Toxicology of Insecticides: Organochlorines, Pyrethrins, and Pyrethroids

TOXICOLOGY 2

COURSE 2

CONTENTS

PESTICIDES

• INSECTICIDES
• ORGANOCHLORINE INSECTICIDES
• PYRETHRINS & PYRETHROIDS
• AMITRAZ

Emanuela Badea assistant professor | DVM | PhD | MSc Faculty of Veterinary Medicine of Bucharest UASVMI.

PESTICIDES

ORGANOPHOSPHATE INSECTICIDES

With the appearance of DDT in 1942, a real avalanche of new chemical compounds with insecticidal properties began, with which nature was invaded. Organochlorine insecticides are obtained by chlorination of some hydrocarbons in a proportion of 33-67%, and they are used against agricultural pests, external parasites in animals and humans, and for the insect control of stables/shelters. With some exceptions (e.g. endosulfans), organochlorine insecticides are very persistent in the environment, resisting chemical and microbial decomposition. The half-life of organochlorine insecticides in soil is up to 4 years for Aldrin, 7 years for Dieldrin, 2 years for Lindane, 4 years for Chlordane, 8 years for Endrin, 10 years for DDT and Toxaphene, and 12 years for Heptachlor. By their chemical structure, organochlorine insecticides can be classified in:

• DDT group:
  • DDT (dichloro-diphenyl-trichloroethane)
  • DDD (dichloro-diphenyl-dichloroethane)
  • Perthane (diethyl-diphenyl-dichloroethane)
  • Methoxychlor (trichloro-para-methoxy-phenylethane)
• HCH group (hexachlorocyclohexane) - Lindane (gamma isomer of HCH)
• Chlorinated dienes group:
  • Aldrin (Hexachlorohexahydro-endo-exo-dimethanonaphthalene)
  • Dieldrin (Hexachloroepoxyoctahydro-endo,exo-dimethanonaphthalene)
  • Endrin (Dieldrin isomer)
  • Isodrin (Aldrin isomer)
• Chlorinated indenes group - Chlordane, Heptachlor
• Chlorinated terpenes group - Toxaphene, Stroban
• Endosulfan group - Thiodan

Due to the fact that most organochlorine insecticides have become prohibited, the incidence of poisoning with these compounds has decreased significantly.

Causes of intoxication

The causes of intoxication may be represented by:

• consumption of contaminated feed often causes acute poisoning
• . administration of bone meal / meat from intoxicated animals
• . the confusion of organochlorine insecticides with mineral premixes (many of them are odourless)
• . external antiparasitic treatments, due to incorrect concentrations or administration
• . long-term consumption of animal feed contaminated with subtoxic amounts of organochlorine pesticides, which leads to chronic intoxications

2Toxicokinetics

These compounds are characterized by their insolubility in water and their solubility in fats and solvents. In the case they are solubilized in an oily medium (especially in vegetal oils), they are also absorbed through intact skin. Dieldrin however is absorbed through intact skin, even as a powder. Organochlorine insecticides can also be absorbed by respiratory route in case they are present in the air, in the form of powders or aerosols, quickly reaching circulation, becoming much more active. In the case of the digestive exposure route, the absorption of organochlorine insecticides is dependent on possible defensive reactions of the body, such as vomiting or diarrhoea, or the abundance of fats in the food. After absorption, organochlorine insecticides (except Methoxychlor) are stored in adipose tissue in different amounts from compound to compound. For example, DDT, ß-HCH and Toxaphene persist in the body for more than 3 months. Organochlorine insecticides do not store in vital organs, with the exception of the adrenals, which is why the samples sent to the laboratory are represented by adipose and adrenal tissue. The elimination of organochlorine insecticides is done by digestive (bile, faeces), renal, mammary routes, as well as through eggs and skin appendages. A major route of excretion of DDT is through milk (reduced amounts of other organochlorine insecticides are also eliminated through this route). For example, the presence of 7-8 ppm DDT in hay (which can be the usual residue found in plants after DDT treatments of pastures) has the effect of 3 ppm DDT being eliminated through cow's milk (thanks to its liposolubility), which is then found in butter in a concentration of 65 ppm DDT. Dieldrin crosses the placenta in humans, sows, cows, guinea pigs, and is thus found in the tissues of foetuses. The toxicity is influenced by a number of factors, which can often be more important than the dose:

• age (young animals are more sensitive);
• sex (e.g., Chlordane is more toxic to females);
• . specie (sheep and goats are more resistant to organochlorine insecticides compared to adult cattle);
• . physiological state (weak and non-lactating animals are more sensitive to the action of Lindane and Toxaphene);
• . stress and other present comorbidities (e.g., the toxicity can be influenced by the functional state of the liver which can partially inactivate these substances);
• the presence of other pesticides or medicinal substances;
• . the route of administration
• . the duration of exposure;
• . the size of particles used in emulsions, aerosols, sprays (larger particles adhere better to skin and long hair);
• skin integrity.

