title: A spreadsheet-based method for estimating the skin disposition of volatile compounds: application to N,N-diethyl-m-toluamide (DEET).
abstract: The disposition of N,N-diethyl-3-methylbenzamide (DEET) applied to split-thickness human cadaver skin was measured in modified Franz cells maintained at 32 degrees C and fitted with a vapor trap. Ethanolic solutions of DEET (1% w/w) spiked with (14)C radiolabel were applied to skin at a dose of 10 microL per cell, corresponding to a DEET dose of 127 microg/cm(2). Room air was drawn over the skin at velocities ranging from 10-100 mL/min. Evaporation of radiolabel from the skin surface and absorption into the receptor solution were monitored for 24 hr post-dose. The percentage of radioactivity collected in the vapor trap after 24 hr increased with airflow, ranging from 16 +/- 4% at 10 mL/min to 59 +/- 7% at 70 mL/min. The percentage of radioactivity absorbed through the skin after 24 hours decreased with increasing airflow, ranging from 69 +/- 7% at 10 mL/min to 20 +/- 1% at 80 mL/min. Tissue retention after 24 hr was 6-14% of the radioactive dose with no clear correlation to airflow. This data as well as DEET absorption data from two previous in vitro studies in which dose and location (fume hood or bench top) was varied were analyzed in terms of a recently developed diffusion/evaporation model for skin implemented on an Excel spreadsheet. A priori model calculations based on independently estimated transport parameters (Model 1) were compared with calculations based on fitted parameters (Models 2 and 3). The analysis of the combined dataset (n = 272 observations) showed that the Model 1 estimates matched the cumulative disposition profiles to within a root mean square error of 12.4% of the applied dose (r(2) = 0.65), whereas the Model 2 and Model 3 fits matched to within 9.4% (r(2) = 0.80) and 6.5% (r(2) = 0.91), respectively. The Model 3 fits were obtained using a concentration-dependent diffusivity of DEET in the stratum corneum, the value of which increased 3.4-fold between low concentrations and saturation. This result was consistent with the mild skin penetration enhancement effect for DEET reported elsewhere. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a word document containing tables and figures including more information on the spreadsheet skin absorption model.]
authors.affiliation: James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, Cincinnati, Ohio 45267-0004, USA. gerald.kasting@uc.edu
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Kasting
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Miller
authors.forename: Varsha D
authors.initials: VD
authors.lastname: Bhatt
mesh_terms: D000392:Air Movements; D002250:Carbon Radioisotopes; D003671:DEET / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007302:Insect Repellents / Q000493:pharmacokinetics*; D008954:Models, Biological; D016273:Occupational Exposure; D011485:Protein Binding; D012869:Skin Absorption
chemical_list: D002250:Carbon Radioisotopes; D007302:Insect Repellents; D003671:DEET