Nerve Agents Research Articles

Organophosphate Level Evaluation for the Poisoning Treatment by Enzyme Activation Regeneration Strategy with Oxime-Functionalized ZIF-8 Nanoparticles.

In this work, two nanometal-organic frameworks (NMOFs) of ZIF-8-1 and ZIF-8-2 were designed and synthesized with a "missing linker" defects strategy by using Oxime-1 and Oxime-2 as coligands, respectively. ZIF-8-2 exhibited an excellent performance in comparison to that of ZIF-8-1 in activating and regenerating the activity of BChE suppressed by demeton-S-methyl (DSM) and could rapidly detoxify DSM in poisoned serum samples within 24 min. Additionally, the synthesized fluorescence probe of IND-BChE with high quantum yields, large Stokes shifts, and superior water solubility could be used for the detection of both butyrylcholinesterase (BChE) and DSM in a lower LOD of 0.63 mU/mL (BChE) and 0.086 μg/mL (DSM). By the difference in fluorescent intensity of IND-BChE with and without ZIF-8-2, a highly linear relationship of IND-BChE with DSM concentration was found (R2 = 0.9889), and the LOD was 0.073 μg/mL. In addition, an intelligent detection platform of ZIF-8-2@IND-BChE@agarose hydrogel combined with a smartphone formed a point-of-care test for DSM -poisoned serum samples and also realized satisfactory results. Unlike other detection methods of nerve agents, this assay first combined an NMOF reactivator for detoxification and detection of BChE enzyme activity and then quantification of OP nerve agents, which was of great significance in treatment of organophosphate poisoning.

Photothermally Active Core-Shell Catalyst Based on UiO-66 and Polydopamine for Highly Effective Detoxification of Nerve Agents.

A new, photothermally active, catalytic composite (Fe3O4@PD@UiO-66) based on UiO-66 and polydopamine (PD) was prepared for the decomposition of chemical warfare agents (CWAs). An iron oxide nanoparticle was introduced to enable rapid recovery after the reaction. The PD layer enabled conversion of the absorbed light into heat under infrared (IR) irradiation and increased the reaction temperature, thereby increasing the reaction rate. Dendrimer-functionalized silica particles (NH2-DS) were used as heterogeneous catalyst regenerators instead of N-ethylmorpholine. Under IR irradiation, a mixture of Fe3O4@PD@UiO-66 and NH2-DS was effective as a heterogeneous catalyst for degrading DMNP, with a 5 min half-life in water. Without IR irradiation, the half-life of DMNP was 45 min using the same catalyst mixture. Various bases including arginine, histidine, and D4 were directly modified on the surface of Fe3O4@PD@UiO-66 and used without NH2-DS or N-ethylmorpholine in order to compare their reactivities. Furthermore, a mixture of Fe3O4@PD@UiO-66 and NH2-DS was used for the decomposition of nerve agents, including sarin (GB), soman (GD), and VX, under IR-LED irradiation. Remarkably, GB was effectively decomposed with a half-life of 4.2 min, and GD demonstrated a half-life of 8.7 min. VX was hydrolyzed with a half-life of 14.0 min.

Evaluation of Malathion, DIMP, and Strawberry Furanone as CWA Simulants for Consideration in Field-Level Interior Building Remediation Exercises.

Field-level exercises with the purpose to assess remediation following the deliberate release of a highly toxic chemical in an indoor environment can be conducted using low(er) toxicity simulants if they are closely linked to the behavior of the toxic chemical itself. Chemical warfare agent (CWA) simulants have been identified on their suitability based on chemical structural similarities and associated physical and chemical properties. However, there are no reported studies that combine measurement of simulant parameters like persistence on surfaces, ability to sample for, and capability to degrade during the decontamination phase such that the level of success of a field-level exercise can be quantified. Experimental research was conducted to assess these gaps using a select number of CWA simulants. The organophosphate pesticide malathion was found to be a suitable simulant for use in field-level exercises that simulate the release of the highly persistent nerve agent VX based on its high persistence, effective surface sampling and analysis using standard analytical equipment, and the in situ degradation in the presence of different oxidizing decontaminants.

Peripheral and central effects of NADPH oxidase inhibitor, mitoapocynin, in a rat model of diisopropylfluorophosphate (DFP) toxicity.

