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PubMed1984

Pathogenesis of skin lesions caused by sulfur mustard.

Sulfur mustard (SM) (di-2-chlorethyl sulfide), used for chemical warfare in World War I, is a highly reactive radiomimetic alkylating agent. When applied to the skin of rabbits and guinea pigs, it produced vascular leakage, leukocyte infiltration, and slow death of basal epidermal cells. Thirty to sixty minutes after exposure to SM, injury to the superficial microvasculature (beneath the SM application site) was detected by measuring vascular leakage with Evans blue dye and also with horseradish peroxidase. At this same time, injury to the superficial fibroblasts was observed ultrastructurally; and an unexpectedly high percentage of basophils was found among the early infiltrating granulocytes. At 2 to 4 hr, the vascular leakage ceased, and had resumed by 8 hr in a more diffuse form. At this time, the basal epidermal cells showed pyknotic nuclei, an increase in their lysosomal enzymes (observed histochemically), and autophagic vacuoles (observed ultrastructurally). Leukocyte infiltration was marked, consisting mostly of heterophils (PMN) with a reduced percentage of basophils. During the next 24 to 72 hr, the entire inflammatory reaction reached its peak; and a superficial, crust-covered ulcer developed. Then, over the next 10 days, the lesion gradually subsided with concomitant repair and healing. Glucocorticosteroids decreased the early edematous phase, but did not affect the rate of healing. These findings suggest that the skin response to sulfur mustard has an immediate and a delayed phase. The immediate phase, i.e., within the first hour, was characterized by injury to the superficial fibroblasts and to the endothelium of superficial capillaries and venules, possibly because of direct damage to their cell membranes. At this time, a restricted vascular leakage and a selective granulocyte infiltration containing many basophils occurred. The delayed phase, which became evident after 8 hr, was characterized by the death of basal epidermal cells, probably because of DNA damage. This phase was accompanied by generalized vascular leakage, by massive heterophil immigration, and eventually by ulceration.

Acid Phosphatase↗
PubMed1989

Sulfur mustard as a carcinogen: application of relative potency analysis to the chemical warfare agents H, HD, and HT.

A relative potency method for assessing potential human health effects from exposures to relatively untested chemicals is presented and documented. The need for such a method in evaluating the carcinogenic potential of the chemical warfare agent sulfur mustard (agent HD) from a limited data base is specifically addressed. The best-estimate potency factor for sulfur mustard relative to benzo[a]pyrene is 1.3, with an interquartile range of 0.6 to 2.9. The method is applied to (1) the estimated fence-boundary air concentrations of mustard during operation of a proposed agent incinerator at Aberdeen Proving Ground (APG), Maryland, and (2) the current approved general population exposure level of 1 X 10(-4) mg HD/m3 and the occupational exposure level of 3 X 10(-3) mg HD/m3. Maximum estimates of excess lifetime cancer risk for individuals at sites along the APG boundary range between 3 X 10(-8) and 1 X 10(-7). Lifetime cancer risk estimates less than or equal to 10(-6) are not now regulated by the U.S. Environmental Protection Agency or the Food and Drug Administration. Maximum estimates of excess lifetime cancer risk assuming daily exposure to the approved standards during the proposed 5 years of incinerator operation are on the order of 10(-5) for the general public and 10(-4) for the worker population. These values are considered upper limit estimates.

Animals↗
PubMed1989

Response of mouse brain to a single subcutaneous injection of the monofunctional sulfur mustard, butyl 2-chloroethyl sulfide (BCS)*.

Exposure to mustard-type vesicants results in alkylation of DNA and vesication. However, the biochemical mechanism for vesicant injury and whether it is localized or diffuse are not clear. We postulated that vesicant damage is mediated by free radicals, resulting in oxidative stress. These free radicals-mediated reactions may propagate systemically distal to the site of exposure. To test this hypothesis, we examined the effects of a single subcutaneous injection of the monofunctional sulfur mustard, butyl 2-chloroethyl sulfide (BCS), on the brain. We injected 3 groups (6 mice/group) of 5-month-old male, athymic, nude mice, weighing 30-35 g, subcutaneously with neat (undiluted) BCS (5 microliters/mouse). After 1, 24, and 48 h, we sacrificed the treated mice along with an untreated control group and analyzed the brains for biochemical markers of oxidative stress. Compared to untreated controls, the activity of glutathione peroxidase increased by 76%, P less than 0.005 at 24 h, and that of glutathione S-transferases by 25-37%, P less than 0.05 over the entire period. Total glutathione content in the brain was significantly lower, 17%, after 1 h and 23% after 24 h. We found also, concomitant with decreased glutathione, almost a 3-fold increase in susceptibility to lipid peroxidation. Because these changes are consistent with oxidative stress, we conclude that the effect of BCS administered subcutaneously may be translocated, reaching mouse brain, and causing oxidative stress.

Animals↗
PubMed1987

2,2'-Dichlorodiethyl sulfide (sulfur mustard) decreases NAD+ levels in human leukocytes.

