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INTRODUCTION: Chemical mass casualty incidents (MCIs) pose a substantial threat to public health and safety, with the capacity to overwhelm healthcare infrastructure and create societal disorder. Computer simulation systems are becoming an established mechanism to validate these plans due to their versatility, cost-effectiveness and lower susceptibility to ethical problems. METHODS: We created a computer simulation model of an urban subway sarin attack analogous to the 1995 Tokyo sarin incident. We created and combined evacuation, dispersion and victim models with the SIMEDIS computer simulator. We analyzed the effect of several possible approaches such as evacuation policy ('Scoop and Run' vs. 'Stay and Play'), three strategies (on-site decontamination and stabilization, off-site decontamination and stabilization, and on-site stabilization with off-site decontamination), preliminary triage, victim distribution methods, transport supervision skill level, and the effect of search and rescue capacity. RESULTS: Only evacuation policy, strategy and preliminary triage show significant effects on mortality. The total average mortality ranges from 14.7 deaths in the combination of off-site decontamination and Scoop and Run policy with pretriage, to 24 in the combination of onsite decontamination with the Stay and Play and no pretriage. CONCLUSION: Our findings suggest that in a simulated urban chemical MCI, a Stay and Play approach with on-site decontamination will lead to worse outcomes than a Scoop and Run approach with hospital-based decontamination. Quick transport of victims in combination with on-site antidote administration has the potential to save the most lives, due to faster hospital arrival for definitive care.

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Quantification of the stable isotopes within a compound aids forensic investigations as it provides a fingerprint which can determine that compound's source substrates, synthetic route, and possible mechanisms of degradation. Previous stable isotope studies have explored 13C and 2H measurements of the sarin precursors methylphosphonic dichloride (DC) and methylphosphonic difluoride (DF) as forensic signatures. However, these measurements required different sample preparations and measurement techniques. Orbitrap isotope ratio mass spectrometry (Orbitrap-IRMS) is a developing technique which can characterize multiple stable isotopes simultaneously. Here, we apply Orbitrap-IRMS to simultaneously observe the 13C and 2H content of methylphosphonic acid (MPA), the hydrolysis product of DC and DF, which can be used as a proxy for the isotopic content of DC and DF. Our method requires 20 min analyses and consumes ≈60 nmol of sample, with precisions of ≈0.9 ‰ (13C) and ≈3.6 ‰ (2H). We apply our method to both commercially acquired MPA and MPA obtained from the hydrolysis of commercially acquired DC. We validate our methods via comparison to elemental-analyzer isotope ratio mass spectrometry (EA-IRMS). The combined 13C and 2H measurement creates a more robust forensic tool than either isotope individually. Our results demonstrate the viability of Orbitrap-IRMS for chemical forensic measurements.

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In the presented study, an efficient and fast analytical method was developed for the determination of parathion ethyl as sarin simulant by gas chromatography-mass spectrometry (GC-MS). Dispersive solid phase extraction (DSPE) was performed to concentrate parathion ethyl from soil, plant and water samples. Reduced graphene oxide-iron (II, III) oxide (rGO-Fe3O4) nanocomposite was used as an adsorbent to collect the target analyte from the aqueous sample solutions. After the optimization of extraction/preconcentration parameters, optimum conditions for adsorbent amount, eluent type, mixing type/period, eluent volume and initial sample volume were determined as 15 mg, acetonitrile, vortex/30 s, 100 µL and 10 mL, respectively. Under the optimum conditions, analytical performance of the developed DSPE-GC-MS method was evaluated in terms of limit of detection (LOD), limit of quantitation (LOQ) and dynamic range. Dynamic range, LOD and LOQ values were figured out to be 0.94-235.15 µg/kg, 0.41 µg/kg and 1.36 µg/kg (mass based), respectively. Satisfactory percent recovery results (90.3-125% for soil, 93.5-108.7% for plant, 88.5-112.9% for tap water) were achieved for soil, plant and tap water samples which proved the accuracy and applicability of the developed method. It is predicted that the DSPE-GC-MS method can be accurately used for the detection of sarin in soil, plant and water samples taken from war territories.

