Clinical Toxicology, 38(2), 111–122 (2000)

Mechanisms of Toxicity, Clinical Features,

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and Management of Acute Chlorophenoxy

Herbicide Poisoning: A Review
Sally M. Bradberry; Barbara E. Watt; Alex T. Proudfoot;
J. Allister Vale

National Poisons Information Service (Birmingham Centre), City Hospital,

Birmingham, United Kingdom
For personal use only.

ABSTRACT

Introduction: Chlorophenoxy herbicides are used widely for the control of

broad-leaved weeds. They exhibit a variety of mechanisms of toxicity including
dose-dependent cell membrane damage, uncoupling of oxidative phosphoryla-
tion, and disruption of acetylcoenzyme A metabolism. Between January 1962
and January 1999, 66 cases of chlorophenoxy herbicide poisoning following
ingestion were reported in the literature. Features following ingestion: Adju-
vants in the formulations may have contributed to some of the features ob-
served. Vomiting, abdominal pain, diarrhea, and, occasionally, gastrointestinal
hemorrhage were early effects. When present, hypotension was predominantly
due to intravascular volume loss, although vasodilation and direct myocardial
toxicity may have contributed in some cases. Neurotoxic features included
coma, hypertonia, hyperreflexia, ataxia, nystagmus, miosis, hallucinations, con-
vulsions, fasciculation, and paralysis. Hypoventilation occurred not infre-
quently, usually in association with central nervous system depression, but re-
spiratory muscle weakness was a factor in the development of respiratory
failure in some patients. Myopathic symptoms including limb muscle weakness,
loss of tendon reflexes, and myotonia were observed and increased creatine
kinase activity was noted in some cases. Other clinical features reported in-
cluded metabolic acidosis, rhabdomyolysis, renal failure, increased aminotrans-
ferase activities, pyrexia, and hyperventilation. Twenty-two of 66 patients died.

Correspondence: Dr. J. Allister Vale, National Poisons Information Service, City Hospital, Birmingham, B18 7QH, United Kingdom.
Tel: 44/121-507-4123; Fax: 44/121-507-5580; E-mail: AllisterVale@npis.org

111
Copyright  2000 by Marcel Dekker, Inc. www.dekker.com
 ORDER REPRINTS

112 Bradberry et al.

Features following dermal and inhalational exposure: Substantial dermal or

inhalational 2,4-dichlorophenoxyacetic acid exposure has occasionally led to
systemic features but no such reports have been published in the last 20 years
and no fatalities have been reported at any time. Substantial dermal exposure
has been reported to cause mild gastrointestinal irritation after a latent period
followed by progressive mixed sensory-motor peripheral neuropathy. Mild,
transient gastrointestinal and peripheral neuromuscular symptoms have also
occurred after occupational inhalation exposure, with or without dermal expo-
sure. Management: In addition to supportive care, alkaline diuresis to enhance
herbicide elimination should be considered in all seriously poisoned patients.
Limited clinical data suggest that hemodialysis produces similar herbicide
clearance to alkaline diuresis without the need for urine pH manipulation and
the administration of substantial amounts of intravenous fluid in an already
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compromised patient. Conclusions: While chlorophenoxy herbicide poisoning

is uncommon, ingestion of a chlorophenoxy herbicide can result in serious and
sometimes fatal sequelae. In severe cases of poisoning, alkaline diuresis or he-
modialysis to increase herbicide elimination should be considered.

INTRODUCTION Table 1

Chlorophenoxy herbicides are widely used for the Pesticide Deaths in England and Wales 1945–1989
(after Casey and Vale 4)
control of broad-leaved weeds in pastures, cereal crops,
and along public rights of way. Structurally, they consist
For personal use only.

