Abstract Military interest in incapacitating biochemical weapons has grown in recent years as advances in science and technology have appeared to offer the promise of new "non-lethal" weapons useful for a variety of politically and militarily challenging situations. There is, in fact, a long and unfulfilled history of attempts to develop such weapons. It is clear that advances are opening up a range of possibilities for future biological and chemical weapons more generally. The treaties prohibiting biological and chemical weapons make no distinction between lethal and "non-lethal" weapons—all are equally prohibited. Indeed, a sharp and technically meaningful distinction between lethal and "non-lethal" biological and chemical weapons is beyond the capability of science to make. Thus, interest in incapacitating biochemical weapons, and efforts on the part of various states to develop them, pose a significant challenge to the treaty regimes, to the norms against biological and chemical warfare that they embody, and, ultimately, to the essential protections that they provide. Preventing a new generation of biological and chemical weapons from emerging will take concerted efforts and action at the local, national, and international levels. Keywords: Biological weaponsChemical weaponsBiochemical weaponsChemical incapacitating agentsNon-lethal weaponsArms controlFentanyl Notes 1. Committee on Advances in Technology and the Prevention of Their Application to Next Generation Biowarfare Threats, Board on Global Medicine, Institute of Medicine and National Research Council, Globalization, Biosecurity and the Future of the Life Sciences (Washington, DC: National Academies Press, 2006), p. 5. See also pp. 178–181 and references at notes 141, 144, and 150 on p. 208 of this report. 2. Elliot Kagan, "Bioregulators as Instruments of Terror," Clinics in Laboratory Medicine 21 (Sept. 2001), pp. 607–618. 3. 3 U.S. Army, Potential Military Chemical/Biological Agents and Compounds, Field Manual 3-11.9, Jan. 10, 2005, p. I–7, . 4. Sweden stated that by the year 2000, the "scientific and technological achievements … may make it possible to produce products of human origin as B-weapons. Such products could be hormones or transmitter substances which to take effect are needed in extremely small quantities." Background Document on New Scientific and Technological Development Relevant to the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction," BWC/CONF.II/4, Geneva, Sept.r 8–26, 1986, p. 3, . The United States, discussing peptides, stated that "[t]heir range of activity covers the entire living system, from mental processes … to many aspects of health such as control of mood, consciousness, temperature control, sleep or emotions, exerting regulatory effects on the body. Even a small imbalance in these natural substances could have serious consequences, inducing fear, fatigue, depression or even causing death." BWC/CONF.II/4, Add.2, p. 3, . 5. National Academies of Science, Press Release, Jan. 31, 2006, "Global Effort Needed to Anticipate and Prevent Potential Misuse of Advances in Life Science," . 6. Kurt Kleiner, "US 'unaware' of emerging bioterror threats," New Scientist.com News Service, Jan. 31, 2006, ; Emily Singer, "Could Terrorists Hijack Your Brain?" Technology Review (Feb. 1, 2006), . 7. Executive Office of the President, Biodefense for the 21st Century, Homeland Security Presidential Directive 10/National Security Presidential Directive 33, Washington, DC, April 28, 2004, . 8. Christopher J. Davis, "Nuclear Blindness: An Overview of the Biological Weapons Programs of the Former Soviet Union and Iraq," Emerging Infectious Diseases 5 (July–Aug. 1999), pp. 509–512. 9. Committee for an Assessment of Non-Lethal Weapons Science and Technology, Naval Studies Board, National Research Council, An Assessment of Non-Lethal Weapons Science and Technology (Washington, DC: National Academies Press, 2003), p. 4. 10. Paul M. Wax, Charles E. Becker, and Steven C. Curry, "Unexpected 'Gas' Casualties in Moscow: A Medical Toxicology Perspective," Annals of Emergency Medicine 41 (Aug. 2003) pp. 700–705. 11. See Neil Davison and Nick Lewer, Bradford Non-Lethal Weapons Research Project Research Report No. 5, (Bradford, UK: Centre for Conflict Resolution, University of Bradford, May 2004), p. 39, . 