Incapacitants

1. Incapacitants Stevan Cordas DO MPH Stevan Cordas DO Incapacitants

2. Definition Under the Department of Defense definition, an incapacitant is an agent that produces temporary physiological or mental effects, or both, which will render individuals incapable of concerted effort in the performance of their assigned duties. Stevan Cordas DO Incapacitants

3. History • 600 BC – Solon used hellebore to cause diarrhea in enemy. • 184 BC – Hannibal used belladonna to create disorientation. • 1500 AD – Hashish used by Muslims. • 1672 AD - Bishop of Muenster proposed belladonna grenades. • 1881 –1908 - Natives in Africa and Vietnam used indigenous plant to cause disorientation in occupying troops. Stevan Cordas DO Incapacitants

4. History • Following WWII the CIA and the DoD began to explore various substances to act as incapacitants. • 1960- 1990 3-quinuclidinyl benzilate termed BZ (NATO) was the only one weaponized. • 1997 - Department of Defense joint non-lethal weapons program (JNLWP). Stevan Cordas DO Incapacitants

5. Types of Psychoactive Incapacitants • Central nervous system stimulants – amphetamines, cocaine etc. • Central nervous depressants – antipsychotics, barbiturates, opioids, benzodiazepines. • Psychedelics –LSD –25, PCP, MDMA etc. • Delerients – scopolamine, BZ, atropine etc. Stevan Cordas DO Incapacitants

6. Epidemiology • Psychoactive drugs and plants readily available worldwide. • BZ is commercially available as QNB. Hard to make in a home lab. • Sudden delirium in a previously healthy person or group of persons should raise suspicion. Stevan Cordas DO Incapacitants

7. Epidemiology • Anticholinergics are readily found in plants such as belladonna (Atropa belladonna), mandrake root, Black henbane (Hyoscyamus niger), the thornapple or Jimson weed (Datura stramonium) and woody nightshade (Solanum dulcamara) and Jerusalem cherry (Solanum pseudocapsicum), all members of the Solanaceae botanical family (along with tobacco coincidentally). • 1998 British report that Iraq had stockpiled Agent 15, a glycolic acid ester, an agent similar to BZ. Stevan Cordas DO Incapacitants

8. Pathophysiology • BZ is an anticholinergic. This is a class of drugs that blocks, as a competitive inhibitor of acetylcholine, the post synaptic and postjunctional muscarinic receptor sites on the peripheral and/or the central nervous system. The nicotinic receptors in the skeletal muscle are not affected. Stevan Cordas DO Incapacitants

9. Pathophysiology • Anticholinergics, such as BZ and Agent 15, work the direct opposite of nerve gas agents and cause an understimulation of muscarinic exocrine gland, central and peripheral nervous system and smooth muscle receptors. Stevan Cordas DO Incapacitants

10. Differential Diagnosis • Lead, mercury. • Solvents. • Alcohol. • Anxiety states. • Recreational drug abuse. • Medical disease –hepatic failure, renal failure, hypothyroidism. Stevan Cordas DO Incapacitants

11. Toxicology of BZ • A stable crystalline solid. Not soluble in water but in DMSO and solvents. Can be aerosolized. Formula C21H23NO3. • MW is 337.41; melting 167° C; Boiling point 320° C. • Safety margin 30. ID50 is 6.2g/kg. • Less than 1 mg will cause delirium in a 70 kg man. Stevan Cordas DO Incapacitants

12. Clinical Manifestations of BZ • Ocular –Mydriasis, loss of near vision, dry eyes. • Oral – Xerostomia. • Cardiac - unpredictable – usually tachycardia lasting one to two days. • Skin – Dry, flushed, hyperthermic. • GU – Bladder distended, decreased force. Stevan Cordas DO Incapacitants

13. Clinical Manifestations of BZ • Dose dependent central effects. • Level of consciousness –drowsy, sedated, stupor to coma. Perceptual – mad as a hatter, hallucinations, illusions. • Attention and memory impairment. • Disturbances in insight and judgment – Vulgarity, confabulation. Stevan Cordas DO Incapacitants

14. Clinical Manifestations of BZ • Deficits in expression and comprehension. – Slurred speech, flat voice, preserveration, semiautomatic speech, handwriting deteriorates, cannot converse. • Disorientation – time and place, picking behaviors, mumbling, vulgarity. • Sharing of illusions and hallucinations. • Paranoia – especially as other symptoms resolve. Stevan Cordas DO Incapacitants

15. Laboratory Testing There are no laboratory tests for BZ and no field detection equipment. Stevan Cordas DO Incapacitants

