Incapacitants

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Incapacitants

• Stevan Cordas DO MPH

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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.

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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.

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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).

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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.

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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.

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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.

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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.

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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.

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Differential Diagnosis

• Lead, mercury.
• Solvents.
• Alcohol.
• Anxiety states.
• Recreational drug abuse.
• Medical disease hepatic failure, renal failure,
  hypothyroidism.

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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.

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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.

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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.

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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.

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Laboratory Testing

• There are no laboratory tests for BZ and no
  field detection equipment.

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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.

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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.

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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.

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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.

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Ricin Toxin

• Stevan Cordas DO MPH

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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.

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Ricinus Communis (Castor Plant)
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Ricin - A 66 Kilodalton Heterodimer With an A
and B Chains
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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.

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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.

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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.

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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.

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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.

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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.

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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).

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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.

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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.

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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.

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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.

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Differential Diagnosis of Ricin Aerosol

• Staphylococcus B enterotoxin
• Organofluorine polymers
• Phosgene
• Oxides of nitrogen
• Paraquat
• ? - Naphthylthiourea (ANTU)

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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.

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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.ht
  m for more details

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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.

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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.

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Prophylaxis

• No prophylaxis is currently possible though it is
  possible with animal experiments using a
  vaccination.

42
Reporting

• Ricin is a putative bioterrorism weapon. Report
  to your local or state health department
  immediately.

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Castor Beans
44
T2 and Other Mycotoxins

• Stevan Cordas DO MPH
• Consultant Texas Department of Health

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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.

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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.

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T2

• (3",4,8")-12,13,-Epoxytrichothec-9-ene-3,4,8,15-t
  etrol 4,15-diacetate 8-(3-methylbutanoate) 3"
  -hydroxy -4, 15-diacetyloxy-8"-(3-methylbutyrylox
  y)-12,13-epoxy -)9 -tricothecene

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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).

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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.

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Iraq

• United nations inspectors reported in 1995 that
  Iraq weaponized a number of biologic agents
  including anthrax, clostridia botulinum and a
  mycotoxin, aflatoxin.
• Aflatoxin is one of the most potent mutagens and
  carcinogens known.

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Toxicology of T2

• Maintained as crystalline powders or liquids. Non
  volatile.
• Can extract from fungal cultures with organic
  acids.
• Cytotoxic to most eukaryotic cells by inhibiting
  protein synthesis.
• LD 50 varies with species. In monkey it is 0.8
  mg/kg.

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Toxicology

• Inhibits protein and DNA metabolism.
• Rapidly crosses pulmonary and intestinal mucosa.
• Slowly absorbs across skin unless a penetrant is
  added.
• Liver is main organ for metabolism of T2.
• Metabolites can be detected up to 28 days.

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Clinical Effects

• Acute gastric and intestinal lesions.
  Hematopoetic and immunological effects are
  radiomimetic.
• CNS lassitude, anorexia, nausea.

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Clinical Effects

• Vascular effects with shock and possibly death.
• Reproduction organ function suppressed.
• Weakness, cough, chest pain, diarrhea often
  bloody.
• Dermal effects if that route was used
  inflammation and necrosis, vesicles.
• Bloody ooze from nose and mouth.

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Chronic Effects of T2

• ATA immediate phase of GI effects, weakness,
  and dizziness followed by leucopoenia primarily
  granulocytes. If exposure continues a dark red
  rash with ulcers and gangrenous areas larynx
  gets involved with death by strangulation. If
  they survive it takes months to recover.

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Chronic Effects

• Since it is a potent inhibitor of replication and
  is most toxic to rapidly proliferating cells. A
  phase I and II Cancer trial was done with a
  similar mycotoxin (anguidine or DAS) given IV 3
  mg/m3 daily for 5 days.
• Life threatening toxicity and severe hypotension
  occurred. Effects included confusion, ataxia,
  chills, vomiting diarrhea and burning erythema.

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Differential Diagnosis

• A sudden attack on a otherwise healthy cohort
  with irritant polysystemic symptoms including
  skin burning in the absence of miosis after being
  exposed to a vapor with yellow or reddish color.
• Staph B does not affect the skin.
• Other vesicants have an odor this does not.

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Laboratory Diagnosis

• Requires a high index of suspicion.
• No detector to warn one ahead of time.
• Obtain samples for presumptive testing by liquid
  - gas chromatography then mass spectroscopy for
  confirmatory testing.
• Screening testing is becoming available.
• White count takes about 48 hours to drop.

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Treatment

• In the military a protective suit and M40 or
  later mask is used. Or N95 mask.
• Remove from area.
• Decontaminate after removing clothing with soap
  and water.
• No specific therapy is known.
• Superactive charcoal may trap some of the T2.

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General Therapeutic Protocol in Animals

• Supercharcoal
• Magnesium sulfate
• Metoclorpramide
• Dexamethasone
• Sodium bicarbonate
• Normal saline

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Prophylaxis

• No vaccine is available though several are in
  research with some efficacy in animals.
• If protective garment and mask is available use
  it.

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Reporting

• T2 is a putative bioterrorist agent and must be
  reported to the local or state health department
  and law enforcement immediately on suspicion.

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Always Contact Local Public Health Department

• Tarrant County Public Health 1101 S. Main Street
  Fort Worth, Texas 76104
• 817-321-4700
• Dallas County Department of Health Human
  Services2377 N. Stemmons Freeway Dallas, Texas
  75207-2710
• 214-819-2004.