Pesticides

Pesticides can be defined as any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating pests. Pests can be insects, rodents, weeds, and a host of other unwanted organisms Thus, pesticides occupy a rather unique position among the many chemicals that we encounter daily they are deliberately added to the environment for the purpose of killing or injuring some form of life Ideally, their injurious action would be highly specific for undesirable targets

Most pesticides are not highly selective, but are generally toxic to many non target species, including humans.

The use of pesticides must minimize the possibility of exposure

of non target organisms to injurious quantities of these chemicals

As there are dozens of drugs with different therapeutical indications and different mechanisms of action, several different classes of pesticides exist, with different uses, mechanisms and, hence, toxic effects in non target

organisms.

Classification
The most common classification of pesticides relies on the target species they act on.

The four major classes are those of

insecticides ( on insects), herbicides (on weeds), fungicides (on fungi, molds), and rodenticides (on rodents)

Roles of Pesticides

Pesticides play a major role in the control of vector

borne diseases, which represent a major threat to the health of large human populations. Pesticides of various types are used in the control of insects, rodents, and other pests that are involved in the life cycle of vector-borne diseases such as malaria,

filariasis, yellow fever, viral encephalitis, typhus, and

many others
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Exposure

Exposure to pesticides can occur via the oral or dermal routes or by inhalation. From a quantitative perspective, oral exposure lies on the extremes of a hypothetical doseresponse curve.

High oral doses, leading to severe poisoning and death, are achieved as a result of pesticide ingestion for suicidal intents, 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
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Regulations exist to ensure that pesticide residues are maintained at levels below those that would cause any adverse effects

Workers involved in the production, transport, mixing and

loading, and application of pesticides, as well as in harvesting of pesticide-sprayed crops, are at highest risk for pesticide

exposure.
Furthermore, deposition of pesticides on clothing may lead to slow penetration through the tissue and/or to potential

exposure of others, if clothes are not changed and washed

upon termination of exposure.
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INSECTICIDES
Insecticides play a most relevant role in the control of insect pests, particularly in developing countries.

All of the chemical insecticides in use today are neuro-toxicants,

and act by poisoning the nervous systems of the target organisms

The central nervous system of insects is highly developed and not unlike that of mammals, and the peripheral nervous system, though less complex, also presents striking similarities

 Insecticides are mostly not species-selective with regard to targets of toxicity, and mammals, including humans, are highly sensitive to their toxicity. When selectivity exists, this is often due to differences in detoxication pathways between insects and mammals, or to differential interactions with their target

Insecticides have higher acute toxicity toward non target

species organophosphates, are involved in a great number of human poisonings and deaths each year.
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 Insecticides Includes;
1. Organophosphates (OP) 2. Carbamates 3. Chlorinated Hydrocarbons (CHC) 4. Pyrethroids 5.Metals/Elementals

Organophosphates (OP)
More than half of the insecticides used are OPs, and some OPs are among the most extensively used pesticides. Absorption: GIT, lungs and skin Mechanism of Action Phosphorylates acetylcholinesterase (AChE) enzyme responsible for hydrolyzing acetylcholine to choline and acetic acid Nerve ending choline reabsorbed and acetylated while acetic acid is excreted Enzyme inhibition leads to excess accumulation of acetylcholine at nerve synapse or neuromuscular receptor

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Health Effects from Overexposure

Muscurinic receptor stimulation
salivation, sweating, tearing, blurred vision (miosis) nausea/vomiting, abdominal pains, diarrhea, chest tightness, wheezing

Nicotinic receptor stimulation

muscle twitching, tremors, weakness, anxiety, irritability, respiratory failure

Aging: Aging describes the permanent irreversible binding of the compound to the cholinesterase Once aging occurs the enzymatic activity is permanently destroyed Can take weeks to synthesize new enzyme
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Treatment of OP Poisoning
Procedures aimed at decontamination and/or at minimizing absorption depend on the route of exposure. In case of dermal exposure, contaminated clothing should be removed, and the skin washed with alkaline soap

Special attention should be exercised by medical personnel,

because passive contamination may occur. In case of ingestion, procedures to reduce absorption from the

gastrointestinal tract do not appear to be very effective

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 Atropine represents the cornerstone of the treatment for OP

poisoning it is Ach receptor antagonist, and thus prevents the action of

accumulating acetylcholine on these receptors

The best clinical approach is to administer doses of atropine large enough to achieve evidence of atropinization:

dry mouth, changes in pupil size, bronchodilator, and

increased heart rate; atropinization should be maintained for at least 48hr

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Oximes, such as pralidoxime (2-PAM) are also used in the therapy of OP poisoning.

