Link to 2.2.7.4.4 Organochlorines Educational Resources


Organochlorine


SUBSTANCE INCLUDED


  • Aldrin
  • Chlordecone
  • DDT
  • Dieldrin
  • Endosulfan
  • Endrin
  • Heptachlor
  • Hexachlorocyclohexane
  • Isobenzan
  • Lindane

OVERVIEW


Organochlorines are extremely toxic pesticides that primarily act as excitatory neurotoxins.
They are extremely lipid soluble and are rapidly distributed into fat stores and subsequently are very slowly eliminated.

MECHANISM OF TOXICITY


Cyclodiene organochlorine pesticides inhibit gamma aminobutyric acid (GABA)ergic neurotransmission by blocking the chloride channel of GABA(A) receptors.

KINETICS IN OVERDOSE


Absorption

All organochlorines are rapidly absorbed from the small intestine. There is some dermal absorption but dermal exposure does not generally lead to significant acute toxicity. Peak concentrations may occur within a few hours.

Distribution

These are all highly lipid soluble compounds that distribute into fat with resulting very large volumes of distribution.

Metabolism - Elimination

Organochlorines are highly lipid soluble, but undergo minimal metabolism. They are excreted to some extent in the bile, however most are then reabsorbed. This recirculation can be reduced by cholestyramine or charcoal. There is very little renal excretion. The terminal elimination half-lives of organochlorine pesticides are several months and residues can be detected in fat years after the last exposure.

CLINICAL EFFECTS


Central nervous system effects

These are due to initial CNS stimulation which is followed by increasing CNS depression leading to coma.
Paraesthesiae, apprehension, dizziness, ataxia, confusion, tremor, myoclonus are the earliest manifestations of toxicity. These may be followed by generalised tonic or clonic seizures.
Coma and paralysis are late manifestations. These may result in respiratory arrest.

Cardiac effects

The heart is sensitised to catecholamines and ventricular tachycardia/fibrillation is a common terminal event.

Pulmonary effects

Pulmonary signs/symptoms may occur from aspiration of the solvent component of the pesticide.

INVESTIGATIONS


ECG

Should be done in moderate to severe poisonings as ventricular tachyarrhythmias may occur.

Biochemistry

Electrolytes, creatinine, urea, liver function,creatinine phosphokinase should be obtained.

Imaging

CXR is indicated in all severe poisonings as aspiration pneumonia (contributed to by hydrocarbon diluents) is not uncommon.

Blood gases

These are indicated in all severe poisonings as aspiration pneumonia (contributed to by hydrocarbon diluents) is not uncommon.

Blood concentrations

These are unhelpful in aiding management.

DIFFERENTIAL DIAGNOSIS


Difficulties in diagnosis usually arise when an unconscious, fitting or delirious patient is known to have ingested an unknown chemical from the garden shed (see differential diagnosis of garden shed poisoning).

DIFFERENCES IN TOXICITY WITHIN THIS CLASS


Organochlorines are very qualitatively similar in terms of their acute toxicity.
However, the concerns about carcinogenesis are toxin specific with some compounds being genotoxic whilst others may have effects through induction of hepatic metabolic pathways and others have rumour promoting activity.

TREATMENT


Supportive

Maintenance of airway, ventilation, IV access and fluids are an early priority as patients may develop seizures without warning.

Staff should
  • Gown and glove (preferably nitrile gloves)
  • Remove (and destroy) patient's clothes
  • Wash the patient a number of times (soap, alcohol and soap) if the skin is contaminated.

Intensive Care admission

Patients with moderate or severe poisoning should be transferred to an Intensive Care facility. Asymptomatic patients who have ingested organochlorine concentrate should also be initially observed in ICU.

GI Decontamination

Activated charcoal
Oral activated charcoal should be given to all patients ingesting organochlorines within 1-2 hours of presentation. Patients with any history, signs or investigation indicating severe poisoning should have elective intubation, consideration of gastric lavage and activated charcoal.

Antidotes
Benzodiazepines and barbiturates antagonise the toxicological effects of organochlorines in the CNS. They are certainly indicated if seizures develop but also would be appropriate treatment for tremor, agitation and other less severe manifestations of CNS excitation.

