Veterans at Risk The Health Effects of Mustard Gas and Lewisite (1993) / Chapter Skim
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9 Dermatological Effects of Mustard Agents and Lewisite
9 Dermatological Effects of Mustard Agents and Lewisite
Pages 148-178
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From page 148... ...
Evidence also links sulfur mustard with the development of cutaneous cancers and precancers in both animals and humans. There is insufficient information, however, regarding the long-term effects of Lewisite on the skin.
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From page 149... ...
~ S: i ~ ~~:-~ -., ~,~ . ~ ,: ~.J~iS.~.~ FIGURE 9 - 1 Anatomy of human skin showing skin layers, hair follicles, sebaceous and sweat glands.
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From page 150... ...
Basal cells produce large quantities of the nucleic acids and nucleoproteins required in the process of cell division.
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From page 151... ...
Sulfur mustard inhibits cell replication within the basal layer of the epidermis and thus disrupts this pattern, resulting in blister formation. Basal cells of the epidermis are attached to the dermis through the basal lamina, which is often referred to as the basement membrane zone, or epidermal-dermal junction (Figure 9-3~.
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From page 152... ...
Unlimited or unrestrained wound healing results in the formation of hypertrophic scars and keloids. Wound infection, which may follow skin injury from sulfur mustard exposure, can cause continued and uncontrolled stimulation of collagen production and ultimately hypertrophic scar and keloid formation.
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From page 153... ...
Profuse sweat contains considerably less of these substances, including sodium chloride, and is often pure water. Sulfur mustard is activated by water, yet in the presence of 5 percent sodium chloride it has a markedly reduced effect on human skin (Renshaw, 1946~.
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From page 154... ...
Subsequent to sulfur mustard skin injury, the large numbers of gram-negative bacteria residing in apocrine areas are often responsible for secondary bacterial infections. Infection, as stated earlier, is frequently associated with hypertrophic scar formation, a common occurrence in the scrotal area of men after sulfur mustard exposure.
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From page 155... ...
A cascade of biochemical-reactions produces melanin, which protects epidermal cells from damage from the sun.
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From page 156... ...
Based on clinical descriptions of individuals exposed to toxic doses of sulfur mustard, sulfur mustard can also potentiate skin pigmentation. Topical nitrogen mustard, when applied to the skin in the treatment of psoriasis and cutaneous T-cell lymphoma, causes increased skin pigmentation through mechanisms that are as yet unknown.
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From page 157... ...
However, even under the most ideal circumstances, only a very small portion, probably only 20 percent, of a single dose of sulfur mustard penetrates human skin (Cullumbine, 1947; Renshaw, 1946~. Of this amount, about 12 percent reacts with components in the skin, principally within the epidermis.
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From page 158... ...
Increased environmental temperature may simply increase body temperature, stimulating eccrine sweat gland activity and a concomitant increase in hydration of the skin. It is also possible that profuse sweating and a concomitant increase in the amount of pure water on the skin cause activation of greater quantities of sulfur mustard at the site.
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From page 159... ...
Clinical and Microscopic Observations The most useful clinical descriptions of acute sulfur mustard effects on human skin have been reported by Moment and colleagues (1992) , Smith and Dunn (1991)
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From page 160... ...
These changes are probably confined principally to basal cells of the epidermis, because basal cells are the most active metabolic cells, actively and continuously synthesizing nucleic acids and nucleoproteins that are vital for cell growth and division. Antineoplastic agents such as sulfur mustard and nitrogen mustard derivatives exert their most prominent cytotoxic effects on cells that are actively producing large quantities of nucleic acids and nucleoproteins in preparation for cell division.
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From page 161... ...
Unlike lower mammalian species, dermal injury in human skin is not often as extensive as epidermal (Renshaw, 1946~. During the early erythema and edema stages of skin injury, dilatation of papillary dermal capillaries, thickening of the capillary wall, and endothelial cell swelling are noted.
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From page 162... ...
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~.
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From page 163... ...
have uncovered evidence that alkylation of DNA, reduced tissue levels of oxidized nicotinamide adenine dinucleotide (NAD+) , and activation of cellular proteases may account for sulfur mustardinduced blister formation in human skin.
