Insecticides

Organochlorines
Chlorinated Ethane Derivatives -- DDT, dichlorodiphenyltrichloroethane -- This agent was initially used as an anti-malarial in 1945.  It exhibits a high potency in insects while being relatively non-toxic in man (there have been no reported fatalities to DDT).
Mechanistically, the organochlorines interfere with neural transmission by altering sodium conductance, decreasing potassium efflux, and inhibiting the Na/K ATPase pump of both sensory and motor neurones.  In high doses DDT may cause tremors, excitation, convulsions, paræsthesias (to the tongue, lips, and face), irritability, and dizziness.  It has also been reported to cause hepatotoxicity in laboratory animals.

A primary concern with DDT is its persistence in the environment.  It is degraded slowly to metabolites (DDD and DDE, the latter with a half-life 10 times that of the parent DDT, 250 days compared to 28 days).  One aspect of environmental concern is the magnification of DDT in the ecological food chain.  One study reported lake levels of DDT at 4 ppm.  However, when the food chain was analysed from aquatic daphnids, through fish to fish-eating birds, the DDT concentration was found to be 1500 ppm in the grebe. This magnification is due primarily to the long half-life (in part due the high lipophilicity of DDT and its metabolites and their subsequent storage in fat) thus exhibiting persistence in living systems as well.  The major environemental effects of these compounds reflect their œstrogenic activity causing reproductive toxicity including thinning of egg shells in birds and reduced egg viability in fishes, amphibians, and reptiles.  The ability of DDT to be stored is also of concern when the animal looses substantial fat stores.  Migratory bats with large amount of stored DDT have been reported to die soon after migration, due to the loss of body fat and liberation of stored DDT.  This effect could also occur in humans.  Lipid storage in mammalian systems usually plateaus with a half-life of 6 months, unless fat loss does occur.

Treatment of acute toxicity is primarily symptomatic and supportive.  Similar compounds include methoxychlor, lindane, and myrex.  Some of these agents such as lindane, though less persistent in the environment,  may be acutely more toxic than DDT; producing CNS excitation, convulsions, and death.

Other organochlorines, which produce similar toxicities but with a greater chance of seizures include:

Cyclodienes -- chlordane, aldrin, dieldrin, hepatochlor, endrin, toxaphene, mirex,  and chlordecone

Hexachlorocyclohexanes -- lindane
 

Acetylcholinesterase Inhibitors
Organophosphates -- Parathion, Malathion, Dichlorvos, Diazinon, Trichlorfon, Ronnel
The OPs were first synthesised in Germany in the 1930s and 1940s.  Some of the first compounds included tetraethyl pyrophosphate (TEPP) originally designed as a nicotine analogue, ethyl N-dimethylphosphono-amidocyanidate (Taban), and i-propylmethylphosphonofluoridate (Sarin).
These agents are also less persistent in the environment, but are also more acutely toxic than DDT.  Examples include parathion and malathion, which exhibits selective toxicity in insects.  Malathion is metabolised predominantly by hydrolysis to inactive metabolites in humans.  However, in insects it metabolised to malaoxon, which inhibits the enzyme acetylcholinesterase.  This mechanism results in cholinergic overload of both peripheral and central neurones and at both muscarinic and nicotinic receptors.  Organophosphate inhibition may be very slowly reversible (phosphinates) are irreversible (phosphates, phosphonates).  The carbamate (example, carbaryl) insecticides produce a slowly reversible inhibition of the enzyme.
Carbamates -- Carbaryl, Bagon, Moban, Aldicarb, Zectram
As stated above and illustrated below, the primary difference between the OPs and the carbamates is the relative irreversibility of the OPs while the carbamates produce a slowly reversible inhibition of cholinesterase.
In humans, cholinesterase inhibitor toxicity presents with typical cholinergic effects, salivation, lacrimation, urination, diarrhœa, et c.  Toxicity will present when approximately 50% of the enzyme has been inhibited with death occurring at 80-90% inhibition.

 
Treatment of organophosphate insecticide toxicity consists of a three step approach
1) institution of artificial respiration
2) atropine, to block the effects of acetylcholine.  In mild cases, this may be sufficient.
3) administration of pralidoxime (2-PAM), which regenerates the enzyme and may also inactivate circulating pesticide.  Inadequacies of 2-PAM include its relative inability to cross the blood brain barrier and the fact that high doses may also inhibit AChE (it is for this reason that 2-PAM should never be administered in carbamate poisoning -- it would accentuate the toxicity, worsening the condition of the patient).

Botanicals
Nicotine -- One of the oldest insecticides, nicotine acts as an agonists at cholingergic nicotinic receptors in the skeletal muscle and paravertebral ganglia, as well as in the CNS.  Their toxicity produces cholinergic overstimulation followed by neuronal and muscle fatigue and is characterised by muscle weakness, salivation, vomiting, fibrillation, and clonic convulsions.

