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Надходження в арсенали озброєнь фосфорорганічних отруйних речовин (ОР) нервово-паралітичної дії знаменувало апогей розвитку хімічної зброї. У 1939 р. було отримано зарин, а наприкінці 1944 р. — зоман, що належали до нового класу смертельних ОР нервово-паралітичної дії й у багато разів перевершували за своєю токсичністю ОР часів Першої світової війни. Промислове виробництво зарину почалося в 1952 р. В середині 1961 р. у США почали виробляти малолетючу стійку фосфорорганічну ОР під шифром VХ, особливо небезпечну при потраплянні навіть невеликих кількостей її на шкіру. За роки Другої світової війни в США на 17 технологічних установках було вироблено 135 тис. т різних ОР, з яких більше половини припадало на іприт. Останнім було споряджено близько 5 млн снарядів і 1 млн хімічних авіаційних бомб. Результатом робіт у галузі ОР, що впливають на центральну нервову систему людини, стало детальне дослідження до 1962 р. 3-хінуклідинілового ефіру бензилової кислоти, що має шифр ВZ. Вона перебувала на озброєнні американської армії і в експериментальному варіанті застосовувалася у В’єтнамі. У післявоєнні роки в армії США на зміну старих речовин подразнюючої дії були прийняті нові речовини — СS і СR, що стали результатом спільних англо-американських досліджень. За подразнюючою дією речовина CS значно перевершує іританти часів Першої світової війни. У 1993 р. було прийнято Міжнародну конвенцію про заборону хімічної зброї, що набрала чинності 29 квітня 1997 р.

Бойові отруйні речовини задушливої та подразнюючої дії були першим видом хімічної зброї, що застосована під час Першої світової війни. Основні отруйні речовини (задушливі — газоподібний фосген, рідкий дифосген; подразнюючої дії — хлорпікрин) поширювалися за допомогою газометів. Усі ці сполуки викликали тяжкі ураження органів дихання, шкірних покривів. Усього з квітня 1915 р. по листопад 1918 р. відбулося понад 50 німецьких газобалонних атак. У цей же період проти німецьких військ було здійснено 150 англійських і 20 французьких газопусків. Французькі війська 15 травня 1916 р. застосовували артилерію з сумішшю фосгену з чотирихлористим оловом і трихлористим миш’яком, хлорпікрином, а також суміш синільної кислоти з трихлористим миш’яком, чотирихлористим оловом у хлороформі (форма венсеніту). Хлорціан і синільна кислота — бойові отруйні речовини загальноотруйної дії. Вперше іприт як шкірно-наривна бойова отруйна речовина був застосований 12 липня 1917 р. під м. Іпр (Бельгія) в артилерійських снарядах. Застосування бойових отруйних речовин у Першій світовій війні викликало протест світової громадськості. Після закінчення війни за Версальським мирним договором (1919) Німеччині та її військовим союзникам було заборонено проводити дослідження, розробку і взяття бойових отруйних речовин на озброєння.

Objective This study aims to assess the prognosis of inpatients with COVID-19 infection who have a history of sulfur mustard exposure. Methods We started a cohort study in October 2020 and ended in May 2021 on inpatients with COVID-19 infection who had been admitted to university healthcare centers. The analytic sample included 960 inpatients having COVID-19 infection (192 with; and 768 without sulfur mustard exposure). The exposed patients were male war veterans, and the unexposed patients were male individually age-matched people. All patients had a positive RT-PCR test and a positive chest CT for COVID-19. The outcome was death within 28 days of admission, and the predictors were clinical features recorded at patients' bedsides. Results There was a significantly higher prevalence for asthma (p = 0.026) and pulmonary disease other than asthma (p

The bis(2-chloroethyl) sulfide, commonly named sulfur mustard, as a vesicant agent and the tabun, sarin, soman, and venomous X as organophosphorus nerve agents are the most notorious, used, and threatening chemical warfare agents which contamination by them make serious health problems. The most efficient method for sulfur mustard detoxification is its selective oxidation to its corresponding sulfoxide, which is a nontoxic product. While for organophosphorus nerve agents, the best strategy is the hydrolysis of their P–X bond. Various mono-functional catalysts have been introducing regarding these methods. In other words, they are only able to selective oxidation of sulfur mustard or hydrolysis of organophosphorus nerve agents or their simulants. However, due to the unpredictable use of these chemical warfare agents, for human and environmental safety, there is a need for dual-functional catalysts capable of both the selective oxidation of sulfur mustard and hydrolysis of organophosphorus agents. In this regard, the reported dual-functional catalysts for oxidation of sulfur mustard and hydrolysis of organophosphorus agents, or their simulants, are reviewed here. These catalysts are mainly polyoxometalates and minorly metal-organic frameworks based catalysts.

The supramolecular detection by image analysis of a simulant chemical warfare agent on a solid device containing a selective molecular sensor based on a BODIPY scaffold is reported. The recognition properties were investigated in solution, demonstrating high affinity (log K 6.60) and sensitivity (LOD 10 ppt). A test strip also confirmed the sensing properties in gas phase. Image analysis of the solid device allows quantitative information about the simulant to be obtained, recovering the sensor almost 5 times and thus confirming the goal of the supramolecular approach., Smart(phone) recognition: A new fluorescent sensor able to interact noncovalently with DMMP, a CWA simulant, has been synthetized and tested both in solution and in the gas phase. The detection limit in solution is much lower than the toxicity values of CWAs; in the gas phase sensing can be performed on a simple smartphone. With acid/base treatment, the solid device can be reused. This prototype paves the way for the smart detection of nerve agents.

