Rodencides Handout

Board Review Course 2014

K Babu. 6.22.2014 FIFRA

• US Federal Inseccide, Fungicide, and Rodencide Act (FIFRA, 1947) • Pescides are any “substance or mixture of substances intended for prevenng, destroying, repelling, or migang any pest, and any substance or mixture of substances intended for use as a plant regulator, defoliant, or desiccant” Pescides

• Rodencides • Inseccides • Herbicides • Fungicides Regulaon

• FIFRA rolled out in 1947, with mulple amendments • EPA given scope to enforce FIFRA in 1970 • FDA and EPA set pescide tolerance concentraons • Other acts giving EPA pescide oversight: – Resource Conservaon Act (1972), Comprehensive Environmental Response, Compensaon and Liability Act (CERCLA, also called the "superfund" Act); the Toxic Substance Control Act (TSCA); the Clean Water Act and the Safe Drinking Water Act. Signal Words

• Category I: DANGER (LD50 < 50 mg/kg)

• Category II: WARNING (LD50 50 - 500 mg/kg)

• Category III: CAUTION (LD50 500 - 5000 mg/kg)

• Category IV: CAUTION (LD50 > 5000 mg/kg) http://www.gpo.gov/fdsys/pkg/CFR-2011-title40-vol24/pdf/CFR-2011-title40-vol24-sec156-64.pdf High Toxicity Agents (“Danger”) Barium

• Found in contrast media, depilatories, inseccides and rodencides • Mulple salts with variable solubility. Barium chloride (highly soluble), barium sulfate (low solubility). Barium carbonate (low solubility) = rodencide • 5-10% of ingested barium absorbed • Peak concentraon at 2 hours • Renal eliminaon 20%, rest in feces Barium

• Hypokalemia due to blockade of K recfier current, and increases K permeability of membranes. Intracellular trapping of K. • Barium intravasaon (from enemas, absorpon aer perforaon) has caused cardiovascular collapse • DDx of hypokalemia: Periodic paralysis, hypothyroidism, toluene toxicity, diurecs, Barium - Sx

• GI upset, hemorrhagic gastris • Hypokalemia at 2 hours aer ingeson • Muscle weakness, respiratory failure, dysrhythmias • Associated hyperlactatemia, hypophosphatemia, • Parkinson-like symptoms with MRI findings of bilateral basal ganglia hyperintensity Barium - Tx

• Oral sodium sulfate or magnesium sulfate may prevent absorpon of barium • Aggressive potassium repleon • Hemodialysis or CVVH to remove barium and correct potassium SMFA (sodium monofluoracetate)

• Naturally occurring in gilaar plant (Dichapetalum cymosum) • Compound 1080 • Used in collars to prevent coyote aacks • Odorless and tasteless white powder • Similar pescide, fluoroacetamide, known as Compound 1081 SMFA (Compound 1080)

• Structural analog of acec acid, and irreversible inhibitor of Krebs cycle • Monofluoroacec acid enters mitochondria, complexing with oxaloacetate to form fluorocitrate • Lag to toxicity may be up to 20 hours due to metabolism to fluorocitrate • Fluorocitrate binds aconitase in “suicide inhibion” SMFA (Compound 1080)

• Shi to anaerobic metabolism, accumulaon of glutamate • Resulng hypocalcemia • Resulng hyperlactatemia, hyperammonemia • No significant fluoride toxicity reported aer exposure SMFA (Compound 1080)

• Shi to anaerobic metabolism, accumulaon of glutamate • Resulng hyperlactatemia, hyperammonemia • No significant fluoride toxicity reported aer exposure • Toxicity generally within six hours; asymptomac paents should be observed for 24 hours SMFA (Compound 1080) - Sx

• Voming, abdominal pain, agitaon, seizures, dysrhythmias • Negave inotropic effect • Low systemic vascular resistance despite fluid resuscitaon

SMFA (Compound 1080)