Rotenone -- Derived from Derris elliptica, rotenone acts as an inhibitor of oxidative phosphorylation, specifically interferring with NAD oxidation.  Toxicity is characterised by conjunctivitis, pharyngitis, rhinitis, GI upset, ulceration, nausea and vomiting, and ultimately respiratory stimulation and convulsions.

Pyrethroids -- Permethrin, Resmethrin, Tetramethrin, Allethrin

These are naturally-occurring (or synthetic analogues) of insecticides found in chrysanthemums.  They have short half-lives and do not present a persistent danger to the environment.
They act by activating sodium channels, prolonging the channel's activated state, and enhancing sodium influx.  They may also produce counter-irritant like sensations with dermal exposure.  If death occurs in acute toxicity it is usually by respiratory arrest.  Anaphylactic reactions may also occur, due to the fact that these are natural products and may be recognised as antigenic substances.
Treatment is primarily supportive and symptomatic.
An added complication of pyrethroid toxicity is the addition of piperonyl butoxide to many products.  This agent increases the absorption of the insecticide in both insects and mammals.  It possesses toxicity independent of the insecticide, producing convulsions and coma.

Chlorphenoxy Compounds -- 2,4 Diphenoxyacetic acid and 2,4,5 Triphenoxyacetic acid (2,4 D; 2,4,5 T) These are broad-leaf herbicides used to control weed growth in corn, grain, sorghum, pastures, and rangeland.   These agents were the active ingredients in "agent orange", used as a defoliant during the conflict in Vietnam.
As herbicides, they exert their effect by mimicking plant growth hormones, causing accelerated growth (beyond the capacity of the plant).

In mammals they exert CNS stimulatory activity similar to some insecticides.  At high doses, they may cause death by ventricular fibrillation.  Lower dose exposure will cause ataxia, paralysis, peripheral neuritis, and protracted coma.

One of the major problems with agent orange and commercial preparations of these herbicides is contamination with 2,3,7,8 tetrachlorodibenzo-p-dioxin.  This dioxin derivative may produce teratogenicity, reproductive toxicity, hepatotoxicity, and a depressed immune response.  It has also been associated with the development of diabetes mellitus.  Treatment is primarily supportive and symptomatic.
 

Bipyridil Compounds
Paraquat (Gramoxone^R) -- This post-emergent herbicide and its analogue diquat bind tightly to soil and does not leech out into the ground water, lessening the environmental impact.
Mechanistically, in plants paraquat inhibits photosynthesis.  In humans it accumulates in Type II epithelia of the lung (surfactant producing cells) and the kidney.  It will initially produce a pulmonary toxicity characterised by a frothy pulmonary exudate.  As toxicity progresses, the lungs and kidneys become fibrotic.  Death is usually due to respiratory failure.  The toxicity is self-perpetuating in that the damage is due to the formation of a free radical by an oxygen (which is freely available) dependent mechanism.  The reduced paraquat may then be oxidised and re-activated to produce further toxicity (note that the enzyme superoxide dismutase plays a role in the free radical formation/regeneration process of paraquat toxicity).  (NOTE ALSO that diquat does not exhibit this toxicity -- its chemistry does not lend it to uptake in pulmonary cells.)  Once paraquat has entered the pulmonary cells, there is no effective treatment for toxicity.   Additionally, it may cause hepatotoxicity, presumably by a similar mechanism.

Diquat (Reward^R) -- Causes CNS excitation, convulsions, GI distention, hepatotoxicity, and nephrotoxicity.  It is not taken up by type II epithelial cells and is therefore devoid of pulmonary toxicity.

Acute ingestion may be treated by the administration of Fuller's Earth as a slurry, which binds the paraquat and prevents its absorption.  Hæmodialysis may also be effective soon after ingestion.  Paraquat is often used in suicide attempts.  It does not usually result in rapid death, but rather the patient will often experience a prolonged and painful progressive toxicity resulting in death due to respiratory failure.
 

Dinitrophenols -- DNOC (4,6 Dinitro-o-cresol), Dinoseb
Mechanism of Action -- Uncouple oxidative phosphorylation
Acute exposure -- nausea, GI upset, restlessness, feelings of warmth, flushing, sweating, tachypnea, tachycardia, fever, cyanosis, collapse, and coma.  Symptoms proceed with a rapid course with either death or a good prognosis for recovery within 48 hours of exposure.

Chronic Exposure -- fatigue, restlessness, diaphoresis, thirst, weight loss, yellow conjunctiva
 

Carbamates -- Prophan, Barban
Mechanism of Action -- Their herbicidal action is due to anti-mitotic effects, reducing plant cellular division.

In humans they act as immunosuppressants.  Unlike the carbamate insecticides, they possess NO cholinesterase inhibitor activity in mammals.  Barban may also produce a photoallergic reaction.
 

Substituted Ureas -- Monuron, Diuron
Mechanism of Action -- The herbicidal action is due to a disruption of the photosynthetic pathway, specifically by inhibiting electron transfer in Photosystem II.

