Pnictogen bond-driven control of the molecular interaction between organophosphorus and acetylcholinesterase enzyme.

This study addresses a comprehensive assessment of the interaction between chemical warfare agents (CWA) and acetylcholinesterase (AChE) systems, focus on the intriguing pnictogen-bond interaction (PnB). Utilizing the crystallographic data from the Protein Data Bank pertaining to the AChE-CWA complex involving Sarin (GB), Cyclosarin (GF), 2-[fluoro(methyl)phosphoryl]oxy-1,1-dimethylcyclopentane (GP) and venomous agent X (VX) agents, the CWA is systematically displaced by increments of 0.1 Å along the PO bond axis, extending its distance by 4 Å from the original position. The AIM analysis was carried out and consistently revealed the presence of a significant interaction along the PO bond. Investigating the intrinsic nature of the PnB, the NBO and the EDA analysis unearthed the contribution of orbital factors to the overall energy of the system. Strikingly, this observation challenges the conventional σ-hole explanation commonly associated with such interactions. This finding adds a layer of complexity to understanding of PnB, encouraging further exploration into the underlying mechanisms governing these intriguing chemical phenomena.

The prediction of acute toxicity (LD50) for organophosphorus-based chemical warfare agents (V-series) using toxicology in silico methods.

Nerve agents are organophosphate chemical warfare agents that exert their toxic effects by irreversibly inhibiting acetylcholinesterase, affecting the breakdown of the neurotransmitter acetylcholine in the synaptic cleft. Due to the risk of exposure to dangerous nerve agents and for animal welfare reasons, in silico methods have been used to assess acute toxicity safely. The next-generation risk assessment (NGRA) is a new approach for predicting toxicological parameters that can meet modern requirements for toxicological research. The present study explains the acute toxicity of the examined V-series nerve agents (n = 9) using QSAR models. Toxicity Estimation Software Tool (ver. 4.2.1 and ver. 5.1.2), QSAR Toolbox (ver. 4.6), and ProTox-II browser application were used to predict the median lethal dose. The Simplified Molecular Input Line Entry Specification (SMILES) was the input data source. The results indicate that the most deadly V-agents were VX and VM, followed by structural VX analogues: RVX and CVX. The least toxic turned out to be V-sub x and Substance 100A. In silico methods for predicting various parameters are crucial for filling data gaps ahead of experimental research and preparing for the upcoming use of nerve agents.

The estimation of acute oral toxicity (LD50) of G-series organophosphorus-based chemical warfare agents using quantitative and qualitative toxicology in silico methods.

The idea of this study was the estimation of the theoretical acute toxicity (t-LD50, rat, oral dose) of organophosphorus-based chemical warfare agents from the G-series (n = 12) using different in silico methods. Initially identified in Germany, the G-type nerve agents include potent compounds such as tabun, sarin, and soman. Despite their historical significance, there is a noticeable gap in acute toxicity data for these agents. This study employs qualitative (STopTox and AdmetSAR) and quantitative (TEST; CATMoS; ProTox-II and QSAR Toolbox) in silico methods to predict LD50 values, offering an ethical alternative to animal testing. Additionally, we conducted quantitative extrapolation from animals, and the results of qualitative tests confirmed the acute toxicity potential of these substances and enabled the identification of toxicophoric groups. According to our estimations, the most lethal agents within this category were GV, soman (GD), sarin (GB), thiosarin (GBS), and chlorosarin (GC), with t-LD50 values (oral administration, extrapolated from rat to human) of 0.05 mg/kg bw, 0.08 mg/kg bw, 0.12 mg/kg bw, 0.15 mg/kg bw, and 0.17 mg/kg bw, respectively. On the contrary, compounds with a cycloalkane attached to the phospho-oxygen linkage, specifically methyl cyclosarin and cyclosarin, were found to be the least toxic, with values of 2.28 mg/kg bw and 3.03 mg/kg bw. The findings aim to fill the knowledge gap regarding the acute toxicity of these agents, highlighting the need for modern toxicological methods that align with ethical considerations, next-generation risk assessment (NGRA) and the 3Rs (replacement, reduction and refinement) principles.

