Pyridostigmine bromide modulates the dermal disposition of [14C]permethrin

The cause of the Gulf War Syndrome may be related to soldiers being exposed to insecticides (e.g., permethrin (P)), insect repellents (e.g., N,N-diethyl-m-toluamide (DEET)), an organophosphate nerve agent simulant (e.g., diisopropyl fluorpohosphate (DFP)), and/or prophylactic treatment (e.g., pyridostigmine bromide (PB)) against potential nerve gas attacks. The purpose of this study was to assess the dermal disposition of [14C]permethrin in ethanol or ethanol:water (3:2) in the isolated perfused porcine skin flap (IPPSF) model with simultaneous dermal exposure to DEET or DFP. These IPPSFs were also simultaneously perfused arterially with or without PB, DFP, or DFP + PB. The results indicated that DFP + PB significantly increased [14C]permethrin absorption compared to controls (1.06% dose vs 0.14% dose). PB significantly increased [14C]permethrin disposition in the stratum corneum (SC) in aqueous mixtures only (9.40 vs 3.35% dose), while topical DEET or topical DFP reduced [14C]permethrin levels in the SC especially in nonaqueous mixtures. PB also significantly enhanced [14C]permethrin penetration into all skin tissues and perfusate in aqueous mixtures, while DEET reversed this effect. PB appeared to influence [14C]permethrin disposition in flowthrough diffusion cells, suggesting that the mechanism of this interaction may be associated predominantly with epidermal permeability, although muscarinic effects in the vasculature in IPPSFs should not be ruled out and requires further investigation. These experiments suggest that intraarterial perfusion of PB and/or DFP and topical application of DFP or DEET can alter the disposition of [14C]permethrin in skin and possibly its bioavailability in soldiers simultaneously exposed to these chemicals.