Toxic Interactions of Prophylactic Drugs and Pesticides

Abstract

Approved for public release; Distribution unlimited 12b. DISTRIBUTION CODE ABSTRACT (Maximum 200 Words/The goal of the present project is to define the mechanisms of neurotoxic interactions following exposure to pyridostigmine bromide (PB, 0.13, 1.3,13 mg/gk in water, oral), DEET (4.0, 40.0, 400.0 mg/kg in ethanol, dermal), and permethrin (0.013, 0.13, 1.3 mg/kg in ethanol, dermal) in male Sprauge-Dawley rats. The results are summarized below. 1. Combined exposure to the three test compounds for 28 days, alone or with stress produced neuropathological alterations in the brain and hepatic lesions. 2. The same treatments increased the permeability of the blood brain barrier (BBB), as assessed by [ 3 H]hexamethonium iodide uptake and horseradish peroxidase (HRP) staining.3. Specific brain region exhibited decreased activity of AChE and ligand binding of m2 muscarinic acetylcholine receptors. 4. Exposure to DEET alone, or with permethrin significantly increased urinary excretion of 8-hydroxy-2'-deoxyguanosine. 5. Within 30 minutes of dermal application of 400 mg/kg DEET alone, or in combination with 1.3 mg/kg permethrin, 55% DEET and 38% permethrin was absorbed. Distribution of permethrin in tissues was slower than DEET.Combined application to both chemicals increased AUC for DEET but did not affect AUC FlasT . a of permethrin. The goal of this project is to evaluate the possible interaction between DEET, permethrin and pyridostigmine bromide (PB) and the biological and pathological consequences of such interactions. Our standing hypothesis is that combined exposure to a mixture of chemicals would have enhanced, and in some cases deterimental toxicological effects than exposure with single chemical. SUBJECT TERMS B) ApproachWe have been testing the stated hypothesis that interactions between combined chemical exposure would result in greater toxicological and pathological changes, and certain environmental modifying factors such as stress would modulate the toxic effects in combined exposure scenario. In the previous year we have carried out dose-response studies ranging from 0.1-10 x the estimated human exposure on DEET, permethrin and PB. In those studies we carried out neurobehavioral as well as neurochemical assessment following exposure to a single or multiple chemicals (See the manuscripts in Appendix). In the current studies, we have focused on the pathological consequences of sub-chronic exposure to single chemical or combined concurrent exposure. Additionally, we studied the effect of one environmental modifier, stress on the neurotoxicity associated with concurrent exposure to PB, DEET and permethrin. The pathological changes were studied by immunohistochemical evaluation of microtubule-associated protein-2 (MAP-2), glialfibrillary acidic protein (GFAP), and microglial activation by lectin binding. Furthermore, we evaluated the possible mechanism(s) of neurotoxic effects of single or combined exposure by assessing the permeability of blood-brain barrier (BBB) and evaluating 8-hydroxy-2'-deoxyguanosine by ...