2-PAM= 2-pyridine aldoxime methyl chloride

2-PAM contains a positively charged atom capable of attaching
to the anionic site of AChE, and facilitate dephosphorylation of the enzyme, thus restoring the catalytic site of AChE to its

function.
However, this chemical reaction occurs only when the phosphorylatedAChE has not undergone aging.

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 2-Pam Administer as soon as possible, though is still can be administered 24 to 48 hours after exposure

Can reverse muscle paralysis if given soon enough before

aging has occurred Response should occur within 10-40 minutes of administration

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Carbamates

Carbamate insecticides have a variety of chemical structures, but all derive from carbamic acid, the

majority being N-methylcarbamates.

They present different degrees of acute oral toxicity, ranging from moderate to low toxicity such as carbaryl, to extremely high toxicity, such as aldicarb Generally only short term persistence and limited

residual activity mine

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 Carbamates do not effective penetrate into CNS, so less central toxicity and no seizures Measurement of cholinesterase activity generally is not useful as it will be relatively normal Mechanism of Toxicity The mechanism of toxicity of carbamates is analogous to that of OPs, in that they inhibit AChE. However, inhibition is transient and rapidly reversible, because there is rapid reactivation of the carbamylated enzyme in the presence of water Additionally, carbamylated AChE does not undergo the aging reaction.
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Carbamate Intoxication
The sign and symptoms of carbamates poisoning are the same as observed following intoxication with OPs, and include:

miosis, urination, diarrhea, salivation, muscle fasciculation, and

CNS effects. However, differently from OPs, acute intoxication by carbamates

is generally resolved within a few hours.

Maximal inhibition is achieved very rapidly, as carbamates are direct AchE inhibitors and do not require metabolic bioactivation, and enzyme activity returns to control levels within two hours
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 The treatment of carbamate intoxication relies on the use of the

muscarinic antagonist atropine Use of oximes is generally not recommended, as 2-PAM has

been shown to aggravate the toxicity of carbaryl

Carbaryl has a very high acute toxicity, is also highly water soluble.

Because of this characteristic, it is not registered for use on any

fruit or vegetable having a high water content,

Its illegal use in hydroponically grown cucumbers, and in watermelons have led to outbreaks of poisoning

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Pyrethrins and Pyrethroids

Pyrethrins are natural insecticides from Chrysanthemum cinerariaefolium.

Pyrethroids are synthetic compounds.

Used in flea control and area sprays. Toxicity is rare, relatively very safe.

Pyrethroids are Type I and Type II, the latter are more toxic.
Absorbed orally, dermally or via lungs. Rapidly metabolized and excreted.

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 Pyrethroids are used widely as insecticides both in the house

and in agriculture, in medicine for the topical treatment of scabies and head lice, and in tropical countries in soaked bed

nets to prevent mosquito bites

Because of their high insecticidal potency, relatively low mammalian toxicity, lack of environmental persistence, and low tendency to induce insect resistance, pyrethroids have encountered much success in the past thirty years, now account for more than 25% of the global insecticide market

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 All pyrethroid insecticides contain an acid moiety, and a central ester bond. The acid moiety contains two chiral carbons, thus pyrethroid typically exist as stereoisomeric compounds (trans and cis). The cis isomers are generally more toxic Mechanism of action

Pyrethroids are known to alter the normal function of insect nerves

by modifying the kinetics of voltage sensitive Na+ channels. sodium channels mediate the transient increase in the sodium permeability of the nerve membrane that underlies the nerve action potential
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 Pyrethroids bind to the subunit of the sodium channel and slow

the activation (opening), as well as the rate of inactivation (closing) of the sodium channel, leading to a stable hyperexcitable state.

