Central Nervous System-Acting Chemicals and the Chemical Weapons Convention: a Former Scientific Adviser’S Perspective

Home , CNS (chemical weapon), Incapacitating agent

Pure Appl. Chem. 2018; 90(10): 1559–1575

Conference paper

Robert J. Mathewsa,* Central Nervous System-acting chemicals and the Chemical Weapons Convention: A former Scientific Adviser’s perspective https://doi.org/10.1515/pac-2018-0502

Abstract: The term Incapacitating Chemical Agents (or Incapacitants) was chosen to describe different classes of chemical warfare agents that were being developed in the 1950s. This article considers some of the types of chemicals and their properties that have been discussed more recently under the terminology of Incapacitat- ing Chemical Agents, including opioids of the fentanyl class, and how these psychochemicals are relevant to the Chemical Weapons Convention. This article argues that the term Incapacitating Chemical Agents is inaccurate and misleading and will be a potential cause of confusion when Member States of the Chemical Weapons Convention are discussing the types of toxic chemicals which are permitted for use for various law enforcement purposes including domestic riot control. This article then argues that the term Central Nervous System-acting chemicals is a more accurate and appropriate description of psychochemicals such as the fentanyls, and use of this term will hopefully facilitate a more constructive discussion within the Organisation for the Prohibition of Chemical Weapons (OPCW). In other words, it is important to ‘get the science clearly understood first’, to enable a more constructive discussion by policy-makers, lawyers and military experts.

Keywords: Central Nervous System-acting Chemicals; chemical warfare; Chemical Weapons Convention 2017; CWC Fourth Review Conference; Law Enforcement Chemicals.

Introduction

Since the 1950s, there have been amazing scientific developments of chemicals which act on the central nervous system (CNS), based partly on the improved understanding of the molecular basis of biology through the increasing convergence of chemistry and biology. This has resulted in a range of new classes of chemicals, including fentanyl and its analogs, which are having a major positive impact on medical treatment [1]. The fentanyl family of opioids, which act on the same set of receptors as morphine and related chemicals found in opium, are among the strongest analgesics (pain relievers) known, and among the fastest acting neurochemical agents.1 In addition to providing relief from pain, the fentanyl class opioids cause sedation and unconsciousness at higher doses. Since the discovery of fentanyl in 1960, the fentanyl class opioids have been widely used for both analgesia and anaesthesia. Despite the high toxicity of these chemicals, they are

1 Fentanyl, for example, is 100 times more potent than morphine and also acts more rapidly (onset time of 1–2 min versus 15– 30 min) and with a shorter duration (1 h versus 3–5 h).

Article note: A special issue containing invited papers on Innovative Technologies for Chemical Security, based on work done within the framework of the Chemical Weapons Convention. aA former member of the OPCW Scientific Advisory Board. The views expressed in this paper are those of the author and do not necessarily reflect those of the Australian Government or any other entity. *Corresponding author: Robert J. Mathews, Faculty of Law, University of Melbourne, Melbourne, Australia, e-mail: [email protected]

© 2018 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/ 1560 R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention safe when used in controlled medical settings or with very accurate doses (e.g. pain patches for humans and veterinary darts to immobilise large animals). Unfortunately, in recent years, as is well known within the general community, there has been an increasingly concerning ‘down-side’ to these developments in medical science in the form of an illicit drug phenom- enon based on some of these chemicals. This has led to a major increase in casualties of drug abuse, and in the case of fentanyl and its analogs, has led to the so-called ‘opioid epidemic’, which currently appears to be spiralling out of control in an increasing number of countries. Fentanyl and its analogs have such high acute toxicity that there are increasing concerns about law enforcement officials and other first responders becoming casualties when they are attending drug-related crime scenes [2]. Another potential ‘down-side’ to these remarkable medical developments, not as well known within the general community, is the potential development of some of these CNS-acting chemicals for ‘law enforcement purposes’ and also possibly as a new class of military chemical warfare agents. The developing and stockpiling of such chemicals for law enforcement purposes would increase the risk of them being used in violation of the Chemical Weapons Convention (CWC or ‘the Convention’),2 the international treaty which prohibits the development, production, stockpiling and use of chemical weapons. This article provides a brief outline of the CWC and the efforts of the ‘CWC community’ to prevent the re-emergence of chemical weapons, which could happen through the potential mis-use of fentanyl and its analogs as ‘incapacitants’3 for ‘law enforcement purposes’, which could then lead to the use of these chemicals in future armed conflict. This article argues that the term ‘incapacitant’ is inaccurate and misleading and a potential cause of confusion when Member States of the CWC are discussing these issues, and suggests that the term ‘Central Nervous System-acting chemicals’ is more accurate and appropriate terminology. The article emphasises the need for diplomats, lawyers, and military experts to understand the science (‘get the science right’) as a first step in their efforts to prevent the re-emergence of chemical weapons, and it high- lights the very valuable role being played by the International Union of Pure and Applied Chemistry (IUPAC) in helping to ‘tend’ (i.e. look after) the CWC.

Overview of the Chemical Weapons Convention

When the negotiation of the CWC was concluded in the Conference on Disarmament in Geneva in 1992, this agreement was recognised as being a revolution in arms control and disarmament [3]. It was the first comprehensively verifiable multilateral treaty that completely bans an entire class of weapons, and firmly limits and monitors activities that may contribute to the production of those weapons. It goes further than any other disarmament treaty in terms of the scope of prohibition, and the extent of verification provisions. Verification under the CWC includes compulsory national declarations about relevant industrial and military activities, and a regime of routine inspections of declared industrial and military facilities. An additional feature is the provision of a ‘challenge inspection’, under which a Member State can request at short notice an inspection

2 The 1993 Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on Their Destruction (‘Chemical Weapons Convention’). Opened for signature 13 January 1993; entered into force 29 April 1997. 3 From the 1950s, the terms ‘Incapacitating Chemical Agent’, ‘Incapacitating Agent’, ‘Chemical Incapacitant’ and ‘Incapacitant’ have been used interchangeably. For convenience, this article will generally use the term ‘incapacitant’ unless quoting from a reference document. In the context of potential chemical warfare or law enforcement purposes, fentanyl and its analogs have also sometimes been referred to non-lethal weapons, but usually within quotation marks (or ‘so-called non-lethal weapons’), to indicate the reality that the use of this class of toxic chemicals for these purposes are likely to result in many serious casualties, including substantial numbers of lethalities. As discussed in Section 7 of this article, since 2015 the term ‘Central Nervous System- acting chemical’ has been increasingly used rather than ‘incapacitant’ or ‘non-lethal weapon’ when referring to fentanyl and its analogs in the context of these highly toxic chemicals being considered for law enforcement purposes or as potential chemical warfare agents. 4 OPCW. ‘Opening Statement by the Director-General to the Conference of the States Parties at its Twenty-Second Session,’ C-22/ DG.20, (27 November 2017). R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention 1561 of any site, or an investigation of alleged use, in another Member State. The treaty also provides for assistance to CWC Member States (when under threat of attack, or attacked, with chemical weapons), and international cooperation to facilitate the development of chemistry for ‘peaceful purposes’. The treaty required the estab- lishment of a new international organisation, the Organisation for the Prohibition of Chemical Weapons (OPCW), to administer it. Since its entry into force on 29 April 1997, the CWC has been increasingly seen as one of the most successful arms control and disarmament treaties. The OPCW has been recognised as playing a critical role in the success of the CWC, including through the verification of destruction of declared chemical weapons stockpiles and related production equipment, to the extent that the OPCW was awarded the Nobel Peace Prize in 2013. By the end of October 2017, 67,857 tonnes (96 %) of the 70,493 tonnes declared stockpiles of chemical warfare agents had been destroyed, and an agreed timetable is in place for the destruction of the remainder of these stockpiles.4 Despite these successful outcomes, the CWC and OPCW continue to face challenges, one of which is preventing the re-emergence of chemical weapons.5 One aspect of this challenge, dating back to the early negotiation of the CWC in the 1970s, is how CWC Member States implement the Convention’s provisions relating to ‘Riot Control Agents’ and ‘Law Enforcement Purposes’. Concerns have been expressed about the lack of clarity in these provisions, which have been described by one highly regarded academic as ‘a fault line within the CW disarmament regime’ [4]. Related concerns are the advances in science and technology (S&T) relevant to production of novel chemical warfare agents, including chemicals that act on the central nervous system. Some of these chemicals, which were originally developed for medical purposes, have been subsequently developed as ‘incapacitants’ for chemical warfare purposes, and more recently have been considered by some CWC Member States for use as so-called ‘non-lethal weapons’ for ‘Law Enforcement Purposes’ [5]. The concerns about implementation of the CWC provisions on ‘Riot Control Agents’ and ‘Law Enforce- ment Purposes’ are exacerbated by the changing nature of armed conflict which is no longer framed in the context of opposing military alliances in a bipolar world of the Cold War era. Indeed, the borderlines between war, civil war, large-scale violations of human rights, revolutions and uprisings, insurgencies and terrorism as well as organized crime are becoming increasingly blurred. As a consequence, distinctions between law enforcement, counter-terrorism, counter-insurgency and low-intensity warfare may get blurred, and certain types of chemical weapons such as incapacitants may appear to offer tactical solutions to operational sce- narios where civilians and combatants cannot easily be separated or distinguished.6