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Variceal bleed represents an important complication of cirrhosis, with its presence reflecting the severity of liver disease. Gastric varices, though less frequently seen than esophageal varices, present a distinct clinical challenge due to its higher intensity of bleeding and associated mortality. Based upon the Sarin classification, GOV1 is the most common subtype of gastric varices seen in clinical practice.

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The simplicity of synthesis, significant toxicity of organophosphorus-containing nerve agents, and ease of use of their in-terrorism attacks highlight the necessity to create efficient probes and precise methods for detecting these chemicals. This study developed luminogenic probe 4-(1 H-phenanthrene imidazole-2-yl) benzaldehyde, PB for selectively recognizing lethal chemical sarin mimicking diethylchlorophosphate (DCP) with µM detection limit. Following the addition of DCP to the PB solution, the fluorescence changed from bluish-cyan to green simultaneously; after the insertion of triethylamine (TEA) into the PB-DCP phosphorylated solution, the fluorescence of the original one came back, and it occurred five times. A paper strip-based test kit and dip-stick experiments have been executed to demonstrate the practical applicability of our sensor PB and instant, on-site recognition of the target analyte DCP. An experiment has been investigated using a smartphone and red-green-blue (RGB) color analysis, which offers a novel way for the fast, on-site visual detection and quantification of DCP in actual samples. It also reduces equipment costs, speeds up detection times, and substantially simplifies the operation procedure.

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The development of refractory status epilepticus (SE) following sarin intoxication presents a therapeutic challenge. Here, we evaluated the efficacy of delayed combined double or triple treatment in reducing abnormal epileptiform seizure activity (ESA) and the ensuing long-term neuronal insult. SE was induced in rats by exposure to 1.2 LD50 sarin followed by treatment with atropine and TMB4 (TA) 1 min later. Double treatment with ketamine and midazolam or triple treatment with ketamine, midazolam and levetiracetam was administered 30 min post-exposure, and the results were compared to those of single treatment with midazolam alone or triple treatment with ketamine, midazolam, and valproate, which was previously shown to ameliorate this neurological insult. Toxicity and electrocorticogram activity were monitored during the first week, and behavioral evaluations were performed 2 weeks post-exposure, followed by biochemical and immunohistopathological analyses. Both double and triple treatment reduced mortality and enhanced weight recovery compared to TA-only treatment. Triple treatment and, to a lesser extent, double treatment significantly ameliorated the ESA duration. Compared to the TA-only or the TA+ midazolam treatment, both double and triple treatment reduced the sarin-induced increase in the neuroinflammatory marker PGE2 and the brain damage marker TSPO and decreased gliosis, astrocytosis and neuronal damage. Finally, both double and triple treatment prevented a change in behavior, as measured in the open field test. No significant difference was observed between the efficacies of the two triple treatments, and both triple combinations completely prevented brain injury (no differences from the naïve rats). Delayed double and, to a greater extent, triple treatment may serve as an efficacious delayed therapy, preventing brain insult propagation following sarin-induced refractory SE.

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Dried urine spot (DUS) is a micro-sample collection technique, known for its advantages in handling, storage and shipping. It also uses only a small volume of urine, an essential consideration in working with small animals, or in acute medical situations. Alkyl-phosphonic acids are the direct and indicative metabolites of organophosphorus chemical warfare agents (OP-CWAs) and are present in blood and urine shortly after exposure. They are therefore crucially important for monitoring casualties in war and terror scenarios. We report here a new approach for the determination of the metabolites of five CWAs in urine using DUS. The method is based on a simple and rapid sample preparation, using only 50 µL of urine, spotted and dried on DBS paper, extracted using 300 µL methanol/water and analyzed via targeted LC-MS/MS. The detection limits for the five CWAs, sarin (GB), soman (GD), cyclosarin (GF), VX and RVX in human urine were from 0.5 to 5 ng/mL. Recoveries of (40-80%) were obtained in the range of 10-300 ng/mL, with a linear response (R2 > 0.964, R > 0.982). The method is highly stable, even with DUS samples stored up to 5 months at room temperature before analysis. It was implemented in a sarin in vivo exposure experiment on mice, applied for the time course determination of isopropyl methylphosphonic acid (IMPA, sarin hydrolysis product) in mice urine. IMPA was detectable even with samples drawn 60 h after the mice's (IN) exposure to 1 LD50 sarin. This method was also evaluated in a non-targeted screening for multiple potential CWA analogs (LC-Orbitrap HRMS analysis followed by automatic peak detection and library searches). The method developed here is applicable for rapid CWA casualty monitoring.