Sodium channels then open at more hyperpolarized potentials, and

are held open longer, allowing more sodium ions to cross and depolarize the neuronal membrane

Type II Pyrethroids, but not type I compounds, also bind to, and
inhibit GABAA-gated chloride channels ( at higher concentrations)

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Selectivity of Pyrethroids

The higher sensitivity of insects to pyrethroid toxicity, compared to mammals, is believed to result from a combination of
higher sensitivity of insect sodium channels

lower body temperature, and

slower biotransformation

Toxicity
restlessness, prostration and paralysis convulsions
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Organochlorines

Also called the chlorinated hydrocarbon insecticides Powerful nerve poisons

Most affect a broad spectrum of non-target organisms

along with the target pests

Highly persistent in environment, fat soluble,

bioaccumulation, biomagnification Rapidly absorbed Metabolized in liver Stored in fat, brain, kidney. Slow excretion
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Organochlorine Compounds

The organochlorine insecticides include:

the chlorinated ethane derivatives, such as: DDT and its analogues; the cyclodienes, such as: chlordane, aldrin,

dieldrin, heptachlor, endrin, and toxaphene;

the hexachlorocyclohexanes, such as: lindane; and the mirex and chlordecone

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Organochlorine Compounds
Their acute toxicity is moderate (less than that of OP) But chronic exposure may be associated with adverse health

effects particularly in the liver and the reproductive system.

Primarily because of ecological considerations, these compounds have been banned in most countries in the past thirty years. Yet, because of their environmental persistence and high lipophilicity, exposure to these compounds continues, most notably through the diet.

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DDT and Its Analogues

DDT (dichlorodiphenyltrichloroethane) Early experiments showed that DDT was effective against
a wide variety of agricultural pests

insects that transmit some of the worlds most serious

diseases, such as typhus, malaria, and yellow fever

Upon absorption, DDT distributes in all tissues, and the highest concentrations are found in adipose tissue

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 Acute exposure to high doses of DDT causes motor unrest, increased frequency of spontaneous

movements, abnormal susceptibility to fear and

hyper susceptibility to external stimuli (light, touch, sound).

This is followed by the development of fine

tremors, progressing to coarse tremors, and eventually tonic clonic convulsions.

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 Signs and symptoms of acute poisoning clearly point at the nervous system as the primary target for DDT toxicity. Both in insects and in mammals, DDT interferes with the sodium channels in the axonal membrane DDT inhibits Na+, K+-ATPase, this action would not contribute to its neurotoxic effect Rather, inhibition of a Ca2+-ATPase (located on the outside of the cell membrane) may be involved in the effects of DDT. As the function of this Ca2+-ATPase is believed to be that of maintaining high external calcium concentrations, its inhibition would lower external calcium and contribute to membrane instability and repetitive firing
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Treatment for DDT poisoning

Removal of clothing and washing skin with soap and water are important Avoid oils on skin as they promote absorption diazepam, phenobarbital may be beneficial to control

convulsions
Exchange resin Cholestyramine or activated charcoal to prevent absorption and enhance excretion

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Hexachlorocyclohexanes and Cyclodienes

Cyclodiene compounds include chlordane, dieldrin, aldrin (which is rapidly metabolized to dieldrin), heptachlor, and endrin

the hexachlorocyclohexanes, include compounds such as: Lindane

These compounds banned in most countries due to their persistence and environmental and human health effects, one

exception being lindane.

Lindane has been used as an insecticide in agriculture and has found many uses as a scabicide and pediculocide in lotions and shampoos.

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 Lindane and cyclodienes have moderate to high acute oral toxicity. However, in contrast to DDT, these compounds are readily absorbed through the skin. The primary target for their toxicity is the central nervous system. Unlike DDT, tremor is essentially absent, but convulsions are a prominent aspect of poisoning. These are due to the ability of these compounds to interfere with

- aminobutyric acid (GABA) mediated neurotransmission.

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 GABA receptors are members of the superfamily of ligand gated ion channels that contain a chloride ionophore; by binding to these receptors, Endogenous GABA causes the opening of chloride channels resulting in hyperpolarization of the membrane. Lindane and cyclodienes bind to a specific site (the picrotoxin site) on the chloride channel, thereby blocking its opening and thus antagonizing the inhibitory action of GABA

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 As with DDT, these compounds are slowly metabolized, and have a tendency to bioaccumulate in adipose tissue; they are also excreted in milk Cyclodienes are inducers of microsomal biotransformation enzymes and cause liver enlargement upon chronic exposure Treatment Removal of clothing and washing skin with soap and water are important Avoid oils on skin as they promote absorption Treatment of acute poisoning is symptomatic; phenobarbital and diazepam can be used as anticonvulsants

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Herbicides
specific pesticide used for controlling weeds any chemical substance used to kill or suppress plant growth They represent a very broad array of chemical classes and act at a large number of sites of metabolic functions and energy transfer in plant cells Last in the environment from a few days to over a year Timing of Application Pre plant---applied to soil or plant foliage before planting Pre emergence---applied to the soil after planting, but before crop

emergence
Post emergence---applied after the crop has emerged.