Treatment of specific complications

Seizures
Control of seizures may be difficult. Thiopentone is likely to be the most efficacious therapy but its use requires intubation and ventilatory support. High dose barbiturates have direct effects on the GABA-chloride channel that are the opposite of cyclodiene organochlorines.

Benzodiazepines, such as diazepam (10-20 mg IV) or clonazepam may be effective in some patients and should be the treatment of first choice followed by phenobarbitone (15 mg/kg) if that fails. Patients whose seizures are refractory to these measures require intubation and thiopentone loading (3-5 mg/kg) and infusion (2-4 mg/kg/hr). Neuromuscular paralysis should be avoided unless there is continuous EEG monitoring.

Phenytoin and other agents that do not act through GABA-ergic mechanisms are unlikely to be helpful.

Ventricular tachycardia
These tend to be associated with centrally mediated catecholamine excess and beta blockers are not ideal treatment as unopposed alpha stimulation could result in coronary artery constriction with ischaemia. Diazepam in large doses may be of value. The excitotoxic mechanism of action of at least the cyclodienes is clinically similar to that of agents such as chloroquine. In one (unreported) case we have used a high dose of diazepam (2-3 mg/kg over 30 min) with significant benefit in life-threatening seizures complicated by recurrent ventricular tachycardia after deliberate endosulfan poisoning.

Elimination enhancement

Some of the chlorinated phenoxy acid herbicides (MCPA) may have increased elimination in alkaline urine.

LATE COMPLICATIONS, PROGNOSIS


Long term neuropsychiatric sequelae have been described for severe poisoning. All these compounds have very long half-life (several months) and some neurotoxic effects may persist for some time.

Other concerns relate to possible carcinogenic risk from organochlorines. The in vitro data and some animal studies suggest possible genotoxic and non-genotoxic mechanisms that can lead to cancer (Dich, et al. 1997). However, epidemiological studies do not suggest a significant increase in cancer risk even with long term exposure (de Jong et al, 1997; Ribbens 1985).

REFERENCES

Karatas AD, Aygun D, Baydin A. Characteristics of endosulfan poisoning: a study of 23 cases. Singapore Med J. 2006 Dec;47(12):1030-2. (fulltext)
Carvalho WA, Matos GB, Cruz SL, Rodrigues DS. Human aldrin poisoning. Brazilian Journal of Medical & Biological Research 1991;24:883-887.
Cohn WJ, Boylan JJ, Blanke RV, Fariss MW, Howell JR, Guzelian PS. Treatment of chlordecone (Kepone) toxicity with cholestyramine. Results of a controlled clinical trial. N Engl J Med 1978;298:243-248.
de Jong G, Swaen GM, Slangen JJ. Mortality of workers exposed to dieldrin and aldrin: a retrospective cohort study. Occupational & Environmental Medicine 1997;54:702-707.
Dich J, Zahm SH, Hanberg A, Adami HO. Pesticides and cancer. Cancer Causes & Control 1997;8:420-443.
Fleming L, Mann JB, Bean J, Briggle T, Sanchez-Ramos JR. Parkinson's disease and brain concentrations of organochlorine pesticides. Annals of Neurology 1994;36:100-103.
Kurt TL, Bost R, Gilliland M, Reed G, Petty C. Accidental Kwell (lindane) ingestions. Vet Hum Toxicol 1986 Dec;28(6):569-71
O'Malley M. Clinical evaluation of pesticide exposure and poisonings. Lancet 1997;349:1161-1166.
Ribbens PH. Mortality study of industrial workers exposed to aldrin, dieldrin and endrin. International Archives of Occupational & Environmental Health 1985;56:75-79.
Taylor JR. Neurological manifestations in humans exposed to chlordecone: follow-up results. Neurotoxicology 1985 Spring;6(1):231-6
Roberts D, Dissanayake W, Sheriff MHR, Eddleston M. Refractory status epilepticus following self-poisoning with the organochlorine pesticide endosulfan. J Clin Neurosci 2004, 11: 760-762.