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Neuroscience Envrio Toxins and Mental Health > Pesticides > Flashcards

Pesticides Flashcards

1
Q

What are Pesticides

A
  • Substances used for preventing, destroying, repelling or mitigating pets
  • Designed to specifically target the undesirable species
  • Often not highly selective and can be toxic to many non target species
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2
Q

Pesticide uses

A
  • The use of pesticides between 1950-1980 then stabilized
  • In the US, half of the most used form of pesticide are herbicides
  • In other countries, larger use of insecticides and fungicides
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3
Q

Pesticide Classification

A
  1. Insecticides
  2. Herbicides
  3. Fungicides
  4. Rodenticides
    - Classifies according to their target species or region- specificity
    - Within each class, there are several subclasses of pesticides, which have substantially different chemical and toxicological characteristics
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4
Q

Exposures

A
  • oral
  • inhalation
  • dermal
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5
Q

Which exposure counts for most of all pesticide exposure

A

Dermal

- accounts for 90% of all pesticide exposure

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6
Q

Occupational Exposure

A
  • Workers involved in production, transport, mixing, loading, and application or pesticides
  • Workers involved in harvesting pesticide-sprayed crops
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7
Q

Absorption Rates

A
  • Rates of absorption through the skin are different for different parts of the body
  • Different areas have higher absorption rates >
  • Absorption is more than 11 times faster in the lower groin are than the forearm (Similar to intravenous injections)
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8
Q

Toxic Effects of each classificantion

A
  1. insecticides = most acutely toxic
  2. herbicides = low to moderate acute toxicity
  3. fungicides = vary in acute toxicity
  4. rodenticides = highly toxic to rats
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9
Q

Range of potential toxic effects in non-target species (6)

A
  1. Mild irritant Effects in skin
  2. Disruption in liver and lung function
  3. Carcinogenic
  4. Reproductive Toxicity
  5. Endocrine Disruption Properties
  6. Neurotoxicity
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10
Q

Mild irritant effects in skin

A
  • Most common effect

- 15-25% of pesticide illness reports

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11
Q

Disruption in liver and lung function

A
  • Construction of bronchial tubes increased secretion, difficulty breathing (shortness of breath).
  • Healthy vs inflammation > can see the issue with restriction
  • 4.5 greater risk of developing asthma before age 5 if exposed to herbicides in the 1st year of life.
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12
Q

Carcinogenic

A
  • Cancer rates in children with a parent that works with pesticides are higher than general populations
  • Examining this in populations:
  • All lymphomas 2 times higher
  • Hodgkin’s lymphomas 2.5 higher
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13
Q

Reproductive Toxicity

A
  • Women using pesticides have 1.5 increased odds of a longer cycle, missing a period
  • May increase time to pregnancy- prohibition of functioning
  • Pesticide exposure may increase the risk of birth defects, such as limb reductions, eye and heart defects, cleft palates, altered brain development, lower birth weight
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14
Q

Endocrine disrupting properties

A
  • Mimic of block hormones or hormonal activity

- E.x., estrogen, androgens, progestin, thyroid, hormones, etc.

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15
Q

Neurotoxicity

A
  • Self-reported or clinical diagnosis of depression in female spouses of pesticide applicators
  • Self-reported neurological symptoms in pesticide applicators associated with cumulative exposure to moderate levels of pesticides
  • Headache, fatigue, insomnia, irritability, depression, numbness in hands or feet
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16
Q

Toxic Effects High Doses

A
  • Suicide attempts, accidental exposure
  • Severe poisoning and death
  • Approx. 3 million hospital admission per year for pesticide poisoning
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17
Q

Toxic Effects Chronic Low Doses

A
  • General public
  • Pesticide residues in food
  • Contaminants in drinking water
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18
Q

Long-term effects of pesticides

A
  • Difficult to study the long-term health effects of pesticides
  • Not one single cause of a disease or other effects
  • E.x., genetic susceptibility
  • Looking at effects in human, make sure you look at as many characteristics of the population as possible to determine the risk and cause.
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19
Q

Risk and Cause Effects

A
  1. Exposure
  2. Individual factors
  3. Health effect
    - Once you have all the three areas and their information you can then infer (still really hard) the cause and reaction basis.
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20
Q

Risk: Exposure

A
  • how we link health effect to pesticide exposure
  • Location
  • Job title
  • Equipment sales
  • Use questionnaire
  • Biological monitoring
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21
Q