% of All
of a simple aliphatic carboxylic acid moiety attached via Pesticide
an ether linkage to a chlorine- (and, in some cases, Pesticide Number Deaths
methyl-) substituted aromatic ring. The most commonly
used herbicide of this class is 2,4-dichlorophenoxyacetic Herbicides 787 77.7
Paraquat 570 56.3
acid (2,4-D). Other examples include 2,4,5-trichlorophe-
Chlorophenoxy compounds 50 4.9
noxyacetic acid (2,4,5-T), 4-chloro-2-methyl-phenoxy-
acetic acid (MCPA), 2-(2-methyl-4-chlorophenoxy) Insecticides 110 10.9
Rodenticides 69 6.8
propionic acid (mecoprop), and dichlorprop 2-(2,4-
dichlorophenoxy) propionic acid. The chemically related Others 46 4.6
herbicide, 3,6-dichloro-2-methoxybenzoic acid (di- Total 1012 100.0
camba), is also often included in this group. Chlorophen-
oxy herbicides are of limited persistence in the envi-
ronment and are considered to be of low-to-moderate
Among 1012 fatal pesticide poisonings recorded during
mammalian toxicity.
this time, the majority (77.7%) involved herbicides, and
Chlorophenoxy herbicide poisoning is uncommon, but
most of these involved paraquat. Fifty deaths involved
may produce severe sequelae. Among over 6.5 million
chlorophenoxy herbicides, accounting for just under 5%
human toxic exposures reported by some 67 US Regional
of all pesticide deaths and 0.05% of all fatal poisonings
Poisons Centers to the American Association of Poison
occurring in England and Wales during the 44-year study
Control Center’s Toxic Exposure Surveillance System
period. This paper discusses potential mechanisms of
(TESS) between 1996 and 1998, only 7976 (0.12%) in-
chlorophenoxy herbicide toxicity and reviews the fea-
volved 2,4-D or 2,4,5-T. At least 28% of the 7976 expo-
tures and optimal management of acute poisoning.
sures involved children under 6 years old and therefore
may not have been toxic exposures.1–3 Twenty patients
developed life-threatening or significant residual effects MECHANISMS OF TOXICITY
and there was only 1 reported fatality. Casey and Vale 4
reviewed all deaths from pesticide poisoning occurring In vivo, the salts and esters of chlorophenoxy com-
in England and Wales between 1945 and 1989 (Table 1). pounds are dissociated or hydrolyzed rapidly, therefore
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Chlorophenoxy Herbicide Poisoning
the toxicity of each compound depends principally on the
acid form of the pesticide.5 These herbicides bind
strongly to serum albumin,6,7 and the extent depends on
chemical structure. Increased length of the acid chain and
increased substitution of the aromatic ring favor binding.
Hence, it can be envisaged that bioavailability and there-
fore toxicity may vary for different herbicides in this
class.
The precise mechanisms of toxicity of chlorophenoxy
herbicides have not been elucidated completely. How-
ever, experimental studies indicate the potential involve-
ment of the following mechanisms:
(i) Effects associated with the plasma membrane;
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(ii) Interference in cellular metabolic pathways involv-
ing acetylcoenzyme A (acetyl-CoA);
(iii) Uncoupling of oxidative phosphorylation [poten-
tially as a consequence of (ii) or following disrup-
tion of intracellular membranes by the herbicide].
(i) Effects Associated with the
Plasma Membrane
Although Rosso et al.6 demonstrated that there is no
For personal use only.
significant penetration of lipid monolayers by 2,4-D at
concentrations of less than 0.1 µM (0.022 mg/L), higher
concentrations (10–1000 µM; 2.2–220 mg/L) increase
bilayer width and cause deep structural perturbation of
the hydrophobic region of model membrane systems.8
These high concentrations have also damaged human
erythrocyte cell membranes; electron microscopic exami-
nation revealed a dose-dependent change in shape to a
spiny (echinocyte) configuration with numerous surface
blebs and/or spinules. The concentrations applied in this
study 8 are similar to those associated with clinical tox-
icity.
This dose-dependent effect on plasma membranes
may explain in part the dose-dependent central nervous
system (CNS) toxicity caused by these herbicides.
Only small amounts of herbicide were found in the brains
of experimental animals administered 100 mg/kg or
less,9–11 consistent with low concentrations having mini-
mal effects on the plasma membranes which comprise
the blood-brain barrier. On exposure to high doses (250–
500 mg/kg) of herbicide, reversible selective damage to
the blood-brain barrier occurred in rats.12 This compro-
mised the integrity of the blood-brain barrier (demon-
strated by the subsequent presence of serum albumin and
IgG in the brain), allowing CNS accumulation of herbi-
cide. In this study, the appearance of blood-brain barrier
damage coincided with the onset of symptoms.12
REPRINTS
113
The severity of herbicide-induced cerebrovascular
damage in rats is reported to increase in the order 2,4,5-
T ⬍ MCPA ⬍ 2,4-D, with 2,4,5-T causing practically
no damage to the brain capillaries nor inducing extravasa-
tion of plasma proteins in rat brain.13 Tyynelä et al.14 dem-
onstrated that 2,4,5-T is more extensively protein-bound
in plasma than 2,4-D or MCPA and hypothesized that
this may contribute to its decreased ability to enter the
CNS.
In addition to causing direct structural plasma mem-
brane damage, chlorophenoxy herbicides have also been
