Manuscript for Kirk-Othmer Encyclopedia of Chemical Technology August 2019 CHEMICAL WARFARE AGENTS This is the pre-print manuscript of an article published in the Kirk-Othmer Encyclopedia of Chemical Technology: https://onlinelibrary.wiley.com/doi/book/10.1002/0471238961 The published version of the article is available at the Wiley website: https://onlinelibrary.wiley.com/doi/10.1002/0471238961.0308051308011818.a01.pub3 How to cite: Costanzi, S. (2020). Chemical Warfare Agents. In Kirk‐Othmer Encyclopedia of Chemical Technology, (Ed.). doi:10.1002/0471238961.0308051308011818.a01.pub3 Stefano Costanzi Department of Chemistry and Center for Behavioral Neuroscience American University, Washington, D.C. [email protected] Chemical weapons are weapons that exploit the toxicity of chemicals to bring about death or harm. The toxic chemicals on which chemical weapons are based are known as chemical warfare agents. The elimination of this entire category of weapons is the aim of the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction, also known as Chemical Weapons Convention or CWC, which was opened for signature in 1993 and entered into force in 1997. Administered and implemented by the Hague- based Organisation for the Prohibition of Chemical Weapons (OPCW), the CWC is an international treaty that enjoys almost universal embracement, having been ratified or acceded by 193 States Parties. Importantly, the CWC poses a complete and absolute ban on chemical weapons, mandating State Parties to renounce “(a) to develop, produce, otherwise acquire, stockpile or retain chemical weapons, or transfer, directly or indirectly, chemical weapons to anyone; (b) to use chemical weapons; (c) to engage in any military preparations to use chemical weapons; (d) to assist, encourage or induce, in any way, anyone to engage in any activity prohibited to a State Party” under the Convention (CWC Article II, Paragraph 1) (1-3). This complete ban marks a substantial departure from previous international treaties or national policies on chemical weapons, which prohibited exclusively their use, chiefly intended, either implicitly or explicitly, as “first use” of these weapons – for instance, see the 1899 Hague Gas Declaration, the 1925 Geneva Protocol, or Richard Nixon’s 1969 “Statement on Chemical and Biological Defense Policies and Programs” (4-6). The complete ban posed on chemical weapons by the CWC mirrors an analogous ban posed on biological weapons and toxins by the Biological Weapons Convention (BWC), which was opened for signature in 1972 and entered into force in 1975. In fact, the BWC explicitly mandated State Parties to conduct negotiations in good faith to reach a similar agreement on the prohibition of chemical weapons (BWC Articles IX and XII) (7). Despite the complete ban posed by the CWC, chemical weapons are far from being relegated to the past. After the entrance into force of the CWC in 1997, for a period of about 15 years, there were no reports of chemical weapons usage. However, beginning in 2012, chemical weapons have been used in several occasions by state and non-state actors as weapons of mass destruction or for targeted assassinations. In particular, they have been used in the Syrian civil war by both state and non-state actors (including the notorious Ghouta attack in August 2013, attributed to the Syrian regime by the United Nations, which led to the death of about 1400 people), in Iraq by non-state actors, in Malaysia for the assassination of Kim Jong-nam, half-brother of North Korea’s leader Kim Jong-un, in February 2017, and in the United Kingdom for the attempted assassination of Sergei Skripal and his daughter in March 2018. This recent trend in the use of chemical weapons has led international security and arms control experts to think about ways of restoring the restraint on the use of chemical weapons. At the same time, the international community formed the International Partnership against Impunity for the Use of Chemical Weapons, launched in Paris in January 2018, with the aim of supplementing the existing international mechanism to combat the proliferation of chemical weapons (6,8-11). This article starts by providing some definitions of chemical weapons and chemical warfare agents as well an overview of key toxicology concepts and some notes on the physicochemical properties of the agents. Subsequently, it illustrates the chemistry, biochemistry, and medical countermeasures of the main classes of chemical warfare agents, namely vesicants, choking agents, blood agents, irritants, nerve agents, and centrally incapacitating agents. This article does not cover personal protective equipment, detection, chemical and biochemical analyses, or decontamination. Similarly, it does not cover biological toxins, beyond discussing their coverage by the CWC in Section 1.1. For these matters, the reader is referred to other sources (12-20). 