Risk: Individual

A
  • the person
  • Diet
  • Genetics
  • Illnesses
  • Smoking
  • Other chemicals
  • Environmental factors
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22
Q

Risk: Health

A
  • how we study the disease
  • Questionnaires
  • Medical records
  • Cancer registries
  • Clinical measurement
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23
Q

Outline Insecticides

A
  • All chemical insecticides in use today are neurotoxic
  • Insecticides are not very species-selective
  • Target sites for insecticides in insects are also found in mammals
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24
Q

Classes of Insecticides

A
  1. Cholinesterase inhibitors (organophosphates and carbamates)
  2. Pyrethroids
  3. Organochlorine compounds (DDT)
  4. Neonicotinoids
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25
Q

Organophosphates (OPs) (insecticide)

A

Acetvcolinesterate inhibitor
Developed in early 1940
Examples: malathion, parathion, chlorpyrifos

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26
Q

Chemical structure of OPs

A
  • Phosphorus (P) atom bound with a double bond to an oxygen (O) or sulphur (S) with single bonds to two alkoxy groups and a leaving group
  • Compounds with a P=O moiety are toxicologically active
  • This state is when it is toxicologically active
  • Taking off sulphur and replacing it with an oxygen
  • Most commonly used OPs contain a sulphur bound to the phosphorus atom
  • Need to metabolically activate to exert toxicological effects
  • Bioactivation is mediated enzymes in the cytochrome P450 family (CPYs)
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27
Q

OPs Mechanism of Action

A
  • Organophosphate bind to acetylcholinesterase and inhibit that enzyme
  • Needed for synaptic transmission
  • Needed it to inactivate acetylcholine
28
Q

Three steps of OPs action

A
  1. Acetylcholine signalling at synapse
  2. ACh Esterase STOPS singling process
  3. OPs inhibit ACh esterase
29
Q

The presence of Phosphate in a cell

A

The present of phosphates > binds to AChE > inactive AChE (phosphorylation)> cannot break down > can be hydrolyzed by water (back to baseline- interact with breaking down acetylcholine) OR > Hydrolysis by oxides (back to baseline) OR > Age (cannot go back)

30
Q

Three processes after AChE is inactivated (phosphorylated by OPs)

A
  1. Hydrolyzed by water
  2. Hydrolyzed by chemical
  3. Age (Organophosphate)
31
Q

Hydrolyzed by water

A
  • Returns to AChE to its active form (original state)
  • Very slow
  • Esteric Site > Organophosphate comes > Hydrolysis between organophosphate and site > returns to active form
32
Q

Hydrolyzed by chemicals

A
  • Returns to AChE to its active form (original state)
  • Used in the treatment of OP poisoning
  • Very fast
  • E.x., Pralidoxime (2-PAM)
  • Esteric site > organophosphate bonded (inactivating AChE)> 2-PAM bonds to organophosphate> Organophosphate bond to AChE is broken > regeneration of AChE
33
Q

Aging (Organophosphate)

A
  • Ageing occurs due to the loss of one of the two alkoxy groups
  • Results in chemical stabilization of the phosphate bond to AChE over time
  • Esteric site > organophosphate bonds > H2O adds to bond > R2OH leaves > bond is now strengthened > can no longer by hydrolyzed
34
Q

OPs Toxicity levels (4)

A
  • Acute cholinergic syndrome
  • Intermediate syndrome
  • Organophosphate - induced delayed polyneuropathy
  • long-term low-dose effect of OPs
35
Q

Acute cholinergic syndrome

A
  • high dose exposure immediate reaction
  • Lasts until AChE levels return to normal
  • Receptors are localized in most organs of the body
  • Widespread effects
  • Symptoms include:
  • Slurred speech
  • Confusion, depression, lethargy
  • Tremors, muscular twitching, paralysis
  • Death (related to respiratory failure)
36
Q

Intermediate Syndrome

A
  • Develops a few days after the poisoning
  • The person may have completely recovered from the initial cholinergic crisis
  • Acetylcholinesterase could return to the original state (back to baseline- interact with breaking down acetylcholine)
  • Seen in 20-50% of acute OP poisoning cases
  • Not related to the inhibition of AChE
  • Mechanisms are unknown
  • Perhaps nicotinic receptor desensitization?
  • Symptoms include respiratory and muscle weakness
37
Q

