Journal of Toxicology and Environmental Health, Part A, 66:133–151, 2003 Copyright© 2003 Taylor & Francis 1528-7394/03 $12.00 + .00 DOI: 10.1080/15287390390155796 133 PERCUTANEOUS ABSORPTION OF TOPICAL N,N-DIETHYL- m-TOLUAMIDE (DEET): EFFECTS OF EXPOSURE VARIABLES AND COADMINISTERED TOXICANTS Jim E. Riviere, Ronald E. Baynes, James D. Brooks, James L. Yeatts, Nancy A. Monteiro-Riviere Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, Raleigh, North Carolina, USA Exposure to N,N-diethyl-m-toluamide (DEET) commonly occurs in the general population and has been implicated as a contributory factor to the Gulf War Illness. The focus of the present studies was to determine the effect of coexposure factors, potentially encountered in a military environment, that could modulate transdermal flux of topically applied DEET. Factors investi- gated were vehicle, dose, coexposure to permethrin, low-level sulfur mustard, occlusion, and simultaneous systemic exposure to pyridostigmine bromide and the nerve agent simulant diiso- propylfluorophosphate (DFP). Studies were conducted using the isolated perfused porcine skin flap (IPPSF), with a few mechanistically oriented studies conducted using in vitro porcine skin and silastic membrane diffusion cells. DEET was quantitated using high-performance liquid chromatography. The vehicle-control transdermal DEET flux in the IPPSF was approximately 2 μ g/cm 2 /h for both 7.5 and 75% DEET concentrations, a value similar to that reported in humans. DEET absorption was enhanced by coinfusion of pyridostigmine bromide and DFP, by the presence of sulfur mustard, or by dosing under complete occlusion. The greatest increase in baseline flux was fivefold. In vitro diffusion cell studies indicated that silastic membranes had two orders of magnitude greater permeability than porcine skin, and showed vehicle effects on flux that were not detected in the IPPSF. These results suggest that coexposure to a number of chemicals that potentially could be encountered in a military environment may modulate the percutaneous absorption of topically applied DEET beyond that seen for normal vehicles at typically applied concentrations. The focus of research into the pathogenesis of the Gulf War Illness has focused on chemical and nonchemical factors that could result in the observed syndrome. Potential factors include repeated vaccinations, oil-well fires, sand, depleted uranium, stress, and exposure to chemicals; the primary candidates are the nerve agent sarin, the nerve agent prophylactic drug pyridostigmine bromide, the insecticide permethrin, and the insect repellent N,N-diethyl- m-toluamide (DEET) (Fulco et al., 2000; Jagannathan et al., 2000; Wessely, 2001). A great deal of research has focused on the potential interactions of pyridostigmine Received 11 March 2002; accepted 27 May 2002. This study was supported by USAMRMC grant DAMD-17-99C-9047. We thank all staff members of the Center for Chemical Toxicology Research and Pharmacokinetics for their technical contributions to this work. Address correspondence to Jim E. Riviere, Center for Chemical Toxicology Research and Pharmaco- kinetics, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA. E-mail:Jim_Riviere@ncsu.edu