Sulfur mustard elimination

Another interesting reaction is cyclization with halide elimination. The case of formation of aziridinium rings from A-(2-chloroethyl) derivatives (nitrogen mustards) has been reviewed in Sect. 11.4.2, as was sulfur mustard. The remainder of this subsection is devoted to comparable reactions in which the product is not a strongly electrophilic aziridinium ion, but another ring type. 

The distribution and rate of elimination of sulfur mustard is partially dependent on the route of exposure and the dose received. Studies with radiolabeled (35S) agent showed that typically 50-80% of an absorbed dose is eliminated in urine, mostly within the first 3 days (2,3). Hambrook et al. (2) showed that >70% was excreted in urine following intravenous (i.v.) or intraperitoneal (i.p.) injection in rats, somewhat less (50-70 %) following cutaneous exposure to vapor. The lower percentage following cutaneous exposure resulted from retention in the... 

The metabolism of nerve agents is much simpler than that of sulfur mustard. The major pathway for elimination is via enzyme-mediated hydrolysis by esterases, plus some chemical hydrolysis, as shown in Figure 10. In the case of the methylphosphonofluoridates and V agents, the major product is an alkyl methylphosphonic acid (alkyl MPA) (16). A small fraction of the nerve agent binds... 

The effects of time, temperature, and humidity on the vapor penetration of HNl and HNS into the forearm skin of human male volunteers were reported by NDRC (1945). Results of this work showed similar effects of temperature and humidity as observed for sulfur mustard, e.g. greater absorption with increased temperature and humidity. The penetration of HN1 and HNS was found to be linear with time (5 to 20 min for HNl and SO-60 min for HNS). At 71-72°F and 50-52% relative humidity, HNl penetration rate was 2.8 pg/cm /min and for HNS was 0.18 pg/cm /min at 72-7S°F and 45-48% relative humidity. At 86-87°F and 47-49% relative humidify, HNl penetration rate increased to 5.2 pg/cm /min and HNS penetration rate increased to O.S pg/cm /min at 85°F and 47 8% relative humidity. Excretion via the urine is likely a major route of elimination, especially due to the water solubihty of the immonium ion (see seetion IV). 

A previous report has implicated a role of calpain in mediating the tissue injury caused by the chemical threat agent sulfur mustard. Specifically, tissue homogenates from mouse ear skin exposed to sulfur mustard displayed a marked increase in calpain activity (170% increase 24 h after treatment Powers et al. 2000). These findings underscore the need to identify effective antiproteases with therapeutic use in reducing, or eliminating, tissue injuries. Since excitotoxicity is related directly to calpain activation, it can be surmised that sulfur mustard exposures may be linked to excitotoxicity. 

In 1990, urine samples from an accidental laboratory exposure to sulfur mustard were obtained (Jakubowski et al., 2000). The erythematous and vesication areas of the individual were estimated to be less than 5% and 1%, respectively, of the total body surface area. The assay measured both free and conjugated TDG using GC-MS (Jakubowski et al., 1990). The maximum TDG urinary excretion rate was 20 (pg/day on day 3. TDG concentrations of 10 ng/mL or greater were observed in some samples for up to a week after the exposure. A first-order elimination was calculated from days 4 through 10 and found to be 1.2 days. A great deal of intraday variability was noted for the TDG urine concentrations. Attempts were made to estimate the total amount of sulfur mustard on the skin of the patient. The estimate was based on two assumptions (1) that the assay for the free and conjugated TDG represents approximately 5% of the total amount of sulfur mustard related products in the blood, and (2) that the bioavailability factor from skin to blood is 10. A total of 0.243 mg of TDG was recovered over a 2 week period. This would represent 4.86 mg in the blood or 48.6 mg on the skin. 

Analysis of Blood Samples. Urinary metabolites undergo relatively rapid elimination from the body, whereas blood components offer biomarkers that have the potential to be used for verification of sulfur mustard exposure long after the exposure incident. Three different approaches have been used for blood biomarker analysis. The intact macromolecule such as protein or DNA with the sulfur mustard adducts still attached can be analyzed. To date, this approach has only been demonstrated for hemoglobin using in vitro experiments. For proteins, an alternate approach is to enzymatically digest them to produce a smaller peptide with the sulfur mustard adduct still attached. Methods of this type have been developed for both hemoglobin and albumin. A third approach has been to cleave the sulfur mustard adduct from the macromolecule and analyze in a fashion similar to that used for free metabolites found in the urine. The later two approaches have both been successfully used to verify human exposure of sulfur mustard. 

Vesicants, including sulfur mustard and lewisite, are the subject of the second main part of this chapter. Coherences of invasion and distribution are presented, and the major processes of biotransformation and elimination caused by binding to proteins [and more prominently, to deoxyribonucleic acid (DNA)] are discussed. Finally, we make some comments about current bioanalytical approaches. This chapter provides readers with a comprehensive overview of tire toxicokinetics of OP nerve agents and vesicants. 

Zhang and Wu (1987) administered an iv dose of 10 mg kg bodyweight to the pig. The rationale behind this dose is not revealed in the paper. The concentration-time profile of sulfur mustard in the blood could be mathematically described as a three compartment model, with a very fast initial distribution phase and a rapid elimination half-life. The AUC is about 3 times higher in the pig than in the rat for the same dose. The ealeulated toxicoki-netic parameters are listed in Table 7.1. 

Zhang and Wu (1987) studied the toxicokinetics of sulfur mustard after sc administration of a dose of 200 mg kg to the pig. Concentrations in arterial blood (carotid artery) were measured up to 90 min after administration and were ca. 360 ng ml at maximum, around 25 min after administration of the agent. The measured concentration-time course could be fitted to a one compartment model with first-order absorption and elimination, see Figure 7.2. The toxicokinetic parameters calculated from the curve fitting equation are shown in Table 7.2. 

BREAKDOWN OF SULFUR MUSTARD BY PHASE TRANSFER CATALYSED HCl ELIMINATION... 

Breakdown of Sulfur Mustard by Phase Transfer Catalyzed HCl Elimination ... 

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