney, L.M. (author), Salmon, F. (author), TNO Kwaliteit van Leven (author)This report describes a physiologically based pharmacokinetic model for cyclohexane and its use in comparing internal doses in rats and volunteers following inhalation exposures. Parameters describing saturable metabolism of cyclohexane are measured in rats and used along with experimentally determined partition coefficients. The model is...article 2009
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de Jong, E. (author), Louisse, J. (author), Verwei, M. (author), Blaauboer, B.J. (author), van de Sandt, J.J.M. (author), Woutersen, R.A. (author), Rietjens, I.M.C.M. (author), Piersma, A.H. (author), TNO Kwaliteit van Leven (author)The embryonic stem cell test (EST) has been proposed as an in vitro assay that might reduce animal experimentation in regulatory developmental toxicology. So far, evaluation of the EST was not performed using compounds within distinct chemical classes. Evaluation within a distinct class of chemically related compounds can define the usefulness...article 2009
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Hissink, A.M. (author), Krüse, J. (author), Kulig, B.M. (author), Verwei, M. (author), Muijser, H. (author), Salmon, F. (author), Leenheers, L.H. (author), Owen, D.E. (author), Lammers, J.H.C.M. (author), Freidig, A.P. (author), McKee, R.H. (author), TNO Kwaliteit van Leven (author)As part of a project designed to develop a framework for extrapolating acute central nervous system (CNS) effects of hydrocarbon solvents in animals to humans, experimental studies were conducted in rats and human volunteers in which acute CNS effects were measured and toxicokinetic data were collected. A complex hydrocarbon solvent, white...article 2007
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Gibbs, S. (author), van de Sandt, J.J.M. (author), Merk, H.F. (author), Lockley, D.J. (author), Pendlington, R.U. (author), Pease, C.K. (author), TNO Kwaliteit van Leven (author)In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental chemical exposure, it is also a potential...article 2007
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Buist, H.E. (author), de Heer, C. (author), van Burgsteden, J.A. (author), van de Sandt, J.J.M. (author), TNO Kwaliteit van Leven (author)The in vitro dermal absorption kinetics of didecyldimethylammonium chloride (DDAC) was studied after single and multiple exposure. In addition, the influence of biocidal formulations on the absorption of DDAC was investigated. Following dermal exposure to DDAC in aqueous solution, less than 0.5% of the applied dose reached the receptor fluid...article 2007
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Sweeney, R.E. (author), Langenberg, J.P. (author), Maxwell, D.M. (author), TNO Defensie en Veiligheid (author)A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(±)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 × LD50), medium (2-3 × LD50) and high (6 × LD50) levels...article 2006
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McKee, R.H. (author), Lammers, J.H.C.M. (author), Hoogendijk, E.M.G. (author), Emmen, H.H. (author), Muijser, H. (author), Barsotti, D.A. (author), Owen, D.E. (author), Kulig, B.M. (author), TNO Kwaliteit van Leven (author)As a preliminary step to evaluating the acute neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, joint neurobehavioral/toxicokinetic studies were conducted which involved administering ethanol to rats and volunteers. The specific objectives of the present studies were to...article 2006