pbk models  (ANSES laboratories)

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: However, as the combination of these different uncertain model parameters will affect the PBK model predictions for the internal dosimetry and urinary levels of both acetamiprid and IM‐2‐1, i.e. the critical PBK model outcomes that are required to answer the assessment question 1b, the WG considered that a translation of the available PBK model in Simcyp to a similar PBK model in PK‐Sim would not result in a PBK model that is sufficiently robust to answer the assessment question 1b of the mandate.

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: However, as the combination of these different uncertain model parameters will affect the PBK model predictions for the internal dosimetry and urinary levels of both acetamiprid and IM‐2‐1, i.e. the critical PBK model outcomes that are required to answer the assessment question 1b, the WG considered that a translation of the available PBK model in Simcyp to a similar PBK model in PK‐Sim would not result in a PBK model that is sufficiently robust to answer the assessment question 1b of the mandate.

Techniques:

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: 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