The prediction of hydrolysis and biodegradation of organophosphorus-based chemical warfare agents (G-series and V-series) using toxicology in silico methods.

Nerve agents (G- and V-series) are a group of extremely toxic organophosphorus chemical warfare agents that we have had the opportunity to encounter many times on a massive scale (Matsumoto City, Tokyo subway and Gulf War). The threat of using nerve agents in terrorist attacks or military operations is still present, even with establishing the Chemical Weapons Convention as the legal framework. Understanding their environmental sustainability and health risks is critical to social security. Due to the risk of contact with dangerous nerve agents and animal welfare considerations, in silico methods were used to assess hydrolysis and biodegradation safely. The environmental fate of the examined nerve agents was elucidated using QSAR models. The results indicate that the investigated compounds released into the environment hydrolyse at a different rate, from extremely fast (<1 day) to very slow (over a year); V-agents undergo slower hydrolysis compared to G-agents. V-agents turned out to be relatively challenging to biodegrade, the ultimate biodegradation time frame of which was predicted as weeks to months, while for G-agents, the overwhelming majority was classified as weeks. In silico methods for predicting various parameters are critical to preparing for the forthcoming application of nerve agents.

Highly Efficient Separation of Ethanol Amines and Cyanides via Ionic Magnetic Mesoporous Nanomaterials.

Simple and efficient sample pretreatment methods are important for analysis and detection of chemical warfare agents (CWAs) in environmental and biological samples. Despite many commercial materials or reagents that have been already applied in sample preparation, such as SPE columns, few materials with specificity have been utilized for purification or enrichment. In this study, ionic magnetic mesoporous nanomaterials such as poly(4-VB)@M-MSNs (magnetic mesoporous silicon nanoparticles modified by 4-vinyl benzene sulfonic acid) and Co2+@M-MSNs (magnetic mesoporous silicon nanoparticles modified by cobalt ions) with high absorptivity for ethanol amines (EAs, nitrogen mustard degradation products) and cyanide were successfully synthesized. The special nanomaterials were obtained by modification of magnetic mesoporous particles prepared based on co-precipitation using -SO3H and Co2+. The materials were fully characterized in terms of their composition and structure. The results indicated that poly(4-VB)@M-MSNs or Co2+@M-MSNs had an unambiguous core-shell structure with a BET of 341.7 m2·g-1 and a saturation magnetization intensity of 60.66 emu·g-1 which indicated the good thermal stability. Poly(4-VB)@M-MSNs showed selective adsorption for EAs while the Co2+@M-MSNs were for cyanide, respectively. The adsorption capacity quickly reached the adsorption equilibrium within the 90 s. The saturated adsorption amounts were MDEA = 35.83 mg·g-1, EDEA = 35.00 mg·g-1, TEA = 17.90 mg·g-1 and CN-= 31.48 mg·g-1, respectively. Meanwhile, the adsorption capacities could be maintained at 50-70% after three adsorption-desorption cycles. The adsorption isotherms were confirmed as the Langmuir equation and the Freundlich equation, respectively, and the adsorption mechanism was determined by DFT calculation. The adsorbents were applied for enrichment of targets in actual samples, which showed great potential for the verification of chemical weapons and the destruction of toxic chemicals.

Novel Application of Metal-Organic Frameworks as Efficient Sorbents for Solid-Phase Extraction of Chemical Warfare Agents and Related Compounds in Water Samples.

In this work, we test metal-organic frameworks (MOFs) as sorbents in the solid-phase extraction (SPE) technique to determine chemical warfare agents (CWAs) and their related compounds in water samples. During this study, we used 13 target compounds to test the selectivity of MOFs thoroughly. Three MOFs were used: MIL-100(Fe), ZIF-8(Zn), and UiO-66(Zr). The obtained materials were characterized using FT-IR/ATR, SEM, and XRD. CWA's and related compounds were analyzed using gas chromatography coupled with tandem mass spectrometry (GC-MS/MS). The effect of the type of elution solvent and the amount of sorbent (MOFs) in the column on the efficiency of the conducted extraction were verified. The LOD ranged from 0.04 to 7.54 ng mL-1, and the linearity range for the analytes tested extended from 0.11/22.62 (depending on the compound) to 1000 ng mL-1. It was found that MOFs showed the most excellent selectivity to compounds having aromatic rings in their structure or a "spread" spatial structure. The best recoveries were obtained for DPAA, CAP, and malathion. Environmental water samples collected from the Baltic Sea were analyzed using an optimized procedure to verify the developed method's usefulness.

