Toxicology of organophosphorus compounds in view of an increasing terrorist threat

Abstract

The implementation of the Chemical Weapon Convention (CWC), prohibiting the development, production, storage and use of chemical weapons by 192 nations and the ban of highly toxic OP pesticides, especially class I pesticides according to the WHO classification, by many countries constitutes a great success of the international community. However, the increased interest of terrorist groups in toxic chemicals and chemical warfare agents presents new challenges to our societies. Almost seven decades of research on organophosphorus compound (OP) toxicology was mainly focused on a small number of OP nerve agents despite the fact that a huge number of OP analogues, many of these agents having comparable toxicity to classical nerve agents, were synthesized and published. Only limited physicochemical, toxicological and medical information on nerve agent analogues is available in the open literature. This implies potential gaps of our capabilities to detect, to decontaminate and to treat patients if nerve agent analogues are disseminated and may result in inadequate effectiveness of newly developed countermeasures. In summary, our societies may face new, up to now disregarded, threats by toxic OP which calls for increased awareness and appropriate preparedness of military and civilian CBRN defense, a broader approach for new physical and medical countermeasures and an integrated system of effective detection, decontamination, physical protection and treatment.

Post-exposure treatment with the oxime RS194B rapidly reverses early and advanced symptoms in macaques exposed to sarin vapor

“…pralidoxime (2-PAM) or its analogues: HI-6, obidoxime, MMB4. However, efficacy of these oximes is limited by steric constraints of an impacted active center gorge limiting pyridinium aldoxime attack, poor oral bioavailability, rapid clearance, and their inability to rapidly cross the blood-brain-barrier (BBB)(6–8). Recent clinical trials using pesticide-poisoned individuals have shown uneven clinical benefits with these oximes (9–11).…”

“…In the last decade, as OP threats have spread widely due to terrorism and to increased agricultural use of pesticides, research has focused on the development of two types of countermeasures: (i) prophylactic stoichiometric and catalytic bio-scavengers (2,12–17), an advanced candidate being butyrylcholinesterase (BChE) that has been shown to prevent OP toxicity in several animal models, and (ii) novel centrally acting, bioavailable oxime reactivators that can restore inhibited AChE activity in the brain post-OP exposure (4,7,8). Because the pharmacokinetics following parenteral delivery of large doses of stoichiometric bioscavengers of high molecular weight, such as BChE, are suboptimal for immediate post-exposure and longer term protection (17), administration of aerosolized (aer) rHuBChE via the pulmonary route is also under consideration to provide a protective pulmonary shield against inhaled volatile agents (18–19).…”

Reversible cholinesterase inhibitors as pretreatment for exposure to organophosphates. A review

“…There is some evidence that Afghan girl schools may have been the target of terrorist attacks with OPC pesticides, but these allegations are controversial (Bartholomew, Lockery, & Najm, 2016;Masson & Nachon, 2017). Moreover, media reports suggest that the terrorist group ISIS may have stolen and employed sarin in Libya (Worek, Wille, Koller, & Thiermann, 2016). OPCs therefore continue to represent a worrying threat to civilians and rescue teams.…”

Acetylcholinesterase: The “Hub” for Neurodegenerative Diseases and Chemical Weapons Convention

“…Cholinesterases are found in two isoforms, AChE (EC 3.1.1.7) and butyrylcholinesterase (BChE), EC 3.1.1.8. Compounds that can inhibit cholinesterases may impact the body positively or negatively and, therefore, be either explored as method of warfare or therapeutically [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67].…”