Toxic effects of Pesticides

By, Abel.A (Msc in Pharmacology)

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PESTICIDES

 Pest:
 The term pest describes harmful, destructive or
troublesome insects, rodents, nematodes, or weeds.
 Pesticide:
 any substance or mixture of substances intended for
destroying, repelling, or mitigating pests.

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1. Insecticides
I. Organochlorine insecticides.
II. Organophosphate & carbamate insecticides.
III. Botanical insecticides- Pyrethrins, nicotine.
 Poisoning from insecticides may result from
ingestion (e.g. at home), as well as dermal &
respiratory exposure to industrial insecticides.
 Insecticides are responsible for:
 Acute dermal and respiratory inflammation.
 Chronic dermal neoplasms.

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A. Organochlorine insecticides(OCl)

 Chlorinated hydrocarbon insecticides, were widely

used during the mid 1940s to mid 1960s as
insecticides for malaria carrying mosquito control
and termite extermination.
 Their properties include:
 Low volatility,
 chemical stability, and
 environmental persistence.
 led to their bioaccumulation.

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 OCls…

 Divided in to four distinct groups;

A. DDT (dichlorodiphenyltrichloroethane) and
related analogs (methoxyclor),
B. Cyclodienes (aldrin, endrin, heptachlor,
dieldrin, chlordane, endosulfan,
chlordecone).
C. Hexachlorocyclohexane (lindane) and
D. Toxaphene and related compounds.

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 Ocls….
 DDT was synthesized in 1873.
 Insecticidal properties were noted in 1939 by Dr. Paul
Mueller.
 During WW-II, large quantities of DDT was used to
control vector-borne diseases, such as typhus and
malaria.
 After the war DDT use became widespread in
agriculture, public health(malaria), and households.
 Its persistence, initially considered a desirable
attribute, later became the basis for public concern.
 Ban of DDT and other chlorinated insecticides 1970’s.
 Cyclodiene insecticides, such as chlordane were
6 used extensively as termiticides into the 1980s but
Mechanism of action
The chlorinated hydrocarbons are neurotoxicants
and cause acute effects by interfering with the
transmission of nerve impulses.
A. Antagonize GABA – mediated inhibition of the
central neurons, leading to hyperexcitability.
B. Sensitize the myocardium to arrhythmogenic
effects of catecholamine.
C. Carcinogenic.

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 Signs & symptoms of acute toxicity
 Inhibition of GABA leads to motor, sensory, and
behavioral changes, typically manifested as
irritability, confusion, sensory disturbances,
dizziness, tremors and seizures.

 The chemical sensitize involuntary autonomic

muscle activity to catecholamines . In particular
myocardial arrhythmias are promptly precipitated.

 In addition, respiratory failure, hepatic damage are

a consequence of large lindane ingestion.

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 Clinical management of acute poisoning
 Treatment involves symptomatic & supportive
management of the condition.
 Surface decontamination, gastric lavage, and
administration of activated charcoal reduce
toxicity after oral ingestion.
» Washing of the affected area may reduce
absorption after dermal exposure.
 Myocardial arrhythmias are managed with
antiarrhythmics such as lidocaine.
 While benzodiazepines are indicated for
preventing or reducing the development of
seizures.
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B. Organophosphate and carbamate
insecticides

The functional class of insecticides known as

anticholinesterases evolved from two chemical
classes of experimental agents synthesized in the
1930s;
 Organophosphorous (OP)
Organophosphorous pesticides (OPs) are
phosphoric acid esters or thiophosphoric acid
esters and are among the most widely used
pesticides for insect control.
 Carbamate esters: derivatives of carbamic acid.

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OP Insecticides

Chemical Name Median Oral

Rodent LD50
(mg/kg)

Tetraethyl pyrophosphate 1.1

Phosdrin 3.7–6.1

Guthion 11

Malathion 1000–1375

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OP Insecticides….
Tetraethyl pyrophosphate (TEPP)
 First OP insecticide.
 Marketed as a substitute for nicotine to control
aphids(a small bug that sucks saps from plant).
 Highly toxic to mammals.
 Rapidly hydrolyzed in water
TEPP was replaced by other OP insecticides.

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Organophosphorus Insecticides….

Chlorpyrifos
 Became one of the largest selling insecticides in the
world.
 Had both agricultural and urban uses.
Parathion
 Widely used insecticide.
 Stabile in aqueous solutions.
 Broad range of insecticidal activity.
 High mammalian toxicity through all routes of exposure.

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Malathion
 Has low mammalian toxicity.
Mammals possess certain enzymes, the
carboxylesterases, that detoxify the compound.
 Insects, by contrast, do not readily hydrolyze this ester, and
the result is its selective insecticidal action.
 The OP insecticides were originally developed as
nerve gases as possible chemical warfare agents
during World War II.
 The biological action of the nerve gases, such as
sarin, tabun, and soman, is similar to, but more toxic
than the OPs.