Cutaneous Exposure to Arsenicals Is Associated with Development of Constrictive Bronchiolitis in Mice.

Organoarsenicals, such as lewisite and related chloroarsine, diphenylchloroarsine (DPCA), are chemical warfare agents developed during World War I. Stockpiles in Eastern Europe remain a threat to humans. The well-documented effects of cutaneous exposure to these organoarsenicals include skin blisters, painful burns, and life-threatening conditions such as acute respiratory distress syndrome. In survivors, long-term effects such as the development of respiratory ailments are reported for the organoarsenical sulfur mustard; however, no long-term pulmonary effects are documented for lewisite and DPCA. No animal models exist to explore the relationship between skin exposure to vesicants and constrictive bronchiolitis. We developed and characterized a mouse model to study the long-term effects of cutaneous exposure on the lungs after exposure to a sublethal dose of organoarsenicals. We exposed mice to lewisite, DPCA, or a less toxic surrogate organoarsenic chemical, phenyl arsine oxide, on the skin. The surviving mice were followed for 20 weeks after skin exposure to arsenicals. Lung microcomputed tomography, lung function, and histology demonstrated increased airway resistance, increased thickness of the smooth muscle layer, increased collagen deposition in the subepithelium, and peribronchial lymphocyte infiltration in mice exposed to arsenical on skin.

Progress towards a standardized model of ocular sulfur mustard injury for therapeutic testing.

Sulfur mustard (SM) remains a highly dangerous chemical weapon capable of producing mass casualties through liquid or vapor exposure. The cornea is highly sensitive to SM toxicity and exposure to low vapor doses can cause incapacitating acute injuries. At higher doses, corneas fail to fully heal and subsequently develop a constellation of symptoms known as mustard gas keratopathy (MGK) that causes reduced quality of life and impaired or lost vision. Despite a century of research, there are no specific treatments for acute or persistent ocular SM injuries. Here I summarize toxicological, clinical and pathophysiological mechanisms of SM vapor injury in the cornea, describe a preclinical model of ocular SM vapor exposure for reproducible therapeutic studies, and propose new approaches to improve evaluation of therapeutic effects. I also describe recent findings illustrating the delayed development of a transient but severe recurrent corneal lesion that, in turn, triggers the emergence of secondary keratopathies characteristic of the chronic form of MGK. Development of this recurrent lesion is SM dose-dependent, although the severity of the recurrent lesion appears SM dose-independent. Similar recurrent lesions have been reported in multiple species, including humans. Given the mechanistic relationship between the recurrent lesion and chronic, secondary keratopathies, I hypothesize that preventing the development of the recurrent lesion represents a novel and potentially valuable therapeutic approach for treatment of severe corneal SM injuries. Although ocular exposure to SM vapor continues to be a challenging therapeutic target, establishing consistent and reproducible models of corneal injury that enhance mechanistic and pathophysiological understanding will help satisfy regulatory requirements and accelerate the development of effective therapies.

Mechanistic understanding of the toxic effects of arsenic and warfare arsenicals on human health and environment.

Worldwide, more than 200 million people are estimated to be exposed to unsafe levels of arsenic. Chronic exposure to unsafe levels of groundwater arsenic is responsible for multiple human disorders, including dermal, cardiovascular, neurological, pulmonary, renal, and metabolic conditions. Consumption of rice and seafood (where high levels of arsenic are accumulated) is also responsible for human exposure to arsenic. The toxicity of arsenic compounds varies greatly and may depend on their chemical form, solubility, and concentration. Surprisingly, synthetic organoarsenicals are extremely toxic molecules which created interest in their development as chemical warfare agents (CWAs) during World War I (WWI). Among these CWAs, adamsite, Clark I, Clark II, and lewisite are of critical importance, as stockpiles of these agents still exist worldwide. In addition, unused WWII weaponized arsenicals discarded in water bodies or buried in many parts of the world continue to pose a serious threat to the environment and human health. Metabolic inhibition, oxidative stress, genotoxicity, and epigenetic alterations including micro-RNA-dependent regulation are some of the underlying mechanisms of arsenic toxicity. Mechanistic understanding of the toxicity of organoarsenicals is also critical for the development of effective therapeutic interventions. This review provides comprehensive details and a critical assessment of recently published data on various chemical forms of arsenic, their exposure, and implications on human and environmental health.

