warfare, terrorism and other - acmt€¦ · biological warfare botulinum toxins vaccine pentavalent...

Terrorism / Hazmat

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Warfare, Terrorism and Other

J. Dave Barry Naval Medical Center Portsmouth

Portsmouth VA

2012 ACMT Toxicology Board Review Course

The Core Content of Medical Toxicology


 Chemical  Nuclear  Biological  Hazardous Materials

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Chemical Agents

 Nerve agents  Blister agents  Incapacitating agents  Riot control agents  Pulmonary agents  Blood Agents (cyanogens)

Chemical Agents Nerve Agents

 History  1930’s – Nazi’s synthesize “G” agents during WWII

 Never used in battle  Tested in concentration camps

 1940’s – Soviet Union begins production after capturing German munitions

 1950’s – US begins production

 1990’s – Aum Shinrikyo Matsumoto ‘94, Tokyo ‘95

 Iraq against Kurds


Goldfrank’s Toxicologic Emergencies – 8th Ed (2006)

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Sympathetic Parasympathetic (cholinergic)

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Aging Half-Life >14h 3h 2-6 min 48h


 Personal Protection  Respiratory  Skin

 Decontamination  Alkaline solutions

 Diluted sodium hypochlorite soln

 Soap & water

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 Treatment  Atropine – combat excess muscarinic Ach

 Goal – dry respiratory secretions

 Diazepam – combat excess nicotinic Ach

 Oximes (Pralidoxime) – combat “aging”

Aging

Half-Time >14h 3h 2-6 min 48h


 Pretreatment  Pyridostigmine

 Carbamate (reversible)  Protect a small % of AchE from irreversible OP aging

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Chemical Agents Blister Agents

 Mustards  Sulfur Mustard (HD)  Nitrogen Mustard (HN)

 Lewisite (L)  Phosgene Oxime (CX)


 History  1917 WWI, Ypres  1930’s Italians vs. Ethiopia  1940’s WWII

 Japanese vs. Chinese  German/Japanese concentration camps

 1960’s Egypt vs. Yemen (alleged)

 1980’s Iraq vs. Iran

High casualty rate, low mortality (>20:1)


Sulfur Mustard (HD

Liquid Pale yellow to dark brown

Garlic, onion or mustard

Hours later

Immediate, but effects delayed til hours later

Fluid filled

2 weeks – 3 years

Lewisite (L)

Liquid Colorless to amber or black

Geranium-like smell

immediate Seconds to minutes

Fluid filled

Days

Phosgene oxime (CX)

Solid or liquid

colorless as solid, yellow-brown as liquid

Irritating Immediate Seconds Solid wheal

2 hours

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Chemical Agents Mustard

 Mechanism  Alkylating agent

 “Cyclization” reactive sulfonium ion  Alkylates sulfhydryl (-SH) and amino

(-NH2) groups

 Depletes glutathione  Increased oxidative stress


 Clinical Effects  Vapor or liquid exposure  Cellular damage w/i 1-2 min  Clinical effects 2-48hrs (usually 4-8hrs)

 Skin  Erythema vesicles blisters/bullae

 Eye  Range: Mild severe conjunctivitis  ‘legal’ blindness possible

 Airways  Bronchospasm, pulmonary edema  Obstruction, hemorrhage in severe cases


 Clinical Effects  Skin  Eye  Airways  GI

 N/V, GI bleed

 Systemic  BM suppression/immunosuppression

 With high doses

 IARC Group I – respiratory cancer

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 Diagnosis  M8, M9 paper, etc  Thiodiglycol

 Urine, blood

 Treatment  Decontamination  Supportive/symptomatic care  No antidote


 Decontamination  Remove large globs or liquid  Soap and water, diluted hypochlorite  Military self decon kits

Chemical Agents Lewisite

 History  less persistent alternative to mustard agents  No confirmed battlefield use

