Publications by authors named "Paula Vanninen"

44 Publications

Osmolal and anion gaps after acute self-poisoning with agricultural formulations of the organophosphorus insecticides profenofos and diazinon: A pilot study.

Basic Clin Pharmacol Toxicol 2022 Feb 3;130(2):320-327. Epub 2021 Dec 3.

South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.

Self-poisoning with organophosphorus (OP) insecticides is an important means of global self-harm. The insecticides are formulated with solvents that may also contribute to toxicity. We set up a study to detect changes in osmolal and anion gaps following ingestion of OP insecticides. We recruited consecutive patients admitted to a Teaching Hospital, Sri Lanka, with a history of OP self-poisoning. The osmolal and anion gaps were calculated on admission and at 4, 24 and 72 h post-ingestion together with ethanol concentration. Forty-nine patients were recruited (28 profenofos, 10 diazinon, one coumaphos, one chlorpyrifos, one phenthoate and eight unknown OP). Only modest increases in osmolal and anion gaps were noted. Small rises in osmolal gap above the upper limit of normal were noted in 16/49 (32.7%) of all cases, 9/28 (32.1%) profenofos cases and 4/10 (40.0%) diazinon cases. The anion gap was raised in 24/49 (49.0%) of all cases, 15/28 (53.6%) profenofos cases and 5/10 (50.0%) diazinon cases. We observed a trend for a fall in osmolal gap during the first 24 h, followed by an increase up to 72 h. There was no correlation between the anion gap and serum lactate concentration, indicating that a lactic acidosis was not responsible for the anion gap. Formate, which could have explained the increased gap, was not detected in any of the samples; ketoacids (beta-hydroxybutyrate and acetoacetate) were not measured. This pilot study found that profenofos and diazinon poisoning caused only modest increases in the osmolal and anion gaps in a minority of cases.
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http://dx.doi.org/10.1111/bcpt.13686DOI Listing
February 2022

Metabolism and cytotoxicity of diphenylarsinic acid, a degradation product of sea-dumped chemical warfare agents, in a rainbow trout liver cell line RTL-W1.

Aquat Toxicol 2021 Dec 12;241:105993. Epub 2021 Oct 12.

Finnish Institute for Verification of the Chemical Weapons Convention (VERIFIN), Department of Chemistry, University of Helsinki, P.O. Box 55, FI-00014 Helsinki University, Helsinki, Finland.

Recent studies have found primary degradation products of phenylarsenic chemical warfare agents (CWAs) accumulating in fish tissues, while the potential effects of these dumped phenylarsenic CWAs, such as Clark I and II, in the Baltic Sea biota are poorly understood. In this study, the metabolism and cytotoxicity of diphenylarsinic acid (DPA), a primary degradation product of phenylarsenic CWA, was studied by incubating rainbow trout cell line RTL-W1 cells in media with 100 mg/L DPA. Previously undescribed metabolites were identified by ultra-high performance liquid chromatography-high resolution mass spectrometry (UPHLCHRMS). Moreover, the cytotoxicity of diphenylarsine glutathione conjugate (DPA-SG), the major metabolite of DPA, was studied. Cytotoxicity of the compounds was evaluated using the Neutral Red retention test (NRR), showing an IC value of 278 mg/L for DPA and 1.30 mg/L for DPA-SG, indicating that the glutathione (GSH) conjugate of DPA is more than two orders of magnitude toxic than DPA itself, suggesting that toxic properties of DPA are increased after conjugation with intracellular GSH leading enhanced toxicity after uptake. Results gained in this study give more detailed information for elucidating biological effects of dumped chemical munitions in marine environment. Moreover, the results help in assessing the environmental and health risks posed by marine munition continued presence and deterioration in the sea bottom.
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http://dx.doi.org/10.1016/j.aquatox.2021.105993DOI Listing
December 2021

Advice on assistance and protection provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 3. On medical care and treatment of injuries from sulfur mustard.

Toxicology 2021 11 4;463:152967. Epub 2021 Oct 4.

Medicinal Chemistry Department, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia.

Blister agents damage the skin, eyes, mucous membranes and subcutaneous tissues. Other toxic effects may occur after absorption. The response of the Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) to a request from the OPCW Director-General in 2013 on the status of medical countermeasures and treatments to blister agents is updated through the incorporation of the latest information. The physical and toxicological properties of sulfur mustard and clinical effects and treatments are summarised. The information should assist medics and emergency responders who may be unfamiliar with the toxidrome of sulfur mustard and its treatment.
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http://dx.doi.org/10.1016/j.tox.2021.152967DOI Listing
November 2021

Parametric Sensitivity in a Generalized Model for Atmospheric Pressure Chemical Ionization Reactions.

J Am Soc Mass Spectrom 2021 Aug 15;32(8):2218-2226. Epub 2021 Jul 15.

VERIFIN, Finnish Institute for Verification of the Chemical Weapons Convention, Department of Chemistry, University of Helsinki, FI-00014 Helsinki, Finland.