Sulfur mustard (SM) is a banned chemical warfare agent recently used in the Syrian Arab Republic conflict causing erythema and blisters characterized by complicated and delayed wound healing. For medical and legal reasons, the proof of exposure to SM is of high toxicological and forensic relevance. SM reacts with endogenous human serum albumin (HSA adducts) alkylating the thiol group of the cysteine residue C34, thus causing the addition of the hydroxyethylthioethyl (HETE) moiety. Following proteolysis with pronase, the biomarker dipeptide C(-HETE)P is produced. To expand the possibilities for verification of exposure, we herein introduce a novel biomarker produced from that alkylated dipeptide by derivatization with propionic anhydride inducing the selective propionylation of the N-terminus yielding PA-C(-HETE)P. Quantitative derivatization is carried out at room temperature in aqueous buffer within 10 s. The biomarker was found to be stable in the autosampler at 15 °C for at least 24 h, thus documenting its suitability even for larger sets of samples. Selective and sensitive detection is done by micro liquid chromatography-electrospray ionization tandem-mass spectrometry (μLC-ESI MS/MS) operating in the selected reaction monitoring (SRM) mode detecting product ions of the single protonated PA-C(-HETE)P (m/z 379.1) at m/z 116.1, m/z 137.0, and m/z 105.0. The lower limit of detection corresponds to 32 nM SM in plasma in vitro and the limit of identification to 160 nM. The applicability to real exposure scenarios was proven by analyzing samples from the Middle East confirming poisoning with SM. Graphical abstract Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659

Sulfur mustard (SM, bis[2-chloroethyl]-sulfide) is a banned chemical warfare agent that was frequently used in recent years and led to numerous poisoned victims who developed painful erythema and blisters. Post-exposure analysis of SM incorporation can be performed by the detection of human serum albumin (HSA)-derived peptides. HSA alkylated by SM contains a hydroxyethylthioethyl (HETE)-moiety bound to the cysteine residue C34 yielding the dipeptide biomarker C(-HETE)P after pronase-catalyzed proteolysis. We herein present a novel procedure for the selective precolumn nicotinylation of its N-terminus using 1-nicotinoyloxy-succinimide. The reaction was carried out for 2 h at ambient temperature with a yield of 81%. The derivative NA-C(-HETE)P was analyzed by micro liquid chromatography-electrospray ionization tandem-mass spectrometry working in the selected reaction monitoring mode (μLC-ESI MS/MS SRM). The derivative was shown to be stable in the autosampler at 15°C for at least 24 h. The single protonated precursor ion (m/z 428.1) was subjected to collision-induced dissociation yielding product ions at m/z 116.1, m/z 137.0, and m/z 105.0 used for selective monitoring without any plasma-derived interferences. NA-C(-HETE)P showed a mass spectrometric response superior to the non-derivatized dipeptide thus yielding larger peak areas (factor 1.3 ± 0.2). The lower limit of identification corresponded to 80 nM SM spiked to plasma in vitro. The presented procedure was applied to real case plasma samples from 2015 collected in the Middle East confirming SM poisoning.

Sulfur mustard (SM) is a chemical warfare agent that has been used throughout recent history and remains a threat today. Exposed soldiers and civilians experience a variety of symptoms primarily in the respiratory system, skin, and eyes. The ocular tissues are highly sensitive to damage by SM and undergo unique manifestations of acute, chronic, and delayed complications that can persist for months and years after exposure. The mechanisms of this unique mustard gas keratopathy are still not fully understood and animal models for the study of this disease are discussed. Recent advances in mechanisms of injury are included in this review. Ophthalmic manifestations of SM injury including persistent epithelial defects, limbal stem cell deficiency, corneal neovascularization, dry eye, and corneal opacification have been reported. A wide variety of medical and surgical therapies have been studied and are reviewed here along with potential future therapies.

Sulfur mustard (SM) is a lipid soluble alkylating agent that causes genotoxic injury. The eye is highly sensitive to SM toxicity and exposures exceeding 400 mg min/m3 can elicit irreversible corneal pathophysiologies. Development of medical countermeasures for ocular SM exposure has been hindered by a limited understanding of dose-dependent effects of SM on corneal injury. Here, clinical, histological and ultrastructural analyses were used to characterize the effects of SM dose on corneal injury progression. Corneas were evaluated for up to 20 wk following exposure to saturated SM vapor for 30−150 s, which corresponds to 300−1,500 mg min/m3. In acute studies, a ceiling effect on corneal edema developed at doses associated with full-thickness corneal lesions, implicating endothelial toxicity in corneal swelling. Recurrent edematous lesions (RELs) transiently emerged after 2 wk in a dose-dependent fashion, followed by the development of secondary corneal pathophysiologies such as neovascularization, stromal scarring and endothelial abnormalities. RELs appeared in 96 % of corneas exposed for ≥ 90 s, 52 % of corneas exposed for 60 s and 0 % of corneas exposed for 30 s. While REL latency was variable in corneas exposed for 60 s, REL emergence was synchronized at exposures ≥ 90 s. Corneas did not exhibit more than one REL, suggesting RELs are part of a programmed pathophysiological response to severe alkylating lesions. In post-mortem studies at 12 wk, corneal edema was positively correlated to severity of endothelial pathologies, consistent with previous findings that endothelial toxicity influences long-term outcomes. These results provide novel insight into long-term corneal pathophysiological responses to acute toxicity and identify exposure conditions suitable for therapeutic testing.

The primary aim of this study was to identify biomarkers of exposure to some so-called Schedule 1 sulfur mustard (HD) analogues, in order to facilitate and expedite their retrospective analysis in case of alleged use of such compounds. Since these HD analogues can be regarded as model compounds for possible impurities of HD formed during synthesis processes, the secondary aim was to explore to which extent these biomarkers can be used for chemical provenancing of HD in case biomedical samples are available. While the use of chemical attribution signatures (CAS) for neat chemicals or for environmental samples has been addressed quite frequently, the use of CAS for investigating impurities in biomedical samples has been addressed only scarcely. Human plasma was exposed to each of the five HD analogues. After pronase or proteinase K digestion of precipitated protein and sample work-up, the histidine (His) and tripeptide (CPF) adducts to proteins were analyzed, respectively. Adducts of the analogues could still be unambiguously identified next to the main HD adducts in processed plasma samples after exposure to HD mixed with each of the analogues, at a 1% level relative to HD. In conclusion, we have identified plasma protein adducts of a number of HD analogues, which can be used as biomarkers to assess an exposure to these Schedule 1 chemicals. We have shown that adducts of these analogues can still be analyzed after work-up of plasma samples which had been exposed to these analogues in a mixture with HD, supporting the hypothesis that biomedical sample analysis might be useful for chemical provenancing.