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Chemical agents have been utilized for centuries in warfare and pose a health threat to civilians and military personnel during armed conflict. Despite treaties and regulations against their use, chemical agent exposure remains a threat and measures to understand their effects and countermeasures for systemic and organ-specific health are needed. Many of these agents have ocular complications, both acute and chronic. This mini-review focuses on key chemical agents including vesicants (mustards, lewisite), nerve agents (sarin, VX), knockdown gasses (hydrogen cyanide), and caustics (hydrofluoric acid). Their ophthalmic manifestations and appropriate treatment are emphasized. Acute interventions include removal of the source and meticulous decontamination, as well as normalization of pH to 7.2-7.4 if alteration of the ocular pH is observed. Besides vigorous lavage, acute therapies may include topical corticosteroids and non-steroid anti-inflammatory therapies. Appropriate personal protective equipment (PPE) and strict donning and doffing protocols to avoid healthcare provider exposure are also paramount in the acute setting. For more severe disease, corneal transplantation, amniotic membrane graft, and limbal stem cell transplantation may be needed. Orbital surgery may be required in patients in whom cicatricial changes of the ocular surface have developed, leading to eyelid malposition. Multidisciplinary care teams are often required to handle the full spectrum of findings and consequences associated with emerging chemical threats.

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INTRODUCTION: We simulated an on-site, multi-hospital mass casualty incident (MCI) to educate emergency medicine providers in the principles of trauma resuscitation and collaboration with administration and staff during an MCI. METHODS: We implemented high-fidelity manikins, inflatable manikins, and actors to simulate a sarin gas bombing. Learners triaged patients at a decontamination tent using the simple triage and rapid treatment (START) tool, or they participated in a simulation in a resuscitation bay. RESULTS: Forty participants anonymously rated the learning impact of the exercise, the clinical relevance to emergency medicine, and the effectiveness of the faculty facilitation and debriefing on a 1-5 Likert scale. The average responses to all questions were 4.45 or greater, and 98% of respondents recommended adding the scenario to the standard curriculum. DISCUSSION: We successfully executed a novel, multi- hospital, MCI drill that was rated to be a better alternative to sequential simulation in a simulation center.

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Chemical weapons continue to be an ongoing threat that necessitates the improvement of existing detection technologies where new technologies are absent. Lower limits of detection will facilitate early warning of exposure to chemical weapons and enable more rapid deployment of countermeasures. Here, we evaluate two colorimetric gas detection tubes, developed by Draeger Inc., for sarin and sulfur mustard chemical warfare agents and determine their limits of detection using active chemical agent. Being that commercial companies are only able to use chemical agent simulants during sensor development, it is imperative to determine limits of detection using active agent. The limit of detection was determined based on the absence of a reasonably perceptible color response at incrementally lower concentrations. A chemical vapor generator was constructed to produce stable and quantifiable concentrations of chemical agent vapor, with the presence of chemical agent verified and monitored by a secondary detector. The limits of detection of the colorimetric gas detection tubes were determined to be 0.0046 ± 0.0002 and 2.1 ± 0.3 mg/m3 for sarin and sulfur mustard, respectively. The response of the sarin detection tube was readily observable with little issue. The sulfur mustard detection tube exhibited a weaker response to active agent compared to the simulant that was used during development, which will affect their concept of operations in real-world detection scenarios.