16. Treatment • Evacuate. • Restrain if necessary. • Treat hyperthermia if it is severe. • Watch for cardiac arrhythmias, destructive behavior and general status. • Give specific antidote IM or IV – Physostigmine. Not effective in the first four hours however. Stevan Cordas DO Incapacitants

17. Physostigmine • IM 2 to 4 mg every one to 4 hours for 4 or 5 doses. • IV, if restrained, 30 g/kg slowly. • A fast bolus IV may cause a fatal cardiac arrhythmia or convulsions. • Available as Antilirium or Eserine. • Other similar agents do not cross the blood brain barrier. Stevan Cordas DO Incapacitants

18. Prophylaxis • If pre-warned, military protective gear will prevent the effects of anticholinergics. • No preventive therapy available for civilians. • Evacuate area as BZ persists especially in water, soil and moist surfaces. Stevan Cordas DO Incapacitants

19. Reporting There are currently no formal reporting requirement for incapacitants. All unusual circumstances that are suspected of being related to terrorist actions must be reported to law enforcement officials. It is also advisable to report such actions voluntarily to local health departments. Stevan Cordas DO Incapacitants

20. Ricin Toxin Stevan Cordas DO MPH Stevan Cordas DO Incapacitants

21. Ricin • Ricin is a glycoprotein toxin derived from castor plant beans. It can be produced relatively easily and inexpensively in large quantities in a fairly low technology setting. Ricin can be prepared in liquid, crystalline or powder form. Stevan Cordas DO Incapacitants

22. Ricinus Communis (Castor Plant) Stevan Cordas DO Incapacitants

23. Ricin - A 66 Kilodalton Heterodimer With an A and B Chains Stevan Cordas DO Incapacitants

24. History of Ricin • Since antiquity, it is known that the oil is helpful but the plant is poisonous. • Ricin, mainly in the seeds, first named 1888. • Ehrlich discovered the basic principle of antibody production using ricin – the beginning of immunology – 1896. • Named compound W after WWI – developed by both U.S. And Great Britain into weapons. Stevan Cordas DO Incapacitants

25. History of Ricin • Allies developed a W bomb in WWII but did not use it. • Increased production and weaponization by both allies and others starting in 1950. • United states ceased biological warfare production in 1969 and destroyed supplies. • Iraq and others produced ricin weaponry as part of their inventory. Stevan Cordas DO Incapacitants

26. History of Ricin • First shown to inhibit tumors in 1951. • Modern use as research tool developed in 1972 by Sharon and Lis. • Chimeric toxins use is currently being studied – native ricin is conjugated to tumor specific monoclonal antibody. • Used by Bulgarian secret police to assassinate a defector in 1978. Stevan Cordas DO Incapacitants

27. Epidemiology • World wide distribution of plant. • Readily separated and concentrated. • Widespread availability. • Implicated with several domestic terrorist incidents. • A cluster of cases in the same locality with severe pulmonary distress must include in differential diagnosis. Stevan Cordas DO Incapacitants

28. Stevan Cordas DO Incapacitants

29. Pathophysiology • B chain has lectin properties - permit binding to galactosides on cell wall and permitting endocytic uptake of the protein. • Once in cell, the A chain acts as an enzyme after a latent period of 8-24 hours in vivo, cell death occurs by cleaving the 28A subunit of RNA. Protein synthesis ceases. • Multiple areas of multifocal ulcerations and hemorrhage. Nephritis, liver necrosis. Stevan Cordas DO Incapacitants

30. Toxicology • Ricin composes about 5% of the Castor plant. Especially in beans and seeds. • Both chains are glycoproteins 32 kd each. • It has been purified and crystallized. • 100 fold variation in toxicity for various animals. • Toxicity varies by route of administration and is 100 times more lethal by injection than orally. Stevan Cordas DO Incapacitants

31. Toxicology • Low oral toxicity is due to poor absorption of toxin. • Target cell receptors are widespread over the body but macrophages and monocytes are the only white cells to contain galactose in cell membrane. • LD50 is 20 mg/kg(100 hours) orally. 4g/kg by inhalation and intravenously. (Mice). Stevan Cordas DO Incapacitants

32. Clinical Manifestations - Oral • Oral – Rauber et el – 751 cases. 14 fatalities. • Death rate in general said to be 6%. • Often just nausea, vomiting, diarrhea sometimes bloody and abdominal cramps with prostration. Also burning eyes noted. • More severe cases also had dilated pupils, shock, anuria, sore throat, fever, vascular collapse, shock and possibly death. Stevan Cordas DO Incapacitants