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From page 164... ...
, using primary cultures of newborn rat epidermal cells. DNA cross-linking in sulfur mustardexposed cells was seen at 5 mM sulfur mustard, but not at a lower dose of 2.5 mM sulfur mustard.
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From page 165... ...
The LD50 often quoted for liquid Lewisite is considered low by many investigators (Goldman and Dacre, 1989~. Less is known about Lewisite than sulfur mustard penetration through human skin.
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From page 166... ...
Studies in the human skin-grafted nude mouse system suggest that epidermal-dermal necrosis precedes epidermal-dermal separation. It is assumed that upon entry of Lewisite into the aqueous medium of the intact skin it is rapidly hydrolyzed to a stable, water-soluble, but highly toxic derivative 2-chlorovinylarsine oxide (Lewisite oxide)
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From page 167... ...
I:ong-term exposure to sulfur mustard vapor also produced squamous cell and basal cell cancers in rats. These experiments, although crude, suggest that similar acute and chronic exposure in humans may be carcinogenic.
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From page 168... ...
The occurrence of skin cancers at the site of old scar formation is an acknowledged biological phenomenon (Novick et al., 1977; Treves and Pack, 1930~. It appears that cutaneous cancers following acute sulfur mustard exposure usually localize in cutaneous scars, whereas those following chronic exposure can occur on any exposed site (Inada et al., 1978~.
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From page 169... ...
Although an adequate control population was not simultaneously studied, 77 workers who were engaged in clerical and guard duty at the same facility, did not develop evidence of long- or short-term defects. The principal drawback to assigning a cause and effect relationship solely to sulfur mustard exposure at this facility may be found in the background comments: before 1937, workers whose tasks were limited to the production of "war gases" worked in the manufacture of gases of all types, including mustard gas and Lewisite (Wade et al., 1962~.
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From page 170... ...
, in a prospective study of delayed toxic effects, has followed a cohort of Iranian solders exposed to mustard gas during the Iran-Iraq war. After two years of observation, 41 percent of the exposed victims are experiencing pigmentary disorders.
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From page 171... ...
Epidemiologic studies have clearly demonstrated a real association between chronic adverse reactions and occupational exposure to inorganic arsenic in pesticides, herbicides, fungicides, and animal disinfectants, and in smelter workers. In medicine, preparations such as Fowler's solution, asiatic pills, and Donovan's solution that contain trivalent elemental arsenic have been associated with long-term effects including dermatitis, hyperpigmentation, loss of hair, disseminated cutaneous keratoses, palmer hyperkeratosis, and cutaneous cancer, including basal cell, squamous cell, and Bowen's intraepidermal squamous cell cancer.
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From page 172... ...
Arsenic may produce keratoses (keratinized protuberances of skin, particularly on the palms and soles) , squamous cell cancer, basal cell cancer, multicentric intraepithelial basal cell carcinoma, and Bowen's intraepidermal squamous cell cancer.
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From page 173... ...
In individuals exposed to inorganic arsenicals through this route, all of the adverse reactions described earlier have been seen. Cutaneous cancers, basal cell, squamous cell, and Bowen's disease have been well described in these populations.
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From page 174... ...
To our knowledge, the only prospective study of long-term cutaneous effects of acute sulfur mustard exposure on human skin is that of Balali (1986~. This study is now in its fourth or fifth year and should provide very valuable information in 1~20 years.
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From page 175... ...
Conclusions Despite the many years that the problem of acute sulfur mustard toxicity to human skin has been known and observed, its long-term effects after acute and chronic exposure remain obscure. Unfortunately, large volumes of pertinent literature on experimental studies of human exposure remain obscure or destroyed.
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From page 176... ...
1978. Multiple Bowen's disease observed in former workers of a poison gas factory in Japan with spenal reference to mustard gas exposure.
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From page 177... ...
1987. Histologic changes in nude mouse skin and human skin xenografts following exposure to sulfhydryl reagents: arsenicals.
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From page 178... ...
1947. Observations on the role of water in the susceptibility of human skin to vesicant injury.
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