Taphonomy
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Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.
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The research presented in this thesis has highlighted (bio)geochemical, hydrological, and wetland ecological processes that interact and enhance ecosystem development on wetlands built on fine sediment. A combination of greenhouse and laboratory experiments were conducted. Some measured data from these experiments formed important input for subsequent analysis in a modeling environment. The findings presented in Chapters 2-6 can be divided into four topics: 1) Plant–soil interactions in the terrestrial zone, 2) wetland–terrestrial processes influencing nutrient availability in the land–water zone, 3) effects of plants on sediment consolidation in the terrestrial zone, and 4) effects of bioturbation on nutrient availability in the aquatic zone. The next sections give a summary of the results for these four topics. The last section summarizes the recommendations formulated for the Marker Wadden project.
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