Toxicology Exam II

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Rx2013
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71350
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Toxicology Exam II
Updated:
2011-03-07 16:25:18
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Pesticides
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Pesticides
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  1. Any substance designed for selective toxicity/lethality ot certain organisms
    pesticides
  2. Pesticides are important to toxicologists because of their
    • toxicity to man via acute or chronic exposure
    • toxicity to non-target organisms in the environment
  3. Four broad groups of pesticides based of target of undesirable organisms
    • insecticides
    • herbicides
    • fungicides
    • rodenticides
  4. Four broad groups of insecticides
    • chlorinated hydrocarbons
    • organophosphates
    • carbamates
    • botanicals
  5. In the US _____ regulates pesticide use under _____ act and _____ act.
    • EPA
    • Federal insecticide, fungicide and rodenticide act
    • Federal food, drug and cosmetic act
  6. Federal insecticide, fungicide and rodenticide act
    EPA registers pesticides for use
  7. Federal food, drug and cosmetic act
    EPA establishes max allowable levels of pesticide residues in foods and animal feeds
  8. Food quality and protection act
    gives EPA the mandate to assess risk of pesticides to infants and children
  9. Other regulations concerning pesticides
    • safe drinking water act
    • clean air act
  10. Chloronated insecticides
    • compounds containing chlorine substituents
    • DDT
    • Chlordane
  11. Absorption & elimination of chlorinated hydrocarbons
    • well absorbed from GIT, skin and inhalation
    • highly lipid soluble = accumulation in fat tissues
    • elimination is not first order, slow release from fat stores
  12. Uses of chlorinated insecticides
    • agriculture
    • structural pest control
    • malaria control programs
  13. chlorinated hydrocarbon used for treatment of head/body lice and scabies
    lindane
  14. Low toxicity chlorinated hydrocarbons
    • LD50 > 1g/kg
    • hexachlorobenzene
    • methoxychlor
  15. Moderate toxicity chlorinated hydrocarbons
    • LD50 > 50mg/kg
    • Chlordane
    • DDT
    • Kepone
    • Lindane
    • Mirex
  16. High toxicity chlorinated hydrocarbons
    • LD50 <50 mg/kg
    • Aldrin
    • Deldrin
    • Endosulfan
  17. Lower toxicity rating =
    less toxic and higher acceptable daily intake (ADI)
