Chlorphenoxy herbicides

2,4-dichlorophenoxyacetic acid (2,4-D)
4-chloro-2-methylphenoxyacetic acid (MCPA)
2,4,5-trichlorophenoxyacetic acid (2,4,5-T)
mecoprop (MCPP)

Chlorophenoxy herbicides are typically present in concentrations of 40-60% and co-formulated with a range of surfactants which may also contribute to toxicity. Multiple products are available and some of these are co-formulated with other herbicides, including dicamba or less often ioxynil. These compounds may also contribute to the clinical toxicity. Chlorophenoxy herbicides are selective against broad-leaved plants, having their main application in agricultural (rice paddy) and residential (grass lawns) uses. 2,4,5-T was the defoliating agent included in Agent Orange during the Vietnam War.

The mechanism of toxicity of chlorophenoxy herbicides is poorly defined. Direct irritant effects may produce the high incidence of gastrointestinal effects that have been reported. Severe toxicity and death is often preceded by multi-system effects suggesting cellular dysfunction. Uncoupling of oxidative phosphorylation appears the most probable mechanism of toxicity, which may contribute to the delay in onset of severe toxicity and death usually noted. The extent to which the surfactant and other co-formulants contribute to toxicity is not known.

Chlorophenoxy herbicides are well absorbed from the gastrointestinal tract, with peak plasma concentrations around 2-6h post-ingestion. There is minimal absorption across the skin, and data regarding other routes of exposure are limited.

Protein binding is saturated with moderate exposures to chlorophenoxy herbicides which increases the volume of distribution. Acidosis may also increase the distribution of chlorophenoxy herbicides given their low pKa (~3.0) From animal and volunteer studies the volume of distribution ranges from 0.1 to >1000 L/kg. The time for distribution appears to be long.

This varies between animals and humans. For example, MCPA is predominantly renally cleared in rats while hepatic clearance is more dominant in dogs. In humans, renal clearance appears to be the main route of elimination, although there is some hepatic processing.
Renal elimination may become saturated with high exposures, prolonging the elimination half life. The plasma elimination half-life in humans is typically in the range of 15-45h, although half lives up to 180h have been reported in some cases of poisoning.

Chlorophenoxy herbicides are locally irritating and the initial presentation is with gastrointestinal toxicity. Moderate and severe poisoning may manifest as multi-system toxicity, including hypotension, pulmonary dysfunction, acidosis, renal failure, cardiac arrest, coma, rhabdomyolysis, seizures or death. Hyperventilation with respiratory alkalosis may be an early sign of severe poisoning.

Spontaneous vomiting, nausea, epigastric and abdominal pain and diarrhoea are seen most frequently. Oral burns may also occur and gastrointestinal haemorrhage has been reported, although this is rare.

Initial hyperventilation with respiratory alkalosis may be noted due to central effects. This may be followed by mild hypoxaemia suggesting the development of acute respiratory distress syndrome or acute pulmonary oedema and respiratory failure requiring intubation and ventilation.

Tachycardia and hypotension are common in severe poisonings which may require pressor amines (such as dopamine and adrenaline). Some cases progress to refractory hypotension which is the usual cause of death. This refractory hypotension in the presence of normovolaemia unresponsive to pressor amines suggests a direct myocardial depressant effect. Consistent with this, cardiac conduction defects progressing to asystole has been noted in patients with severe poisoning.

Miosis, confusion, agitation or sedation has been reported. Coma and seizures may occur with severe poisoning.

Metabolic acidosis and fever is noted in patients with severe poisoning which may be related to uncoupling of oxidative phosphorylation. This may be associated with hypokalaemia or hypocalcaemia.

A variety of renal abnormalities occur including oliguria and darkened urine which may progress to acute renal failure. Rhabdomyolysis has also been noted in some patients which might exacerbate renal dysfunction. Muscle weakness, fasciculations or myalgias persisting for a number of days are also reported.

The assessment of severity of an exposure is determined primarily by clinical toxicity.

The correlation between dose ingested and severity of toxicity is not well defined. Large exposures (reports of up to 100 mL) have been associated with mild or moderate toxicity only. However, ingestion of volumes less than 100 mL has been associated with severe toxicity and death.

Patients who remain asymptomatic for 6h post-ingestion are unlikely to progress to severe toxicity. Patients who develop symptoms should be monitored until asymptomatic. Severe toxicity may not develop in some patients until 24-48h post-exposure.

Asymptomatic: No abnormalities on physical or laboratory examination
Mild: Predominantly gastrointestinal symptoms with stable vital signs and no other organ involvement
Moderate: Gastrointestinal symptoms lasting longer than 24 hours Hypotension, responsive to intravenous fluids Pulmonary dysfunction not requiring intubation Acid base disturbance Evidence of transient renal damage or temporary oliguria Myalgia Sedation
Severe: Pulmonary dysfunction requiring intubation Renal failure requiring dialysis Hypotension requiring pressor amines Acid-base disturbance Cardiac arrest Coma Seizures Death (may occur in > 5% of exposures, depending on the chlorophenoxy herbicide)

Patients should have serum electrolytes, creatinine, urea, liver function tests, glucose and arterial blood gases (including lactate).

Baseline then as indicated clinically.

Chest X-ray should be performed in any patient with abnormal gas exchange or clinical signs of pulmonary involvement.

Urine output should be monitored, and maintenance of a good output (>1 mL/kg body weight) is a priority in patients with moderate to severe poisoning. This may prevent the onset of renal dysfunction and increase clearance of the chlorophenoxy herbicide.
Hypotension may develop several hours after ingestion. Cardiac monitoring should be available. Hypotension should be treated initially with intravenous fluids and if unresponsive with pressor amines. There is a risk of pulmonary oedema so aggressive fluid resuscitation is inadvisable.
Acidosis should be treated aggressively with bicarbonate therapy and respiratory support since it may exacerbate toxicity (similar to salicylate poisoning).

Respiratory function should be monitored closely, oxygenation assured and intubation with assisted ventilation may be required. If pulmonary oedema occurs positive respiratory pressure may be of value, although care should be exercised if there is evidence of cardiac dysfunction.

Intravenous bicarbonate for urinary alkalinisation may be a useful antidote for chlorophenoxy herbicide poisoning on the basis of animal studies and limited human data. It appears reasonable to induce Urine alkalinisation (urine pH>7.5) in patients with moderate-severe poisoning using the same rationale and regimen as for salicylate poisoning.

Oral activated charcoal should be given if the patient presents within 1 hour of ingestion. Because absorption of chlorophenoxy herbicides appears to continue beyond 1h, it is not unreasonable to administer oral activated charcoal to cooperative patients up to 6h post-ingestion.

Multiple dose activated charcoal has not been noted to improve outcomes, although it has been trialled in a limited number of cases only.
From the pharmacokinetic parameters of chlorophenoxy herbicides, haemodialysis may be of theoretical value. Clinical benefits and increased clearance were noted in a small number of patients with 2,4-D poisoning who received haemodialysis. Haemodialysis may be of value for renal failure or acidosis which does not respond to bicarbonate.

The differential diagnosis should include any garden shed poisonings and depending on regional availability, paraquat.
There are similarities in clinical signs between chlorophenoxy herbicides and anticholinesterase insecticides. Chlorophenoxy herbicides do not inhibit cholinesterase (unlike the organophosphate or carbamate insecticides), which can be a useful test to differentiate between these groups of compounds.

There is the potential for long term lung injury if significant ARDS occurs. The occurrence of neuromuscular sequelae has been extensively debated.

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