Negotiation of the CWC: Provisions on Riot Control Agents and Law Enforcement

In the late 1960s, there were increasing concerns about chemical and biological weapons, at least in part because of the widespread use of CS tear gas (2-chlorobenzalmalonitrile) and herbicides in the Vietnam War, which many States had regarded as chemical warfare and in violation of the 1925 Geneva Protocol [6]. This led to the decision for the United Nations (UN) disarmament committee7 in Geneva to attempt to develop a treaty that would comprehensively prohibit both chemical and biological weapons, including their development, production and stockpiling.

5 OPCW. Note by the Technical Secretariat, ‘The OPCW in 2025: Ensuring a World Free of Chemical Weapons’ S/1252/2015 (6 March 2015). 6 OPCW. ‘Note by the Director-General, Report of the Advisory Panel on Future Priorities of the Organisation for the Prohibition of Chemical Weapons,’ S/951/2011, pp. 4–5, (25 July 2011). 7 In the late 1960s, this committee was referred to as the Eighteen Nation Disarmament Committee (ENDC). In 1969, with the ex- pansion of its membership to 26 members its name was changed to the Conference of the Committee on Disarmament (CCD). The ENDC and CCD were forerunners to the Conference on Disarmament (CD), which currently has 65 members. 1562 R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention

To this end, in 1968 the UN Secretary-General was requested to prepare a report, with the assistance of consultant experts, for consideration by the Geneva disarmament committee when dealing with chemical disarmament. To assist the UN experts in the preparation of their report, in January 1969 the UN Secretary- General requested the Director-General of the World Health Organization (WHO) to provide such information as the WHO thought useful for the UN report. The UN report became available on 1 July 19698 and received detailed consideration and endorsement by the disarmament committee in its 1969 summer session.9 The WHO, using its own group of consultants, provided the requested information in the first part of 1969, and the WHO subsequently published this information in a second report.10 While the WHO report was some- what more detailed than the UN report, the two reports arrived at essentially the same technical conclusions, including in the various issues associated with the definitions and understandings on the different types of chemical warfare agents (CWAs). The UN and WHO reports both noted that from a military point of view, CWAs have been developed with three quite different tactical functions in mind, quoting from the WHO report: 1. ‘Lethal agents’, used either to kill an enemy or to injure him so severely as to necessitate his evacuation and medical treatment; 2. ‘Incapacitating agents’, used to put an enemy completely out of action for several hours or days, but with a disablement from which recovery is possible without medical aid; and 3. ‘Harassing agents’ (also referred to as ‘Short-term incapacitants’), used to disable an enemy for as long as he remains exposed [7].

The WHO report made clear that the above classifications are not clear-cut toxicological categories, because the effects of a particular CWA will depend as much on the way it is used as on its toxicological properties, and the effects described above are those caused by typical battlefield concentrations of the CWA. In other words, if unprotected people are exposed to substantially higher than typical battlefield concentrations of a ‘Harassing agent’, then those people may be killed or suffer severe injury, and likewise, if unprotected people are exposed to substantially lower than typical battlefield concentrations of a ‘Lethal agent’, then those people may be limited to incapacitating or harassing effects. The WHO report also concluded that not all military harassing agents (sensory irritants) are suited to police use, referring to ‘police type irritant’ (or ‘riot control agent’), which are characterised by a combination of physical and toxicological properties that will ensure that lethal exposures will be extremely rare, and that the harassing effects will be relatively benign [8]. In the preliminary phase of the negotiation of the CWC in the early 1970s, there was agreement that the definition of ‘chemical weapon’ should be based on the concept of ‘general purpose criterion’, which would essentially mean that any toxic chemical is a chemical weapon if it is used for purposes prohibited by the CWC, a concept agreed as the means to define ‘biological weapons’ in the then recently concluded text of the Biological Weapons Convention [9]. The early CWC negotiators also attempted to define different toxicity categories (‘super-toxic lethal’, ‘other lethal’, and ‘other harmful’) with different classes of toxic chemicals to be listed under each category. It was clear from working papers submitted to the disarmament committee11 as well as from the bilateral discussions that took place between the USSR and United States in the late 1970s that both countries supported the proposed sub-division of toxic chemicals into these three categories, with ‘psychochemical incapacitants’ to be covered in the category of ‘other harmful’ chemicals’.12 In the latter

8 UN. Report of the Secretary-General, Chemical and Bacteriological (Biological) Weapons and the Effects of their Possible Use, Document A/7575/Rev.1 (New York, 1969). 9 Fourteen members of the ENDC specifically welcomed the UN Report in working papers that they presented at the 1969 Summer Session of the ENDC. 10 WHO. Health Aspects of Chemical and Biological Weapons, (Geneva, 1970). 11 See, for example: United States of America, ‘Working Paper concerning incapacitating chemical warfare agents’, CCD/531 (28 March 1977). In this working paper, the United States stated that it supported the inclusion in the future CW arms control agreement of incapacitants including psychochemicals, paralysants, and pain producers (including urushiol, the active principle of poison ivy). 12 Letter dated 7 July 1980 to the Chairman of the Committee on Disarmament from the Representatives of the USSR and the United States to the Committee on Disarmament, CD/112 (7 July 1980). R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention 1563 stages of the negotiations, these three categories were merged into a single definition of ‘toxic chemical’,13 based on the recognition that there are no firm borders between ‘lethal’ and ‘non-lethal’ CWAs, as it is the dose that determines the toxic effect caused by a particular CWA (as had already been highlighted some years earlier in the UN and WHO reports). In addition to the broad definition of chemical weapons, the CWC lists three Schedules of Chemicals deemed to pose a particular risk to the object and purpose of the Convention. These lists of chemicals form the basis of the mandatory declarations and routine inspections under the CWC.14 However, the regulation of Riot Control Agents (RCAs) (that is, the subset of short-term sensory irritant incapacitants deemed suitable for use by police forces as tear gas) was one of the most difficult issues faced by the negotiators of the CWC. Tear gases such as CS had been used extensively in the Vietnam War as a ‘method of warfare’ against enemy combatants, that is, as a method intended to cause casualties (‘hors de combat’) as well as use against non-combatants. Within the Conference on Disarmament, at one end of the spectrum were a number of States wanting all use of tear gases (RCAs) in military operations to be prohibited by the CWC; and at the other end of the spectrum a number of States wanting RCAs to be totally excluded from the provisions of the CWC, with the military use of tear gases such as CS to be covered by existing national regulations.15 A further complication, particularly during the latter stages of the negotiations, was whether chemicals other than RCAs should be permitted for various law enforcement purposes.16 Eventually, in the ‘end-game’ of the negotiation of the CWC in 1992, a definition of Riot Control Agent was agreed,17 and it was also agreed that toxic chemicals could be used for ‘law enforcement purposes including domestic riot control’.18 At the time of the conclusion of the CWC negotiations in Geneva, it was realised that a certain lack of clarity in these provisions was necessary to ensure that the CWC text would achieve agreement in Geneva and then subsequently receive endorsement by the UN General Assembly in New York. For example, there were different views as to whether the provisions outlined above would mean that other toxic chemicals (i.e. chemicals not meeting the CWC definition of RCA) would be permitted for various law enforcement purposes other than riot control. In addition, there were no definitions of ‘method of warfare’ and ‘law enforcement’ within the Convention text, which also allowed for various interpretations.19 At that stage, it was the intention of at least some of the Geneva negotiators that these provisions would be revisited during the Preparatory Commission to develop agreed understandings of these provisions. However, the latter stages of the Preparatory Commission became fraught with its own set of unresolved issues associated with several verification-related provisions [10], and it turned out that the incapacitant issues would not be considered by CWC Member States until 2002 in the lead-up to the First CWC Review Conference, as discussed below.

