Weapons of Mass Destruction: Chemical Agents and Toxins

1
Weapons of Mass Destruction Chemical Agents and
Toxins

• Esequiel Barrera, SM (TOX)
• Biol/Chem Safety Officer University of Texas
  Southwestern Medical Center at Dallas

2
Points of Discussion

• Agent characteristics
• History of use
• Modes of action
• Clinical Manifestations
• Medical treatment
• Personal Protective Equipment
• Decontamination

• Acute Toxicity
• Chlorine gas
• Cyanide gas
• Mustard gas
• Incapacitants
• Nerve gas
• Botulinum toxin
• Ricin
• T2 Mycotoxin

3
Chlorine Gas

• Chlorine is a powerful oxidizing agent
• Household chemicals such as sodium
  hypochlorite/pool chlorine tablets and muriatic
  acid (HCl) when mixed produce chlorine gas
• Chlorine and anhydrous ammonia are the most
  common hazardous materials in interstate commerce

4
Chlorine Physical Characteristics

• Chlorine gas is a respiratory irritant which
  affects the mucous membranes
• Chlorine is a toxic, corrosive, greenish yellow
  gas
• Gas is two and a half times heavier than air. It
  becomes a liquid at -34 C (-29 F)

5
Chlorine Health risks

• Contact may cause burns to skin and eyes however
  the major concern is inhalation toxicity
• It can be fatal after a few breaths at 1000 ppm.
• Chlorine odor threshold 0.3 to 0.5 ppm
• Medical treatment move individual(s) to fresh
  air, administer oxygen if necessary
• Post-exposed Individuals generally recover to
  normal state

6
Chlorine Symptoms

• Cough (52-80)
• Shortness of breath (20-51)
• Chest pain (33)
• Burning sensation in the throat and substernal
  area (14)
• Nausea or vomiting (8)
• Ocular and nasal irritation (4-6)

7
Incapacitant

• 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

8
Incapacitants

• The chemical warfare agent 3-quinuclidinyl
  benzilate (QNB, BZ) is an anticholinergic agent
  that affects both the peripheral and central
  nervous systems (CNS). It is one of the most
  potent anticholinergic psychomimetics known, with
  only small doses necessary to produce
  incapacitation. It is classified as a
  hallucinogenic chemical warfare agent.

9
Incapacitants

• QNB usually is disseminated as an aerosol, and
  the primary route of absorption is through the
  respiratory system. Absorption also can occur
  through the skin or gastrointestinal tract. It is
  odorless. QNB's pharmacologic activity is similar
  to other anticholinergic drugs (eg, atropine) but
  with a much longer duration of action.

10
First generation chemical agents

• WWI agents such as cyanide and mustard gases
  introduced the horror of chemical warfare
• http//www.superevil.tv/rommel/rommel.htm

11
Hydrogen Cyanide Gas

• Easy to obtain potassium cyanide or other salts
  and react with acid to release cyanide gas cloud
• First synthesized in 1782
• Colorless gas, bitter almond odor
• A characteristic sign of cyanide poisoning is the
  bright red color of the blood in the comatose
  patient (some exceptions have been observed) due
  to the blood remaining fully oxygenated
• Blood agent

12
Cyanide Toxicology

• Median lethal dose of potassium cyanide in man is
  200 mg (taken orally) and death occurring in 1 to
  2 minutes
• Hydrogen cyanide can cause rapid death due to
  metabolic asphyxiation.
• LC(50) in humans is 270 ppm in 6 to 8 minutes.
• Medical treatment nitrate-thiosulfate
  combination antidote

13
Cyanide Biochemical

• Lipid Peroxidation
• Elevated cell calcium
• Acidosis
• Ribosylation of mitochondrial protein
• Elevated blood ammonia and amino acids

14
Cyanide chronic exposure

• Headaches, weakness, changes in taste and smell,
  irritation of the throat, vomiting, effort
  dyspnea, lacrimation, abdominal colic, precordial
  pain, and nervous instability.

15
Mustard Gases

• First synthesized in 1859
• There are two types of mustards the sulfur
  mustard and the nitrogen mustard and both share
  common chemistry in the formation of cyclic onium
  cation and free chloride anion
• Both liquid and vapor forms are readily soluble
  in oils, fats and organic solvents, can be
  quickly absorbed through the skin

16
Mustard Gases Mode of action

• 2-4 hours experience chest tightness, sneezing,
  lacrimation, rhinorrhea, epistaxis, hacking cough
• Vesicant (blistering) properties, 2-3 days later.
• Immediate exposure determination upon detection
  of garlic/onion-like odor
• No effective medical treatment due to nonspecific
  alkylating nature of agent
• http//www.opcw.org/resp/html/mustard.html

17
Mustard gas

• More individuals have died of mustard gas than
  any other chemical agent or toxin
• Most of these deaths happened during WWI
• Emergency care effective less than 3 of WWI
  casualities results in death.
• http//www.opcw.org/resp/html/mustard.html

18
Mustards Decontamination

• Efforts must be made to treat the symptoms. By
  far the most important measure is to rapidly and
  thoroughly decontaminate the patient and thereby
  prevent further exposure. This decontamination
  will also decrease the risk of exposure to staff.
  