 Mechanism  Unclear

 similar to other arsenicals?  Inhibition of pyruvate dehydrogenase  Inhibition of other lipoamide enzymes

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Chemical Agents Lewisite

 Clinical Effects  Immediate effects (unlike mustard)

 Similar to mustard  Skin – erythema, vesicles, blisters

 Eyes - conjunctivitis

 Airways – MM irritation, pulmonary edema

 Treatment  Same as mustard  BAL (British Anti-Lewisite) (dimercaprol)

 Topical / systemic

Chemical Agents Phosgene Oxime

 Background  No battlefield use  Penetrates garments more quickly than other

agents  Rapid onset severe and prolonged effects

 Mechanism  Unclear  Not a true vesicant  Irritant or “nettle” agent

Chemical Agents Phosgene Oxime

 Clinical Effects  Immediate severe tissue damage

 Skin – erythema, wheals, urticaria

 Eyes – conjunctivitis

 Airways – pulmonary edema

 Treatment  Supportive  No antidote

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Chemical Agents Incapacitating Agents

 US experimented with multiple agents

 Antimuscarinics felt to be most promising

 BZ (3-quinuclidinyl benzilate)

 Physostigmine is potential antidote

 Opioids  Kolokol-1 (fentanyl analogue)

 2002 Chechen Moscow Theatre Siege

Chemical Agents Riot Control Agents

 CN (chloracetophenone) Mace®

 CS (o-chlorobenzilidene malenonitrile)

 Capsaicin (“pepper spray”)

 Chloropicrin (trichloronitromethane)

 DM (adamsite)(vomiting agent)

Chemical Agents Riot Control Agents

 OC - Capsaicin (“pepper spray”)  better safety margin / more potent  Release of Substance P - “neurogenic inflammation”

 depletion

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Chemical Agents Pulmonary Agents

 Phosgene (CG)  Diphosgene (DP)  Chlorine (Cl)

 Nitrogen Oxides (NOx)  Perfluoroisobutylene (PFIB)

Chemical Agents Pulmonary Agents

Chlorine (Cl) Yellow-green Gas, with pressure and cooling can be liquid

Strong bleach Intermediate Immediate irritation, pulmonary edema 2-24hrs later

Phosgene (CG)

Colorless or white to pale-yellow cloud

Gas, with pressure and cooling can be liquid

Freshly mown hay, green corn

Poor Delayed up to 48hrs (usually 2-6 hrs)

Diphosgene (DP)

Colorless gas Freshly mown hay, green corn

Poor Delayed up to 48hrs (usually 2-6 hrs)

Nuclear/Radiological

 Atomic Radiation Primer  Measurement  Acute Radiation Syndrome/Dosimetry  Treatment of Radiation Injuries  Scenarios  Specific Radionuclides

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Nuclear/Radiological Atomic Radiation Primer

 Nonionizing radiation  Doesn’t have enough

energy to disrupt atoms or molecules

 Ionizing radiation  Radiation with enough

energy to disrupt an atom or molecule that it hits


 Ionizing Radiation Effects  DNA effects

 Repairable Damage  Mutations  Cell Death


 Ionizing Radiation Effects  DNA effects

 Repairable Damage  Mutations  Cell Death

 Free Radical Formation  Hydroxyl free radicals

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 Ionizing Radiation Effects

 Dose absorbed depends on:  Time  Distance (1/R2)  Shielding


Nuclear/Radiological Measurement

Geiger Counter

Gamma Spectroscopy

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Nuclear/Radiological Acute Radiation Syndrome

Nuclear/Radiological Acute Radiation Syndrome

 CXR – 0.25 mRem  Abd CT – 5-60 mRem  Whole body dose limit – 5 Rem/yr

0.7-10 Gy

70-1000 Rads

10-50 Gy

1000-5000 Rads

>50 Gy

>5000 Rads

Nuclear/Radiological Dosimetry

 Nonspecific/GI symptoms (time to vomit)  <0.7Gy (70Rads): no effects  1-2Gy (100-200Rads): vomiting in 50% w/i 6hrs  3Gy (300Rads): vomiting w/i 4hrs LD50/60

without medical care

 8Gy (800Rads): early, severe vomiting

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 Lymphocyte reduction  Drop in lymphocytes q6hrs  Dose � rate of decline of

lymphocytes


 Chromosomal cytogenetics  # abberations �

dose

Nuclear/Radiological Treatment

 Treat conventional (lifethreatening) injuries first!