A common feature of fluorescent sensing materials for detecting chemical warfare agents (CWAs) and simulants is the presence of nitrogen-based groups designed to nucleophilically displace a phosphorus atom substituent, with the reaction causing a measurable fluorescence change. However, such groups are also basic and so sensitive to acid. In this study we show it is critical to disentangle the response of a candidate sensing material to acid and CWA simulant. We report that pyridyl-containing sensing materials designed to react with a CWA gave a strong and rapid increase in fluorescence when exposed to Sarin, which is known to contain hydrofluoric acid. However, when tested against acid-free diethylchlorophosphate and di-iso-propylfluorophosphate, simulants typically used for evaluating novel G-series CWA sensors, there was no change in the fluorescence. In contrast, simulants that had been stored or tested under a standard laboratory conditions all led to strong changes in fluorescence, due to acid impurities. Thus the results provide strong evidence that care needs to be taken when interpreting the results of fluorescence-based solid-state sensing studies of G-series CWAs and their simulants. There are also implications for the application of these pyridyl-based fluorescence and other nucleophilic/basic sensing systems to real-world CWA detection. Chemical warfare agents and simulants are commonly detected with fluorescent sensing materials containing nitrogen-based groups, however these groups’ basicity can cause false positives in the presence of acids. Here, the authors disentangle the response of pyridyl-containing sensing materials to acid-containing and acid-free Sarin and simulants.

Sulfur mustard (SM) is a chemical warfare agent which use is banned under international law and that has been used recently in Northern Iraq and Syria by the so-called Islamic State. SM induces the alkylation of endogenous proteins like albumin and hemoglobin thus forming covalent adducts that are targeted by bioanalytical methods for the verification of systemic poisoning. We herein report a novel biomarker, namely creatine kinase (CK) B-type, suitable as a local biomarker for SM exposure on the skin. Human and rat skin were proven to contain CK B-type by Western blot analysis. Following exposure to SM ex vivo, the CK-adduct was extracted from homogenates by immunomagnetic separation and proteolyzed afterwards. The cysteine residue Cys282 was found to be alkylated by the SM-specific hydroxyethylthioethyl (HETE)-moiety detected as the biomarker tetrapeptide TC(-HETE)PS. A selective and sensitive micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (µLC-ESI MS/HRMS) method was developed to monitor local CK-adducts in an in vivo study with rats percutaneously exposed to SM. CK-adduct formation was compared to already established DNA- and systemic albumin biomarkers. CK- and DNA-adducts were successfully detected in biopsies of exposed rat skin as well as albumin-adducts in plasma. Relative biomarker concentrations make the CK-adduct highly appropriate as a local dermal biomarker. In summary, CK or rather Cys282 in CK B-type was identified as a new, additional dermal target of local SM exposures. To our knowledge, it is also the first time that HETE-albumin adducts, and HETE-DNA adducts were monitored simultaneously in an in vivo animal study.

A number of recent terrorist attacks make it clear that rapid response, high sensitivity and stability are essential in the development of chemical sensors for the detection of chemical warfare agents. Nerve agent sarin [2-(fluoro-methyl-phosphoryl) oxypropane] is an organophosphate (OP) compound that is recognized as one of the most toxic chemical warfare agents. Considering sarin’s high toxicity, being odorless and colorless, dimethyl methylphosphonate (DMMP) is widely used as its simulant in the laboratory because of its similar chemical structure and much lower toxicity. Thus, this review serves to introduce the development of a variety of fabricated chemical sensors as potential sensing materials for the detection of DMMP in recent years. Furthermore, the research and application of carbon anotubes in DMMP polymer sensors, their sensitivity and limitation are highlighted. For sorption-based sensors, active materials play crucial roles in improving the integral performances of sensors. The novel active materials providing hydrogen-bonds between the polymers and carbon nanotubes are the main focus in this review.

Active chlorine decontaminants like hypochlorite are used to destroy chemical warfare agents (CWAs) such as HD, VX and GD due to the former's strong oxidation capacity and high nucleophilicity. In this paper, experiments were performed to identify the main factors affecting agent recovery from decon water. Based on the results, a method to recover residual CWAs from hypochlorite decon water before quantitative determination by GC was developed. The results showed that the extraction solvent was a critical determinant of high CWA recovery. Dichloromethane was more suitable than petroleum either, especially for samples containing GD or low residual CWAs. For VX-containing samples, the use of an alkali solution improved VX recovery. Neutralization was also important for a high CWA recovery, especially for samples with low CWA concentrations and/or strong decontaminant reactivity. The use of 15% sodium sulfite as the neutralization solution gave the best results for hypochlorite decon water. When the optimized conditions of simultaneous sodium sulfite neutralization and dichloromethane extraction were used, the recovery of HD, VX and GD in hypochlorite decon water was greater than 85% at a concentration range of 20 mg/L to 10,000 mg/L.

Metal organic frameworks (MOFs) have been suggested as promising materials for application in the degradation of chemical warfare agents, with the majority of studies to date focusing on nerve agents. One of the most prominent MOFs used in the detoxification of nerve agents is UiO-66, which is of interest as a future nerve agent decontaminant. However, blister agents, which constitute one of the most toxic and highly reactive categories of chemical agents, are yet to be examined as gas-phase decontamination targets using MOF structures. In this study, a novel type of UiO-66 with a smaller particle size, namely, UiO-66S, was used as a decontaminant for the blister agent simulant, 2-chloroethyl ethyl sulfide (2-CEES). The gas-phase chemical adsorption and decomposition of 2-CEES were demonstrated for the first time, with an estimated t1/2 of 1.34 h. This value is the highest reported value for an MOF in gas-phase reaction conditions. The obtained nontoxic degradation products were identified, and the reaction mechanism was studied using density functional theory calculations. Furthermore, the synthesized UiO-66S catalyst also exhibits superior catalytic ability toward nerve agent simulants (diisopropyl fluorophosphate).The results of the study provide a firm basis for the use of UiO-66S as a future decontaminant for both nerve and blister agents.

