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Chapter: Modern Medical Toxicology: Hydrocarbons and Pesticides: Pesticides

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Organochlorines - Insecticide

Organochlorine pesticides are one variety of chlorinated hydro-carbons.

Organochlorines

Organochlorine pesticides are one variety of chlorinated hydro-carbons. There are 4 distinct categories of these pesticides:

·      DDT and analogues—for example, DDT (dichlorodiphe-nyltrichloroethane), and methoxychlor.

·      Benzene hexachloride group—for example, benzene hexachlo-ride (BHC), and gamma-hexachlorocyclohexane (lindane).

·      Cyclodienes and related compounds—for example, aldrin,dieldrin, endosulfan (thiodan), endrin, isobenzan, chlordane, chlordecone (kepone), heptachlor, mirex (dechlorane).


·      Toxaphene and related compounds—for example, toxaphene.Table 28.4 lists Indian brand names of organochlorinepesticides.

Physical Appearance

These compounds are available as dusting powders, wettable powders, emulsions, granules and solutions.

Uses

·              Insecticide.

·              Gamma benzene hexachloride is used as a scabicide (treat- ment of scabies), and a pediculocide (eradication of head lice). It is available as topical ointment, cream, or lotion. Some Indian brand names include Bexarid (Shalaks), Gab (Gufic), Gamaric (Euphonic), Scaboma (Glenmark), and Ultrascab (Perch).

Usual Fatal Dose

·              DDT, lindane: 15 to 30 grams.

·              Aldrin, dieldrin, endrin : 2 to 6 grams.

Toxicity Rating: Dieldrin is placed in the “extremely toxic” category (LD50: 1 to 50 mg/kg), while DDT, endosulfan, andlindane are considered “highly toxic”(LD50: 51 to 500 mg/kg), as per the Insecticide Rules, 1971.

In addition, the following are extremely toxic: endrin, aldrin, chlordane, and toxaphene, while these are highly toxic: kepone, heptachlor, mirex. The following are least toxic:

methoxychlor, perthane, kelthane, chlorobenzilate, and hexa-chlorobenzene.

Acute hazard potential may be ranked (highest to lowest) approximately as: endrin, aldrin, dieldrin, chlordane, toxa-phene, kepone, heptachlor, DDT and methoxychlor.

Toxicokinetics

Commercial preparations of organochlorines are commonly dissolved in petroleum distillates which form emulsions when added to water. All the organochlorines can be absorbed trans-dermally, orally, and by inhalation. Gastrointestinal absorption of these agents is generally efficient, particularly in the pres-ence of absorbable lipid (animal or vegetable) fat. DDT is the least well absorbed transdermally, while dieldrin is very well absorbed. Many of these compounds are metabolised slowly and persist in tissues (especially fat) for prolonged periods. High residue levels from organochlorine insecticide poisonings are found in adipose tissue. However, unlike other organochlo-rine pesticides, methoxychlor does not substantially accumulate in fatty tissues of humans.

Excretion of organochlorine compounds does not follow first order kinetics. As body stores get lower, the half-life for the remaining store increases dramatically. This is probably due to complex lipoprotein binding, wherein different bound forms exhibit different dissociation characteristics. It is still possible to classify the organochlorines roughly in terms of the rapidity of excretion from storage levels that represent an acute toxic threat:

·              Excreted or metabolised within hours to a few days:

o     chlordane (except the heptachlor component)

o     chlorobenzilate

o     endosulfan

o     endrin

o     kelthane

o     methoxychlor

o     perthane

o     toxaphene.

·              Excreted within several weeks to a few months:

o     Aldrin

o     Dieldrin

o     Heptachlor

o     hexachlorobenzene.

·              Excreted only over several months or years:

o     beta isomer of benzene hexachloride

o     DDT

o     Kepone

o     mirex.

Mode of Action

Organochlorines do not depress cholinesterase enzymes.

These compounds act by various other mechanisms.

·              DDT and analogues affect the sodium channel and sodium conductance across the neuronal membrane especially of the axon. They also alter the metabolism of serotonin, noradrenaline and acetylcholine.

·              The cyclodienes and lindane appear to inhibit the GABA- mediated chloride channels in the CNS.

·              The neurotoxic mechanism of endosulfan involves inhibi-tion of the calmodulin-dependant Ca2+ -ATPase activity,alterations in the serotoninergic system, and inhibition ofGABA receptors.