 Decontaminate (if necessary)  External decon (remove clothes, decontaminate wounds first)  Internal decon

 Dosimetry screen  Cbc w diff q6  Absolute lymphocyte count (ALC)

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 Internal decontamination  Antacid (decrease absorption)

 Precipitate to insoluble salt

 Saturate critical organ with stable isotope  KI (I131)

 Chelation  DTPA (239Pu), prussian blue (137Cs), BAL, etc.

 Catharsis (decrease residence time)


 Supportive care  Antimicrobials, antiemetics, anxiolytics,

antidiarrheals, fluids, electrolytes, analgesics, burn therapy, psychosocial care

 Surgical intervention in first 36hrs

 Stimulation of the hematopoetic system  cytokines, colony stimulating factors

Nuclear/Radiological Sources/Scenarios

 Simple Radiological Device  RED: radiological emitting device

 Radiological Dispersal Device

 Reactor Accident - ’meltdown’ (criticality)

 Improvised Nuclear Device

 Nuclear Weapon

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Nuclear/Radiological Specific Radionuclides

Radioactive elements act the same in the body as regular elements, they just give off radiation.

 131I  Radon  Depleted Uranium


 Iodine (131I)  T1/2 = 8.03 days, emits beta/gamma radiation  Low levels in hospital nuclear medicine departments  Nuclear reactor accidental releases / nuclear bombs

 Accumulates in thyroid tissue  if incorporated – thyroid damage

 Prophylactic treatment with Potassium Iodide (KI)


 Radon (222Rn)  Heaviest noble gas, alpha/gamma emissions  Product of the natural decay of uranium in soil,

concentrated indoors  Largest component of

background radiation

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 Radon (222Rn)

  incidence of lung cancer (IARC I) (EPA estimates 21,000 deaths/yr)

 Avoidance: enclosed space ventilation, detectors, don’t smoke


 Depleted Uranium (238U)  Natural uranium is mixture of 235U (0.7%) and 238U

(99.3%). Reactors and weapons require the more radioactive 235U

 After enrichment, 238U is left  0.7 X as radioactive as natural uranium  T1/2 45billion years (very little decay)  Alpha, beta, gamma emmitter


 Depleted Uranium (238U)

 Low risk radiation hazard  internal contamination (inhalation) is

controversial.

 Primarily a chemical toxicity (renal toxicity)

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Biological Warfare

 Toxins  Bacteria  Viruses

Biological Warfare Toxins

 Botulinum Toxins  Ricin  Staphylococcal Enterotoxin B (SEB)  T-2 Mycotoxins

Biological Warfare Botulinum Toxins

 Produced by Clostridium Botulinum  7 antigenic types: A-G

 Military relevance  Most potent toxins known  Easily produced  Weaponized by several countries

 Soviet Union, Iran, Iraq, North Korea, Syria  1960’s US – Agent X  Terrorists – Aum Shinriky� (1990-1995)

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 Inhibits Ach release at peripheral NMJ  Heavy chain binds to cell membrane, endocytosis

allows entry to cell  Light chain cleaves specific sites of SNARE proteins,

inhibiting exocytosis and Ach release  Doesn’t cross BBB

JAMA. 2001;285:1059-1070


 Foodborne: toxin ingestion after production by bacteria in (canned) food

 Infant: intestinal colonization

 Wound: colonization

 Inhalational: weaponized agents

 All have similar clinical picture:  Progressive descending flaccid paralysis

 Always starts with cranial nerves/bulbar involvement


 Diagnosis  Mouse neutralization assay  ELISA  Wound or stool Culture

JAMA. 2001;285:1059-1070

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 Treatment  Supportive care  Antitoxin (equine)