Sulfur mustard (SM), a chemical warfare agent, is a strong alkylating compound that readily reacts with numerous biomolecules. The goal of the present work was to define and validate new biomarkers of exposure to SM that could be easily accessible in urine or plasma. Because investigations using SM are prohibited by the Organization for the Prohibition of Chemical Weapons, we worked with 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM. We developed an ultra-high-pressure liquid chromatography - tandem mass spectrometry approach (UHPLC-MS/MS) to the conjugate of CEES to glutathione and two of its metabolites, the cysteine and the N-acetyl-cysteine conjugates. The N7-guanine adduct of CEES (N7Gua-CEES) was also targeted. After synthesizing the specific biomarkers, a solid phase extraction protocol and a UHPLC-MS/MS method with isotopic dilution were optimized. We were able to quantify N7Gua-CEES in the DNA of HaCaT keratinocytes and of explants of human skin exposed to CEES. N7Gua-CEES was also detected in the culture medium of these two models, together with the glutathione and the cysteine conjugates. In contrast, the N-acetyl-cysteine conjugate was not detected. The method was then applied to plasma from mice cutaneously exposed to CEES. All four markers could be detected. Our present results thus validate both the analytical technique and the biological relevance of new, easily quantifiable biomarkers of exposure to CEES. Because CEES behaves very similarly to SM, the results are promising for application to this toxic of interest., Analytical and Bioanalytical Chemistry, Springer Verlag, 2020

Chemical warfare agents (CWAs) pose an inevitable threat, both to soldiers and civilians. There have been many incidents where CWAs have claimed thousands of lives and contaminated many more people. In this regard, strict control and proper decontamination are equally important. Here, we present a visualization method to locate sulfur mustard (HD)-contaminated surfaces using a water-based sprayable polymer containing a sulfur mustard fluorescent probe (DPXT). After confirming the high sensitivity (0.9 μM) and selectivity of DPXT in aqueous solution toward sulfur mustard, a sprayable material was developed by immobilizing the DPXT in a water-soluble polymer. This method enables the localization of HD-contaminated areas through a fluorescence response detectible by the naked eye. Sprayable HD sensors present obvious advantages over other sensors since they do not necessitate damage to the surface of interest. In our perception, this sensing protocol also holds great potential in sensing and localizing other CWAs, and will be a powerful tool for monitoring decontamination processes.

International audience; The understanding of the thermal decomposition chemistry of chemical warfare nerve agents is largely limited by the scarcity of kinetic data. Because of the high toxicity of these molecules, experimental determination of their chemical properties is very difficult. In the present work, a comprehensive detailed kinetic model for the decomposition of sarin and some simulants, i.e. di-isopropyl methyl phosphonate (DIMP), diethyl methylphosphonate (DEMP), and triethyl phosphate (TEP) were developed, containing possible molecular and radical pathways. The importance of unimolecular pericyclic decomposition led to evaluate precisely the rate constants of these reactions with high level theoretical calculations. The QCISD(T)/cc-PV∞QZ//B2PLYPD3/6-311+G(2d,d,p) level of theory was selected after a benchmark. The contribution of hindered rotors was included with the 1D-HR-U approach. Tunneling was taken into account for H-atom transfer. Transition state theory was used to calculate high-pressure limit rate constants and pressure dependent rate constants were calculated using Master Equation modelling. The model was validated against experimental pyrolysis and oxidation experimental data available in literature. Flux analyses showed that whatever the conditions are, the first step of decomposition of the studied phosphorus compounds are pericyclic eliminations leading to successive decompositions, whereas bondbreaking or H-atom abstraction remain negligible, even at high temperature.

The potential threat that has originated from chemical warfare agents (CWAs) has promoted the development of advanced materials to enhance the protection of civilian and military personnel. Zr-based metal–organic frameworks (Zr-MOFs) have recently been demonstrated as excellent catalysts for decomposing CWAs, but challenges of integrating the microcrystalline powders of Zr-MOFs into monoliths still remain. Herein, we report hierarchically porous monolithic UiO-66-X xerogels for the destruction of CWAs. We found that the UiO-66-NH2 xerogel with a larger pore size and a higher surface area than the UiO-66-NH2 powder possessed better degradability of 2-chloroethyl ethyl sulfide (2-CEES), which is a sulfur mustard simulant. These UiO-66-X xerogels exhibit outstanding performance for decomposing CWAs. The half-lives of vesicant agent sulfur mustard (HD) and nerve agent O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) are as short as 14.4 min and 1.5 min, respectively. This work is, to the best of our knowledge, the first report on macroscopic monolithic UiO-66-X xerogels for ultrafast decomposition of CWAs.

[Image: see text] Organophosphorus esters (OPs) were originally developed as pesticides but were repurposed as easily manufactured, inexpensive, and highly toxic chemical warfare agents. Acute OP toxicity is primarily due to inhibition of acetylcholinesterase (AChE), an enzyme in the central and peripheral nervous system. OP inhibition of AChE can be reversed using oxime reactivators but many show poor CNS penetration, indicating a need for new clinically viable reactivators. However, challenges exist on how to best measure restored AChE activity in vivo and assess the reactivating agent efficacy. This work reports the development of molecular imaging tools using radiolabeled OP analog tracers that are less toxic to handle in the laboratory, yet inhibit AChE in a similar fashion to the actual OPs. Carbon-11 and fluorine-18 radiolabeled analog tracers of VX and sarin OP agents were prepared. Following intravenous injection in normal Sprague–Dawley rats (n = 3–4/tracer), the tracers were evaluated and compared using noninvasive microPET/CT imaging, biodistribution assay, and arterial blood analyses. All showed rapid uptake and stable retention in brain, heart, liver, and kidney tissues determined by imaging and biodistribution. Lung uptake of the sarin analog tracers was elevated, 2-fold and 4-fold higher uptake at 5 and 30 min, respectively, compared to that for the VX analog tracers. All tracers rapidly bound to red blood cells (RBC) and blood proteins as measured in the biodistribution and arterial blood samples. Analysis of the plasma soluble activity (nonprotein/cell bound activity) showed only 1–6% parent tracer and 88–95% of the activity in the combined solid fractions (RBC and protein bound) as early as 0.5 min post injection. Multivariate analysis of tracer production yield, molar activity, brain uptake, brain area under the curve over 0–15 min, and the amount of parent tracer in the plasma at 5 min revealed the [(18)F]VX analog tracer had the most favorable values for each metric. This tracer was considered the more optimal tracer relative to the other tracers studied and suitable for future in vivo OP exposure and reactivation studies.

