Novichoks: What is there to worry about?


By Lt. Col. Tanos, Brazilian Military Institute of Engineering, and Prof. Kuča, University of Hradec Kralove, Czech Republic

“Newcomer” is the translation of the Russian word “novichok” (Новичо́к in Cyrillic). This was the name given to a new kind of chemical weapon supposedly developed in the former Soviet Union between the 1970s and 1990s, with the purpose of cheating the chemical weapons convention (CWC). At least that’s the story told by the Russian defector exiled in the United States Vil S. Mirzayanov in his book titled: “State Secrets: An inside chronicle of the Russian chemical weapons program”, published in 2009 by Outskirts Press, Inc. Rumors about the existence of novichoks, as well as non-conclusive speculations about their actual chemical structures and physical-chemical properties, could already be found before Mirzayanov’s book, in publications from the beginning of this century. However these chemicals only showed up in the headlights after the attempted assassination of the former Russian spy Sergei Skripal, and his daughter Yulia on UK soil, on February 2018. Once a novichok agent was suspected by the British experts, as the chemical used in this episode, the premier Theresa May accused the Russian Government of involvement, triggering a diplomatic crisis between the two countries, not seen since the cold war times. But after all what is there about novichoks to justify such rash reaction? What are the reasons for concern?

Experts classify the chemical weapons in four generations. The first one includes the chemicals used in the I world war (chocking, blood, and blister agents) like phosgene, hydrogen cyanide and mustards, while the second generation includes the nerve agents of the series G (like tabun, soman and sarin) and V [like VX and Russian VX (RVX)], developed around the II world war. The third generation refers to the binary weapons, developed by the United States of America (USA) in the 1970-1980’s, and the fourth are the binary novichok’s supposedly developed by the Soviet Union in the 1980-1990’s as a response to the USA binary program. Binary weapons are ammunitions designed to produce the chemical agent, during the flying time to the target, through the reaction between less toxic precursors. They were conceived to reduce the risks in the production, storage, transport, and even destruction of the toxic agent. Novichoks are the binary weapons meant to deliver RVX and the nerve agents of the A-series. According to Mirzayanov the nerve agents of the A-series are derivatives from the agents of the series G and V containing nitrogen in their structure. He worked for 26 years at the State Scientific Research Institute for Organic Chemistry and Technology in Moscow, abbreviated in Russian language as GOSNIIOKhT (ГосНИИОХТ in Cyrillic), and claims to have witnessed in early 1970’s, the Russian scientist Petr Kirpichev and his assistants developing the nerve agents of the A-series. According to his testimony 5 chemicals were synthesized and named A-230, A-232, A-234, A-242 and A-262 (Figure 1). A-230 presented toxicity 5-8 times higher than the RVX, while A-232 and A-234 had toxicity similar to RVX, but were much more volatile and less stable to hydrolysis, and A-242 and A-262 were probably the first solid neurotoxic agents synthesized.

Figure 1: Chemical Strutures of the A-series nerve agents reported by Mirzayanov in tridimensional representation. Grey = Carbon; Blue = Nitrogen; Red = Oxygen; Orange = Phosphorus; Light blue = Fluorine; White = Hydrogen.

Mirzayanov reports that A-232 was the only agent of the A-series to be weaponized as a binary weapon, before the funding for the novichok project disappearing after the collapse of the Soviet Union. However, other authors report that A-234 also was transformed in binary weapon. Besides being resistant to cold temperatures, these agents were capable of circumventing the list of chemical agents controlled by the CWC, because they belong to the class of phosphoramidofluoridates, being similar to the majority of the organophosphates (OP) used in agriculture (pesticides and herbicides). Those compounds were not included in the schedules of CWC, because all known OP used as chemical weapons so far were phosphonates.

