Developing physiologically-based toxicokinetic (PBTK) models to - - PowerPoint PPT Presentation
Developing physiologically-based toxicokinetic (PBTK) models to assess occupational exposure to haloxyfop- methyl ester. PHE/ ICL Alex Cooper Intro to PBTK modelling & aims Results Further work --/--/2017 PBTK modelling
Construct rodent PBTK models for herbicides Calibrate models with rodent toxicokinetic data Exposure reconstruction with human biomonitoring data Extrapolate models to humans
Calibrate parameters common to both species Calibrate human- specific parameters Calibrate mouse- specific parameters Mouse toxicokinetic data Human toxicokinetic data Human biomonitoring data
Exposure reconstruction
Hypothesis: PBTK models can be calibrated and used to accurately calculate tissue exposures for use in risk assessment.
PBTK model and human biomonitoring data. Aims:
fitting toxicokinetic data in the same rodent PBTK model, and once extrapolated to humans, whether these have different implications for internal exposure assessment.
human PBTK model.
Acceptable Operator Exposure Limit (AOEL) is 0.005 mg/ Kg/ day
may be exposed (from all absorption routes) without adverse health effects’ (European Commission)
Inhibits ACCase liver toxicity (NOAEL is 0.5 mg/ Kg bw/ day) ÷ 100 peroxisome proliferation
model calibration
resemble physiological conditions (37 °C, using PBS pH 7.4 for aqueous layer).
(p = 0.85,α = 0.05; n = 10).
PPARα receptor binding Model liver transporter activity (NO PPARα receptor binding) Fit liver toxicokinetic data
Extrapolate from mouse (with PPARα receptor binding) Extrapolate from mouse (with liver transporter activity)
Maximum tissue exposure (individual C) Concentration (ng/ g-tissue)
Extrapolate from mouse (with PPARα receptor binding) Extrapolate from mouse (with liver transporter activity)
UK-POEM model German model
AOEL
Dose (mg/ Kg bw) Dose (mg/ Kg bw)
A B C A B C