George R. Famini, PhD Chemical Preparedness and Defense Consultant 1 *CTRA = Chemical Terrorism Risk Assessment 2 Relative Risk High Medium Low • Toxic industrial chemicals • Chemical warfare agents • Chemical warfare agents (TICS) that are easily that require synthesis that require greater skill in accessible • TICS that have moderate synthesis and production • TICS that are produced and toxicity but are readily • TICS that have lower transported in large available toxicity or are more quantities • Other pesticides that are of difficult to acquire • OP Pesticides that are high or moderate toxicity • Biological agents that are available in large quantity • Biological agents that are not readily available in the • Biological agents that are available in the environment available in the environment, but require • Biological agents that have environment, can be greater technical skill to relatively higher LD50s produced using low to produce and disseminate • Radiological agents with moderate technical effectively low production potential capabilities and have a low or environmental stability high mortality associated • Radiological agents with infection (i.e., low LD50) • Nuclear detonation (consequence driven) 3 Chemical Uses/Misuse are in the News Items Oct-Dec news every day 120 Events in Syria/Iraq is driving 100 awareness up 80 Toxic Industrial Chemicals are 60 pervasive and commonly available 40 20 Common household products can be 0 used to make toxic chemicals 4 Toxic Chemical Taxonomy Toxic Industrial Chemicals Hemolytic Pharmaceuticals Encephalpothy Sympathomimetic Chemical Agents Irritant/ Opioid Corrosive Metabolic Pulmonary Vesicants Blood Cholinergic Convulsant Anticoagulants Pesticides 5 What Do We Worry About? Pesticides Toxic Industrial Chemicals Chemical Warfare Agents Sulfur Mustard Pharmaceuticals VX Cl2 HCN TETS Fentanyl Phorate Diacetyl morphine Nitrogen Mustard Carbaryl (Sevin) Methylcyclohexyl Methanol Sarin 6 Nerve agents are potent acetylcholinesterase inhibitors causing the same signs and symptoms regardless of the exposure route. However, the initial effects depend on the dose and route of exposure. Children are much more vulnerable than adults to nerve agent toxicity. Manifestations of nerve agent exposure include: ◦ Neuromuscular - pinpoint pupils (highly indicative of nerve agent exposure in a mass casualty situation), muscle twitching, confusion, seizures, flaccid paralysis, and coma. ◦ In many instances children present with only neurological signs and symptoms. ◦ Pulmonary - chest tightness, wheezing, shortness of breath, respiratory failure. ◦ Gastrointestinal - nausea, vomiting, abdominal cramps, involuntary defecation. ◦ Other - runny nose, excessive salivation and sweating, and urination. 7 Nerve agents (NAs) are the most toxic of the known chemical warfare agents. They are chemically similar to organophosphate pesticides (OPs) and exert their biological effects by inhibiting acetylcholinesterase enzymes. Nerve agents can cause loss of consciousness and convulsions within seconds and death from respiratory failure within minutes of exposure. Nerve agent vapor is readily absorbed by inhalation and ocular contact and produces rapid local and systemic effects. Two Types of Nerve Agents Volatile Agents ◦ G-type agents (Tabun, Sarin, Soman, CycloSarin) ◦ Relative high vapor pressure, Primarily a vapor hazard, non-persistent ◦ Usually disseminated as rapidly evaporating liquid aerosol; Hydrolyzes rapidly in water Low Volatility Nerve Agents ◦ Mostly V series agents; very low vapor pressure; Disseminated as liquid aerosol drops ◦ Persistent, will remain on ground will a little evaporation (still a vapor threat) Liquid nerve agent is readily absorbed through the skin; however, effects may be delayed for several minutes to up to 18 hours. Taken from https://chemm.nlm.nih.gov 8 Ethyl {[2-[di(propan-2-yl) amino] ethylsulfanyl} methylphosphinate Classified as a weapon of mass destruction Production and stockpiling of VX was outlawed by the Chemical Weapons Convention of 1993. VX is one of a family of organophosphates, known as phosphonothiolates V series developed in the late 1940s by the British as pesticides. VX selected by the United States for mass production as its second generation nerve agent in 1958. USSR develop VR as their V agent. VX may have used against the Kurds in Northern Iraq. In the early 1990s VX was synthesized and used to commit assassinations by the Aum Shinrikyo organization in Japan. 