title: Percutaneous penetration and distribution of VX using in vitro pig or human excised skin validation of demeton-S-methyl as adequate simulant for VX skin permeation investigations.
abstract: The organophosphorus (OP) chemical warfare V agent O-ethyl-S-[2(di-isopropylamino)ethyl] methyl phosphonothioate (VX), is a highly toxic compound which mainly penetrates the body via percutaneous pathways. Hence, the following prerequisite: to ascertain compound absorption and percutaneous profile distribution with a view to further assessing the efficacy of topical skin protectants. We first selected the most appropriate receptor fluid to carry out in vitro VX absorption experiments, namely: Hanks's Balanced Salt Solution (HBSS). After a 24-h topical exposure time lapse, we measured altogether the percentage of applied dose unabsorbed and absorbed, penetration rate, lag time, permeability coefficient (K(p)), and dose of VXeq present in skin. To such an end, we used full-thickness and split-thickness pig-ear or human abdominal skin membranes. Further, we scrutinised the potential use of two specific molecules as suitable surrogates for VX percutaneous penetration analyses: thus, we compared the present VX toxicokinetic parameters to earlier findings from our research unit, with respect to OP insecticides demethon-S-methyl (DSM) and paraoxon (POX). Within the framework of our study, we wish to highlight the following evidence: (a) pig-ear skin proves a relevant model to predict in vitro human abdominal skin, taking into account a 2-fold higher skin permeability to VXeq; (b) both full or split-thickness skin membranes may be used indiscriminately to gauge penetration rate and absorbed dose; (c) DSM applied on full-thickness pig-ear skin is the most relevant model to mimic the in vitro VX absorption through full-thickness skin model.
authors.affiliation: Department of Toxicology, Centre de Recherche du Service de Santé des Armées, 38702 La Tronche cedex, France. vvallet@crssa.net
authors.forename: V
authors.initials: V
authors.lastname: Vallet
authors.forename: C
authors.initials: C
authors.lastname: Cruz
authors.forename: J
authors.initials: J
authors.lastname: Licausi
authors.forename: A
authors.initials: A
authors.lastname: Bazire
authors.forename: G
authors.initials: G
authors.lastname: Lallement
authors.forename: I
authors.initials: I
authors.lastname: Boudry
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000493:pharmacokinetics*; D008875:Middle Aged; D063086:Organothiophosphates / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000493:pharmacokinetics*; D010261:Paraoxon / Q000493:pharmacokinetics*; D010539:Permeability / Q000187:drug effects; D012869:Skin Absorption / Q000187:drug effects*; D013552:Swine
chemical_list: D002619:Chemical Warfare Agents; D007306:Insecticides; D063086:Organothiophosphates; D009946:Organothiophosphorus Compounds; D010261:Paraoxon; C009680:VX-agent; C030064:demeton-S-methyl