Pesticide Toxicity

Definition of Pesticide
 Any substance or mixture of substances deliberately added
to the environment and intended for preventing,
destroying, repelling, or mitigating pests

 Pesticides may be more specifically identified as

insecticides (insects), herbicides (weeds), fungicides (fungi
and molds), rodenticides (rodents), acaricides (mites),
molluscides (snails and other mollusks), miticides (mites),
larvicides (larvae), and pediculocides (lice)

 In addition, “pheromones” plant regulators, repellants,

and attractants often also fall in this broad classification of
chemicals
 Use of pesticides

 Pesticides are often, if not always, used as multi-agent

formulations, in which the active ingredient is present
together with other ingredients to allow mixing,
dilution, application, and stability…."inert" or "other“
(e.g., formaldehyde, sulfuric acid, benzene, toluene, other
organic solvents )
 “Others”

 “Others”: Though they do not have pesticidal action,

such inert ingredients may not always be devoid

of toxicity, thus, an ongoing task of manufacturers and
regulatory agencies is to assure that inert ingredients
do not pose any unreasonable risk of adverse health
effects
 US Pesticide Use

 4.5 billion pounds chemicals per

year
• 890 active ingredients, 30,000
formulations
• Uses
 75% agricultural

 25% home, garden,

structural
 Exposure

 Exposure to pesticides can occur via the oral or dermal

routes or by inhalation
 High oral doses, leading to severe poisoning and death,
are achieved as a result of pesticide ingestion for suicidal
intent, or of accidental ingestion, commonly due to
storage of pesticides in improper containers
 Chronic low doses, on the other hand, are consumed by
the general population as pesticide residues in food or as
contaminants in drinking water
 Exposure
 Workers involved in the production, transport, mixing
and loading, and application of pesticides, as well as in
harvesting of pesticide-sprayed crops, are at the highest
risk for pesticide exposure
 Dermal exposure during normal handling or application
of pesticides, or in case of accidental spillings, occurs in
body areas not covered by protective clothing, such as
the face or the hands, or by inhalation
 Furthermore, pesticides deposited on clothing may
penetrate the skin and/or potentially expose others, if
clothes are not changed and washed on termination of
exposure
 Human Poisoning
 Pesticides are not always selective for their
intended target species…..adverse health effects can
occur in nontarget species, including humans

 Concerns range from acute human poisoning to a

possible association between pesticide exposure
and increased risk of cancer

 Several million poisonings and a couple hundred

thousand of deaths….World Health Organization
(WHO) classified pesticides by hazard, where acute
oral or dermal toxicities in rats were considered
Table 22–1 WHO-recommended classification of
pesticides by hazard (2009).

WHO Class LD50 for the rat

(mg/kg body weight)

Oral Dermal
Ia Extremely hazardous <5 < 50
Ib Highly hazardous 5–50 50–200
II Moderately hazardous 50–2000 200–2000
III Slightly hazardous Over 2000 Over 2000
U Unlikely to present acute hazard 5000 or higher
 Diagnosis of Pesticide Toxicity

 Exposure history (most important)

• Occupational and environmental history
• Duration, dose, route of potential exposure
• information about the patient job, hobbies, home use
of chemicals, and proximity of residence to industrial
sites, including agriculture
 Symptom review
• Important to remember that symptoms may be caused
by “inert” ingredients and therefore may not be
typical of the active pesticidal ingredient in a
formulation
 Physical exam & lab findings
 Insecticides
 All of the chemical insecticides in use today are
neurotoxicants, and act by poisoning the nervous
systems of the target organisms

 Cholinesterase Inhibitors
• Carbamates
• Organophosphates

 Pyrethrins & Pyrethroids

 Organochlorines
 Cholinesterase Normal Function
1. Nerve signal releases ACh

Acetyl CoA + Choline

5. Choline reuptake

Acetylcholine (ACh)

Cholinergic Nerve Terminal

Choline +
Acetyl
2. ACh binds Acetylcholinesterase
to receptor

4. Choline regeneration
3. End organ activates in by acetylcholinesterase
presence of acetylcholine
 Inhibition of Cholinesterase
1. Nerve signal releases ACh

4.
Cholinesterase
Acetylcholine inhibitor binds
to the enzyme,
preventing Ach
degredation
Cholinergic R1 R2
Nerve Terminal O==P
2. ACh binds O
to receptor

3. Activity of end organ does not cease

 Cholinesterase Blood Tests

 Two cholinesterase enzymes

• RBC, NMJ and neural synapses
 “true”/ acetylcholinesterase
• Plasma
 “pseudo”/ butyrylcholinesterase

 Preferential inhibition possible

• Dichlorvos: plasma > RBC cholinesterase
Insecticides: Cholinesterase Inhibitors