Organophosphates (OP) are highly toxic chemical nerve agents that have been used in chemical warfare. Currently, there are no effective medical countermeasures (MCMs) that mitigate the chronic effects of OP exposure. Oxidative stress is a key mechanism underlying OP-induced cell death and inflammation in the peripheral and central nervous systems and is not mitigated by the available MCMs. NADPH oxidase (NOX) is one of the leading producers of reactive oxygen species (ROS) following status epilepticus (SE). In this study, we tested the efficacy of the mitochondrial-targeted NOX inhibitor, mitoapocynin (MPO) (10 mg/kg, oral), in a rat diisopropylfluorophosphate (DFP) model of OP toxicity. In DFP-exposed animals, MPO decreased oxidative stress markers nitrite, ROS, and GSSG in the serum. Additionally, MPO significantly reduced proinflammatory cytokines IL-1β, IL-6, and TNF-α post-DFP exposure. There was a significant increase in GP91phox, a NOX2 subunit, in the brains of DFP-exposed animals 1-week post-challenge. However, MPO treatment did not affect NOX2 expression in the brain. Neurodegeneration (NeuN and FJB) and gliosis [microglia (IBA1 and CD68), and astroglia (GFAP and C3)] quantification revealed a significant increase in neurodegeneration and gliosis after DFP-exposure. A marginal reduction in microglial cells and C3 colocalization with GFAP in DFP + MPO was observed. The MPO dosing regimen used in this study at 10 mg/kg did not affect microglial CD68 expression, astroglial count, or neurodegeneration. MPO reduced DFP-induced oxidative stress and inflammation markers in the serum but only marginally mitigated the effects in the brain. Dose optimization studies are required to determine the effective dose of MPO to mitigate DFP-induced changes in the brain.

Terrorism at Rise with the Chemicals Insight: Use of Chemical Warfare Agents an Issue of Global Concern

Crime has led to a worldwide increase with a main weapon of offence including not only a physical object but show the incidences of involvement of chemicals also. Chemical warfare agents are one such example commonly employed by large group of people, mainly violent criminals who not only wants to create a terror or threat in the world but to cause war scale destruction. There are numerous of incidents reported from past showing the involvement of hazardous chemicals for committing crimes. Chemical Warfare Agents (CWA) are synthetic chemicals used in the warfare as weapons, which are highly toxic and lethal to the extent that can cause temporary incapacitation, permanent health damage and even death of the targets. Common examples of these agents are nerve agents, vesicants, incapacitating agents, blood agents, and riots control agents. These agents are variedly classified as per the above-mentioned categories depending onto the effects and adverse effects they poses on human health and on society. The rate of crime commission using these hazardous agents is very rapid, thus making it an issue of serious concern to take measures to prevent innocent individuals.

Water-Accelerated Transport: Vapor-Phase Nerve Agent Simulant Delivery within a Catalytic Zirconium Metal-Organic Framework as a Function of Relative Humidity.

Zirconium-based metal-organic frameworks (MOFs) are candidate materials for effective nerve agent detoxification due to their thermo- and water stability as well as high density of catalytic Zr sites. However, as high-porosity materials, most of the active sites of Zr-MOFs can only be accessed by diffusion into the crystal interior. Therefore, the transport of nerve agents in nanopores is an important factor in the catalytic performance of Zr-MOFs. Here, we investigated the transport process and mechanism of a vapor-phase nerve agent simulant, dimethyl methyl phosphonate (DMMP), through a representative Zr-MOF, NU-1008, under practical conditions of varying humidity. Confocal Raman microscopy was used to monitor the transport of DMMP vapor through individual NU-1008 crystallites, where the relative humidity (RH) of the environment was tuned to understand the impact of water. Counterintuitively, water in the MOF channels, instead of blocking DMMP transport, assists DMMP diffusion; indeed, the transport diffusivity (Dt) of DMMP in NU-1008 is one order of magnitude higher at 70% than 0% RH. To understand the mechanism, magic angle spinning NMR and molecular dynamics simulations were performed and suggested that high water content in the channels prevents DMMP from hydrogen-bonding with the nodes, allowing for faster diffusion of DMMP in the channels. The simulated self-diffusivity (Ds) of DMMP is observed to be concentration-dependent. At low loading of DMMP, Ds is higher at 70% RH than 0% RH, while at high loadings the trend reverses due to the DMMP aggregation in water and the reduction of free volume in channels.