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In the last decades, Chemical, Biological, Radiological and Nuclear (CBRN) threats have become serious risks prompting countries to prioritize preparedness for such incidents. As CBRN scenarios are very difficult and expensive to recreate in real life, computer simulation is particularly suited for assessing the effectiveness of contingency plans and identifying areas of improvement. These computer simulation exercises require realistic and dynamic victim profiles, which are unavailable in a civilian context. In this paper we present a set of civilian nerve agent injury profiles consisting of clinical parameters and their evolution, as well as the methodology used to create them. These injury profiles are based on military injury profiles and adapted to the civilian population, using sarin for the purpose of illustration. They include commonly measured parameters in the prehospital setting. We demonstrate that information found in military sources can easily be adjusted for a civilian population using a few simple assumptions and validated methods. This methodology can easily be expanded to other chemical warfare agents as well as different ways of exposure. The resulting injury profiles are generic so they can also be used in tabletop and live simulation exercises. Modeling and simulation, if used correctly and in conjunction with empirical data gathered from lessons learned, can assist in providing the evidence practices for effective and efficient response decisions and interventions, considering the contextual factors of the affected area and the specific disaster scenario.

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CONTEXT: In contrast to un-catalyzed hydrolysis of organophosphorus (OP) compounds, metal ions or/and their complexes with chelating ligands show catalytic effects in several ways depending upon the nature of the metal, ligand, substrate, and medium. It is known that Cu(II)-en chelate containing copper complexes accelerate the hydrolysis of OP compounds. However, the mechanism for this rate enhancement in the Cu(II)-en chelate catalytic hydrolysis reaction of sarin remains unexplored. We have examined possible mechanisms involving a Cu(II)-en with hydroxide nucleophile for the reaction pathway of the hydrolysis of O-isopropyl methylphosphonofluoridate (sarin) computationally. The density functional (B3LYP) employed in this study has reproduced the experimental Gibb's free energy of activation value 15.5 kcal/mol for alkaline hydrolysis of sarin. Earlier proposal of push-pull mechanism for metal ion chelate-catalyzed hydrolysis of OP compounds has been found to be unfavorable in the present study. The role of water molecules in catalyzing the hydrolysis of sarin with Cu(II)-en chelate is crucial. The catalytic process involving Cu(II)-en chelate with one water molecule is the more plausible pathway to achieve the hydrolysis of sarin with Cu(II)-en chelate complexes. METHODS: The most popular B3LYP method was used for optimization of given geometries. Except LANL2DZ for Cu atom, all the atoms are described using the 6-31 + G(d) basis set. The stability test has been performed for the wave functions as we are dealing with the open-shell molecules in order to ensure stable electronic configuration form, and the stable wavefunction is used as the initial configuration for the subsequent optimization. Harmonic frequency calculations and thermodynamic corrections were performed at the same level of theory. PCM method has been used for solvation effects. In order to ensure that each saddle point is linked to a minimum, IRC calculations were performed in forward and reverse directions to ensure the eigenvectors associated with the unique negative eigenvalues of the Hessian matrix. All energies discussed are solvated Gibbs free energies corrected to 298.15 K for the relative stability of the chemical structure. All calculations were performed using the Gaussian 09 code.

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Introduction: Sarin is a highly toxic organophosphorus nerve agent that irreversibly inhibits neuronal enzyme acetylcholinesterase. In the prevailing scenario, it is of paramount importance to develop early diagnosis and medical countermeasures for sarin exposure. A deeper understanding of the molecular mechanism of sarin intoxication and perturbations in the associated cellular processes is likely to provide valuable clues for the elucidation of diagnostic markers and therapeutic targets for sarin exposure. Methods: Present study, uncovered the changes in phosphorylation patterns of multiple proteins in different rat brain regions after sarin intoxication using 2-DE/MS approach. It provided a holistic view of the phosphorylation-mediated changes in the cellular proteome and highlighted various signaling and response pathways affected at an early time point of sarin intoxication. Results: We found total 22 proteins in the cortex, 25 proteins in the corpus striatum, and 17 proteins in the hippocampus, showed ≥1.5 fold changes (hyper- or hypo- phosphorylated) with respect to control, either at 2.5 h or 1 d after sarin exposure. These results indicated the differential expression of phosphoproteins involved in protein folding in the endoplasmic reticulum, carbon metabolism, metabolic function, and energy metabolism. Conclusion: Four candidates (protein disulfide-isomerase A3, heat shock cognate 71 kDa protein, alpha-enolase, and creatine kinase B-type), hyperphosphorylated in all three brain regions, can be further studied to understand the molecular mechanism behind neurodegenerative changes mediated by sarin exposure. The study sheds light on major pathogenic processes initiated during sarin intoxication and provides putative diagnostic markers/therapeutic targets for further validation.

