Pesticides

Mustofa
Department Pharmacology and Toxicology
Faculty of Medicine, Gadjah Mada University

Pesticide:
Any substance or mixture of substances
intended for preventing, destroying,
repelling, or mitigating any pest.
Any physical, chemical or biologic agent
that will kill an undesirable plant or
animal pest

Pest :
harmful, destructive, or troublesome
animal, plant or microorganisms.

Pesticides

Insecticides
Herbicides
Fungicides
Ascaricides
Miticides
Mollucides
Pediculicides
Rodenticides
Scabicides
Pheromones
Defoliants
Desiccants
Repellants
Plants growth regulator

Insecticides
Neurotoxic and act by poisoning the nervous
systems of the target organisms.
Inhibit the membrane transport of sodium,
potassium, calcium.
Inhibition of selective enzymatic activities
Influence to the release and/or the
persistence of chemical transmitters at
nerve endings.

Insecticidal chlorohdrocarbons
Organophosphorus insecticides

Insecticides

Insecticidal carbamates

Naturally insecticides and its analogous

Miscellaneous classes

Organochlorine insecticides
DDT was first synthesized in 1874.
The effectiveness against household
and crop insect pest was demonstrated
in 1940.
In 1943, the first medical use in the
suppression of a typhus in Naples.
In 40s-60s, were used extensively in
agriculture and forestry, in building
and structural protection, human
situation.

Classification of organochlorine
Dichlorodiphenylethanes

- DDT, DDD
- Dicofol, Methoxychlor
- Perthane, Methlochlor

Cyclodines

- Aldrine, Dieldrin,
- Heptachlor, Chlordane
- Endosulfane

Chlorinated benzenes cyclohexanes

- HCB, HCH
- Lindane

Organochlorine insecticides
1.High insecticidal activity.
2.Low acute mammalian activity.
3.Wide spectrum
4.Simple manufacture and handling.
5.Low price
6.Long duration activity.

Low volatility, Chemical stability,

Lipid solubility, slow rate
biotransformation, degradation

Effective
insecticides

Toxic effect

Persistence in the environment,

Bioconcentration, biomagnification
within food chains etc.
Lethal or reproductive effect

Insecticides

Wildlife and
lab. species

Potent estrogenic
Enzymes-inducing

Interfered with
Fertility &
reproduction

Avian species

Fish

Steroid metabolisms
interference
Immobilize calcium

Accumulation of
residues & metabolite
Slow elimination

The entry of bacteria

Death of the embryo

Bioconcentration
in the yolk sac

Affects in
reproduction

Lethal Dose (LD50) of organochlorine

Insecticide
DDT
Methoxychlore
Aldrin
Dieldrin
Hepatachlore
Chlordane
Lindane
Mirex

LD50 (mg/kg/BW) on mice

oral
perdermal
217
2510
5000
7000
39
98
18
18
100
195
335
840
88
1000
740
>2000

Signs and symptoms of poisoning

DDT
Parathesia, apprehension, irritability,
hypersusceptibility, dizziness, vertigo
tremor, tonic and clonic convulsions.
Poisoning can be associated with CNS
effects, pathologic change (liver & reproductive organs) in animal.
Symptoms appear 6-24 hours
Dose of 10 mg/kg will cause signs of
poisoning in human

Cyclodiene
Tend to induce convulsions before

serious signs occur

Follows headaches, nausea, vertigo,
clonic jerking, hyperexcibility,
hyperreflexia
Reduction in fertility & increased
pup mortality
Neurotoxicity, teratogenic

Hexachlorocyclohexane
Exposure HCH produce signs that
resemble those caused by DDT
(i.e. tremors, ataxia, convulsions,
stimulated respirations, prostration)
Degenerative change in the liver and
renal tubules
Technical grade HCH contains a mixture
isomer that can cause CNS depressants
and hepatocellular tumors

Chlordecone
Developed a severe neurologic syndrome
(Kepone shakes) tremor, altered gait,
behavioral changes, ocular flutter,
arthralgia, headache, arthralgia, chest
pains, weight loss, hepatomegaly,
splenomegaly, impotence.
reduced sperm mortality
decreased in the population axon, damage
to Schwann cells, vacuoliwation of un
myelinated fibers etc.

Site and mechanism of toxic actions

DDT
affect the permeability to potassium
ions, reducing across the membrane
interfering with active transport of
sodium out of the nerve axon during
repolarization
inhibits ATPase that play vital roles in
neuronal repolarization
inhibits the ability of calmodulin to
transport calcium ions

Cyclodiene, benzene, HCH

Different from DDT in the intoxicated
individual and in the mechanism
(localized more in the CNS)
antagonizing GABA receptor results in
partial repolarization and a state of
uncontrolled excitation
potent inhibitor of Ca++ and Mg++ ATPase
essential for the transport calcium

Biotransformation, distribution, storage

Biotransformation rate is slow.