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Chlorophenoxy Compounds Chlorophenoxy herbicides are characterized by an aliphatic carboxylic acid moiety attached to a chlorine-or-methyl-substituted aromatic ring. The most commonly used compound of this class is 2,4-dichlorophenoxyacetic acid (2,4-D), while others are 2,4,5-trichlorophenoxyacetic acid (2,4,5-

T) and 4-chloro-2 methylphenoxyacetic acid

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 Chlorophenoxy herbicides are chemical analogues of auxin, a plant growth hormone, and produce uncontrolled and lethal growth in target plants. Because the auxin hormone is critical to the growth of many broad-leaved plants, but is not used by grasses,

chlorophenoxy compounds can suppress the

growth of weeds without affecting the grass.
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 The precise mechanisms of toxicity of

chlorophenoxy herbicides have not been completely elucidated, But experimental studies indicate the possible involvement of three actions:
Cell membrane damage; interference with metabolic pathways involving

acetyl-coenzyme A;
Uncoupling of oxidative phosphorylation
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 Ingestion of 2,4-D has caused several cases of acute poisoning in humans, usually at doses above 300 mg/kg, though lower doses have been reported to elicit

symptoms.
Vomiting, burning of the mouth, abdominal pain, hypotension, myotonia and CNS involvement including coma, are among the clinical signs observed Management of 2,4-D poisoning appears to be aided by urine alkalinization, through intravenous administration of bicarbonate
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Bipyridil Compounds
Include Paraquat and diquat Ingestion responsible for most deaths

Death has also been reported after transdermal exposure,

ingestion and inhalation Severe local irritant and devastating systemic toxin Ingested, it is absorbed rapidly Plasma concentrations peak within 2 hours of ingestion

Distributed to most organs, with kidneys and lungs having the

highest concentration
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 Acute exposure causes liver and renal necrosis, that is followed within a few weeks by pulmonary fibrosis Accumulated in the alveolar cells of the lungs, where it is

transformed into a reactive oxygen species a superoxide

radical Responsible for lipid peroxidation that leads to degradation of

cell membranes, cell dysfunction and cell death

Two phases Initial destructive phase causes inflammatory cells and hemorrhage, but these changes may be reversible

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 Second proliferative phase involves fibrosis in the interstitium and alveolar spaces Myocardial injury and necrosis of the adrenals may occur

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 Three hypotheses have been proposed to account for

the ensuing cytotoxicity.
The generation of superoxide anion and subsequently of hydroxy radicals, would initiate lipid peroxidation, ultimately leading to cell death. oxidation of NADPH, leading to its cellular depletion, which is augmented by the detoxification of hydrogen peroxide formed in the glutathione peroxidase/reductase enzyme system to regenerate GSH Mitochondrial damage

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Toxicity

Caustic effects produce local skin irritation and ulceration, as well as corneal injury in eye exposures

Upper Respiratory tract exposure may result in

mucosal injury and epistaxis Inhalation may lead to cough, dyspnea, chest pain, pulmonary edema and hemoptysis Ingestion causes gastrointestinal mucosal lesions and ulcerations

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 Hypovolemia occurs from GI fluid losses and decreased peroral intake CV collapse may occur early in intoxication Seizures, GI perforation and hemorrhage and hepatic failure may occur Massive ingestions lead to multisystem failure and death within a few days

Renal and hepatocellular necrosis develop b/n the

2nd and 5th days,
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Treatment
Charcoal hemoperfusion is known to remove paraquat and should be instituted as soon as possible and continued for 6-8 hours Clothing removed and skin decontaminated with soap and water, but do not cause further abrasions that might increase systemic absorption Ocular irrigation with copious amounts of water or saline must take place Fluid and electrolyte losses need to be replaced Treat pain (from lesions) with opioids Emesis is common but gastric lavage via orogastric tube is recommended despite risk of perforation
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 Early and vigorous decontamination! Any exposure to paraquat is a medical emergency with hospitalization indicated even if patient is

asymptomatic
Attempt should be made to discourage superoxide radical formation by using low inspired oxygen to produce a hypoxemia to reduce pulmonary injury
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RODENTICIDES
Rats and mice can cause health and economic damages to humans.