Gas phase reactions between hydrated protons H(HO) and a substance M, as seen in atmospheric pressure chemical ionization (APCI) with mass spectrometry (MS) and ion mobility spectrometry (IMS), were modeled computationally using initial amounts of [M] and [H(HO)], rate constants to form protonated monomer (MH(HO)) and to form proton bound dimer (MH(HO)), and diffusion constants. At 1 × 10 cm (0.4 ppb) for [H(HO)] and vapor concentrations for M from 10 ppb to 10 ppm, a maximum signal was reached at 4.5 μs to 4.6 ms for MH(HO) and 7.8 μs to 46 ms for MH(HO). Maximum yield for protonated monomer for a reaction time of 1 ms was ∼40% for from 10 to 10 cm·s, for / = 0.8, and specific values of [M]. This model demonstrates that ion distributions could be shifted from [MH(HO)] to [MH(HO)] using excessive levels of [H(HO)], even for [M] > 10 ppb, as commonly found in APCI MS and IMS measurements. Ion losses by collisions on surfaces were insignificant with losses of <0.5% for protonated monomer and <0.1% for proton bound dimer of dimethyl methylphosphonate (DMMP) at 5 ms. In this model, ion production in an APCI environment is treated over ranges of parameters important in mass spectrometric measurements. The models establish a foundation for detailed computations on response with mixtures of neutral substances.
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http://dx.doi.org/10.1021/jasms.1c00158DOI Listing
August 2021

Optimized method for analysis of ethanolamines, hydrolysis products of nitrogen mustards, from urine samples using LC-MS/MS.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jun 18;1176:122762. Epub 2021 May 18.

Finnish Institute for Verification of the Chemical Weapons Convention (VERIFIN), Department of Chemistry, University of Helsinki, P.O. Box 55, FI-00014 Helsinki, Finland.

Highly polar ethanolamines (EAs), excreted in urine, are hydrolysis products of nitrogen mustards (NMs), which are prohibited by the Chemical Weapons Convention (CWC). The methods established for biological matrices are essential for verification analysis of the CWC related chemicals. This paper describes a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method developed for qualitative and quantitative analysis of EAs, N-ethyldiethanolamine (EDEA), N-methyldiethanolamine (MDEA) and triethanolamine (TEAOH) from urine samples. After optimization of sample preparation and chromatographic conditions, the method was fully validated. Silica solid-phase extraction (SPE) cartridges and a porous graphite carbon (PGC) column were selected for validation studies. The method is linear from 5 to 500, 0.5 to 250, and 0.5 to 500 ng/mL for TEAOH, EDEA, and MDEA, respectively. It is also precise and accurate. A minimum sample amount of 0.5 mL urine was used. The limit of quantification using this approach was 0.4, 5.5, and 6.3 ng/mL for MDEA, EDEA and TEAOH, respectively. The combination of the PGC column and high pH eluents in analysis retained and separated the studied EAs. Retention times were 2.11, 2.56 and 2.98 min for MDEA, EDEA and TEAOH, respectively. The method is applicable for verification analysis of the CWC.
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http://dx.doi.org/10.1016/j.jchromb.2021.122762DOI Listing
June 2021

Acute aquatic toxicity of arsenic-based chemical warfare agents to Daphnia magna.

Aquat Toxicol 2021 Jan 25;230:105693. Epub 2020 Nov 25.

Institute of Oceanology, Polish Academy of Sciences, Sopot, Poland. Electronic address:

Sea dumping of chemical warfare (CW) took place worldwide during the 20th century. Submerged CW included metal bombs and casings that have been exposed for 50-100 years of corrosion and are now known to be leaking. Therefore, the arsenic-based chemical warfare agents (CWAs), pose a potential threat to the marine ecosystems. The aim of this research was to support a need for real-data measurements for accurate risk assessments and categorization of threats originating from submerged CWAs. This has been achieved by providing a broad insight into arsenic-based CWAs acute toxicity in aquatic ecosystems. Standard tests were performed to provide a solid foundation for acute aquatic toxicity threshold estimations of CWA: Lewisite, Adamsite, Clark I, phenyldichloroarsine (PDCA), CWA-related compounds: TPA, arsenic trichloride and four arsenic-based CWA degradation products. Despite their low solubility, during the 48 h exposure, all CWA caused highly negative effects on Daphnia magna. PDCA was very toxic with 48 h D. magna LC50 at 0.36 μg × L and Lewisite with EC50 at 3.2 μg × L. Concentrations at which no immobilization effects were observed were slightly above the analytical Limits of Detection (LOD) and Quantification (LOQ). More water-soluble CWA degradation products showed no effects at concentrations up to 100 mg × L.
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http://dx.doi.org/10.1016/j.aquatox.2020.105693DOI Listing
January 2021

Fast, Miniaturized, Real-Time Unit for Sampling, Modulation, and Separation in Detection of Hazardous Chemicals.

Anal Chem 2020 11 20;92(21):14589-14593. Epub 2020 Oct 20.

VERIFIN, Finnish Institute for Verification of the Chemical Weapons Convention, Department of Chemistry, University of Helsinki, P.O. Box 55, FI-00014 Helsinki, Finland.

A sampling, modulation, and separation (SMS) unit was tested for detection of hazardous chemicals. The SMS unit, designed and developed for on-site sampling and analysis, consists of a dynamic inlet system coupled with a fast, miniaturized gas chromatograph (GC). Feasibility of the SMS unit was evaluated together with a hazardous chemical vapor generator. The performance of the SMS unit was tested with automated thermal desorption after SMS to collect samples for GC-mass spectrometry (GC-MS) measurements. Detection of sarin nerve agent was verified. Additionally, the vapor generator was connected to the SMS unit, which was hyphenated with a photoionization detector (PID), thus creating a fast GC-PID system. This system gave a positive response for degradation products of sulfur mustard, thereby indicating suitability of the SMS-PID unit for field drone applications.
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http://dx.doi.org/10.1021/acs.analchem.0c02898DOI Listing
November 2020

Detection of chemical warfare agent related phenylarsenic compounds and multibiomarker responses in cod (Gadus morhua) from munition dumpsites.

Mar Environ Res 2020 Dec 23;162:105160. Epub 2020 Sep 23.

Finnish Institute for Verification of the Chemical Weapons Convention (VERIFIN), Department of Chemistry, University of Helsinki, A.I. Virtasen Aukio 1, FI-00014, University of Helsinki, Finland.