 Bivalent (A,B)  Type E

 Immune Globulins (BIG)  BIG (BabyBIG)  Heptavalent (A-G) (dBIG)(Fab2 fragment)


 Vaccine  Pentavalent (A-E) (IND)

Biological Warfare Ricin

 Ricinus Communis (castor Bean)  attractive as a biological weapon since it’s

widely available, cheap and has a heat stable toxin

 History  Compound W (WWII)  Georgi Markov (1978)

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 Mechanism  Inhibits protein

synthesis  B Chain

 Binds to cell surface, undergoes endocytosis to enter cell

 A Chain  Binds and inhibits

60S ribosome, inhibiting protein synthesis


 Symptoms vary based on route of exposure

 In general: Local tissue irritation regional lymph node necrosis multi-organ failure

 PO  N/V/D, vascular collapse, shock

 IM  Local pain, regional painful swollen lymph nodes, multi-

organ failure

 Inhalational  Pulmonary edema, pneumonia, mediastinal lymphadenitis,

multi-organ failure


 Diagnosis  ELISA assay of nasal swab, blood or other fluids

 Treatment  Supportive care

 AC may bind orally ingested toxin  No antidote

 Prophylaxis  None, vaccine being investigated

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Biological Warfare Staphylococcal Enterotoxin B

 Military relevance  potent compared to chemical agents  Incapacitating (usually not lethal)

 Studied by US in 1960’s as a biological incapacitant (PG)


 “superantigens”  Profound activation of the immune system

 Bind monocytes (MHC Class II molecules) - stimulation of helper T-cells - massive release of cytokines (interferon gamma, interleukin-6, TNF-�) - intense inflammatory response


 GI Syndrome  Identical to staph food poisoning

 Pulmonary Syndrome  inhalation of weaponized toxin

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Biological Warfare Bacteria

 Anthrax  Plague  Tularemia  Brucellosis  Q Fever

Biological Warfare Anthrax

 Bacillus anthracis  Gram +, capsulated, spore-forming bacillus

 Virulence factors  Antiphagocytic capsule  Lethal toxin  Edema toxin


 Virulence factors  Antiphagocytic capsule

 No virulence without this capsule

 Lethal toxin  Zinc metalloprotease

 Stimulates macrophages to release TNF and IL-6

 Edema toxin  Calmodulin-dependent adenylate cyclase

  cAMP leads to massive edema and impaired neutrophil function

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 General Pathophysiology  Spores exist worldwide in the soil  Spores enter the body, are ingested by

macrophages and germinate  Incubation period 1-6 days

 Bacteria multiply in local lymph nodes leading to:  edema,  hemorrhage  tissue necrosis


 Cutaneous  Inhalational  GI


 Cutaneous  95% of cases, 2000 annually worldwide  Vesicle – painless necrotic ulcer –

lymphadenitis – black eschar – scar  Septicemia is rare.

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 Cutaneous  Inhalational

 Woolsorters disease  Aerosol release from

Biological weapons

 Fever, malaise, myalgia, fatigue chest pain, respiratory distress cyanosis, shock, death

 Wide mediastinum  Hemorrhagic meningitis is common  Anticipated mortality essentially 100%


 Cutaneous  Inhalational  GI

 Rare, but high mortality 25-60%  Ingestion of poorly cooked, contaminated meat  N/V/D, abdominal pain ascites, hematemesis