2,2'-Dichlorodiethyl sulfide (sulfur mustard, HD) extensively alkylates DNA in a concentration-dependent manner in many cell types. We have proposed a biochemical hypothesis that explains HD-induced injury by linking DNA alkylation and DNA breaks with activation of poly(ADP-ribose) polymerase, resulting in depletion of cellular NAD+. This hypothesis was tested by treating human leukocytes with HD to determine whether NAD+ depletion occurred as predicted. These cells demonstrated a decrease in NAD+ levels which was dependent on both concentration of HD and time after exposure. Inhibitors of poly(ADP-ribose) polymerase or substrates for NAD+ synthesis were able to prevent the HD-induced NAD+ decrease.

Granulocytes↗
PubMedDate not supplied

Detection of mustard gas bis(2-chloroethyl)-sulfide in urine.

Extraction procedure and detection of bis(2-chloroethyl)sulfide from urine samples of two patients are described using gas chromatography-mass spectrometry. Concentrations are found in the low ppb-range. The result is discussed in connection with the reactivity of this substance and the corresponding metabolites.

Chemical Warfare↗
PubMed2002

Influence of sex on reflex jaw muscle activity evoked from the rat temporomandibular joint.

Injection of glutamate into the rat temporomandibular joint (TMJ) evoked a concentration-dependent increase in jaw muscle activity. We investigated whether there are sex-related differences in glutamate-evoked jaw muscle activity that are mediated by sex hormones and whether prior injection of glutamate into the TMJ alters the magnitude of jaw muscle activity evoked by a subsequent injection of the algesic and inflammatory compound mustard oil (MO) into the TMJ. The magnitude of glutamate-evoked digastric and masseter muscle activity was significantly greater in female than male rats when 1000 mM glutamate was injected into the TMJ. Gonadectomy significantly reduced the magnitude of glutamate-evoked digastric muscle activity in female rats. Treatment of gonadectomized female rats with estrogen (20 microg/day) increased the magnitude of glutamate-evoked digastric muscle activity. Glutamate-evoked jaw muscle activity in gonadectomized and estrogen-treated gonadectomized males was not significantly different from intact males. Prior injection of glutamate over a concentration range of 10-1000 mM significantly increased digastric muscle activity evoked by MO injection into the TMJ 30 min later. In contrast, MO-evoked masseter muscle activity was significantly increased by prior injection of 250 mM glutamate only. There were, however, no sex-related differences in the enhancement of MO-evoked jaw muscle activity by prior injection of glutamate. These findings indicate that there are sex-related differences in glutamate-evoked jaw muscle activity that are dependent on female sex hormones, and increased glutamate concentrations sensitize the TMJ to noxious chemical stimuli.

Animals↗
PubMed1988

Thin-layer chromatography of mustard and its metabolites.

Since its recently alleged use in the Middle East armed conflict, the chemical agent mustard has been in the news. Exposure to mustard causes extremely painful physiological manifestations. On entering the biological system, it is metabolized and converted into various products. This paper describes a rapid screening method for the identification of some of its common metabolites.

Biotransformation↗
PubMed1988

Chemical warfare. Cutaneous lesions from mustard gas.

Cutaneous lesions of eight patients evacuated from the Iran-Iraq war zone are reported. The patients were exposed to mustard gas, and there was a spectrum of dermatologic lesions. In the mild cases only there was a sunburnlike erythema, but in the most severe cases this erythema was followed by large and disseminated bullae, which histologically showed a subepidermal location with full-thickness epidermal necrosis. The resorption of these blisters was followed by hyperpigmentation, which was more evident in the intertriginous areas. In these last cases there also were ocular, respiratory, and gastrointestinal manifestations. In the skin this mustard gas seems to act through a primary irritant mechanism and without allergic contact sensitization.

Adolescent↗
PubMed1975

[Carcinogenesis due to mustard gas exposure in man, important sign for therapy with alkylating agents].

Sulphur-mustard and nitrogen-mustard are known to act as carcinogens in animal experiments. A similar effect in humans was demonstrated in 245 workers previously exposed occupationally to mustard gas and followed for over 20 years. There was a statistically significant increase in malignant tumours, especially bronchial carcinoma, bladder carcinoma and leukaemia. These findings underline the need for using alkylating agents of the mustard type exclusively in the treatment of malignant neoplasms. Immunosuppression with alkylating agents in the treatment of chronic inflammatory diseases associated with a long life expectancy is no longer justified.

Adult↗
PubMed1987

[Lung parenchymatous changes following mustard gas poisoning].

The authors present a late sequel of poisoning with dichlorodiethyl sulphide, also known as mustard gas or Ypérite, in a patient of 22 years of age--a late sequel not described in the literature to date. After the poisoning, a severe pulmonary fibrosis with pulmonary artery hypertension developed. A mediastinal emphysema that had so far been observed only during the acute intoxication phase, was evident even two years after the intoxication. Perivascular collections of air in the left lung communicating via the left hilus with the mediastinal air point to the existence of bronchus or lung parenchyma fistulas.

Adult↗
PubMed1988

Macromolecular metabolism of a differentiated rat keratinocyte culture system following exposure to sulfur mustard.

