Pesticides
Michael Eddleston
Michael Eddleston ScD FRCPE FEAPCCT is Professor of Clinical Toxicologyat the University of Edinburgh and Honorary Consultant Physician at the Edinburgh Royal Infirmary. His research interests include the management and prevention of pesticide self-poisoning and the clinical pharmacology of antidotes for poisoning. Competing interests: none declared.
Abstract
Over 300,000 people die eachyear from pesticide poisoning. Most result from self-poisoning by ingestion, rather than occupational or accidental exposures which are typically topical or inhalational. Severe pesticide poisoning is more commonin the rural developing world where pesticides are widely used in smallholder agricultural practice and therefore freely available. Significant acute poisoning is much less common in industrialized countries and here it is the long-term effects of low-dose chronic exposure that most concern the population. Organophosphorus (OP) and carbamate insecticide poisoning causes most severe cases and deaths, although thesenumbersare falling as the most highly toxic compounds are withdrawn from agricultural practice. Severe OP poisoning requires urgent resuscitation and administration of oxygen, atropine and oximes. Paraquat and aluminium phosphide are major problems in some countries with case fatality usually exceeding 50% and no effective treatments. Newer pesticides that have become widely used over the last 30 years, for example glyphosate and neonicotinoid and phenylpyrazole insecticides, are more selective in their toxicity to pests, resulting in far less human toxicity and few deaths. Poisoning with these pesticides usually requires only careful supportive care.
Keywords: Aluminiumphosphide;atropine;carbamates;neonicotinoids; organochlorineinsecticides;organophosphorusinsecticides;oximes;paraquat;solvents
‘Pesticide’ is the term used to describe a range of chemicals utilised as insecticides, fungicides, herbicides, and rodenticides.1Despite the large number of new pesticide classes that have been introduced intro agricultural practice over the last 50 years, most deaths and severe poisonings are still caused by a small number of older compounds. OP and carbamate insecticides and the herbicide, paraquat, are the most important; the rodenticide, aluminium phosphide, is a major problem in parts of rural Asia.2Newer agents (such as pyrethroids, glyphosate, and neonicotinoids) cause far fewer deaths.
The potential for occupational exposure is high, particularly in developing countries where climatic conditions militate against the wearing of the recommended protective equipment. However, exposures that occur by inhalation or dermal exposure are usually smaller than those occurring by ingestion; most pesticide poisoning deaths therefore result from self-harm and intentional ingestion.Most exposures in developed countries are accidental and do not result in harm.
The case fatality for pesticide poisoning in general will fall as newer, safer pesticides are introduced into global agricultural practice and highly toxic pesticides removed.
Role of solvents and other co-formulants in agricultural pesticide toxicity
Agricultural pesticides are formulated with other compounds to allow their effective use, incorporating for example solvents and surfactants. Studies with glyphosate (see below) and the OP insecticide dimethoate 3 indicate that these co-formulants may be toxic in their own right and fully responsible for a pesticide’s toxicity or additive with the active pesticide ingredient. Where the active ingredient itself has low mammalian toxicity, e.g. flufenoxuron (see below), any human toxicity noted is likely due to co-formulants.
Organophosphorus insecticides
OP insecticides are estimated to cause more than 100,000 deaths and two million hospital admissions every year, nearly all in developing countries. In industrialised countries, public concern about these agents focuses on the possible long-term health effects of single or repeated exposure to low concentrations of pesticide (see below). OPs are readily absorbed through the gut, lung, and to a lesser extent the skin.
Mechanisms of toxicity
OPinsecticides phosphorylate multiple enzymes and proteins throughout the body. However, the clinical relevance of this process remains unclear for the great majority of targets. Instead, it is inhibition of the synaptic enzyme acetylcholinesterase that is thought to be responsible for toxicity. The speed of onset, severity, and duration of toxicity caused by different OPs vary considerably and depend on several factors including their chemical structure. High tissue concentrations and high affinity for acetylcholinesterase increase toxicity.
Reactivation of inhibited enzyme, which curtails toxicity, occurs slowly spontaneously but can be speeded up with an oxime acetylcholinesterase-reactivating drug, such as pralidoxime or obidoxime.4Alternatively,the enzyme can become ‘aged’, a process in which the phosphoryl group deposited on the enzyme changes chemically, preventing both spontaneous and oxime-induced reactivation. The faster aging occurs, the less effective reactivation therapy will be. Recovery then depends on the slow synthesis of new acetylcholinesterase.Aging occurs very quickly for OP insecticides with an S-alkyl structure (e.g. profenofos) but relatively more slowly for dimethyl (e.g. dimethoate) and particularly diethyl (e.g. parathion) OP insecticides.
