8 Toxicology of Organophosphate Nerve Agents

FYX FYX JWBK130-08 JWBK130-Marrs et al February 28, 2007 16:15 Char Count= 8 TOXICOLOGY OF ORGANOPHOSPHATE NERVE AGENTS Timothy C. Marrs Edentox Associates, Edenbridge, UK INTRODUCTION very high mammalian toxicity, were synthesized by Schrader in 1937 and a small pilot produc- The organophosphate (OP) anticholinesterases tion plant was set up at Münster-Lager. Later, include the chemical warfare nerve agents, a va- at Dühernfurt near Breslau in Prussian Silesia riety of OP pesticides (Ballantyne and Marrs, (now Bzerg Dolny and Wroclaw in Poland), a 1992) and, less well-known, a natural compound, production plant for these agents was established anatoxin-As (Dittmann and Wiegand, 2005). The and both tabun and sarin were manufactured in active ingredients of OP pesticides are used as quantity: in the case of tabun, 12 000 tonnes were drugs in human medicine, e.g. malathion to treat produced. Soman, another nerve agent, was also head-lice and metrifonate/trichlorfon in tropi- synthesized in Germany during the war, but only cal medicines. OPs are also used in veterinary manufactured in small quantities. Strangely, per- medicine notably as ectoparasiticides (Beesley, haps in view of the large stocks held by Ger- 1994). The chemical warfare nerve agents have a many, the nerve agents were not used in World much higher mammalian acute toxicity, particu- War II (UK Ministry of Defence, 1972) and ap- larly via the percutaneous and inhalation routes, pear to have been dumped in the Baltic sea. The than the OP pesticides. Additionally many chem- V agents similarly arose out of studies of puta- ical warfare agents are phosphonofluoridates and tive insecticides and VX has been variously re- phosphonothioates, while many pesticides are ported as being first synthesized at the Chemical = S type-phosphorothioates. Qualitatively, the Defence Experimental Establishment (CDEE) at anticholinesterase toxicology of the OP nerve Porton Down, UK (now Dstl, Porton Down) agents and pesticides is similar and in general or by Ghosh at Imperial Chemical Industries in treatment strategies are alike so that much infor- 1952 (SIPRI, 1971). Other nerve agents were de- mation on OP pesticides is relevant to nerve agent veloped subsequently and stocks have been held toxicology. by a number of countries, including USA, the for- mer USSR and successor states, the UK, France and Iraq. However, nerve agents have rarely been History used in warfare; the only notable instance of use OP compounds were intensively investigated being by Iraq against that country’s own Kur- in Germany in the 1930s. The German con- dish population (le Chêne, 1989). There have glomerate IG Farbenindustrie looked at a num- also been allegations of use of OP nerve agents ber of these compounds for use as insecticides during the Iran/Iraq war. The nerve agent sarin, and a programme of synthesis of a large num- in an impure form, was used in two terrorist at- ber of compounds was undertaken. Tabun and tacks in Japan, respectively, in Matsumoto 1994 sarin, OPs of little use as insecticides but of (Okudera, 2002) and Tokyo in 1995 (Nagao et al., Chemical Warfare Agents: Toxicology and Treatment (2nd Edition) Edited by Timothy C. Marrs, Robert L. Maynard and Frederick R. Sidell C 2007 John Wiley & Sons, Ltd 191 FYX FYX JWBK130-08 JWBK130-Marrs et al February 28, 2007 16:15 Char Count= 192 CHEMICAL WARFARE AGENTS Table 1. Possible targets for nerve agents in warfare.a Adapted and reproduced from Chapter 34, ‘Organophosphorus compounds as chemical warfare agents’, by Maynard RL and Beswick F, in Clinical and Experimental Toxicology of Organophosphates and Carbamates (B Ballantyne and TC Marrs, eds), 1992, with the kind permission of the publishers, Elsevier, and the authors Type of agent Target Sarin Soman VX Delivery system Rear areas Airports/airfields — L L Aircraft (bombs, cluster spray bombs, spray tanks, missiles) Seaports — L L Aircraft (bombs, cluster spray bombs, spray tanks, missiles) Railways, especially — L L Aircraft (bombs, cluster) junctions Headquarters and — L L Aircraft (bombs, missiles) communication centres Storage sites — L L Aircraft (bombs, cluster missiles) Troop concentrations — L L Aircraft (bombs, spray tanks) Forward areas Nuclear delivery weapons, L — L Multiple rocket launchers, aircraft other key weapons (bombs, rockets) and systems Defence positions L — L Multiple rocket launchers, artillery, mortars, aircraft (bombs), rockets Own flanks L — L Mines Own defence L — L Artillery, mortars, mines front generally To produce casualties, L — L Multiple rocket launchers, artillery, to harass and reduce mortars, aircraft (bombs, rockets) combat efficiency To deny ground — L L Aircraft (spray, mines) Harass civilian L — — Aircraft (bombs, rockets, sprays) populations Note: a