A method for producing a stratified, squamous epithelium in vitro by cultivating rat keratinocytes on nylon membranes has been developed in this laboratory. This epidermal-like culture is being used to obtain a better understanding of the mechanism of skin vesication after topical exposure to the sulfur mustard bis(beta-chloroethyl) sulfide (BCES) dissolved in a selected solvent. Radiolabeled macromolecular precursors (thymidine, uridine, and leucine) have been used to study the effect of BCES on the synthesis of DNA, RNA, and protein, respectively, after topical exposure to the mustard at concentrations of 0.01-500 nmol/cm2 dissolved in 70% dimethyl sulfoxide (DMSO). From these and other studies it has been determined that exposure to even the low concentration of 0.01 nmol BCES/cm2 for 30 min results in significant inhibition of [3H]thymidine incorporation, although complete recovery occurs by 24 h. Significant inhibition of [3H]uridine and [14C]leucine incorporation is observed only after exposure to much higher concentrations of BCES (10-500 nmol/cm2). This suggests a very early lesion in macromolecular metabolism with DNA being the primary target.

Animals↗
PubMed1989

Pretreatment of primary rat cutaneous epidermal keratinocyte culture with a low concentration of MNNG: effect on DNA cross-linking measured in situ after challenge with bis-2-chloroethyl sulfide.

Bis-2-chloroethyl sulfide- (BCES-) induced DNA cross-links in confluent, primary cultures of newborn rat cutaneous epidermal keratinocytes were detected using an assay that includes in situ unwinding of the DNA followed by separation of single-stranded DNA and double-stranded DNA (DSDNA) with hydroxylapatite. DNA cross-links in BCES-challenged cultures were inferred from increases in the percentage of DNA that remained double-stranded, compared with control cultures, after a 60-min alkaline unwinding incubation. The amount of DNA cross-linking after 5 or 10 microM BCES was increased when keratinocytes were first pretreated with 0.05 microM MNNG for 1 h at 8 a.m., 2 p.m., and 8 p.m. for two consecutive days and challenged with BCES the following morning. This increase was statistically significant (p less than .05, by ANOVA). For example, after 5 microM BCES challenge, cultures not pretreated with MNNG had 114.14% control DSDNA, whereas MNNG pretreated cultures had 122.78% control DSDNA. The level of BCES-induced cross-linking was maximal immediately after 30-min challenge and decreased during postchallenge incubation. At 24 and 48 h post 5, 10, or 20 microM BCES challenge, the level of DSDNA was actually depressed below unchallenged levels. This postchallenge decrease in the level of DSDNA, indicative of SSB in DNA, suggests repair activity by glycosylases and endonucleases. However, completion of repair (i.e., a return to control levels of DSDNA) was not seen in these experiments. The activity that resulted in decreases in the level of DSDNA during postchallenge incubation response was unaffected by MNNG pretreatment.

Animals↗
PubMed1989

A method for correlating skin exposure to S-mustard vapor with skin damage.

An experimental procedure is described as a means for assessing the efficiency of skin-protecting measures against the vapors of hazardous substances. Bis(2-chloroethyl)sulfide (S-mustard) is used as the test substance. A continuous flow of S-mustard vapor is conducted through an exposure cell which is attached to the inner side of a rabbit's ear. From the difference in the concentrations measured before and behind the exposure cell, the absorption and the permeation rate of mustard into the skin is calculated. The skin damage, consisting of a reversible erythema, is quantified by measuring the optical transmittance of the exposed skin area during the following days and correlated with the respective absorption (dose) and exposure parameters (ct-product, with c = 3-50 ng/cm3 and t = 60 and 120 min). Reversible, i.e., completely healing, erythema are evoked by ct-products in the range of 250-2000 ng.min/cm3 corresponding to doses from about 0.1 to 1.1 micrograms/cm2. A comparison with older data reveals that human skin, in this respect, is about eight times more sensitive than the inner side of the rabbit's ear.

Animals↗
PubMed1989

Release of chloroethyl ethyl sulfide-modified DNA bases by bacterial 3-methyladenine-DNA glycosylases I and II.

Treatment with chloroethyl ethyl sulfide introduces the following modified bases into DNA: 7-ethylthioethylguanine, 3-ethylthioethyladenine, and O6-ethylthioethylguanine. Using the ethylthioethylated bases as models for DNA modifications involving relatively bulky alkyl groups, we have investigated the release of these bases by Escherichia coli 3-methyladenine-DNA glycosylases I and II. 3-Methyladenine-DNA glycosylase I releases only 3-ethylthioethyladenine from chloroethyl ethyl sulfide-modified DNA, but does so at a rate which exceeds the rate of release of 3-methyladenine (m3A) from methyl nitrosourea-modified DNA under these conditions. 3-Methyladenine-DNA glycosylase II releases both 3-ethylthioethyladenine and 7-ethylthioethylguanine at rates approximating or exceeding the rate of release of m3A from methylnitrosourea-modified DNA. We conclude that these glycosylases may offer some protection against the toxicity of agents which introduce bulky groups into E. coli DNA.

Adenine↗