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  Similar process was developed for VR

+ S VX

20  VX is detectable by a number of instruments (field and laboratory) ◦ While vapor/aerosol detection is possible, response will not be immediate, and there may be instrumental “clear down” issues ◦ For most VX scenarios, a liquid detector may be preferable ◦ Some devices, which rely on fragmentation of VX, may not detect some of the VX analogs (such as VR, VM, VE or VG) ◦ Presumptive identification (with a field instrument) is useful, but laboratory confirmation is always needed

 Preferred Detectors: ◦ M8, M9 chemical agent detector paper (liquid agents), ◦ M18A3 chemical agent detectors (vapor), ◦ M256A1 chemical agent detector kit (liquid and vapor), ◦ Draeger CDS Kit (vapor and aerosol), ◦ Chemical Agent Detector C2 Kit (liquid and vapor), ◦ Chemical Agent Monitor (CAM) (vapor)

A comprehensive source for the selection of chemical identification equipment is the Guide for the Selection of Chemical Detection Equipment for Emergency First Responders, Guide 100-06, January 2007, 3rd Edition published by the Department of Homeland Security 21  Was the VX identified from presumptive field analysis or laboratory analysis (or both)?  Are there clinical samples that might be able to be further analyzed? CDC has a method for analyzing AChE bound with Nerve Agent.  Was there any positive detection at the attack site?  Were there any other exposures?  Did the suspects receive any VX exposure?

22 23 CSAC Toxidromes Description Alteration of blood coagulation that results in abnormal bleeding indicated by excessive bruising, and Anticoagulant bleeding from mucous membranes, the stomach, intestines, urinary bladder, wounds, and other body sites such as intracranial and retroperitoneal Inability to use oxygen, leading to acute-onset gasping, convulsions, loss of consciousness, breathing Blood cessation, and cardiac arrest. Over stimulation of cholinergic receptors leading to first activation, and then fatigue of target organs, Cholinergic (CWA) leading to pinpoint pupils (miosis), seizing, wheezing, twitching, and leaking all over. Over stimulation of cholinergic receptors leading to first activation, and then fatigue of target organs, Cholinergic (Other) leading to pinpoint pupils (miosis), seizing, wheezing, twitching, and leaking all over. Central nervous system excitation (GABA antagonism and/or glutamate agonism and/or glycine Convulsant antagonism) leading to generalized convulsions. Primarily impacting on level of consciousness and global central nervous system (CNS) function, without Encephalopathy prominent convulsions or impact on respiratory or cardiovascular systems. Impaired oxygen delivery to cells based on disruption of red blood cell itself (hemolysis) or oxidation of Hemolytic/ Methemoglobinemia hemoglobin (methemoglobinemia) leading to impaired oxygen carrying and releasing capacity. Predominantly composed of inorganic metals/metalloids which act via interference with multiple Metabolic receptors and/or intracellular processes, leading to multiple organ dysfunction. Many of these share early gastrointestinal symptoms, with subsequent hair, nail, kidney, and/or neurological abnormalities. Opioid agonism leading to pinpoint pupils (miosis), and central nervous system and respiratory Opioid depression. Stress- or toxicant-induced catecholamine excess or central nervous system excitation leading to Sympathomimetic/Stimulant confusion, panic, and increased pulse, respiration, and blood pressure INH - Immediate effects to the respiratory/pulmonary tract presenting as nasal and oral secretions, coughing, wheezing, and/or respiratory distress that may progress to rapid systemic toxicity Irritant/Corrosive (to include upper/lower INH ING - Immediate effects to the oropharynx and gastrointestinal (GI) tract presenting as burns, drooling, subdivisions) nausea, vomiting, and diarrhea that may progress to rapid systemic toxicity. TOP - Immediate effects range from minor irritation to severe skin, eye, and mucosal membrane effects, which may progress to rapid systemic toxicity. Vesicant Same as irritant/corrosive