Despite a recent dramatically increased risk of using chemical warfare agents in chemical attacks and assassinations, fundamental interactions of toxic chemicals with other materials are poorly understood, and micromechanisms of their chemical degradation are yet to be established. This represents an outstanding challenge in both fundamental science and practical applications in combat against chemical weapons. One of the most versatile and multifunctional oxides, TiO2, has been suggested as a promising material to quickly adsorb and effectively destroy toxins. In this paper, we explore how sarin (also known as GB) adsorbs and decomposes on dry nanoparticles of TiO2 anatase and rutile phases. We found that both anatase and rutile readily adsorb sarin gas molecules because of a strong electrostatic attraction between the phosphoryl oxygen and surface titanium atoms. The sarin decomposition most likely proceeds via a propene elimination; however, the reaction is exothermic on the rutile (110) surface and endothermic on the anatase (101) surface. High energy barriers suggest that sarin would hardly decompose on pristine dry surfaces of TiO2, and degradation reactions can be triggered by defects or contaminants under realistic operational conditions.

Highly porous zirconium-based metal–organic frameworks (MOFs) have been widely studied as materials for sorption and destruction of chemical warfare agents (CWAs). It is important to understand the...

A low-cost differential mobility spectrometer (DMS) was constructed using polytetrafluoroethylene printed circuit boards with two pairs of gold electrodes. The printed circuit boards were used to c...

Mustard gas (sulfur mustard, SM), a highly vesicating chemical warfare agent, was first deployed in warfare in 1917 and recently during the Iraq–Iran war (1980s) and Syrian conflicts (2000s); however, the threat of exposure from stockpiles and old artillery shells still looms large. Whereas research has been long ongoing on SM-induced toxicity, delineating the precise molecular pathways is still an ongoing area of investigation; thus, it is important to attempt novel approaches to decipher these mechanisms and develop a detailed network of pathways associated with SM-induced toxicity. One such avenue is exploring the role of microRNAs (miRNAs) in SM-induced toxicity. Recent research on the regulatory role of miRNAs provides important results to fill in the gaps in SM toxicity–associated mechanisms. In addition, differentially expressed miRNAs can also be used as diagnostic markers to determine the extent of toxicity in exposed individuals. Thus, in our review, we have summarized the studies conducted so far in cellular and animal models, including human subjects, on the expression profiles and roles of miRNAs in SM- and/or SM analog–induced toxicity. Further detailed research in this area will guide us in devising preventive strategies, diagnostic tools, and therapeutic interventions against SM-induced toxicity.

In the long and intensive search for effective treatments to counteract the toxicity of the chemical warfare (CW) agent sulphur mustard (H; bis(2-chloroethyl) sulphide), the most auspicious and consistent results have been obtained with the drug N-acetylcysteine (NAC), particularly with respect to its therapeutic use against the effects of inhaled H. It is a synthetic cysteine derivative that has been used in a wide variety of clinical applications for decades and a wealth of information exists on its safety and protective properties against a broad range of toxicants and disease states. Its primary mechanism of action is as a pro-drug for the synthesis of the antioxidant glutathione (GSH), particularly in those circumstances where oxidative stress has exhausted intracellular GSH stores. It impacts a number of pathways either directly or through its GSH-related antioxidant and anti-inflammatory properties, which make it a prime candidate as a potential treatment for the wide range of deleterious cellular effects that H is acknowledged to cause in exposed individuals. This report reviews the available literature on the protection afforded by NAC against the toxicity of H in a variety of model systems, including its efficacy in treating the long-term chronic lung effects of H that have been demonstrated in Iranian veterans exposed during the Iran-Iraq War (1980-1988). Although there is overwhelming evidence supporting this drug as a potential medical countermeasure against this CW agent, there is a requirement for carefully controlled clinical trials to determine the safety, efficacy and optimal NAC dosage regimens for the treatment of inhaled H., Graphical abstract Image 1, Highlights • N-Acetylcysteine (NAC) reduces the toxicity of sulphur mustard (H) in multiple cell types. • NAC reduces the toxic effects of H lung exposure in animal models. • Delayed (∼18 yrs) NAC treatment improves lung function in individuals exposed to H. • NAC is considered to be a safe and well tolerated medication in humans.

Recently, efforts have been made to adapt surface acoustic waves (SAWs) for use in chemical sensors for detection of chemical warfare agents (CWAs). In this study, a four-channel real-time CWA detection system was constructed using four 250-MHz SAW sensors. Each system consists of three different chemical sensors and one reference sensor. The reference sensor compensates for frequency variations according to humidity and temperature conditions. Signals from the SAW sensors can be checked on a PC-based graphical user interface without additional measuring equipment. To measure dimethyl methylphosphonate (DMMP), a simulant of sarin gas, polyhedral oligomeric silsesquioxane (POSS) and thiourea (TU)-based synthetic polymers were used as sensing materials. The reference sensor was not coated, whereas the three different chemical sensors were coated with POSS, TU-1, and TU-2. The maximum frequencies of POSS, TU-1, and TU-2 were shifted 15.86, 13.85, and 0.944 kHz, showing significant values. We also found a relatively good linear relation between the frequency shift and the concentration of DMMP. The three sensing materials selected-POSS, TU-1, and TU-2-responded significantly to DMMP and triethylphosphate in the selectivity tests. This response is due to the chemical bonding of the sensing materials with the phosphonate in the nerve-agent simulants. These results indicate that the four-channel SAW monitoring system described in this paper shows potential as a portable real-time monitoring system to detect a variety of toxic vapors simultaneously, without using complex measuring equipment. In addition, this approach has demonstrated potential for developing excellent portable sensors to detect different types of CWAs.

Nerve agents and neurobiological weapons are among the most devastating and lethal of weapons. Acetylcholinesterase inhibitors act by increasing the amount of acetylcholine in the neuromuscular junction, resulting in flaccid paralysis. Tabun, VX, soman, and sarin are the major agents in this category. Exposure to nerve agents can be inhalational or through dermal contact. Neurotoxins may have peripheral and central effects on the nervous system. Atropine is an effective antidote to nerve agents. Neurobiological weapons entail using whole organisms or organism-synthesized toxins as agents. Some organisms that can be used as biological weapons include smallpox virus.

