Pesticides Flashcards
Give an example of an agricultural crop insectiside
- organophosphates
= for aphids, grasshoppers, orange wheat blossom midge
Give an example of a Agricultural animal insecticides
- organophosphates
= for scabies/mites ect or using diazino for sheep dips
List the 4 types of domestic insecticides and give examples
- Garden plant (pyrethroids) for aphids
- Home (pyrethroids) for flies, ant, woodworm
- Medical treatment (organophosphates) headlice/scabies
- Pet flea control (organophosphates) Diazinon flea collars
what is the use of triticonazole
stop black spots on plants, mildew
what is the use of ketoconazole
Fungicides = dandruff, athletes foot, nail infection
Outline the benefit/risks of using pesticides
they are useful because they are harmful
Benefits = improves/protect our healths (control vector borne disease like malaria), allow production of abundant, inexpensive agricultural products
Risk = Toxicity to non-target species, some are pervasive in environment (e.g organochlorines like DDT)
how is the risk associated with pesticides decreased
- using pesticides that are selective for target e.g neonicotinoides
- regulation to reduce exposure
All insecticides are _ and act by targeting the insect __
neurotoxicants
nervous systems
how do isecticides work
cause hyperexcitability of nervous system leading to paralysis and death of isects
- by variety of different mechanisms of action
- majority generally non-selective so affect mammalial NS target
what are organophosphates and what some uses barr insecticides
Organic derivatives of phosphates, phosphonates or phosphinates (e.g. Diazinon, chlorpyrifos)
OP class is large (100s) and applications diverse
Lubricants e.g. motor oil or hydraulic fluids e.g. aviation due to their viscosity and high pressure and fire resistant properties.
Flame retardants in textiles, furniture etc e.g. triphenyl phosphate
Given an example of organophsosphates nerve agents
soman, VX, sarin, tabun, novichok
Despite having different LD50s, most organophosphates induce _
same acute toxicity - just depends on dose
what are the symptomology of parasympathetic innervation due to acute toxicity due to organophosphates
Lacrimation (tears), Salivation, Sweating, Bronchoconstriction / bronchospasm, Bronchorrhea, Diarrhoea, bradycardia (slow heart rate), miosis
= parasympathetic innervation =
what are the symptomology due neuromuscular junction activation to acute toxicity due to organophosphates
Fasiculation (involuntary muscle twitches), tachycardia (fast heart rate), hypertension, muscular weakness
what is the cellular reason for toxicity due to organophosphates
Parasympathetic NS = activation of muscarinic cholinergic receptors
Neuromuscular junction = activation of nicotinic cholinergic receptors
CNS = activation of muscarinic and nicotinic cholinergic receptors
↑ Acetylcholine = Hypercholinergic toxicity
what are the symptomology due to CNS activation to acute toxicity due to organophosphates
Anxiety, confustion, tremor, convulsion, respiratory depression, coma
How are organophosphates effected by the cells
Most OPs are bioactivated.
P=S -> P=O -> potent acetylcholinesterase inhibitors
(some OPs already have P=O bonds e.g sarin)
Phase I metabolism by CYP450 causes this oxidative desulfaration to Oxons
What happens to oxons in the cells
Hydrolysed by esterases
1- catalytic hydrolysis by A-esterases (PON1)
2 - non-catalytic hydrolysis by B-esterases (AChE)
How does AChE normally work
AChE hydrolysis ACh in the synaptic cleft
However bond between active site on AChE and acetate relatively weak, so AChE recovers quickly and the cycle returns
Hoe does AChE cause acute toxicity when interacting organophosphates
AChE hydrolyses OP oxon instead of ACh
Bond between active site on AChE and P of oxon more stable - can take hours/days to break bond
Therefore AChE cannot hydrolyse ACh i.e. inhibited = build up of ACh
How is organophosphates detoxificated
- A-esterases e.g. liver ands plasma PON1 hydrolyse the oxon so AChE reactivated = hydrolysis products excreted
PON1 polymorphisms have _
differing catalytic efficiencies towards OPs
Evidence some people are therefore more susceptible to OP toxicity
what is Aging and how does it effect OP acute toxicity
- hydrolysis of one of the alkyl groups
- if aging occurs AChE is irreversibly inhibited
= need to make new AChE which takes days
how does oximes work and given an example of one
(hydroxylamine derivatives) = pralidoxime (2-PAM)
attaches to AChE, breaking the bonds between the phosphates of oxon and AChE therefore AChE is reactivated
= must occur before aging !