• Clothes are removed, the skin is decontaminated
  with a suitable decontaminant and washed with
  soap and water. If hair is suspected to be
  contaminated then it must be shaved off. Eyes are
  rinsed with water or a physiological salt
  solution for at least five minutes.

19
Anticholinesterase chemical classes

• Organophosphorus Esters
• Carbamate Esters
• Organophosphorus ester insecticides were first
  synthesized in 1937 by a group of German chemists
  led by Gerhard Schrader

20
Inhibitors of acetylcholinesterase

• Soman, Sarin and VX these chemicals strongly bind
  to acetylcholinesterase and effectively cause the
  over stimulation of nicotinic and muscarinic
  receptor by the lack of acetylcholine breakdown

21
SOMAN

• Soman half-life is 82 hours at pH 7.0, 20 C
• Liquid and gaseous forms are odorless and
  colorless
• Can be absorbed through the skin but generally
  considered non-persistent

22
SARIN

• Evidence of sarin usage by Iraq in 1988 against
  Kurdish villages in northern Iraq.
• Odorless and colorless chemical can be absorbed
  through the skin, non-persistent
• 1995 Tokyo Sarin attack by Aum Shinrikyo
  religious cult

23
VX gas

• Most potent chemical nerve agent with highest
  dermal absorption rate
• Chemical is odorless and colorless gas
• VX droplets would remain on shrubbery or other
  surface for about a week. In the absence of
  sunlight, toxicant has a half-life of 996 hours,
  pH 7, 25 C.

24
Chemical Nerve Agents Clinical symptoms

• Eye Miosis, dim vision or blurred vision
• Nose Rhinorrhea
• Mouth Excessive salivation
• Pulmonary tract Bronchoconstriction and
  secretions, cough, complaints of tight chest,
  shortness of breath
• Gastrointestinal increase secretions, vomiting,
  diarrhea, abdominal cramps, pain
• Skin Excess sweating
• Muscular twitching of muscle groups, flaccid
  paralysis, twiching
• Cardiovascular decrease or increase in heart
  rate
• Central nervous system loss of consciousness,
  convulsions, depression of respiratory center to
  produce apnea, coma

25
Treatment of Nerve Agents

• Atropine (muscarinic cholinergic antagonist) is
  the standard treatment applied individuals
  showing symptoms of sweating, dilation of the
  pupil and salivation. Intravenous application of
  atropine is administered every 20-30 minutes
  until symptoms disappear. In addition,
  Pralidoxime administration (2PAM-Cl) has also
  been indicated.
• Prophylactic deployed during the Persian Gulf War
  consisted of pyridostygmine-bromine compounds

26
Decontamination and isolation

• Generally all chemical agents noted are
  susceptible to hypochlorite treatment. For
  environmental decontamination consider 10
  hyperchlorite application. For skin, 0.5
  hyperchlorite application has been suggested.
• Note that for chlorine and G-agents are generally
  too volatile to remain on the skin long enough to
  allow absorption of much of the deposited dose
  and are too polar to penetrate the skin well.
  However, if agent is placed on clothing and
  covered it would penetrate the skin.

27
Details about chemical agents

• Cyanide, Mustard gas, Soman, Sarin and VX gases
  are difficult to handle due to the low vapor
  pressure and susceptibility to environmental
  conditions
• Open spaces with wind influence will quickly
  dilute toxic gases (except for VX) and most
  agents are susceptible to ultraviolet light
  inactivation over time. The problem are closed
  spaces such as buildings, gyms, convention halls.
  These areas require physical decontamination or
  increased ventilation actions. Note VX always
  requires inactivation for the environmental
  surroundings.
• Deployment would not involve an conventional
  explosive device but rather a pressure cylinder
  mechanism or glass container release in the HVAC
  intake for silent aerosol exposure

28
Lethal Concentrations for humans (LCt50)

• Hydrogen cyanide 2500 to 5000 mg x min per cubic
  meter
• Sarin 100 mg x min per cubic meter
• Soman 50 mg x min per cubic meter
• VX 10 mg x min per cubic meter
• Unlike toxins, Sarin, Soman, VX, should not be
  treated with soap and water for skin exposure
  instead use 0.5 hypochlorite solution if
  available. Skin absorption too quick.

