Toxicology 2 Course 3: Pesticides, Molluscicides, and Fungicides by Uasvm

PESTICIDES

MOLLUSCICIDES

Molluscicides are substances used to control mollusks (i.e., terrestrial and aquatic snails or slugs). They cause direct or indirect damage, being intermediate hosts for various parasites (e.g., Fasciola hepatica).

Various chemical compounds have been used and are being used for the destruction of mollusks, such as pentachlorophenols, copper-based compounds, dinitrophenols, dithiocarbamates and, mainly, metaldehyde.

METALDEHYDE

Metaldehyde (commercial products: Meta Gold, Optimol, Agrosan, etc.) is a tetramer of acetaldehyde, obtained by polymerization. It is in the form of white crystals, with a formalin odour, insoluble in water, soluble in organic solvents (benzene, chloroform), and flammable. Metaldehyde may be purchased in liquid, powder, granular, or pelleted formulations.

The bait is highly palatable and potentially addictive, which often results in consumption of large quantities. Most avian and mammalian species are susceptible.

It is used in the form of baits, in which the concentration of metaldehyde reaches 3.5% (1.5% - 5%) or in the form of aerosols, on pastures. In contact with metaldehyde, snails secrete a large amount of mucus and thus die by dehydration.

Causes of intoxication

Poisoning in farm animals, game, fish, and bees occurs accidentally through the consumption of contaminated plants and / or water. Birds, swine and canids can be intoxicated by eating baits and / or intoxicated snails on pastures or near lakes. In humans, intoxication occurs through the use of metaldehyde as a heating source ("white coal", "solidified alcohol"), in stoves located indoors (emits ethanol).

The lethal oral dose ranges from ~100-600 mg/kg in various species. LD in dogs is 400 mg/kg, 500 mg/kg in birds, and 300 mg/kg in ducks and sheep.

Toxicokinetics

After ingestion, metaldehyde undergoes partial hydrolysis in the stomach to produce acetaldehyde. Both metaldehyde and acetaldehyde are readily absorbed from the GI tract. The nature of the stomach contents and the rate of gastric emptying influence the rate of absorption and the onset of the clinical syndrome.

2Acetaldehyde is metabolized to carbon dioxide and eliminated by the lungs. Urinary excretion as metaldehyde is less than 1% of dose.

Enterohepatic recirculation may prolong retention of metaldehyde in the animal.

Toxicodynamics

Clinical manifestations are attributed primarily to metaldehyde, although acetaldehyde does play a role in the clinical syndrome. Metaldehyde exposure alters a variety of neurotransmitter concentrations and enzyme activities. Metaldehyde reduces concentrations of y-aminobutyric acid, an inhibitory neurotransmitter that causes CNS excitation. Reduced concentrations of brain serotonin (5-hydroxytryptamine) and norepinephrine decrease the threshold for convulsions. Monoamine oxidase activity is increased after metaldehyde exposure. Increased muscle activity and the production of acidic metaldehyde metabolites cause severe electrolyte disturbances and metabolic acidosis.

Clinical signs

The clinical syndrome is similar in most species. Neurologic manifestations, which predominate, develop within 1-3 hours after ingestion. Severe muscle tremors, anxiety, hyperesthesia, ataxia, tachycardia, and hyperthermia (42.2℃) may be evident initially.

As the acidosis becomes more severe, depression and tachypnoea may become more evident. As the syndrome progresses, opisthotonos and continuous tonic convulsions that are unresponsive to external stimuli (in contrast to those in strychnine poisoning) are typical manifestations.

Emesis, diarrhoea, hypersalivation, colic, cyanosis, mydriasis, sweating (horses), and nystagmus (cats) are often reported.

Anatomopathological changes

No consistent pathognomonic gross or histologic lesions are seen with metaldehyde poisoning. Hepatic, renal, and pulmonary congestion and intestinal ecchymosis and petechial hemorrhages, which may be associated with prolonged hyperthermia, are common. Neuronal degeneration in the brain and hepatic degeneration with cellular swelling are often present histologically.

Diagnosis

A history of exposure plus the presence of typical clinical signs is suggestive of metaldehyde intoxication. Stomach contents often have a distinctive acetaldehyde (fruity smell) or apple cider-like odour. Rapid analysis of stomach contents submitted frozen for metaldehyde and acetaldehyde may be useful to confirm the diagnosis. Analysis of urine, blood, or liver may be useful but is often unreliable.

Neurologic, GI, and pulmonary disease caused by other agents may be confused with metaldehyde intoxication. Potential differential diagnoses include intoxications by organophosphates, carbamates, organochlorines, pyrethroids, strychnine, sodium fluoroacetate, zinc phosphide, bromethalin, cyanide, blue-green algae, roquefortine, and tremorgenic mycotoxins. Nontoxic conditions such as epilepsy, various encephalitic infections, 3lysosomal storage diseases, or metabolic diseases such as hypocalcaemia may also resemble metaldehyde intoxication.

Treatment

There is no specific treatment for metaldehyde poisoning, although aggressive symptomatic treatment during the first 24 hours will enable most affected animals to make a full recovery within 2-3 days.

Inducing vomiting in severe exposure may not be necessary because metaldehyde is a stomach irritant. In recent exposures, if vomiting has not occurred yet, emetics are recommended; however, vomiting should never be induced in a convulsing patient because of the severe risk of aspiration pneumonia. Gastric lavage with sodium bicarbonate is also recommended, to prevent hydrolyzation of metaldehyde into acetaldehyde. Activated charcoal and purgatives may be administered to assist in decontamination and to reduce enterohepatic cycling of metaldehyde.

