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vesicles show signs of necrosis. Capillary thrombosis and disruption of capillary wall integrity do not occur until there is evidence of dermal necrosis. Inflammation is increased in the presence of vesiculation and, in fact, may become quite extensive throughout the papillary and reticular dermis. Mononuclear and polymorphonuclear leukocytes appear equally prominent in the presence of epidermal and dermal necrosis. Langerhans cells appear to migrate from the epidermis and collect in clusters at the dermal-epidermal junction.

Fibroblasts, cells that are principally engaged in collagen formation and are basically resting cells in the absence of tissue injury, appear to experience some injury even during the erythematous stage. Pyknosis of the nuclei of fibroblasts becomes prominent and increases as local tissues enter the stage of epidermal and dermal necrosis. Collagen bundles appear not to be affected by injury, retaining a fairly normal morphologic appearance through, and up to, the appearance of blisters.

Mechanisms of Skin Injury

Our ability to explain or understand the mechanisms that lead to sulfur mustard injury in human skin has been encumbered by the lack of an appropriate animal model system. There are no animals in which it has been possible to reproduce, in its entirety, the effects of sulfur mustard on human skin (Mitcheltree et al., 1989; Renshaw, 1946). Numerous investigators using rabbits, pigs, cows, rats, mice, and guinea pigs, both normal and hairless varieties, have made attempts to replicate sulfur mustard human skin injury. Some gross and microscopic similarities to human skin responses have been noted in a few animal species, but for as-yet-undiscovered anatomical and physiological reasons human and animal injury differ to a significant degree. Sulfur mustard penetration of mammalian skin, other than human, occurs rapidly and to fairly deep levels. For a given dosage, higher dermal concentrations are achieved in nonhuman mammalian skin, and hence more profound tissue damage is noted in the dermis rather than epidermis. Injuries to animal skin develop and heal more rapidly than injuries to human skin, despite the same degree and severity of injury. Microblisters rather than macroblisters characteristically appear in the skin of all laboratory species tested. This response seems to occur at all effective dosage levels. The lack of a suitable animal model has also severely limited research directed toward the development of potential prophylactic or treatment agents.

To date, in vitro studies using primary cultures of newborn rat epidermal keratinocytes, or human skin grafts placed on athymic nude mice, have provided the largest body of useful information relative to sulfur mustard toxicity in skin (Papirmeister et al., 1991). These studies

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