Roden&cides*Handout - ACMT...Signal*Words* • Category*I:**DANGER*(LD 50 *
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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&ga&ng 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
Regula&on • FIFRA rolled out in 1947, with mul&ple amendments
• EPA given scope to enforce FIFRA in 1970 • FDA and EPA set pes&cide tolerance concentra&ons
• Other acts giving EPA pes&cide oversight: – Resource Conserva&on Act (1972), Comprehensive Environmental Response, Compensa&on 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 concentra&on at 2 hours • Renal elimina&on 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 intravasa&on (from enemas, absorp&on ager perfora&on) 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 ager 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 akacks • 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 inhibi&on”
SMFA (Compound 1080)
• Shig to anaerobic metabolism, accumula&on of glutamate
• Resul&ng hypocalcemia • Resul&ng hyperlactatemia, hyperammonemia • No significant fluoride toxicity reported ager exposure
SMFA (Compound 1080)
• Shig to anaerobic metabolism, accumula&on of glutamate
• Resul&ng hyperlactatemia, hyperammonemia • No significant fluoride toxicity reported ager exposure
• Toxicity generally within six hours; asymptoma&c pa&ents should be observed for 24 hours
SMFA (Compound 1080) -‐ Sx
• Vomi&ng, abdominal pain, agita&on, seizures, dysrhythmias
• Nega&ve inotropic effect • Low systemic vascular resistance despite fluid resuscita&on
SMFA (Compound 1080)
• Hypocalcemia cardinal finding • Elevated crea&nine, hyperkalemia, acidosis • SMFA and fluoroacetamide can be confirmed in blood and urine by TLC, GC/MS
• Elevated serum citrate concentra&on • Delayed CT ager 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 • Occupa&onally, associated with phossy jaw (mandibular osteonecrosis)
White Phosphorus
• Very reac&ve • Ignites spontaneously in air • Forms phosphorus pentoxide (P4O10) • Garlic-‐like odor • Well-‐absorbed ager 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 cessa&on of motor ac&vity)
Thallium
• Odorless, colorless powder • Rapid absorp&on through skin • Primary elimina&on in feces • Undergoes enterohepa&c recircula&on • 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, op&c neuri&s
• Sudden cardiac death may occur weeks ager exposure
• Neuropsychiatric symptoms may persist
Thallium -‐ Tx
• Possible role for ac&vated charcoal given enterohepa&c recircula&on
• Prussian Blue for decontamina&on – 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, na&ve to India)
• Available consumer prepara&ons (0.3-‐0.5%), commercial exterminator (5%)
• Found as an adulterant in heroin and cocaine • Found in Southeast Asian herbal prepara&ons
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&mula&on
• May result in respiratory arrest, lac&c acid genera&on, acute kidney injury, DIC, hyperthermia
Strychnine -‐ Tx
• Nons&mula&ng 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 oxida&ve phosphoryla&on
Metal Phosphides -‐ Sx
• Inges&on results in severe GI irrita&on • Nausea, vomi&ng, epigastric pain in virtually all cases; may cause black emesis
• Hypotension, tachypnea, acidosis, tetany due to hypocalcemia, palpita&ons
• 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 ager one feeding
• Withdrawn in 1979, but reports of toxicity un&l 2002 • PNU destroys beta-‐islet cells leading to DKA • Associated with GI perfora&on, 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 pancrea&c 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 mobiliza&on from bone
• Ca2+ deposi&on in mul&ple organs, and dysrhythmias
• Possible hypervitaminosis D with symptoma&c 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 dura&on 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 Interna&onal Normalized Ra&o (INR); usually Q24h ager 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 effec&vesness of treatment
Bromethalin • Neurotoxin; marketed as green pellets • Metabolized to desmethylbromethalin (more potent)
• CNS effects due to uncoupling of mitochondrial phosphoryla&on, decreased ATP produc&on, vacuole development, and decreased nerve conduc&on
• Leads to paralysis and death in rodents • Death reported in young man; cerebral edema • Suppor&ve care, and observa&on 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 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 contrac&on in Norway rats
• Intense peripheral vasoconstric&on • No known receptor in humans, large animals • Suppor&ve care
Other
• Tres pasitos (Aldicarb, carbamate pes&de) – Cholinergic symptoms
• Chloralose – CNS depressant, used as veterinary anesthe&c – Causes seda&on, myoclonus, and coma
• Salmonella-‐based roden&cides – Based on Phage type 6a – Responsible for human illness
Roden&cide Keywords
• Hypercalcemia? Cholecalciferol • Bleeding disorder, elevated INR? Superwarfarin
• Nausea, vomi&ng, bradycardia, hyperkalemia? Red squill (digoxin-‐like)
• Dyspnea, pleural effusions, ALI, hypothermia? ANTU
• Tremors, myoclonus, depressed mental status? Bromethalin
Roden&cide Keywords
• Hyperglycemia, neuropathy? PNU (Vacor) • Bloody diarrhea, painful paresthesias, myopathy, seizures? Arsenic
• Oropharyngeal and skin burns, smoking vomitus and stools, garlic odor, GI and hepa&c injury? Yellow phophorus
• Roken fishy odor, renal injury, leukopenia, cardiovascular collapse? Metal phosphides
Roden&cide Keywords
• “Awake” or “spinal” seizures, rigidity, opisthotonos, CNS s&mula&on? Strychnine
• Diarrhea, alopecia, paresthesias? Thallium • CNS excita&on, irritability, seizures, coma, ventricular dysrhythmias? SMFA (Compound 1080) and tetramine
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