• Hypocalcemia cardinal finding • Elevated creanine, hyperkalemia, acidosis • SMFA and fluoroacetamide can be confirmed in blood and urine by TLC, GC/MS • Elevated serum citrate concentraon • Delayed CT aer exposure may show cerebral atrophy SMFA (Compound 1080) - Tx

• Ethanol and glycerol monoacetate (monacen) used as acetate donors, and may prevent inhibion of aconitase Phosphorus

• Phosphorus = “light bringer” • White phosphorus – spontaneously combusts • Use in incendiary rounds during World War I (Willie Pete round for White Phosphorus) • Used in strike anywhere matches • Occupaonally, associated with phossy jaw (mandibular osteonecrosis) White Phosphorus

• Very reacve • Ignites spontaneously in air

• Forms phosphorus pentoxide (P4O10) • Garlic-like odor • Well-absorbed aer ingeson, dermal exposure (as seen in large BSA burns) • Internally absorbed white phosphorus associated with very high mortality rates Tetramine

• White powder • Found primarily in China • Non-compeve GABA antagonism • Seizures, refractory status epilepcus, coma, cardiac ischemia • Treatment with benzodiazepines, barbiturates, and paralycs (for cessaon of motor acvity) Thallium

• Odorless, colorless powder • Rapid absorpon through skin • Primary eliminaon in feces • Undergoes enterohepac recirculaon

• LD50 10 mg /kg Thallium –Sx

• Immediate – voming, abdominal pain • Within 24 to 48 hours – painful paresthesias of hands and feet • Aer 10 days – alopecia (spares facial hair, lashes, and axillary hair) • Other late findings: psychosis, delirium, Mee’s lines, opc neuris • Sudden cardiac death may occur weeks aer exposure • Neuropsychiatric symptoms may persist Thallium - Tx

• Possible role for acvated charcoal given enterohepac recirculaon • Prussian Blue for decontaminaon – Adult 3 grams d x six weeks – Children (2-12 yo) 1 gram d x six weeks • Potassium diuresis may worsen symptoms • Unknown role for hemoperfusion/ HD Strychnine

• Alkaloid from the seeds of Strychnos nux vomica (tree, nave to India) • Available consumer preparaons (0.3-0.5%), commercial exterminator (5%) • Found as an adulterant in heroin and cocaine • Found in Southeast Asian herbal preparaons Strychnine

• Blocks uptake of glycine (excitatory neurotransmier) • Inhibion primarily at level of postsynapc spinal motor neurons • Rapidly absorbed – symptoms within 15-20 minutes Strychnine - Sx

• “Awake seizures” (spinal seizures) • Trismus, risus sardonicus (sardonic smile), opisthotonos [may appear similar to tetanus] • Individual seizures may be brief, and precipitated by any sensory smulaon • May result in respiratory arrest, lacc acid generaon, acute kidney injury, DIC, hyperthermia Strychnine - Tx

• Nonsmulang environment • Benzodiazepines • Pentobarbital • Paralycs

Metal Phosphides

• Aluminum and Zinc • Used primarily to protect stored grains from rodents • Phosphine gas liberated on contact with water or dilute acids (roen fish odor) • Phosphine may inhibit cytochrome C oxidase, leading to uncoupling of oxidave phosphorylaon Metal Phosphides - Sx

• Ingeson results in severe GI irritaon • Nausea, voming, epigastric pain in virtually all cases; may cause black emesis • Hypotension, tachypnea, acidosis, tetany due to hypocalcemia, palpitaons • Pulmonary edema, jaundice, prolonged QRS • Deaths due to myocardial injury Metal Phosphides - Tx

• Supporve care • Electrolyte and calcium repleon • Immediate cleanup of all body fluids (emesis and stool) since phosphine can be offgassed Vacor (PNU, Pyriminil)

• Released in 1975 as a rodencide that was lethal aer one feeding • Withdrawn in 1979, but reports of toxicity unl 2002 • PNU destroys beta-islet cells leading to DKA • Associated with GI perforaon, pneumonia • Death from DKA or cardiac dysrhythmias within hours • Sequelae include brile DM, postural hypotension, and neuropathies (motor and sensory) Vacor (PNU, Pyriminil)

