Site‐specific percutaneous absorption of methyl salicylate and VX in domestic swine

Abstract

The site specificity of the percutaneous absorption of methyl salicylate (MeS) and the organophosphate nerve agent VX (O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate) was examined in anaesthetized domestic swine that were fully instrumented for physiological endpoints. Four different anatomical sites (ear, perineum, inguinal crease and epigastrium) were exposed to the MeS and the serum levels were measured over a 6-h time period. The dose absorbed at the ear region was 11 microg cm(-2) with an initial flux of 0.063 microg cm(-2)min(-1), whereas at the epigastrium region the dose absorbed was 3 microg cm(-2) with an initial flux of 0.025 microg cm(-2)min(-1). For this reason further studies were carried out with VX on the ear and the epigastrium only. In animals treated with agent on the epigastrium, blood cholinesterase (ChE) activity began to drop 90 min after application and continued to decline at a constant rate for the remainder of the experiment to ca. 25% of awake control activity. At this time there were negligible signs of poisoning and the medical prognosis was judged to be good. In contrast, the ChE activity in animals receiving VX on the ear decreased to 25% of awake control values within 45 min and levelled out at 5-6% by 120 min. Clinical signs of VX poisoning paralleled the ChE inhibition, progressing in severity over the duration of the exposure. It was judged that these animals would not survive. The dramatic site dependence of agent absorption leading to vastly different toxicological endpoints demonstrated in this model system has important ramifications for chemical protective suit development, threat assessment, medical countermeasures and contamination control protocols.

Evaluation of Chemical Warfare Agent Percutaneous Vapor Toxicity: Derivation of Toxicity Guidelines for Assessing Chemical Protective Ensembles.

“…Please note that the studies of Riviere et al (2001) and Duncan et al (2002) were performed in the years following publication of NRC/BAST (1997), and members of the Standing Committee would not have had access to these more recent data comparing MeS and agent absorption through the skin of swine.…”

“…The Craig et al (1977) study also provided evidence that the skin can act as a storage depot for VX, with agent transfer from this depot promoted by increasing ambient temperature. Duncan et al (2002) have performed in vivo regional variation studies of liquid VX absorption on specific skin sites of domestic swine, a species with skin permeability similar to that of humans (Bartek et al 1972;Dick and Scott 1991). Agent VX absorption was estimated by determination of blood cholinesterase (ChE) activity measured at various times post-exposure and expressed as a percentage of the control ChE activity.…”

“…"Dramatic" site dependence was displayed in the rates and levels of ChE inhibition following same-dose topical application to skin of the ear or epigastrium. Of the two sites compared, the skin of the ear is far more permeable and allows a larger systemic dose to be delivered over a shorter time period (Duncan et al 2002). The Duncan et al (2001) work demonstrates that the total effective systemic dose is the collective result of independent exposures and consequent absorption from separate body regions through a process such as described by body region hazard analysis (please see NRC/BAST 1997 for background information on body region hazard analysis).…”

“…Further, its rapid hydrolysis and metabolism to salicylic acid and derivatives in the body of mammals allows ready monitoring of MeS in blood serum as a measure of systemic absorption (Duncan et al 2002). Recent studies comparing percutaneous absorption and skin deposition of HD to MeS in the isolated perfused porcine skin flap has determined that the cutaneous disposition of HD and MeS are very similar (Riviere et al 2001).…”

“…The Riviere et al (2001) work demonstrates that MeS simulates the HD dose acquisition process and strongly supports the use of MeS as a dermal simulant for agent HD exposure and hazard assessment. Topical application of MeS to 4 skin sites (skin of the ear, perineum, inguinal crease, epigastrium) on the domestic pig have identified the following rank order for MeS permeation: ear > perineum > inguinal crease ³ epigastrium (Duncan et al 2002). It is reasonable to consider the rank order of permeation would be similar for agent HD in contact with these same skin sites on the human body.…”