Recently, sea-dumped chemical weapons (CWs) containing toxic chemical warfare agents (CWAs) have raised international attention. It is well known that CWAs are leaking from corroded munitions causing a risk to the surrounding marine environment, while the impact on marine biota is still unknown. In this study, cod (Gadus morhua) was used as a model species to study the possible bioaccumulation of phenylarsenic CWAs and their negative effects at multiple levels of biological organization on fish living in the vicinity of a major CWs dumpsite in the Bornholm Basin in the Baltic Sea. In total, 14% of the cod muscle samples collected close to the main dumpsite contained trace levels of phenylarsenic CWAs. However, most of the biomarkers measured did not show clear differences between this area compared with a lesser contaminated reference area. On the other hand, significant changes in some biomarkers were observed in individuals containing trace levels of CWA-related chemicals. The results gained in this study have significant importance for environmental risk assessment and for evaluating the risk of CWA contamination for human seafood consumers.
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http://dx.doi.org/10.1016/j.marenvres.2020.105160DOI Listing
December 2020

Derivatization and rapid GC-MS screening of chlorides relevant to the Chemical Weapons Convention in organic liquid samples.

Anal Methods 2020 05;12(19):2527-2535

VERIFIN, Department of Chemistry, University of Helsinki, P.O. Box 55, FIN-00014 Helsinki, Finland.

A simple derivatization technique was developed for the analysis of seven Schedule 3 chemicals and one Schedule 2 chemical listed in the Chemical Weapons Convention (CWC). Phosgene, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, sulfur monochloride and sulfur dichloride (Schedule 3) as well as arsenic trichloride (Schedule 2) were derivatized using 1-propanol in 40% pyridine solution for analysis with gas chromatography-mass spectrometry (GC-MS). Derivatization temperature and concentration of the derivatization solution were optimized for maximum derivatization recovery. The stabilities of the target analytes and their derivatives in different solvents were studied. The derivatization yield showed a linear response within the analyte concentration range of 0.1-2 mM (10-200 μg ml-1) with correlation coefficients >0.99 (r2), except for AsCl3 which did not show a linear response after derivatization. Good reproducibility with relative standard deviations (RSDs) from 3 to 13% was achieved. The derivatization recovery was 66% for phosgene and 67-80% for the P-containing chemicals phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride. Recommendations to use the method for screening the presence of these chemicals in organic liquid samples are given. The method is used when CWC-related samples are screened at VERIFIN.
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http://dx.doi.org/10.1039/d0ay00263aDOI Listing
May 2020

Quantum mechanical reference spectrum simulation for precursors and degradation products of chemicals relevant to the Chemical Weapons Convention.

Magn Reson Chem 2021 02 8;59(2):117-137. Epub 2020 Sep 8.

VERIFIN, Department of Chemistry, University of Helsinki, Helsinki, Finland.

A selection of acidic, alkaline and neutral degradation products relevant to the Chemical Weapons Convention was studied in wide range of pH conditions to determine their spin systems as well as spectral parameters. The pH dependence of chemical shifts and J couplings was parameterized using Henderson-Hasselbalch-based functions using dichloromethane as additional shift reference in TSP-d referenced spectra. The resulting parameters allowed calculation of precise chemical shifts and J coupling constants in arbitrary pH conditions. The validity of the obtained spin system definitions and parameters as a source of quantum mechanically simulated reference data in chemical verification analysis is demonstrated.
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http://dx.doi.org/10.1002/mrc.5090DOI Listing
February 2021

Exposure status of sea-dumped chemical warfare agents in the Baltic Sea.

Mar Environ Res 2020 Oct 15;161:105112. Epub 2020 Aug 15.

PNA, Polish Naval Academy, Ul. Śmidowicza 69, 81-127, Gdynia, Poland.

About 50 000 tons of chemical weapons (CW) were dumped to the Baltic Sea after the Second World War. Munitions are located in the deep areas of the Baltic Sea, and there they act as a point source of contamination to the ecosystem. Corroded munitions release chemical warfare agents (CWAs) to nearby water and sediments. In this study we investigated known dumpsites (Bornholm, Gotland and Gdansk Deep) and dispersed chemical munitions, to evaluate the extent of contamination of nearby sediments, as well as to assess the degradation process of released CWA. It was found that CWA-related phenylarsenic chemicals (Clark I, Clark II and Adamsite) and sulfur mustard are released to the sediments and undergo environmental degradation to chemicals, of which some remain toxic. The extent of pollution of released CWAs and their corresponding degradation products reaches more than 250 m from the CW objects, and seem to follow a power curve decrease of concentration from the source. Bornholm Deep is characterised with the highest concentration of CWAs in sediments, but occasional concentration peaks are also observed in the Gdansk Deep and close to dispersed munitions. Detailed investigation of spreading pattern show that the range of pollution depends on bottom currents and topography.
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http://dx.doi.org/10.1016/j.marenvres.2020.105112DOI Listing
October 2020

Biological effects of dumped chemical weapons in the Baltic Sea: A multi-biomarker study using caged mussels at the Bornholm main dumping site.

Mar Environ Res 2020 Oct 16;161:105036. Epub 2020 Jun 16.

Finnish Environment Institute, Marine Research Centre, Agnes Sjöbergin katu 2, FI-00790, Helsinki, Finland.

