Journal: ALTEX

Article Title: Probabilistic Risk Assessment – The Keystone for the Future of Toxicology

doi: 10.14573/altex.2201081

Figure Lengend Snippet: Major workshops on physiology-based pharmacokinetic/toxicokinetic modeling (PBPK) for risk assessment

Article Snippet: EPAA & EURL ECVAM: Potential for further integration of toxicokinetic modelling into the prediction of in vivo dose-response curves without animal experiments, 2011, Joint Research Centre, Italy ( ) , The aim of the workshop was to critically appraise PBK modelling software platforms as well as a more detailed state-of-the-art overview of non-animal based PBK parameterization tools. Such as: 1) Identification of gaps in non-animal test methodology for the assessment of ADME. 2) Addressing user-friendly PBK software tools and free-to-use web applications. 3) Understanding the requirements for wider and increased take up and use of PBK modelling by regulators, risk assessors and toxicologists in general. 4) Tackling the aspect of obtaining in vivo human toxicokinetic reference data via micro-dosing following the increased interest by the research community, regulators, and politicians.

Techniques: In Vitro, Comparison, In Vivo, Biomarker Discovery, Software, Selection, In Silico, Construct

Journal: EFSA Journal

Article Title: Statement on the toxicological properties and maximum residue levels of acetamiprid and its metabolites

doi: 10.2903/j.efsa.2024.8759

Figure Lengend Snippet: Overview of identified major uncertainties related to metabolism and excretion processes of the available PBK model for acetamiprid.

Article Snippet: Although the Simcyp human PBK model was considered to be relevant, it could not be applied by the WG to answer assessment question 1b, since Simcyp Simulator software is a proprietary software that can only be used following a dedicated training.

Techniques: Radioactivity, Selection, In Vivo

Journal: EFSA Journal

Article Title: Statement on the toxicological properties and maximum residue levels of acetamiprid and its metabolites

doi: 10.2903/j.efsa.2024.8759

Figure Lengend Snippet: Schematic overview of interrelation of identified uncertainties related to metabolism and excretion processes of acetamiprid and IM‐2‐1 in the available PBK model for acetamiprid. The PBK model parameter values chosen for the kinetic processes related to U1, U2 and U4 impact on predicted internal and urinary acetamiprid concentrations (U6). The PBK model parameter values chosen for the kinetic processes related to U1–U5 impact on predicted internal and urinary IM‐2‐1 concentrations (U7).

Article Snippet: Although the Simcyp human PBK model was considered to be relevant, it could not be applied by the WG to answer assessment question 1b, since Simcyp Simulator software is a proprietary software that can only be used following a dedicated training.

Techniques:

Journal: Toxicology in Vitro

Article Title: Automated workflows for modelling chemical fate, kinetics and toxicity

doi: 10.1016/j.tiv.2017.03.004

Figure Lengend Snippet: A. Concentration – time profile curves from the PBK model built for caffeine and relevant metabolites (corresponding to the PBK model workflow in A). B. PBK model simulation of viability – dose response for oral and dermal exposure (corresponding to the PBK model workflow in B).

Article Snippet: The aim of this work was to illustrate how the PBK model and VCBA, both biologically-based mathematical models, can be implemented in KNIME, thereby providing a user-friendly tool for scientists and safety assessors.

Techniques: Concentration Assay

Journal: Toxicology in Vitro

Article Title: Automated workflows for modelling chemical fate, kinetics and toxicity

doi: 10.1016/j.tiv.2017.03.004

Figure Lengend Snippet: Viability - dose response curve from IVIVE workflow, including the extrapolation table from which the selected dose or viability (input) versus the corresponding predicted viability or dose, respectively (corresponding to the PBK model workflow in ).

Article Snippet: The aim of this work was to illustrate how the PBK model and VCBA, both biologically-based mathematical models, can be implemented in KNIME, thereby providing a user-friendly tool for scientists and safety assessors.