Clinical features
Acute poisoning is characterized by widespread muscarinic and nicotinic effects caused by inhibition of acetylcholinesterase at autonomic nerve endings and neuromuscular junctions, and in the central nervous system (CNS). Muscarinic symptoms usually first occur in the system through which the pesticide enters (Table 1).Secretory effects (salivation, bronchorrhoea) as well as pinpoint pupils (miosis) are common. Nicotinic effects include profuse sweating, fasciculation, progressive flaccidity, and weakness of proximal muscle groups, in particular the neck flexors followed later by the extra-ocular muscles and muscles of respiration. Respiratory failure is common in severe poisoning5and the major cause of death;it results from a direct effect on central respiratory drive as well as from muscle weakness, bronchospasm and retention of bronchial secretions. In patients with severe poisoning, initial mild excitatory CNS effects (e.g. anxiety, restlessness, dizziness) may be followed by coma and, less commonly, seizures.6Severe hypotension is noted with some OP pesticides;6 tachycardia can result from direct nicotinic effects but also from hypovolaemia and sepsis. Hyperglycaemia and glycosuria are common.
Diagnosis
This is usually made clinically in combination with the characteristic smell of formulated OP insecticides. It is then confirmed by measuring plasma or, preferably, red cell acetylcholinesterase activity to demonstrate inhibition. Clinical management should not await results of these assays.
Management
Initial treatment
The initial aims are to resuscitate and stabilize the patient with support of the airway, ventilation, and circulation.7Oxygen and intravenous fluids should be given and convulsions controlled with intravenous diazepam. Even in the absence of convulsions, intravenous administration of diazepam (10 mg in adults) reduces anxiety and restlessness and may improve outcome. Decontamination of the patient should await patientstabilisation with administration of antidotes (see below) as necessary.
Antidotes
The specific antidotes are atropine and oxime reactivators.8
Atropine can be used rapidly to block muscarinic effects and improve cardiorespiratory function. It is given intravenously (initially, adult 1–3 mg, child 0.02 mg/kg [20 mcg/kg]) andrepeated in doubling doses at five-minute intervals until bronchorrhoea and bronchospasm are abolished and cardiovascular function restored (systolic blood pressure >80 mmHg, pulse >80 bpm).7,9Once these thresholds have been attained, atropine can be continued as a constant infusion to sustain adequate cardiorespiratory function. Patients with severe poisoning may require very large doses of atropine. However, if there is evidence of atropine intoxication (dry mouth, tachycardia, agitation or confusion, dry skin, ileus), then the infusion should be stopped temporarily and restarted at around 70% of the previous rate once toxicity has settled. Patients must alsobe observed carefully for the recurrence of cholinergic features requiring bolus atropine.
Oximes such as pralidoxime and obidoxime reactivate phosphorylated cholinesterases, provided they are not given after aging has occurred.4 They may restore muscle power, reduce fasciculations, and improve the patient’s level of consciousness, but effectiveness is not confirmed.10 Pralidoxime chloride (or obidoxime) should be given, preferably in a critical care environment, as a loading dose of 30 mg/kg (or obidoxime 250 mg) by slow intravenous injection over 30 to 60 minutes followed by an infusion of 8–10 mg/kg/hr (or obidoxime32 mg/hr), continued for 2-3 days. If muscle weakness then gets worse on stopping oximes, they can be restarted with daily attempts at withdrawal.
Long-term health effects
OP pesticides (particularly those used in sheep dips) are thought by some to be responsible for a long-term debilitating illness with numerous symptoms.11 Neuromuscular complaints (lethargy, irritability, poor concentration, mood swings, depression, insomnia, paraesthesiae, muscle aches and pains) predominate. A few affected individuals are so disabled that they become housebound and their quality of life is extremely poor. Assessment and management of such patients is difficult.
A detailed history is required to establish the time relationship between symptoms and pesticide exposure, the frequency and duration of exposure, and all the pesticides (and their solvents) and other chemicals to which the patient has been exposed, whether at work or in leisure activities; the patient is best able to compile this list. Exclusion of other explanations is an essential component of the assessment. Clinical examination and extensive investigation often fail to identify any significant abnormality or cause. Subtle impairment of nerve conduction velocities and performance in some neuro-behavioural tests has been reported, but theirrelevance to the symptoms remains unclear. Management focuses on symptom control and psychological support.
Carbamate insecticides
Features and management
Carbamate insecticides act in the same manner as OP insecticides and features of poisoning are similar. However, carbamate poisoning is generally less severe and of shorter duration because carbamate-inhibited acetylcholinesterase reactivates comparatively rapidly. Chronic effects are less reported.