shown to disrupt cell membrane transport mechanisms.
An important example is the organic anion transport sys-
tem in the choroid plexus that facilitates the removal of
potentially toxic anions (including endogenous neuro-
transmitter metabolites and exogenous organic acids)
from the brain to the blood. Experimental studies have
demonstrated competitive inhibition and ultimately satu-
ration of this system by chlorophenoxy herbicides.10,15,16
This results in the accumulation in the brain of not only
the herbicide but also of acidic endogenous neurotrans-
mitter metabolites. In support of this mechanism, homo-
vanillic acid and 5-hydroxy-3-indoleacetic acid, metabo-
lites of the neurotransmitters dopamine and serotonin,
accumulate in the CNS of rats following 2,4-D adminis-
tration.16,17
2,4-D-induced inhibition of ion channels has also been
demonstrated, with the potential to severely disrupt the
regulation and maintenance of cellular functions. It has
been shown to inhibit the compartmentalization of Ca 2⫹
in rat muscle tissue, leading to long-lasting and finally
irreversible activation of the actin-myosin system and de-
generation of myofibrils.18 Although 2,4-D toxicity has
been associated with increased concentrations of intracel-
lular calcium in hepatocytes, it is not an early increase
and is therefore likely to be a consequence of loss of cell
viability rather than a cause of cytotoxicity.19
Another consequence of the disruption of plasma
membranes is direct cytotoxicity. Due to its central role
in the metabolism of xenobiotics, the liver is potentially
vulnerable to the toxic effects of these herbicides. 2,4-D
1–10 mM (220–2200 mg/L) has been shown in vitro to
induce dose-dependent hepatocytoxicity.20 The depletion
of hepatic protective agents such as glutathione and pro-
tein thiols has also been demonstrated in vitro,20,21 and
there is evidence for the occurrence of lipid peroxida-
tion,21 although it is not known whether this is a primary
or secondary event in the cellular toxicity.
Chlorophenoxy herbicides and their analogues have
been shown to inhibit human platelet aggregation 22–24 and
thromboxane production 24 in vitro. This phenomenon
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114
may be linked to the incidence of coagulopathy that has
occurred in experimental animals poisoned with these
herbicides.25
(ii) Interference with Cellular Metabolic
Pathways
The formation of acetyl-CoA is an important step in
several biochemical pathways. It is utilized in the citric
acid cycle, in the synthesis of fatty acids and therefore
lipids, and in the synthesis of cholesterol and ultimately
steroid hormones. Acetyl-CoA also reacts with choline
to produce the neurotransmitter, acetylcholine.
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Chlorophenoxy acids are related structurally to acetic
acid and are able to form analogues of acetyl-CoA (e.g.,
2,4-D-CoA) in vitro.26,27 The formation of such analogues
has the potential to disrupt several cellular metabolic
pathways involving acetyl-CoA. For example, analogues
can enter the acetylcholine (ACh) synthetic pathway,
with the subsequent formation of choline esters (e.g., 2,4-
D-ACh)26,27 which may act as false cholinergic messen-
gers at muscarinic and nicotinic synapses.26,27 This mech-
anism could account, in part, for the development of
myotonia, a common feature of chlorophenoxy herbicide
For personal use only.
poisoning in experimental animals, and for muscle
twitching and cardiac arrhythmias. Chlorophenoxy deriv-
atives of CoA could alternatively enter other acetyl-CoA
metabolic pathways and interfere with energy metabo-
lism and with the utilization of two-carbon fragments in
the citric acid cycle. Chlorophenoxy herbicides have been
shown to alter serum cholesterol levels28 and increase β-
oxidation of fatty acids,29 perhaps also via this mecha-
nism.
(iii) Uncoupling of Oxidative
Phosphorylation
Chlorophenoxy herbicides may alter energy metabo-
lism in rat liver mitochondria by uncoupling oxidative
phosphorylation,30,31 possibly by disruption of the phos-
pholipid bilayer of mitochondrial membranes. Electron
microscopy studies have demonstrated swelling and deg-
radation of muscle mitochondria following 2,4-D admin-
istration.32 Severe and rapid depletion of adenosine tri-
phosphate (ATP) has been demonstrated, consistent with
this uncoupling mechanism.20 A variety of cellular activi-
ties may thus be compromised: the ability of the cell to
maintain ionic gradients through the function of ATP-
dependent translocases (e.g., Na⫹ /K⫹ ATPase); DNA and
protein synthesis; and the polymerization of microfila-
ments and mictrotubules, leading to disruption of the cy-
REPRINTS
Bradberry et al.
toskeletal system and maintenance of cell shape. Failure
of ion pumps due to ATP depletion may explain some of
the neuromuscular effects. For example, 2,4-D increases
potassium influx in nervous tissue, and myotonia may
be triggered via continued depolarization of the sarco-
lemma.33 Reduction in ATP concentration may also pre-
vent the operation of the sarcoplasmic reticulum Ca2⫹-
ATPase pump, causing disturbances in calcium regula-
tion in muscle cells, and resulting in sustained muscle
contraction.
In conclusion, in vitro and animal studies suggest that
the primary effect of chlorophenoxy herbicides is likely
to occur at plasma membranes, leading to some internal-