Epigenetic analysis in a murine genetic model of Gulf War illness.

Of the nearly 1 million military personnel who participated in the 1990-1991 Gulf War, between 25% and 35% became ill with what now is referred to as Gulf War Illness (GWI) by the Department of Defense. Symptoms varied from gastrointestinal distress to lethargy, memory loss, inability to concentrate, depression, respiratory, and reproductive problems. The symptoms have persisted for 30years in those afflicted but the basis of the illness remains largely unknown. Nerve agents and other chemical exposures in the war zone have been implicated but the long-term effects of these acute exposures have left few if any identifiable signatures. The major aim of this study is to elucidate the possible genomic basis for the persistence of symptoms, especially of the neurological and behavioral effects. To address this, we performed a whole genome epigenetic analysis of the proposed cause of GWI, viz., exposure to organophosphate neurotoxicants combined with high circulating glucocorticoids in two inbred mouse strains, C57BL/6J and DBA/2J. The animals received corticosterone in their drinking water for 7days followed by injection of diisopropylfluorophosphate, a nerve agent surrogate. Six weeks after DFP injection, the animals were euthanized and medial prefrontal cortex harvested for genome-wide DNA methylation analysis using high-throughput sequencing. We observed 67 differentially methylated genes, notably among them, Ttll7, Akr1c14, Slc44a4, and Rusc2, all related to different symptoms of GWI. Our results support proof of principle of genetic differences in the chronic effects of GWI-related exposures and may reveal why the disease has persisted in many of the now aging Gulf War veterans.

Experimental and chemical kinetic modeling study of high-temperature oxidation of diisopropyl methylphosphonate (DIMP) - A sarin simulant

Chemical warfare (CW) agent simulants are used in laboratory experiments to study the combustion characteristics of CW agents due to their high toxicity. A crucial CW agent simulant with a chemical structure similar to the deadly nerve agent Sarin (GB) is diisopropyl methylphosphonate (DIMP), an organophosphate compound (OPC). In this study, the high-temperature oxidation of DIMP is investigated in a shock tube at temperatures between 1440 K and 1710 K and a pressure of 1–2 atm. The carbon monoxide mole fraction time histories near 4.9 µm were obtained using laser absorption spectroscopy. The rate parameters for DIMP's H-abstraction reactions with O, and OH radicals were determined using molecular simulations. The rates of reactions involving smaller phosphorous species were also calculated at the CBS-QB3 level. These reactions along with the isopropanol sub-mechanism from the literature were added to the LLNL model to obtain an improved chemical kinetic mechanism for DIMP. Since isopropanol was a major intermediate in DIMP decomposition, validations were conducted with CO time histories during the oxidation of isopropanol. The new model predicted CO during isopropanol oxidation reasonably well. Both the LLNL model and the model developed in this work could predict CO time histories during DIMP oxidation satisfactorily. To comprehend the CO formation pathways and sensitive reactions during DIMP oxidation, reaction path analysis and sensitivity analysis were also carried out. The reaction mechanism developed here will help in the design, development, and optimization of efficient, effective and secure CW destruction techniques.

Self-Assembled MOF-on-MOF Nanofabrics for Synergistic Detoxification of Chemical Warfare Agent Simulants.

The development of protective fabrics that are capable of capturing and detoxifying a wide range of lethal chemical warfare agents (CWAs) in an efficient way is of great importance for individual protection gears/clothing. In this work, unique metal-organic framework (MOF)-on-MOF nanofabrics were fabricated through facile self-assembly of UiO-66-NH2 and MIL-101(Cr) crystals on electrospun polyacrylonitrile (PAN) nanofabrics and exhibited intriguing synergistic effects between the MOF composites on the detoxification of both nerve agent and blistering agent simulants. MIL-101(Cr), although not catalytic, facilitates the enrichment of CWA simulants from solution or air, thereby delivering a high concentration of reactants to catalytic UiO-66-NH2 coated on its surface and providing an enlarged contact area for CWA simulants with the Zr6 nodes and aminocarboxylate linkers compared to solid substrates. Consequently, the as-prepared MOF-on-MOF nanofabrics showed a fast hydrolysis rate (t1/2 = 2.8 min) for dimethyl 4-nitrophenylphosphate (DMNP) in alkaline solutions and a high removal rate (90% within 4 h) of 2-(ethylthio)-chloroethane (CEES) under environmental conditions, considerably surpassing their single-MOF counterparts and the mixture of two MOF nanofabrics. This work demonstrates synergistic detoxification of CWA simulants using MOF-on-MOF composites for the first time and has the potential to be extended to other MOF/MOF pairs, which provides new ideas for the development of highly efficient toxic gas-protective materials.