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Mechanism of toxicity
 Both organophosphorous and carbamate ester
insectcides inhibit nervous tissue AChE.
 Excess ACh accumulates in cholinergic synapses
producing initial hyper-stimulation of most cholinergic
receptors.
 Although the mechanisms of inhibition by these
inhibitors are similar, they differ in some important
qualitative and quantitative aspects.

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Mechanism of toxicity…
A. Organophosphates
 Clinical and toxicologic effects of OP are due to their
actions at cholinergic synapses, where OP inhibit and bind
irreversibly to cholinesterase.
 Also associated with delayed neurotoxicity, known as
organophosphorus-induced delayed neuropathy (OPIDN).
 Bilateral paralysis of the distal muscles, occurring some 7
to 10 days following ingestion.
 Not all OP compounds cause delayed neuropathy.
B. Carbamate compounds
 These agents are reversible cholinesterase inhibitors;
carbamates spontaneously hydrolyze from the
cholinesterase enzymatic site within 24 hrs.
 Carbamates also poorly penetrate the BBB. E.g. Carbaryl.
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 Mechanism of toxicity…
 OP and carbamate insecticides are relatively nonpersistent
in the environment.
 These compounds, in contrast to the organochlorine
insecticides, do not represent a serious problem as
contaminants of soil and water and rarely enter the human
food chain.
 Generally persist from only a few hours to several months.
 Since esters, these compounds are susceptible to
hydrolysis, and their breakdown products are generally
nontoxic.
 Are applied to the crop or directly to the soil as systemic
insecticides.
 Direct contamination of food by concentrated compounds or
dermal exposure has been the cause of poisoning episodes.
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Symptoms of OP and Carbamate toxicity
 Acute symptoms
 Miosis, hyper secretion, brocnchoconstriction, diarrhea,
cramps, urination, bradycardia, cardiac arrest, muscle
fasciculation, tremor, weakness, paralysis, restlessness,
ataxia, lethargy, confusion, loss of memory, convulsion,
respiratory depression, coma.
 Chronic symptoms
 Loss of ambition and libido, autonomic dysfunction,
cephalgia, GIT symptoms, delayed and lasting neuropathy
and neuropsychological dysfunction, emotional lability,
confusion, memory loss, anxiety, depression, insomnia,
ataxia, speech difficulty, muscle weakness, neurological
deficits.

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  Clinical management of acute OP poisoning
Decontamination, airway stabilization, and
activated charcoal are important initial supportive
measures for OP intoxication.
Washing dermal areas with a mild soap, removal
of contaminated clothes , and rinsing the eyes is
necessary for dermal or ocular exposure.
Atropine and pralidoxime(2-PAM) and diacetyl-
monoxime(DAM) follow as specific OP antidotes.
In adults, atropine (1-2 mg IV) counteracts the
excessive bronchial and autonomic secretions
and normalizes heart rate.
 The dose is repeated every 5-10 minute depending on
improvement of respiration.
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 Pralidoxine is effective when administered soon after
exposure, before the poisoned enzyme complex has
“aged” and becomes resistant to the effects of the
antidote.
 An initial dose of 1-2 g, by continuous IV infusion is
followed by 500mg/h for 24h, in order to maintain
effective therapeutic levels of 4 µg/l.

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 Carbamates
– Carbamate esters are another important group that
also act as acetylcholine esterase inhibitors.
– They react at the enzyme active site by binding to
serine.
– However , instead of phosphorylating the enzyme,
they carbamylate it.
– The result is an inhibited enzyme which is however
subject to rapid hydrolysis and enzyme
regeneration.

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 Treatment of carbamate poisoning
 Initial treatment of carbamate poisoning is the
same as for organophosphorous compound.
 Atropine is the antidote of choice and is
administered for muscarinic symptoms.
 Use of pralidoxime in carbamate poisoning is not
required .

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 C. Botanical Insecticides
Nicotine
 Extracts from plants have been used for centuries to
control insects.
 Nicotine is an alkaloid occurring in Tobacco plants.
 First used as an insecticide in 1763.
 Nicotine is quite toxic orally as well as dermally.
 Symptoms of acute nicotine poisoning occur rapidly.
 Death may occur with a few minutes as a result of
respiratory failure.
 Treatment -support of respiration.