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Sarin is a potent organophosphorus nerve agent that causes cognitive dysfunction, but its underlying molecular mechanisms are poorly understood. In this study, a rat model of repeated low-level sarin exposure was established using the subcutaneous injection of 0.4 × LD50 for 21 consecutive days. Sarin-exposed rats showed persistent learning and memory impairment and reduced hippocampal dendritic spine density. A whole-transcriptome analysis was applied to study the mechanism of sarin-induced cognitive impairment, and a total of 1035 differentially expressed mRNA (DEmRNA), including 44 DEmiRNA, 305 DElncRNA, and 412 DEcircRNA, were found in the hippocampus of sarin-treated rats. According to Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and Protein-Protein Interaction (PPI) analysis, these DERNAs were mainly involved in neuronal synaptic plasticity and were related to the pathogenesis of neurodegenerative diseases. The circRNA/lncRNA-miRNA-mRNA ceRNA network was constructed, in which Circ_Fmn1, miR-741-3p, miR-764-3p, miR-871-3p, KIF1A, PTPN11, SYN1, and MT-CO3 formed one circuit, and Circ_Cacna1c, miR-10b-5p, miR-18a-5p, CACNA1C, PRKCD, and RASGRP1 constituted another circuit. The balance between the two circuits was crucial for maintaining synaptic plasticity and may be the regulatory mechanism by which sarin causes cognitive impairment. Our study reveals the ceRNA regulation mechanism of sarin exposure for the first time and provides new insights into the molecular mechanisms of other organophosphorus toxicants.

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A benzoxazole-based fluorosensor (IMP) has been synthesized and employed for the selective and sensitive detection of sarin surrogate, diethylchlorophosphate (DCP) in solution, and gas phase, respectively. Remarkable turn-on fluorescence is observed due to the introduction of DCP in the solution of IMP because of inhibition of the intramolecular charge transfer process and disruption of the excited state intramolecular proton transfer (ESIPT) mechanism. The synthesized IMP-based fluorescence sensor exhibits excellent selectivity, high sensitivity, and a wide linear range of 15-60 µM with a detection limit of 44 nM. Low-intense to highly intensified visible violet color could be seen by the naked eye under a portable 365 nm UV lamp due to the addition of DCP in the solution of IMP. IMP-stained paper strips-based test kit experiment has been demonstrated to detect traces of DCP in stockpiles of related analytes. A dip-stick experiment for the detection of DCP vapor has also been demonstrated. The effectiveness of IMP in detecting DCP established that it might be used as a signal tool for real sample analysis.

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Nerve agents have been used recently in the Syrian civil war. Collecting relevant samples for retrospective identification of an attack is often problematic. The article deals with the possibility of using contaminated gloves as an analytical sample for evidence of the chemical weapons use. There have not yet been published studies dealing with the identification of chemical warfare agents in this type of matrix, where the diversity of chemical properties of gloves and the lifetime of the contaminated sample would be considered. Sarin, soman, and cyclosarin were used as contaminants in the study. Nitrile, latex, and vinyl disposable gloves were chosen as matrices. The identification method was gas chromatography. Six solvents commonly used in military laboratories were tested as extractants. The extraction procedure was optimized in terms of the appropriate method (vortex) and the required extraction time (1 min) and resulted in significant reduction in sample preparation time. The chromatographic background of the extracts was also monitored in order to find a method with the least number of peaks interfering in the identification. Suitable solvents were hexane and acetonitrile. The lifetime of the sample was also investigated. The worst result was recorded for latex. For individual contaminants, the time varied depending on the volatility. The developed procedures were successfully validated within a sample handling effects scenario. The results demonstrate that in the event of an ongoing military risk at the site of an attack, even discarded disposable rubber glove type samples can be used as evidence.