Quantum Dot-DNA FRET Conjugates for Direct Analysis of Methylphosphonic Acid in Complex Media.

Rapid detection of nerve agents from complex matrices with minimal sample preparation is essential due to their high toxicity and bioavailability. In this work, quantum dots (QDs) were functionalized with oligonucleotide aptamers that specifically targeted a nerve agent metabolite, methylphosphonic acid (MePA). These QD-DNA bioconjugates were covalently linked to quencher molecules to form Förster resonance energy transfer (FRET) donor-acceptor pairs that quantitatively measure the presence of MePA. Using the FRET biosensor, the MePA limit of detection was 743 nM in artificial urine. A decrease in the QD lifetime was measured upon DNA binding and was recovered with MePA. The biosensor's flexible design makes it a strong candidate for the rapid detection of chemical and biological agents for deployable, in-field detectors.

The Multifaceted Role of Senescence Marker Protein 30 in Health and Diseases

Senescence marker protein 30 (SMP30) is an age-linked marker protein, the expression of which declines with aging. SMP30 binds with calcium; however, the absence of a calcium-binding EF-hand motif makes it different from other calcium-binding proteins like calmodulin. Interestingly, previous studies have shown that it binds with other divalent metal co-factors also and catalyzes the cyclisation of L-gulonate required for the biosynthesis of ascorbate in non-primates. Remarkably, SMP30 is conserved among vertebrates indicating that it isa crucial protein performing certain physiological functions. Apparently, in primates, including humans, calcium homeostasis could be the primary function of SMP30 due to the absence of ascorbic acid biosynthesis in these species. In this review, we have discussed the expression pattern of SMP30 in various cells and tissues. SMP30 expression is modulated by different internal and external factors, which we have extensively discussed here. Subsequently, its role in calcium homeostasis, cell proliferation, apoptosis, and liver regeneration has also been explored. Further, the potentiality of SMP30 as a prophylactic agent against organophosphorus nerve agent poisoning has been elucidated due to its organophosphate hydrolysing activity as a promiscuous substrate.

NiCr2O4 nanozyme based portable sensor kit for on-site quantification of nerve agent mimic for environment monitoring

Nerve agents are among the most dangerous chemical known to the human being. On account of an incident by utilizing nerve agents, the fabrication of a cost-effective and ready-to-use device for the convenient identification of nerve agents is needed. Herein, we developed a easy-to-use, portable sensor kit based on NiCr2O4 artificial nanozyme mimic to quantify diethyl-chloro-phosphate (DCP). The synthesized NiCr2O4 artificial nanozyme showed good oxidase and peroxidase-like catalytic activity for the conversion of colorless tetramethylbenzidine (TMB) to bluish-green oxTMB. It is recognized that the presence of DCP can assist the oxidation of TMB due to the easy binding of DCP with the amine group of TMB and enhance the catalytic process. Therefore, this mechanism is utilized to fabricate a colorimetric sensor kit for naked-eye quantification of DCP, which gives yellowish color after interaction with oxTMB. Furthermore, the practicability of a portable sensor kit was performed for the quantification of DCP in soil and water samples, and results showed a detection limit of 15.4 nM (3σ method). Thus, the proposed portable sensor kit’s naked eye detection paves the way for an affordable and practical platform for the easy-to-use, reliable, and quick colorimetric quantification of DCP for environment monitoring.

