Scientific Opinion on the application of physiologically based kinetic (PBK) modelling for the quantitative in vitro to in vivo extrapolation (QIVIVE) of developmental neurotoxicity in vitro battery (DNT IVB) data for pesticide active substances

EFSA requested the Panel on Plant Protection Products and their Residues (PPR Panel) to produce a Scientific Opinion on the application of physiologically based kinetic (PBK) modelling for the quantitative in vitro to in vivo extrapolation (QIVIVE) of data from the 17-assay developmental neurotoxicity in vitro battery (DNT IVB) for pesticide active substances. PBK modelling-supported QIVIVE is essential for the integration of in vitro data in hazard and risk assessment and may be conducted via forward dosimetry (estimating internal exposure from external exposure to a chemical) or reverse dosimetry (deriving an external exposure from an internal exposure). The request was accomplished via targeted expert discussions and EFSA-internal and -external review. A scientifically robust QIVIVE requires accurate characterisation of two interrelated exposure metrics: the in vitro concentration eliciting a biological response (e.g. free or cellular concentration) and the corresponding in vivo internal concentration predicted by PBK modelling that reflects the same biologically relevant exposure. These metrics are influenced by chemical-specific properties, assay design and physiological variability, requiring a case-by-case assessment of uncertainties. Each QIVIVE assessment should include, as a minimum, a low-tier PBK model using conservative assumptions to avoid underestimation of internal exposure. Where sufficient kinetic data exist, higher tier models may be applied to enhance prediction accuracy. All modelling parameters, assumptions and validation steps must be transparently documented to facilitate regulatory appraisal. QIVIVE outcomes are to be documented in the overall weight of evidence for the DNT assessment. The PPR Panel identified the following three key uncertainty domains: (a) defining the appropriate in vitro exposure metric, (b) predicting internal exposure metrics via PBK modelling and (c) aligning PBK modelling-derived internal exposure with the in vitro exposure. Addressing these uncertainties will strengthen regulatory confidence in using DNT IVB data for hazard and risk assessment of pesticide active substances.