These agents have been shown to cause lung tumours in rats.
 

Triazines -- Atrazine, Simazine (Princep^R)
MOA -- These agents also inhibit the Photosystem II by interferring with electron transfer.

These agents are relatively non-toxic in mammals with rats surviving daily doses of 2500 mg/Kg for 30 days larger animals surviving doses of 50 mg/Kg for 30d and 250 mg/Kg for 3d.  Recall, however, that they do possess anti-androgenic effects and may produce a reproductive toxicity.
 

Amitrole -- A triazine-like compound structurally, with a different mechanism of herbicidal activity.
MOA -- Blocks carotenoid synthesis.  Carotenoids are used by plants as an antioxidant to protect chlorophyll from photo-oxidation.  Therefore, amitrole will allow oxidation of chlorophyll and produce "bleaching" of the plant.

Amitrole has anti-thyroid activity in mammals (probably by inhibiting thyroidal peroxidase) and has been shown to be carcinogenic, especially in the thyroid gland.
 

Amides -- Propanil, Alachlor (Lasso^R)
MOA -- Disrupt photosynthesis by inhbiting Photosystem II electron transer.  Propanil is especially effective in weed control in rice, since rice selectively metabolises it to a non-toxic compound, thus protecting the rice while preserving toxicity in the weed.

Exposure may cause CNS depression and methaemoglobinaemia (probably through an active aniline-derivative metabolite).
 

Nitriles -- Dichlobenil, Ioxynyl
MOA -- uncouple oxidative phosphorylation
Dinitroanilines -- Trifluralin (Treflan^R)
MOA -- Prevent microtubule polymerisation, thereby inhibiting cell division and cell wall formation.

Relatively non-toxic in mammals with the LD₅₀ in rats greater than 10,000 mg/Kg.  Rats and dogs exhibited no adverse effects to doses of 1000 ppm in their diet for 2 years.

Trifluralin is being investigated with promising results as a treatment for human leishmaniasis.
 

Glyphosate (Roundup^R)
MOA -- inhibits 5-enolpyruvyl-shikimate-3-phosphate synthase (5-EPSP synthase), thus inhibiting plant amino acid synthesis.

Exposure has cause ocular effects, but no permanent lesions and oral ingestion has produced oesophogeal erosion and pneumonitis that may be due to the vehicle rather than the active ingredient.

Pentachlorophenol -- PCP -- This agent, in addition to its fungicidal activity, is used as a wood preservative.  It also has insecticidal and herbicidal actions.  It is rapidly and thoroughly absorbed by the skin.

Mechanistically, PCP uncouples oxidative phosphorylation, resulting in anoxic anoxia.  It may also cause chloracne and hepatotoxicity commonly seen with other organochlorine pesticides.  At least two deaths and numerous poisonings have been reported in infants who were exposed to contaminated diapers.  This occurred in nurseries where PCP was (inappropriately) used as a fungicidal agent in the laundry room.
Treatment is primarily supportive and symptomatic.
Dicarboximides -- Captan, Folpet
These agents may be potential teratogens and carcinogens
Dithiocarbamates -- Ziram, Ferbam, Maneb, ZIneb, and Nabam
These are metal-based fungicides, having respectively, Zinc, Iron, Manganese, Zinc, and Sodium

They are also potentially teratogenic and carcinogenic

Fluoroacetate is a naturally occurring plant toxin that is indigenous to Australia, Africa, and South America (where native animals have developed a tolerance to the effects).

Mechanistically, it inhibits the citric acid (Krebs) cycle by blocking the conversion of citrate to isocitrate through fluoridation of the enzyme responsible for the conversion.  Target areas in humans are primarily the heart and CNS.  Initial response to exposure to fluoracetate is nausea/vomiting and cardiac irregularities.  These progress to cyanosis, convulsions, ventricular fibrillation, respiratory arrest and death.  There is some species specificity.  In humans and other primates, horses, and rabbits, death is most often due to V fib.  In dogs, death most often occurs due to respiratory failure.  It is used specifically as a possum poison in New Zealand and is marketed as a general rodenticide in other countries.
Treatment is supportive and symptomatic but also involves the administration of acetate (as glycerol monoacetate) as an antidote.  This drug will allow the conversion of citrate to isocitrate by displacement of the fluoride moiety with acetate.
Norbromide
Mechanistically, this rodenticide causes smooth muscle contraction including vascular smooth muscle, thus causing diffuse ischaemia and ultimate death of the rat or mouse.

Toxicitiy in rats occurs at a dose of 5-15 mg/Kg.  It is practically non-toxic in cats, dogs, chickens, ducks, sheep, swine, and primates.
 

Red Squill (Scilliroside) -- a naturally-occurring aquatic toxin that has digitalis-like effects

Warfarin and other coumarins -- cause internal bleeding and death by blood loss

Strychnine -- Causes death by paralysis of respiratory muscles.  It is also used as an ursicide in Japan.

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