12. Donald Voet, Biochemistry, 3rd ed. (New York: Wiley, 2004), p. 13. 13. Eva S. Istvan and Johann Deisenhofer, "Structural Mechanism for Statin Inhibition of HMG-CoA Reductase," Science 292 (May 11, 2001), pp. 1160–1164. 14. Bruce D. Roth, "The Discovery and Development of Atorvastatin, a Potent Novel Hypolipidemic Agent," Progress in Medicinal Chemistry 40 (2002), pp. 1–22. For sales data see IMS Health, "Leading Products by Global Sales, 2005," at . 15. Field Manual 3-11.9, p. I–6. 16. James S. Ketchum and Frederick R. Sidell, "Incapacitating Agents," in Frederick R. Sidell, Ernest T. Takafugi, and David R. Franz, eds., Medical Aspects of Chemical and Biological Warfare, TMM series, Part I (Washington, DC: TMM Publications, 1997), p. 288. 17. Field Manual 3-11.9, p. I–6. 18. U.S. Army Field Manual 8-285, Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries, (Dec. 22, 1995), P. 3–1, available at . 19. U.S. Army Field Manual 8-285, Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries, (Dec. 22, 1995), P. 3–1, available at . 20. See information for Remifentanil at "Opioids" at . 21. Ketchum and Sidell, "Incapacitating Agents," p. 291. 22. Ketchum and Sidell, "Incapacitating Agents," p. 291. For TL 2636 see Caitriona McLeish, "The Governance of Dual-Use Technologies in Chemical Warfare," M.Sc. dissertation, University of Sussex, 1997, pp. 55–65. 23. Joan M. Lakoski, W. Bosseau Murray, and John M. Kenny, The Advantages and Limitations of Calmatives for Use as a Non-Lethal Technique (University Park, PA: Applied Research Laboratory, Pennsylvania State University, 2000), p. 48. 24. Martin Furmanski, "Military Interest in Low-lethality Biochemical Agents: The Historical Interaction of Advocates, Experts, Pragmatists and Politicians," (June 2005), p. 19, . 25. Furmanski, "Military Interest;" See also: Malcolm Dando, "The UK's Search for an Incapacitating ('Non-Lethal') Chemical Agent in the 1960s," Bradford Science and Technology Report No. 6 (Bradford, UK: Dept. of Peace Studies, University of Bradford, Jan. 2006); ; Stockholm International Peace Research Institute, The Problem of Chemical and Biological Warfare (New York: Humanities Press, 1971), Vol. 2, pp. 124, 154, 265, 273, and Vol. 5, pp. 47–49, 127–128; J. P Perry Robinson, "Disabling chemical weapons: some technical and historical aspects," paper delivered to the Second Workshop of the Pugwash Study Group on Implementation of the CBW Conventions, Den Haag/Noordwijk, Netherlands, May 27–29, 1994. 26. U.S. Dept. of Defense, Directive 3000.3 Policy for Non-Lethal Weapons (July 9, 1996), p. 2. 27. Lt. Col. Randy Copeland, "Joint Non-Lethal Weapons Program," (June 2002), slide 2, . U.S. Marine Corps, "Joint Concept for Non-Lethal Weapons" (Jan. 5, 1988), available at . 28. Naval Studies Board, An Assessment of Non-Lethal Weapons, pp. 12–15, 20, 26, and 27. See also US/UK Non-Lethal Weapons (NLW)/Urban Operations Executive Seminar Assessment Report (Nov. 30, 2000), p. 28, at ; U.S. Marine Corps, "Joint Concept"; Nick Lewer, "Introduction" in Nick Lewer, ed., The Future of Non-Lethal Weapons: Technologies, Operations, Ethics and Law (London/Portland, OR: Frank Cass, 2002), p. 1; Brian Rappert, Non-Lethal Weapons as Legitimizing Forces? (London/Portland, OR: Frank Cass, 2003), pp. 63–65, 228–234. 29. U.S. Marine Corps, "Joint Concept." For in depth information about, and arguments for and against, "nonlethal" weapons more generally, see John B. Alexander, Future War: Non-Lethal Weapons in 21st Century Warfare (New York: St. Martin's Press, 1999); Graham T. Allison, Paul X. Kelley, and Richard L. Garwin, Non-lethal Weapons and Capabilities, Report of an Independent Task Force sponsored by the Council on Foreign Relations (New York: Council on Foreign Relations Press, 2004); Malcolm Dando, A New Form of Warfare: The Rise of Non-Lethal Weapons (London: Brassey's, 1996); Lewer, The Future of Non-Lethal Weapons; Douglas C. Lovelace and Steven Metz, Nonlethality and American Land Power (Carlisle, PA: Strategic Studies Institute, U.S. Army War College, 1998); Rappert, Non-Lethal Weapons. 30. Ketchum and Sidell, "Incapacitating Agents," p. 295. Compare to value for VX in Table 30-2 in David R. Franz, "Defense Against Toxin Weapons," in Sidell,. Takafugi, and Franz, Medical Aspects of Chemical and Biological Warfare, p. 607. 