- toxemia, shock, death


Med Sci Monit. 2003;9(11):RA276-283

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 Immunization  Cell free vaccine

 attenuated, unencapsulated strain

 Main ingredient is ‘protective antigen’  FDA approved for “at risk” populations


 Immunization  Prophylaxis

Med Sci Monit. 2003;9(11):RA276-283

Biological Warfare Plague

 Biologic Warfare History  Crimean port city of Caffa 1346-1347

 First attempt at biologic warfare

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 WWII Japanese Unit 731  Suspected use against the Chinese




 WWII Japanese Unit 731  Suspected use against Chinese

 Soviet Union 1970’s-1980’s  Reported to have genetically engineered, dry,

antibiotic resistant form of plague


 Yersinia pestis  Gram -, nonsporulating, anaerobic bacillus  More deaths than any other infectious agent in

history

 Virulence Factors  Antiphagocytic fraction, pH 6 antigen, Yop H, Yop E, Yop M,

V antigen, plasminogen activator

 environmental signals within the host (pH, temp, etc) induce the synthesis and activity of these factors, contributing to virulence.

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 General Pathophysiology  Introduction by flea, ingestion or inhalation  Initially susceptible to phagocytisis but

induction and synthesis of virulence factors leads to resistance

 Spread to regional lymph nodes

(1-8d incubation)  Septicemia and multi-organ involvement if untreated


 Bubonic  Pneumonic

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 Bubonic  Bubo

 Painful lymphadenopathy (90% inguinal or femoral)

 Constitutional symptoms (F/C, HA, etc)  5-15% develop 2o pneumonic plague


 Bubonic  Pneumonic

 1o: inhalation of aerosols  human-human or weaponized

 2o: hematogenous spread

 Productive cough with blood-tinged sputum  Bilateral alveolar infiltrates


JAMA. 2000; 283:2281-2290

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JAMA. 2000; 283:2281-2290


 Vaccination  Killed whole cell vaccine  Not effective against pneumonic plague

 Other vaccine development underway

Biological Warfare Viruses

 Smallpox  Equine Encephalitis  Viral Hemorrhagic Fevers (VHF)

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Biological Warfare Smallpox

 Variola a poxvirus  large enveloped DNA virus  Certified by WHO as eradicated in 1977

 Military Relevance  Infectious as aerosol  Increasingly naive population (not immunized)  Easy large scale production, stable virus


 Incubation – not contagious, 7-17 days

 Prodrome – viral syndrome, 2-4 days

 Rash – centrifugal, highly contagious

 Vesicular - pustular - umbilicated - scab Scabs form 10-14d after onset of rash

 Recovery – immunity  not contagious once all scabs separate

14-28 d after rash onset

  Centrifugal  Hands/face

  Synchronous  All in same

stage

  Highly contagious by aerosol

  30% mortality in unvaccinated population

Smallpox Rash

Day 3 of rash

Day 5 of rash

Day 7 of rash

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 Complications  Bronchitis, pulmonary edema  Arthritis, osteomyelitis  Encephalitis  Keratitis, corneal ulcer  Infection in pregnancy

 High perinatal fatality



 Lab Diagnosis –  virus isolation from pharyngeal swab or scab

material (PCR, ELISA)

 Treatment  Supportive care  Isolation (and vaccination) of patient and all

contacts for 17 days  Vaccination (w/i 4 days)  VIG (w/i 1 week)  Cidofovir

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 Vaccination  Vaccinia – a poxvirus related to cowpox

 Scarification with a bifurcated needle  Contraindicated in:

 Immunosuppresed  HIV  Eczema  other skin diseases  Pregnancy  Children < 18mo

Hazardous Materials

 Treaties  Incident Command System, Site Safety  National Pharmaceutical Stockpile  Regulatory/Legal Acts

end

Hot Zone Cold Zone WarmZone

Hazardous Materials Control Zones

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health

flammability

instability

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 Chemical  Nuclear  Biological  Hazardous Materials

warfare, terrorism and other - acmt€¦ · biological warfare botulinum toxins vaccine pentavalent...

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