13 CWC Article II, Paragraph 1(a), and Article 2, Paragraph 2. This broad definition was necessary because there are many dual- use chemicals which can be used for legitimate peaceful purposes which can also be used in the development of chemical weapons (e.g. chlorine), and also because it was important to ensure that all new toxic chemicals discovered or developed in the future (e.g. CNS-acting chemicals and ‘mid-spectrum’ agents) would also be captured by the CWC prohibition of chemical weapons. 14 For example, Schedule 1 includes blister agents, nerve agents (and their binary precursors) and two toxins (ricin and saxi- toxin). Schedule 2 contains other toxic chemicals (including Amiton nerve agent and BZ psychochemical) and key precursors to a range of CW agents. Schedule 3 contains some of the other CWAs used in World War I (including phosgene and hydrogen cyanide) as well as other precursors (including earlier precursors for nerve agents). 15 Most notably, U.S. Executive Order 11850: Renunciation of Certain Uses in War of Chemical Herbicides and Riot Control Agents (U.S. President Gerald Ford, The White House, April 8, 1975) listed examples of the use of herbicides and riot control agents in ‘defensive modes to save lives’ which the United States argues are not prohibited by the 1925 Geneva Protocol. 16 It was noted at that time, that one scheduled chemical was being used in at least one country for implementing the death penalty. 17 CWC Article II, Paragraph 7: ‘Riot Control Agent’ means: Any chemical not listed in a Schedule, which can produce rapidly in humans sensory irritation or disabling physical effects which disappear within a short time following termination of exposure.’ 18 CWC, Article II, Paragraph 9(d): ‘Purposes Not Prohibited Under this Convention’ means … Law enforcement including domestic riot control purposes.’ 19 Interested readers are encouraged to read the very comprehensive discussion of these issues in: J. P. R. Robinson, ‘Non-Lethal Warfare and the Chemical Weapons Convention’, Further HSP Submission to the OPCW Open-ended Working Group on Preparations for the Second CWC Review Conference, (12 October 2007). 1564 R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention

a CN O O Cl CN OH N O O Cl N

CN CS CR BZ b Ph Ph Ph Ph Et N H Et N CH2OMe Et N CO2Me Et N CO2Me

O O O O N N S N N O

OMe Fentanyl Sufentanil Carfentanil Remifentanil

Fig. 1: Chemicals of interest. (a) The riot control agents CN, CS and CR, which act predominantly on the peripheral nervous system and have large safety margins, and the CNS-acting chemical BZ, weaponised in the past, which acts on the central nervous system to cause hallucinatory effects and has a narrow safety margin. (b) Structures of fentanyl and three anaesthetic/ analgesic analogues known as sufentanil, carfentanil and remifentanil.

Development of incapacitants

In the 1950s, a number of countries commenced research programs to develop new classes of CWAs that were specifically designed to be incapacitating in effect. Several classes of chemicals were investigated including indole derivatives, pyrrole derivatives, aminoalkanoic acids and esters, benzimidazoles, phthalimides, tremorine and analogs, cyanoalkylamines, sulpholanes, glycolates and various natural products. This led to the weaponization of two sensory irritants CS and CR (dibenz(b,f)-1,4-oxazepine) (Figure 1A) by a number of countries including the United Kingdom.20 Several countries also considered the development of other classes of chemicals including psychochemicals. For example, the US military requirements for a new psychochemical incapacitant included: onset of action in less than one hour; and no permanent effect (a desirable but not essential characteristic). The United States considered a range of anaesthetic gases, sedatives, opiates, and muscle paralysing agents. A glycolate anticholinergic, BZ (3-quinuclidinyl benzilate) (Fig. 1a), despite its shortcomings, which included up to eight hours for exposed personnel to receive the full effect and a ‘safety margin’ estimated to be approximately 40 [11], was selected as an interim capability in 1961 for production and weaponization. By 1964, the United States had produced and weaponised approximately 60 tonnes of BZ. However, the United States subsequently chose to unilaterally destroy its BZ stockpile in the late 1980s (i.e. well before it was under any international treaty obligation to do so), partly because of the lower than ideal safety margin of BZ, and the realisation, determined during military field trials, that depending on a number of factors, including the motivation of the fighting unit, the performance of the fighting unit might actually increase rather than diminish under the influence of certain concentrations of BZ [12]. Other countries are reported to have considered the development of incapacitants during the Cold War, including the Soviet Union, but it is not known whether other countries actually produced and weaponised psychochemical incapacitants. For example, it is known that Iraq obtained precursors for BZ in the mid-1980s [13] but apparently Iraq chose not to produce and weaponise BZ.21 However, because of the ongoing interest in BZ, the CWC negotiators decided to include BZ in Schedule 2 of the CWC, which means that chemical (pharmaceutical) industry facilities producing or using quantities of BZ above specified thresholds are subject to routine verification under the provisions of the CWC.

20 J. R. Walker. Britain and Disarmament: The UK and Nuclear, Biological and Chemical Weapons and Arms Control Programmes 1956–1975, pp. 17–30, Ashgate, UK (2012). 21 UN, ‘Report of the Secretary-General on the status of the implementation of the Special Commission’s plan for the ongoing monitoring and verification of Iraq’s compliance with relevant parts of section of Security Council resolution 687 (1991),’ Docu- ment S/1995/864 (11 October 1995). R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention 1565

From the early 1970s, there was increasing interest by the United States and other countries in developing incapacitants with very rapid onset incapacitating effects, at least in part as a response to a number of aircraft hijackings and other hostage-taking situations. This was in recognition that BZ and the other psychochemicals that had been evaluated up until that time would not provide a sufficiently rapid response [14]. So in addition to very low lethality and no long-term side effects to those exposed to a ‘field concentration’ of such a chemical, the incapacitant would need to have an almost instant ‘knock-out’ effect (instantaneous unconsciousness) so that the hostage-takers would be incapable of destroying the lives of the hostages before they had become totally incapacitated. For example, the United States conducted research and development activities on a range of ‘chemical systems for antipersonnel non-lethal weapons’ including ‘calmatives’ and ‘chemical immobilisers’ based on the fentanyl family of opioids [15]. Part of this development project was being conducted under the ‘Advanced Riot Control Agent Device’ (ARCAD) project, with the background information indicating that the US military had plans for ARCAD to be used with so-called ‘non-lethal chemicals’ such as fentanyls rather than the CS sensory irritant [16]. This caused concerns about the possibility of serious long-term casualties as people who had become immobilised would continue to receive an increasing dose until either the agent had dispersed, or the exposed person had stopped breathing, or the exposed person had received appropriate medical support.22 Apparently none of the fentanyl analogs were found to act rapidly enough to meet the requirements of a ‘rapid knock down agent’ necessary for hostage-type situations. Nor did the fentanyls have a sufficient safety margin, as one of the side-effects of fentanyls in humans is respiratory depression. This has resulted in assessments that some members of the fentanyl class (for example, sufentanil and carfentanil) (Fig. 1b) have a safety margin as low as from 10 to 20, and may result in these two fentanyl analogs being even more toxic than the nerve agent VX (O-ethyl-S-[2(diisopropylamino)ethyl] methylphosphonothioate). The United States attempted to overcome these drawbacks, including by mixing a fentanyl type agonist with an antagonist which blocks the respiratory depression, but apparently without success [17]. Very little information appears to be available in the public domain about the efforts by the former Soviet Union, and subsequently Russia, in their programs to develop incapacitants from opioids such as the fentanyl class. However, the use of a ‘disabling chemical’ (a mixture containing carfentanil and remifentanil) (Fig. 1b) by Russian special forces when storming the Dubrovka theatre as a means to end the Moscow Theatre siege in October 2002 would suggest that Russia has had an active program in this area, including the stockpiling of substantial quantities of such chemicals.23