 N-methyl Carbamates (carbamic acid)

• Carbaryl, Carbofuran, Aldicarb
R O
N C Generic structure for N—
methyl carbamates
R X
 Dermal skin penetration by carbamates is increased by
organic solvents and emulsifiers present in most
formulations
 Carbamates inhibit AChE reversibly……susceptible to a
variety of enzyme-catalyzed biotransformation reactions,
(oxidation and hydrolysis)
Insecticides: Cholinesterase Inhibitors

 Organophosphates (OPs)
• Chlorpyrifos, Diazinon, Malathion

RO O
Generic structure for
P OX organophosphates
RO

• Compounds that contain a sulfur bound to the

phosphorus, metabolic bioactivation is necessary for
their biological activity to be manifest…..only
compounds with a P=O moiety are effective inhibitors
of AChE (cytP450)
• Structures of some
organophosphorus
insecticides and of
the nerve agent sarin
• Most commonly used
compounds are
organophosphorothio
ates (i.e., have a P=S
bond), but some,
including sarin, have
a P=O bond and do
not require
metabolic activation
 Insecticides: organophosphate

 Phosphorylated AChE is hydrolyzed by water slowly,

and the rate of "spontaneous reactivation" depends
on the chemical nature of the R substituents

 When there is loss of one of the two alkyl (R) groups,

the enzyme-inhibitor complex has "aged“ and
reactivation of phosphorylated AChE does not occur

 The enzyme is considered to be irreversibly inhibited,

and synthesis of new enzyme is required to restore
activity, a process that may take days
 Table 22–4 Signs and symptoms of acute poisoning with
anticholinesterase compounds.

Site and Receptor Affected Manifestations

Exocrine glands (M) Increased salivation, lacrimation, perspiration

Eyes (M) Miosis, cyclospasm

Gastrointestinal tract (M) Abdominal cramps, vomiting, diarrhea
Respiratory tract (M) Increased bronchial secretion,
bronchoconstriction
Bladder (M) Urinary frequency, incontinence
Cardiovascular system (M) Bradycardia, hypotension
Cardiovascular system (N) Tachycardia, transient hypertension
Skeletal muscles (N) Muscle fasciculations, twitching, cramps,
generalized weakness, flaccid paralysis

Central nervous system (M, N) Dizziness, lethargy, fatigue, headache, mental

confusion, depression of respiratory centers,
convulsions, coma

M: muscurinic receptor
N: nicotininc receptor
 Commonly-used Acronyms for
Cholinesterase Inhibition Syndromes

 Salivation  Defecation
 Lacrimation  Urination
 Urination  Miosis
 Diarrhea  Bronchospasm
 Excessive salivation
 Lacrimation
 Salivation sweating
 Treatment of Pesticide Intoxication Decontamination

 Procedures aimed at decontamination and/or at

minimizing absorption depend on the route of
exposure:
• Collect serum, urine, & clothing samples…..save for
residue analysis
• Dermal exposure: contaminated clothing should be
removed, and the skin washed with soap. Scrub under
fingernails
• Ingestion: administer activated charcoal or gastric
lavage in case of large ingestions, caution: possibility
of seizures or rapidly changing mental status
Specific Management for AChI Poisoning

 Respiratory distress: maintain ABC; Oxygen,

bronchodilators if indicated
 Atropine (i.v), (muscarinic receptor antagonist),
prevents the action of accumulating acetylcholine on
these receptors
 Administration of pralidoxime (2-PAM) early after
exposure can help prevent AChE aging
 Diazepam may be used to relieve anxiety in mild
cases, and control convulsions in the more severe
cases
 Treatment: Atropine
 Reverses SLUD, DUMBELS syndrome
 Give atropine in escalating doses until
clinical improvement is evident. Begin with
2–5 mg IV initially
 Double the dose administered every 5
minutes until respiratory secretions have
cleared.
 Note: Atropine will reverse muscarinic but
not nicotinic effects
 2-PAM Treatment Regimen
 Loading dose (30–50 mg/kg, total of 1–2 g in adults)
over 30 minutes
 followed by a continuous infusion of 8–20 mg/kg/h
 Most effective if started early, before aging
 but may still be effective if given later, particularly
after exposure to highly lipid-soluble compounds
released into the blood from fat stores over days to
weeks
 Continue pralidoxime for 24 hours after the patient
becomes asymptomatic, or at least as long as
atropine infusion is required
 Insecticides
 All of the chemical insecticides in use today are
neurotoxicants, and act by poisoning the nervous
systems of the target organisms

