Roden&cides Handout Board Review Course 2014 K Babu. 6.22.2014 FIFRA • US Federal Insec&cide, Fungicide, and Roden&cide Act (FIFRA, 1947) • Pes&cides are any “substance or mixture of substances intended for preven&ng, destroying, repelling, or mi&gang any pest, and any substance or mixture of substances intended for use as a plant regulator, defoliant, or desiccant” Pes&cides • Roden&cides • Insec&cides • Herbicides • Fungicides Regulaon • FIFRA rolled out in 1947, with mul&ple amendments • EPA given scope to enforce FIFRA in 1970 • FDA and EPA set pes&cide tolerance concentraons • Other acts giving EPA pes&cide 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, insec&cides and roden&cides • Mul&ple salts with variable solubility. Barium chloride (highly soluble), barium sulfate (low solubility). Barium carbonate (low solubility) = roden&cide • 5-10% of ingested barium absorbed • Peak concentraon at 2 hours • Renal eliminaon 20%, rest in feces Barium • Hypokalemia due to blockade of K rec&fier current, and increases K permeability of membranes. Intracellular trapping of K. • Barium intravasaon (from enemas, absorp&on aer perforaon) has caused cardiovascular collapse • DDx of hypokalemia: Periodic paralysis, hypothyroidism, toluene toxicity, diure&cs, Barium - Sx • GI upset, hemorrhagic gastri&s • Hypokalemia at 2 hours aer inges&on • 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 absorp&on of barium • Aggressive potassium reple&on • Hemodialysis or CVVH to remove barium and correct potassium SMFA (sodium monofluoracetate) • Naturally occurring in giilaar plant (Dichapetalum cymosum) • Compound 1080 • Used in collars to prevent coyote aacks • Odorless and tasteless white powder • Similar pes&cide, fluoroacetamide, known as Compound 1081 SMFA (Compound 1080) • Structural analog of ace&c acid, and irreversible inhibitor of Krebs cycle • Monofluoroace&c 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) • Shig to anaerobic metabolism, accumulaon of glutamate • Resul&ng hypocalcemia • Resul&ng hyperlactatemia, hyperammonemia • No significant fluoride toxicity reported aer exposure SMFA (Compound 1080) • Shig to anaerobic metabolism, accumulaon of glutamate • Resul&ng 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 • Vomi&ng, 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 (monace&n) used as acetate donors, and may prevent inhibi&on 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 reac&ve • Ignites spontaneously in air • Forms phosphorus pentoxide (P4O10) • Garlic-like odor • Well-absorbed aer inges&on, 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-compe&&ve GABA antagonism • Seizures, refractory status epilep&cus, coma, cardiac ischemia • Treatment with benzodiazepines, barbiturates, and paraly&cs (for cessaon of motor ac&vity) Thallium • Odorless, colorless powder • Rapid absorp&on through skin • Primary eliminaon in feces • Undergoes enterohepac recirculaon • LD50 10 mg /kg Thallium –Sx • Immediate – vomi&ng, abdominal pain • Within 24 to 48 hours – painful paresthesias of hands and feet • Ager 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 ac&vated 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 neurotransmiker) • Inhibi&on primarily at level of postsynap&c 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 s&mulaon • May result in respiratory arrest, lac&c acid generaon, acute kidney injury, DIC, hyperthermia Strychnine - Tx • Nons&mulang environment • Benzodiazepines • Pentobarbital • Paraly&cs Metal Phosphides • Aluminum and Zinc • Used primarily to protect stored grains from rodents • Phosphine gas liberated on contact with water or dilute acids (roken fish odor) • Phosphine may inhibit cytochrome C oxidase, leading to uncoupling of oxidave phosphorylaon Metal Phosphides - Sx • Inges&on results in severe GI irritaon • Nausea, vomi&ng, 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 • Suppor&ve care • Electrolyte and calcium reple&on • Immediate cleanup of all body fluids (emesis and stool) since phosphine can be offgassed Vacor (PNU, Pyriminil) • Released in 1975 as a roden&cide that was lethal aer one feeding • Withdrawn in 1979, but reports of toxicity un&l 2002 • PNU destroys beta-islet cells leading to DKA • Associated with GI perforaon, pneumonia • Death from DKA or cardiac dysrhythmias within hours • Sequelae include brikle DM, postural hypotension, and neuropathies (motor and sensory) Vacor (PNU, Pyriminil) • Mechanism unknown • Niacinamide analog – interferes with pentose monophosphate shunt, par&cularly in brain, liver and pancreac islet cells • Niacinamide (nico&namide) could be an an&dote, but not available • Niacin (nico&nic 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, vomi&ng, pulmonary edema and effusions • No deaths reported • Suppor&ve treatment Cholecalciferol (Vitamin D3) • Rodents are extremely sensi&ve to Ca2+ homeostasis • Cholecalciferol increases Ca2+ absorp&on from gut and mobilizaon from bone • Ca2+ deposi&on in mul&ple organs, and dysrhythmias • Possible hypervitaminosis D with symptomac hypercalcemia • Tx: furosemide, cor&costeroids, calcitonin, bisphosphonates, hemodialysis • Normal serum Ca2+ at 48 hours excludes toxicity Low Toxicity Agents (“Cau&on”) 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 ini&al 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 produc&on, vacuole development, and decreased nerve conducon • Leads to paralysis and death in rodents • Death reported in young man; cerebral edema • Suppor&ve care, and observaon for 12 hours Red Squill • Derived from Urginea mari7ma (sea onion) • Cardiac glycosides: Scillaren A and Scillaren B • Potent eme&c • Cardiac glycoside with symptoms and findings similar to digoxin • Presence of squill may be