11 - Pesticide tox

Question 1

WHO classification of pesticide toxo

Answer 1

• Ia - EXTREMELY hazardous (e.g. Parathion)
• Ib - HIGHLY hazardous (e.g. Cyfluthrin)
• II - Moderately hazardous (e.g. Propoxur)
• III - Slightly hazardous (e.g. Glyphosate)

Question 2

What is the “WHO classification of pesticide toxo” based on?

Answer 2

Human safety
* doesn’t seperate into classes

Question 3

Similarities between insects and mammals

Answer 3

Similar nervous control
* ACh receptors
* Na Channel
* Common neurotransmitters

Question 4

Differences between insects and mammals

Answer 4

Differences biotransformation, required dose, action at target
* E.g carboxylesterase catalytic hydrolysis of carboxylic ester of malathion > rapid detox in mammals

Question 5

Acute toxicity of insecticides

Answer 5

Generally have higher acute toxicity toward nontarget species compared to other pesticides

Question 6

General structure of OP compounds

Answer 6

1. Leaving group (X)
2. R1 & R2 (most commonly alkoxy groups)
3. O (can be S, substituted to O in metabolism)
4. P in the middle

Question 7

Four Classes of Organophosphate Compounds

Answer 7

1. Phosphorylcholines (agents developed as weapons)
2. Fluorophosphates
3. Cyanophosphates (other halophosphates)
4. Multiple constituents (most insecticides in this group)

Question 8

Group 1: Phosphorylcholines

Answer 8

Can directly stim AChR due to resemblance to ACh
* Leaving group: substituted quaternary nitrogen
* E.g. Echothiophate iodide

Question 9

Group 2: Fluorophosphates

Answer 9

• Leaving group: fluorine
• E.g. Dimefox, sarin, mipafox

Question 10

Group 3: Cyanophosphates, other halophosphates

Answer 10

• Leaving group: CN, SCN, OCN, halogen other than fluoride
• E.g. Tabun

Question 11

Group 4: Multiple constituents

Answer 11

• Leaving group: Dimethoxy or Diethoxy
• E.g. Parathion, phorate, phosfolan, TEPP

Question 12

Phosphorothioates

Answer 12

Have Sulphur group that needs to be replaced
* Oxidative desulfuration mediated by CYP450s
* Diazinon ➔ 2C19
* Chlorpyrifos ➔ 2B6s

Question 13

General scheme of biotransformation of dialkyl, aryl phosphorothioate insecticides

Answer 13

1. R1 bioactivation to oxon
2. R2-5 detoxifications
3. R2 & 4 dealkylation
4. R3 dearylation
5. R5 hydrolytic reaction catalysed by paraoxonase 1 (PON1)

Question 14

OP MOA

Answer 14

1. Phosphorylate serine hydroxyl group @ active site in AChE cleft (form Michaelis complex)
2. Leaving group splits off ➔ stable, reversible bond remains between OP and AChE
3. AChE inactived when leaving group leaves ➔ stronger bond
4. AGING can occuring in inactive state

Question 15

Reverse AChE inactivation by OP

Answer 15

Can be reactivated via hydroxyl ion attack, phosphate removal releases active enzyme (slow)
* If aging occurs antidotes does not work

Question 16

What is occuring during “aging” of AChE?

Answer 16

The alkyl side-chain of the phosphoryl moiety is removed nonenzymatically leaving OH group

Question 17

Pralidoxime (2-PAM)

Answer 17

Catalyzes regen of active AChE by exerting nucleophilic attack on phosphoryl group, transferring it from phosphorylated AChE to itself
* Pralidoxime STRONG nucleophile

Question 18

Signs & Symptoms of Acute Poisoning with Anticholinesterase/OP

Answer 18

1. nAChR in CNS and CV (Mental confusion, dizziness, lethargy, headache, depression of respiratory centres, convulsions, coma)
2. mAChR throughout the body (Pupillary constriction > blurred vision)

Question 19

Genetic Susceptibility to OP Poisoning Effects

Answer 19

PON1 polymorphism have effect on resistance/susceptibility
* PON1(R192) ➔ resistant, fits Chlorpyrifos oxon better
* PON1(Q192) ➔ more susceptible

Question 20

Carbamates

Answer 20

Carbamic acids ➔ C atom bonded to amino group (NH2), hydroxyl group (OH), and carbonyl group (C=O)
* Molecules containing OC=ON linkage are termed carbamates

Question 21

Carbamate toxicity

Answer 21

• Don’t require metabolic activation
• Metabolic deactivation (mostly)
• MOA like OPs but no ageing, and reactivation rapid in H2O

