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Sulfur mustard has been used as a chemical warfare agent for the past century. After its introduction by the Germans in World War I, investigators quickly began studying its impact on the human body including its deleterious effects on skin. This review focuses on two groups in particular who conducted experiments from 1917 to 1918: the United States Army at the American University Experiment Station Laboratories and Torald Sollmann at Western Reserve University. Through this work, these researchers proved far ahead of their time by anticipating dermatologic phenomena not described in the literature until later in the twentieth century. These include regional variation of percutaneous penetration, effect of vehicle on penetration and predicting immunologic contact urticaria. The work conducted by these researchers set the groundwork for much of twentieth century dermatotoxicology. [ABSTRACT FROM AUTHOR]

This study used a damaged skin, porcine model to evaluate the in vivo efficacy of WoundStat™ for decontamination of superficial (non-haemorrhaging), sulphur mustard-contaminated wounds. The dorsal skin of 12 female pigs was subjected to controlled physical damage and exposed to 10 μL 14C-radiolabelled sulphur mustard (14C-SM). Animals were randomly assigned to either a control or a treatment group. In the latter, WoundStat™ was applied 30 s post exposure and left in situ for 1 h. Skin lesion progression and decontaminant efficacy were quantified over 6 h using a range of biophysical measurements. Skin, blood and organ samples were taken post mortem for histopathological assessment, 14C-SM distribution and toxicokinetic analyses. Application of SM to damaged skin without decontamination was rapidly followed by advanced signs of toxicity, including ulceration and decreased blood flow at the exposure site in all animals. WoundStat™ prevented ulceration and improved blood flow at the exposure site in all decontaminated animals ( n = 6). Furthermore, significantly smaller quantities of 14C-SM were detected in the blood (45% reduction), and recovered from skin (70% reduction) and skin surface swabs (99% reduction) at 6 h post-challenge. Overall, the distribution of 14C-SM in the internal organs was similar for both groups, with the greatest concentration in the kidneys, followed by the liver and small intestine. WoundStat™ significantly reduced the amount of 14C-SM recovered from the liver, a key organ for SM metabolism and detoxification. This study demonstrates that WoundStat™ is a suitable product for reducing the ingress and toxicity of a chemical warfare agent. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