Organophosphate-induced delayed polyneuropathy

A
  • weeks post
  • Can occur 2 to 3 weeks after a single exposure
  • Symptoms include
  • Tingling of hands and feet
  • Sensory loss
  • Progressive muscle weakness and flaccidity
    Ataxia
  • Not related to AChE inhibition
38
Q

long-term low-dose effect of OPs

A
  • Low dose chronic exposure (coffee and wine)
  • Have been linked to cancers, diabetes, depression, neurodegenerative diseases
  • Mechanisms underlying these effects are unknown
  • Delayed polyneuropathy > lesions > axonal deterioration
  • Potential mechanisms include
  • disruption of the cholinergic system
  • persistent alterations in axonal transport and cytoskeletal proteins
  • induced free radical generation – enhanced oxidative stress
  • disruption of lipid membrane and lipid rafts
39
Q

Carbamates (Insecticide)

A
  • Developed in 1950’s
  • Acetvcolinesterate inhibitor
  • Already toxicologically active (don’t need additions)
40
Q

Carbamates vs OPs

A
  • Mechanism of toxicity is similar to OPs
  • Inhibit AChE
  • Unlike OPs
  • Carbamates do not require metabolic bioactivation
  • And inhibition of AChE is transient and rapidly reversible
  • Symptoms are the same (except for time or resolution)
41
Q

Carbamates symptoms

A
  • Binding is temporary
  • Returning to baseline much faster
  • No longer seeing long stimulation of acetylcholine at the synapse
42
Q

Pyrethroids (synthetic insecticide)

A
  • Developed in 1970’s
  • Derived form pyrethrins
  • Widely used as agricultural and household insecticides
  • Considered to have low mammalian toxicity
  • Toxicity occurs when ingested (not readily through the skin)
43
Q

Pyrethroids chemical structure

A
  • Very lipophilic - can pass the blood-brain barrier

- Divided into two classes: Type I and Type II compounds

44
Q

Type I compounds of Pyrethroids

A
  • short duration of effects
  • symptoms of poisoning include
  • marketed behavioural arousal
    reflex hyper excitability
  • increased startle response
  • sympathetic activation
  • body tremor
    E.x., pyrethrin
45
Q

Type II compounds of Pyrethroids

A
  • larger active due to the addition of cyan0 group (C triple bond to N)
  • more toxic and as a result have longer lasting, more severe symptoms
  • symptoms of poisoning include
  • salivation
  • coarse tremor
  • sympathetic activation
  • seizure
  • choreoathetosis
    E.x., fenvalerate
46
Q

Pyrethroids mechanisms of action

A
  • Bind to sodium > keeping sodium channels open > no resolution of re-polarizing effect (is now delayed)
  • Bind to voltage-dependent Na+ channels keeping them in the open conformation and delaying inactivity
  • Allows for the continuous entry of Na+
47
Q

Type I compounds or Pyrethroids mechanism of action

A
  • More sodium to come in than usual > depolarized membrane (reaching the threshold for depolarization) > action potential generated
  • Hold Na+ channels open for < 10 msec
  • Depolarize membrane above the threshold for action potential generation leading to the repetitive firing
48
Q

Type II compounds or Pyrethroids mechanism of action

A
  • Hold Na+ channels open for >10msec
  • Sodium > increased depolarization > balance of sodium equalizes across the membrane > effects generation ability to generate action potential and amplitude of secondary action > depolarization-dependent block
  • Cause greater membrane depolarization, diminishing the Na+ electrochemical gradient and amplitude of subsequent action potentials
  • Membrane becomes depolarized to a point at which the generation of an action potential is not possible
  • Called depolarization-dependent block
  • Also, inhibit GABAA chloride channels and voltage-dependent chloride channels
49
Q

Organochlorine Compounds (OCs) (insecticide)

A
  • developed in the 1940’s
  • Acute toxicity is moderate (less than OPs)
  • Chronic toxicity is thought to be associated with adverse health effects
    E.x., DDT
50
Q

DDT mechanism of Action - how it affects NA+

A
  • DDT delays the closing of Na+ channels and prevents the opening of the potassium gates
  • results in repetitive firing (hyper-excitability)
51
Q

DDT mechanisms of Action- how it affects Ca-2

A
  • inhibit the ability to transport Ca-2
  • This may affect the release of neurotransmitters
    Effects calcium levels > disrupting synapse and release of neurotransmitters
    Sodium and potassium channels > extended depolarization preventing polarization of the membrane
52
Q

Human ingestion of DDT

A
  • Below 10 mg/kg- produce no or few symptoms
  • Between 10-16 mg/kg - produces moderate to severe symptoms
  • > 20 mg/kg - produces convulsions and death
53
Q