Question 22

Pyrethroids

Answer 22

Synthetic versions developed in 70s
* WERENT light-labile
* Generally low mammalian toxicity
* Fatalities generally only with high doses

Question 23

Pyrethroid Structure

Answer 23

Contain an acid moiety, a central ester bond, and an alcohol moiety ➔ several chiral carbon
* Type I
* Type II - CN containing, enhances binding affinity
* Trans-isomers less toxic to mammals

Question 24

Pyrethroid MOA

Answer 24

Na channel disruption
* Bind to α-subunit slowing in/activation
* Type I - repetitive firing
* Type II - depolarisation-dependent block (delay inactivation longer)

Question 25

MODIFIED Pyrethroid MOA

Answer 25

*Normally*, to ***limit*** **depolarization** *length*. But MODIFIED ➔ remain ***open*** when depolarization **ends**, resulting in a ***“tail”*** current. * Type **I** - more ***APs*** * Type **II** - **↑** in ***AP*** but then produces ***block/tail***

Question 26

Organochlorine Compounds

Answer 26

1. **DDT** ➔ chlorinated ***ethane*** derivatives 2. **Chlordane**, dieldrin… ➔ ***cyclodienes*** 3. **Lindane** ➔ ***HCH*** 4. Mirex, chlordecone ➔ *caged* structure

Question 27

DDT MOA

Answer 27

1. DDT ***slows*** closing **Na+** channels once they have opened 2. *Inhibits* extracellular **Ca-ATPase** that normally maintains high extracellular Ca2+ producing **membrane** ***instability*** 3. *Inhibits* **NaK-ATPase** and *disrupts* **neurotransmitter** conc.

Question 28

Hexachlorocyclohexanes (HCH) and cyclodienes

Answer 28

Bind to ***picrotoxin*** site on **chloride** channel ➔ ***block*** opening ➔ **antagonising** ***inhibitory*** action of **GABA**

Question 29

Mirex and Chlordecone

Answer 29

*Exact* MOA ***not*** well understood * Maybe **inhibition** of ***catecholamine*** *uptake* and **inhibition** of ***NaK-*** and ***Mg***- ATPases?

Question 30

Chlordecone

Answer 30

*Persistent* organic **pollutant** * causes ***enlarged*** liver, liver ***cancer***, and ***0 sperm*** count

Question 31

Neonicotinoids

Answer 31

Contain a *nitro**methylene***, *nitro**imine*** or ***cyanoimine*** groups * MOA: ***activation*** of **post**synaptic **nAChRs** located exclusively in the ***CNS*** (in insects) * Does ***not*** readily cross **BBB**

Question 32

Neonicotinoids toxicity to animals

Answer 32

* ***Imida***cloprid ➔ toxic to **birds** * ***Thia***cloprid ➔ toxic to **birds** + **fish** * Impair **bee** *immune* systems? * Temporary **ban** on ***imida***cloprid, ***clothianidin***, and ***thiamethoxan*** in EU

Question 33

Rodenticides

Answer 33

1. ***1080*** 2. ***Strych***nine 3. ***War***farin 4. **Zinc** ***Phosphide***

Question 34

Sodium Monofluoroacetate: 1080

Answer 34

Structural ***analogue*** to **acetic** acid * **Irreversible** *inhibition* of **TCA** * *Highly* **toxic** to ***mammals***

Question 35

1080 Toxicity

Answer 35

1. ***Monofluoroacetic*** acid enters mitochondria 2. *Converted* to *fluoro**acetyl-CoA*** by acetate **thiokinase** (AKA acetyl-CoA synthetase) 3. *Fluoro**acetyl-CoA*** enters ***TCA*** 4. *Fluoro**citrate*** formed by *enzymatic* **condensation** of with ***oxaloacetate*** ➔ catalysed by citrate ***synthase*** 5. Fluoro**citrate** ***covalently*** binds **ACONITASE** 6. TCA ***cannot*** move forward ➔ Cell **death**

Question 36

Strychnine

Answer 36

*Naturally* occurring poison in **Nux vomica** * *Inhibits* **glycine** binding to glycinergic ***chloride*** channel in **spinal** cord * Loss of inhibitory **reflex** arc ➔ ↑ ***impulse*** transmission ➔ *generalized* muscular **contraction** (Spasmodic)

Question 37

Zn3P2 (Zinc Phosphide)

Answer 37

Produces ***phosphine*** gas (PH3 ) on reaching **stomach** acid * Causes *widespread* **cellular** toxicity with injury to ***heart, liver, kidney***, and ***NS*** via **oxidative** *stress*