·              An important property of the chlorinated hydrocarbons,particularly toxaphene, chlordane, DDT, and lindane is theircapacity to induce the drug-metabolising enzymes of theliver. Most of these agents cause liver necrosis and they arepotent enzyme inducers. Evidence suggests an importantrole of benzoquinones in the hepatotoxicity of chlorin-ated hydrocarbons as opposed to traditional epoxides. Cytochrome P450 appears to be associated with covalent protein binding of reactive metabolites.

Clinical Features

Acute Poisoning:

·              GIT: nausea, vomiting, abdominal pain, hyperaesthesiaor paraesthesia of the mouth and face.

·              CNS: headache, vertigo, myoclonus, tremor, ataxia,nervousness, amnesia, rapid and dysrhythmic eye movements, mydriasis, weakness, agitation, confusion, and convulsions. Occasional reports have associated peripheral neuropathy with exposure to organochlo-rines.

·              Other systems: fever, aspiration pneumonitis, renalfailure. Coronary spasm, hypotension, and sinus tachycardia may occur following exposure. Dieldrin, endrin, chlordane, toxaphene, and DDT are direct respiratory depressants. Severe metabolic acidosis has been reported.

·              Organochlorine pesticides such as DDT pass through the placenta, with an average level in the newborn blood reaching around a third of that in maternal blood. They can also be found in breast milk.

Chronic Poisoning:

Long-term exposure to some of these compounds (chlordecone, chlordane, heptachlor) results in cumulative toxicity with manifestations such as weight loss, tremor, weak-ness, opsoclonus, ataxia, pseudotumour cerebri, abnormal mental changes, oligospermia, and increased tendency to leukaemias, thrombocytopenic purpura, aplastic anaemia, hepatomegaly, centrilobular hepatic necrosis and liver cancer.

The International Agency for Research on Cancer (IARC) has listed some of these agents (e.g. DDT) as “possibly carci-nogenic to humans”, although it also categorises them as being inadequately assessed for human carcinogenic potential. For other agents (e.g. aldrin), carcinogenicity has been demon-strated in animal studies, but insufficient data has accrued from human studies. 

Diagnosis

·      Abdominal radiograph may reveal the presence of certain organochlorines which are radiopaque.

·      Organochlorines can be detected in serum, adipose tissue, and urine by gas chromatography.

·     Blood chlorinated hydrocarbon levels are not clinically useful following acute exposure. For most compounds they reflect cumulative exposure over a period of months or years rather than recent exposure.

·      Measurement of organic halogen compounds in urine is suggested as an indicator of exposure. Sensitivity is as low as 1 mcg of organic halogen per 100 ml of urine.

Treatment

·      Decontamination—the same measures as detailed under organophosphate poisoning must be undertaken.

o     Move patient from the toxic environment to fresh air.

o     Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis. Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta adrenergic agonists if bronchospasm develops.

o     Exposed skin and eyes should be flushed with copious amounts of water. Remove contaminated clothing and jewelry; wash skin, hair and nails vigorously with repeated soap washings. Leather absorbs pesticides; all contaminated leather should be discarded. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects.

·      Do NOT give oils by mouth. They tend to increase intestinal absorption of these lipophilic toxicants.

·      Seizures should be controlled with benzodiazepines, phenytoin, or phenobarbitone in the usual way. If they are not effective enough, sodium thiopentone can be adminis-tered IV, or neuromuscular blockade is done.

·      Monitor for respiratory depression, hypotension, arrhyth-mias, and the need for endotracheal intubation. Evaluate for hypoxia, electrolyte disturbances, and hypoglycaemia (if present, treat with intravenous dextrose: 50 ml IV (adult), or 2 ml/kg (child) of 25% dextrose).

·      Cholestyramine, a non-absorbable bile acid binding anion exchange resin is effective in enhancing the faecal excretion of organochlorine compounds, particularly chlordecone. It is administered at a dose of 16 gm/day for several days. It can be mixed with fruit juice and given orally (4 gm, 6th hourly). It can interfere with absorption of other therapeutic drugs which must therefore be administered either 1 hour before, or 4 hours after each dose of cholestyramine.

·      Hyperthermia should be managed aggressively with cooling.

·      Supportive measures—special attention must be paid to the airway and breathing, and adequate circulation should be maintained.

·      The following are contraindicated—oil-based cathartics, adrenaline, and atropine. Do NOT administer adrenergic amines, which further increase myocardial irritability and produce refractory ventricular arrhythmias.

·              Haemodialysis and haemoperfusion have not been proven effective.

 

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