Medical Pharmacology Topics   

Toxicology: Pesticides

A pesticide is any substance intended for preventing, destroying, repelling or mitigating any pest: insecticides, fungicides, herbicides, rodenticides, etc. Pesticides can be classified into one of four generations. First generation pesticides were natural products. Second generation pesticides include the moden organochloride insecticides and herbicides. Third generation pesticides include the organophosphate and carbamate insecticides and 2,4 D herbicide. Forth generation pesticides are being developed by genetic engineering. Strategies include secretion of insecticides by modified plants and plants made resistant to herbicides.

Natural Agents

Sulfur was used as a fumigant in China since 1000 B.C. Arsenic has been used as a pesticide since the 16th century, tobbacco plant extract (nicotine) as an insecticide since the 18th century. Of more recent use are the pyrethrins and their synthetic analgs the pyrethroids.

Pyrethrins are derive from the chrysanthemum plant. They are relatively non-toxic to humans because they are detoxified by MFOS. Insect cannot detoxify these compounds leading to inhibition of the Ca/Mg ATPase, which prevents calcium removal from nerves and interferes with their function. This agents are fast acting (kill insects instantly) and have very little persistence.

Nicotine is still used as an insecticide in some applications. It is extreamely toxic and absorbed by contact. Nicotine mimics the action of acetylcholine at the neuromuscular junction, muscle fasiculations, convulsions, neuromuscuar blockade, and paralysis of respiratory muscles (death).

Organochloride Insecticides

Aldrin, dieldrin, DDT and hexachlorobenzene (linane) are organochloride pesticides. DDT was first synthesized by Ziedler in 1874 and rediscovered by Paul Muller in 1939 (won Nobel Prize in 1948). The oganochlorides are excellent insectides with low human toxicity. They are carcinogens in rodent liver.

In the only known fatal poisoning in humans after accidental exposure, a 1-year old child ingested one ounce of 5% DDT. Clinical signs included coughing and vomiting, followed by tremorsand convulsion before coma and death. Doses as high as 285 mg DDT/kg body weight have been ingested accidentally wit no fatalities.

The organochlorides do not break down easily and are very lipid soluble. They accumulate in fat and are very persistent in the environment. While this is an advantage when combating mosquito-borne diseases, they also bioaccumulate in the food chain and will affect predators. Rachel Carson's "Silent Spring" drew attention to this persistence in the environment and its effect on avian life. They seem to interfere with the ability of birds to mobilize sufficient calcium for stable egg shell formation.

DDT acts on the central nervous system by interfering with the movement of ions through neuronal membranes. There appear to be at least four mechnisms by which DDT affects ion movement, all possibly functioning simultaneously:

• Delays the closing of Na channels
• Prevents full opening of K channels.
• Targets a specific neuronal ATPase that controls the rate of Na, K and Ca fluxes through nerve membranes, playing an important role in neuronal repolarization.
• Inhibits the ability to transport Ca in nerves, possibly by binding a Ca/Mg ATPase

These actions combine to maintain nerve membranes relatively depolarized, potentiating the release of neurotransmitters. This leads to CNS excitation, manifested by excitability, tremors and convulsions.

Organophosphates and Carbamates

The organophosphates and carbamates are currently the moe widely used insecticides. Some chemicals in this clases were developed as chemical warfare agents. Their use as insecticides started in the 1930 and increased after organochloride pesticides were banned in some contries in the 1970's. They are prefferd to the organochlorides because they degrade rapidly in the environment, thus do not bioaccumulate. However, they have a greater potential for human toxicity and insect resistance than the organochlorides.

The organochlorides and carbamates are acethylcholinesterase inhibitors. Initially, a weak reversible bond forms between the pesticide and acetyl cholinesterase. After some time, a more permanent phosphate bond forms (aging) and recovery will depend on enzyme de novo synthesis (about 2 weeks). The toxic effects are directly related to the amount and rate of acetylcholinesterase inhibition. A critical mass of enzyme must be inactivated before poisoning signs and symptoms are manifested.

Plasma cholinesterase (aka pseudocholinesterase) is more liable than red blood cell (RBC) cholinesterase, but also more quickly regenerated in the liver. RBC cholinesterase is the same enzyme as found in the nervous system, and its measurement better reflects the degree of enzyme inactivation at neuroeffectos sites. Stll, it is difficult to interpret cholinesterase measurements without baselie values since there can be diverecens up to 4x between individuals. Inhibition of 20% to 5-% of the enzyme is usually regarded as evidence of toxicity.

Both RBC cholinesterase and pseudocholinesterase activity tests are needed for proper diagnosis and treatment. The insecticides are detected in blood in usine only if sampled very soon after exposure. Metabolites are detectable in urine up to 48 hours, in blood only for a few hours.

Accumulation of acethylcholine in the CNS may cause sensory and behavioural disturbances, incoordination, respiratory failurre and death. Other effects depend on enzyme inhibition at cholinergic ANS muscarinic junctions and voluntary skeletal muscle nicotinic junctions. The organophosphates produce muscarinic, nicotinic and CNS effects. Carbamates cause predominantly muscarinic effects.

The organophosphates and carbamatesare readily absorbed by inhalation, skin exposure and ingestion, resulting in systemic poisoning. These agents are used for crop and home application, thus farm workers and professional exterminators are at a higher risk of toxicity. Children are more sucerible than adults. Individuls with inherited lower cholinesterase levels are also more succeptible.

Several organophosphates cause delayed peeripheral neuropathy due to distal axon degeneration.Tis organophosphate induced distil neuropaty, or OPIDN, is seen 7-14 days after exposure as an overall motor disorder including flaccidity ot paralysis of extremities, and hyperactive reflexes. OPIDN may involve hands and forearm paralysis and may mimic Guillain-Barre syndrome.

Organosphosphate symptoms include the usual muscarinic signs and muscle weakness. Carbamates should oly provoke muscarinic symptoms. Pralidoxime (2-PAM) and atropine are used to treat acute organophosphate poisoning. Pralidoxime removes the toxin if given before aging and reverse muscle weakness. Atropine will improve muscarinic symptoms but will not reverse muscle weakness.

Herbicides

The chlorophenoxy compounds 2,4-D and 2,4,5-T have been used since the 1940's. They mimic the action of plant auxins that stimulate growth, and have no hormonal effect on humans or other mammals. 2,4-D has very little mammalian toxicity. 2,4.5-T causes develoopmental effects and is sometimes contaminated with TCDD (doxin), a very toxic agent.

Diquat and paraquat concentrate in the lungs and produce reactive oxygen species, thus injuring the lungs by oxidative damage. Once the chemical has been absorbed, there is little that can be done to prevent lung damage. Death will occur at high concentrations.

Rodenticides

A good rodenticides will selectively kill rodents, having little toxicity in humans or pets, and will kill rodents in an acceptable (humane) manner. Cyanide ands strichnine are often used because but are toxic to other animals. Red squill is cardiotoxic and emetic, but since rodents cannot vomit it is more selective. Warfarin, an anticoagulant, is also used.

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