Sulfur mustard distribution

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... 

J.L. Hambrook, D.J. Howells and C. Schock, Biological fate of sulfur mustard (l,l -thiobis(2-chloroethane)) uptake, distribution and retention of 35S in skin and in blood after cutaneous application of 35S-sulfur mustard in rat and comparison with human blood in vitro, Xenobiotica, 23, 537-561 (1993). 

Distribution studies of 35S-sulfur mustard in rats after cutaneous exposure to sulfur mustard, and human blood treated in vitro, showed that a small percentage of radioactivity remained associated with the hemoglobin and persisted for the lifetime of the... 

THIS CHAPTER contains a brief description of the methods used by toxicologists at Oak Ridge National Laboratory (ORNL) to derive the U.S. Army s interim reference doses (RfDs) for GA, GB, GD, VX, sulfur mustard, and lewisite. Those methods were based on the procedures outlined by the U.S. Enviromnental Protection Agency for Superfund risk assessment guidelines (EPA 1989) and for reference concentrations (EPA 1994). An alternative method, the benchmark-dose (BD) approach (Crump 1984) is also described. Because uncertainty factors are integral to both approaches, further consideration is also given to the statistical distribution and confidence associated with them. 

ORNL also considered calculating an SF on the basis of the U.S. Environmental Protection Agency s (EPA 1991) estimated inhalation unit risk (8.5 x 10 per pg/m ) of sulfur mustard. Normalizing the inhalation unit risk for a 70-kg person inhaling 20 m of air per day would yield an SF of 0.3 per pg/kg per day. ORNL decided not to use this method because the inhalation study (McNamara et al. 1975) used to estimate the inhalation unit risk resulted in rat skin tumors that appeared to be caused by dermal exposure rather than by systemic absorption and distribution to the skin, and inhalation-to-oral extrapolation was not considered appropriate. Furthermore, the McNamara et al. (1975) study contained a number of deficiencies, such as outdated testing protocols, brief exposures, and small numbers of animals, which made quantitative analysis difficult. 

The skin and eyes are especially sensitive to the toxic effects of sulfur mustard. When applied to human skin, about 80% of the dose evaporates and 20% is absorbed (Vogt et al., 1984). About 12% of the amount absorbed remains at the site and the remainder is distributed systemically (Renshaw, 1946). Doses up to 50 pg/ cm cause erythema, edema, and sometimes small vesicles. Doses of 50-150 pg/cm cause bullous-type vesicles, and larger doses cause necrosis and ulceration with peripheral vesication. Droplets of liquid sulfur mustard containing as little as 0.0025 mg may cause erythema (Ward et al., 1966). Eczematous sensitization reactions were reported in several early studies and may occur at concentrations below those causing direct primary irritation (Rosenblatt et al., 1975). In humans, the LCtso (estimated concentration x exposure period lethal to 50% of exposed individuals) for skin exposures is 10,000 mg-min/m (DA, 1974) (for masked personnel however, the amount of body surface area exposed was not reported). The ICt 50 (estimated concentration x exposure period incapacitating to 50% of exposed individuals) for skin exposures is 2000 mg-min/m at 70-80°F in a humid enviromnent and 1000 mg-min/m at 90°F in a dry enviromnent (DA, 1974, 1992). The ICtso for contact with the eyes is 200 mg-min/m (DA, 1974, 1992). The LDl for skin exposure is 64 mg/kg and the LD50 is estimated to be about 100 mg/kg (DA, 1974,1992). 

Watson and Griffin (1992) have summarized information on the distribution of unitary chemical weapon stockpiles in the USA. The chemical and physical properties of sulfur mustard (agent HD) are shown in Table 8.2. 

Amir, A., Kadar, T., Chapman, S., Turetz, J., Levy, A., Babin, M., Ricketts, K., Brozetti, J., Logan, T., Ross, M. (2003). The distribution kinetics of topical C-sulfur mustard in rabbit ocular tissues and the effect of acetylcysteine. J. Toxicol. 22 201-14. 

Obviously, these findings confirm the theoretical assumption that the lipophilic properties of sulfur mustard result in a distribution, primarily in lipophilic tissues. High concentrations found in the brain may also explain why the central nervous system is one of the organs exhibiting systemic effects of sulfur mustard poisoning, even though it is not a site of rapidly proliferating cells. 

More recent in vitro experiments, using human skin, have confirmed the presence of unhydrolyzed sulfur mustard in the lipophilic stratum comeum and the upper epidermis. Twenty-four hours post-exposure, the distribution ratio between the epidermis and the dermis has been determined at 62 to 38%. Ctulcott and colleagues (2000) also suggested that efforts to remove or neutralize the agent from these deposits might have a clinical benefit for the patient. 

Mustard gas is a substance used in chemical warfare. It is the popular name for the compound with the chemical designaticn l,l-thiobis(2-chloroethane) (chemical fonnula C1-CH2-CH2-S-CH2-CH2-C1). Mustard gas has a number of other names by which it has been known over the years, including H, yprite, sulfur mustard and Kampstcff Lost. Because the impure substance is said to have an odor similar to that of mustard, garlic or horseradish, the name mustard gas is most commonly applied. However, in the pure form, mustard gas has neither cdcr nor odor. The gas was used for the first time as an agent of chemical warfare during World War I, when it was distributed with devastating effect near Ypres in Flanders on July 12,1917. 