how is organophosphate acute toxicity treated
Atropine (muscarinic Rec antagonist) - blocks mAChR stimulation by ACh
Benzodiazepines (GABAa receptor allosteric modulators) - anticonvulsants
Supportive care - clear airways of mucus, oxygen administration and artificial respiration
what is organophosphates intermediate syndrome
- develops 24-96h post cholinergic crisis
- 20-50% of acute poisoning cases
= weakness/paralysis of muscles innvervation by cranial nerves (neck, intercostals, proximal limbs)
= respiratory paralysis so need ventilation (no treatment, only support)
= may lead to death (15-40%), recovery can take up to 30 days
what is the toxicological mechanism of intermediate syndrome
- receptor desensitisation at neuromuscular junction from overstimulation
- muscle damage by localised hypercontractions at the NMJ
What OP-induced delayed neuropathy
Tend to be OPs with industrial uses (e.g tri-ortho-cresyl phosphate, TOCP)
Develops 2-3 weeks after exposure = Tingling of hands, feet, sensory loss, muscle weakness and flaccidity of muscles at extremities
= Axonpathy = degeneration of axon at distal end and at terminals
- NOT RELATED TO AChE -
What is the mechanism behind OP-induced delayed neuropathy
Inhibits another esterase = Neuropathy target esterase (NTE) in nerve tissues. NTE phosphorylated by OP but has to age to cause OPIDN
- Mechanism remains obscure -
May be because NTE important for membrane phospholipid homeostasis
there is evidence that low level repeated exposure to organophospahtes -
1 - Memory and attentional deficits
2- Increased risk of anxiety disorders and depression
Mostly occupational exposures (sheep dippers/field sprayers)
- Contradictory findings = Contentious
what is the neuropsychological caused by organophosphates
- 5-HT heavily implicated in aetiology of anxiety and depression
- Evidence that prenatal exposure alters expression of 5-HT proteins
- Maybe OPs have another primary mechanism of action besides cholinesterase inhibition? or the effects on 5-HT (proteins, anxiety and behaviour) are secondary neuroadaptations?
where in the brain shows the greatest cholineresterase inhibition following in vivo OP exposure
dorsal raphe nucleus
Using clincial test - what two receptors are responsibel for increase in nueronal activity after organophsopahte application
muscarinic
glutamate
In vivo diazinion exposure causes what -
- alters 5-HT proteins and increases neuronal activaty in the dorsal raphe nucleus
- decrease in inhibitory 5-HT1a receptor sensitivity
- decrease in 5-HT transporter
- increase in firing rate
how is the possible link between OP exposure and depression/anxiety explained
- decrease in inhibitory 5-HT1a receptor sensitivity in dorsal raphe nucleus
- this is seen in depression and OP exposure
what is carbamates
- derivatives of carbamic acid (NH2COOh) e.g aldicarb
what is the symptoms of acute toxicity from high levels of carbamates
Confusion, headache, restlessness, anxiety, poor concentration, tremor, ataxia, hypotension, respiratory depression, convulsions and coma
= CNS effects the same as OP toxicity
= AChE inhibitors
How is carbamylation of AChE different to phosphorylation by OPs
carbamylation = short lasting (reversible)
phosphorylation by OPs = irreversible
= rapid regeneration of AChE compareed to inhibition by organophosphate
what is the uses of carbamates
- Physostigmine (eserine) = alkaloid of the calabar bean, improves muscle tone in GI tracts to treatment poor gut motility
- Rivastigmine = used as treatment in Alzheimers disease, improves cholinergic transmission in the CNS to compensate for neurodegeneration
what are organochlorines and given examples
Organic compunds (contains carbon & hydrogen) that contains at least one covalently bonded chlorine atom CL2
- Chlorinated ethane derivatives e.g. DDT
- Hexachlorocyclohexanes e.g. Lindane