Review of Scientific Advances relevant to the Convention

It was clear to the negotiators in the Conference on Disarmament in Geneva that a multilateral treaty as complex as the CWC, with significant impact on military activities as well as a substantial part of the global chemical industry, would require regular comprehensive review to ensure that it was operating effectively. Thus, the negotiators agreed that a Review Conference (RevCon) should be convened approximately every five years to ‘undertake reviews of the operation’ of the CWC and that the reviews would ‘take into account any relevant scientific and technological developments’.24 The negotiators also agreed on provisions to estab-

22 One key difference between psychochemicals (incapacitants) and sensory irritants (RCAs) that the US military personnel involved in the ARCAD project did not appear to take fully into account is that the effects caused by exposure to a sensory irritant encourage the exposed persons to evacuate the area, whereas psychochemical incapacitants such as fentanyl that immobilise the exposed persons will result in the dose of the toxic chemical increasing for as long as the immobilised person is in the aerosol cloud/contaminated area. Additional complications, in terms of the necessity for immediate medical treatment, include the likeli- hood that a significant number of exposed people will collapse in ways that block their airway, or will aspirate vomit and choke. 23 The Russian Health Ministry subsequently announced that 129 of the 763 hostages had died, of whom all but five had been killed by the toxic chemical. See: HSP CBW Bulletin News Chronology (26 October 2002). 24 CWC, Article VIII, Paragraph 22. 1566 R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention lish a Scientific Advisory Board (SAB) as a subsidiary body of the OPCW to assist the OPCW Director-General in providing specialised advice in S&T to CWC Member States.25 Every five years, the SAB prepares a comprehensive report covering the advances in S&T relevant to the Convention that have taken place in the previous five years for submission to the RevCon. Two of the issues of particular interest to the SAB have been the rapid advances in the life sciences, including the ‘convergence’ of biology and chemistry, and nanotechnology. These advances promise many benefits to humankind, including more efficient food production, improvements to medicines and to health care, the generation of renewable energy sources, and the enhancement of pollution management. There are also many potential benefits of the convergence of chemistry and biology (and related aspects of nanotechnology) for protection against chemical weapons, including development of enhanced equipment for the detection of CWAs, medical countermeasures, decontamination, and laboratory analysis and identification techniques, including bio-forensics [18]. Scientific advances of particular interest relate to the classes of chemicals which act on the central nervous, which are being driven by the medical research community, include chemicals causing analgesia, sedation, hypnosis and anaesthesia. Potential medical developments, based on the improved understanding of the mechanisms of action of these chemicals, include more effective delivery systems for existing CNS- acting chemicals (for example, using nanotechnology to enhance the transmission of existing CNS-acting chemicals across the blood-brain barrier) as well as the discovery of chemicals with new structures which may have enhanced desirable effects on the central nervous system without the side-effects of existing medications. The IUPAC has played a very important role in supporting the SAB and CWC Member States in their reviews of advances in S&T. For example, in the lead-up to the 1st RevCon in 2003, the IUPAC together with the OPCW organised a workshop in Bergen (Norway) to consider the impact of scientific developments on the Convention. The objective was to assist the OPCW and its Member States in preparing for the RevCon. These discussions, and the subsequent report of the meeting, greatly assisted the SAB in the preparation of its own report to the OPCW. This most valuable partnership between IUPAC and the OPCW has continued, with similar OPCW/IUPAC Conferences held in Zagreb (Croatia) in advance of the 2nd RevCon which was convened in 2008, and in Spiez (Switzerland) in advance of the 3rd RevCon which was convened in 2013. Simi- larly, IUPAC has been providing support in the lead up to the 4th RevCon which will be convened from 21 to 30 November 2018 [19].

Consideration of Incapacitants by the OPCW and CWC Member States

First Review Conference (28 April – 9 May 2003)

The IUPAC and SAB reports prepared for the 1st RevCon, highlighted developments in organic synthesis, the evolution in chemical plant design, and developments in analytical chemistry, and of particular relevance to potential novel CWAs (including incapacitants). The IUPAC report noted that new methods for rapid synthesis and screening of new chemicals, especially as the molecular basis of biology becomes better understood, will provide much potential for production of new toxic chemicals that could be mis-used as chemical weapons [20]. The reports also noted that the science related to the development of new RCAs, and other so-

25 The OPCW’s SAB was established by the Director-General in accordance with CWC Article VIII, subparagraph 21(h), and paragraph 45, so that the Director-General could offer to the Conference of the States Parties, the Executive Council, and CWC Mem- ber States specialised advice in those areas of science and technology that are relevant to the Convention. The SAB, which is composed of 25 independent experts selected from OPCW Member States, meets once or twice each year. The SAB reports to the Director-General of the OPCW, who then submits the SAB report, alongside his own response, to the OPCW. R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention 1567 called ‘non-lethal weapons’ utilising certain toxic chemicals (including incapacitants, calmatives and vomit- ing agents) is rapidly evolving, and that results of current programmes to develop such so-called ‘non-lethal agents’ should be monitored and assessed in terms of their relevance to the Convention. However, the SAB noted that, based on past experience and the fact that many of these chemicals act on the central nervous system, it appeared unlikely from a scientific point of view that chemicals with a sufficient safety ratio would be found.26 During the 1st RevCon, issues associated with incapacitants including RCAs were considered, as well as the use of toxic chemicals for law enforcement purposes [21]. Despite the availability of the IUPAC and SAB reports to CWC Member States well in advance of the RevCon, with few exceptions, there appeared little interest by most delegations in addressing these issues. The Swiss delegation emphasised that the CWC prohibits all chemical weapons, including so-called ‘non-lethal’ chemical agents, and suggested that the RevCon Final Document could ask Member States to declare all toxic chemicals that they hold for law enforcement purposes.27 However, there was no agreement to include specific mention of these issues in the RevCon Final Document.

Second Review Conference (7–18 April 2008)

With respect to incapacitants, the IUPAC report noted that many of the chemicals that are being synthesized and screened as part of current drug discovery efforts interact with the central nervous system and will have incapacitating properties that could make them suitable as so-called ‘non-lethal’ agents. The report noted that some CWC Member States have argued that such chemicals may have utility for use in law enforcement, and that efforts are reportedly underway in some Member States to develop chemicals with ‘non-lethal’ properties for use in law enforcement situations. But such chemicals may also be thought to have utility in counter-terrorism or urban warfare situations. The report further noted that if these developments were to continue unchecked (with regard to the possible use of toxic chemicals for these purposes), there is a serious danger that the prohibitions of the CWC would be undermined, as activities to develop ‘non-lethal’ weapons based on incapacitating agents would not easily be distinguishable from aspects of an offensive chemical weapons program. The report concluded that a clear need exists for CWC Member States to address these risks to the object and purpose of the CWC and to agree on the CWC compatibility (or incompatibility) of endeavours to develop and field ‘non-lethal’ weapons that utilize toxic (e.g. incapacitating) chemicals for law enforcement purposes; and that should the development and acquisition of such weapons be accepted, clearly there would be a need for an agreement on declaration provisions for such weapons (types, quantities, and delivery systems) [22]. The SAB Report echoed the concerns raised in the IUPAC report, noting that although many extremely potent compounds that act on the central nervous system had been discovered in the period from the 1950s to the 1970s, only two types, anticholinergics and opioids, appear to have been developed into CWAs or so-called ‘non-lethal’ agents for use in law-enforcement. The SAB further noted that the potential risks to the Convention associated with advances in S&T would increase significantly, should dedicated chemical weapons programs exist and should they take advantage of new toxic chemicals. There is therefore good reason to call for transparency in chemical-defence programs, and to assess carefully the compatibility with the Convention of the development of weapons that employ toxic chemicals for law-enforcement purposes (including so-called ‘non-lethal weapons’). The SAB concluded that such so-called ‘non-lethal