No abstract is available for this article. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that haemostatic products with an absorptive mechanism of action retain their clotting efficiency in the presence of toxic materials and are effective in decontaminating chemical warfare (CW) agents when applied to normal, intact skin. The purpose of this in vitro study was to assess three candidate haemostatic products for effectiveness in the decontamination of superficially damaged porcine skin exposed to the radiolabelled CW agents, soman (GD), VX and sulphur mustard (HD). Controlled physical damage (removal of the upper 100 μm skin layer) resulted in a significant enhancement of the dermal absorption of all three CW agents. Of the haemostatic products assessed, WoundStat™ was consistently the most effective, being equivalent in performance to a standard military decontaminant (fuller's earth). These data suggest that judicious application of haemostatic products to wounds contaminated with CW agents may be a viable option for the clinical management of casualties presenting with contaminated, haemorrhaging injuries. Further studies using a relevant animal model are required to confirm the potential clinical efficacy of WoundStat™ for treating wounds contaminated with CW agents. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The risk of penetrating, traumatic injury occurring in a chemically contaminated environment cannot be discounted. Should a traumatic injury be contaminated with a chemical warfare (CW) agent, it is likely that standard haemostatic treatment options would be complicated by the need to decontaminate the wound milieu. Thus, there is a need to develop haemostatic products that can simultaneously arrest haemorrhage and decontaminate CW agents. The purpose of this study was to evaluate a number of candidate haemostats for efficacy as skin decontaminants against three CW agents (soman, VX and sulphur mustard) using an in vitro diffusion cell containing undamaged pig skin. One haemostatic product (WoundStat™) was shown to be as effective as the standard military decontaminants Fuller's earth and M291 for the decontamination of all three CW agents. The most effective haemostatic agents were powder-based and use fluid absorption as a mechanism of action to sequester CW agent (akin to the decontaminant Fuller's earth). The envisaged use of haemostatic decontaminants would be to decontaminate from within wounds and from damaged skin. Therefore, WoundStat™ should be subject to further evaluation using an in vitro model of damaged skin. Copyright © 2014 Crown copyright. Journal of Applied Toxicology © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The treatment of penetrating, haemorrhaging injuries sustained within a hazardous environment may be complicated by contamination with toxic chemicals. There are currently no specific medical countermeasures for such injuries. Haemostats with an absorbent mechanism of action have the potential to simultaneously stop bleeding and decontaminate wounds. However, a primary requirement of a 'haemostatic decontaminant' is the retention of clotting function in the presence of chemical contaminants. Thus, the aim of this study was to investigate the haemostatic efficacy of seven commercially available haemostats in the presence of toxic chemicals (soman, VX, sulphur mustard, petrol, aviation fuel and motor oil). Clot viscosity was assessed ex vivo using thrombelastography following treatment of pig blood with: (i) toxic chemical; (ii) haemostat; or (iii) haemostat in combination with toxic chemical. Several contaminants (VX, petrol and GD) were found to be pro-haemostatic and none had an adverse effect on the rate with which the test products attained haemostasis. However, the total clot strength for blood treated with certain haemostats in the presence of sulphur mustard, soman and petrol was significantly decreased. Three test products failed to demonstrate haemostatic function in this ex vivo (thrombelastography) model; this was tentatively ascribed to the products achieving haemostasis through a tamponade mechanism of action, which can only be replicated using in vivo models. Overall, this study has identified a number of commercial products that may have potential as haemostatic decontaminants and warrant further investigation to establish their decontaminant efficacy. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2 days after exposure and a second peak dominated by macrophages 29 days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT As part of a continuous effort to develop efficient counter measures against sulfur mustard injuries, several unique NSAID prodrugs have been developed and screened for anti-inflammatory properties. Presented herein are three classes of prodrugs which dually target inflammation and cholinergic dysfunction. Compounds 1-28 contain common NSAIDs linked either to choline bioisosteres or to structural analogs of acetylcholinesterase (AChE) inhibitors. These agents have shown utility as anti-vesicants and anti-inflammatory agents when screened in a mouse ear vesicant model (MEVM) against both 2-chloroethyl ethyl sulfide (CEES), a blistering agent, and 12-O-tetradecanoylphorbol-13-acetate (TPA), a common topical irritant. Many of the prodrugs have activity against CEES, with 5, 18, 22 and 27 reducing inflammation by more than 75% compared with a control. Compounds 12, 13, 15 and 22 show comparable activity against TPA. Promising activity in the MEVM is related to half-lives of NSAID release in plasma, moderate to high lipophilicity, and some degree of inhibition of AChE, a potential contributor to sulfur mustard-mediated tissue damage. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article offers information on the study of mustard gas (MG) toxicity. It explores the acute and chronic effects of mustard gas when used in the eyes, skin, respiratory tract and other physiological systems. It likewise discusses the aspects of the management of patients suffering from MG poisoning.

The article presents a study which investigates the effect of sulfur mustard on the shift of oxidants and antioxidants levels in rats. In this study, a cyclic voltammetry were used to assay oxidant and antioxidant levels in intoxicated rats as an in vivo model. Significant shifts were found in both the oxidant and antioxidant levels. The data of the study indicates that on an extensive scale of exposure to sulfur mustard, antioxidants were significantly increased while oxidants were decreased.

The article presents a study on an immunochromatographic detection method or strip assay that can be used to detect the degradation of laminin-5 in sulfur mustard (SM)-exposed normal human epidermal keratinocytes (NHEK) extract. It states that sulfur mustard is an alkylating vesicant agent, used as a chemical weapon in various battles during the 20th century. It suggests that the immunochromatographic detection method in this study may function as a rapid SM-exposure diagnostic and screening procedure that could be applied directly to skin extracts of individuals who have supposedly been exposed to SM.

The article presents a study which examines the potential of doxycycline to reduce sulphur mustard (HD) cytotoxic effects on keratinocyte cultures in human. It states that HD is a chemical warfare agent known for its mutagenic and carcingenic properties that affects the respiratory system, skin and the eyes. One characteristic of HD is the slow recovery of skin injuries which has been associated with its ability to alkalyte. The study makes use of doxycycline treatment with other MMP inhibitors.

The article discusses the applicability of an in-vivo model for the assessment of the percutaneous absorption of sulfur mustard (SM) and the efficacy of candidate protectants through the chemical detection of a compound directly related to the toxicant in the skin. It stated that the penetration of the toxicant was described through the evaluation of thiodigylcol levels in the dialysates. However, the efficacy of three penetrations, which were expected to be effective as topical prophylactics, was tested to verify the suitability of the model.