  18. Mechanism of action with chlorinated hydrocarbons
    • inhibit calcium ion transprot
    • interfere w/ inactivation of sodium channels
    • cause rapid firing of neurons
  19. Acute sx of ingestion of chlorinated hydrocarbons
    • n/v
    • paresthesia of tongue/lips/face
    • confusion
    • tremor/coma/seizures
    • respiratory depression
  20. Duration of toxicity with hydrocarbons may be prolonged due to ____ results in
    • high lipid solubility
    • recurrent or delayed onset of seizures
    • arrhythmias due to sensitization to catecholamines
  21. Treatment of chlorinated hydrocarbon ingestion
    • no specific antidote
    • treat sx
    • ventricular arrhythmias may respond to bbs such as propranolol
  22. Use of chlorinated hydrocarbon insecticides has been banned in ____ and ____ because of _____.
    • North America
    • Europe
    • Environmental impact
  23. Once chlorinated hydrocarbons ____ into the soil, they do not ____. ____ may be poor in ____.
    • adsorb
    • desorb
    • adsorption
    • sandy soil
  24. Best known organochlorine insecticide introduced to control malaria
    DDT
  25. Dose of DDT required for acute toxicity in humans
    10 mg/kg
  26. DDT is metabolized in animals by ___ and ____ is more persistent than the parent compound.
    • cytochrome P450
    • DDE
  27. T1/2 for DDT stored in fat
    6 months
  28. Acceptable yearly intake for humans given by _____ guidelines is _____/yr.
    • FAO/WHO
    • 255mcg/yr
  29. DDT is more harmful in the ____ rather than the ____.
    • blood
    • fat
  30. Discontinuation of use of DDT mainly due to
    environmental impact on wildlife rather than toxicity to humans
  31. Organophosphates and carbamates
    • largely replaced organochlorinated hydrocarbons
    • known as cholinesterase inhibitors
    • used as pesticides or warfare agents
  32. organophosphates used as warfare agents
    • GA (Tabun)
    • GB (Sarin)
    • GD (Soman)
    • GF and VX
    • extremely potent organophosphates
  33. Hosehold insect sprays often contain
    low potency organophosphates or carbamates
  34. Many commercial products contain solvents such as
    toluene or xylene
  35. Organophosphate mechanism of toxicity
    • irreversible inhibition of acetylcholinesterase through phosphorylation at the esteratic site allowing accumulation of ACH
    • results in AchE aging unless antidotal treatment is given
    • also phosphorylate neuropathy esteraces leading to paralysis and axonal degredation
  36. Malathion
    • requires metabolism to malaoxon
    • takes place redily in insects but not humans
    • selective toxicity
  37. Carbamate mechanism of toxicity
    • inhibit AchE by carbamoylation of esteratic site
    • binding is reversible
    • toxicity is breif and self limited
  38. Fenitrothion (organophosphate)
    highly lipophilic and stored in fat tissue = persisting toxic effects
  39. Carbamate kinetics
    • poorly absorbed across the skin compared with organophosphates
    • except aldicarb (concentration in fruit)
  40. Organophosphate kinetics
    well absorbed by inhalation, ingestion and through the skin
  41. Degree of toxicity with organophosphoates/carbamates affected by:
    • rate of exposure
    • metabolic degredation of the agent
    • rate of metabolism of organophosphates to the more toxic "oxon" derivatives
  42. "nerve gases"
    • developed for chemical warfare
    • direct and powerful AchE inhibitors
  43. Clinical presentation of organophosphate/carbamate poisoning occurs within ___ of exposure
    occur w/in 1-2 hrs of exposure (may be delayed w/ skin exposure)
  44. Clinical manifestation of OP/C exposure
    • muscarinic, nicotinic and CNS effects
    • possibility of chemical pneumonitis if hydrocarbon solvent is aspirated
  45. Muscarinic manifestations of OP/C poisoning
    • vomiting, diarrhea, abd. cramps (GI activation)
    • bronchospasm
    • miosis
    • bradycardia
    • salivation & sweating
    • dehydration and shock may result
  46. Nicotinic effects of OP/C poisoning
    • muscle fasciculation/tremor and weakness
    • death caused by respiratory muscle paralysis
  47. CNS effects of OP/C
    • agitation
    • seizure
    • coma
    • peripheral neuropathy
  48. Intermediate syndrome with OP/C
    • recurrent muslce weakness may occur within several days of exposure (up to 15 days)
    • occurs in 20-50% of cases
    • not an effect of AchE inhibition
  49. Labs for OP poisoning
    • plasma pseudocholinesterase level
    • red blood cell acetylcholinesterace activity
    • wide inter-individual variability
  50. More reliable measure of OP toxicity
    • 25% depression in activity in red blood cells
    • PschE may be depressed due to genetic deficiency
  51. Carbamate poisoning
    • reversible AchE inhibition
    • spontaneous recovery within several hours
    • no intermediate syndrome
    • assay of blood and urine for specific agents (not available for several hours)
  52. Treatment of OP/C poisoning
    • antimuscarinic agent (atropine)
    • Pralidoxime (2-PAM) - specific antidote
    • Diacetylmonoxime (DAM) - binds oxime groups
  53. Atropine use in OP/C poisoning
    • most clinically important in pt with wheezing or bronchorrhea.
    • will reverse muscarinic bu not nicotinic effects
  54. Pralidoxime (2PAM)
    • specific antidote for OP toxicity
    • acts to regenerate the enzyme
    • does not reactivate plasma cholinesterase
    • reverse muscle weakness
    • most effective if started w/in 24hr of exposure
    • not recommended for carbamate toxicity
  55. Should be given empirically if the exact toxic agent is not identified and the pt shows significant toxic effects
    2-PAM
  56. Botanical insecticides
    • insecticides derived from natural sources
    • Nicotine
    • rotenone
    • pyrethrum
  57. Nicotine
    • free alkaloid (not salt) readily absorbed through skin
    • binds post synaptic ACH receptors
  58. Toxic dose of nicotine causes
    stimulation rapidly followed by blockade of nerve transmission
