Warfare, Terrorism and Other - ACMT€¦ · 1960’s Egypt vs. Yemen (alleged) 1980’s Iraq vs....
Transcript of Warfare, Terrorism and Other - ACMT€¦ · 1960’s Egypt vs. Yemen (alleged) 1980’s Iraq vs....
Warfare, Terrorism and Other
J. Dave Barry Naval Medical Center Portsmouth
Portsmouth VA
2012 ACMT Toxicology Board Review Course
Views expressed are solely those of the speaker and in no way reflect the official policy, position or doctrine of the US ARMY, US NAVY, DOD or the US Government.
The contents of this presentation are not endorsed in any way by the US ARMY, US NAVY, DOD, or the US Government.
Disclosure
The Core Content of Medical Toxicology
Warfare, Terrorism and Other
Chemical Nuclear Biological Hazardous Materials
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
Chemical Agents Nerve Agents
Goldfrank’s Toxicologic Emergencies – 8th Ed (2006)
C
T
L
S
N
N
N
N
M
M
N
ne
ne
Sympathetic Parasympathetic (cholinergic)
M mio
sec
sec
hr
sec
mot
mict
sec
agit
Sz
Fasic
paraly
hr vasoconstr
rr
Aging Half-Life >14h 3h 2-6 min 48h
Chemical Agents Nerve Agents
Personal Protection Respiratory Skin
Decontamination Alkaline solutions
Diluted sodium hypochlorite soln
Soap & water
Chemical Agents Nerve Agents
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
Chemical Agents Nerve Agents
Pretreatment Pyridostigmine
Carbamate (reversible) Protect a small % of AchE from irreversible OP aging
Chemical Agents Blister Agents
Mustards Sulfur Mustard (HD) Nitrogen Mustard (HN)
Lewisite (L) Phosgene Oxime (CX)
Chemical Agents Blister Agents
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)
Chemical Agents Blister Agents
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
Chemical Agents Mustard
Mechanism Alkylating agent
“Cyclization” reactive sulfonium ion Alkylates sulfhydryl (-SH) and amino
(-NH2) groups
Depletes glutathione Increased oxidative stress
Chemical Agents Mustard
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
Chemical Agents Mustard
Clinical Effects Skin Eye Airways GI
N/V, GI bleed
Systemic BM suppression/immunosuppression
With high doses
IARC Group I – respiratory cancer
Chemical Agents Mustard
Diagnosis M8, M9 paper, etc Thiodiglycol
Urine, blood
Treatment Decontamination Supportive/symptomatic care No antidote
Chemical Agents Mustard
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
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
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
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
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
Nuclear/Radiological Atomic Radiation Primer
Ionizing Radiation Effects DNA effects
Repairable Damage Mutations Cell Death
Nuclear/Radiological Atomic Radiation Primer
Ionizing Radiation Effects DNA effects
Repairable Damage Mutations Cell Death
Free Radical Formation Hydroxyl free radicals
Nuclear/Radiological Atomic Radiation Primer
Ionizing Radiation Effects
Dose absorbed depends on: Time Distance (1/R2) Shielding
Nuclear/Radiological Atomic Radiation Primer
Nuclear/Radiological Measurement
Geiger Counter
Gamma Spectroscopy
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
Nuclear/Radiological Dosimetry
Lymphocyte reduction Drop in lymphocytes q6hrs Dose � rate of decline of
lymphocytes
Nuclear/Radiological Dosimetry
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)
Nuclear/Radiological Treatment
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)
Nuclear/Radiological Treatment
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
Nuclear/Radiological Specific Radionuclides
Radioactive elements act the same in the body as regular elements, they just give off radiation.