ization of the agent in cells. This can lead to more specific
toxicity in the CNS (and other organs) and disruption of
acetyl-CoA metabolism. It has also been shown that chlo-
rophenoxy herbicides can uncouple oxidative phosphory-
lation.
Most features observed in cases of poisoning are likely
to be multifactorial. For example, animal and human
studies indicate that chlorophenoxy herbicides may cause
disruption of the neuromuscular junction. This may arise
as a consequence of interference in acetylcholine produc-
tion, by direct effects on plasma membranes causing ion
channels to fail or via uncoupling of oxidative phosphor-
ylation where ATP depletion causes disturbed Ca2⫹ regu-
lation in muscle.
CLINICAL FEATURES
Chlorophenoxy Herbicide Ingestion
Sixty-six cases of chlorophenoxy herbicide ingestion
were published in the literature over the 37-year period,
January 1962 to January 1999.34–63 Reports were excluded
if the formulation consumed contained other pesticides,
such as organophosphorus pesticides,64,65 ioxynil,66 or car-
bamates.67 The clinical features reported in these 66 cases
form the basis of the following review. Most cases in-
volved the ingestion of 2,4-D, either alone or in combina-
tion with other chlorophenoxy herbicides, although it has
to be accepted that other constituents, such as surfactants
or solvents, may have contributed to some of the ob-
served effects. Nevertheless, many of the features re-
ported are consistent with the potential mechanisms
of chlorophenoxy herbicide toxicity and have occur-
red with several chlorophenoxy herbicides. Twenty
two 34–39,41–43,45,49,50,53,54,59,60 of the 66 cases died.
Vomiting was a prominent early feature of chloro-
phenoxy herbicide ingestion, occurring in at least one
third of all reported cases,35,37,40,42,44,46,49,52–55,59–63 and was
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Chlorophenoxy Herbicide Poisoning
accompanied by burning in the mouth,54,61 abdominal
pain,54 diarrhea,54,59,63 and occasionally gastrointestinal
hemorrhage.44,53,59,60 Severe corrosive effects were proba-
bly due in part to other chemicals in the formulations
ingested. Gastrointestinal fluid loss may have precipi-
tated hypovolemic shock and, in at least 3 reported
cases,53,59,60 this led to death from cardiogenic shock or
multiorgan failure and its associated complications, in-
cluding disseminated intravascular coagulation.53 Hypo-
tension, which often could not be explained solely by in-
travascular volume loss, was a prominent early feature
in approximately one third of cases.36,38,40,41,49,52–55,58,60,61 Re-
duced total peripheral vascular resistance was demon-
Clinical Toxicology Downloaded from informahealthcare.com by University of Laval on 05/30/14
strated in 1 case, suggesting possible chlorophenoxy her-
bicide-induced vasodilation.52 Hypotension might also
reflect direct myocardial toxicity, a suggestion supported
by the occurrence of transient ECG changes and arrhyth-
mias in some patients. Electrocardiographic changes
cited include T wave flattening or inversion 46 and QT in-
terval prolongation.58 Rhythm disturbances have included
supraventricular and ventricular tachycardia and, rarely,
sinus bradycardia.54 In severe cases, gastrointestinal fea-
tures were followed by the onset of coma (within the first
few hours), which was sometimes preceded by a period
For personal use only.
of agitation and confusion.46,53,60
As discussed above, there are potential mechanis-
tic reasons for the vulnerability of the CNS in chloro-
phenoxy herbicide poisoning. Coma was an almost
invariable feature of fatal cases 34–39,41–43,49,50,53,54,59,60 and
occurred in over two-thirds of reported nonfatal inges-
tions.40,46–48,51,52,54,55,58,63 In patients who survived, coma
usually lasted for several days.46,48 Other features of CNS
toxicity observed suggested upper motor neurone in-
volvement with hypertonia, hyperreflexia, or clonus be-
ing described in 10 of 66 cases 36,40,42,46,48,53,54 and extensor
plantar responses in 1 report.38 Evidence of CNS demy-
elination at postmortem has been reported.42 Other re-
ported neurological features include miosis, reported in
some 10% of 66 cases,36,40,46,55,58,63 nystagmus,41,54 ataxia,54
hallucinations,54 and convulsions.36
Coma was associated in at least 21 of 66 published
cases 35,36,38,40,41,43,46–48,50–55,58–60,63 with respiratory distress as
shown by tachypnea, inadequate ventilation, and occa-
sionally pulmonary edema. CNS depression causing hy-
poventilation was the primary cause of hypoxia, although
a possible contribution from weakness of the respiratory
muscles was suggested in some patients, which occurred
as part of a generalized myopathy with weakness,46,63 loss
of or reduced tendon reflexes,38,40,41,46,55,58 and increased
creatine kinase activity.46,52,55 The latter might also have
reflected rhabdomyolysis occurring in the context of pro-
REPRINTS
115
longed coma. Aspiration of gastric contents contributed
to pulmonary complications in several cases.40,41 Hemop-
tysis was described occasionally.44
Some degree of peripheral neuromuscular involve-
ment occurred in approximately one-third of reported
cases 36,38,40–42,44,46,48,52–55,58,61–63 although the presentation
was variable. For example, complete loss of reflexes was
reported in at least 7 cases,38,41,46,53,55,58,62 twitching or fas-
ciculation in at least 5,36,40,44,52 weakness in at least 4,46,61–63