The following medication can be used to control tremors: diazepam (0.5-1 mg/kg IV bolus; repeat 5 minutes later if seizure has not subsided; supplement with other control methods if seizures continue), phenobarbital (4-16 mg/kg IV), methocarbamol (50-150 mg/kg IV to effect). Seizures are frequently resistant to anticonvulsants and require general inhalation anesthesia for control.

Acute care for metabolic acidosis may be essential to successful treatment. Treatment should be adjusted according to laboratory blood gas results. If venous blood gas analysis reveals a severe metabolic acidosis (pH < 7.0, BE ≤ 15, HCO3 < 11), sodium bicarbonate should be considered (0.5 - 1 mEq/kg slowly over 1-3 hours, IV).

Control hyperthermia with cool water baths, ice packs, IV fluids, etc., until temperature reaches 39.7ºC; cooling measures should be discontinued at this temperature and regulated frequently.

Aggressive IV fluid therapy is often necessary to aid in cooling measures, treat the metabolic acidosis, correct dehydration, correct electrolyte imbalances, and aid in tissue perfusion.

Xylazine is an effective treatment in horses to reduce neurologic manifestations.

Metaldehyde and acetaldehyde are rapidly eliminated. Consequently, tissue residues in food- producing animals are not a major concern. Withdrawal times, if established, will be relatively short.

Prophylaxis

The treated pasture or hay must be mowed and raked, and the resulting hay must be burned. The access of pigs, birds, and other animals to the treated lands or areas should be forbidden for 30 days from the molluscicide applications.

FUNGICIDES

ORGANOMERCURIAL FUNGICIDES

Organomercurial fungicides are used to treat cereal seeds against blight, embers, fusarium species, etc. Organomercurials are also widely used in vegetable growing.

The general formula of organomercurial fungicides is R-Hg-X, where R is an alkyl or aryl radical, and X is an acidic radical.

Organomercurial compounds are toxic to humans, other mammals, birds, fish, and bees. Due to the wide spectrum of use and the large number of living creatures prone to intoxication, it is necessary to handle them very carefully, because by direct contact or by inhalation of mercury vapors, they can have a lethal action. In addition, treated plants that are harvested in a short time are dangerous, as these organomercurial compounds have a high persistance.

Sometimes, for a better effect, organomercurial fungicides are used in combination with various insecticides (e.g., Lindane, Sevin, Dieldrin, Heptachlor). In this case, the danger of intoxication is greatly increased.

The organomercurial compounds most frequently used are:

• ethyl mercury chloride
• ethyl mercury phosphate
• phenyl-mercury chloride
• phenyl-mercury bromide
• methoxy-ethyl-mercury silicate
• methoxy-ethyl-mercury acetate
• methoxy-ethyl-mercury chloride

Sometimes, for a better effect, organomercurial fungicides are used in combination with various insecticides, such as FB-7 (contains ethyl mercury chloride and lindane)

The LD50 per os of ethyl mercury chloride is 50 mg/kg.

Toxicokinetics

In general, for large ruminants, a quantity of 1-2 kg of treated seeds/animal is sufficient to trigger acute intoxication after 8-14 hours.

Intoxication triggering is dependent on a number of toxicity factors, such as:

• degree of solubility of organomercurial compounds
• their entrance path into the body
• functional integrity of the digestive tract and mucous membranes
• the amount of organomercurials
• continuity of feeding with contaminated feed
• association with other potentially toxic substances
• species (ruminants are very sensitive to mercury)

5· organ disorders (cardiac, renal, hepatic)

Organomercurial compounds can enter the body through the digestive tract, skin (even through intact skin), respiratory tract (in the form of aerosols), and the transplacental route.

Absorption is generally rapid, blood and lymph carry mercury in all tissues of the body, but especially in the liver, kidneys, spleen, brain and muscle tissue. In the liver and kidneys, mercury is found in an amount of approx. 200 times more than in other tissues.

Elimination occurs more slowly than absorption, and is done through the digestive tract, kidneys and salivary glands. The kidney clears approximately 95% in 24 hours, the removal being considered to be completed only 30 days after a single ingestion. The slaughter of animals is allowed only after the complete elimination of mercury.

Toxicodynamics

In the body, mercury acts as a cytoplasmic toxicant, precipitating the proteins with which it forms mercury albuminate.

At the same time, mercury acts unfavorably on cellular metabolism as a specific inhibitor of hydrogen sulfide groups, similar to the mechanism of action of arsenic and cadmium. Mercury combines easily with thiol groups in glutathione, cysteine, to form mercaptides, which impair cell function.

At the same time, mercury acts neurotoxically, due to the increased affinity for the nervous system, due to the toxic's liposolubility. Convulsions, shivers, paresis and paralysis occur clinically due to damage to the nervous system and the release of histamine.

In the kidneys, mercury blocks the thiol groups of enzymes (especially succinate dehydrogenase, which is in the distal segment of the renal tubules), causing changes in the resorption of water, proteins, carbohydrates and electrolytes.

Penetrated into the body in small doses or in the form of low soluble compounds, mercury accumulates in internal organs, bones and the nervous system, leading to nervous and locomotor disorders.

Mercury, by exposure to small and repeated doses, also has a local action on the skin, where it initially produces an itchy rash, which eventually becomes purulent, covered with a film of mercury albuminate, under which the hair falls, the skin thickens, and, after healing, scars remain visible.

Clinical signs

In the acute form (which occurs when the amount of mercury ingested was high) the signs appear 5-15 hours after ingestion and translate to nervous signs expressed by seizures, muscle contractions, epileptiform spasms, strabismus, restlessness accompanied by screaming and roaring, dry mouth, hyperesthesia (due to the subcutaneous inflammatory oedema), sialorrhea, champing (empty chewing), decreased visual acuity, locomotor disorders (animals prefer the decubital position).

Seizures are repeated more and more often, and the severity of the manifestations requires the necessary slaughter of animals.