After World War II, thousands of tons of highly toxic chemical warfare agents (CWA) were deposited in the Baltic Sea, the main dumping site locating in the Bornholm Basin. In the present study, Baltic mussels (Mytilus trossulus) were transplanted in the area in cages at two hotspot sites and a reference site at the depths of 35 and 65 m for 2.5 months to study bioaccumulation and biological effects of CWA possibly leaking from the corroding warfare materials. No traces of degradation products of the measured phenylarsenic CWA could be detected in the tissues of mussels. Nevertheless, several biochemical and histochemical biomarkers, geno- and cytotoxicity indicators, and bioenergetic parameters showed significant responses. The Integrated Biomarker Index calculated from the single biomarkers also showed a higher total response at the two hotspot areas compared to the reference site. Although no direct evidence could be obtained confirming the responses being caused specifically by exposure to CWA, the field exposure experiment showed unambiguously that organisms in this sea area are confronting environmental stress affecting negatively their health and this is likely related to chemical contamination, which is possibly connected to the sea-dumped CWA.
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http://dx.doi.org/10.1016/j.marenvres.2020.105036DOI Listing
October 2020

Identification of Degradation Products of Sea-Dumped Chemical Warfare Agent-Related Phenylarsenic Chemicals in Marine Sediment.

Anal Chem 2020 04 16;92(7):4891-4899. Epub 2020 Mar 16.

Finnish Institute for Verification of the Chemical Weapons Convention, VERIFIN, Department of Chemistry, P.O. Box 55, FI-00014University of Helsinki, Finland.

Previously unknown phenylarsenic chemicals that originated from chemical warfare agents (CWAs) have been detected and identified in sediment samples collected from the vicinity of chemical munition dumpsites. Nontargeted screening by ultrahigh-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) was used for detection of 14 unknown CWA-related phenylarsenic chemicals. Methylated forms of Clark I/II, Adamsite, and phenyldichloroarsine were detected in all analyzed sediment samples, and their identification was based on synthesized chemicals. In addition, other previously unknown CWA-related phenylarsenic chemicals were detected, and their structures were elucidated using MS/HRMS technique. On the basis of relative isotope ratios of protonated molecules and measures of exact masses of formed fragment ions, it could be concluded that some of these unknown chemicals contained a sulfur atom attached to an arsenic atom. In addition to that, some of the samples contained chemicals that had formed via addition of an OH group to the aromatic ring. However, it is not possible to say how these chemicals are formed, but the most plausible cause is activities of marine microbes in the sediment. To our knowledge, these chemicals have not been detected from sediment samples previously. Sensitive analytical methods are needed for these novel chemicals to assess the total CWA burden in marine sediments, and this information is essential for the risk assessment.
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http://dx.doi.org/10.1021/acs.analchem.9b04681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497621PMC
April 2020

Studying the metabolism of toxic chemical warfare agent-related phenylarsenic chemicals in vitro in cod liver.

J Hazard Mater 2020 06 3;391:122221. Epub 2020 Feb 3.

Finnish Institute for Verification of the Chemical Weapons Convention (VERIFIN), Department of Chemistry, University of Helsinki, P.O. Box 55, FI-00014 University of Helsinki, Finland.

Large quantities of chemical warfare agents (CWAs), such as phenylarsenic chemicals, were disposed by sea-dumping after World War II. Nowadays, the release of these toxic chemicals from munitions poses a potential threat to living organisms. This study investigates the fate of these chemicals in fish by exposing selected CWA-related phenylarsenic chemicals and their oxidation products to cod (Gadus morhua) liver S9 fraction in vitro. Clark I (DA), Adamsite (DM) and their corresponding oxidation products as well as triphenylarsine oxide (TPA[ox]) and phenylarsonic acid (PDCA[ox]) were used as chemicals in in vitro experiments. Glutathione (GSH) conjugates of DA, DM and PDCA-related chemicals were found to be the most dominant metabolites, and methylated metabolites were detected as well, suggesting that these compounds are metabolised in the presence of cod liver enzymes. TPA[ox] was the only compound tested that did not form a GSH conjugate or methylated metabolite, indicating a different biotransformation pathway for this compound. Furthermore, hydroxylated metabolites were detected for each tested chemical. Due to their reactive nature, GSH conjugates may be difficult to detect in fish samples from CWA dumpsites. In contrast, both methylated and hydroxylated metabolites of phenylarsenic chemicals are promising target chemicals for the detection of CWA-related contamination in fish.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122221DOI Listing
June 2020

A pilot clinical study of the neuromuscular blocker rocuronium to reduce the duration of ventilation after organophosphorus insecticide poisoning.

Clin Toxicol (Phila) 2020 04 31;58(4):254-261. Epub 2019 Jul 31.

South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.

A common manifestation of organophosphorus insecticide self-poisoning is prolonged respiratory failure due to neuromuscular junction dysfunction and likely nicotinic receptor overstimulation. We aimed at collecting preliminary data on whether addition of the competitive nicotinic antagonist rocuronium to standard early therapy might be clinically feasible and associated with reduced duration of ventilation. A pilot three-arm dose-response phase II trial was set up to compare bolus doses of rocuronium bromide titrated to produce initial >95% or 50% inhibition of neuromuscular function, measured using acceleromyography, plus standard treatment, versus standard treatment alone. After attaining inhibition, patients receiving bolus rocuronium then received rocuronium infusions for a maximum of 120 h. Primary outcome was duration of intubation; secondary outcome was case fatality. Plasma butyrylcholinesterase activity was measured throughout the inpatient stay. Blood was analysed to confirm the organophosphorus insecticide ingested. Forty-five patients were randomised to receive: rocuronium to initially attain 95% inhibition (Roc>95,  = 15), rocuronium to initially attain 50% inhibition (Roc50,  = 14), or no rocuronium (control,  = 16). The most commonly ingested pesticide was profenofos (29/45, 64.4%). Butyrylcholinesterase activity remained severely inhibited for the duration of the study for most patients. Case fatality was 9/45 (20%) and similar across study arms: control 3/16 (18.8%), Roc50 4/14 (28.6%) and Roc>95 2/15 (13.3%) ( = .5842). When excluding patients who died, median [IQR] duration of intubation was significantly longer in the Roc50 (259.5 [176-385] h) and Roc>95 (226.8 [186-355] h) groups compared to controls (88.5 [47-160] h,  = .0162 and  = .0016, respectively). In this pilot dose-response study, we found no evidence that rocuronium in addition to standard therapy reduced the duration of intubation. It is possible that it worsened neuromuscular junction function. Further clinical research, including testing of shorter duration regimens, needs to be performed before nicotinic antagonists can be used in the clinical management of OP poisoning.
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http://dx.doi.org/10.1080/15563650.2019.1643467DOI Listing
April 2020