31. Malcolm Dando and Martin Furmanski, "Midspectrum Incapacitant Programs," in Mark Wheelis, Lajos Rozsa, and Malcolm Dando, eds., Deadly Cultures: Biological Weapons Since 1945 (Cambridge, MA: Harvard University Press, 2006), pp. 246–249. 32. Malcolm Dando and Martin Furmanski, "Midspectrum Incapacitant Programs," in Mark Wheelis, Lajos Rozsa, and Malcolm Dando, eds., Deadly Cultures: Biological Weapons Since 1945 (Cambridge, MA: Harvard University Press, 2006), pp. 246–249. 33. Malcolm Dando and Martin Furmanski, "Midspectrum Incapacitant Programs," in Mark Wheelis, Lajos Rozsa, and Malcolm Dando, eds., Deadly Cultures: Biological Weapons Since 1945 (Cambridge, MA: Harvard University Press, 2006), p. 243. 34. Ketchum and Sidell, "Incapacitating Agents," p. 295. 35. Jean Pascal Zanders, "Assessing the Risk of Chemical and Biological Weapons Proliferation to Terrorists," Nonproliferation Review 6 (Fall 1999), pp. 23–25. 36. Furmanski, "Military Interest," p. 19. 37. John M. Kenny, "Human Effects Advisory Panel Program," presentation at the Non-Lethal Defense IV Conference, sponsored by the National Defense Industrial Association, March 20–22, 2000, slide 23, . 38. Lynn Klotz, Martin Furmanski, and Mark Wheelis, "Beware the Siren's Song: Why 'Non-Lethal' Incapacitating Chemical Agents are Lethal," Scientists Working Group on Biological and Chemical Weapons, March 2003, . 39. V.L. Klochikhin, A.A. Lushnikov, V.A. Zagaynov, A.V. Putilov, V.V. Selivanov, and M.A. Zatevakhin, "Principles of Modeling of the Scenario of Calmative Application in a Building With Deterred Hostages," paper presented to the 3rd European Symposium on Non-Lethal Weapons, Stadthalle, Germany, May 10–12, 2005. 40. L.E. Mather, "Clinical pharmacokinetics of fentanyl and its newer derivatives," Clinical Pharmacokinetics 8 (Sept.–Oct. 1983), pp. 422–46; Center for Nonproliferation Studies, Chemical and Biological Weapons Nonproliferation Program, "The Moscow Theater Hostage Crisis: Incapacitants and Chemical Warfare," (Nov. 4, 2002) . 41. Wax et al., "Unexpected 'Gas' Casualties." 42. Tufts Center for the Study of Drug Development, "Outlook 2005," p. 1, . 43. On the use of anesthesia in clinical settings, see, for example, David A.E. Shephard, "The changing pattern of anesthesia, 1954–004: A review based on the content of the Canadian Journal of Anesthesia in its first half-century," Canadian Journal of Anesthesia 52 (March 2005), pp. 238–248. 44. See, for example, Roche Pharmaceuticals, "Versed (midazolam HCl) Injection," package insert, ; Bedford Laboratories, "Propofol Injectable Emulsion 1%," package insert, . 45. Alan S. Nies, "Principles of Therapeutics," in Joel G. Hardman and Lee E. Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (New York: McGraw-Hill Professional, 2001), p. 51. 46. See, for example, Ketchum and Sidell, "Incapacitating Agents," p. 296. 47. Nies, "Principles of Therapeutics," p. 48. 48. The principle of individualized treatment is the result of extensive clinical experience with the use of powerful pharmaceutical agents such as anesthetics. 49. Klochikhin et al., "Principles of Modeling," arrive at the following important conclusion on the basis of their study: "If the level of 95% efficiency is absolutely required to neutralize terrorists and to prevent mass destruction, there is no chance to eliminate hard consequences and fatalities. Calculations show that the majority of hostages can get serious poisoning and part of them—fatality. This is the cost of releasing if no other solutions left," p. 3. See also, Furmanski, and Wheelis, "Siren's Song," p. 4. 50. Guy Gugliotta, "U.S. Finds Hurdles in Search for Nonlethal Gas," Washington Post, Nov. 1, 2002, p. A30, quoting C. Parker Ferguson. In 1994, U.S. Army researchers had this to say about the problem: "For many scenarios the desired characteristics of chemical immobilizers are similar to these depicted in James Bond films. In fiction, a chemical agent knocks out people instantaneously. In reality the onset time for immobilization or unconsciousness takes longer, even when deploying the most potent anesthetic materials known. For other scenarios, a delayed onset or a less severe degree of immobilization may be desired. The other myth usually associated with stereotypical immobilizers is rapid recovery and lack of side effects." See Edgewood Research, Development & Engineering Center (hereafter ERDEC), "Demonstration of Chemical Immobilizers," Research Proposal , April 27, 1994, . 