In Vitro Investigation of Gulf War Illness Brain Effects: Use of a Physiologically-Based Pharmacokinetic Array Model to Inform an Electrophysiology Study
Abstract
Military deployed during the Gulf War (1990-1991) frequently exhibit signs of a neurological disorder known as Gulf War Illness (GWI). Published animal studies indicate a mixtures exposure of 1.3 mg/kg pyridostigmine bromide (PB, oral), 40 mg/kg diethyltoluamide (DEET, dermal) and 0.13 mg/kg permethrin (PER, dermal), dosed daily for 28 days, to be effective in inducing GWI-like symptoms in rats. An in vitro study was designed to measure the electrophysiological effects of this mixture in rat hippocampus brain slices. Physiologically-based pharmacokinetic (PBPK) modeling was utilized to predict tissue doses from exposures mirroring the in vivo studies. An array (vector) PBPK model was constructed to simultaneously predict brain concentrations of GWI compounds in the rat. Array models use a unified model structure to simulate single or multiple compounds. Each GWI compound was parameterized individually using kinetic data sets from literature sources. Cis- and trans-PER isomers required separate kinetic parameters. The model predicted effective brain concentration ranges of 0.10.5, 0.04-0.1 and 0.06-0.6 g/mL for PB, DEET and PER (55:45 cis:trans), respectively. Directed by these predictions, slices of male Sprague-Dawley rat hippocampus incubated in0.097, 013, and 0.5 g/mL PB, DEET and PER, respectively, resulted in an increase in paired pulse facilitation and a decrease in input-output response of hippocampal neurons; these effects were not statistically significant. A 10X mixture produced statistically significant dose-dependent changes. The array PBPK model was useful in predicting tissue doses and reducing the number of animals/iterations required for successful in vitro testing.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 30, 2019
- Accession Number
- AD1092796
Entities
People
- Elaine A. Merrill
- Joyce G. Rohan
- Molly K. Miklasevich
- Nathan M. Gargas
- Peter J. Robinson
- Teresa R Sterner
- Tori Ethridge
Organizations
- 711th Human Performance Wing
- Henry M. Jackson Foundation for the Advancement of Military Medicine
- Naval Medical Research Unit Dayton
- Oak Ridge Institute for Science and Education