Concurrent activation of poly (ADP-ribose) polymerase (PARP) and DNA ligase was observed in cultured human epidermal keratinocytes (HEK) exposed to the DNA alkylating compound sulfur mustard (SM), suggesting that DNA ligase activation could be due to its modification by PARP. Using HEK, intracellular 3H-labeled NAD+ (3H-adenine) was metabolically generated and then these cells were exposed to SM (1 m M). DNA ligase I isolated from these cells was not 3H-labeled, indicating that DNA ligase I is not a substrate for (ADP-ribosyl)ation by PARP. In HEK, when PARP was inhibited by 3-amino benzamide (3-AB, 2 m M), SM-activated DNA ligase had a half-life that was four-fold higher than that observed in the absence of 3-AB. These results suggest that DNA repair requires PARP, and that DNA ligase remains activated until DNA damage repair is complete. The results show that in SM-exposed HEK, DNA ligase I is activated by phosphorylation catalysed by DNA-dependent protein kinase (DNA-PK). Therefore, the role of PARP in DNA repair is other than that of DNA ligase I activation. By using the DNA ligase I phosphorylation assay and decreasing PARP chemically as well as by PARP anti-sense mRNA expression in the cells, it was confirmed that PARP does not modify DNA ligase I. In conclusion, it is proposed that PARP is essential for efficient DNA repair; however, PARP participates in DNA repair by altering the chromosomal structure to make the DNA damage site(s) accessible to the repair enzymes. Published in 2006 by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs), a class of enzymes responsible for the degradation of extracellular matrix proteins, play important roles in inflammatory and immune responses. In skin, MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are normally inactive but can be expressed during tissue injury. Both degrade collagen IV and other critical components of the basement membrane zone that separates the epidermis from the dermis. The expression of MMP-2 and -9 was studied in sulfur mustard (SM)-exposed ear skin from mice to determine their role in tissue vesicant injury. Punch biopsies of mouse ears were collected between 6 and 168 h after exposure to 97.5 m (0.08 mg) SM diluted in CH2Cl2. They were examined histologically and assayed for MMP-2 and -9 expression by gelatinase activity assays, real-time reverse transcriptase-polymerase chain reaction and Western blot analysis. A time-related increase in overall gelatinase activity was observed in SM-treated ears. At 168 h after SM exposure, the relative levels of MMP-9 mRNA were increased 27-fold and MMP-9 protein 9-fold when compared with the control (CH2Cl2 treated) ears. In contrast, there were no observable increases in the MMP-2 mRNA or protein levels between treated and control ears. These observations suggest the differential expression of MMP-2 and -9 during the cutaneous response to SM injury and suggest a role for MMP-9 in SM-induced injury. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The ability of sulphur mustard (HD) to induce DNA damage places limits on the efficacy of approaches aimed at protecting human cells from the cytotoxic effects of HD using a variety of protective agents such as thiolcontaining esters and protease inhibitors. In the present study, potential alternative strategies were investigated by examining the differential effects of HD on G361, SVK14, HaCaT and NCTC 2544 human skin cells.The G361 cell line was more resistant to the cytotoxic effects of HD than the NCTC, HaCaT and SVK14 cell lines at HD doses of >3 and <100 M HD as determined by the MTT assay. At 72 h after exposure to 60 M HD there was up to an 8.8-fold difference (P < 0.0001) between G361 and SVK14 cell culture viability. Buthionine sulphoximine (BSO) pretreatment increased the sensitivity of all four cell lines to HD. A substantial proportion of the resistance of G361 cells to HD was attributable to BSO-mediated effects on antioxidant-mediated metabolism, although G361 cultures still retained a high degree of viability at 30 M HD following BSO pretreatment. Cell cycle analysis confirmed that SVK14 cells were relatively more sensitive to HD, as shown by the 2.1-fold reduction (P < 0.0001) in the percentage of cells in G0[sol ]G1 phase 24 h after HD exposure compared with control cultures. This compared well with a 1.2-fold increase (P < 0.05) in the percentage of G361 cells in G0[sol ]G1 phase following HD exposure, suggesting the existence of a more efficient G0[sol ]G1 checkpoint control mechanism in this cell line. Manipulation of the cell cycle using various modulating agents did not increase the resistance of cell lines to the cytotoxic effects of HD. Crown copyright 2005. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This study examines the transcriptional response of human epidermal keratinocytes (HEK) to sulfur mustard (HD) in order to gain a better understanding of the intracellular events that result in cytotoxicity. Differential display polymerase chain reaction technology was used to examine the relative transcriptional activity of healthy cells to those exposed to subvesicating or vesicating concentrations of HD for 4 h. Approximately 2% of the HEK transcriptome had altered expression. Sixty of the most prominently altered transcripts were characterized. Important upregulated genes include NADH dehydrogenase III, GADD45 and ubiquitin. Key downregulated genes include type I keratin 14, α-enolase and caltractin. Many of the identified transcripts protein products presently do not have an assigned function and eleven transcripts were unidentifiable. These transcriptional alterations provide one of the first molecular insights into the intracellular events induced by HD. Published in 2003 by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Focuses on the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry for the verification of sulphur mustard toxicology in the U.S. Analysis on the hydrolysis products of chemical warfare agents; Capacity in identifying casualties from biological and chemical attacks; Determination of high-molecular-weight biomolecules.

