A population physiologically based kinetic and toxicodynamic model for acute diazinon exposure

Organophosphate (OP) pesticide residues are frequently found in the environment and food products, with their acute exposures to humans posing a risk of neurotoxicity through acetylcholinesterase (AChE) inhibition. The aim of the present study is to develop a New Approach Methodology (a population-based physiologically based kinetic and toxicodynamic (PBK-TD) model) to define a health-based guidance value (HBGV) for acute exposure to diazinon as the model OP, taking into account human interindividual variability in physiology, toxicokinetics and toxicodynamics. Physiological and chemical-specific inputs for the PBK-TD model were obtained from literature or by in silico-in vitro strategies. Using this population model and Monte Carlo simulations, the dose-dependent response for DZN-induced erythrocyte AChE inhibition was generated to provide a point of departure (POD) for defining an acute reference dose (ARfD). The model simulates the toxicokinetic and toxicity data observed in humans well, and results reveal that toxicokinetic and not toxicodynamic variations are the main driver of the overall interindividual variability in susceptibility towards acute DZN exposure. The POD predicted for the sensitive adults is in agreement with a previously reported human no-observed-adverse-effect level (NOAEL). It is concluded that the population PBK-TD modeling defines a novel way to derive a POD for human health risk assessment with the incorporation of interindividual differences. In the next step, the inclusion of correlations between certain model parameters as well as cholinesterase inhibition in tissues other than the blood is expected to be a further refinement.