Insecticides will be sequestered in

body tissues (liver, kidneys,
nervous, adipose tissues).
Insecticides are slowly eliminated
from storage sites in vivo.

Treatment and poisoning

The life-threatening is associated with
the tremors, the motor seizures and the
interference with respiration function
The general decontamination and
supportive treatment (diazepam or
phenobarbital)
Therapy to enhance the rate of excretion
of stored from the body (cholestyramine)

Organophosphorus ester

X
Y

O or S
Z

Tetraethylpyrophospate (TEPP)
Parathion (E605)
Paraoxon
Diazinon

Signs and symptoms of poisoning

Inhibition of the (AChE)
Accumulation ACh
ACh
receptor

Muscarinic
receptor

Nicotinic
receptor

Clinical manifestations

Toksisitas insektisida organofosfat

Senyawa

LD50 pada tikus betina

(mg/kg)

Tidak timbul efek

(mg/kg/hari)

ADI
(mg/kg)

Oral

Dermal

TEPP

1,1

2,4

Mevinfos

6,1

4,7

Disulfoton

6,8

15

Azinfosmetil

13

220

Tikus/anjing 0,125

0,0025

Paration

13

21

Tikus/manusia 0,05

0,005

Metil paration

14

67

Klorfenvinfos

15

31

Tikus/anjing 0,05

0,002

Diklorvos

80

107

Tikus 0,5

0,004

Diazinon

108

200

Tikus 0,1; anjing 0,02

0,002

Dimetoate

215

260

Tikus 0,4; manusia 0,04

0,002

Triklorfon

630

2000

Tikus 2,5; anjing 1,25

0,01

Klorotion

880

1500-4500

Malation

1375

4444

Tikus 0,5; manusia 0,02

0,002

Ronnel

1250

5000

Tikus 0,5; anjing 1,0

0,01

Abate

8000

4000

ADI : Acceptable Daily Intake

Clinical manifestations
gejala berupa sesak pada rongga dada,
wheezing pernafasan akibat bronkokontriksi,
kenaikan sekresi kelenjar bronkus,
salivasi,
lakrimasi,
berkeringat,
kenaikan tonus dan peristaltik gastrointestinal
tract nausea, vomiting, kram perut, diare,
tesnesmus, defeksasi tak terkendali,
bradikardi yang bisa menyebabkan henti
jantung,
urinasi tak terkendali,
miosis.

Terapi keracunan organofospat

1. respirasi buatan,
2. pemberian atropin sulfat 2-40 mg secara intravena
segera setelah gejala sianosis terjadi.
3. ulangi setiap 5 atau sepulu menit sehingga tampak
gejala atropinasi. Dosis atropin yang dibutuhkan
umumnya lebih tinggi dibanding untuk tujuan lain,
oleh karena penderita yang keracunan lebih toleran
terhadap atropin,
4. setelah tampak gejala atropinasi, penderita
diberikan 2-piridine aldoxine methiodid (2-PAM), 1
g perlahan secara intravena. 2-PAM berfungsi
untuk regenerasi aktivitas asetilkolinesterase.
5. dekontaminasi kulit, perut, mata dari organofosfat
baru bisa dilakukan setelah tindakan 1-4 diatas.

Carbamate esters

OH

R
C N

X, Y = alkyl, alkoxy, amido

Z = aryl, alkyl, alkoxy R = aryl, alkyl
Propoxur
Carbaryl
Temic (Aldicarb)
Zectram

Intoxication by carbamate
The signs and symptoms by carbamate
are quite similar to organophosphorus.
The carbamate have relatively short
duration and mild to moderate of signs
- carbamates are reversible inhibitor,
unlike most of organophosphorus
- carbamate are rapidly biotransformed
in vivo

Lethal Dose (LD50) of carbamate ester

Insecticide
Propoxur
Carbaryl
Mobam
Temic
Zectram

LD50 (mg/kg/BW) on mice

oral
perdermal
83,0
>2400
850
>4000
150
>2000
0,8
3
37
1500-2500

Biotransformation, distribution, storage

Both insecticides undergo

extensive biotransformation
The route and the rate are highly
species specific and dependent on
the substituent groups
Tissue enzymes of both phase I and
phase II are responsible for the
species sensitivity and resistance to
insecticides

Treatment and poisoning

Monitroring of plasma & erythrocyte
AChE
The life-threatening (respiratory
depression, bronchospasm, bronchial
secretion, pulmonary edeme, muscular
weakness)
Treatment with the specific antidotal
chemical
Diazepam for counteract some aspects
of the CNS and neurological signs

Pyrethroid insecticides
Synthesized from pyrethrum
(pyrethrins, cinerins, jasmolins)
extracted from (Chrysanthemum
cinerariaefolium, C. coccineum)
The major active principles are
pyrethrin I (esters of chrysanthemic
acid) and pyrethrin II (esters
pyrethric acid)
Pyrethrin I is the most active
ingredient