Techniques:

Journal: Toxicological Sciences

Article Title: Predictive Performance of Next Generation Physiologically Based Kinetic (PBK) Model Predictions in Rats Based on In Vitro and In Silico Input Data

doi: 10.1093/toxsci/kfab150

Figure Lengend Snippet: Ratios between PBK model-predicted C max values and in vivo -observed C max values observed for 44 reference compounds in rat. Per chemical, different predicted C max values are obtained by running simulations with the different input approaches ( in vitro or in silico approaches to parameterize a certain input parameter) as presented in Table 1 . Each predicted C max is then compared with the in vivo C max values for the chemical in the dataset. The median of these predicted/observed ratios is depicted along the individual datapoints. Datapoints within the dotted, dot-dashed, or dashed horizontal lines are within 2-fold, 5-fold or 10-fold of the observed C max , respectively. Compounds for which the median predicted C max is more than 10-fold overestimated are depicted in light gray.

Article Snippet: The minimal PBK model approach was applied on 5 in-house BASF compounds as case study to test whether similar results are obtained with respect to the range in predicted:observed ratios and the type of compounds that are likely to be predicted within 10-fold (ie, low or high clearance compounds). provides an overview of the in vitro and in silico input data that are available for the 5 compounds as well as the C max predictions that are obtained with the generic PBK model.

Techniques: In Vivo, In Vitro, In Silico

Journal: Toxicological Sciences

Article Title: Predictive Performance of Next Generation Physiologically Based Kinetic (PBK) Model Predictions in Rats Based on In Vitro and In Silico Input Data

doi: 10.1093/toxsci/kfab150

Figure Lengend Snippet: Ratios between PBK model-predicted C max values and in vivo -observed C max values observed for 44 reference compounds in rat after removal of the simulations based on input methods that led to significant worst predictions as described in the main text.

Article Snippet: The minimal PBK model approach was applied on 5 in-house BASF compounds as case study to test whether similar results are obtained with respect to the range in predicted:observed ratios and the type of compounds that are likely to be predicted within 10-fold (ie, low or high clearance compounds). provides an overview of the in vitro and in silico input data that are available for the 5 compounds as well as the C max predictions that are obtained with the generic PBK model.

Techniques: In Vivo

Journal: Archives of Toxicology

Article Title: Inter-individual variation in chlorpyrifos toxicokinetics characterized by physiologically based kinetic (PBK) and Monte Carlo simulation comparing human liver microsome and Supersome ™ cytochromes P450 (CYP)-specific kinetic data as model input

doi: 10.1007/s00204-022-03251-z

Figure Lengend Snippet: Geometric mean values, the 95th and the 99th percentile values of the distribution for the predicted free blood maximum concentration ( C max) of CPO after a single oral CPF dose of 0.47 mg/kg bw in Monte Carlo simulations, and its resulting CSAFs in the Supersome ™ -based PBK model and the HLM-based PBK model approach when taking only metabolism-related kinetic parameters into account or taking all influential parameters into account

Article Snippet: Therefore, in the Supersome ™ -based PBK model, the variation in the activity of CYP2B6 and CYP2C19 was characterized by considering different phenotype abundances and relative frequencies in the general population obtained from Simcyp (Simcyp Simulator V18 Release 1, Certara, Sheffield, UK) in the Monte Carlo analysis.

Techniques: Concentration Assay

Journal: Archives of Toxicology

Article Title: Inter-individual variation in chlorpyrifos toxicokinetics characterized by physiologically based kinetic (PBK) and Monte Carlo simulation comparing human liver microsome and Supersome ™ cytochromes P450 (CYP)-specific kinetic data as model input

doi: 10.1007/s00204-022-03251-z

Figure Lengend Snippet: The predicted in vivo dose–response curves for AChE inhibition upon CPF exposure in human using the Supersome ™ -based PBK model (green solid line for average population, green dash line for 99th percentile sensitive individuals, and green dot line for 1st percentile sensitive individuals), the HLM-based PBK model (non-biphasic, blue solid line) and the HLM-based PBK model (biphasic, red solid line for average population, red dash line for 99th percentile sensitive individuals, and red dot line for 1st percentile sensitive individuals) for the reverse dosimetry. The individual data points represent available in vivo data for RBC AChE inhibition in human upon oral exposure to CPF at different dose levels as reported by USEPA and Timchalk et al. (color figure online)

Article Snippet: Therefore, in the Supersome ™ -based PBK model, the variation in the activity of CYP2B6 and CYP2C19 was characterized by considering different phenotype abundances and relative frequencies in the general population obtained from Simcyp (Simcyp Simulator V18 Release 1, Certara, Sheffield, UK) in the Monte Carlo analysis.

Techniques: In Vivo, Inhibition