  59. Treatment of Nicotine toxicity
    • maintain vital signs
    • suppress convulsions
  60. Rotenone mechanism and toxicity
    • inhibits mitochondrial e- transport system
    • GIT irritation
    • conjunctivitis
    • rhinitis/pharyngitis
    • dermatitis
    • treatment is symptomatic
  61. Pyrethrum consists of six known insecticidal esters which are
    • pyrethrin I & II
    • Cincerin I & II
    • Jasmolin I & II
  62. Pyrethrums are found in
    a lot of household spray insecticides
  63. Toxicities with pyrethrums
    • contact dermatitis
    • sodium channel paralysis (not high in mammals)
    • CNS excitation and convulsion (large dose) - treat with diazepam
    • cutaneous paresthesia observed in workers spraying pyrethrums
  64. Herbicides
    • chlorophenoxy herbicides
    • dipyridyl hermicides
  65. Major chlorphenoxy compounds
    • 2,4-D (dichlorophenoxyacetic acid)
    • 2,4,5-T (trichlorophenoxyacetic acid)
  66. Agent orange
    mixture of di & trichlorophenoxy acetic acid + TCCD (tetrachlorodienzo-p-dioxin)
  67. commercially available 2,4-D
    does not contain TCDD
  68. concentrated 2,4-D formulations contain
    petroleum solvents
  69. Mechanism of toxicity for chlorophenoxy herbicides in plants
    growth hormone stimulator
  70. Mechanism of toxicity for chlorophenoxy herbicides in animals
    • widespread muscle dmg
    • death due to v-fib
    • mechanism unknown
    • occupational exposure => non-hodgkins lymphoma or soft tissue sarcoma
  71. Clinical presentation of chlorophenoxy poisoning and treatment
    • tachycardia
    • muscle weakness & spasms
    • intractable hypotension
    • coma
    • death w/ in 24 hours
    • treatment is symptomatic
  72. Dipyridyl herbicides & use
    • paraquat - large scale control of marijuana
    • diquat
    • used for weed control and defoliants
  73. Paraquat is available in the US as
    20-37% liquid
  74. Diquat is available in the US as
    8-36% liquid
  75. Mechanism of action for dipyridyl herbicides
    • react with NADPH producing highly reactive free radicles which destroy tissue through peroxidation
    • accumulates in alveolar type I and II cells
  76. paraquat is taken up into the lungs and retained by an active process because of structural similarity to
    • diamines & polyamines such as:
    • putrescine
    • spermine
    • spermidine
  77. paraquat in the lungs causes
    • lung edema
    • alveolitis
    • progressive fibrosis of the lung
  78. smoking marijuana sprayed with diquat or paraquat causes
    delayed fibrosis of the lung
  79. Signs of dipyridyl toxicity
    • first sign is hematemesis & bloody stool
    • respiratory distress may appear within a few days
  80. Treatment of dipyridyl toxicity
    • limit absorption by admin. of activated charcoal followed by lavage with 1% bentonite solution of fuller's earth which adsorbs paraquat
    • avoid excessive O2 administration; may aggrivate peroxidation in lungs
    • hydrocortisone & furosemide & dialysis
  81. Fungicides
    • chlorinated hydrocarbons
    • alkyl mercury compounds
  82. alkyl mercury compounds 3 different forms
    • elemental
    • inorganic
    • organic - readily absorbed
  83. use of mercury containing fungicides has led to
    water contamination via run-off from fields
  84. Toxicity associated with mercury compounds
    • Organic mercury is lipid soluble and distributes to the CNS where it is oxidized
    • causes neurological damage
    • metal ions interact with -SH on proteins
    • crosses placenta & is teratogenic
  85. fetal red blood cells concentration methyl mercury ____% more than adult rbcs
    30%
  86. symptoms of acute fungicide poisoning
    • memory loss
    • paresthesia
    • ataxia
    • narrowing of the visual field
    • loss of muscle coordination
    • emotional instability
    • cerebral palsey
  87. most severly affected by fungicide poisoning
    children and new borns born with cerebral palsy
  88. methylmercury T1/2
    70 days
  89. Rodentocides
    • fluoroacetate
    • warfarin
  90. fluoroacetate is also known as
    • compound 1080
    • sodium fluoracetate
    • sodium mono-fluoracetate (SMFA)
  91. SMFA
    • one of the most toxic substances known
    • inhibits aconitase in krebs cycle
  92. Fluoroacetate
    • tasteless, odorless, water soluble white powder
    • removed from market b/c of hazard
  93. fluroacetamide
    • compound 1081
    • similar toxicity
  94. Mechanism of toxicity for fluoroacetate
    • incorporated into the krebs cycle as fluoroacetyl CoA which binds the enzyme aconitase
    • cellular metabolism is blocked
    • cells & tissues die
    • clinical effects delayed 30min to several hours until fluocitrate is metabolized
  95. Toxic dose of fluorocitrate
    • 1 mg = serious toxicity
    • 5 mg/kg = death
  96. Clinical manifestation of fluroacetate toxicity
    • n/v/d
    • metabolic acidosis
    • renal failure
    • agitation/confusion
    • seizure/coma
    • respiratory arrest, pulmonary edema
    • ventricular arrhythmias
  97. Treatment of fluroacetate poisoning
    • no antidote
    • monoacetin (glyceryl monoacetate) used in monkeys but not approved in humans
  98. Warfarin
    • inhibits hepatic synthesis of Vitamin K dependent coagulation factors II, VII, IX and X.
    • Only synthesis of new factors are effected
    • effect is delayed until currently circulating factors are degraded
  99. Most common anticoagulant rodenticide available today is the
    • long acting super warfarins:
    • brodifacoum
    • pindone
    • valone
    • may produce effects for weeks to months
  100. Peak effects of warfarin
    • 2-3 days
    • duration of a single dose is 2-7 days
  101. Clinical presentation of warfarin toxicity
    • excessive anticoagulation
    • ecchymoses
    • conjunctival hemorrhage
    • bleeding gums
    • hematuria
  102. Treatment for warfarin toxicity
    • vitamin K1 (phytonadione)
    • not vitamin K3 (menadione)

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