51. This list of requirements summarizes information synthesized from a wide variety of sources. For some particular requirements, see the following: Lakoski, Murray, and Kenny, Advantages and Disadvantages, p. 5; Naval Studies Board, Assessment of Non-Lethal Weapons, pp. 22, 27, and 107; Ketchum and Sidell, "Incapacitating Agents," p. 288; U.S. Army Field Manual 8-825, p. 3–1. The last three requirements are of particular importance according to the committee of the Naval Studies Board: "Major research and development … issues involving the use of calmatives are (1) the quantification of the effectiveness and margin of safety for these materials and (2) the development of the method of delivery that can rapidly provide the appropriate dose." The committee added: "to elicit the desired level of mood alteration without causing a dangerous level of respiratory depression … requires a tight control on dose level," p. 27. See also their comment on p. 107: "Few reliable, low-risk, and low-cost methods exist for delivering and dispensing chemical NLWs precisely and accurately. This capacity … becomes critical in the delivery of calmatives, where proper doses must be achieved." The committee recommended the development of microencapsulation to create more deliverable forms of incapacitants and sensor systems to achieve accurate delivery on target at the proper dose level. Weapons developer C. Parker Ferguson said that "major challenges remained to developing an incapacitant both potent enough to be effective and safe enough to be used," stating "[i]t's often a tradeoff." Quoted in David Ruppe, "New Research Offers Safer Incapacitating Chemicals," Global Security Newswire, Nov. 6, 2002, . 52. Klotz et al., Beware the Siren's Song. 53. Mark Wheelis and Malcolm Dando, "Neurobiology: A case study of the imminent militarization of biology," International Review of the Red Cross 87 (Sept. 2005), p. 561. See also Malcolm R. Dando, "The Danger to the Chemical Weapons Convention from Incapacitating Chemicals," First CWC Review Conference Paper Number 4 (Bradford, UK: Dept. of Peace Studies, University of Bradford, March 2003), pp. 5, 11. 54. See entry for "Acetylcholine receptors, muscarinic" at the IUPHAR Receptor Database, . 55. For reviews of some of these important developments, see Robert J. Lefkowitz, "Historical review: a brief history and personal retrospective of seven-transmembrane receptors," Trends in Pharmacological Sciences 25 (Aug. 2004), pp. 413–422; Soloman H. Snyder and Gavril W. Pasternak, "Historical overview: Opioid receptors," Trends in Pharmacological Sciences 24 (April 2003), pp. 198–205; Mark S. Boguski and Allan R. Jones, "Neurogenomics: at the intersection of neurobiology and genome sciences," Nature Neuroscience 7 (May 2004), pp. 429–433; Seth G. N. Grant, "Systems biology in neuroscience: Bridging genes to cognition," Current Opinion in Neurobiology 13 (Oct. 2003), pp. 577–582. 56. Mark Wheelis, "Biotechnology and Biochemical Weapons," Nonproliferation Review 9 (Spring 2002), pp. 48–53. For example, Committee on Advances, Globalization, Biosecurity"; Richard Kramer and Dalia Cohen, "Functional Genomics to New Drug Targets," Nature Reviews Drug Discovery 3 (Nov. 2004), pp. 965–972. 57. U.S. Food and Drug Administration, Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products (Washington DC, March 2004), . 58. Robinson, "Disabling Chemical Weapons"; J.P. Perry Robinson, "Disabling Chemical Weapons: A Documentary Chronology of Events, 1945–2003," unpublished working paper, Harvard Sussex Program, University of Sussex, Nov. 1, 2003 (hereafter Robinson Chronology); David Brown and Peter Baker, "Moscow gas likely a potent narcotic," Washington Post, Nov. 11, 2002, p. A12; Naval Studies Board, Assessment of Non-Lethal Weapons, pp. 63–64. The author is indebted to J.P. Perry Robinson for sharing his documentary chronology, which provides by far the most complete account of publicly available information on attempts to develop and use incapacitants between 1945 and 2003. 