Resuscitation and supportive measures should be implemented as required together with administration of oxygen, fluids, and atropine. Oximes are seldom needed.
Neonicotinoid insecticides
These compounds are synthetic nicotine analogues that were developed in the 1970s-90s and include acetamiprid, imidacloprid, and thiamethoxam. Imidacloprid is now the best-selling insecticide worldwide. Neonicotinoids cause their effects by stimulation of nicotinic acetylcholine receptors in insect CNS. Human toxicity occurs due to effects on post-synaptic (predominantly 42) nicotinic acetylcholine receptors.
Features and management
Human toxicity is relatively mild due to selective toxicity for insects over vertebrates (partly due to a higher affinity for insect receptors) and to poor CNS penetration. Severe poisoning causes nicotinic receptor overstimulation, resulting in respiratory failure and fasciculation. Treatment is supportive with mechanical ventilation as required; no antidote is available.12,13
Organochlorine and N-phenylpyrazole insecticides
Both organochlorine (e.g. endosulfan, lindane) and the more recent N-phenylpyrazole (e.g. fipronil) insecticides inhibit GABA receptors resulting in seizures if ingested. However, phenylpyrazole insecticides are far more specific for insect GABA receptors than human GABA receptors, resulting in less severe poisoning after ingestion.14
Features and management
By contrast, severe organochlorine insecticidepoisoning can result in fatal status epilepticus.15Therapy is supportive with incremental administration of benzodiazepines, barbiturates, and thiopental general anaesthesia.
Other insecticides
Other insecticides that mayrequire intensive care following substantial ingestion of the concentrated agricultural formulations include the avermectins (fungus-derived activators of chloride channels),16 the formamidine insecticide amitraz (centrally acting 2 adrenergic agonist),17and the benzoylphenylurea insecticide flufenoxuron.18 Each can cause hypotension and coma, sometimesrequiring mechanical ventilation.Flufenoxuron also causes a severe metabolic acidosis;toxicity is likely due to its solvent (see above).
Bipyridyl herbicides (paraquat and diquat)
Paraquat is now banned in Europe; however, poisoning remains common in parts of Asia, Pacific, and the Caribbean. Paraquat poisoning is often fatal despite strenuous therapeutic efforts. Deaths normally result from deliberate ingestion; a few relate to accidental percutaneous absorption. Diquat poisoning is less common and may beless severe due to the lower concentration formulations, although it can produce multiple organ failure as well.20
Clinical features of paraquat poisoning21
Initial features include nausea, vomiting and abdominal pain. Doses greater than 20 mL of a 20% solution cause death from multi-organ failure (including coma, metabolic acidosis, pulmonary oedema, and myocardial depression) within a few hours. Clinical features in patients who have ingested smaller doses and survive for 3-4 days is dominated by severe, painful ulceration of the lips, tongue, pharynx and larynx, leading to dysphagia, cough, dysphonia, and inability to clear saliva. Acute renal failure is common by 4-5 days after ingestion; liver damage may occur. Increasing breathless-ness and pulmonary opacities herald almost certain death within a few days or weeks as extensive and progressive pulmonary fibrosis develops.
Diagnosis
For paraquat, outcome can be predicted by relating plasma paraquat concentration to the time since ingestion.22
Management
Many treatments for paraquat poisoning have been advocated, but none seem effective.23 Early gastric lavage and administration of activated charcoal may reduce absorption; thereafter, the aim is to keep the patient pain free and comfortable. There is no high quality evidence that high dose immunosuppression saves lives by preventing lung fibrosis.
Glyphosate
Glyphosate is widely used globally as a post-emergence herbicide. It has low direct toxicity for humans since it interferes with synthesis of amino acids in the plant restricted shikimate pathway. However, it is usually formulated with 7-15% polyoxyethyleneamine (POEA) surfactant; this compound is cardiotoxic to mammals.
Features and management
Poisoning usually results in only gut signs (vomiting, diarrhoea); severe cases develop cardiorespiratory toxicity and coma, with GI haemorrhage.24 Management is supportive; no antidote exists.
Chlorphenoxyacetate herbicides
Acute severe poisoning with herbicides such as 2,4-D and MCPA is now uncommon and almost always follows ingestion.
Features and management
Clinical featuresinclude a burning sensation in the mouth and throat, nausea and vomiting, followed in severe cases by sweating, hyperventilation, coma, and myositis (including pain, fasciculation, myotonia, myoglobinuria).25Managementinvolves resuscitation and supportive care. There are no antidotes buturine alkalinization may enhance renal elimination of these weak acids and improve outcome. Unfortunately, no trials have yet been performed to test effectiveness.