33. Clinical Manifestations - Injection • Low doses 18-20g/kg in cancer patients could be tolerated with fatigue and flu like symptoms. Vascular leak syndrome seen. • Lasted 1-2 days after a latent period of 4 to 6 hours. Stevan Cordas DO Incapacitants

34. Clinical Manifestations - Injection • Markov was assassinated in London by the Bulgarian KGB with 500g. Immediate local pain. 15-24 hours later high fever, nausea, vomiting. • 36 hours later localized lymphadenopathy,then suddenly hypotensive, cardiac rate 160 then complete AV block, GI bleeding, anuria, shock and death. • Death 3-5 days. Stevan Cordas DO Incapacitants

35. Clinical Manifestations - Inhalation • Allergic reaction to castor beans in workers rhinitis, asthma and conjunctivitis seen. • Inhalation of ricin would produce same picture as by subcutaneous except that experimentally a diffuse necrotizing pneumonitis occurs with alveolar flooding. An 8 hour latent period is noted. Dose dependent. Tracheitis and mediastinal purulent lymphadenitis also seen. Stevan Cordas DO Incapacitants

36. Differential Diagnosis of Ricin Aerosol • Staphylococcus B enterotoxin • Organofluorine polymers • Phosgene • Oxides of nitrogen • Paraquat •  - Naphthylthiourea (ANTU) Stevan Cordas DO Incapacitants

37. Laboratory Diagnosis • ELISA analysis of swab of nasal mucosa if obtained within 24 hours of exposure. • Survivors after about 2 weeks develop antibodies. Identification in body fluids is difficult as it is bound rapidly and metabolized. • Immunohistochemical means on autopsy or tissue. Stevan Cordas DO Incapacitants

38. Field Testing • Field screening testing is now possible using tests such as the RAMP Ricin field test. This is a 15 minutes immunochromatographic test. See http://www.responsebio.com/productsbiodefense1c.htm for more details Stevan Cordas DO Incapacitants

39. Treatment • No vaccine or immunization is available for humans. Toxoid has been submitted to the FDA for an IND. • Experimentally inhalation of protective antibody (passive protection) is highly effective after exposure. • For oral – super activated charcoal and IV fluids. Stevan Cordas DO Incapacitants

40. Treatment • For aerosol – supportive measures -positive end expiratory ventilatory pressure, iv fluids, anti-inflammatory drugs and analgesics. • Research drugs to block enzymatic action of A protein. • Detoxify (decontaminate) using water or dilute bleach. Wear N95 mask if inhalation source. Stevan Cordas DO Incapacitants

41. Prophylaxis • No prophylaxis is currently possible though it is possible with animal experiments using a vaccination. Stevan Cordas DO Incapacitants

42. Reporting • Ricin is a putative bioterrorism weapon. Report to your local or state health department immediately. Stevan Cordas DO Incapacitants

43. Castor Beans Stevan Cordas DO Incapacitants

44. T2 and Other Mycotoxins Stevan Cordas DO MPH Consultant Texas Department of Health Stevan Cordas DO Incapacitants

45. Fungi • Over 100,000 species of fungi found in four phyla. • Consists of mushrooms, lichens, corals, molds and others. • Just as mushrooms can be used beneficially but some can be fatal, molds also can be viewed in this manner. Stevan Cordas DO Incapacitants

46. Molds • 75% of fungi belong to the family Ascomycota which produce the sexual spores internally in a structure called the ascus. • These fungi are molds that can produce products that are fatal to plants, animals and humans. • One product is called T2. Stevan Cordas DO Incapacitants

47. Stevan Cordas DO Incapacitants

48. T2 • (3",4$,8")-12,13,-Epoxytrichothec-9-ene-3,4,8,15-tetrol 4,15-diacetate 8-(3-methylbutanoate); 3" -hydroxy -4$, 15-diacetyloxy-8"-(3-methylbutyryloxy)-12,13-epoxy -)9 -tricothecene Stevan Cordas DO Incapacitants

49. T2 • T2 is a mycotoxin. • It was the only such toxin to be weaponized until Sadam Hussein weaponized aflatoxin. • It is the only biologic agent that can kill by transdermal absorption. • Oral ingestion probably caused ATA (alimentary toxic aleukia). Stevan Cordas DO Incapacitants

50. History of T2 • Evidence of T2 use as “yellow rain” in Laos, Cambodia and Afghanistan by Soviets and their surrogates. • May have been used in the Iran- Iraq war. • No conclusive human case from a biological attack of T2 has been documented. Stevan Cordas DO Incapacitants