Molecularly Imprinted Polymer Materials as Selective Recognition Sorbents for Explosives: A Review.

Polymers (Basel) 2019 May 15;11(5). Epub 2019 May 15.

UFZ-Helmholtz Centre for Environmental Research, Department Monitoring and Exploration Technologies, Permoserstraße 15, D-04318 Leipzig, Germany.

Explosives are of significant interest to homeland security departments and forensic investigations. Fast, sensitive and selective detection of these chemicals is of great concern for security purposes as well as for triage and decontamination in contaminated areas. To this end, selective sorbents with fast binding kinetics and high binding capacity, either in combination with a sensor transducer or a sampling/sample-preparation method, are required. Molecularly imprinted polymers (MIPs) show promise as cost-effective and rugged artificial selective sorbents, which have a wide variety of applications. This manuscript reviews the innovative strategies developed in 57 manuscripts (published from 2006 to 2019) to use MIP materials for explosives. To the best of our knowledge, there are currently no commercially available MIP-modified sensors or sample preparation methods for explosives in the market. We believe that this review provides information to give insight into the future prospects and potential commercialization of such materials. We warn the readers of the hazards of working with explosives.
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http://dx.doi.org/10.3390/polym11050888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572358PMC
May 2019

Toxic effects of chemical warfare agent mixtures on the mussel Mytilus trossulus in the Baltic Sea: A laboratory exposure study.

Mar Environ Res 2019 Mar 7;145:112-122. Epub 2019 Feb 7.

Swedish Defence Research Agency, Cementvägen 20, 90182, Umeå, Sweden.

Baltic blue mussels (Mytilus trossulus) were implemented to assess potential toxicity, health impairments and bioaccumulation of dumped chemical warfare agents on marine benthic organisms. Mussels were collected from a pristine cultivation side and exposed under laboratory conditions to different mixtures of chemical warfare agents (CWAs) related phenyl arsenic compounds, Clark I and Adamsite as well as chloroacetophenone. Using a multi-biomarker approach, mussels were assessed thereafter for effects at different organisational levels ranging from geno-to cytotoxic effects, differences in enzyme kinetics and immunological responses. In an integrated approach, chemical analysis of water and tissue of the test organisms was performed in parallel. The results show clearly that exposed mussels bioaccumulate the oxidized forms of chemical warfare agents Clark I, Adamsite (DAox and DMox) and, to a certain extent, also chloroacetophenone into their tissues. Adverse effects in the test organisms at subcellular and functional level, including cytotoxic, immunotoxic and oxidative stress effects were visible. These acute effects occurred even at the lowest test concentration.
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http://dx.doi.org/10.1016/j.marenvres.2019.02.001DOI Listing
March 2019

Advice on assistance and protection provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 1. On medical care and treatment of injuries from nerve agents.

Toxicology 2019 03 9;415:56-69. Epub 2019 Jan 9.

OPCW Scientific Advisory Board Secretary, 2011-2016, The Netherlands.

The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice on assistance and protection in relation to the Chemical Weapons Convention. In this, the first of several papers describing the SAB's work on this topic, we describe advice given in response to questions from the OPCW Director-General in 2013 and 2014 on the status of available medical countermeasures and treatments to organophosphorus nerve agents. This paper provides the evidence base for this advice which recommended to the OPCW pretreatments, emergency care, and long-term treatments that were available at the time of the request for this class of chemical warfare agent (CWA). It includes a bibliography of over 140 scientific references, which can be used as a platform for watching future medical countermeasure developments. The information provided in this paper should serve as a valuable reference for medical professionals and emergency responders who may have no knowledge of the symptoms and treatment options of exposure to nerve agents.
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http://dx.doi.org/10.1016/j.tox.2019.01.004DOI Listing
March 2019

Advice from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons on riot control agents in connection to the Chemical Weapons Convention.

RSC Adv 2018 Dec 19;8(73):41731-41739. Epub 2018 Dec 19.

Pakistan Atomic Energy Commission Islamabad Pakistan.

Compounds that cause powerful sensory irritation to humans were reviewed by the Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) in response to requests in 2014 and 2017 by the OPCW Director-General to advise which riot control agents (RCAs) might be subject to declaration under the Chemical Weapons Convention (the "Convention"). The chemical and toxicological properties of 60 chemicals identified from a survey by the OPCW of RCAs that had been researched or were available for purchase, and additional chemicals recognised by the SAB as having potential RCA applications, were considered. Only 17 of the 60 chemicals met the definition of a RCA under the Convention. These findings were provided to the States Parties of the Convention to inform the implementation of obligations pertaining to RCAs under this international chemical disarmament and non-proliferation treaty.
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http://dx.doi.org/10.1039/c8ra08273aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092081PMC
December 2018

Advice on assistance and protection from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 2. On preventing and treating health effects from acute, prolonged, and repeated nerve agent exposure, and the identification of medical countermeasures able to reduce or eliminate the longer term health effects of nerve agents.

Toxicology 2019 02 27;413:13-23. Epub 2018 Nov 27.

OPCW Office of Strategy and Policy, Intern Summer 2018, The Netherlands.

The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice in relation to the Chemical Weapons Convention on assistance and protection. We present the SAB's response to a request from the OPCW Director-General in 2014 for information on the best practices for preventing and treating the health effects from acute, prolonged, and repeated organophosphorus nerve agent (NA) exposure. The report summarises pre- and post-exposure treatments, and developments in decontaminants and adsorbing materials, that at the time of the advice, were available for NAs. The updated information provided could assist medics and emergency responders unfamiliar with treatment and decontamination options related to exposure to NAs. The SAB recommended that developments in research on medical countermeasures and decontaminants for NAs should be monitored by the OPCW, and used in assistance and protection training courses and workshops organised through its capacity building programmes.
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http://dx.doi.org/10.1016/j.tox.2018.11.009DOI Listing
February 2019

Advice on chemical weapons sample stability and storage provided by the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons to increase investigative capabilities worldwide.

Talanta 2018 Oct 27;188:808-832. Epub 2018 Apr 27.

OPCW Headquarters, The Hague, The Netherlands.

The Scientific Advisory Board (SAB) of the Organisation for the Prohibition of Chemical Weapons (OPCW) has provided advice on the long-term storage and stability of samples collected in the context of chemical weapons investigations. The information they compiled and reviewed is beneficial to all laboratories that carry out analysis of samples related to chemical warfare agents and is described herein. The preparation of this report was undertaken on request from the OPCW Director-General. The main degradation products for chemicals on the Schedules in the Annex on Chemicals of the Chemical Weapons Convention are tabulated. The expertise of the 25 scientists comprising the SAB, a review of the scientific literature on environmental and biomedical sample analysis, and answers to a questionnaire from chemists of nine OPCW Designated Laboratories, were drawn upon to provide the advice. Ten recommendations to ensure the long-term storage and stability of samples collected in relation to the potential use of chemical weapons were provided and are repeated here for the consideration of all laboratories worldwide.
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http://dx.doi.org/10.1016/j.talanta.2018.04.022DOI Listing
October 2018

pH-Dependent Piecewise Linear Correlation of H,P Chemical Shifts: Application in NMR Identification of Nerve Agent Metabolites in Urine Samples.

Anal Chem 2018 07 29;90(14):8495-8500. Epub 2018 Jun 29.

VERIFIN, Department of Chemistry , University of Helsinki , P.O. Box 55, FIN-00014 Helsinki , Finland.

The NMR-observable nuclei of the acidic and basic compounds experience pH dependence in chemical shift. This phenomenon can be exploited in NMR titrations to determine p K values of compounds, or in pH measurement of solutions using dedicated pH reference compounds. On the other hand, this sensitivity can also cause problems in, for example, metabolomics, where slight changes in pH result in significant difficulties for peak alignment between spectra of set of samples for comparative analysis. In worst case, the pH sensitivity of chemical shifts can prevent unambiguous identification of compounds. Here, we propose an alternative approach for NMR identification of pH-sensitive analytes. The H and X (C, N, P, ...) chemical shifts in close proximity to the acidic or basic functional group should, when presented as ordered pairs, express piecewise linear correlation with distinct slope, intercept, and range. We have studied the pH dependence of H and P chemical shifts of the CH-P moiety in urinary metabolites of nerve agents sarin, soman and VX using 2D H-P fast-HMQC spectroscopy. The H and P chemical shifts of these chemicals appear in very narrow range, and due to subtle changes in sample pH the identification on either H or P chemical shift alone is uncertain. However, if the observed H and P chemical shifts of the CH-P moiety of individual compounds are presented as ordered pairs, they fall into distinct linear spaces, thus, facilitating identification with high confidence.
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http://dx.doi.org/10.1021/acs.analchem.8b01308DOI Listing
July 2018

Detection of Chemical Warfare Agent-Related Phenylarsenic Compounds in Marine Biota Samples by LC-HESI/MS/MS.

Anal Chem 2017 10 25;89(20):11129-11134. Epub 2017 Sep 25.

VERIFIN, Finnish Institute for Verification of The Chemical Weapons Convention, Department of Chemistry, University of Helsinki , P.O. Box 55, FI-00014 Helsinki, Finland.

A new method has been developed to determine oxidation products of three chemical warfare agent (CWA) related phenylarsenic compounds from marine biota samples by a liquid chromatography-heated electrospray ionization/tandem mass spectrometry (LC-HESI/MS/MS). The target chemicals were oxidation products of Adamsite (DM[ox]), Clark I (DPA[ox]), and triphenylarsine (TPA[ox]). Method was validated within the concentration range of 1-5, 0.2-5, and 0.2-5 ng/g for DM[ox], DPA[ox], and TPA[ox], respectively. The method was linear, precise and accurate. Limits of quantification (LOQ) were 2.0, 1.3, and 2.1 ng/g for DM[ox], DPA[ox], and TPA[ox], respectively. A total of ten fish samples and one lobster sample collected from near Swedish coast, Måseskär dumpsite were analyzed. Trace concentrations below LOQ values were detected in three samples and the elemental composition of oxidized form of Clark I and/or II was confirmed by LC-HESI/HRMS. To our knowledge, this is the first study that provides the presence of CWA related chemicals in marine biota samples.
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http://dx.doi.org/10.1021/acs.analchem.7b03429DOI Listing
October 2017

Identification of gymnodimine D and presence of gymnodimine variants in the dinoflagellate Alexandrium ostenfeldii from the Baltic Sea.

Toxicon 2016 Mar 29;112:68-76. Epub 2016 Jan 29.

VERIFIN, Department of Chemistry, P.O. Box 55, A. I. Virtasen aukio 1, FI-00014, University of Helsinki, Finland.

Gymnodimines are lipophilic toxins produced by the marine dinoflagellates Karenia selliformis and Alexandrium ostenfeldii. Currently four gymnodimine analogues are known and characterized. Here we describe a novel gymnodimine and a range of gymnodimine related compounds found in an A. ostenfeldii isolate from the northern Baltic Sea. Gymnodimine D (1) was extracted and purified from clonal cultures, and characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS), nuclear magnetic resonance (NMR) spectroscopy, and liquid chromatography-high resolution mass spectrometry (LC-HRMS) experiments. The structure of 1 is related to known gymnodimines (2-5) with a six-membered cyclic imine ring and several other fragments typical of gymnodimines. However, the carbon chain in the gymnodimine macrocyclic ring differs from the known gymnodimines in having two tetrahydrofuran rings in the macrocyclic ring.
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http://dx.doi.org/10.1016/j.toxicon.2016.01.064DOI Listing
March 2016

Characterization of Ricin and R. communis Agglutinin Reference Materials.

Toxins (Basel) 2015 Nov 26;7(12):4906-34. Epub 2015 Nov 26.

Biological Toxins, Centre for Biological Threats and Special Pathogens, Robert Koch Institute, Seestr. 10, 13353 Berlin, Germany.

Ricinus communis intoxications have been known for centuries and were attributed to the toxic protein ricin. Due to its toxicity, availability, ease of preparation, and the lack of medical countermeasures, ricin attracted interest as a potential biological warfare agent. While different technologies for ricin analysis have been established, hardly any universally agreed-upon "gold standards" are available. Expert laboratories currently use differently purified in-house materials, making any comparison of accuracy and sensitivity of different methods nearly impossible. Technically challenging is the discrimination of ricin from R. communis agglutinin (RCA120), a less toxic but highly homologous protein also contained in R. communis. Here, we established both highly pure ricin and RCA120 reference materials which were extensively characterized by gel electrophoresis, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI MS/MS), and matrix-assisted laser desorption ionization-time of flight approaches as well as immunological and functional techniques. Purity reached >97% for ricin and >99% for RCA120. Different isoforms of ricin and RCA120 were identified unambiguously and distinguished by LC-ESI MS/MS. In terms of function, a real-time cytotoxicity assay showed that ricin is approximately 300-fold more toxic than RCA120. The highly pure ricin and RCA120 reference materials were used to conduct an international proficiency test.
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http://dx.doi.org/10.3390/toxins7124856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690106PMC
November 2015

Comparison of in vitro metabolism and cytotoxicity of capsaicin and dihydrocapsaicin.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Jan 25;1009-1010:17-24. Epub 2015 Nov 25.

VERIFIN, Finnish Institute for Verification of the Chemical Weapons Convention, Department of Chemistry, P.O. Box 55, FI-00014, University of Helsinki, Finland.

Capsaicin and dihydrocapsaicin are the major active components in pepper spray products, which are widely used for law enforcement and self-protection. The use of pepper sprays, due to their irreversible and other health effects has been under a strong debate. In this study, we compared metabolism and cytotoxicity of capsaicin and dihydrocapsaicin using human and pig liver cell fractions and human lung carcinoma cell line (A549) in vitro. Metabolites were screened and identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Using liver cell fractions, a novel aliphatic hydroxylated metabolite (m/z 322) was detected to dihydrocapsaicin but no structure was found corresponding to capsaicin. Instead, a novel phase I metabolite of capsaicin, corresponding to the structure of aliphatic demethylation and dehydrogenation (m/z 294) was identified. In addition, two novel conjugates, glycine conjugates (m/z 363 and m/z 365) and bi-glutathione (GSH) conjugates (m/z 902 and m/z 904), were identified for both capsaicin and dihydrocapsaicin. The medium of the exposed A549 cells contained ω-hydroxylated (m/z 322) and alkyl dehydrogenated (m/z 304) forms, as well as a glycine conjugate of capsaicin. As to dihydrocapsaicin, an alkyl dehydrogenated (m/z 306) form, a novel alkyl hydroxylated form, and a novel glycine conjugate were found. In A549 cells, dihydrocapsaicin evoked vacuolization and decreased cell viability more efficiently than capsaicin. Furthermore, both compounds induced p53 protein and G1 phase cell cycle arrest. Usefulness of the found metabolites as biomarkers for capsaicinoid exposures will need further investigations with additional toxicity endpoints.
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http://dx.doi.org/10.1016/j.jchromb.2015.11.042DOI Listing
January 2016

Optimization of Sample Preparation for the Identification and Quantification of Saxitoxin in Proficiency Test Mussel Sample using Liquid Chromatography-Tandem Mass Spectrometry.

Toxins (Basel) 2015 Nov 25;7(12):4868-80. Epub 2015 Nov 25.

VERIFIN (Finnish Institute for Verification of the Chemical Weapons Convention), Department of Chemistry, University of Helsinki, P.O. Box 55, A. I. Virtasen aukio 1 FI-00014, Finland.

Saxitoxin (STX) and some selected paralytic shellfish poisoning (PSP) analogues in mussel samples were identified and quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Sample extraction and purification methods of mussel sample were optimized for LC-MS/MS analysis. The developed method was applied to the analysis of the homogenized mussel samples in the proficiency test (PT) within the EQuATox project (Establishment of Quality Assurance for the Detection of Biological Toxins of Potential Bioterrorism Risk). Ten laboratories from eight countries participated in the STX PT. Identification of PSP toxins in naturally contaminated mussel samples was performed by comparison of product ion spectra and retention times with those of reference standards. The quantitative results were obtained with LC-MS/MS by spiking reference standards in toxic mussel extracts. The results were within the z-score of ±1 when compared to the results measured with the official AOAC (Association of Official Analytical Chemists) method 2005.06, pre-column oxidation high-performance liquid chromatography with fluorescence detection (HPLC-FLD).
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http://dx.doi.org/10.3390/toxins7124853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690103PMC
November 2015

Results of a Saxitoxin Proficiency Test Including Characterization of Reference Material and Stability Studies.

Toxins (Basel) 2015 Nov 25;7(12):4852-67. Epub 2015 Nov 25.

VERIFIN (Finnish Institute for Verification of the Chemical Weapons Convention),Department of Chemistry, P.O. Box 55, A. I. Virtasen aukio 1, University of Helsinki,FI-00014 Helsinki, Finland.

A saxitoxin (STX) proficiency test (PT) was organized as part of the Establishment of Quality Assurance for the Detection of Biological Toxins of Potential Bioterrorism Risk (EQuATox) project. The aim of this PT was to provide an evaluation of existing methods and the European laboratories' capabilities for the analysis of STX and some of its analogues in real samples. Homogenized mussel material and algal cell materials containing paralytic shellfish poisoning (PSP) toxins were produced as reference sample matrices. The reference material was characterized using various analytical methods. Acidified algal extract samples at two concentration levels were prepared from a bulk culture of PSP toxins producing dinoflagellate Alexandrium ostenfeldii. The homogeneity and stability of the prepared PT samples were studied and found to be fit-for-purpose. Thereafter, eight STX PT samples were sent to ten participating laboratories from eight countries. The PT offered the participating laboratories the possibility to assess their performance regarding the qualitative and quantitative detection of PSP toxins. Various techniques such as official Association of Official Analytical Chemists (AOAC) methods, immunoassays, and liquid chromatography-mass spectrometry were used for sample analyses.
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http://dx.doi.org/10.3390/toxins7124852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4690102PMC
November 2015

Application of comprehensive NMR-based analysis strategy in annotation, isolation and structure elucidation of low molecular weight metabolites of Ricinus communis seeds.

Phytochem Anal 2016 Jan-Feb;27(1):64-72. Epub 2015 Oct 14.

VERIFIN, Department of Chemistry, University of Helsinki, P.O. Box 55, FIN-00014, Helsinki, Finland.

Introduction: Powder-like extract of Ricinus communis seeds contain a toxic protein, ricin, which has a history of military, criminal and terroristic use. As the detection of ricin in this "terrorist powder" is difficult and time-consuming, related low mass metabolites have been suggested to be useful for screening as biomarkers of ricin.

Objective: To apply a comprehensive NMR-based analysis strategy for annotation, isolation and structure elucidation of low molecular weight plant metabolites of Ricinus communis seeds.

Methodology: The seed extract was prepared with a well-known acetone extraction approach. The common metabolites were annotated from seed extract dissolved in acidic solution using (1)H NMR spectroscopy with spectrum library comparison and standard addition, whereas unconfirmed metabolites were identified using multi-step off-line HPLC-DAD-NMR approach.

Results: In addition to the common plant metabolites, two previously unreported compounds, 1,3-digalactoinositol and ricinyl-alanine, were identified with support of MS analyses.

Conclusion: The applied comprehensive NMR-based analysis strategy provided identification of the prominent low molecular weight metabolites with high confidence.
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http://dx.doi.org/10.1002/pca.2600DOI Listing
October 2016

Applying human and pig hepatic in vitro experiments for sulfur mustard study: screening and identification of metabolites by liquid chromatography/tandem mass spectrometry.

Rapid Commun Mass Spectrom 2015 Jul;29(14):1279-87

VERIFIN, Finnish Institute for Verification of the Chemical Weapons Convention, Department of Chemistry, University of Helsinki, P.O. Box 55, FI-00014, Finland.

Rationale: Sulfur mustard is a chemical warfare agent (CWA) with high toxicity and complex metabolism. This study aimed at identification of new metabolic biomarkers for sulfur mustard using in in vitro exposures and various mass spectrometric techniques.

Methods: Human and pig liver subcellular fractions were used as biocatalysts. Metabolites were screened by liquid chromatography and tandem mass spectrometry (LC/MS/MS) using positive electrospray ionization (ESI). For structural identification, product ion scans (MS/MS, MS(3) ) and accurate mass measurements using liquid chromatography/time-of-flight mass spectrometry (LC/TOFMS) were acquired.

Results: Sulfur mustard is metabolized in vitro by S-oxidation and glutathione (GSH) conjugations. One S-oxidized metabolite, bis(2-chloroethyl) sulfoxide (m/z 175), was formed in both species only when liver microsomes were present in incubations, and it was the main metabolite if GSH was not added into the reaction mixture. However, conjugation with GSH was found to be a spontaneous reaction in physiological pH and buffered solution. Three GSH conjugates of sulfur mustard were detected and identified, among which two were novel; 2-((2-(S-glutathionyl)ethyl)thio)ethanol (m/z 412) and 2-((2-(S-glutathionyl)ethyl)thio)ethyl phosphate (m/z 492).

Conclusions: To our knowledge, this was the first time that S-oxidized metabolites and GSH conjugates of sulfur mustard have been detected and identified from human samples in vitro by LC/MS/MS. The usefulness of the GSH conjugates to serve as biomarkers for sulfur mustard exposure in human samples requires further studies.
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http://dx.doi.org/10.1002/rcm.7218DOI Listing
July 2015
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