26 OPCW, Note by the Director-General, ‘Report of the Scientific Advisory Board on Developments in Science and Technology,’ RC-1/DG.2, p. 15 (23 April 2003). 27 Switzerland was apparently encouraged by a number of Member States not to proceed with this proposal during the First Rev- Con, on the basis that it was considered ‘contentious’ by some Member States who expressed the view that a detailed debate on this issue may have jeopardised the successful conclusion of the RevCon. See: HSP CBW Conventions Bulletin, News Chronology, 28 April 2003. 1568 R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention weapons’ required thorough study, and that the terminology surrounding so-called ‘non-lethal incapacitants’ also needed further elaboration.28 During the 2nd RevCon, there appeared little interest by many delegations in these issues, despite the serious concerns raised in both the IUPAC and SAB reports, both of which were available to CWC Member States well in advance of the RevCon. The most obvious exception was Switzerland which was the only Member State to provide a national working paper on this issue.29 But as was the case during the 1st RevCon, most Member States appeared reluctant to discuss these issues in a substantial way. Draft language was proposed which would have included formal consideration of these issues within the Executive Council, but once again, at the end of the day there was no agreement to include specific mention of these issues in the RevCon Final Document [23].

Third Review Conference (8–19 April 2013)

Following the lack of success in dealing with the incapacitants issue at the 2nd RevCon, in 2009 the OPCW Director-General expressed his concern about developments related to matters where the Convention might be – perhaps purposely – ambiguous or have lacunae, and which might impact on the ultimate effectiveness of the ban on chemical weapons, including the area of incapacitants. The Director-General expressed the hope that the SAB could help shed some light on this matter and that the 3rd RevCon might offer the appropriate context for an initial formal look into these issues.30 Thus, incapacitants continued to be one of the main issues discussed by the SAB at its meetings between the 2nd and 3rd RevCons. In addition, several international meetings on incapacitants were convened between the 2nd and 3rd RevCons, including one meeting organised jointly by the Spiez Laboratory in Switzerland and the Finnish Institute for the Verification of the Chemical Weapons Convention (VERIFIN) in 2011,31 and two meetings organised by the International Committee of the Red Cross (ICRC) in 201032 and 2012.33 The scientific aspects of incapacitants discussed by experts at these various meetings fed into the IUPAC workshop held in Spiez in February 2012 in advance of the 3rd RevCon held in 2013. The conclusions drawn from previous SAB, IUPAC, ICRC and other meetings, together with the discussions at the Spiez workshop, resulted in a comprehensive summary of the current status of incapacitants in the report of the Spiez workshop (paragraph 2.2.4, which is reproduced in its entirety below) [24]. This comprehensive summary is significant as it subsequently became the basis of recommendations of the SAB to the 3rd RevCon, as well as the ‘Joint Initiative’ (discussed in Section 7.1) and the SAB report to the 4th RevCon.

‘Certain classes of chemicals effect biological organisms through action on the central nervous system (CNS) in a manner commonly referred to as incapacitating (e.g. fentanyl derivatives and other opioids). These chemicals are highly toxic (some with LD50 values comparable to VX). Many biological factors, including age, gender, and pre-existing health conditions, influence the individual effects of exposure to these chemicals at carefully managed therapeutic levels. The development

28 OPCW. Note by the Director-General, ‘Report of the Scientific Advisory Board on Developments in Science and Technology,’ RC-2/DG.1, 15 (28 February 2008). 29 OPCW. Switzerland, ‘Riot Control and Incapacitating Agents under the Chemical Weapons Convention,’ RC-2/NAT.12 (9 April 2008). 30 OPCW. ‘Opening Statement by the Director-General to the Conference of States Parties at its Fourteenth Session,’ C-14/DG.13, 27–28 (30 November 2009). 31 Switzerland Federal Office for Civil Protection. ‘Technical Workshop on Incapacitating Agents,’ Report of Meeting held in Spiez, Switzerland, 8–9 September 2011. 32 ICRC. ‘Incapacitating Chemical Agents: Implications for International Law’, Report from Meeting held in Montreux, Switzer- land, 24–26 March 2010. 33 ICRC. ‘Incapacitating Chemical Agents: Law Enforcement, Human Rights Law and Policy Perspectives’, Report from Meeting held in Montreux, Switzerland, 24–26 April 2012. The ICRC subsequently announced its position, on 6 February 2013, that based on many years of analysis, that ‘the use of toxic chemicals as weapons for law enforcement purposes should be limited exclusively to riot control agents’ highlighting the ‘serious risks to life and health, risks undermining international law prohibiting chemical weapons, and risks creating a ‘slippery slope’ towards the reintroduction of chemical weapons into armed conflict.’ R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention 1569

of these chemicals and improved understanding of their mechanisms of action are being driven by medical research, such as the development of new anaesthetics. Medical research is also driving significant interest in the continued development of effective methods for delivering chemicals into the central nervous system, particularly across the blood-brain barrier. Several medical applications for the delivery of therapeutics such as anti-cancer agents were discussed at the Spiez workshop. As these scientific developments related to CNS-modulating chemicals and the deliveries of such chemicals to targeted biological tissues intersect, they have implications for their potential use in law enforcement as so-called ‘incapacitating chemical agents’ (ICAs). Unlike use of chemical agents in traditional CW contexts, which are used in excess amounts to saturate an area so as to ensure their intended effect, the employment of ICAs for law enforcement would require delivery techniques that ‘titrate’ a target group (control the exposure) so that the desired incapacitating effect is achieved without an unacceptable level of lethality. This in itself would be a challenge but in addition, law enforcement uses would also have to ensure effect and selectivity across individual variations in characteristics such as age, health, or sensitivities to particular agents. The decision on the appropriateness of the development and use of ICAs for law enforcement purposes, including whether such use would be permitted under the provisions of the CWC, is an issue which requires political, legal, and other inputs. S&T on classes of chemicals which could possibly be employed as ICAs is continuing to advance; however, the discussions at the Spiez workshop indicated that the currently available S&T does not have the capabilities required to enable the delivery of such ‘incapacitating chemical agents’ for law enforcement purposes in a ‘safe’ manner [25].’

With respect to issues associated with incapacitants, the SAB Report for the 3rd RevCon closely echoed the conclusions from the IUPAC/OPCW meeting at Spiez. In particular, the SAB re-affirmed that the term ‘non- lethal’ is inappropriate when referring to chemicals intended for use as incapacitants, because for all chemicals toxicity is a matter of dosage. It was further noted that chemicals considered to have high safety margins (on the basis of therapeutic ratios (LD50/ED50) (Fig. 2) in the context of controlled pharmaceutical use) can have very low safety margins when factors such as uneven dissemination, variability in human response, and the possible need for a rapid onset are required. The SAB report also noted that there are large species differences in the reaction to morphine-like drugs which act on the central nervous system, such as the fentanyls, which appear to have attracted the greatest attention as potential incapacitants. In the view of the SAB, the technical discussion on the potential use of toxic chemicals for law-enforcement purposes has been exhaustive, but the SAB would be prepared to continue its discussions on incapacitants once technical information about specific candidate chemicals and/or dissemination systems was made available to the Board. Finally, the SAB recommended to the Secretariat that it start preparations for verification activities that could

100 Therapeutic Toxic effect effect ected

Therapeutic index 50

Normal Incapacity Death ercentage of people aff P

0 ED50 TD50

Concentration of drug increases

Fig. 2: The potency of a drug is the dose required to produce a given effect, usually measured as a 50 % maximal effect. The