131I Radon Depleted Uranium
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)
Biological Warfare Botulinum Toxins
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
Biological Warfare Botulinum Toxins
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
Biological Warfare Botulinum Toxins
Diagnosis Mouse neutralization assay ELISA Wound or stool Culture
JAMA. 2001;285:1059-1070
Biological Warfare Botulinum Toxins
Treatment Supportive care Antitoxin (equine)
Bivalent (A,B) Type E
Immune Globulins (BIG) BIG (BabyBIG) Heptavalent (A-G) (dBIG)(Fab2 fragment)
Biological Warfare Botulinum Toxins
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)
Biological Warfare Ricin
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
Biological Warfare Ricin
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
Biological Warfare Ricin
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
Biological Warfare Bacteria
Anthrax Plague Tularemia Brucellosis Q Fever
Biological Warfare Viruses
Smallpox Equine Encephalitis Viral Hemorrhagic Fevers (VHF)
Hazardous Materials
Treaties Incident Command System, Site Safety National Pharmaceutical Stockpile Regulatory/Legal Acts
end
Warfare, Terrorism and Other
Chemical Nuclear Biological Hazardous Materials
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)
Biological Warfare Staphylococcal Enterotoxin B
“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
Biological Warfare Staphylococcal Enterotoxin B
GI Syndrome Identical to staph food poisoning
Pulmonary Syndrome inhalation of weaponized toxin
Biological Warfare Anthrax
Bacillus anthracis Gram +, capsulated, spore-forming bacillus
Virulence factors Antiphagocytic capsule Lethal toxin Edema toxin
Biological Warfare Anthrax
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
Biological Warfare Anthrax
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
Biological Warfare Anthrax
Cutaneous Inhalational GI
Biological Warfare Anthrax
Cutaneous 95% of cases, 2000 annually worldwide Vesicle – painless necrotic ulcer –
lymphadenitis – black eschar – scar Septicemia is rare.
Biological Warfare Anthrax
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%
Biological Warfare Anthrax
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
Biological Warfare Anthrax
Med Sci Monit. 2003;9(11):RA276-283
Biological Warfare Anthrax
Immunization Cell free vaccine
attenuated, unencapsulated strain
Main ingredient is ‘protective antigen’ FDA approved for “at risk” populations
Biological Warfare Anthrax
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
Biological Warfare Plague
Biologic Warfare History Crimean port city of Caffa 1346-1347
First attempt at biologic warfare
WWII Japanese Unit 731 Suspected use against the Chinese
Biological Warfare Plague
Biologic Warfare History Crimean port city of Caffa 1346-1347
First attempt at biologic warfare
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
Biological Warfare 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.
Biological Warfare Plague
Biological Warfare Plague
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
Biological Warfare Plague
Bubonic Pneumonic
Biological Warfare Plague
Bubonic Bubo
Painful lymphadenopathy (90% inguinal or femoral)
Constitutional symptoms (F/C, HA, etc) 5-15% develop 2o pneumonic plague
Biological Warfare Plague
Bubonic Pneumonic
1o: inhalation of aerosols human-human or weaponized
2o: hematogenous spread
Productive cough with blood-tinged sputum Bilateral alveolar infiltrates
Biological Warfare Plague
JAMA. 2000; 283:2281-2290
Biological Warfare Plague
JAMA. 2000; 283:2281-2290
Biological Warfare Plague
Vaccination Killed whole cell vaccine Not effective against pneumonic plague
Other vaccine development underway
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
Biological Warfare Smallpox
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
Biological Warfare Smallpox
Complications Bronchitis, pulmonary edema Arthritis, osteomyelitis Encephalitis Keratitis, corneal ulcer Infection in pregnancy
High perinatal fatality
Biological Warfare Smallpox
Biological Warfare Smallpox
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
Biological Warfare Smallpox
Vaccination Vaccinia – a poxvirus related to cowpox
Scarification with a bifurcated needle Contraindicated in:
Immunosuppresed HIV Eczema other skin diseases Pregnancy Children < 18mo
Hot Zone Cold Zone WarmZone
Hazardous Materials Control Zones
health
flammability
instability
special
Nuclear/Radiological Specific Radionuclides
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)
Nuclear/Radiological Specific Radionuclides
Radon (222Rn) Heaviest noble gas, alpha/gamma emissions Product of the natural decay of uranium in soil,
concentrated indoors Largest component of
background radiation
Nuclear/Radiological Specific Radionuclides
Radon (222Rn)
incidence of lung cancer (IARC I) (EPA estimates 21,000 deaths/yr)
Avoidance: enclosed space ventilation, detectors, don’t smoke
Nuclear/Radiological Specific Radionuclides
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
Nuclear/Radiological Specific Radionuclides
Depleted Uranium (238U)
Low risk radiation hazard internal contamination (inhalation) is
controversial.
Primarily a chemical toxicity (renal toxicity)