Abstract: The key goal of this project is to test the hypothesis that exposure to mixtures of the test compounds, PB (oral), DEET (dermal), and permethrin (dermal) reduces the body's ability for their detoxification, resulting in increased bioavailability of the parent compounds and of their enhanced delivery to the toxicity site(s), leading to pronounced toxicity. The results reported in this Annual Report support this hypothesis as follows: 1) Although exposure to single compounds caused locomotor and sensorimotor performance deficit in rats, combined exposure resulted in greater deficit even at one-tenth of real-life exposure doses. 2) Combined exposure to the three test compounds with stress increased the permeability of the blood-brain barrier (BBB) as shown by the uptake of 3Hhexamethonium iodide, penetration of horseradish peroxidase and immunostaining for endothelial-barrier antigen (EBA), and inhibition of brain acetylcholinesterase. 3) Exposure to DEET and/ or permethrin for 60 days, and PB, DEET, and permethrin in combination with stress for 28 days caused neuronal cell death in cerebral cortex and hippocampus, and Purkinje cells in the cerebellum. These alterations are consistent with the neurobehavioral changes and breakdown of the BBB. 4) Combined exposure to chemicals and stress caused liver damage and decreased detoxification of test compounds. 5) Combined exposure increased the bioavailability of test compounds because liver damage and because of competition for the diminished amount of available enzyme(s) in the plasma and liver. These results are consistent with recent DOD report that Gulf war veterans are prone to neurologic diseases such as amyotrophic lateral sclerosis (ALS).
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Description: |
Annual rept. 21 Dec 2000-20 Dec 2001 |
| Pages: |
155 |
| Report Date: |
JAN 2002 |
| Contract Number: |
DAMD17-99-1-9020 |
| Report Number: |
A811614 |
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Keywords relating to this report:
