Poisoning by organophosphorus nerve agents and pesticides: An overview of the principle strategies and current progress of mass spectrometry-based procedures for verification

Abstract

Highlights Evidence of poisoning with organophosphorus (OP) nerve agents requires biomedical verification. OP nerve agents undergo common biotransformation pathways producing valuable biomarkers. Internationally accepted methods target remaining poison, hydrolysis products and protein-adducts. Mass spectrometry-based methods provide optimum selectivity and sensitivity for identification. Methods, strategies, current proceedings, quality criteria and real cases of poisoning are presented.

Evidence of sulfur mustard poisoning by detection of the albumin‐derived dipeptide biomarker C(‐HETE)P after nicotinylation

“…As the exposure to SM has caused a high number of victims within the recent years 1–6,8 reliable bioanalytical procedures are mandatory that allow the detection of related biomarkers for toxicological, clinical, and forensic reasons. Even though some peptide‐based biomarkers are already accepted internationally, 1,14–16,19 specialized laboratories continue efforts for expanding and improving the related methods 23,26,28 . Accordingly, the N‐terminal derivatization of peptide biomarkers represents an option to modulate chromatographic and mass spectrometric properties.…”

“…These peptides represent well‐established and internationally accepted long‐term biomarkers of exposure to SM detectable for up to four weeks after exposure using liquid chromatography‐electrospray ionization tandem‐mass spectrometry (LC‐ESI MS/MS) techniques 1,8,14 . Nevertheless, the current incidents of poisoning with chemical warfare agents—also including the highly toxic organophosphorus nerve agents 11,20,21 —demand the search for potential novel biomarker molecules 17,22–29 as well as the continuous optimization of already established methods 16,30–32 . Therefore, we addressed the precolumn derivatization of C(‐HETE)P to produce a derivative suited as an additional biomarker of exposure.…”

“…As the t R of C(-HETE)P (t R 4.6 min) and NA-C(-HETE)P (t R 9.5 min) are quite different, the detection of the derivative might represent a useful completion for biomedical analysis, specifically when any donor-specific matrix-derived interference deteriorates the detection of the non-derivatized C(-HETE)P. In addition, simple sample splitting allows parallel analysis targeting both the derivatized and the non-derivatized biomarker dipeptide thus allowing unambiguous verification of SM exposure. The application to other peptide-based biomarkers of poisoning, for example, the phosphylated butyrylcholinesterase-derived nonapeptide or the phosphylated HSA-derived tyrosine residue12,28 will be addressed in future studies.…”

“…[14][15][16]19 Following proteolysis of the HETE-HSA-adduct found at C 34 with pepsin the alkylated dodecapeptide LQQC 34 (-HETE) PFEDHVKL is produced, 1 with proteinase K the alkylated tripeptide C(-HETE)PF is generated 1,14 and pronase-catalyzed hydrolysis yields the alkylated dipeptide C(-HETE)P. 15,19 These peptides represent wellestablished and internationally accepted long-term biomarkers of exposure to SM detectable for up to four weeks after exposure using liquid chromatography-electrospray ionization tandem-mass spectrometry (LC-ESI MS/MS) techniques. 1,8,14 Nevertheless, the current incidents of poisoning with chemical warfare agents-also including the highly toxic organophosphorus nerve agents 11,20,21 -demand the search for potential novel biomarker molecules 17,[22][23][24][25][26][27][28][29] as well as the continuous optimization of already established methods. 16,[30][31][32] Therefore, we addressed the precolumn derivatization of C(-HETE)P to produce a derivative suited as an additional biomarker of exposure.…”

Identification of organophosphate modifications by high‐resolution mass spectrometry

“…2 In the 21st century, with the development of organophosphate (OP) and nerve agent detection techniques, several cases have been reported, showing that the Syrian government sprayed a sarin agent to the militia during the Syrian Civil War in 2013. 3 Third, the death of Kim Jong-Nam, a member of the North Korean dictator's family, was reported at a Malaysia airport in 2017 from exposure to V-type nerve agent (VX), 4 which was probably made in Russia by Russian military intelligence officer Sergei Skripla and his daughter Yulia Skripal, who defected to the United Kingdom from Russia in 2018. 5 Fourth, cases of poisoning with a putative Novichok agent have been reported.…”