Organophosphorus agents (OP) are widely used as pesticides due to their cost effectiveness, yet they present a significant public health risk owing to their high toxicity, especially in cases of occupational exposure in agriculture, during suicide attempts using pesticides, and as nerve agents in warfare. Their vigorous permeability through inhalation, ingestion, and dermal exposure results in a high number of reported OP poisoning cases and alarming mortality rates. Initial first-aid management involves decontamination, ventilation, and hemodialysis. Additionally, current treatment guidelines recommend prompt administration of atropine as a first-line antidote, oximes as a follow-up, benzodiazepines for seizure control, and pyridostigmine for prophylaxis. Nevertheless, current treatment options are associated with several challenges. Thus, recent research has focused on investigating novel approaches for their potential in improving current management strategies. This article intends to review recent advances in OP poisoning treatment, including agents investigated for their use as an alternative or adjunctive therapy, novel formulations such as nasal drops or sublingual tablets for emergency administration of atropine, as well as innovative strategies for enhanced oximes delivery and overall efficacy. However, two major barriers may limit these innovations, ethical issues associated with their clinical assessment in emergencies, and limited profitability in countries where most cases occur.

International audience; Novel 6-alkyl- and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesised by using a mild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2-pyridinaldoxime scaffolds, without altering the reducible, unprotected, sensitive oxime functionality and the C-F bond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximes may find medicinal application as antidotes to organophosphate poisoning. Indeed, one low-molecular-weight compound exhibited increased affinity for sarin-inhibited acetylcholinesterase (hAChE) and greater reactivation efficiency or resurrection for sarin-inhibited hAChE, compared with those of 2-pyridinaldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]methoxy}methyl)-2-[(hydroxyimino)methyl]pyridinium chloride (HI-6), two pyridinium salts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showed increased in vitro blood-brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promising features of novel low-molecular-weight alkylfluoropyridinaldoxime open up a new era for the design, synthesis and discovery of central non-quaternary broad spectrum reactivators for organophosphate-inhibited cholinesterases.

Chemical warfare (CW) exposure could be fatal to military and civilians through skin contamination. Our work and others focus on investigating stratum corneum reservoir with less regards to skin appendageal routes including hair follicles. Here, C-14 CW simulants (CWS) with specific activity of 0.1 mCi/ml were tested on abdominal and scalp human cadaver skin using flow-through diffusion system. Quantitative analysis of simulants in skin compartments were performed using scintillation counter. Scalp permeation of dipropylene glycol monomethyl ether (DPGME), diisopropyl methylphosphonate (DIMP) and methyl salicylate (MeS) exceed abdominal skin by 8%, 15%, and 6% (p value0.05) of applied dose, respectively. DPGME and DIMP (most hydrophilic) showed earlier permeation peak time (Tmax) through scalp skin at 2 and 4 h, respectively, comparing with 6 h with abdominal skin. The percentage of applied dose of DPGME and DIMP retained in human skin membrane (SC, epidermis, and viable dermis) showed no statistically significant difference between tested abdominal and scalp skin samples (p value0.05). The percentage of applied dose of MeS in scalp showed higher partitioning in stratum corneum and viable epidermis than abdominal skin (p value0.05). In conclusion, human scalp showed greater total skin absorption than abdominal skin. This work points to a qualitative importance of high follicular density body regions in percutaneous penetration and suggests that transfollicular pathway might have a significant role in early stage permeation of chemical warfare simulants. However, the difference noticed here between scalp and abdominal skin could be attributed to regional variability in anatomy, physiology, and barrier characteristics.

Inspired by recent breakthroughs with Zr(OH)4-type materials that decompose chemical warfare agents (CWAs), we explore aerogel forms of zirconium oxyhydroxide (ZrOxHy) as reactive sorbents for dime...

Therapeutic efficacy of antidotal treatment of acute poisoning by nerve agents is generally assessed by the evaluation of LD50 values of nerve agents over 24 h following poisoning without or with a...

Sulfur mustard (SM) is a toxic chemical warfare agent deployed in several conflicts within the last 100 years and still represents a threat in terroristic attacks and warfare. SM research focuses on understanding the pathophysiology of SM and identifying novel biomarkers of exposure. SM is known to alkylate nucleophilic moieties of endogenous proteins, for example, free thiol groups of cysteine residues. The two-dimensional-thiol-differences in gel electrophoresis (2D-thiol-DIGE) technique is an initial proteomics approach to detect proteins with free cysteine residues. These amino acids are selectively labeled with infrared-maleimide dyes visualized after GE. Cysteine residues derivatized by alkylating agents are no longer accessible for the maleimide-thiol coupling resulting in the loss of the fluorescent signal of the corresponding protein. To prove the applicability of 2D-thiol-DIGE, this technology was exemplarily applied to neat human serum albumin treated with SM, to lysates from human cell culture exposed to SM as well as to human plasma exposed to CEES (chloroethyl ethyl sulfide, an SM analogue). Exemplarily, the most prominent proteins modified by SM were identified by matrix-assisted laser desorption/ionization time-of-flight (tandem) mass spectrometry, MALDI-TOF MS(/MS), as creatine kinase (CK) from human cells and as alpha-1 antitrypsin (A1AT) from plasma samples. Peptides containing the residue Cys282 of CK and Cys232 of A1AT were unambiguously identified by micro liquid chromatography-electrospray ionization high-resolution tandem-mass spectrometry (μLC-ESI MS/HR MS) as being alkylated by SM bearing the specific hydroxyethylthioethyl-(HETE)-moiety. Both peptides might represent potential biomarkers of SM exposure. This is the first report introducing these endogenous proteins as targets of SM alkylation.

Nitrogen mustard (NM) and sulfur mustard are cytotoxic alkylating agents that cause severe and progressive damage to the respiratory tract. Evidence indicates that macrophages play a key role in the acute inflammatory phase and the later resolution/profibrotic phase of the pathogenic response. These diverse roles are mediated by inflammatory macrophages broadly classified as M1 proinflammatory and M2 anti-inflammatory that sequentially accumulate in the lung in response to injury. The goal of the present study was to identify signaling mechanisms contributing to macrophage activation in response to mustards. To accomplish this, we used RNA sequencing to analyze the gene expression profiles of lung macrophages isolated 1 and 28 days after intratracheal exposure of rats to NM (0.125 mg/kg) or phosphate-buffered saline control. We identified 641 and 792 differentially expressed genes 1 and 28 days post-NM exposure, respectively. These genes are primarily involved in processes related to cell movement and are regulated by cytokines, including tumor necrosis factor-α, interferon-γ, and interleukin-1β. Some of the most significantly enriched canonical pathways included STAT3 and NF-κB signaling. These cytokines and pathways may represent potential targets for therapeutic intervention to mitigate mustard-induced lung toxicity.

