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