• Mechanism unknown • Niacinamide analog – interferes with pentose monophosphate shunt, parcularly in brain, liver and pancreac islet cells • Niacinamide (niconamide) could be an andote, but not available • Niacin (niconic acid) has been used instead • 500 mg iv, then 100-200 mg Q4 x 48 hours Moderate Toxicity Agents (“Warning”) ANTU (α-naphthylthiourea)

• Causes pulmonary edema and effusions in rats • Dogs immune to effects • In humans, dyspnea, cyanosis, voming, pulmonary edema and effusions • No deaths reported • Supporve treatment Cholecalciferol (Vitamin D3) • Rodents are extremely sensive to Ca2+ homeostasis • Cholecalciferol increases Ca2+ absorpon from gut and mobilizaon from bone • Ca2+ deposion in mulple organs, and dysrhythmias • Possible hypervitaminosis D with symptomac hypercalcemia • Tx: furosemide, corcosteroids, calcitonin, bisphosphonates, hemodialysis • Normal serum Ca2+ at 48 hours excludes toxicity Low Toxicity Agents (“Cauon”) Warfarin and Superwarfarins

• Superwarfarins = brodifacoum, bromadiolone, difenacoum, and chlorophacinone • All warfarins inhibit vitamin K epoxide reductase and vitamin K reductase • Superwarfarins have longer duraon of effect (weeks to month, versus 5-7 days with

warfarin); T½ brodifacoum = 56 days Warfarin and Superwarfarins

• Effect can be measured with Prothrombin Time (PT) and Internaonal Normalized Rao (INR); usually Q24h aer inial exposure • Normal INR at 48-72h rules out signficant exposure • Superwarfarin exposure may require weeks of vitamin K tx; recommended dose 50-200 mg daily • Serial INRs to assess effecvesness of treatment Bromethalin • Neurotoxin; marketed as green pellets • Metabolized to desmethylbromethalin (more potent) • CNS effects due to uncoupling of mitochondrial phosphorylaon, decreased ATP producon, vacuole development, and decreased nerve conducon • Leads to paralysis and death in rodents • Death reported in young man; cerebral edema • Supporve care, and observaon for 12 hours Red Squill

• Derived from Urginea marima (sea onion) • Cardiac glycosides: Scillaren A and Scillaren B • Potent emec • Cardiac glycoside with symptoms and findings similar to digoxin • Presence of squill may be confirmed with digoxin assays, but level may not correlate with toxicity • Treatment with digoxin-Fab (may require high doses) Norbormide

• Looks like corn meal • Causes smooth muscle contracon in Norway rats • Intense peripheral vasoconstricon • No known receptor in humans, large animals • Supporve care Other

• Tres pasitos (Aldicarb, carbamate pesde) – Cholinergic symptoms • Chloralose – CNS depressant, used as veterinary anesthec – Causes sedaon, myoclonus, and coma • Salmonella-based rodencides – Based on Phage type 6a – Responsible for human illness Rodencide Keywords

• Hypercalcemia? Cholecalciferol • Bleeding disorder, elevated INR? Superwarfarin • Nausea, voming, bradycardia, hyperkalemia? Red squill (digoxin-like) • Dyspnea, pleural effusions, ALI, hypothermia? ANTU • Tremors, myoclonus, depressed mental status? Bromethalin Rodencide Keywords

• Hyperglycemia, neuropathy? PNU (Vacor) • Bloody diarrhea, painful paresthesias, myopathy, seizures? Arsenic • Oropharyngeal and skin burns, smoking vomitus and stools, garlic odor, GI and hepac injury? Yellow phophorus • Roen fishy odor, renal injury, leukopenia, cardiovascular collapse? Metal phosphides Rodencide Keywords

• “Awake” or “spinal” seizures, rigidity, opisthotonos, CNS smulaon? Strychnine • Diarrhea, alopecia, paresthesias? Thallium • CNS excitaon, irritability, seizures, coma, ventricular dysrhythmias? SMFA (Compound 1080) and tetramine