ED50 (effective dose 50) is the drug concentration where half the people exposed experience a therapeutic effect. The TD50 (toxic dose 50) is the drug concentration where half the people experience a toxic effect. As the dose of drug increases, a lethal dose can be reached, and that point is often quoted as the LD50 (the drug concentration at which half those exposed die). As the concentration increases, the physiological effect transitions from beneficial to incapacitating to lethal. The therapeutic index is the TD50/ED50 and the larger this ratio, the greater the safety margin of the drug. Fentanyls have low safety margins in humans. If misused, and delivered for military purposes as respirable aerosols, the dose would be uncontrolled, and because of the low safety margin, result inevitably in deaths through respiratory depression. 1570 R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention be required in an Investigation of Alleged Use (IAU) of chemical weapons, including developing analytical methods and procedures, as well as collecting analytical reference data for the analysis of such chemicals, and that the Secretariat should invite laboratories in Member States to contribute to this effort.34 Unlike the reluctance displayed by diplomats at the 1st and 2nd RevCons to discuss incapacitant-related issues, the 3rd RevCon spent a substantial amount of time considering the language which had been developed on ‘incapacitating chemical agents’ by the Working Group for the Preparation of the Third Review Conference.35 However, after much discussion, including particular delegations apparently referring back to Capitals for additional guidance on at least one occasion, the RevCon failed to reach agreement on what many Member States regarded as a very modest proposal. The draft report language, following further redrafting during the RevCon negotiations, proved to be controversial because it would have resulted in the further consultations on this issue within Executive Council to have included issues associated with riot control agents as well as more toxic incapacitants. This lack of agreement occurred despite the concerns expressed by Swit- zerland and echoed by several other delegations that ‘the risks of inaction are far greater than the benefits of keeping the current uncertainty’ [26].

Activities within the OPCW since the 3rd RevCon

At the end of the 3rd RevCon, there was an even greater sense of disappointment, frustration and concern among those Member States wishing to see progress on the issues associated with the potential use of so- called incapacitants for law enforcement purposes, than there had been at the end of the 2nd RevCon. A considerable amount of information on the various aspects of ‘incapacitants’, including scientific, policy, legal and military, had been assembled, and made available to CWC Member States (including the meetings already referred to which had been convened by the ICRC, the Swiss Government and VERIFIN). But despite the high level of activity from outside the OPCW formal meeting processes, and wealth of valuable information com- piled from the various meetings, there were still no formal meetings on this topic among CWC Member States at the OPCW. As explained below, informal discussions continued.

Reconsideration of Terminology/Joint Initiative on CNS-acting chemicals

There was a sense during the negotiations in the 3rd RevCon that some of the terminology may have been causing confusion, even among users of the English language. For example, at least until recently, the UK law enforcement manuals have continued using the term ‘Incapacitants’ when referring to sensory irritants including CS,36 whereas the United States has continued to use the term ‘Riot Control Agents’ for sensory irritants including CS, even in its Military Manual, and has listed fentanyl and similar toxic chemicals under the term ‘Incapacitants’.37 Furthermore, an increasing number of CWC Member States and others interested in this issue were now using the terms Incapacitant (or Incapacitating Chemical Agent) within quotation marks, thus ‘incapacitant’

34 OPCW. ‘Report of the Scientific Advisory Board on Developments in Science and Technology for the Third Special Session of the Conference of the States Parties to Review the Operation of the Chemical Weapons Convention,’ RC-3/DG.1, 20–21 (29 October 2012). 35 OPCW. Working Group for the Preparation of the Third Review Conference, ‘Draft Provisional Text (dated 21 March 2013)’. Paragraph 21 of the draft text read: ‘The Third Review Conference noted that consultations by the policy-making organs could be convened on any developments or issues that States Parties consider relevant to the object and purpose of the Convention, including on (incapacitating chemical agents).’ 36 Association of Chief Police Officers of England, Wales and Northern Ireland, Guidance on the Use of Incapacitant Spray, London (May 2009). 37 US Department of the Army, Multi-Service Doctrine for Chemical, Biological, Radiological, and Nuclear Operations, Annex 4, US Army Headquarters (July 2011). R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention 1571

(or ‘ICA’) to indicate that they did not regard the term incapacitant as accurate terms for chemicals as toxic as fentanyl and its analogs. However, the use of the term incapacitant within quotation marks was not considered satisfactory, and another term was sought. One suggestion in 2010, in response to the early findings and conclusions of the SAB, was that chemicals such as fentanyl and its analogs be referred to as ‘Central Nervous System Incapacitants’, which did not immediately find favour.38 At about the same time, there was a suggestion that the term ‘Pharmaceutical-Based Incapacitants’ or ‘Pharmaceutical-Based Agents’ (PBAs) be used rather than ‘incapacitants’.39 However, these terms were not generally accepted because they were considered to be too broad (i.e. only a small subset of pharmaceuticals was being considered for application as so-called ‘incapacitants’), and it was also felt that the pharmaceutical industry would not appreciate being associated with potential new classes of chemical warfare agents. By 2014, during the preparation of an Australian National Paper on this issue, it had become clear that many Member States recognised the value in using the term CNS-acting chemicals, rather than ‘incapacitants’ or ‘PBAs’.40 In its National Paper, presented at the 19th Conference of the States Parties (CSP-19) in November 2014, Australia confirmed that it is not developing, producing, stockpiling or intending to weaponise or use any CNS-acting chemicals such as anaesthetics, sedatives or analgesics for law enforcement purposes. The Paper called on other CWC Member States to make their positions known on this matter, and called for consultations, in particular among members of the Executive Council, with a view to commencing discussions on this issue within the policy-making organs of the OPCW.41 A joint paper on this subject initiated by Australia and Switzerland was published at the 20th Conference of the States Parties (CSP-20) in 2015 with 20 co-sponsors.42 By the end of 2017, the number of co-sponsors had nearly doubled to 39 including Member States from all regional groups.43 Australia and Switzerland have co-hosted a side-event in the margins of each CSP since 2015, to raise awareness of this issue. Through this informal process, a number of CWC Member States have announced that they have not (and are not) producing such chemicals for law enforcement purposes, and have sought similar assurances from other Member States. It is hoped that this Joint Initiative will assist in achieving a decision at the 4th RevCon to commence formal consultations on this issue by the Executive Council.

Chemical Sampling and Analysis for Verification of Fentanyls

As discussed above, one of the recommendations of the SAB in its report for the 3rd RevCon was that the Tech- nical Secretariat should start preparations for verification activities that could be required in an IAU involving fentanyl or its analogs, including developing analytical methods and procedures, as well as collecting analytical reference data for the analysis of such chemicals.44 The Director-General responded in the affirmative,

38 R. J. Mathews. ‘Riot Control Agents and Incapacitating Chemical Agents under the Chemical Weapons Convention: Reflections and personal perspectives,’ Discussion paper prepared for the ICRC Workshop: ‘Incapacitating Chemical Agents: Implications for International Law’, held in Montreux, Switzerland, 24–26 March 2010. 39 ICRC. ‘Incapacitating Chemical Agents: Law Enforcement, Human Rights Law and Policy Perspectives’, Report from Meeting in Montreux, Switzerland, 24–26 April 2012, p. 22. 40 This is still not an ideal term because other classes of CWAs can also affect the central nervous system. For example, traditional G and V nerve agents whose primary effect is inactivation of acetylcholinesterase also effect the central nervous system. But at least the ‘CNS-acting chemicals’ terminology leaves no doubt that the class of chemicals being discussed contain highly toxic chemicals. 41 OPCW. Australia, ‘Weaponisation of Central Nervous System-Acting Chemicals for Law Enforcement Purposes,’ C-19/NAT.1 (14 November 2014). 42 OPCW. Joint Paper, ‘Aerosolisation of Central Nervous System-Acting Chemicals for Law Enforcement Purposes’, C-20/NAT.2/ Rev.2 (3 December 2015). 43 OPCW. Joint Paper, ‘Aerosolisation of Central Nervous System-Acting Chemicals for Law Enforcement Purposes’, C-22/NAT.5 (28 November 2017). 44 OPCW. ‘Report of the Scientific Advisory Board on Developments in Science and Technology for the Third Special Session of the Conference of the States Parties to Review the Operation of the Chemical Weapons Convention,’ RC-3/DG.1, 20–21 (29 October 2012). 1572 R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention and staff-members in the OPCW Laboratory are now working with laboratories in Member States to develop appropriate sampling and analysis methods. Early consideration of the sampling and analysis requirements of the OPCW for CNS-acting chemicals indicated that the current methodology for the analysis of traditional CWAs could be a suitable starting point for the development of wide-scope analysis methods [27]. This was not surprising as the sampling and analysis methods which have been developed for investigations of illicit drug situations involving fentanyl and its analogs involve environment and biomedical sampling (including in some cases, post-mortem), appropriate handling of samples including chain of custody, and analysis methods typically include gas-chromatography/mass spectrometry and/or liquid chromatography/mass spectrometry [28]. The methods of sampling and analysis developed by the UN Office on Drugs and Crime (UNODC)45 will also be relevant as the OPCW develops Recommended Operating Procedures (ROPs). The recently revised ROPs for Analysis in the Verification of Chemical Disarmament (the ‘Finnish Blue Book’) contains a chapter which describes the testing and evaluation of current ROPs for sample preparation, analysis, screening and identification of selected CNS-acting chemicals (fentanyl and amphetamine) from environmental samples. The authors of that chapter have recommended that the analytical methods being developed for CNS-acting chemicals might be tested in Confidence Building Exercises among interested laboratories [29].