3Toxicodynamics

The mechanism of action is not fully elucidated. Some organochlorines interfere with sodium channel kinetics in nerve membranes. Sodium inflow is enhanced and potassium outflow is inhibited. Others may inhibit the inhibitory neurotransmitter GABA. All mechanisms will lead to an enhanced initiation of action potentials manifested by an increase in nervous activity, initially in the cerebellum, then in other regions of the brain, causing tremors and convulsions.

Clinical signs

The early signs of the acute form include hypersalivation, vomiturition, and vomiting but they are inconsistent. Early neurologic signs include nervousness, agitation, apprehension, tremors, hyperexcitability, incoordination. Then, intermittent clonic-tonic seizures can appear (progressing from the cranial to the caudal extremity), which are triggered by external stimuli, opisthotonos, paddling, champing of the jaws, dyspnoea, hyperthermia. Animals have intermittent periods of depression or appear almost normal between seizures. Cattle and equine may assume abnormal postures (e.g., resting the sternum on the ground, while the hindlimbs remain in the standing position; keeping the head between the forelimbs, with empty chewing; etc.), walk backwards, or chew or lick excessively. Birds can present depression, disorientation, abnormal postures, apparent blindness, and even sudden death. The chronic form resembles the expressions of the acute form, fine tremors of the neck and head appearing first, which gradually expand, increasing in intensity, turning into convulsions.

Anatomopathological changes

In the acute form, myocardium with degeneration stopped in systole, hydropericardium, pulmonary congestion and/or oedema, cerebral and medullary oedema, increased amount of CSF, gastroenteritis. In the chronic form the same lesions are observed as those visible in the acute form, but hepatic degeneration (sometimes necrosis) and renal degeneration can also be found. Histologically, in DDT poisoning, centrilobular hepatic necrosis is observed.

Diagnosis

Diagnosis is easy to put on the basis of anamnestic data (e.g., performing external antiparasitic treatments before illness) and clinical signs. Confirmation of the diagnosis is carried out by laboratory examinations consisting on the dosing of organochlorine insecticides from milk, adipose tissue, or adrenal glands. Differential diagnosis is required to rule out salt, Pb, or urea intoxication, meningoencephalitis, tetanus, rabies, Aujeszky's disease, or necrosis of the cerebral cortex.

4Prognosis

The prognosis should not be influenced by the severity of symptoms, since after very dramatic seizures the animals can recover spectacularly. Remission of clinical signs in 24-36 hours can be considered auspicious, but in the case of intoxication with Aldrin, Chlordane, and Dieldrin relapses are possible, even after 2-3 weeks.

Treatment

In organochlorine insecticide intoxication, animals should be isolated in spaces that protect them from external stimuli. Cutaneous decontamination aims at removing the toxic from the surface of the skin with water and soap; the procedure may be required to be repeated, since organochlorine insecticides are oily. Long haired animals are recommended to be trimmed before washing. In case of oral exposure, induction of vomiting or a gastric or ruminal lavage can be done for recent ingestions. Repeated doses of activated charcoal should be administered, in order to prevent the enterohepatic recirculation of the toxic. The first dose of charcoal should be administered together with a saline purgative; it is prohibited to use oily purgatives (except paraffin oil which is absorbed in negligible amounts) and milk, due to the insecticides' high liposolubility. Fluid therapy should aim at correcting dehydration and provide the necessary amounts for maintenance, together with calcium gluconate IV (which may stop the onset of liver damage). Nervous signs should be treated with tranquilizers (e.g., Phenobarbital 10 mg/kg/day IM, Penthobarbital, Diazepam, Xylazine, Acepromazine, etc). Organochlorine insecticides have no specific antidote that can be administered after the absorption of the compounds.

Prophylaxis

Prophylaxis consists in:

• . non-administration of feed treated with organochlorine insecticides until after the retention period of the insecticide has passed
• . chemical analysis of any feed newly introduced into the farm, or of feed harvested from fields known to be treated with organochlorine insecticides
• . abundant watering of animals before anti-parasitic bathing
• proper storage of organochlorine insecticides
• rigorous control of the storage, handling and use of organochlorine insecticides

PYRETHRINS & PYRETHROIDS

Pyrethrins are derived from flowers of the genus Chrysanthemum. They are esters of chrysanthemumdicarboxylic acid with ketoalcohols, pyrethrolone and cinerolone, and include pyrethrin I, pyrethrin II, cinerin I, cinerin II, jasmolin I, and jasmolin II. Pyrethroids are synthetic derivatives of pyrethrins, with a higher toxicity, divided into type I pyrethroids, which contain no cyano group (allethrin, bifenthrin, permethrin, phenothrin, resmethrin, sumithrin, tefluthrin, tetramethrin) and type II pyrethroids, which contain a cyano 5