Jain and Wei (1977) developed a distributed parameter model for the distribution of small solutes (methotrexate and sulfur mustard) in vascularized tumors. The model included regional variations in vascular volume, surface area, and perfusion, and described the radial distribution of methotrexate and sulfur mustard as a function of time. The model showed... 

The skin and eyes are especially sensitive to the toxic effects of sulfur mustard. When applied to human skin, about 80% of the dose evaporates and 20% is absorbed (Vogt et al. 1984). Skin penetration is at a rate of about 1 ig cm" min at a temperature of 75 °F (Renshaw 1946). About 12% of the amount absorbed remains at the site and the remainder is distributed systemically (Renshaw 1946). Doses to 50 pg/cm cause erythema, edema, and sometimes small vesicles. Doses of 50-150 pg/cm cause bullous-type vesicles, and larger doses cause necrosis and ulceration with peripheral vesication. Droplets of liquid sul-... 

Axelrod, D.J., Hamilton, J.G., 1947. Radio-autographic studies of the distribution of lewisite and mustard gas in skin and eye tissues. Am. J. Pathol. 23,389-411. Bast, C., Young, R., McGinnis, P.M., et al., 2013. Provisional Advisory Level (PAL) development for Lewisite and sulfur mustard. Toxicologist 132 (1), 473. Boursnell, J.C., Cohen, J.A., Dixen, M., et al., 1946. Studies on mustard gas (2,2-dichlorodiethyl sulphide) and some related compounds. 5. The fate of injected mustard gas (containing radioactive sulphur) in the animal body. Biochem. J. 40, 756-764. 

Maisonneuve, A., Callebat, I., Debordes, L., et al, 1994. Distribution of (14C) sulfur mustard in rats after intravenous exposure. Toxicol. Appl. Pharmacol. 125, 281-287. 

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. 

Czerwinski et al., 2006). In the case of vesicant agents, such as sulfur mustard and lewisite, the skin is both a target organ, susceptible to severe local effects, and a pathway for absorption of the agent, leading to its distribution and subsequent systemic effects. The protective skin architecture is provided by a sophisticated and effective barrier built of two main components the outer epidermis and the underl3ung inner dermis. 

Benson et al. (2011) presented a respiratory exposure study using -labeled sulfur mustard. Anesthetized rats with transorally placed tracheal catheters were exposed to 250mg sulfur mustard vapor/m for lOmin. A total of 18.1 3pg sulfur mustard per animal was absorbed. Within 2h postexposme, inhaled sulfur mustard was distributed and more than 70% were deposited in the carcass and pelt. 

As mentioned previously, Benson et al. (2011) confirmed that 90% of percutaneously absorbed sulfur mustard was deposited in skin, whereas more than 70% absorbed sulfur mustard was distributed to the carcass and pelt after respiratory exposure. The distribution of sulfur mustard is highly dependent on the original route of exposure. It was confirmed that a considerable amoimt of sulfur mustard was still present in deep lipophilic compartments even after the end of exposure. 

Benson, J.M., Tibbetts, B.M., Weber, W.M., et al, 2011. Uptake, tissue distribution, and excretion of 14C-sulfur mustard vapor following inhalation in F344 rats and cutaneous exposure in hairless guinea pigs. J. Toxicol. Environ. Health A 74, 875-885. 

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. 

Benson et al. (2011) exposed F344 rats via a transorally placed tracheal catheter to ca. 250 mg m of C-sulfur mustard for 10 min, after which the radioactivity was measured in various tissues at several time points up to 7 days after ending the exposure. By exposing the animals in this way the absorption of sulfur mustard in the upper airways was circumvented. At 2 h after ending the exposure, more than 70% of the inhaled body burden was located in the carcass, pelt and intestines. The remainder of radioactivity was located in the liver, lungs and blood. Radioactivity in these tissues decreased with time, whereas that in the kidney increased up to 7 days after exposure. Since only radioactivity was measured and the identity of the radioactive species was not elucidated, it is unknown to what extent the distribution of intact sulfur mustard and/or its C-retaining metabolites was measured. 

Riviere et aL (1995) studied the toxicokinetics of topically administered C-sulfur mustard in their isolated perfused porcine skin flap (IPPSF) model to support the correlation between eritical steps in the vesication process and concentrations of the agent in different skin regions. About 90% of the radioactivity was not recovered due to evaporation of the agent from the skin. No attempts were made to avoid evaporation, since occlusion was not considered to be a realistic exposure condition. Absorption mainly occurred within the first hour after application, with the majority of the absorbed radioactive dose either in the skin or venous blood stream of the IPPSF. A large fraction of the measured radioactivity was probably not intact sulfur mustard however, the identity of the radioactive species was not established. A multicompartmental toxicokinetic model was developed to predict penetration into and distribution within the IPPSF. The authors report that sulfur mustard decreased the vascular volume of distribution in IPPSF in a dose dependent way, a phenomenon that should be incorporated into the toxicokinetic model. 

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