DDT symptoms

A
  • The early effect is paresthesia of the mouth and face
  • Altered motor function leading to ataxia
  • Dizziness, confusion, general malaise, headache, fatigue
  • Tremor of the hands
  • Conclusions
54
Q

DDT: Endocrine Disruption (hormonal system)

A
  • Endocrine disruption is not an effect, but a mechanism of toxicity
  • Can have many effects including infertility, low sperm count, early puberty, brain development etc.
  • Low doses of DDT have been shown to mimic or block certain hormones
  • Estrogenic effects
  • Anti-androgenic effects
  • Anti-progestin effects
  • Anti-thyroid effects
55
Q

DDT and Thyroid Disease

A
  • Hyperthyroidism (overactive)
    Produce too much thyroxine (T4)
  • Hypothyroidism (underactive)
    Don’t produce enough T4
56
Q

Herbicides

A
  • Chemicals that are toxic to plants
  • The mechanism of action of herbicides are usually unique to plants
  • Usually less toxic to humans than insecticides (targeting organisms in plants that mammalians do not have)
  • Except for paraquat
57
Q

Examples of plant processes inhibited by herbicides

A
  • Photosynthesis
  • Amino acids and proteins
  • Growth regulation
58
Q

Glyphosate (Herbicide)

A
  • The primary active ingredient in Roundup (Monsanto)
  • Inhibits plant enzymes EPSP synthesis
  • Mechanisms of toxicity are different in humans as we do not have EPSP enzymes
59
Q

Glyphosate (Herbicide) Neurotoxicity

A
  • Decreased levels of glutamine syntheses, aspartate amino- transferase (AST), and alanine amino amino- transferase (ALT)
  • interferes with glutamate metabolism
  • Increase glutamate in the synapse (excitotoxicity)
  • Associated with oxidative stress and neuroinflammation
60
Q

Glyphosate Neurotoxicity in Rats

A
  • what happens in the rat hippocampus when exposed to Glyphosate
  • Decrease glutamate uptake (is being released and staying in the synapse)
  • Concerning as it is the underlying mechanism to cytotoxicity
61
Q

Paraquat (Herbicide)

A
  • Has one of the highest acute toxicity among herbicides
  • Very toxic when ingested
  • Skin absorption is poor
  • Inhalation is a possible route of exposure
  • The lethal dose is 1-4 grams
62
Q

Paraquat effects on humans

A
  • Paraquat primarily accumulates in lung and secondarily in the kidneys
  • Inhalation exposure. Organs used for excretion
63
Q

Paraquat chemical structure

A
  • Paraquat is positively charges and water soluble
  • Argued that it cannot easily pass the blood-brain barrier
  • Not lyophilic
  • Animal studies have shown that it can cause CNS effects
  • Neutral amino acid transporters (LAT-1) may transport paraquat into the brain
64
Q

Paraquat and MPP+

A
  • Paraquat charges positively look similar to lipophilic MPP+ (neuro-degeneration) and MPTP
  • A similar structure can infer through similarity that it acts in similar ways
65
Q

Paraquat and Free Radicals

A
  • Paraquat undergoes redox cycling to form superoxide free radical
  • The process is cyclic so once the first superoxide free radical formed it can do it all over again
  • Free radicals are extremely reactive with potential for widespread targets including cell membranes and enzymes
  • Redox cycling: Repetition of free radical
  • Cause damage and inflammation throughout the brain
66
Q

Neurotoxicity of Paraquat

A
  • Exposure to paraquat has been linked to the etiology of Parkinson’s disease (PD)
  • A major target of paraquat in the CNS are dopaminergic neurons
  • Exposure to paraquat can also induce α-synuclein aggregation (Lewy bodies) inside neurons
67
Q

α-synuclein aggregation in neurons - paraquat

A
  • Aggregation > larger in size > more damage
  • Reducing the number of dopamine vesicles > more dopamine outside of dopamine
  • Easily metabolized into a reactive substance > damage from inside to out of the dopamine cell
  • Triggering cell death of dopamine by stimulating the Lewy bodies
  • Hypothesized that α-synuclein Lewy bodies reduce vesicle number in dopamine neurons
  • This results in the accumulation of dopamine in the cytoplasm
  • In cytosol, dopamine is metabolized by monoamine oxidase which generates reactive oxygen species
  • May trigger oxidative stress and the initiation of the apoptotic cascade

Neuroscience Envrio Toxins and Mental Health (6 decks)

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