Glyphosate

Glyphosate is a non-selective herbicide that acts by inhibiting the enzymatic synthesis of aromatic
amino acids in plants. This target enzyme is not present in humans. Both readyto-use (≈1–5%) and
concentrated (≈30–50%) formulations requiring dilution are available.

Glyphosate is absorbed from the gastrointestinal tract and does not penetrate the skin to a
significant extent. Respiratory, ocular and dermal symptoms may occur following occupational
use but are usually of minor severity. Ingestion is the most significant route of exposure in clinical
toxicology.

Mechanism of toxicity

The mechanism of toxicity of glyphosate-containing herbicides in humans is inadequately

described. Experimentally, there appears to be minimal (if any) mammalian toxicity from
glyphosate itself. Toxicity has been largely attributed to surfactant co-formulants and potentially
the type of glyphosate salt. Polyoxyethyleneamine (POEA; tallow amine) is the most common
surfactant formulated in these products.

Poisoning is more severe following ingestion of concentrated formulations. This may reflect either
the total dose ingested or direct effects of the highly irritating/corrosive compounds present in
these products.

Patients with severe poisoning manifest multisystem effects. This suggests that glyphosate-
containing herbicides may be non-specific in their action or that they interfere with physiological
functions that are common to a number of systems. Proposed mechanisms include disruption of
cellular membranes and uncoupling of oxidative phosphorylation, although these may be inter-
related.

Clinical features

Abdominal pain with nausea, vomiting and/or diarrhoea are the most common manifestations of
acute poisoning. These may be mild and self-resolving but, in severe poisoning (particularly due
to the concentrated solutions), there may be inflammation, ulceration, haemorrhage or infarction
of the gastrointestinal tract. Severe diarrhoea may also occur and vomiting may be recurrent,
leading to dehydration.
Multiorgan dysfunction is noted with severe poisoning, including hypotension, kidney or liver
dysfunction, pulmonary oedema or pneumonitis, altered level of consciousness and/or metabolic
acidosis. It is not understood which of these clinical features reflect primary or secondary toxic
effects of the glyphosate-containing herbicides. These effects may be transient or severe,
progressing over 12–72 h to shock and death. Some patients who subsequently died demonstrated
only mild symptoms at the time of admission.

Differential diagnosis

The differential diagnoses are wide, including any poisoning or medical condition associated with
gastrointestinal symptomatology and progressive multisystem toxicity.

Clinical investigations

There are no specific clinical investigations to guide management. Targeted laboratory and
radiological investigations should be conducted in patients demonstrating anything more than mild
gastrointestinal symptoms. Serial blood gases may be useful for detection of metabolic
disequilibria. Hyperkalaemia is reported with products where glyphosate is formulated as the
potassium salt.

Although glyphosate plasma concentrations appear to correlate with outcomes, this assay is not
available for clinical use.

Endoscopy can identify erosions or ulceration of the gastrointestinal tract, but this investigation is
associated with a risk of viscus rupture.

Criteria for diagnosis

The principal criterion for diagnosis of acute poisoning with a glyphosate-containing herbicide is
a history of exposure. Therefore, a high index of suspicion is necessary for diagnosis. A number
of clinical criteria for the classification of severity have been suggested, but none has been
validated.

Treatment
All patients presenting with a history of acute ingestion should be observed for a minimum of 6 h.
Patients reporting a history of intentional ingestion and gastrointestinal symptoms should be
observed for at least 24 h given that the severity of poisoning may progress.

Treatment of acute poisoning with glyphosate-containing herbicides is empiric. All patients should
receive prompt resuscitation and supportive care. Activated charcoal may be given orally if the
patient presents within 1–2 h of ingestion, although a randomized controlled trial did not support
its efficacy for pesticides in general. Intravenous fluids should be administered to replace
gastrointestinal losses. Because the aetiology of hypotension may be multifactorial, including fluid
losses or a decrease in cardiac output and/or peripheral resistance, haemodynamic monitoring is
recommended to guide treatment of hypotension not responding to routine volumes of intravenous
fluids. Biochemical and acid–base abnormalities should be corrected where possible.

No specific antidote has been proposed or tested for the treatment of acute poisoning with
glyphosate-containing herbicides. This relates largely to the unknown mechanism of toxicity of
these products.

The literature is conflicting regarding the role of haemodialysis outside of the more common
indications (resistant acidaemia, hyperkalaemia or fluid overload in the context of kidney injury).
If it is to be used, it is anticipated that early initiation would optimize outcomes.

Prognosis

All intentional exposures should be considered significant. A correlation between increasing dose
and glyphosate plasma concentration, increasing age and delayed presentation to hospital with
severe poisoning and death has been suggested.

Mortality from acute poisoning with glyphosate-containing herbicides varies between studies
(reflecting various biases) but may be as high as 30%. The mortality was 3.2% in a prospective
multicentre study in rural hospitals in Sri Lanka with limited medical resources.

Tools for estimating prognosis in acute poisoning with glyphosate-containing herbicides have not
been described in detail. Patients developing marked multiorgan dysfunction, including kidney
injury, hypotension, pulmonary oedema, sedation, arrhythmias) are more likely to die. Patients
with more extensive erosions of the upper GI tract developed more severe systemic poisoning and
required prolonged admission.