Site and mechanism of toxic actions

Based on the symptoms produced, the
pythroids fall into two distinct classes :
Type I poisoning syndrome is produced
by esters lacking the cyano subtituent
The type II syndrome is produced by
those containing the cyano substituent

Site and mechanism of toxic actions

Type I pyrethroid esters

affect sodium channel in nerve causing
repetitive neuronal discharge and a
prolongation negative after-potential

Type II pyrethroid esters

produce a longer delay in sodium
channel inactivation, leading to
presistent depolarization without
repetitive discharge

Biotransformation, distribution, storage

The microsomal monooxigenase

sytem is extensively involved in the

detoxification

Treatment and poisoning

No specific treatment, other than

symptomatic and supportive

therapies

Botanical insecticides
Nicotine
Nicotiana tobacum & N. rustiana

LD50: 50-60 mg/kg) in rat

Rotenoids
Derris eliptica & Lonchocarpus utilis
Rotenon is the most potent
LD50 : 60, 132, 3000 mg/kg in guine
pigs, rats and rabbits

Herbicides
any compound that is capable of
either killing or severely injuring
plants and may be used in the
elimination of plant growth or killing
of the plant parts.
Classification of herbicides :
- by chemical structure
- by to how and when the agent are
applied (Preplanting,
preemergent, postemergent)

Chlorophenoxy compounds
In plant this compound mimic the
action of auxins, hormone related to
indoleacetic that stimulated growth
Toxic action poorly understood,
associated with its pharmacokinetic
biotransformation, elimination
Temperature, pulse and respiratory
rates , blood pressure, sweating,
oliguria, blood urea , coma

Bipyridyl derivatives
Paraquat
Intoxication involves lethargy, hypoxia,
dyspnea, tachycardia, hyperapnea,
diarrhea, ataxia, convulsions
pulmonory and renal toxic
a highly polar, poorly absorbed
Diquat
major target organ GI, liver and kidneys
rapidly acting contact herbicide
poorly absorbed, eliminated via urine

Fungicides
Derived from variety structure from
simple inorganic (sulfur, copper
sulfat) through the aryl- and alkyl
mercurial compounds, chlorinated
phenol, metal- containing
thiocarbamic acid
May be used as foliar fungicides,
soil fungicides or dressing fungicides
Protective-, curative-, eradicative
fungicides

 To be an effective fungicide:
- have low toxicity to the plant
- be active or be capable of
conversion in a toxic intermediate
- have the ability to penetrate
fungal spores to reach a site action
- it must form a protective,
tenacious deposit on the plant
surface

Hezalochlorobenzene
Properties
stable, environmental persistence, slow
degradation, slow metabolism,
bioaccumulation, induce microsomal
enzymes
Toxicity
hepatomegaly, porphyria, local alopecia,
dermal itching, eruption, anorexia,
neurotoxicity, immunosuppression

Organomercurials
Compounds
methyl-/methoxyethyl mercury chloride,
dyciandiamide, phenylmercuri acetate,
tolymercuric acetate, ethylmecuric ptoluene sulfanilide
Toxicity
neurotoxicity, gastrointestinal toxic,
nephrotoxic, disastrous effect on
developing CNS

Pentachlorophenol
Mechanism of action
acts cellularly to uncouple oxidative
phosphorylation, N+, K+ ATPase
Toxicity
altered plasma enzymes, increased
hepatic and renal weight, hepatocellular
degeneration, changes in blood biochem
elevated temperature, dehydration,
marked loss appetite, decrease BW,
nausea, vomiting, headache,
incoordination etc.

Rodenticides
Ideally, a rodentia must
it must not be unpalatable to the target
species, must be quite potent
it must not induce bait shyness so the
animal will be continue to it
death should occur in a manner that
does not raise the suspicions
it should make the intoxicated go out
into the open to die
it should species specific

Zinc phosphide
Mechanism of action
formation the toxic phosphine (PH3)
after hydrolytic reaction with water in
stomach necrosis GI, injury to the
liver, kidneys
Toxicity
vomiting, diarrhea, cyanosis,
tachycardia, restlessness, fever,
albuminoria

Fluoroacetic acid and derivatives

Mechanism of action
incorporation fluoroacetate into
fluoroACoA inhibit the enzyme
aconitase and prevent conversion citrate
to isocitrate
Toxicity
tachycardia, hypotension, renal failure,
muscle spasm, CNS symptoms

Pyrinimil
Mechanism of action
interferes with nicotinamide metabolism,
direct effect on glucose metabolism,
distroying beta cells
Toxicity
impotency, hypotension, constipation,
diarrhea, neurophaty
nausea, vomiting, abdominal pain,
myalgia, polyuria, dyspnea, malaise,
weakness