Aluminium phosphide
Aluminium phosphide is a rodenticide and fumigant used to protect grain. It has the highest case fatality of any pesticide – usually more than 65% of people who ingest the pesticide die.26On contact with water in the stomach, phosphine gas is liberated which has direct toxic effects on multiple organs.
Features and management
Death results from cardiogenic shock and hypotension. Management requires resuscitation and supportive care. As yet, there is no good evidence that any proposed intervention offers clinical benefit.
Anticoagulant rodenticides
Anticoagulant rodenticides are discussed on page xxx of this issue.
Table 1. Muscarinic features of OP and carbamate insecticide poisoning
Eye•Miosis
•Blurred vision
•Eye pain
Ingestion
•Hypersalivation
•Nausea
•Vomiting
•Abdominal cramps
•Diarrhoea
•Tenesmus
Inhalation
•Cough
•Expectoration of frothy secretions
•Chest tightness and wheeze
•Pulmonary oedema
References
1 World Health Organization. The WHO recommended classification of pesticides by hazard and guidelines to classification: 2009. Geneva: WHO, 2010.
2 Eddleston M. Patterns and problems of deliberate self-poisoning in the developing world. Q J Med 2000; 93: 715-31.
3 Eddleston M, Street J M, Self I et al. A role for solvents in the toxicity of agricultural organophosphorus pesticides. Toxicology 2012; 294: 94-103.
4 Eyer P. The role of oximes in the management of organophosphorus pesticide poisoning. Toxicol Rev 2003; 22: 165-90.
5 Eddleston M, Mohamed F, Davies J O J et al. Respiratory failure in acute organophosphorus pesticide self-poisoning. Q J Med 2006; 99: 513-22.
6 Eddleston M, Eyer P, Worek F et al. Differences between organophosphorus insecticides in human self-poisoning: a prospective cohort study. Lancet 2005; 366: 1452-59.
7 Eddleston M, Dawson A, Karalliedde L et al. Early management after self-poisoning with an organophosphorus or carbamate pesticide - a treatment protocol for junior doctors. Crit Care 2004; 8: R391-R397.
8 Johnson M K, Jacobsen D, Meredith T J et al. Evaluation of antidotes for poisoning by organophosphorus pesticides. Emergency Medicine 2000; 12: 22-37.
9 Abedin M J, Sayeed A A, Basher A et al. Open-label randomized clinical trial of atropine bolus injection versus incremental boluses plus infusion for organophosphate poisoning in Bangladesh. J Med Toxicol 2012.
10 Buckley N A, Eddleston M, Li Y et al. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst Rev 2011; 2: CD005085.
11 Committee on toxicity of chemicals in food c p a t e. Statement on long-term neurological, neuropsychological and psychiatric effects of low-level exposure to organophosphates in adults. 2014.
12 Mohamed F, Gawarammana I, Robertson T A et al. Acute human self-poisoning with imidacloprid compound: a neonicotinoid insecticide. PLoS One 2009; 4: e5127.
13 Tomizawa M, Casida J E. Neonicotinoid insecticide toxicology: mechanisms of selective action. Annu Rev Pharmacol Toxicol 2005; 45: 247-68.
14 Mohamed F, Senarathna L, Azhar S et al. Acute human self-poisoning with the N-phenylpyrazole insecticide fipronil - a GABA-gated chloride channel blocking pesticide. J Toxicol Clin Toxicol 2004; 42: 955-63.
15 Moon J M, Chun B J. Acute endosulfan poisoning: a retrospective study. Hum Exp Toxicol 2009; 28: 309-16.
16 Chung K, Yang C C, Wu M L et al. Agricultural avermectins: an uncommon but potentially fatal cause of pesticide poisoning. Ann Emerg Med 1999; 34: 51-57.
17 Demirel Y, Yilmaz A, Gursoy S et al. Acute amitraz intoxication: retrospective analysis of 45 cases. Hum Exp Toxicol 2006; 25: 613-17.
18 Jeong H H, Yeom S R, Han S K, Park S W. Rapidly progressive lactic acidosis in patients with flufenoxuron poisoning. Hong Kong J Emerg Med 2014; 21: 181-84.
19 Dawson A H, Eddleston M, Senarathna L et al. Acute human lethal toxicity of agricultural pesticides: a prospective cohort study. PLoS Med 2010; 7: e1000357.
20 Jones G M, Vale J A. Mechanisms of toxicity, clinical features, and management of diquat poisoning: a review. J Toxicol Clin Toxicol 2000; 38: 123-28.