and myotonia, a feature described widely in experimental
chlorophenoxy herbicide poisoning, in 3.42,46,61 Occasion-
ally there was evidence of primary peripheral neuronal
damage with electromyographic evidence of a peripheral
neuropathy in at least 2 cases.46,62
The neuromuscular effects described in the cases of
chlorophenoxy herbicide ingestion suggest these pesti-
cides have the potential to exert both a neurotoxic and
direct myopathic effect, which is consistent with the cho-
linergic system and cell membrane effects discussed
above. Absent reflexes, fasciculation, and weakness are
consistent with disordered neurological transmission to
muscle while weakness and diminished tendon reflexes
also occur in myopathic disorders. Myotonia implies
damage to the muscle cell membrane and impaired ion
conductance. In some patients, neuromuscular effects
persisted for weeks to months.46,48,62
Metabolic acidosis was observed in several pa-
tients46,54 and probably was caused by circulatory failure
in these cases. Pyrexia in the absence of infection was
noted occasionally,46,54,63 sometimes in association with
hyperventilation,46,54 which may have reflected chloro-
phenoxy herbicide-induced uncoupling of oxidative
phosphorylation. Renal failure occurred secondary to hy-
povolemic shock 36,59 or rhabdomyolysis 52 or, less com-
monly, was due to primary renal injury.47 Increased
aspartate and alanine aminotransferase activities and lac-
tate dehydrogenase activity have been reported in severe
poisoning.47,55 Since the isoenzymes involved were not
clarified, these abnormalities could reflect either skeletal
muscle and/or hepatic or cardiac muscle damage. Less
commonly reported features included thrombocyto-
penia,52,60 hemolytic anemia, and hypocalcemia.53
Although the prognosis was poor in patients who rap-
idly became shocked and comatose,36,38,45,49,50,60 full recov-
ery ensued in some patients over weeks to months despite
initial severe toxicity and prolonged neuromuscular ef-
fects.46,62 It is not possible to derive a dose/response rela-
tionship from these cases since the dose was rarely, if
ever, known with accuracy. In addition, there is no defin-
itive relationship between total plasma chlorophenoxy
herbicide concentrations and toxicity, although Flanagan
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116
et al.54 claimed that a total plasma chlorophenoxy herbi-
cide concentration in excess of 500 mg/L was associated
with severe toxicity. Similarly, it is difficult to comment
on the relative toxicities of the different chlorophenoxy
compounds, because with the exception of only 10
cases,36,38,40,52,54,56,57,61 all involved 2,4-D, either alone or in
combination with other chlorophenoxy herbicides.
Inhalational and/or Dermal Exposure
Despite widespread use of these agents, few reports
of systemic toxicity following inhalational and/or dermal
exposure have been published. Toxicokinetic data from
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volunteer and occupational studies have shown that der-
mal chlorophenoxy herbicide absorption is generally
poor (some 6% of an applied dose 68 ) and that inhalation
does not contribute significantly to user exposure.69 Both
factors would tend to make acute occupational chloro-
phenoxy herbicide poisoning uncommon. Five cases of
systemic toxicity following predominantly cutaneous
chlorophenoxy herbicide exposure were published be-
tween 1959 and 1963.70–72 Each involved inadvertent
spillage of 2,4-D on the limbs, in the context of little or
no protective clothing or safety precautions and no
For personal use only.
prompt skin decontamination. In several other cases, ad-
verse effects have been reported following predominantly
inhalational exposure.73–78 Interpretation of these cases is
complicated by the fact that some undoubtedly involved
dermal as well as inhalational exposure, and possibly also
ingestion. Moreover, and appropriately, the etiological
role of chlorophenoxy herbicides in many of these cases
has been challenged.79 It is also noteworthy that there
have been no published reports of acute chlorophenoxy
herbicide poisoning following dermal or inhalational ex-
posure in at least the last 20 years, and no reported fatali-
ties from such exposures in the history of chlorophenoxy
herbicide use.
Berkley and Magee 70 described a 39-year-old farmer
who experienced ‘‘excessive’’ cutaneous exposure to a
40% aqueous solution of the diethylamine salt of 2,4-D
while crop spraying over 4 days. Some inhalation of the
solution may also have occurred. On completing this
work, he complained of paresthesiae in the fingers and
toes and myalgia. Over the next 2 weeks, he developed
weakness and incoordination of the hands with reduced
biceps, triceps, and ankle reflexes. Position, vibration,
and light touch sensation were reported as impaired in the
distal extremities but electromyographic (EMG) studies
were normal. Symptoms resolved almost completely over
the ensuing 9 months. No blood or urine 2,4-D concentra-
tions were measured.
REPRINTS
Bradberry et al.
In each of 4 other cases of peripheral neuropathy fol-
lowing cutaneous 2,4-D exposure described in the early
literature,71,72 there was typically a latent period of several
days before onset of nausea and vomiting,71,72 sometimes
with anorexia 71 or diarrhea.72 Pain, paresthesiae, and