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Gulf War Illness (GWI) encompass a spectrum of maladies specific to troops deployed during the Persian Gulf War (1990-1991). There are several hypothesized factors believed to contribute to GWI, including (but not limited to) exposures to chemical agents and a foreign environment (e.g., dust, pollens, insects, and microbes). Moreover, the inherent stress associated with deployment and combat has been associated with GWI. While the etiology of GWI remains uncertain, several studies have provided strong evidence that chemical exposures, especially neurotoxicants, may be underlying factors for the development of GWI. This mini style perspective article will focus on some of the major evidence linking chemical exposures to GWI development and persistence decades after exposure.

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The Deuterium/Hydrogen (D/H) isotope ratios of sarin (5), diisopropyl methylphosphonate (3) and their precursors Isopropanol (1), methylphosphonic acid dichloride (2) and methylphosphonic acid difluoride (4) were measured by the 2H SNIF-NMR technique. The D/H isotope ratios of 1 show a large variation. It is shown, that the formation of 3 by reaction of 1 with 2, the fluorination of 2 to form 4 and the reaction of 4 with 1 to form 5, the D/H isotope ratios of the methyl and isopropyl moieties in 3, 4 and 5 are not significantly changed compared to 1 and 2.

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Over 40% of veterans from the Persian Gulf War (GW) (1990-1991) suffer from Gulf War Illness (GWI). Thirty years since the GW, the exposure and mechanism contributing to GWI remain unclear. One possible exposure that has been attributed to GWI are chemical warfare agents (CWAs). While there are treatments for isolated symptoms of GWI, the number of respiratory and cognitive/neurological issues continues to rise with minimum treatment options. This issue does not only affect veterans of the GW, importantly these chronic multisymptom illnesses (CMIs) are also growing amongst veterans who have served in the Afghanistan-Iraq war. What both wars have in common are their regions and inhaled exposures. In this review, we will describe the CWA exposures, such as sarin, cyclosarin, and mustard gas in both wars and discuss the various respiratory and neurocognitive issues experienced by veterans. We will bridge the respiratory and neurological symptoms experienced to the various potential mechanisms described for each CWA provided with the most up-to-date models and hypotheses.

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Rapid detection of Chemical Warfare Agents (CWAs) is of great significance in protecting civilians in public places and military personnel on the battlefield. Two-dimensional (2D) molybdenum disulfide (MoS2) nanosheets (NSs) can be integrated as a gas sensor at room temperature (25°C) due to their large specific surface area and excellent semiconductor properties. However, low sensitivity and long response-recovery time hinder the pure MoS2 application in CWAs gas sensors. In this work, we developed a CWAs sensor based on in-situ niobium-doped MoS2 NSs (Nb-MoS2 NSs) via direct chemical-vapor-deposition (CVD) growth. Characterization results show that the high content of Nb elements (7.8 at%) are homogeneously dispersed on the large-area 2D structure of MoS2. The Nb-MoS2 NSs-based CWAs sensor exhibits higher sensitivity (-2.09% and -3.95% to 0.05 mg/m3 sarin and sulfur mustard, respectively) and faster response speed (78 s and 30 s to 0.05 mg/m3 sarin and sulfur mustard, respectively) than MoS2 and other 2D materials at room temperature. And the sensor has certain specificity for sarin and sulfur mustard and is especially sensitive to sulfur mustard. This can be attributed to the improvement of adsorption properties via electronic regulation of Nb doping. This is the first report about CWAs detection based on two-dimensional (2D) transition metal dichalcogenides (TMDs) sensing materials, which demonstrates that the high sensitivity, rapid response, and low limit of detection of 2D TMDs-based CWAs sensor can meet the monitoring needs of many scenarios, thus showing a strong application potential.