Theses and Dissertations

Issuing Body

Mississippi State University

Advisor

Chambers, Janice E.

Committee Member

Ross, Matthew K.

Committee Member

Chambers, Howard W.

Committee Member

Pruett, Steven

Committee Member

Crow, Allen

Date of Degree

12-15-2007

Document Type

Dissertation - Open Access

Major

Environmental Toxicology

Degree Name

Doctor of Philosophy

College

College of Veterinary Medicine

Department

Department of Basic Sciences

Abstract

A physiologically-based toxicokinetic and toxicodynamic (PBTK/TD) model was developed, from the open literature, to predict the toxicokinetic disposition and toxicodynamic response (acetylcholinesterase inhibition) of a ternary organophosphorus (OP) insecticide mixture: chlorpyrifos (CP), methyl parathion (MP) and parathion (P). In vivo studies were conducted in adult male Sprague-Dawley rats, orally administered one of two CP/MP/P mixtures (2.5, 0.5, 0.5 mg/kg or 5, 1, 1 mg/kg) with selected tissues (blood, brain, diaphragm, liver, lung and skeletal muscle) collected at 30min, 4, 12 and 24hr postdosing. Low dosages were studied so the mixture did not result in significant disruption of cardiovascular function nor invalidate the model’s underlying general physiological assumptions. The data were used to validate the model. CP and its metabolites (CP-oxon, 3,5,6-trichloro-2-pyridinol (TCP)), as well as MP, P and 4-nitrophenol, were quantified in the tissues of interest. Peak concentrations of CP were attained by 4hr in all tissues with the exception of the liver, whose peak occurred at 30min; MP, 30min in all tissues; P, 12hr in all tissues with the exception of the liver, 30min. This was supported by the model simulations. MP, P, and their respective oxons were below limits of quantitation for the lower dosage. No toxicokinetic interactions were observed in the present study. Cholinesterase inhibition in the tissues ranged from 11- 37% for the lower dosage, and 29-93% for the higher dosage group; with few exceptions, inhibition was generally additive and was also supported by the model simulations. This study demonstrates the utility of using previously developed individual PBTK/TD models and in vitro/in vivo data from the open literature to construct reliable mixture PBTK/TD models.

URI

https://hdl.handle.net/11668/19107

Comments

PBTK/TD Model||Mixtures||Organophosphorus Insecticides||Esterase Inhibition||PBPK/PD Model

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