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Weapons of Mass Destruction: Chemical Agents and Toxins

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Title: 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.
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