Abstract
The present study predicts in vivo human and rat red blood cell (RBC) acetylcholinesterase (AChE) inhibition upon diazinon (DZN) exposure using physiological based kinetic (PBK) modelling-facilitated reverse dosimetry. Due to the fact that both DZN and its oxon metabolite diazoxon (DZO) can inhibit AChE, a toxic equivalency factor (TEF) was included in the PBK model to combine the effect of DZN and DZO when predicting in vivo AChE inhibition. The PBK models were defined based on kinetic constants derived from in vitro incubations with liver fractions or plasma of rat and human, and were used to translate in vitro concentration–response curves for AChE inhibition obtained in the current study to predicted in vivo dose–response curves. The predicted dose–response curves for rat matched available in vivo data on AChE inhibition, and the benchmark dose lower confidence limits for 10% inhibition (BMDL10 values) were in line with the reported BMDL10 values. Humans were predicted to be 6-fold more sensitive than rats in terms of AChE inhibition, mainly because of inter-species differences in toxicokinetics. It is concluded that the TEF-coded DZN PBK model combined with quantitative in vitro to in vivo extrapolation (QIVIVE) provides an adequate approach to predict RBC AChE inhibition upon acute oral DZN exposure, and can provide an alternative testing strategy for derivation of a point of departure (POD) in risk assessment.
Highlights
Diazinon (DZN) is the common name for O,O-diethyl O-2-isopropyl-6-methylpyrimidin-4-yl phosphorothioate (Fig. 1), which is used as a pesticide in agriculture or veterinary medicine (JMPR 2016)
The rat DZN model was built and evaluated first and used as the basis for developing the human DZN model since less human in vivo data are available for model evaluation (EFSA 2006; JMPR 2016; USEPA 2016)
The results obtained reveal that the developed rat model adequately predicted the toxicokinetic profile of DZN in rat, and could adequately convert the in vitro concentration–response curve to an in vivo dose response curve for DZN-mediated AChE inhibition, resulting in a BMDL10 value comparable to the BMDL10 reported for inhibition of rat brain AChE and 2.6fold different from the reported B MDL10 for inhibition of rat red blood cell (RBC) AChE, respectively (EFSA 2006; JMPR 2016; USEPA 2016)
Summary
Diazinon (DZN) is the common name for O,O-diethyl O-2-isopropyl-6-methylpyrimidin-4-yl phosphorothioate (Fig. 1), which is used as a pesticide in agriculture or veterinary medicine (JMPR 2016). DZN belongs to the class of thiophosphate insecticides for which acute toxicity is associated with irreversible inhibition of acetylcholinesterase (AChE) resulting in accumulation of acetylcholine at the synaptic cleft (Colovic et al 2013). Different physiological symptoms such as headache, abdominal cramps, difficulty in breathing, and even death can result from acute DZN exposure (Burgess et al 2008). The bioactivation of DZN is mediated by especially CYP2B6, CYP2C19 and CYP3A4, while the detoxification is catalysed by CYP1A1, CYP1A2, CYP2B6, CYP2C19 and CYP3A4 (Ellison et al 2012; Kappers et al. Vol.:(0123456789)
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