Renewable adsorption/desorption of sarin on TM-doped CNTs: First principle calculations

Sarin, isopropyl methylphosphonofluoridate (C4H10O2FP), is a highly toxic nerve agent that can paralyze the central nervous system of human. The use of advanced materials with high adsorption capacity and easy regeneration for adsorbing sarin is an effective strategy to remove sarin. In the present work, we investigate sarin adsorption on TM-doped CNT(TM-CNT) by using DFT method (TM=Co, Cu, Cr, Fe, Mn, Ni, Zr). It is found that TM-CNT has a strong adsorption capacity for sarin molecule with the adsorption energy ranging from -1.55 to 2.11 eV. More important, the interaction between sarin molecule and adsorbent can be changed by applying an external electric field. When the added electric field is -0.005 a.u, adsorption energy became positive and sarin can release from the substrate easily. In addition, the adsorption of sarin changes the optical properties of the substrate obviously, which makes TM-CNT a promising candidate to detect sarin in the environment.

Rapid detection of carbamate nerve agent analogues using dually functionalized gold nanoclusters.

Carbamate nerve agents (CMNAs) are a type of lethal cholinesterase inhibitor with one or more quaternary amine centres and aromatic rings. CMNAs have been recently added to the Annex on Chemicals of the Chemical Weapons Convention (CWC) and Schedules of Controlled Chemicals of China. In this study, a rapid, sensitive and selective method was developed for the fluorescence detection of ambenonium chloride (AC) through host-guest and electrostatic dual interactions between AC and cyclodextrin/11-mercaptoundecanoic acid (CD/MUA) dually functionalized gold nanoclusters (AuNCs). Through this method, AC was detected with a limit of detection of 10.0 ng/mL. Method evaluation showed high selectivity towards AC over other related compounds. The practical applicability was verified, as satisfactory recoveries were obtained for AC spiked in river water and urine, as well as Proficiency Test samples from Organisation for the Prohibition of Chemical Weapons (OPCW). In addition, a fluorescence sensing array comprising four AuNCs was designed to distinguish six carbamates and structurally similar compounds. This method provides a potential approach for the rapid, sensitive and selective recognition and detection of CMNAs.

Evidence of nerve agent VX exposure in rat plasma by detection of albumin-adducts in vitro and in vivo

VX is a highly toxic organophosphorus nerve agent that reacts with a variety of endogenous proteins such as serum albumin under formation of adducts that can be targeted by analytical methods for biomedical verification of exposure. Albumin is phosphonylated by the ethyl methylphosphonic acid moiety (EMP) of VX at various tyrosine residues. Additionally, the released leaving group of VX, 2-(diisopropylamino)ethanethiol (DPAET), may react with cysteine residues in diverse proteins. We developed and validated a microbore liquid chromatography-electrospray ionization high-resolution tandem mass spectrometry (µLC-ESI MS/HR MS) method enabling simultaneous detection of three albumin-derived biomarkers for the analysis of rat plasma. After pronase-catalyzed cleavage of rat plasma proteins single phosphonylated tyrosine residues (Tyr-EMP), the Cys34(-DPAET)Pro dipeptide as well as the rat-specific LeuProCys448(-DPAET) tripeptide were obtained. The time-dependent adduct formation in rat plasma was investigated in vitro and biomarker formation during proteolysis was optimized. Biomarkers were shown to be stable for a minimum of four freeze-and-thaw cycles and for at least 24 h in the autosampler at 15 °C thus making the adducts highly suited for bioanalysis. Cys34(-DPAET)Pro was superior compared to the other serum biomarkers considering the limit of identification and stability in plasma at 37 °C. For the first time, Cys34(-DPAET)Pro was detected in in vivo specimens showing a time-dependent concentration increase after subcutaneous exposure of rats underlining the benefit of the dipeptide disulfide biomarker for sensitive analysis.