Evaluates the use of a skin diffusion cell system for assessing decontaminants against sulphur mustard (SM). Absorption rates of SM; Effectiveness of decontaminants; Disparity in the ranking of decontaminants between epidermal membranes.

Examines the measurement of sulfur mustard offgassing in weanling swine. Exposure of swine to saturated sulfur mustard exposure; Removal of vapor cap; Use of animal models in medical research.

Examines the use of matrix-assisted laser desorption ionization time of flight mass spectrometry in confirming sulfur mustard (HD) exposure. Interaction of HD with hemoglobin; Occurrence of HD cross-linking; Deionization of hemoglobin.

Develops a standard operating procedure for analysis of sulfur mustard adducts to the N-terminal valine in hemoglobin. Assessment of adduct formation with albumin; Purification of solid-phase extraction; Exposure of human callus to mustard gas.

Examines the protective effect of povidone iodine ointment against skin lesions. Employment of mustard gas as chemical weapon; Interval between exposure and treatment; Lipophilic properties of mustard gas.

Examines the acute ocular effects of mustard gas (HD) in rabbits. Characterization of HD ocular toxicity; Changes in the antigenicity of bullous pemphigoid protein; Development of specific HD prophylaxis.

Develops a cutaneous full-thickness sulfur mustard burn model in weaning swines. Urinary excretion of thiodiglycol; Performance of routine analysis; Collection of blood samples.

Evaluates the sulfur-mustard-induced skin burns in weanling swine. Histopathological assessment of epidermal ulceration and necrosis epidermis; Increase of wound size and severity; Exhibition of dermal pathology.

Presents therapeutic approaches to dermatoxicity by sulfur mustard (HD). Usefulness of mouse ear edema in studying skin responses; Effect of pharmacological agents against HD-induced skin injury; Pharmacological modulation of HD injury.

Examines the protective effects of pharmacological compounds against topically sulfur mustard (HD) in mouse ear vesicant model. Measurement of HD injury in mouse ear; Reduction in edema; Application of methylene chloride in the right ear.

Presents a procedure for assessing myeloperoxidase and inflammatory mediator responses in hairless mouse skin. Exposure of mice to sulfur mustard (HD) vapor; Excision of dorsal tissue; Dermal pathology of HD.

Examines the effectiveness of calmodulin antagonists in treating sulfur mustard-induced skin injuries in hairless mice. Use of a pig model to determine the effectiveness; Application of plutonic base ointments; Induction of severe skin injury.

Examines the treatment for sulfur mustard (HD)-induced lung injury. Biochemical indicators of HD-induced lung injury; Use of bronchoalveolar lavage technique in monitoring pulmonary toxicity; Decrease of inflammatory responses.

Examines the mechanism underlying cell death and injury induced by vesicant sulfur mustard. Association of inflammatory reactions with inducing endothelial cells; Release of endothelial-derived cytokines; Exposure of skin to sulfur mustard.

Examines the effects of sulfur mustard on the basal cell adhesion complex. Growth of human epidermal keratinocytes from normal skin; Structural bonds between basal cells and basement membrane; Expression of keratin filaments in the skin.

Examines the beneficial effects of topical anti-inflammatory drugs against sulfur mustard (HD)-induced ocular lesions in rabbits. Characterization of ocular lesions; Exposure of rabbit eyes to HD vapor; Consequences of cytotoxic damage.

Examines the effect of sulfur mustard 2-chloroethyl ethyl sulfide on inflammatory mediators, heat shock protein 70A in two skin models. Histologic evaluation of tissues; Susceptibility of tissues to alkylating agent; Administration of antiinflammatory agents.