- Cyclodienes e.g. Dieldrin
why should organochlorines be carfully observed when in use
Are not easily metabolised and very lipophilic so bioaccumulate in humans and animals and in the environment = persistent organic pollutant
what is the acute toxicity of DDT
- quite rare
first sign often hyperesthesia of the mouth followed by paraesthesia
Headaches, fatigue, tremor, muscle weakness, convulsion
CNS effect - often reversible
very high dose of the organochlorines DDT can cause
death due to CNS effects
Explain how chronic low level exposure to the organochlorines DDT effects
associated with psychological illness, peripheral neuropathy, parkinsonism
what is the mechanism linked to chronic low level of the organochlorine DDT toxicity
- increase excitability of CNS
-slows closure of Na channels so depolarising phase of action potential is prolonged = ↑ probability of repetitive firing
In contrast to DDT, lindane are _ _ through _ but do not cause _
readily absorbed
skin
tremor
how does lindane cause acute toxicity
Convulsion
↑ excitability by blocking inhibitory GABAA receptor channel opening
how does lindane mechanically cause acute toxicity
block GABA receptors channel opening by binding to picrotoxin site
how is lindane caused tremor/convulsions treated
diazepam
what is Pyrethrin
extract from the flower heads of chrysathemum
what is pyrethroids
a synthetic pyrethrins
why are Pyrethrin/ Pyrethroids used as a insceticides
high insceticidal potency compared to mammalian potency = safer
widely used in people homes
what is the symptoms of acute toxicity caused by Pyrethrin/ Pyrethroids
tremors, seizures, death
occupational exposure = burning/tingling of the face
(short lived)
why was the synthetic analogue pyrethroid developed
pyrethrins decomposed rapidly with light
what are the toxic signs in rats when exposed to pythrethroids
Type 1 - arousal, aggression and fine tremor
Type 2 - profuse salivation, coarse tremors and convulsion
what are convulsion caused by pyrethroids thought to be caused by
Action of type 2 pyrethrodis at blocking GABAA receptors abeit at much higher concentrations
How does pyrethroids thought to cause symptoms
The main mechanism of action is at sodium channels
Very similar to ddt, they stop sodium channels from closing – the type 1 , similar time to ddt so cause repetitive firing. Type 2 keep channels open much longer and end up causing depolarization dependent block.
Therefore neurotransmission associated toxicity but evidence of apoptosis
how does pyrethroids cause apoptosis
activates Na+ channels, leads to repetitive firing
Increase Calcium influx
what is the evidence that leads scientist to belive that developmental exposure to pyrethroids increase the risk of ADHD
Levels of the pyrethroid metabolite 3-PA measured in urine of children = pyrethroids exposure
Children with 3-PBA levels above limits of detection more likely to be diagnosed with ADHD
Animal study shows exposure to deltamethrin (pyrethriods) causes hyperactivity and impulsive behaviour
how, cellularly, does developmental exposure to deltamethrin (pyrethroid) cause ADHD
- Increases dopamine transporter levels in mice
- subsequent decrease in extracellualr dopamine levels cause compensatory increase in dopamine 1 receptors
- cause an increase in activity and impulsive behaviour
Describe how fungicides may be toxic
- Fungicides tend to have very low acute toxicity in mammals (some exceptions)
- Fungicides maneb and mancozeb associated with 2-fold increased risk of Parkinson Disease
Neurotoxicity as mancozeb organometallic pesticide exposure as manganese known to cause neurotoxicity in dopaminergic neurones
how may herbicides cause dopaminergic toxicity
Generally disrupt the metabolic function and energy transfer in plant cells
But daily subacute paraquat exposure lead to decrease in both muscle function and substantial nigra dopamine level