29
Toxins as Weapons of Mass Destruction

• Botulinum Toxin
• Most potent toxin known to man
• Toxin is produced by a bacteria
• Ricin Toxin
• Recent events involving ricin
• Toxin is produced by a plant
• T-2 Mycotoxins
• Difficult to detect (not recognized by M8 paper
  or M256 kit used for Mustard gases
• Toxin is produced by a fungus

30
Botulinum toxin

• Clostridium botulinum
• Anaerobic, gram positive, rod shaped bacteria
• Food poisoning cases
• LD50 is 0.001 ug/kg, most potent toxin known to
  man
• FDA approved Botox
• http//microvet.arizona.edu/Courses/MIC420/lecture
  _notes/clostridia/clostridia_neurotox/gram_c_botul
  inum.html

31
Botulinum Toxin Clinical Symptoms

• Ptosis, generalized weakness, dizziness, dry
  mouth and throat, blurred vision and diplopia,
  dysarthria, dysphonia, and dysphagia followed by
  symmetrical descending flaccid paralysis and
  development of respiratory failure. Symptoms
  begin as early as 24-36 hours but may take
  several days after inhalation of toxin.

32
Botulinum Toxin Medical Treatment

• Treatment Intubation and ventilatory assistance
  for respiratory failure. Tracheostomy may be
  required. Administration of heptavalent botulinum
  antitoxin (IND product) may prevent or decrease
  progression to respiratory failure and hasten
  recovery.

33
Botulinum Toxin Decontamination and Isolation

• Standard Precautions for healthcare workers.
  Toxin is not dermally active and secondary
  aerosols are not a hazard from patients.
  Hypochlorite (0.5 for 10-15 minutes) and/or soap
  and water.

34
Differences between chemical nerve agents and
Botulinum toxin

• Chemical Agent
• Minutes
• Convulsions, Muscle twitching
• Ocular Small pupils
• Atropine/2-PAM-Cl responsive

• Botulinum toxin
• Hours (12-48)
• Progressive paralysis
• Ocular Large pupils
• Atropine/2-PAM-Cl no effect

35
Ricinus communis plant
36
Bean Pods

• Seed color varies from white to brown with wave
  patterns
• http//waynesword.palomar.edu/plmar99.htmflow

37
Castor Beans

• Worldwide one million tons of castor beans are
  processed annually in the production of castor
  oil (waste mash is 5 ricin by weight)
• Castor oil used as a mechanical lubricate,
  contains no ricin
• http//museum.gov.ns.ca/poison/castor1.htm

38
RICIN OVERVIEW

• Ricin is a heterodimeric protein toxin, 64Kd.
• The ricin A chain is able to cross the membrane
  of intracellular compartments to reach the
  cytosol where it catalytically inactivates
  protein synthesis. It is linked via a disulfide
  bond to the B chain, a galactose-specific lectin,
  which allows ricin binding at the cell surface
  and endocytosis.
• Cancer and autoimmune treatment applications

39
Ricin History and Significance

• Assassination of Bulgarian exile Georgi Markov in
  London (1978)
• Minnesota Patriots Council (1994 and 1995) and
  Thomas Leahy, Wisconsin (1997)
• Deborah Green, Kansas (1995)
• al Qaeda cell, London (2003)

40
Ricin Toxicology

• Potent protein and DNA synthesis inhibitor
• LD50 for mice is 3.0 ug/kg
• Comparative lethality LD50 for Botulinum toxin
  (bacterium) is 0.001 and for VX gas (chemical
  agent) is 15.0
• LD50 for humans is uncertain and varies with
  route of entry (ricin vs ricinine)

41
Ricin Agent Characteristics

• Ricin is environmentally stable with 3 day
  survival in dry conditions
• No person to person transmission
• Lethality is high with death occurring 10-12 days
  for ricin ingestion and 3-4 days for inhalational
  exposure

42
Ricin Identification

• Gold Standard technique is enzyme linked
  immunosorbent assays (ELISA)
• -antigen detection
• -IgG immunoassay
• -IgM immunoassay

43
Ricin Prophylaxis

• There is currently no commercial vaccine or
  prophylactic antitoxin available for human use
  albeit animal immunization studies have been
  promising
• Protective mask and engineering controls are
  currently the best protection

44
Inhalational ricin exposure Signs and Symptoms

• 4 to 8 hours Acute onset of fever, chest
  tightness, cough, dyspnea, nausea and arthralgias
  