Rapid Non-Contact Detection of Chemical Warfare Agents by Laser Photoacoustic Spectroscopy.

Nerve agents have recently been used in battlefield operations, espionage wars, and terrorist attacks. These compounds, like some pesticides, cause organophosphate poisoning. The rapid, noncontact detection of a sarin simulant in the liquid phase has been demonstrated at the Diagnostics and Metrology Laboratory of the Italian National Agency for New Technologies, Energy and Sustainable Economic Development using laser photoacoustic spectroscopy, an infrared absorption technology. The first measurements, carried out with an experimental system based on a quantum cascade laser and developed for the assessment of food authenticity in the "fingerprint region", show that a detection limit of one nanolitre is within the reach of the instrument when chemometric analysis is applied.

Superelastic and Photothermal RGO/Zr-Doped TiO2 Nanofibrous Aerogels Enable the Rapid Decomposition of Chemical Warfare Agents.

To date, the reckless use of deadly chemical warfare agents (CWAs) has posed serious risks to humanity, property, and ecological environment. Therefore, necessary materials able to rapidly adsorb and securely decompose these hazardous toxics are in urgent demand. Herein, three-dimensional (3D) reduced graphene oxide/Zr-doped TiO2 nanofibrous aerogels (RGO/ZT NAs) are synthesized by feasibly combining sol-gel electrospinning technology and a unidirectional freeze-drying approach. Benefiting from the synergetic coassembly of flexible ZT nanofibers and pliable RGO nanosheets, the hierarchically entangled fibrous frameworks feature ultralow density, superior elasticity, and robust fatigue resistance over 106 compressive cycles. In particular, the RGO incorporation is attributed to the achieved increased surface area, stronger light absorption, and decreased recombination of charge-carriers for photocatalysis. The highly porous 3D RGO/ZT NAs deliver enhanced photothermal catalytic activity for CWA degradation as well as excellent recyclability and good photostability. This work opens fresh horizons for developing advanced 3D aerogel-based photocatalysts in a controlled fashion.

Regional variation in percutaneous absorption in in vitro human models: a systematic review.

Percutaneous absorption is of importance given its role in topical medicaments, transdermal drug systems, and dermatotoxicology. Many factors influence percutaneous penetration, including anatomical region, although little is currently known regarding this parameter. Hence, the aim of this study was to summarize existing data on regional variation in percutaneous penetration in in vitro human models. PubMed, Embase, Web of Science, and US patent literature were explored, and relevant data collected. Eight eligible articles were identified, which together, explored 15 anatomical locations. Four investigations compared percutaneous penetration between scalp and abdominal skin, and all concluded that the former was more permeable. Within those four studies, 10 penetrants of varying physical/chemical properties were tested indicating that in those particular study conditions, anatomical location exerted a greater effect on percutaneous absorption than the physicochemical properties of the penetrants. In addition, torso area was less absorptive than scrotum in both studies in which these sites were compared. In conclusion, the scrotum and scalp appear to be highly susceptible to percutaneous absorption compared to other locations such as the abdomen. This is postulated to be largely due to the high density of hair follicles in these areas, enabling greater penetration via the appendageal pathway. However, there is a paucity of conclusive data regarding the penetrability of other anatomical locations. Investigations testing and ranking the susceptibility of different anatomical regions is of vital importance given the importance of (1) transdermal drug delivery and decontamination protocols and (2) understanding the underlying mechanisms and degree of these variances might aid our pharmacologic/toxicologic judgments.