1. Definitions 1.1. Chemical weapons and chemical warfare agents. Chemical weapons are weapons intended to cause death or incapacitation through the toxic properties of chemicals. Chemical weapons are clearly defined in Article II of the CWC, according to which chemical weapons “means the following, together or separately: (a) toxic chemicals and their precursors, except where intended for purposes not prohibited under this Convention, as long as the types and quantities are consistent with such purposes; (b) munitions and devices, specifically designed to cause death or other harm through the toxic properties of those toxic chemicals specified in 2 subparagraph (a), which would be released as a result of the employment of such munitions and devices; (c) any equipment specifically designed for use directly in connection with the employment of munitions and devices specified in subparagraph (b)” (CWC Article II, Paragraph 1) (1,3). Of extreme importance to understanding chemical warfare agents which, as explained are the toxic chemicals on which chemical weapons are based, is the second paragraph of Article II of the CWC. According to this paragraph, toxic chemicals are defined as “any chemical (emphasis added) which through its chemical action on life processes can cause death, temporary incapacitation or permanent harm to humans or animals. This includes all such chemicals, regardless of their origin or of their method of production, and regardless of whether they are produced in facilities, in munitions or elsewhere…” (CWC Article II, Paragraph 2) (1). The definition of chemical weapons provided by the CWC is broad and comprehensive. Any weapon designed to bring about death, temporary incapacitation, or permanent harm through the toxic properties of chemicals is considered a chemical weapon. As one can notice, the CWC does not establish any toxicity threshold in its definition of toxic chemicals. In fact, toxicity thresholds cannot be established because the toxicity of chemicals is entirely dependent on the amount of the chemical (the dose) to which an individual is exposed. As it had already been noted by Paracelsus, “all things are poison, and nothing is without poison; only the dose permits something not to be poisonous” (21). In other words, if administered at a high enough dose, all substances can exert a toxic effect. This implies that comprehensive lists of chemical warfare agents cannot be established. Some chemicals, for instance nerve agents, have no known legitimate uses. Hence, it is straightforward to classify these chemicals as tout court chemical warfare agents. Other chemicals, for instance chlorine or phosgene, have many legitimate uses in chemical industry. Despite their legitimate uses, such dual use chemicals are indeed considered chemical warfare agents if they are employed to intentionally cause death, incapacitation, or harm through their toxicity, and weapons based on such chemicals are indeed considered chemical weapons. Beyond the toxic chemicals themselves, paragraph 1 of Article 2 of the CWC extends the definition of chemical weapons to their precursors, i.e. the chemicals used to synthesize them (1). Some precursor chemicals have little or no use beyond serving as reactants for the synthesis of chemical warfare agents. However, in the majority of cases, precursors are dual use chemicals that, beyond their role in the synthesis of chemical warfare agents, also have legitimate, peaceful applications. Just as in the case of dual use toxic chemicals, dual use precursors indeed fall within the CWC prohibitions if they are intended to be employed for the synthesis of chemical warfare agents. In its Annex on Chemicals, the CWC lists three schedules of chemicals, Schedule 1, Schedule 2, and Schedule 3 (2). These schedules are not intended to provide a comprehensive list of chemical warfare agents and their precursors – as mentioned, that would be an unfeasible task, as any chemical becomes a chemical warfare agent when it is intentionally employed to kill or harm through its toxic properties. Instead, the schedules are intended to support the CWC 3 verification regime, by identifying chemicals of concern that are subject verification measures under the auspices of the OPCW and must be declared by States Parties. Schedule 1 identifies chemicals that are considered exclusively or primarily as chemical warfare agents or chemical warfare agent precursors. Schedule 2 and Schedule 3 identify dual use chemicals of concern, i.e. chemical warfare agents and precursors that have also legitimate uses,