Organophosphorus compounds, such as chemical warfare nerve agents and pesticides, are known to cause neurological damage. This study measured nerve agent-related neuropathology and determined whether quantitative T2 MRI could be used as a biomarker of neurodegeneration. Quantitative T2 MRI was performed using a 9.4 T MRI on rats prior to and following soman exposure. T2 images were taken at least 24 h prior, 1 h and 18–24 h after soman exposure. Rats were pre- and post-treated with HI-6 dimethanesulfonate and atropine methyl nitrate. A multicomponent T2 acquisition and analysis was performed. Brains were stained with Fluoro-Jade C to assess neurodegeneration. Rats exposed to soman developed behavioral expression of electrographic seizures. At 18–24 h after soman exposure, significant increases in T2, a possible marker of edema, were found in multiple regions. The largest changes were in the piriform cortex (before: 47.7 ± 1.4 ms; 18–24 h: 82.3 ± 13.4 ms). Fluoro-Jade C staining showed significant neurodegeneration 18–24 h post exposure. The piriform cortex had the strongest correlation between the change in relaxation rate and percent neurodegeneration (r = 0.96, p 2 relaxivity and histopathology supports the use of T2 as a marker of injury.

Exposure to vesicants, including sulfur mustard and nitrogen mustard, causes damage to the epithelia of the respiratory tract and the lung. With time, this progresses to chronic disease, most notably, pulmonary fibrosis. The pathogenic process involves persistent inflammation and the release of cytotoxic oxidants, cytokines, chemokines, and profibrotic growth factors, which leads to the collapse of lung architecture, with fibrotic involution of the lung parenchyma. At present, there are no effective treatments available to combat this pathological process. Recently, much interest has focused on nutraceuticals, substances derived from plants, herbs, and fruits, that exert pleiotropic effects on inflammatory cells and parenchymal cells that may be useful in reducing fibrogenesis. Some promising results have been obtained with nutraceuticals in experimental animal models of inflammation-driven fibrosis. This review summarizes the current knowledge on the putative preventive/therapeutic efficacy of nutraceuticals in progressive pulmonary fibrosis, with a focus on their activity against inflammatory reactions and profibrotic cell differentiation.

The decontamination ability of montmorillonite-based acid-activated clay (AACL) toward the chemical warfare agents (CWAs) mustard gas (HD), soman (GD), and venomous agent X (VX) is evaluated using ...

Highly toxic organophosphorous nerve agents (OPAs) have been used in several armed conflicts and terror attacks in the last few decades. A new method for retrospective determination of alkyl methylphosphonic acid (AMPA) metabolites in urine after exposure to VX, GB and GF nerve agents was developed. This method enables a rapid, sensitive and selective determination of trace levels of the nerve agent biomarkers ethyl methylphosphonic acid (EMPA), isopropyl methylphosphonic acid (IMPA) and cyclohexyl methylphosphonic acid (CMPA) in urine. The new technique involves a unique combination of two solid phase extraction (SPE) cartridges: a Ba/Ag/H cartridge for urine interference removal, and a ZrO2 cartridge for selective reconstitution and enrichment of the AMPAs. Extraction of AMPAs from the ZrO2 cartridge was accomplished with a 1% ammonium hydroxide (NH4OH) solution and was followed by analysis via liquid chromatography–mass spectrometry (LC–MS). The limits of quantitation (LOQs) were in the range of 10–100 pg/mL with recoveries of 64–71% (± 5–19%) after fast sample preparation and a total LC–MS analysis cycle time of 15 min and 13 min, respectively. This method was successfully applied in vivo in a rabbit that was exposed to 0.5 LD50 (7.5 µg/kg, i.v.) sarin for retrospective monitoring of the IMPA metabolite in urine. For the first time, IMPA was determined in rabbit urine samples for 15 days post-exposure, which is longer than any reported post-exposure method for AMPAs. To the best of our knowledge, this new method is the most sensitive and rapid for AMPA determination in urine by LC–MS/MS analysis.

Sarin is a highly toxic nerve agent that was developed for chemical warfare during World War II and is used in present conflicts. Immediate effects of acute sarin exposure are established; however, whether effects persist after initial signs have subsided is debated. The National Toxicology Program (NTP) conducted a systematic review to evaluate the evidence for long-term neurological effects following acute (

A simple method to improve the thermal decomposition of chemical warfare agent simulants is reported. Utilizing pyrolyzed cotton balls as a substrate for the delivery of an incendiary agent into a bulk volume of chemical warfare agent simulants, significant enhancements in the burning rates were achieved with respect to either other wicks or the incendiary agent by itself. To perform the decomposition experiments and follow the reaction in real time, while still addressing the important safety considerations related to experiments involving chemical warfare agent simulants and incendiary agents, a simple instrument was assembled in a laboratory hood, where all experiments were performed. Under ambient conditions, this method was able to enhance the decomposition of simulants for both sulfur mustard (HD) and sarin (GB) chemical warfare agents. Overall, the proposed approach represents one of the simplest and more cost-effective ways to improve the decomposition of these dangerous substances, presenting options for field expedient and low-cost processes that could be applied in the near future to the safe destruction of an actual CWA.

Exposure of rats to 2-chloroethyl ethyl sulfide (CEES), an analog of sulfur mustard, can cause acute lung injury (ALI), resulting in increased inflammation and coagulation and altered levels of plasma microRNAs (miRNAs). Rats were exposed to aerosolized CEES and euthanized 12 h later for collection of tissue and plasma. Profiling of miRNAs in plasma, using a TaqMan-based RT-PCR array, revealed 14 differentially expressed miRNAs. Target gene prediction and pathway analysis revealed miRNA-mediated regulation of organismal injury, inflammation, and respiratory diseases. miR-140-5p, a marker of ALI, was downregulated in the plasma, lung, liver, and kidney of CEES-exposed rats, with a concomitant increase in the expression of the inflammation markers IL-6 and IL-1α and the coagulation marker tissue factor (F3). Exposure of rat airway epithelial cells (RL-65) to CEES (0.5 mM) caused cell death and a decrease in miR-140-5p both in cells and media supernatant. This was accompanied by an increase in cellular mRNA levels of IL-6, IL-1α, and F3, as well as FGF9 and EGR2, putative targets of miR-140. Knockdown of miR-140 by specific oligos in RL-65 cells mimicked the in vivo CEES-mediated effects, leading to significantly increased mRNA levels of IL-6, IL-1α, F3, FGF9, and EGR2. Our study identifies miR-140-5p as a mediator of CEES-induced ALI, which could potentially be targeted for therapy.