• 18-24 hours Airway necrosis and pulmonary
  capillary leak leading to pulmonary edema
• 36-72 hours severe respiratory distress and
  death from hypoxemia

45
Ricin Medical Sampling

• Early Post-exposure (0-24 h) nasal swabs,
  induced respiratory secretions for PCR
  (contaminating castor bean DNA) and Serum for
  toxin assays
• Clinical (36-48 h) serum for toxin assay and
  tissues for immunohistological stain in pathology
  samples
• Postmortem (gt6 days) Serum for IgM and IgG

46
Ricin Treatment

• Ingestional entry Gastric lavage and cathartics
  are indicated. Charcoal application is of little
  value for large molecules such as ricin
• Inhalation entry Pulmonary edema treatment and
  supportive management

47
Ricin Decontamination

• Ricin inactivation can be accomplished with
  bleach (1 sodium hypochlorite, 20 min) or
  autoclave treatment (80C for 10 min)
• Intact skin surface decontamination use soap and
  water (dilution).

48
T-2 Mycotoxins

• Trichothecene (T-2) mycotoxins produced by the
  fungi of genus Fusarium (common grain mold)
• Extremely stable in the environment
• Toxin is dermally active causing blisters
  (minutes to hours after exposure)

49
T2 History and Significance

• Shortly after WWII, flour contaminated with
  Fusarium unknowingly baked into bread and
  ingested by civilians. Exposed individuals
  developed a protracted lethal illness called
  alimentary toxic aleukia (ATA).
• Yellow rain incidents in Laos (1975-81),
  Kampuchea (1979-81) and Afghanistan (1979-81).

50
T2 Toxin Characteristics

• Trichothecene are relatively insoluble in water
• Compounds are extremely stable to heat and
  ultraviolet light inactivation
• Bioactivity retained even after standard
  autoclaving (inactivation requires 1500 F for 30
  minutes)
• Hypochlorite solution alone does not inactive the
  toxins
• Toxin rapidly inhibit protein and nucleic acid
  synthesis

51
T2 Clinical Features

• Routes of exposure penetration through the
  skin, inhalation and ingestion.
• Contaminated clothing can serve as a reservoir
  for further toxin exposure
• Early symptoms (minutes after skin exposure)
  burning skin, redness, tenderness, blistering and
  progression to skin necrosis with leathery
  blackening and sloughing of large areas of the
  skin
• Pulmonary/tracheobronchial toxicity produces
  dyspnea, wheezing and cough.
• Gastrointestinal toxicity causes pain and blood
  tinged saliva and sputum
• Death may occur in minutes, hours or days
• Most common symptoms vomiting, diarrhea, skin
  involvement with burning pain, redness, rash or
  blisters, bleeding and dyspnea.

52
T2 DIAGNOSIS

• Physical clues yellow, red, green or other
  pigmented oily liquid
• Contact with the skin (unlike ricin) forms
  characteristic symptoms
• Generally considered odorless
• Serum and urine should be collected to be sent to
  a reference lab for antigen detection (gas liquid
  chromatography-mass spectrometry technique)

53
T2 MEDICAL TREATMENT

• Toxin inactivation requires 0.1M NaOH added to 1
  hypochlorite solution for a duration of one hour.
• No specific antidote or therapeutic regimen is
  currently available.
• Exposed individuals remove clothing, wash skin
  with soap and water.
• Standard burn care is indicated for cutaneous
  involvement
• Toxin ingestion use superactivated charcoal
• Aerosol attack respiratory support may be
  required, rinse out eyes with saline or water.
• Only physical protection of the skin, mucous
  membranes and airway are the only proven
  effective methods of protection during an attack.

54
Text References

• Klaassen, Curtis D. (1996) Casarett and Doulls
  Toxicology, The Basic Science of Poisons, fifth
  edition. The McGraw-Hill Companies, Inc.
• Somani, Satu M. (1992) Chemical Warfare Agents,
  Academic Press, Inc.
• Satellite Broadcast September 26-28, 2000
  Biological Warfare and Terrorism, Medical Issues
  and Response (Student Material Booklet).
  Sponsored by the United States Army Medical
  Research Institute of Infectious Diseases and the
  Food and Drug Agency

55
Acknowledgements

• Gulf War Syndrome Research
• UT Southwestern Department of Epidemiology
• Christopher Sinton, PhD.
• Robert Haley, MD.
• Ricin Research Endeavors
• UT Southwestern Cancer Immunobiology Center
• Joan Smallshaw, PhD.
• Ellen Vitetta, PhD.