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 1/4/13 among the many chemicals that we 11

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

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in non target organisms.

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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)

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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 dose response 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
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pesticides in improper containers

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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 neurotoxicants, 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

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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

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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
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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 1/4/13 destroyed

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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

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from the gastrointestinal tract do not appear to be

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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

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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

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The mechanism of toxicity of

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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.

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However, differently from OPs, acute 1818

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

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1919 Carbaryl has a very high acute

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.
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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

1/4/13 2121 potency, relatively low mammalian

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.

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sodium channels mediate the transient increase in the

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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
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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 biotransformation

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Organochlorines

Also called the chlorinated hydrocarbon insecticides

Powerful nerve poisons Most affect a broad spectrum of nontarget organisms along with the target pests

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2525 Highly persistent in environment, fat

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;

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the hexachlorocyclohexanes, such as: 2626

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.

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Primarily because of ecological 2727

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, 2828

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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

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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

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3030 DDT inhibits Na+, K+-ATPase, this

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

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Exchange resin Cholestyramine or 3131

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

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These compounds banned in 3232 most

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.

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Unlike DDT, tremor is essentially 3333

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
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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

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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
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number of sites of metabolic functions 3636

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

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of this class is 2,4-

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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

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plants, but is not used by grasses,

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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;

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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,

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myotonia and CNS involvement 4040

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

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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

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4242 Responsible for lipid peroxidation that

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

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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,

4545 dyspnea, chest pain, pulmonary

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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

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Massive ingestions lead to

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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 1/4/13 4747

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

1/4/13 4848 discourage superoxide radical

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;

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They can occasionally bite people; 4949

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

1/4/13 5050 highest species selectivity; in some

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 1/4/13

is an enzyme that catalyses the5151 stereo-specific

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

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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

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enterohepatic recycling of

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Anticoagulant Rodenticides

Coumarin derivatives:

Warfarin dicoumarol brodifacoum bromadiolone difenacoum

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Indandione derivatives:

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.
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One often reported case involved a Korean family that consumed a diet of corn containing warfarin over a twoweek period.

Symptoms (massive bruises, hematomata, gum and nasal hemorrhage) appeared about 10 days after the beginning of the warfarin
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consumption.

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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

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difenacoum,

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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). 1/4/13 5858

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