Chemical warfare agents (CWAs), such as sarin and sulfur mustard, continue to be a threat due to their high toxicity coupled with worldwide usage. Metal–organic frameworks (MOFs) are efficient mate...

In this review we focused our attention on sulfur mustard [bis(2-chloroethyl) sulphide], the main vesicant chemical warfare agent (CWA), which has been widely used in different military conflicts, including World War I and the Iran-Iraq war. Moreover, the evolution of the recent Iraq and Syria conflicts suggests that terrorist groups are aware of the significant psychological and media effects that would be produced by the mere attempt to use CWAs. Sulfur mustard can produce the alkylation of macromolecules bearing sulfhydryl groups, such as DNA and proteins. This vesicant can also generate free radicals which can develop toxicity in the areas exposed, such as the eyes, skin, respiratory tract (inhalation) and gastrointestinal tract (ingestion). In this respect, we advance and propose three salvage mechanisms through which a broad-spectrum multipotent molecule, melatonin, could facilitate neutralization of the toxic damage induced by sulfur mustard radical scavenging. We also speculate that the long-term effects of varying severity can appear after acute poisoning. Besides, melatonin-based therapy strategies can modulate of epigenetic mechanisms and become very suitable for the clinical treatment of victimized patients. However, the utilization of melatonin as a “therapeutic bullet” addressed to counteract the vesicant CWAs needs much additional in vitro research as well as systematic animal studies and controlled translational trials.

Sulfur mustard (SM) is a highly toxic war chemical that causes significant morbidity and mortality and lacks any effective therapy. Rats exposed to aerosolized CEES (2-chloroethyl ethyl sulfide; 10% in ethanol), an analog of SM, developed acute respiratory distress syndrome (ARDS), which is characterized by increased inflammation, hypoxemia and impaired gas exchange. We observed elevated levels of extracellular nucleic acids (eNA) in the bronchoalveolar lavage fluid (BALF) of CEES-exposed animals. eNA can induce inflammation, coagulation and barrier dysfunction. Treatment with hexadimethrine bromide (HDMBr; 10 mg/kg), an eNA neutralizing agent, 2 h post-exposure, reduced lung injury, inhibited disruption of alveolar–capillary barrier, improved blood oxygenation (PaO2/FiO2 ratio), thus reversing ARDS symptoms. HDMBr treatment also reduced lung inflammation in the CEES-exposed animals by decreasing IL-6, IL-1A, CXCL-1 and CCL-2 mRNA levels in lung tissues and HMGB1 protein in BALF. Furthermore, HDMBr treatment also reduced levels of lung tissue factor and plasminogen activator inhibitor-1 indicating reduction in clot formation and increased fibrinolysis. Fibrin was reduced in BALF of the HDMBr-treated animals. This was further confirmed by histology that revealed diminished airway fibrin, epithelial sloughing and hyaline membrane in the lungs of HDMBr-treated animals. HDMBr completely rescued the CEES-associated mortality 12 h post-exposure when the survival rate in CEES-only group was just 50%. Experimental eNA treatment of cells caused increased inflammation that was reversed by HDMBr. These results demonstrate a role of eNA in the pathogenesis of CEES/SM-induced injury and that its neutralization can serve as a potential therapeutic approach in treating SM toxicity.

Sulfur mustard (SM) is a vesicant chemical warfare agent which affects ocular, respiratory, and cutaneous system. In this study, we aimed to share recent experiences on medical management of chemical casualties that were exposed to SM in Middle East. We reported medical management of 17 contaminated patients. After the evacuation from the hot zone, all chemical casualties should be transferred to the designated intensive care units. After detailed medical decontamination and stabilization, biological samples should be collected from all chemical casualties as soon as possible for the verification of the exposure. Medical history and existing symptoms reveal the clinical diagnosis of SM exposure. Medical management of SM casualties should focus on "good nursing care" including treatment of pain and itching, fluid and electrolyte replacement therapy, respiration and nutrition support. Despite of improved clinical skills, treatment of SM lesions is still non-specific which aims to relieve symptoms and to prevent infections. Existing diagnostic capabilities and treatment approaches could be improved by sharing recent clinical experiences on medical management of SM casualties where there are still important major gaps.

Background: Sulfur mustard (SM), also known as mustard gas, was first widely used in the Iraq–Iran. After SM exposure, the most prominent clinical signs are the development of extensive non-healing...

This work presents a literature review concerning the construction, properties and application of different sensors used to detect dimethyl methylphonate (DMMP), which is the simulant of sarin. Sensors sensitive to mass are described, together with such sensors as: SAW, QCM, MEMS, also chemical capacitors, semiconductors, and field effect transistors.

The chemical warfare agent sulfur mustard (SM) affects all cells in the epidermis including melanocytes which are responsible for melanin synthesis. After exposure to SM, pigment abnormalities like hypo- and hyperpigmentation can occur. The underlying molecular pathomechanisms of SM exposure on human melanogenesis have not been elucidated so far. In our study, we investigated the effect of SM on human melanocytes and melanogenesis. Normal human epidermal melanocytes (NHEM) were used as in vitro model and they were exposed to different concentrations of SM (4.5 μM-100 μM). Melanin production was analyzed by absorption measurements at 405 nm. In addition, quantitative real-time PCR (qPCR) and Western blot experiments were performed to determine the expression of essential melanogenesis-related proteins including tyrosinase (TYR), tyrosinase-related protein (TRP) 1 and 2 and microphthalmia transcription factor (MITF). Our findings demonstrated that exposure to low SM concentrations increased melanin synthesis accompanied with an increase in protein expression. In contrast, high SM concentrations led to decreased melanin content and a downregulation in expression of all investigated melanogenesis-associated proteins. We concluded that low SM concentrations may cause hyperpigmentation while high SM concentrations decreased melanin content which may explain hypopigmented skin areas in SM exposed patients.