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Pyrethrin
 Refers to 6 active compounds (pyrethrin I, pyrethrin
II, jasmolin I, jasmolin II, cinerin I, cinerin II) found
in pyrethrum, which is an extract of dried
chrysanthemums.
 Pyrethrin is applied at low doses and is considered
to be nonpersistent.
 Mammalian toxicity to pyrethrins is quite low.
Rapidly metabolized into inactive components by
liver microsomal enzymes and estrases.
 The most frequent reaction to pyrethrins is contact
dermatitis and allergic respiratory reactions,
probably as a result of other constituents in the
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Pyrethroid Insecticides
 Synthetic analogues of pyrethrins.
 Overcome the lack of persistence of pyrethrins.
 Pyrethroids, have greater insecticidal activity and
are more photostable than pyrethrins.
 They are generally applied at low doses and have
low mammalian toxicities.

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 Pyrethrins and pyrethroids are common ingredients
in household insecticides and are usually combined
with a synergist such as piperonyl butoxide to retard
degradation.
 They are also available in several over the counter
pediculicides and scabicides.
Human toxicity from these compounds is quite
low, and they are considered to be among the
safest insecticides to humans.

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 Mechanism of toxicity
In insects:
 Pyrethrins and pyrethroids rapidly cause death by paralyzing
the nervous system through disruption of the membrane ion
transport system in nerve axons, and
 Pyrethroids prolong sodium influx and also may block
inhibitory pathways.
In mammals:
 Are generally able to metabolize these compounds rapidly
and thereby render them harmless.

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Clinical presentation
 After ingestion, both Pyrethrins and pyrethroids
undergo rapid biotransformation by liver enzymes,
which also limits systemic toxicity.
 Allergic and hypersensitivity reactions are the most
common manifestations of pyrethrin toxicity but are
uncommon after pyrethroid exposure.
 Allergic rhinitis, contact dermatitis, asthma,
hypersensitivity pneumonitis, and an anaphylactoid
reaction have been reported.
 Treatment
 Administer diphenhydramine PO, IM, or IV, 25-50mg q6-q8h
PRN for adults or 5 mg/kg/day divided q6-8hPRN for
children.

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2. Herbicides

 C on t r ol weed s a n d a r e t h e mos t wi d el y u s ed c l a s s of

pesticides

 They constitute a wide variety of chemicals whose main

classes include:
I. Chlorophenoxy acids and their esters

II. Triazines: contaminate surface and groundwater supplies

III. Dipyridyl derivatives

IV. Imidazolinones

 New class of herbicides continue to be developed:

 Applied at low doses

 Relatively nonphytotoxic to beneficial plants

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 Environmental friendly
Chloro phenoxy herbicides

- 2,4-dichlorophenoxy acetic acid and 2,4,5-trichlorophenoxy-

acetic acid

- Are systemic acting compounds to control broadleaf plants

- Have been in use since the 1940s

- The oral toxicities of these compounds are low

- The primary routes of exposure are dermal and inhalation

- Chl orophenoxy compounds a ct by uncoupl i ng oxi da t i ve

phosphorylation and decreasing oxygen consumption in tissue

- These compounds are rapidly excreted and do not accumulate

in the body
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Triazines:
- Another family of herbicides, the triazines, continues to
cause concern to environmentalists and toxicologists
because of the contamination of surface and groundwater
supplies that become public drinking water

- The herbicide, atrazine is used primarily on corn

- This herbicide has been found in surface and ground waters

worldwide with widely varying concentrations

- US EPA considers triazines as possible human carcinogens

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 Dipyridyl derivatives

Paraquat and diquat

- Are the most commonly used herbicides

- Toxicity results from lung injury resulting from both the preferential

uptake of paraquat by the lungs and the redox cycling mechanism

Paraquat

- It is a very water soluble contact herbicide that is active against a

broad range of plants and is used as a defoliant on many crops

- The compound binds tightly to soil particles following application

and becomes inactivated

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 Mechanism of toxicity

- Paraquat is extremely toxic to humans and laboratory animals

- The dipyridyl herbicides are extremely potent systemic toxins

when absorbed and can cause multiple system organ damage

- In alveolar cells, paraquat under goes NADPH dependent one-

electron reduction to form a free radical

 leading to cell death and tissue destruction through lipid

peroxidation

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- Paraquat is preferentially accumulated by Type I and Type II

alveolar cells by a diamine/polyamine transport system

- Exposure causes intra-alveolar hemorrhage, congestion and

pulmonary fibrosis

- Diquat is not taken up by pulmonary alveolar cells and does

not cause pulmonary fibrosis

 Accumulates in the kidney, causing renal failure

 Associated with GI fluid sequestration

 Also cause cerebral and brainstem hemorrhagic infarctions

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 Clinical management of acute poisoning