9 Most States that have, or had offensive programs, know how to produce and weaponize VX or other V series agents ◦ Production is complicated Small scale application (assassination) is relatively simple VX would require significant effort for most terrorist groups ◦ Toxic Industrial Chemicals are most attractive (even for State programs) ◦ G agents are easier to synthesize, does not require Scheduled chemicals 10 Nerve Agent enters the body Atropine Nerve Agent Binds at the esteratic site of AChE, removes Acetyl preventing AChE to react with Acetyl Choline Choline Acetyl Choline builds up in the synapse At this point, the Nerve Agent reaction is reversable and the AChE can be reactivated After some time (depending on series and alkyl Oxime group), the Nerve Agent “ages” (expelling the alkyl X reactivates AChE group), and the reaction becomes irreversible 11 12 VR VG VM VE VX 13 LCt50: 25-50 mg-min/m3 ECt50 (severe): 22.2 mg-min/m3 ECt50 (mild): 0.17 mg-min/m3 LD50 (percutaneous): 262 mg/70 kg man ED50 (severe percutaneous injury): 150 mg /70 kg man[17] No VR toxicity estimates are available for humans, but the VR subcutaneous LD50 in guinea pigs is 11.3 μg/kg, similar to the VX LD50 of 8.9 μg/kg. Lethal human VR doses by other routes are expected be similar to those for VX There are no reliable human toxicity estimates for the other V Agents, although they are expected to be similar. 14 Aerosol Inhalation ◦ Readily absorbed from the respiratory tract as a liquid aerosol. ◦ Heavier than air. Liquid Skin/Eye Contact ◦ Readily absorbed from the skin and eyes. ◦ Ocular effects may result from both direct contact and systemic absorption. ◦ Effects of dermal exposure may be delayed for several hours, depending on dose Liquid Ingestion ◦ ingestion is expected to be relatively rare compared to inhalation exposure or dermal contact. ◦ VX is readily absorbed from the GI tract and are highly toxic. 15 SLUDGE Salivation: stimulation of the salivary glands Lacrimation: stimulation of the lacrimal glands (tearing) Urination: relaxation of the internal sphincter muscle of urethra, and contraction of the detrusor muscles Diarrhea: Gastrointestinal distress: Smooth muscle tone changes causing gastrointestinal problems, including cramping Emesis: Vomiting An extension is SLUDGEM, where the additional M indicates: Miosis: stimulation of the pupillary constrictor muscles • Severe symptoms - these include unconsciousness, convulsions, apnea, and flaccid paralysis. • Mild/ Moderate symptoms - these include localized swelling, muscle fasciculations, nausea and vomiting, weakness, shortness of breath. • Delayed Effects from skin exposure to liquid nerve agent may not develop for up to 18 hours following exposure. 16 The diagnosis in a severely intoxicated individual is straightforward. The combination of miosis, copious secretions, bronchospasm, generalized muscle fasciculations, and seizures is characteristic. Look carefully for miosis (if present will be helpful). Miosis may not be present initially following a low volatility nerve agent exposure. A mild vapor exposure may mimic a child having allergic rhinitis/conjunctivitis. A mild vapor may present with only visual complaints such as narrowing of the visual field or a sense that everything is getting dark. GI symptoms by themselves could be confusing and they could be the only presenting signs. Opiod abuse can include miosis, apnea, seizures etc. 17 In the U.S., currently two atropine/pralidoxime autoinjector formulations exist: ◦ Mark 1 Kit - each kit contains one 600 mg pralidoxime autoinjector, one 2 mg atropine autoinjector ◦ Duodote - a single autoinjector contains approximately 600 mg of pralidoxime and 2 mg of atropine Requires ◦ AChE reactivator: generally an oxime: Pralidoxime, HI-6, HLo, ◦ Acetyl Choline scavanger: Atropine Anticonvulsant often benefical ◦ In most cases, an anticonvulsant (diazepam or midazolam) is required to control seizures Mild effects: ◦ Miosis alone ( no respiratory symptoms)- No antidotes. However, if eye/head pain or N&V (in the absence of other systemic signs suggesting a liquid exposure) are severe, use atropine ophthalmic drops. ◦ Miosis and severe rhinorrhea - Atropine (use autoinjectors, if available). 18 Oximes critical for reactivation of AChE until body can create more ◦ Pralidoxime most commonly used ◦ HI-6 being used by UK and Canada ◦ Hlo-7 being used in Germany and Europe ◦ MMB-4 in Advanced Development in U.S. to replace Pralidoxime Used in conjunction with Atropine, which scavenges acetyl choline 19 VX is very dangerous to the user. It is possible a binary process was used. During the 1970s and 19802, U.S. developed a “binary” process for both G agents and V agents. Binary weapons mix two non-toxic (or less toxic) reactants at the point of delivery to rapidly generate the toxic agent. For VX2 ◦ O-Ethyl O-2-diisopropylaminoethyl methylphosphonite (QL) is in container 1 ◦ Elemental sulfur is in container 2 ◦ When mixed, VX is produced as about a 30-65% yield