Infant and Child Neurotoxicity Studies: Subtle and Long-Term Effects

Abstract

Diazinon (DZN) is an organophosphorus pesticide with the possibility for widespread exposures. The toxicological effects of DZN are primarily mediated through the effects of its toxic metabolite, DZN-oxon on acetylcholinesterases, which results in accumulation of acetylcholine at neuronal junctions. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed to quantitatively assess the kinetics of DZN and its metabolites in blood and the inhibition of cholinesterases in plasma, RBC, brain, and diaphragm. Focused in vivo pharmacokinetic studies were conducted in male Sprague–Dawley rats and the data were used to refine the model. No overt toxicity was noted following doses up to 100 mg/kg. However, cholinesterases in plasma, RBC, brain and diaphragm were substantially inhibited at doses of 50 mg/kg. In plasma, total cholinesterase was inhibited to less than 20% of control by 6 h post dosing with 100 mg/kg. Inhibition of brain acetylcholinesterase (AChE) following 100 mg/kg exposures was approximately 30% of control by 6 h. Diaphragm butyrylcholinesterase (BuChE) inhibition following 100 mg/kg dosing was to less than 20% of control by 6 h. The PBPK/PD model was used to describe the concentrations of DZN and its major, inactive metabolite, 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP) in plasma and urinary elimination of IMHP. The fit of the model to plasma, RBC, brain, and diaphragm total cholinesterase and BuChE activity was also assessed and the model was further validated by fitting data from the open literature for intraperitoneal, intravenous, and oral exposures to DZN. The model was shown to quantitatively estimate target tissue dosimetry and cholinesterase inhibition following several routes of exposures. This model further confirms the usefulness of the model structure previously validated for chlorpyrifos and shows the potential utility of the model framework for other related organophosphate pesticides.