Apparently the nerve agents of the A-series have the same mechanism of action as the other nerve agents. This means that they act by disturbing the cholinergic transmission of nerve impulses in the central and peripheral nervous systems due to its capacity of inhibiting the enzyme acetylcholinesterase (AChE). This result in the cholinergic syndrome also referred as the SLUDGEM (Salivation, Lachrymation, Urination, Defecation, Gastrointestinal, Emesis, and Miosis) syndrome, causing a collapse of the organism due to the loss of control of most of the body voluntary and involuntary functions. Death usually follows from cardiorespiratory arrest. The cholinergic syndrome can be stopped through the administration of an antidote capable of reversing the inhibition of AChE by removing the nerve agent from its active site, restoring its enzymatic activity and, therefore, the cholinergic transmission. But if the responders fail in administering the antidote or it is not administered on time, the complex formed between AChE and the nerve agent surfer what’s called aging. If this happens, AChE becomes permanently inactivated once there is no antidote today capable of restoring the activity of aged AChE.

As the A-series nerve agents act similarly to the other series, it’s expected that the conventional prophylaxis through the administration of the cocktail containing an anticholinergic, an anticonvulsant, and an antidote capable of reactivating the inhibited AChE, would work against intoxications with this kind of agent. However, the few literature sources available speculate that the A-series inhibited AChE ages rapidly. If this is true recovering of victims through administration of the commercially available antidotes would be a really hard task. This means that no antidote against intoxication with novichoks would exist today and the only strategy to deal with this problem would be symptomatic therapy associated to the administration of bioscavengers, i.e. enzymes capable of catching the nerve agent in the blood stream before it reaches the binding to AChE, like the enzyme butyrylcholinesterase.

Therefore novichoks in fact represent a matter of concern today. Despite being just nerve agents structurally similar to the agents of the G and V-series, the A-series can be more toxic and also harder to counteract with the commercial antidotes available today. Additionally, the lack of conclusive information about their actual chemical structures make it difficult both its inclusion on the CWC list of controlled chemical agents and the consequent development of ways of detection and treatment. Besides, some of these compounds were reported to be solid. This fact can opens new possibilities for those with terrorist ideas in mind.

About the Authors

Lt. Col. Tanos Celmar Costa França is Professor of Chemistry and Chemical Defense at the Military Institute of Engineering at Rio de Janeiro/RJ – Brazil. He obtained his BSc in Chemical Engineering at the Federal Rural University of Rio de Janeiro (Brazil) in 1993, his MSc in Organic Chemistry at the Federal University of Rio de Janeiro (Brazil) in 1998, and his PhD in Chemistry at the Military Institute of Engineering (Brazil) in 2004. Worked as visitor scholar at the Skaggs School of Pharmacy and Pharmaceutical Sciences of the University of California (San Diego, United States) in 2012/2013, and visitor researcher at the Concordia University in Montreal, Canada, in 2015/2016. Currently, is invited professor at the Department of Chemistry, Faculty of Science, of the University of Hradec Kralove in Czech Republic. He is also member of the Brazilian Chemical Society, the American Chemical Society, and the editorial board of the journal Military Medical Science Letters. Develops research mainly on the design of new antidotes against chemical warfare agents and drugs against biological warfare agents. Publications: 107 papers in peer-reviewed journals, 92 meeting communications, 01 edited book, 12 book chapters. H Index in the Web of Science = 17.

Prof Kamil Kuča is/was working for several academic institutes (University of Hradec Kralove, Czech Republic; University of Defence, Czech republic; University Hospital Hradec Kralove, Czech republic; Florida International University, USA; Yangtze University, China; University Technical Malaysia, Malaysia, etc.). He is recently rector of the University of Hradec Kralove. He was also technology scout focused on biomedicine in the past. His research interests are toxicology, pharmacology, drug design, technology transfer, pharmacoeconomy, chemical and biological terrorism, etc. He was/is principal investigator on numerous national and international projects (EU, NATO, GACR, IGA MZ, MSMT etc.). He has published more than 350 IF research papers. He is working with several companies as a scientific advisor. He has lots of cooperators throughout the world (e.g. Korea, Croatia, United Arab Emirates, USA, France, Turkey, China, Singapore, Sweden, and Brazil). His Hindex is 46 (April 2019), number of citation in WoS is over 6000.

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