Chemical forensic profiling and attribution signature determination of sarin nerve agent using GC-MS, LC-MS and NMR.

Sarin is a highly toxic nerve agent classified by the Chemical Weapon Convention as a Schedule 1 chemical with no use other than to kill or injure. Moreover, in recent times, chemical warfare agents have been deployed against both military and civilian populations. Chemical warfare agents always contain minor impurities that can provide important chemical attribution signatures (CAS) that can aid in forensic investigations. In order to understand the trace molecular composition of sarin, various analytical approaches including GC-MS, LC-MS and NMR were used to determine the chemical markers of a set of sarin samples. Precursor materials were studied and the full characterisation of a synthetic process was undertaken in order to provide new insights into potential chemical attribution signatures for this agent. Several compounds that were identified in the precursor were also found in the sarin samples linking it to its method of preparation. The identification of these CAS contributes critical information about a synthetic route to sarin, and has potential for translation to related nerve agents.

A review of chemical warfare agents linked to respiratory and neurological effects experienced in Gulf War Illness.

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.

Efficacy of water-only or soap and water skin decontamination of chemical warfare agents or simulants using in vitro human models: A systematic review.

Water-only or water and soap are widely recommended as preferred solutions for dermal decontamination. However, limited efficacy data exist. We summarized experimental studies evaluating in vitro efficacy of water-only or soap and water in decontaminating chemical warfare agents (CWA) or their simulants from human skin models. Embase, Covidence®, MEDLINE, PubMed, Web of Science, and Google Scholar were searched for articles using water-only or soap and water decontamination methods for removal of CWA/CWA simulants in in vitro human skin models. Data extraction was completed from seven studies, yielding seven contaminants. Water-only decontamination led to partial decontamination in all skin samples (100%, n = 81/81). Soap and water decontamination led to partial decontamination in all skin samples (100%, n = 143/143). Four studies found decontamination to either paradoxically enhance absorption of contaminants or their penetration rates, known as the "wash-in" effect. Despite recommendations, water-only or water and soap decontamination were found to yield partial decontamination of CWA or their simulants in all human in vitro studies. Thus, more effective decontaminating agents are needed. Some studies demonstrated increased or faster penetration of chemicals following decontamination, which could prove deadly for agents such as VX, although these findings require in vivo validation. Heterogeneity in experimental setups limits interstudy comparison, and it remains unclear when water-only or water and soap are ideal decontaminants, which requires more studies. Pending manuscripts will summarize in vivo human and animal efficacy data. International harmonized efficacy protocol should enable more efficient public health decisions for evidence-based public health decisions.

Efficacy of water skin decontamination in vivo in humans: A systematic review.

With the constant possibility of occupational exposures, chemical warfare, and targeted attacks, increased attention has been given to determining effective and timely dermal decontamination strategies. This systematic review summarises experimental studies reporting decontamination with water-based solutions of dermal chemical contaminants with in vivo human data. Embase, MEDLINE, PubMed, Web of Science, and Google Scholar databases were comprehensively searched using search terms ("cutaneous" or "skin" or "dermal" or "percutaneous") and ("decontamination" or "decontaminant" or "skin decontamination") to include 10 studies, representing 18 chemical contaminants, 199 participants, and 351 decontamination outcomes. Three studies included data from decontamination with water (10.8%, n = 38/351 decontamination outcomes), seven with soap and water (68.4%, n = 240/351 decontamination outcomes), and two with 10% isopropanol distilled water (20.8%, n = 73/351 decontamination outcomes). Results of dermal decontamination using water showed complete decontamination (CD) outcomes in 52.6% (n = 20/38) and partial decontamination (PD) in 47.4% (n = 18/38); using soap and water showed PD outcomes in 92.9% (n = 223/240) and minimal to no effect in 7.1% (n = 17/240); and using 10% isopropanol distilled water achieved PD outcomes in 100.0% (n = 73/73). Available data show that decontamination with water, soap and water, and 10% isopropanol distilled water is incomplete. Much remains to be learned about decontamination of the large variety of chemical contaminants including a range of molecular weights, lipid and water solubilities, melting points, volatility, and hydrogen bonds, as well as clinically relevant anatomic sites. A major void exists in data confirming or denying the completeness of decontamination by measuring absorption and excretion. The development of effective decontamination solutions is of high priority.