weakness affecting mainly the lower limbs followed.71,72
Clinical findings were of a flaccid paresis (in 2 cases so
severe that the patients could not walk) with impaired
light touch, pain and temperature sensation, and reduced
or absent reflexes. There was EMG evidence of denerva-
tion in 2 cases,71 described as ‘‘minimal’’ in one of these.
Fasciculation affecting all limbs but without weakness
was the principal feature in another case.71 All patients
recovered although mild weakness was present at 2–3
year follow-up in 3 cases.71,72
Gastrointestinal and peripheral neuromuscular symp-
toms were also reported following occupational exposure
in which inhalation was an important route of exposure
either alone or in combination with cutaneous expo-
sure.73–76 Features described included nausea and vom-
iting,73–76 constipation,75 abdominal pain,73,74 limb pares-
thesiae and pain,76 myalgia,75 weakness,73,74 and
hypertonia.75 In some cases,73 features persisted for sev-
eral weeks after a single exposure. Dizziness,73,74 ver-
tigo,76 and brief loss of consciousness73,74 also occurred.
Cardiac features including intermittent nodal tachycar-
dia,75 chest pain, and palpitation 76 have also been reported
rarely. In another case, Alix et al.77 described the devel-
opment of pericarditis in a 43-year-old man who some
12 hours earlier had applied MCPA to a field. Clinical
features resolved over some 2 weeks. The authors sug-
gested an ‘‘allergic’’ etiology.
Huep and Hesselmann 78 described a 48-year-old
farmer who sprayed Banvel M (containing 12 g dicamba
and 130 g MCPA in 40 L of water) for half an hour in
light clothing against the wind, and was presumably ex-
posed by inhalation percutaneously. Over the next 2 days,
he was anorexic and felt generally unwell. He subse-
quently complained of abdominal pain and 6 days post-
exposure had a coffee-ground vomit. An upper gastro-
intestinal endoscopy showed acute hemorrhagic
gastroduodenitis that responded to conventional treat-
ment. The patient was reported to be healthy 18 months
later.
MANAGEMENT
The evaluation and management of exposures to chlo-
rophenoxy herbicides should follow generally accepted
guidelines of current practice for external and gut decon-
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Chlorophenoxy Herbicide Poisoning
tamination and supportive care. In vitro studies demon-
strate that chlorophenoxy herbicides are adsorbed to acti-
vated charcoal.80 If ingestion or systemic uptake from
dermal or inhalation exposure is suspected, blood and
urine for chlorophenoxy herbicide concentration mea-
surement should be taken. Oral quinidine sulfate was re-
ported to relieve muscle tenderness effectively in a 46-
year-old farmer who accidentally ingested 30 mL of a
mixture of 2,4-D, a carbamate, and epichlorohydrin,67 but
this therapy has not been subjected to controlled study.
The primary clinical controversy in the management
of chlorophenoxy herbicide poisoning lies with the use
of alkaline diuresis or hemodialysis to enhance elimina-
Clinical Toxicology Downloaded from informahealthcare.com by University of Laval on 05/30/14
tion, and these techniques deserve careful review.
Alkaline Diuresis
A 39-year-old male was severely poisoned after the
ingestion of a preparation containing 2,4-D 10% and
mecoprop 20% as the amino salts.46,81 The authors calcu-
lated from the plasma concentration and the volume of
distribution that the patient had ingested 2,4-D 6.8 g. The
admission urine pH was 6.4 and the plasma 2,4-D con-
centration was 400 mg/L. An alkaline diuresis was insti-
For personal use only.
tuted between 42 46 and 51 81 hours postingestion by the
administration over the ensuing 48 hours of 14 L of fluid
containing sodium bicarbonate 69.3 g (825 mmol).46
However, a urine pH greater than 7.5 was not achieved
until 70–75 hours postingestion. The renal 2,4-D clear-
ance corrected for urine flow (adjusted to 1 mL/min) was
directly related to urine pH (r ⫽ 0.99) and renal 2,4-D
clearance was estimated to increase almost 5-fold for
each unit increase in urine pH. The authors cited a mean
corrected 2,4-D renal clearance of 0.28 mL/min over the
urine pH range 5.1–6.5 and 9.6 mL/min over the pH
range 7.55–8.8 (Table 2).81 At pH 5.1 and 8.3, the uncor-
rected 2,4-D renal clearances were 0.14 mL/min and 63
Table 2
Effect of Urinary Alkalinization on Plasma Half-Life
and Mean Corrected Renal Clearance of 2,4-D and
Mecoprop (after Park et al.82 )
2,4-D Mecoprop
Urine pH Clearance t 1/2 Clearance
Range (mL/min) (h) (mL/min)
5.10–6.5 0.28 219 0.38
6.55–7.5 1.14 42 0.65
7.55–8.8 9.60 4.7 2.08
REPRINTS
117
mL/min, respectively.46 The plasma half-life of 2,4-D
was approximately 219 hours before alkaline diuresis and
3.7 hours over the period 96–112 hours postingestion
when the urine pH exceeded 8.0.46,81 The amount of 2,4-D
recovered in the urine was 6.66 g.
In this case, the renal mecoprop clearance corrected
for urine flow (adjusted to 1 mL/min) was directly related
to urine pH (r ⫽ 0.94) and clearance was estimated to
double for each unit increase in urine pH.46,81 The authors
cited a mean corrected renal mecoprop clearance of 0.38
mL/min over the urine pH range 5.1–6.5 and 2.08 mL/
min over the pH range 7.55–8.8 (Table 2).81 The plasma
half-life of mecoprop was shortened from 39 to 14 hours
with alkaline diuresis.46,81 The amount of mecoprop re-
covered in the urine was 7.64 g. In this patient, clinical
