Vesicants distribution

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). 

Vesicants including sulfin" mustard and lewisite are the subject of the second main part of this contribution. Coherences of invasion and distribution are presented and the major processes of metabolism and elimination caused by binding to proteins and more prominently to DNA are discussed. The part closes with comments on current bioanalytical approaches. 

The herb Cleome viscosa (syn. cleome icosandra)y which is widely distributed in India, has long been recognized by the native population to serve as a rubefaciant, vesicant, and anthelmintic agent. As a consequence of these reputed properties, three research groups undertook almost simultaneously in the late 1970 s to determine the principal active constituent of this sticky, odoriferous plant [82,83]. On the basis of the NMR, X-ray, and CD data, the substance was determined to be the macrocyclic diterpene lactone 160 and named cleomeolide. The structural features of this macrolide are unusual in several respects (a) the double bond positioned a,p to the lactone carbonyl resides at a bridgehead site, a... 

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-... 

Such exposure events that lead to poison uptake and its distribution in an organism are part of the invasion process, whereas all steps causing a decrease in poison (e.g., elimination by degradation, biotransformation, and excretion) are part of the evasion process. For a better understanding of the pathophysiology and toxicokinetics of CWAs, an overview of the routes of poison incorporation is given in the next section, with a special emphasis on 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. 

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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