Fast Response-Recovery and High Selectivity Chemicapacitive Detection of a Nerve Agent Simulant Vapor

Early detection of chemical warfare agents (CWAs) is critical in minimizing the exposure to chemical threats. This study presents a fast response-recovery chemicapacitive sensor (chemicapacitor) for a nerve agent simulant, dimethyl methylphosphonate (DMMP), with high selectivity and sensitivity. Chemicapacitors with interdigitated electrodes were fabricated on a SiO2/Si wafer by aligning single-walled carbon nanotubes (SW-CNTs) coated with polyhedral oligomeric silsesquioxane-supported 1,1,1,3,3,3-hexafluoro-2-propanol (POSS-HFIP) receptors. The stable, nano-sized three-dimensional structure with multiple terminal alcohol groups played a crucial role as a high-performance receptor via efficient hydrogen-bonding interaction with the CWA simulant. The response and recovery times of the fabricated chemicapacitors were estimated to be 13 and 88 s, respectively, outperforming chemiresistive sensors in terms of response-recovery dynamics. The capacitive responses were obtained at varying DMMP vapor concentrations, ranging from 25 to 150 ppm, and they exhibited superior sensitivity compared to receptor-free sensor devices. The concentration-dependent sensitivity was well-fitted with the Langmuir isotherm model, indicating that the sensing mechanism is based on the adsorption/desorption process. In addition, excellent selectivity was realized by introducing different toxic molecules (sulfur dioxide, ammonia, and ethylene oxide) and a blood agent (cyanogen chloride), where the fabricated POSS-HFIP/SW-CNTs chemicapacitor selectively responded to the DMMP vapor. The limit-of-detection was calculated to be 0.70 ppm. The proposed POSS-HFIP/SW-CNTs chemicapacitor demonstrated rapid response-recovery characteristics (with improved selectivity towards DMMP), suggesting its potential in reducing casualties or injuries by early identification of CWAs.

A PET and ESIPT-communicated ratiometric, turn-on chromo-fluorogenic sensor for rapid and sensitive detection of sarin gas mimic, diethylchlorophosphate

Fast and precise identification of toxic G-series nerve agents in the solution and vapor phase is urgently needed to save human beings from unwanted wars and terrorist attacks, which is challenging to execute practically. In this article, we have designed and synthesized a sensitive and selective phthalimide-based chromo-fluorogenic sensor, DHAI, by a simple condensation process that shows ratiometric and turns on chromo-fluorogenic behavior towards Sarin gas mimic diethylchlorophosphate (DCP) in liquid and vapor phases, respectively. A colorimetric change, from yellow to colorless, is observed in the DHAI solution due to the introduction of DCP in daylight. A remarkable cyan color photoluminescence enhancement is noticed in the presence of DCP in the DHAI solution, which is observable to the naked under a portable 365nm UV lamp. The mechanistic aspects of the detection of DCP by employing DHAI have been revealed by time-resolved photoluminescence decay analysis and 1H NMR titration investigation. Our probe DHAI exhibits linear photoluminescence enhancement from 0 to 500μM with a detection limit of nanomolar range from non-aqueous to semi-aqueous media. For practical utility, a DHAI-stained test kit employing Whatman-41 filter paper has been fabricated and used as a portable and displayable photonic device for on-site detection of Sarin gas surrogate, DCP. Also, a dip-stick experiment has been demonstrated to identify the vapor of Sarin gas mimics DCP colorimetrically and fluorometrically. The concentrations of DCP in various water samples have been evaluated with the help of a standard fluorescence curve for real sample analysis.

Pyridinic-N-rich carbon dots in IFE-based Turn-off Fluorometric detection of nerve agent Mimic- Diethyl chlorophosphate and multicolor cell imaging.

Fluorometric sensors for the detection of nerve agent mimics have received a lot of interest nowadays due to their high sensitivity and selectivity, ease of operation, and real-time monitoring. Pyridinic-N-rich carbon dots (NCDs) prepared through microwave-assisted pyrolysis of l-Malic acid and urea have been explored first time in this work as a novel turn-off fluorescent probe for the sensitive and selective detection of diethyl chlorophosphate (DCP), a nerve agent mimic. The as-prepared carbon dots contained a large amount of pyridinic nitrogen on their surface, which can modulate the photoluminescence properties of the NCDs. The blue emissive NCDs possessed both excitation wavelength-dependent and independent emission behavior. The detection of DCP was premised on quenching of the fluorescence emission intensity of NCDs in the presence of similar chemical reagents (e.g., trimethyl phosphate, triethyl phosphate, triethyl phosphonoacetate, triphenyl phosphate, diphenyl phosphate, tributyl phosphate). Fluorescence quenching of the NCDs in the presence of DCP has been attributed to the inner filter effect (IFE). From the linear Stern-Volmer plot (R2=0.9992), the limit of detection (LOD) was found to be 84μM for sensing DCP for the concentration ranging between 3 and 15mM. The biocompatibility of NCDs was assessed through cytotoxicity assay on MDA-MB-231 breast cancer cells. Fluorescence imaging demonstrated that NCDs have low cytotoxicity and can be employed successfully in cell imaging.

