Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Pesticide Diazinon
Organophosphate (OP) insecticides like diazinon (DZN) constitute a large class of chemical insecticides that are widely utilized. The potential exists for significant exposures to a combination of OP pesticides from multiple routes. The objective of this research was to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model capable of predicting the relationships between exposure route, bioactivation, detoxification, and acetylcholinesterase (AChE) inhibition. CYP450-mediated metabolism of DZN to the active oxon leads to inhibition of AChE at nerve endings. CYP450s also mediate detoxification of DZN to its pyrimidinol and A-esterase detoxifies the oxon to the pyrimidinol. The ultimate goal is to use this model to quantify systemic dosimetry and biological response from available environmental and personal exposure data. The model structure integrates CYP450 and esterase metabolism, route-dependent absorption, target tissue dosimetry, and dynamic response, to predict circulating blood levels of DZN and esterase inhibition in target organs. Metabolic rate constants for the CYP450-mediated conversion to the active oxon and the inactive pyrimidinol and the esterase-mediated deactivation of the oxon have been measured in vitro. The inhibition of AChE activity is a sensitive and relatively easy measure of exposure and is therefore the preferred descriptive endpoint. Esterase inhibition and regeneration rates have been described using in vitro calculations and parameter optimization to fit the model to AChE inhibition data. This descriptive model for DZN has been developed and has been shown to predict blood levels of the parent chemical and AChE inhibition in animal models. This PBPK/PD model will be linked to a existing PBPK model for chlorpyrifos to estimate the effects of exposures to a mixture of OPs and to describe target tissue dosimetry and effects in humans. These biologically relevant PBPK models will be integral to risk assessments for DZN and OP mixture exposures under a variety of scenarios. (Sponsored by CDC/NIOSH Grant R01 OH03629-01A2).
- Research Organization:
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC05-76RL01830
- OSTI ID:
- 877082
- Report Number(s):
- PNWD-SA-6814; NRTXDN; TRN: US200608%%465
- Journal Information:
- Neurotoxicology, Vol. 25, Issue 6; ISSN 0161-813X
- Country of Publication:
- United States
- Language:
- English
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