Examines the use of poly(adenosine triphosphate-ribose) polymerase in regulating the mechanism of sulfur mustard-initiated cell death in human lymphocytes. Reduction of cell damage; Formation of bacterial viruses inhibited by mustard gas; Mechanism underlying alkylating-agent-mediated cell death.

Examines the effects on sulfur mustard toxicity on the downregulation of cell proliferation and metabolic rates. Proliferation of basal cells in the skin; Determination of cell viability; Inhibition of cellular metabolic processes.

Examines the influence of sulfur mustard in inducing apoptosis and necrosis in SCL II cells. Assessment of necrosis rate by nuclear morphology and gel electrophoresis of the DNA; Depletion of adenosine triphosphate; Patterns of cell death.

Examines the role of inflammation in sulfur mustard (HD) toxicity. Contribution of human epidermal keratinocytes to HD pathology; Promotion of C1q binding; Expression of Fc receptor on the surface of human epidermal keratinocytes.

Examines the inflammatory cytokine response in sulfur mustard (HD)-exposed skin in mice. Assessment of anti-inflammatory therapies against sulfur mustard; Measurement of cytokine content by enzyme immunosorbent assay; Biomarkers associated with HD-induced skin toxicity.

Examines the responses of normal human keratinocytes to sulfur mustard (HD). Use of enzyme-linked immunosorbent assay kits in measuring cytokine release; Collection of supernatants from cell culture flasks; Pathology of HD injury.

Examines the role of protease stimulation at the dermal-epidermal junction for the skin blistering action of sulfur mustard (HD). Factors contributing to the formation of lesions and blisters on human skin; Regulation of serine protease; Exposure of HD to human skin.

Examines the effect of dexamethasone (DEX) on sulfur mustard-exposed macrophages. Decrease in the number of alveolar macrophages recovered by bronchoalveolar lavage; Influence of DEX treatment on apoptosis enhancement; Pathogenesis of lung injury.

Examines the role of calmodulin and poly(adenosine diphosphate-ribose) polymerase on the apoptopic process of sulfur mustard (HD). Induction of terminal differentiation and apoptosis; Ability of HD to cause DNA breaks; Role of calcium in the etiology of HD-induced cytotoxicity.

Compares the cell size in sulfur mustard (HD)-induced death of keratinocytes and lymphocytes. Distinction of apoptopic from necrotic cell death; Decrease in recoverable DNA; Increase of HD concentration and time.

Examines the ability of sulfur mustard (HD) to deplete the nicotinamide adenine dinucleotide content in several cell systems and tissues. Mechanism of sulfur mustard blister formation; Efficacy of candidate drugs in treating HD-induced skin and lung injury; Development of Cobas FARA clinical analyzer.

Examines the absorption and intra-epidermal fate of S-radiolabelled sulphur mustard (SM) in human skin. Penetration rates of SM; Hydrolysis of SM; Effects of SM on the epithelial tissues of the eye, respiratory system and the skin.

Determines human cellular stress gene (SG) profiles following sulfur mustard exposure. Modulation of SM toxicity; Association of SG with DNA damage; Characterization of sulfur mustard.

Sulfur mustard (HD; 2,2'-dichlorodiethyl sulfide) can produce incapacitating blisters in humans following dermal exposure. Most non-human animal models, however, do not form the large fluid-filled blisters observed in humans. Many models, nevertheless, do produce similar damage at the dermal/epidermal junction when evaluated by histopathology. In this study, it was observed that the hairless guinea pig (HGP) exhibits similar histopathological responses following exposure to HD vapor. Two sets of HGPs were exposed percutaneously for various lengths of time to HD vapor. In one set, the HGPs were sacrificed 24 h after exposure, and skin specimens were collected and processed for histopathology. In the other set, light reflectance was measured at skin test sites 4, 5, 6 and 24 h after exposure, to assess erythema. The Nikolsky’s sign test was also performed 24 h after exposure by rotating a metal disk glued to the skin test site and inspecting the skin for loss of epidermis. Probit analysis of data indicated that the exposure durations that produced a 50% incidence of microblisters and Nikolsky’s sign were ca. 7.5 and 4.5 min, respectively. Maximum erythema was observed 6 h following a 6 min exposure. Operating parameters for assessing the efficacies of skin protectants have been characterized. [ABSTRACT FROM AUTHOR]