59. The WorldWide Anaesthetist Web Site, "Opioids," . 60. P.L. Bailey, J. Wilbrink, P. Zwanikken, N.L. Pace, and T.H. Stanley, "Anesthetic induction with fentanyl," Anesthesia and Analgesia 64 (Jan. pp. 48–53. Ketchum and Sidell, "Incapacitating Agents," p. Dando and Furmanski, "Midspectrum McLeish, Robinson Pharmaceuticals, Injection," package insert, The package with potent is by respiratory depression … which may or in the See also Mather, "Clinical and a of extremely potent with safety pp. Stanley, "Human the experience in Moscow the European Journal of (June 2003), pp. see also Brian D. and M. Grant, for Chemical and Institute of Report National Laboratory, Jan. Weapons: New for Law Science and Technology, of the International of of (Dec. p. 3, a safety of 4 for in the The for this is For example, Center for Nonproliferation Studies, "The Moscow Theater Hostage Crisis: Incapacitants and Chemical Warfare," . et al., and a potent and extremely safe in and pp. The WorldWide Anaesthetist Web Site, Pharmaceuticals, J. L. R. R. and B. study of and side effects of 8 in (March pp. see also Klotz et al., Beware the Siren's p. of the Army, with U.S. Number Nov. 10, The WorldWide Anaesthetist Web Site, clinical experience that the can have significant effects in a of when at doses required for anesthesia, and even at doses required for are safe in can be individualized and for the in the has this to in Pharmaceuticals, S. and C. with in (Jan. 2000), pp. L.E. Mather, and of of Journal of Clinical (July pp. Franz, "Defense Against Toxin Weapons," p. 607. Stanley, "Human Naval Studies Board, An Assessment of Non-Lethal Weapons, p. 27. U.S. Number Snyder and Pasternak, Robinson entry for Nov. Robinson entry for Jan. and Grant, John Dept. for Non-Lethal Washington Post, March 23, 1994, p. See also U.S. Dept. of National Institute of Research (Washington, DC: Dept. of 1995), p. 20, of with the Dept. of is with the Dept. of Homeland See Security Research presentation Jan. 2004, Mark Wheelis, Chemical Weapons: A in Science and Technology (Spring by that U.S. with Naval Studies Board, An Assessment of Non-Lethal Weapons, p. 27. Ruppe, "New Naval Studies Board, An Assessment of Non-Lethal Weapons, p. See Neil Davison and Nick Lewer, Bradford Non-Lethal Weapons Research Project Research Report No. (Bradford, UK: Centre for Conflict Resolution, University of Bradford, March 2006), p. for in Malcolm Dando, and technological and the future of the The of 4 (2002), p. The WorldWide Anaesthetist Web Site, also see J. and L. and of a from (July pp. C. M. P. C. P. D. G. and a of the and (March pp. and B. of and in the Research (Dec. 5, 1997), pp. R. S. M. P. E. J. and of effect and in the Nature (Oct. 31, 1996), pp. R. E. L. and of and on respiratory and in and Journal of (Dec. 2003), pp. Wheelis and Dando Dando, John G. and of as and Warfare Agents," (June 28, 2002), p. 1, Lakoski, et al., Advantages and p. 5, stating that the of the pharmaceutical in the with the in the of anesthesia, and has a of that produce a as a or Naval Studies Board, An Assessment of Non-Lethal Weapons, pp. 5, U.S. Army, Agents for Non-lethal Innovation Research Agents for Non-Lethal I from the Copeland, "Joint Non-Lethal Weapons see also U.S. Non-Lethal Weapons Non-Lethal Weapons as in Bradford Non-Lethal Weapons Research Research Report 3 (Bradford, UK: Dept. of Peace Studies, University of Bradford, 2001), Robert ed., Nonlethal Weapons: and Paper U.S. Force Institute for National Security 1996), p. 10, Calmatives with and as in a presented by the in March Col. "The U.S. Dept. of Defense Non-Lethal Weapons Program, March presentation at the Non-Lethal Defense IV Conference, sponsored by the National Defense Industrial Association, March 20–22, 2000, slide 10, Naval Studies Board, An Assessment of Non-Lethal Weapons, p. 24. is control is also as See Robert J. "Joint Non-Lethal Weapons Non-Lethal presentation at National Defense 2003 Conference, 2003, for presentation at National Defense in rapid delivery of doses of biochemical incapacitants by far the challenge use agents or agents likely to be in the a technical review of the development by effective is critical for remained

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