 Cholinesterase Inhibitors
• Carbamates
• Organophosphates

 Pyrethrins & Pyrethroids

 Organochlorines
 Insecticides
Pyrethrins & Pyrethroids

 Pyrethrins
• Natural insecticides developed from extracts of the
flower head of Chrysanthemum cinerariaefolium
• Unstable
 Pyrethroids
• Synthetic derivatives
• Used with piperonyl butoxide to
Prolong their activity
 Pyrethroid Insecticides
• Pyrethroids now account for >25% of the global
insecticide market
 High insecticidal potency
 Relatively low mammalian toxicity (not well
absorbed from skin and GIT),
 Lack of environmental persistence, and
 low tendency to induce insect resistance,

• used widely as insecticides in :

 in the house and in agriculture,
 in medicine topically for Tx of scabies and head lice
 in tropical countries as soaks to prevent mosquito
bites
 Pyrethrins & Pyrethroids
Mechanism of Toxicity

 Pyrethroid structure
 Type I (non-cyano) Pyrethroid structure

· Shorter inactivation
Compound R R’

· Type II (-cyano)
· Longer inactivation
 Pyrethrins & Pyrethroids
Mechanism of Toxicity

• They are axonic poisons and cause paralysis of an

organism

• The chemical causes paralysis by keeping the

sodium channels open in the neuronal membranes
of an organism

• Pyrethroids are rapidly metabolized through both

type I and type II reaction (hydrolysis and oxidation
as well as conjugation)
 Pyrethroids Toxicity

• Dermal contact with pyrethroids is paresthesia (from

a direct effect on cutaneous nerve endings)
• Symptoms include continuous tingling & tickling or,
when more severe, burning
• Ingestion of large dose the CNS may be affected,
resulting in seizures, coma, or respiratory arrest.
• Chronic studies indicate that at high dose levels they
cause slight liver enlargement accompanied by some
histopathologic changes

• Little evidence of teratogenicity and mutagenicity

 Pyrethroid Toxicity Treatment

 Symptomatic relief
 Decontamination
 Topical application of vitamin E?? (in part
due to sequestration of lypophilic pyrethroid into
the vitamin E)
• In prophylaxis, or after 15-20 min of exposure.
(oil/vaseline)
 administer activated charcoal orally
 Enhanced elimination. …no role…rapidly
metabolized
 Insecticides
 All of the chemical insecticides in use today are
neurotoxicants, and act by poisoning the nervous
systems of the target organisms

 Cholinesterase Inhibitors
• Carbamates
• Organophosphates

 Pyrethrins & Pyrethroids

 Organochlorines
 Insecticides: Organochlorines

 Chlorinated ethane derivatives (DDT)

(prototype)
 Cyclodienes (Chlordane, aldrin, dieldrin,
heptachlor, endrin, toxaphene)

 Hexachlorocyclohexane (Lindane)
 DDT and Its Analogs
 DDT effective against agricultural pests, and insects
that transmit serious diseases (malaria & yellow fever)
 DDT has a moderate oral acute toxicity and its dermal
absorption is very limited
 The earliest symptom DDT poisoning is pyresthesia of
the mouth and lower part of the face
 High doses also causes motor unrest, increased
frequency of spontaneous movements, abnormal
susceptibility to fear, to external stimuli, followed by
the development of tremors, and eventually
convulsions
 DDT and Its Analogs
 Both in insects and in mammals, DDT interferes with
the sodium channels in the axonal membrane by a
mechanism similar to that of pyrethroids
 An important target for chronic DDT exposure is the
liver……increase liver weight and cause hepatic cell
hypertrophy and necrosis
 Potent inducers of cytochrome P450s
 Both DDE and DDD (breakdown product), are
carcinogenic in rodents, causing primarily an increase
in hepatic tumors
Hexachlorocyclohexanes and Cyclodienes

• These two families of organochlorine insecticides

comprise a large number of compounds that share a
similar mechanism of neurotoxic action
• Lindane and cyclodienes have moderate to high
acute oral toxicity….readily absorbed through the
skin
• The primary target for their toxicity is the

central nervous system…..bind to

the chloride channel, blocking its opening and
antagonizing GABA action
• Tremor is absent, but convulsions are a prominent
aspect of poisoning
 Other Insecticides
Nicotine
• Oral LD50 is 50-60 mg/kg
• Is readily absorbed through skin
• Mimics the action of acetylcholine

Rotenoids At least six rotenoid esters (rotenone)

• Isolated from Derris root
• Toxicity due to its ability to inhibit, at nanomolar conc., the
mitochondrial respiratory chain
• Toxicity varies greatly in different species
• Very toxic to fish - Used to paralyze fish for capture and
consumption
• Low acute toxicity in humans, but causes allergic reactions
• Poisoning symptoms: increased respiratory and cardiac
rates, muscular depression, followed by respiratory
depression