A retrospective screening method for carbamate toxicant exposure based on butyrylcholinesterase adducts in human plasma with ultra-high performance liquid chromatography–tandem mass spectrometry

Carbamate pesticides are extensively used in agriculture for their inhibition to acetylcholinesterase and damages to the insects’ neural systems. Because of their toxicity, human poisoning incidents caused by carbamate pesticide exposure have occurred from time to time. What’s more, some lethally toxic carbamate toxicants known as carbamate nerve agents (CMNAs) have been supplemented in Schedule 1 of the Annex on Chemicals in the Chemical Weapons Convention (CWC) by Organisation of the Prohibition of Chemical Weapons (OPCW) from 2020. And some other carbamates, like physostigmine, have been used in clinical treatment as anticholinergic drugs and their misuse may also cause damages to the body. Similar to organophosphorus toxicants, carbamate toxicants would react with butyrylcholinesterase (BChE) in plasma when entering the human body, resulting in the BChE adducts, based on which the exposure of carbamate toxicants could be detected retrospectively. In this study, methylcarbamyl nonapeptide and dimethylcarbamyl nonapeptide from pepsin digestion of BChE adducts were identified with ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) in product ion scan mode. Carbofuran was chosen as the target to establish the detection method of carbamate toxicant exposure based on methylcarbamyl nonapeptide digested from methylcarbamyl BChE. Procainamide-gel affinity purification, pepsin digestion and UHPLC–MS/MS analysis in multiple reaction monitoring (MRM) mode were applied. Under the optimized conditions of sample preparation and UHPLC–MS/MS MRM analysis, the limits of detection (LODs) reached 10.0 ng/mL of plasma exposed to carbofuran with satisfactory specificity. The quantitation approach was established with d3-carbofuran-exposed plasma as the internal standard (IS) and the linearity range was 30.0–1.00 × 103 nmol/L (R2 >0.998) with the accuracy of 95.6%–107% and precision of ≤9% relative standard deviation (RSD). The applicability was also evaluated by N,N-dimethyl-carbamates with the LODs of 30.0 nmol/L for pirimicarb-exposed plasma based on dimethylcarbamyl nonapeptide. Because most of carbamate toxicants has methylcarbamyl or dimethylcarbamyl groups, this approach could be applied on the retrospective screening of carbamate toxicant exposure including CMNAs, carbamate pesticides or carbamate drugs. This study could provide an effective means in the fields of CWC verification, toxicological mechanism investigation and down-selection of potential treatment options.

Chemical Weapons: VX Nerve Agents

Abstract: In light of earlier research completed by Dr. Gerhard Schrader, a scientist working for IG Farben in Germany during the 1930s, VX, also known as "venomous specialist X," is one of the most amazing known about the V nerve specialists. It was first discovered at Porton Down in England during the mid-1950s. They are currently a part of a larger V-series of specialists and go by the label of nerve specialists. They have been used as a substance weapon in numerous documented dangerous assaults. VX is more potent than sarin, another nerve agent with a similar component of activity, in that it causes death with exposure to multiple milligramme levels through inhalation or absorption through skin. Such candour has some experts really upset. A delayed neuromuscular bar, limp loss of motion of the relative variety of body muscles, including the stomach, and asphyxiation are the results of these specialists' serious disruption of the body's motioning between the worried and strong frameworks. VX in particular poses a problem because it is relatively non-unpredictable and does not dissipate and circulate as a fume; rather, it remains directly exposed to the chemical specialist where it was initially dispersed. These physical and biological properties of VX make it a weapon that can be used in a wide range of environments. The Chemical Weapons Convention of 1993 forbids the production and storage of VX above 100 grammes (3.53 oz) each year as a substance weapon and classifies it as a weapon of mass destruction. "Examination, clinical or drug purposes outside a single limited scope office in total amounts not exceeding 10 kg (22 lb) each" is the primary exception.