New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose–response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals.
MULTIFILE
Deployment and management of environmental infrastructures, such as charging infrastructure for Electric Vehicles (EV), is a challenging task. For policy makers, it is particularly difficult to estimate the capacity of current deployed public charging infrastructure for a given EV user population. While data analysis of charging data has shown added value for monitoring EV systems, it is not valid to linearly extrapolate charging infrastructure performance when increasing population size.We developed a data-driven agent-based model that can explore future scenarios to identify non-trivial dynamics that may be caused by EV user interaction, such as competition or collaboration, and that may affect performance metrics. We validated the model by comparing EV user activity patterns in time and space.We performed stress tests on the 4 largest cities the Netherlands to explore the capacity of the existing charging network. Our results demonstrate that (i) a non-linear relation exists between system utilization and inconvenience even at the base case; (ii) from 2.5x current population, the occupancy of non-habitual charging increases at the expense of habitual users, leading to an expected decline of occupancy for habitual users; and (iii) from a ratio of 0.6 non-habitual users to habitual users competition effects intensify. For the infrastructure to which the stress test is applied, a ratio of approximately 0.6 may indicate a maximum allowed ratio that balances performance with inconvenience. For policy makers, this implies that when they see diminishing marginal performance of KPIs in their monitoring reports, they should be aware of potential exponential increase of inconvenience for EV users.
Project objectives Radicalisation research leads to ethical and legal questions and issues. These issues need to be addressed in way that helps the project progress in ethically and legally acceptable manner. Description of Work The legal analysis in SAFIRE addressed questions such as which behavior associated with radicalisation is criminal behaviour. The ethical issues were addressed throughout the project in close cooperation between the ethicists and the researchers using a method called ethical parallel research. Results A legal analysis was made about criminal law and radicalisation. During the project lively discussions were held in the research team about ethical issues. An ethical justification for interventions in radicalisation processes has been written. With regard to research ethics: An indirect informed consent procedure for interviews with (former) radicals has been designed. Practical guidelines to prevent obtaining information that could lead to indirect identification of respondents were developed.