Consideration of synergies and potential overlaps between relevant CWC provisions and other regulatory frameworks

There are already a number of international agreements and other regulatory frameworks which have responsibilities relating to CNS-acting chemicals, including the UN Single Convention on Narcotic Drugs, the UN Convention on Psychotropic Substances, International Humanitarian Law (Law of Armed Conflict), and Human Rights Law [30]. There have been informal discussions between some members of the CWC community and personnel involved with these other international agreements, including at the workshop hosted by the ICRC in 2010.46 It has become clear that there will be considerable benefits if the OPCW is able to work in a collaborative and cooperative manner with other international agencies, for example, the UNODC which already have responsibilities related to opiates such as fentanyl and its analogs. However, the discussions that have taken place so far have been hampered because of the lack of decision by the CWC Member States to discuss these issues within the OPCW policy-making organs. This is most unfortunate as the OPCW has several issues in common with other international agencies, including at least partial overlap in the scope of the various prohibitions and regulatory frameworks, and similar requirements related to safety issues, the detection of relevant materials in operational environments, laboratory analysis of relevant substances, medical treatment and decontamination.

Preparations of the SAB Report for the Fourth Review Conference

In relation to the various scientific issues associated with CNS-acting chemicals, the recently released report of the SAB for the 4th RevCon47 essentially reinforces the advice and recommendations that the SAB provided in their report for the 3rd RevCon.

45 UNODC. ‘Recommended Methods for the Identification and Analysis of Fentanyl and its Analogues in Biological Specimens, Manual for Use by National Drug Analysis Laboratories,’ UN Vienna (2017). 46 ICRC. ‘Incapacitating Chemical Agents: Implications for International Law’, Report of Meeting held in Montreux, Switzerland, 24–26 March 2010. 47 OPCW. ‘Report of the Scientific Advisory Board on Developments in Science and Technology for the Fourth Special Session of the Conference of the States Parties to Review the Operation of the Chemical Weapons Convention,’ RC-4/DG.1, 20–21 (30 April 2018). R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention 1573

In particular, the SAB report states that the technical discussions of CNS-acting chemicals remain exhausted, and that the SAB sees no value in revisiting this topic as scientific facts have remained unchanged since the SAB first considered the issue (more than 15 years ago). A brief summary of the relevant part of the SAB report is provided in Section 8 of this article. In view of the increasing availability of such chemicals, the SAB again recommended that the OPCW should be prepared to develop capabilities that could be required to conduct missions involving an IAU of CNS-acting chemicals for hostile purposes, including sample collection and the addition of analytical data to the OPCW Central Analytical Database. With respect to assistance to victims of use of chemical weapons, the SAB noted that because of the dramatic increase in opioid abuse as a public health problem, research is underway to develop vaccines against synthetic opioids such as fentanyls, but that an effective vaccine may be years away. The SAB report also recognised the value of drawing on the experience of other international organisations in obtaining and making use of advice on scientific and technological developments relevant to its own work. The SAB has established informal links with other science advisory mechanisms and scientific societies with policy and science advice interests to share best practices and provide valuable insights; such links should be expanded and the SAB recommends seeking further opportunities to engage with scientific advisory boards of other relevant international organisations. The SAB has placed great importance on its practice of holding workshops and producing reports in support of the scientific review to the 4th RevCon in cooperation with partners such as the IUPAC.

Concluding comments

The issues associated with the classification of CWAs have a long history, with more than a little confusion, especially with the terms ‘incapacitant’ and ‘non-lethal weapon’. Indeed, there is a sense that the failure to reach agreement at the 3rd RevCon for the ‘incapacitant issues’ to be discussed by the OPCW policy-making organs may have been at least partly a result of confusion about the properties of the chemicals under consideration and the terminology. Thus, it is important that diplomats, lawyers and military experts understand the science (‘get the science right’) as a first step in their efforts to prevent the re-emergence of chemical weapons, based on the relevant properties of the various types of chemicals under consideration. Based on the consideration of the SAB and scientific advisers from Member States over many years, with valuable input from IUPAC and other experts, the following conclusions have been reached, which are reflected in the Report of the SAB to the 4th RevCon.

Riot Control Agents

–– RCAs act primarily on the sensory nerves of the peripheral nervous system of the eyes, nose, respiratory tract and skin to produce an immediate disabling effect on personnel. RCAs have limited or no effect on the central nervous system. Many military harassing agents (sensory irritants) do not fulfil the criteria for RCAs as defined in the CWC.48

48 For example, at its 3rd Session in 2000, the OPCW SAB recommended that Adamsite should no longer be used as an RCA as it fails to meet contemporary concerns for safety and environmental protection. More recently, the SAB has determined that only 17 of a list of 59 chemicals that had either been developed, used or considered for use as military harassing agents (sensory irritants) fulfil the criteria for RCAs as defined in CWC Article II, Paragraph 7. See: OPCW, ‘Response to the Director-General’s Request to the Scientific Advisory Board to provide consideration on which Riot Control Agents are subject to Declaration under the Chemi- cal Weapons Convention’, SAB-25/WP.1 (27 March 2017). This advice from the SAB fully accords with the conclusion from the UN and WHO Reports, discussed in Section 3 of this article, that only a small subset of the chemicals that have been used as military harassing agents have the necessary combination of physical and toxicological properties that make them suitable for to ‘police type’ riot control purposes, in particular to ensure that the harassing effects will be relatively benign and that lethal exposures will be extremely rare. 1574 R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention

Central Nervous System-acting chemicals

–– CNS-acting chemicals, such as fentanyl and its analogs, are chemicals that selectively modify central nervous system functions, which are considered safe when used under controlled medical conditions, but which have a very low safety margin when delivered as an aerosol, based on factors including uneven dissemination, variability in human response, and a need for rapid onset of action. –– CNS-acting chemicals are not RCAs as they do not meet the criteria specified in Article II Paragraph 7. Indeed, some CNS-acting chemicals among the fentanyl analogs are as lethal as nerve agents, e.g. sarin.49 –– None of the fentanyl class opioids have a sufficient safety margin for so-called ‘non-lethal operations’. The term ‘non-lethal’ is inappropriate when referring to CNS-acting chemicals which are intended for use as ‘incapacitants’, because for all chemicals toxicity is a matter of the dosage.

In view of the above factors, 39 Member States involved in a ‘Joint Initiative’50 and the SAB have recently commenced referring to chemicals which act on the central nervous system, including fentanyl and its analogs, as CNS-acting chemicals rather than ‘incapacitants’ or ‘non-lethal’ chemicals. It is hoped that the use of the more accurate and appropriate term CNS-acting chemicals for toxic chemicals such as fentanyl and its analogs will facilitate the achievement of useful outcomes from the 4th RevCon. The ‘Joint Initiative’ involving 39 Member States is also adding its collective voice calling for agreement by all Member States to consider the challenges facing the CWC through CNS-acting chemicals. It is thus hoped that the delegations at the 4th RevCon to be convened this November will appreciate the importance of the initiation of formal discussions of these issues within the OPCW policy-making organs. A decision by the 4th RevCon to initiate formal discussions of these issues within the OPCW would also facilitate more effective cooperation between the OPCW and other international agencies (e.g. UNODC) which already have responsibilities related to opiates such as fentanyl and its analogs, which will be of considerable benefit to the OPCW and the other international agencies. And as a final reflection, the importance of ‘tending’ (that is, taking good care) of the treaty during the deliberations on these complex issues cannot be overemphasised. It is useful to recall the very salient words of Charles Flowerree, the US Ambassador for Disarmament in 1980–1981, who has written:

‘The means by which these agreements survive and adapt to changing conditions after they enter into force deserve as much attention as the negotiations that produced them in the first place. They cannot simply be left to fend for themselves’ [31].