Rodents are vectors for several human diseases, including

plague, endemic rickettsiosis, spirochetosis, and several others;

They can occasionally bite people; They can consume large quantities of postharvest stored foods Can contaminate foodstuff with urine, feces, and hair, that may

cause diseases.

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 Hence, there is a need to control rodent population.

The compounds used as rodenticides comprise a diverse range of chemical structures having a variety of mechanisms of action. The ultimate goal is to obtain the highest species

selectivity; in some cases advantage has been taken of

the physiology and biochemistry unique to rodents. Toxicologic problems can arise from acute accidental ingestions or from suicidal/homicidal attempts.
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Fluoroacetic Acid And Its Derivatives

Sodium fluoroacetate and fluoroacetamide are the main representatives of this class of rodenticides.

They are white in color and odorless, and due to their high
mammalian toxicity, their use is restricted to trained personnel The main targets of toxicity are the CNS and the heart. Fluoroacetate is incorporated into fluoracetyl coenzyme A, which condenses with oxolacetate to form fluorocitrate, which inhibits

mitochondrial aconitase
Aconitase is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate
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 Blockage of energy metabolism is believed to

account for most signs of toxicity

The general response to the toxicity includes:

nausea, vomiting, and abdominal pain initially

Followed by respiratory failure, seizures, loss

of consciousness, coma and muscle spasm

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Treatment
No known antidote for sodium monofluoroacetate poisoning Treatment is non specific and supportive

Repeated gastric lavage & catharsis seem empirically useful

because of enterohepatic recycling of fluoroacetate

Use of charcoal Use of glycerol monoacetate as a substrate that would compete with, or by pass, the inhibition of citrate metabolism caused by

fluoroacetate
Use of diazepam and phenobarbitol for treatment of seizures
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Anticoagulant Rodenticides
Coumarin derivatives:
Warfarin

dicoumarol
brodifacoum bromadiolone

difenacoum

Indandione derivatives:
Pindone

chlorphacinone
diphacinone
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Mechanism of action

Inhibit the recycling of Vit K1 by inhibiting Vit K1 epoxide reductase

Inhibits activation of the inactive Vit K1 dependent caogulation factors II,VII,IX,X

They are fairly safe for human beings due to the low concentration of the active ingredient. However, there is a significant number of suicide or

homicide attempts or of accidental consumption of

warfarin.
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 One often reported case involved a Korean family

that consumed a diet of corn containing warfarin over a two-week period. Symptoms (massive bruises, hematomata, gum and nasal hemorrhage) appeared about 10 days after the

beginning of the warfarin consumption.

Consumption of warfarin in this episode was estimated to be in the order of 12 mg/kg/d

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The appearance of rats resistant to warfarin and to other early anticoagulant rodenticides, led to the development of second generation anticoagulants.

Some are coumarins, such as the superwarfarins brodifacoum or difenacoum,

whereas others are indan- 1,3 -dione derivatives (diphacinone, chlorophacinone).

These compouds act like warfarin, but have prolonged half-lives

e.g., brodifacoum 156 hours vs. warfarin 37 hours), and cause very long-lasting inhibition of coagulation.

Some are extremely toxic to most mammalian species; for example the oral LD50 of brodifacoum is about 0.3 mg/kg in rat, rabbit, and dog
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Treatment
If there has been no bleeding, but the PT is prolonged, give vitamin K1 10-50 mg orally two to four times a day (paediatric

dose 0.4 mg/kg/dose).

For prolonged PT with less severe bleeding, give vitamin K1 10 to 15 mg SC or IM (for a child 1 to 5 mg). In severe haemorrhage with prolonged prothrombin time (PT) give vitamin K1 (phytomenadione) 20 mg by slow IV injection (0.6 mg/kg for children under 12 years). In severe bleeding, it may be necessary to give fresh frozen plasma or fresh blood.
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