improvement paralleled the fall in 2,4-D and mecoprop
concentrations and consciousness was regained on the
fourth day postingestion when the plasma 2,4-D and mec-
oprop concentrations were approximately 100 mg/L.
The uncorrected renal 2,4-D clearance (0.14 mL/min
at urine pH 5.1) 46 in this patient was similar to that found
by Wells et al.47 (0.17–1.4 mL/min). However, a high
2,4-D renal clearance was achieved only when the urine
pH exceeded 7.5 and the urine flow rate was greater than
200 mL/h. The maximal uncorrected 2,4-D renal clear-
ance of 63 mL/min at pH 8.3 46 would have required a
urine flow rate of approximately 600 mL/h. In these latter
circumstances, 2,4-D clearance compares favorably with
that achieved with hemodialysis (56.3–72.9 mL/min).58
However, it must be stressed that the corrected renal
clearance data show that the effect of urine alkalinization
without high urine flow is markedly less efficient than
hemodialysis as a means of removing 2,4-D. The less
beneficial effect of alkaline diuresis on mecoprop clear-
ance compared to 2,4-D clearance may be explained by
the much greater clearance of mecoprop by metabolism
than 2,4-D. In addition, mecoprop is a weaker organic
acid than 2,4-D, as shown by the respective pKa values
(pKa of 2,4-D is 2.73, pKa of mecoprop is 3.78 82 ) and
its renal clearance would be affected less by changes in
urine pH.
Friesen et al.55 described a 61-year-old female found
comatose an undetermined time after ingesting 2,4-D 38–
50 g (as the amino salt). Alkaline diuresis (specific details
were not given) was instituted 12 hours after admission
t 1/2 ‘‘to maintain a urine pH ⬎ 7.5 and urine output above
(h) 300 mL/h’’ and continued for 24 hours. The hourly urine
output was documented 5 times (values between 290 and
39
820 mL/h) and urine pH on 4 occasions (values between
22
7.5 and 8.5) during the 24-hour period of alkaline diure-
14
sis. The authors cited a plasma 2,4-D half-life of 39.5
 ORDER
118
hours prior to alkaline diuresis and 3.7 hours when alka-
line diuresis was discontinued. The patient was extubated
22 hours after admission and made a full recovery. Be-
cause no renal clearance data correlating with urine pH
were presented, it is impossible to define the impact of
urine alkalinization alone on 2,4-D elimination. Nonethe-
less, the use of urine alkalinization with high urine flow
produced a reduction in the plasma half-life of 2,4-D
from 39.5 to 3.7 hours.
Flanagan et al.54 reported a case series of 30 patients
poisoned with chlorophenoxy herbicides alone and 11
who had ingested a mixture of a chlorophenoxy herbicide
and ioxynil. Seven of these patients died prior to hospital
Clinical Toxicology Downloaded from informahealthcare.com by University of Laval on 05/30/14
admission and 15 of the remaining 34 received support-
ive care only, while the other 19 patients (16 in the chlo-
rophenoxy only group and 3 in the ioxynil group) under-
went ‘‘alkaline diuresis’’ (specific details not given). The
authors stated that plasma chlorophenoxy half-lives after
alkalinization were below 30 hours but results were de-
scribed for only 4 patients, 3 of whom ingested 2,4-D in
combination with another chlorophenoxy herbicide (or
dicamba). The patient who ingested a mixture of 2,4-D
and dicamba had a plasma 2,4-D concentration of 670
mg/L 8 hours postingestion. The authors state that he
For personal use only.
‘‘recovered after being given alkaline diuresis cautiously
over 3 days.’’ In fact, a urine pH above 7.0 was not
achieved until some 50 hours after ingestion and was
seemingly maintained for only some 24 hours. The elimi-
nation half-life of 2,4-D was calculated as 12.3 hours
prior to alkaline diuresis (pH ⱖ 7.5) and 3.0 hours to-
wards the end of alkaline diuresis.
The second patient reported 54 had ingested some 200
mL of a mixture of 2,4-D and dichlorprop. ‘‘Alkaline
diuresis’’ was stated by the authors to have been insti-
tuted 26 hours postexposure but the first alkaline urine
pH (7.5) was not recorded until approximately 60 hours
postexposure. Three further urine pH measurements were
recorded between 60 and 132 hours postingestion (values
7.5 or 7.8). Between approximately 80 and 110 hours,
the authors calculated the elimination half-lives for 2,4-
D and dichlorprop were 7.8 and 14.2 hours, respectively.
This patient died 4 weeks postingestion following multi-
ple complications.
The third patient reported 54 was found collapsed after
ingesting an unknown quantity of 2,4-D and 2,4,5-T.
‘‘Alkaline diuresis’’ was started 28.5 hours postingestion
and ‘‘was associated with increases in plasma 2,4-D and
2,4,5-T concentrations. . . . Thereafter urinary excretion
of these compounds was enhanced . . .’’ However, the
urine pH did not exceed 7.0 until approximately 38 hours
postingestion. Between 38 and approximately 42 hours
REPRINTS
Bradberry et al.
postingestion, when the urine pH was maintained be-
tween 7.0 and approximately 7.4, the plasma 2,4-D and
2,4,5-T concentrations fell sharply, although the plasma
2,4-D and 2,4,5-T half-lives during this time were not
stated. Moreover, there is no evidence that a urine pH of
7.5 or greater was achieved at any time in this patient.
There were also possible errors in graphical data presen-
tation (inconsistent timescale on x-axis).
The fourth patient reported 54 had ingested 250 mL of
a mixture of ioxynil and mecoprop plus ethylene glycol.
