Pesticide 1 Flashcards
Pesticide Exposure
Primarily by oral or dermal routes or by inhalation
High oral dose are primarily via suicide attempts or by accidental ingestion from storage in improper containers
Chronic low doses are consumed by most people via contaminated foods or drinking water
Organophosphorus(OP) compounds
For all compounds that contain a sulfur bound to a phosphorus, bioactivation is required as an oxygen bound to phosphorus is needed to inhibit the enzymes
General structure: p=O w/ 2 R groups and X varies, p=S is inert until it gets inside body
OP mech
Aging(nonenzymatic hydrolysis of one of the two alkyl groups)=irreversible***
Rate of aging depend on nature of alkyl group
Inhib ACHE via phosph of serine active site
OP toxicity
Hi acute tox with LD50s below 50mg/kg in rat Easily absorbed through the skin(highly lipophilic) As ACh rise, get cholinergic syndrome Increase sweating and salivation Bronchial secretion Bronchoconstriction Diarrhea, increased GI motility Tremor and muscle twitch Respiratory failure
Treatment(DOAP) for OP
Atropine-IV muscarinic R block
Diazepam:BZ work through GABA-A recep=prevent muscle twitching and convulsions
Pralidoxime:IV bind OP when it first binds AChE
Oxime: + charge atom that can attach to anionic site of AChE=dephosph of active site
Note: does not cross BBB and if the AChE aged, has no effect
Pralidoxime(2-PAM)
Used to treat OP poisoning-Only works if enzyme has not undergone aging
Strong Nu and facilitates dephosphorylation of AChE-RAPID RECOVERY
The intermediate syndrome:
Develops in 20-50% of acute poisoning OP, 1 to several days after initial poisoning
Marked weakness of respiratory, neck, proximal limb muscles
Mortality = resp paralysis as hi as 40%
NOT AChE MEDIATED AND MECH UNKNOWN
OP-induced delayed polyneuropathy(OPIDP)
Not related to ACheE inhibition
Tingling in extremities, sensory loss, progressive muscle weakness, ataxia
Cause: degen on distal axon and terminals
Due to interaction w/ diff esterase, NTE(neuropathy target esterase)=swiss cheese brain damage
FOR OPIDP, AGING OF NTE MUST FIRST OCCUR
Organochlorine Compounds
Ex. Chlorinated ether derivatives(DDT)
Structure: two aromatic rings(p,p DDT 10X toxic as o,p DDT) w/ C attached to Cl’s
DDT and analogues toxicity
Acute tox less than OP, but more chronic issues
DDT LD50 = 250mg/kg orally, 10-20mg’kg illness in human
Toxicity from dermal exposure is low, tend to accumulate in Adipose tissue
Acute = motor unrest Increase frequency of spont movements Abnormal susceptibility to fear Hypersusceptibility to stimuli Progresses to fine tremor, then coarse Eventually tonic-clonic seizures Death usually by respiratory failure 24-72hr after exposure
DDT and pyrethroids molecular Mech
Target: both target voltage-gated sodium channels
They PROLONG opening of sodium channels
Closing of open channel is slowed down, this increase probability of repetitive firing
Longer treatment, inc distribution in lipid bilayer=increase EAD
Chronic DDT
DDt and metabolites increase liver weight and lead to hepatic cell hypertrophy and necrosis and induce CYP2B and CYP3A
Classified as a possible human carcinogen
Metabolites (DDE) can still be found in human although DDT banned in 1970-especially human milk
High DDE/DDT ratio means environmental persistence
Low DDE/DDT means recent exposure to DDT(t1/2 shorter than DDE)
Pyrethroids
Account for 25% insecticide bc low toxicity in human LD50s = 100-10000mg/kg
Primary target: neuronal voltage-gated soidum channels
Type 1 pyrethroids(allethrin): affect sodium channels only
Act much like DDT-induce repetitive firing
Type 2(deltamethrin): affect sodium channels and at hi conc inhibit GABA-A recep CN group makes more stable in env Open channel for so long that membrane potential becomes so depolarized that AP not possible-Depolarization-dependent block
Limited absorption through skin
Deaths occur via accidental or deliberate ingestion
TYPE 1 and 2 have different symptomes
Pyrethroid mechanism
Bind to Alpha subunit in voltage-gated sodium channels
Slow rate of activation(opening) and inactivation(closing)=hyperexcitable state
Sodium channel open at more hyperpolarized potentials and are held open longer=more sodium enter EAD
Type 2 hold channel open longer than Type 1(pooping takes longer)
Type 2 inhibit GABA-A receptor function at hi conc
Result of human pyrethroid exposure
Primary effect is paresthesia
Feels like tingling, prickling or burning
Reverse in 24hr
Chronic exposure can = liver enlargement
NO specific treatment except vit E for dermal exposure