L, likely use. 1997), as was, almost certainly, VX, but this tabun is easier than the other G agents, so that agent was used for assassination of individuals tabun is more likely to be used in terrorist sce- (Nozaki et al., 1995). narios (see below). The reason is that tabun has no fluorine in its structure. Incorporation of the fluorine leaving group requires the use of hy- Use drofluoric acid during the synthesis and this is, Possible roles of OP nerve agents in warfare are of course, corrosive to glass. Early bulk synthe- outlined in Table 1. Until the use of sarin in Mat- sis of nerve agents with fluorine leaving groups sumoto and Tokyo, the use of chemical weapons was carried out using special apparatus made or as terrorists’ tools had been considered unlikely. lined with pure silver. Such a process is inevitably Since then, and the emergence of al-Qaida, this costly, although the difficulties did not deter a has been reconsidered and Table 2 gives some Japanese terrorist group (the Aum Shinrikyo). It of the roles whereby terrorists might make use is of interest that the nerve agent likely to have of chemical weapons. Note that the synthesis of been used by Iraq against the Kurds was tabun, FYX FYX JWBK130-08 JWBK130-Marrs et al February 28, 2007 16:15 Char Count= TOXICOLOGY OF ORGANOPHOSPHATE NERVE AGENTS 193 Table 2. Possible terrorist targets for nerve agents while tabun does not contain a fluorine atom and is a cyanidate. The G agents include GB Major target Specific target (sarin, isopropyl methylphosphonofluoridate), Air transport Airport terminals/interiors GD (soman, pinacolyl methylphosphonofluori- of planes date), GA (tabun, ethyl N,N-dimethylphospho- Railways/subway Stations, ramidocyanidate) and GF (cyclosarin, cyclo- systems interiors of carriages hexyl methylphosphonofluoridate). The V agents Road transport Freeways/motorways, are phosphonothioates of the P–O type in which especially intersections the leaving group is linked to phosphorus through and service stations a sulphur atom, except for VG which is a Public meeting places Concert halls, phosphorothioate. The V agents are exemplified major sporting events, political meetings, by VX (O-ethyl S- (2-(diisopropylamino)ethyl) churches and synagogues methylphosphonothioate). Financial centres Headquarters of financial All of the nerve agents are colourless liq- institutions, uids, although impure agents may be yellow to exchanges, e.g. trading brown in colour. However, these compounds dif- floors fer amongst themselves in physical properties Energy supply Power stations, (Table 4), for example, the V agents are much gas terminals, less volatile than the G agents, the latter being oil terminals volatile liquids (tabun less volatile than sarin or Communications Television and radio broadcasting stations, soman). Soman may be thickened to increase per- telephone exchanges sistence (Marrs and Maynard, 2001). VX is a non-volatile liquid with the result that the VX (unless aerosolized) is not an inhalation hazard, the first nerve agent to be synthesized on a large a fact that may significantly affect its role in war- scale. fare. Tabun is said to have a fruity odor, while the other agents are said to be odorless. Sarin may be mixed with tributylamine (sarin type I) or di- Structure and physical properties isopropylcarbodiimide (sarin type II), to prevent The nerve agents comprise a group of OPs of high spontaneous hydrolysis. acute mammalian toxicity. They are derivatives As is discussed below, more information of phosphoric or phosphonic acids (more often on cyclosarin (GF, cyclohexyl methylphospho- the latter) and contain two alkyl groups (R and R) nofluoridate) has accumulated recently, because, and a leaving group. The general formulae of the during operations ‘Desert Shield’ and ‘Desert OP nerve agents is similar to the OP pesticides: Storm’, it was discovered that cyclosarin was among the nerve agents that Iraq possessed. O Thus, some limited information is now avail- able on the physical properties of this nerve agent ′ RRP (gulflink, 2005). The material is a liquid at room ◦ X temperature with a boiling point of 239 C and a freezing point of −30◦C. The vapour pres- The nerve agents are traditionally divided into sure is 0.044 mmHg at 20◦C and the volatility the G agents and V agents (Table 3). Accord- is 438 mgm−3 at 20◦C. ing to Watson et al. (2005), G stands for Ger- man and V for venom. In the case of the G agents the leaving group is often a fluorine atom TOXICOLOGY and, exceptionally in GF (cyclosarin), one of the alkyl groups is replaced by a cyclohexyl Until recently, attention has almost entirely been group. Soman is distinguished by the fact that given to the acute toxicity of nerve agents and, one of its alkyl groups is a bulky pinacolyl

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