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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For almost fifteen years, the availability and regulatory acceptance of new approach methodologies (NAMs) to assess the absorption, distribution, metabolism and excretion (ADME/biokinetics) in chemical risk evaluations are a bottleneck. To enhance the field, a team of 24 experts from science, industry, and regulatory bodies, including new generation toxicologists, met at the Lorentz Centre in Leiden, The Netherlands. A range of possibilities for the use of NAMs for biokinetics in risk evaluations were formulated (for example to define species differences and human variation or to perform quantitative in vitro-in vivo extrapolations). To increase the regulatory use and acceptance of NAMs for biokinetics for these ADME considerations within risk evaluations, the development of test guidelines (protocols) and of overarching guidance documents is considered a critical step. To this end, a need for an expert group on biokinetics within the Organisation of Economic Cooperation and Development (OECD) to supervise this process was formulated. The workshop discussions revealed that method development is still required, particularly to adequately capture transporter mediated processes as well as to obtain cell models that reflect the physiology and kinetic characteristics of relevant organs. Developments in the fields of stem cells, organoids and organ-on-a-chip models provide promising tools to meet these research needs in the future.
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This entry begins by reviewing the definitions of “human”, “environment” and “dichotomy”, consequently turning to the debates concerning the human–environment relationship. Synthesizing various studies, the capability of advanced tool use; language, hyper-sociality, advanced cognition, morality, civilization, technology, and free will are supposed to be distinctly human. However, other studies describe how nonhuman organisms share these same abilities. The biophysical or natural environment is often associated with all living and non-living things that occur naturally. The environment also refers to ecosystems or habitats, including all living organisms or species. The concepts of the biophysical or natural environment are often opposed to the concepts of built or modified environment, which is artificial - constructed or influenced by humans. The built or modified environment typically refers to structures or spaces from gardens to car parks. Today, one of the central questions in regard to human-environment dichotomies centres around the concept of sustainability. https://onlinelibrary.wiley.com/doi/book/10.1002/9781118924396 LinkedIn: https://www.linkedin.com/in/helenkopnina/
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Taking artistic, creative and pedagogic experience as perspectives, the research will consider the embodiment of rhythm and duration as experienced by practicing musicians and utilized by composers, exploring neurophysiological questions such as how temporal resolution relates to human physiology, the relationship between speed and emotion and how musicians keep track of time. The expressive qualities of speed in music will be explored, taking into account practices of performance, composition and notation.