Acknowledgments: The author is very grateful to Dr Christopher Timperley, Defence Science and Technology Laboratory (Dstl), Porton Down, Salisbury, Wiltshire, SP4 0JQ, United Kingdom for providing Figs. 1 and 2.

References

[1] P. A. J. Janssen and J. F. Gardocki. Method for Producing Analgesia, US Patent Office 3,141,823, Filed 4 September 1962, Patented 21 July 1964. [2] US National Academy of Science, Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Opioid Use, National Academy Press, USA (2017). [3] M. Letts, R. J. Mathews, T. L. McCormack, C. Moraitis. Arms Control 14, 311 (1993).

49 And as discussed in Section 2 of this article, it is clear that all CNS-acting chemicals are captured by the CWC prohibition of chemical warfare, based on the definitions of ‘Chemical Weapons’ and ‘Toxic Chemical’, contained in CWC Article II, Paragraph 1(a) and Paragraph 2, respectively, as they form a category of dual-use chemicals which are used for legitimate peaceful purposes, but which could also be used in the development of chemical weapons. 50 OPCW. Joint Paper, ‘Aerosolisation of Central Nervous System-Acting Chemicals for Law Enforcement Purposes’, C-22/NAT.5 (28 November 2017). R. J. Mathews: Central Nervous System-acting chemicals and the Chemical Weapons Convention 1575

[4] J. P. R. Robinson. ‘Non-Lethal Warfare and the Chemical Weapons Convention’, Further Harvard Sussex Program (HSP) Sub- mission to the OPCW Open-ended Working Group on Preparations for the Second CWC Review Conference, p. 4, (12 October 2007). [5] A. M. Pearson. in Promise or Peril? Incapacitating Biochemical Weapons, A. M. Pearson, M. Chevrier and M. Wheelis, (eds.), pp. 67–80, Lexington Books, Maryland, USA (2007). [6] The 1925 Geneva Protocol, negotiated within the League of Nations, prohibits the ‘first use’ of chemical or biological weapons in armed conflict. See: R. J. Mathews. in Routledge Handbook on the Law of Armed Conflict, R. Liivoja and T. McCormack (eds.), pp. 212–232, Routledge, London, (2016). [7] WHO. Health Aspects of Chemical and Biological Weapons, (Geneva, 1970), p. 23. [8] WHO. Health Aspects of Chemical and Biological Weapons, (Geneva, 1970), pp. 23–53. [9] Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction, (BWC), opened for signature 10 April 1972; entered into force 26 March 1975. [10] R. J. Mathews. ‘Preparation for Implementation of the CWC: Progress in 1996’, Verification 1997: The VERTIC Yearbook, pp. 93–100, Westview Press, UK (1997). [11] The ‘safety margin’ or therapeutic index of a drug is the ratio of the drug dose that causes a severe effect or lethality in 50 % of the target population (LD50) to the drug dose that causes the desired effect in 50 % of that population (ED50). The estimated safety margin of 40 for BZ was generally considered inadequate. See: A. Pearson. in Promise or Peril? Incapaci- tating Biochemical Weapons, A. M. Pearson, M. Chevrier and M. Wheelis (eds.), pp. 68–69, Lexington Books, Maryland, USA (2007). [12] M. Furmanski. in Promise or Peril? Incapacitating Biochemical Weapons, A. M. Pearson, M. Chevrier and M. Wheelis (eds.), p. 57, Lexington Books, Maryland, USA (2007). [13] R. J. Mathews. HSP CBW Conventions Bulletin 21, 1, (1993). [14] For example, following an airplane/hostage situation in 1970, the US military specialists in chemical incapacitants informed the specialist agencies dealing with a particular aircraft hijacking that none of the chemical incapacitants developed thus far by the US military would have been able to be pumped into the airliner without the hijackers possibly react- ing violently and killing passengers prior to the hijackers becoming incapacitated. See: J. S. Ketchum. Chemical Warfare: Secrets Almost Forgotten, p. 226, Chembooks, USA (2006). [15] J. M. Lakoski, W. B. Murray, J. M. Kerry. The Advantages and Limitations of Calmatives for Use as a Non-Lethal Weapon, Pennsylvania State University Press, Pennsylvania, USA (2000). [16] A. M. Pearson. in Promise or Peril? Incapacitating Biochemical Weapons, A. M. Pearson, M. Chevrier and M. Wheelis, (eds.), pp. 67–80, Lexington Books, Maryland, USA (2007). [17] J. S. Ketchum and F. R. Sidell. in Medical Aspects of Chemical and Biological Warfare, (F. R. Sidell, E. T. Takafuji, D. R. Franz, eds.), p. 293, Borden Institute, Washington, DC (1997). [18] R. J. Mathews. ‘The Convergence of Chemistry and Biology: Implications for the CWC’, OPCW Today, pp. 20–21, (August 2012). [19] It should be noted that the IUPAC’s contribution has gone well beyond its support to the review of advances in science, including studies of CW destruction technologies and the development and promotion of issues of ethics and codes of conduct for scientists. See: L. K. Sydnes. ‘IUPAC, OPCW, and the Chemical Weapons Convention,’ Chemistry International, pp. 6–8, (July–August 2013). [20] G. W. Parshall, G. S. Pearson, T. D. Inch, E. D. Becker. Pure Appl. Chem. 74, 2327 (2002). [21] R. J. Mathews. in The Chemical Weapons Convention: Implementation, Challenges and Opportunities, R. Thakur and E. Haru (eds.), pp. 44–74, UN University Press, Tokyo (2006). [22] M. Balali-Mood, P. S. Steyn, L. K. Sydnes and R. Trapp. Pure Appl. Chem. 80, 185 (2008). [23] R. Guthrie. The HSP CBW Conventions Bulletin 79, 1 (2008). [24] K. Smallwood, R. Trapp, R. Mathews, B. Schmidt, L. Sydnes. Pure Appl. Chem. 85, 851 (2013). [25] K. Smallwood, R. Trapp, R. Mathews, B. Schmidt, L. Sydnes. Pure Appl. Chem. 85, 854 (2013). [26] Despite the lack of agreement on the way ahead, the discussions were considered very informative for those delegates (in particular, Capital-based officials) who had previously not been able to follow this issue closely. In addition, two Member States, Germany and the United Kingdom both indicated they would not use incapacitants more toxic than would fit the definition of RCAs for law enforcement purposes. The United States expressed concern that development of incapacitants for ‘law enforcement’ purposes could be used to conceal an offensive chemical weapons program. See: R. Guthrie, ‘High- lights from the General Debate at the Third Review Conference,’ OPCW Today, 2, 14–16 (July 2013). [27] M. Soderstrom. in Report of Technical Workshop on Incapacitating Agents, held in Spiez, Switzerland, 8 and 9 September 2011, pp. 42–43. [28] N. F. J. Van Nimmen, H. A. F. Veulemans. J. Chromatogr. A 1035, 249 (2004). [29] T. Koli, P. Vanninen, C. Timperley, J. Riches, N. Roughley. in Recommended Operating Procedures (ROPs) for Analysis in the Verification of Chemical Disarmament, (2017 Edition), Ministry of Foreign Affairs, Finland (2017). [30] F. J. Hampson. in Promise or Peril? Incapacitating Biochemical Weapons, A. M. Pearson, M. Chevrier and M. Wheelis (eds.), pp. 231–260, Lexington Books, Maryland, USA (2007). [31] C. C. Flowerree. ‘On Tending Arms Control Agreements,’ The Washington Quarterly, pp. 199–214 (Winter 1990).