Nanoflake-Engineered Zirconic Fibrous Aerogels with Parallel-Arrayed Conduits for Fast Nerve Agent Degradation.

Chemical warfare agents (CWAs) pose huge threats to ecological environments, agriculture, and human health due to the turbulent international situation in contemporary society. Zirconium hydroxide (Zr(OH)4) has captured the prime focus as an effective candidate for CWA decomposition but is often hindered by the isolated powder form. Here, we demonstrate a scalable three-dimensional space-confined synthetic strategy to fabricate nanoflake-engineered zirconic fibrous aerogels (NZFAs). Our strategy enables the stereoscopic Zr(OH)4 nanoflakes vertically and evenly in situ grown on the interconnected fibrous framework, remarkably enlarging the surface area and providing rich active sites for CWA catalysis. The as-synthesized NZFAs exhibit intriguing properties of ultralow density (>0.37 mg cm-3), shape-memory behavior under 90% strain, and robust fatigue resistance over 106 compression cycles at 40% strain. Meanwhile, the high air permeability, prominent adsorptivity, and reusability make them state-of-the-art chemical protective materials. This work may provide an avenue for developing next-generation aerogel-based catalysts and beyond.

Aminal-Linked Porphyrinic Covalent Organic Framework for Rapid Photocatalytic Decontamination of Mustard-Gas Simulant.

Covalent organic frameworks (COFs) are appealing photocatalysts for toxic chemical degradation. Great efforts have been devoted to regulate the photocatalytic performance of COFs by tuning their organic building blocks, but the relationship between COF linkage and photochemical properties has rarely been explored. Herein, we report the synthesis and characterisation of a novel aminal-linked porphyrinic COF, namely Por-Aminal-COF. Por-Aminal-COF (0.25 mol %) showed excellent photocatalytic activity toward the detoxification of the sulfur mustard simulant with a half-life (t1/2 ) of 5 min, which is far lower than that of traditional imine-linked Por-COF (t1/2 =16 min). Transient absorption spectroscopy indicated that the aminal linkages of Por-Aminal-COF facilitated the intersystem crossing process. Thus, Por-Aminal-COF showed higher triplet-state generation efficiency compared with Por-COF, consequently promoting the activation of oxygen molecular to singlet oxygen.

Ultrathin Zirconium Hydroxide Nanosheet-Assembled Nanofibrous Membranes for Rapid Degradation of Chemical Warfare Agents.

Organophosphorus-based chemical warfare agents (CWAs) are highly poisonous, and recent attacks using nerve agents have stimulated researchers to develop breakthrough materials for their fast degradation. Zr-based materials have been identified as the most effective catalysts for breaking down CWAs, but in their powdered form, their practical application in personal protective equipment is limited. Herein, a surface-confined strategy for the direct growth of vertically aligned zirconium hydroxide (Zr(OH)4 ) nanosheets with ultrathin and tortuous structures on nanofibers is reported. The freestanding Zr(OH)4 nanosheet-assembled nanofibrous membranes (NANMs) show superior catalytic performance to degrade dimethyl methylphosphonate, a nerve agent simulant, with a half-life of 4 min. In addition, intriguing membrane-type NANMs feature integrated properties of exceptional breathability, prominent flexibility, and robust fatigue resistance over one million buckling loads. This facile strategy provides a novel route to manufacture new classes of nanosheet-supported membranes for chemical-protective materials, in particular for gas filters, protective suits, and clothing.

Catalytic Processes for the Neutralization of Sulfur Mustard.

Research on the decontamination of the chemical warfare agent sulfur mustard pursues several objectives that include the neutralization of spared ammunition, the cleaning of affected areas, and also the development of protective equipment or tools. Neutralization of vesicant sulfur mustard involves different chemical routes such as hydrolysis, dehydrochlorination, oxidation, or complete mineralization. This review weighs the pros and cons associated with the different systems reported in the literature, with an emphasis on catalytic procedures, to selectively convert sulfur mustard or its simulants into harmless products.