 In general, PQ poisoning is managed aggressively with

symptomatic and supportive care

 Evaluation of esophageal erosion and determination of

serum and gastric f lu id levels of PQ are benef ic ial in

predicting outcome

 Activated charcoal , gastric lavage, and /or administration

of a cathartic may prevent further absorption

 Fo rc e d d i ure si s and hyd rat i o n are e ffe c t i v e o nl y i f

intervention is attempted soon after ingestion and in the

presence of lower doses of the herbicide
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Imidazolinones

- Inhibit the action of aceto-hydroxyacid synthase that

produces branched-chain amino acids in plants

- These herbicides have low toxicities to mammals, f is h,

insects, and birds

 Since the enzyme is produced only in plants

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3. Rodenticides

 Used to control rodents that cause yearly losses of

20% to 30% in grain and other food storage facilities.

 These pests harbor diseases in the form of fleas that

carry bacteria and other organisms.

 Rodenticides are a diverse group of chemically and

structurally unrelated compounds.

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 Human poisonings associated with rodenticides
usually result from accidental or suicidal ingestion
of the compounds.

 Classified based on whether they are anticoagulants

or non anticoagulants , time of onset of signs and
symptoms, and degree of toxicity.

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Non anticoagulants
A. Aluminium phosphide
 Commonest agents of suicidal poisoning in countries
where its availability is not tightly regulated.
 Very potent rodenticide.
 Widely used in India.
 Has high rate of accidental and suicidal poisoning.

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Mechanism of toxicity

 ALP acts by reacting with air or moisture to liberate

phosphine gas.

 ALP poisoning is associated with numerous

complications usually related to the inhibition of
cytochrome oxidase and lipid peroxidation of
membranes.

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 Signs and symptoms of acute toxicity
 Upper airway and ophthalmic injuries;
Distinguished by local inflammation and irritation
of ocular, oral and nasal mucous membranes.
Include conjunctivitis, lacrimation, rhinitis, and
pharyngitis.
 LRT symptoms include cough, wheezing, and tightness of
chest with painful breathing.
 Early symptoms include nausea, fatigue, tremors, dizziness,
and hypotension, followed by pulmonary edema,
cardiogenic shock, central nervous system depression,
convulsions, and coma.

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 Clinical management of acute poisoning
 Is primarily supportive and symptomatic.
 use gastric lavage, as well as administration of activated
charcoal and sodium bicarbonate to reduce absorption
and neutralize acidity, respectively.
 Treatment and decontamination should be instituted soon
after exposure or upon dermal contact.
 Induction of vomiting is not generally recommended , due
to phosphate’s potentially corrosive nature.
 Cardiopulmonary support, renal perfusion, prevention of
circulatory collapse , and oxygenation may be required.

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B. Thallium sulfate
 Is a heavy metal with moderate to high acute
toxicity that is used by industry and rodenticide at
home.
 Common poisoning responsible for suicides and
homicidal deaths.
 Mechanism of toxicity
 Combines with mitochondrial sulfhydyl groups,
interfering with oxidative phosphorylation.

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 Signs and symptoms of acute toxicity
 Early GI symptoms.
 After 2-5d, painful paresthesias, myalgias, muscle weakness,
headache, lethargy, tremors, ataxia, delirium, seizures and
comma.
 Death from respiratory failure and dysrrythmias.
 Treatment
 Supportive care.
 Multiple doses of activated charcoal or prussian blue
(potassium ferric hexaniacinate) interrupt enterohepatic
circulation and increase elimination in stool.

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Anticoagulants

 Warfarin
 Potent toxicant with an oral LD50 of 3.0 mg/kg (rat).
 Animals bleed to death in a week.
 “Super warfarins” (brodifacoum, indanediones) are
popular rodenticides
Mechanism of toxicity
 Warfarin is vitamin K antagonist that inhibits vitamin K
dependent clotting factor proteins.

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 Signs and symptoms of acute toxicity
 Gingival bleeding , epistaxis, joint and muscle pain, easy
bruising and an abnormal PT time are among the initial
features of anticoagulant overdose.
 Intentional ingestion of high doses, or chronic repeated
administrations are associated with severe coagulopathies ,
including hematuria, bloody stools, intracranial hemorrhage,
and shock.

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Clinical management of poisoning

 Replacement of blood loss and reversal of the

anticoagulant effects are the primary goals of
therapy.

 Chronic anticoagulant management necessitates the

administration of vitamin-k1 (phytomenadione).

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Fumigants
 Fumigants are extremely toxic gases used to protect
stored products, especially grains, and to kill soil
nematodes.

 They present a special hazard due to inhalation

exposure and rapid diffusion into pulmonary blood.

 Extreme care must be taken when handling and

applying this class of pesticides.
Examples: methyl bromide, carbonmonoxide, sulphur
dioxide…etc.

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