24 Toxidromes/Chemicals

Convulsant Cholinergic (CWA) Cholinergic (Other) “General” Chlorosarin Aldicarb 4-aminopyridine Chlorosoman Anatoxin Bifenthrin Cyclosarin (GF) Carbofuran Hydrazine Diisopropylfluorophosphate (DFP) Chlorfenvinphos Methyl hydrazine Methylphosphonic difluoride (DF Chlorpyrifos Picrotoxin R-33 (R-VX) Dicrotophos TETS Sarin (GB) Disulfoton Soman (GD) Methamidophos “Strychnine” Tabun (GA) Methanesulfonyl fluoride Strychnine VG (Amiton) Methomyl VM (EDEMO) Parathion VX Phorate Encephalopathy Phosphamidon 3-Quinuclidinyl benzilate Sulfotep Dimethylmercury Metabolic Tetraethyl pyrophosphate (TEPP) Tetraethyllead Arsenic trichloride Arsenic trioxide Mercuric chloride Anticoagulant Brodifacoum N-ethylmaleimide Bromadiolone Sodium arsenite Diphacinone Sodium fluoride Sodium selenate Thallium sulfate

“Carbon Disulfide” Carbon disulfide

25 Toxidromes/Chemicals

Sympthomimetic/Stimulant Vesicant Blood (Cyanide-Like)

Caffeine “Delayed” onset 2-fluoroethanol Nicotine Nitrogen mustard (HN3) Acrylonitrile 2,4 – dinitrophenol Sulfur mustard (HD) Aluminum phosphide “Rapid Lewisite” onset Cyanogen chloride (CK) Hemolytic/Methemoglobinemia Lewisite (L) Fluoroacetamide Aniline Hydrogen cyanide Arsine (SA) “Rapid Phosgene Oxime” onset Hydrogen sulfide Ethyl Nitrite Phosgene oxime (CX) Hydroxyacetonitrile Isobutyronitrile Opioid Malononitrile Diacetylmorphine Methyl acrylonitrile Methyl Fluoroacetate Methylthiocyanate Potassium cyanide Propionitrile Sodium azide Sodium fluoroacetate

26 Toxidromes/Chemicals

Irritant/Corrosive - Upper Airway Acrolein Chlorosulfonic acid Hydrogen chloride Silicon tetrachloride Allyl alcohol Cyclohexylamine Isopropyl chloroformate Silicon tetrafluoride Ammonia Diborane Methanesulfonyl chloride Sulfur dioxide Ammonium metavanadate Diphenylchloroarsine Methanethiol Sulfur tetrafluoride Aq. Ammonia Diphenylcyanoarsine (DC) Methyl vinyl ketone Sulfur trioxide Aq. Hydrochloric acid Disulfur dichloride Nitric acid (conc.) Thiophosphoryl chloride bis(Chloromethyl) ether Ethyl chloroformate Nitric oxide Titanium tetrachloride Boron trichloride Ethyl dichloroarsine (ED) Oleum Trichloromethylsilane Boron trifluoride Ethylenediamine Osmium tetroxide Trimethylchlorosilane Boron trifluoride etherate Ethyleneimine (Aziridine) Phenyl isocyanate Vanadium pentoxide Bromomethane Formalin Phosphorus oxychloride Ziram Chloroacetone Hexafluoroacetone Phosphorus trichloride Irritant/Corrosive - Upper Airway – HF Chloromethyl methyl ether Hydrogen bromide Propyleneimine Aq. Hydrogen fluoride (continues in next column) (continues in next column) (continues in next column) Hydrogen fluoride

Irritant/Corrosive – Lower Pulmonary Irritant/Corrosive – Lower Pulmonary “Mid” onset “Delayed” onset 2-butanone peroxide Epichlorohydrin 3-(Triethoxysilyl)propyl isocyanate Adamsite (DM) Ethyl chloroacetate Cadmium oxide Aq. Chlorine dioxide Ethyl isocyanate Methyl isocyanate (MIC) Benzenethiol Ethylene oxide Paraquat Bromine Fluorine Pentacarbonyliron Bromopropyne Hexachlorocyclopentadiene (HEX) Phosgene (CG) Chlorine Hydrogen selenide Tungsten hexafluoride Chloroform Metham-sodium Chloropicrin (PS) Perchloromethylmercaptan Cyclohexyl isocyanate Perfluoroisobutene Dimethyl sulfate Phosphine (continues in next column) α, α-dimethylbenzyl hydroperoxide (DMBHP) 27