On admission (less than 2 hours postingestion), the
plasma mecoprop concentration was approximately 400
mg/L (precise value not stated) with a blood ethylene
glycol concentration of 800 mg/L. ‘‘Alkaline diuresis’’
(in addition to intravenous ethanol) was commenced 1.5
hours postingestion. The first urine pH greater than 7.5
was recorded approximately 15 hours postingestion and
the urine pH was then maintained between 7.0 and 8.0
for the next 40 hours. The plasma mecoprop half-life was
calculated as 18.7 hours over approximately the first 28
hours postingestion and was 6.8 hours between approxi-
mately 30 and 50 hours postingestion.
The interpretation of these case data 54 is difficult be-
cause they are presented graphically and are limited in
scope. The precise relationship among urine pH, urine
flow, and renal herbicide clearance is not determinable,
although the half-lives calculated in some patients ap-
peared to fall during alkaline diuresis.
Schmoldt et al.61 described a patient who presented
within 2 hours of ingesting 50–100 g MCPA (as the di-
methylammonium salt). A ‘‘forced diuresis’’ was insti-
tuted within the first few hours of admission (day 1) when
the plasma MCPA concentration was 546 mg/L, but by
day 4 the plasma MCPA concentration had fallen only
to 379 mg/L. At this stage, ‘‘forced alkaline diuresis’’
was commenced and on day 5 the plasma MCPA concen-
tration was 78 mg/L. The authors calculated a fall in the
MCPA plasma half-life from approximately 133 hours
prior to forced diuresis to 12.6 hours after alkali was
added. The patient recovered fully. Details of the forced
alkaline diuresis employed and the urine pH values ob-
tained, were not documented, and neither were renal
clearance data given, making the findings uninterpret-
able.
No controlled trials of alkaline diuresis have been car-
ried out for chlorophenoxy herbicide poisoning. Only for
the patient reported by Park et al.81 and Prescott et al.46
are there sufficient renal clearance data to infer enhanced
chlorophenoxy elimination with urine pH manipulation
and, in addition, the impact of a high urine flow on herbi-
cide elimination was substantial. Prescott et al.46 demon-
 ORDER
Chlorophenoxy Herbicide Poisoning
strated that urine alkalinization and a high urine flow (of
the order of 600 mL/h) are required to achieve a renal
2,4-D clearance comparable to that achieved with hemo-
dialysis.
Hemoperfusion and Hemodialysis
Durakovic et al.58 described 4 patients with 2,4-D poi-
soning by ingestion who were treated by hemodialysis.
In 2 cases, resin hemoperfusion was also instituted. The
dialysis clearance in 1 patient was 68.7 mL/min and in
the 2 patients receiving combined therapy the clearances
were 56.3 mL/min and 72.9 mL/min; all 4 patients sur-
Clinical Toxicology Downloaded from informahealthcare.com by University of Laval on 05/30/14
vived. These data suggest that hemodialysis is more effi-
cient than urinary alkalinization alone, although urine al-
kalinization and a high urine flow produce similar 2,4-D
clearance data.46,81 Nonetheless, in all severe cases, hemo-
dialysis should be considered as the preferred elimination
treatment because it produces good herbicide clearance
without the need for urine pH manipulation and the ad-
ministration of substantial amounts of intravenous fluid
in an already compromised patient.
For personal use only.
Plasmapheresis
Lankosz-Lauterbach et al.62 instituted plasmapheresis
on the 10th, 16th, and 23rd hospital days in a 3-year-old
female with profound flaccid quadriparesis and sensory
deficits following exposure (probably by ingestion) to
2,4-D (amount unknown). It was claimed that the first
procedure ‘‘arrested further progression of the symp-
toms’’ and the subsequent 2 procedures produced ‘‘evi-
dent improvement in the muscle strength and senso-
rium.’’ The child was walking with crutches by the 9th
week of hospital admission with full recovery over 1
year. This case is unusual in that the child did not become
comatose or develop respiratory failure, nor was there
evidence of muscle toxicity (total creatine kinase activi-
ties were repeatedly normal and an EMG was consistent
with denervation rather than a myopathy). The presence
of dichlorophenoxy acid metabolites in the urine con-
firmed exposure in this case although they were not quan-
tified or were given blood concentrations. The authors
commented on the similarity of the presentation and re-
sponse to plasmapheresis to that in the Guillain-Barré
syndrome and suggested a sensitivity reaction may have
been etiologically significant.
At present, there is insufficient evidence to advocate
the use of plasmapheresis in patients with severe chloro-
phenoxy herbicide poisoning.
REPRINTS
119
CONCLUSIONS
Although chlorophenoxy herbicide poisoning is un-
common, ingestion can result in serious and sometimes
fatal sequelae. The mechanisms of chlorophenoxy herbi-
cide toxicity are incompletely understood but are likely
to involve disruption of cell membrane structure and
function, uncoupling of oxidative phosphorylation, and
interference with acetyl-CoA metabolism.
In addition to supportive care, alkaline diuresis should
be considered in all severely poisoned patients because
it enhances herbicide elimination. However, limited data
indicate that hemodialysis produces similar herbicide
clearances to alkaline diuresis without the need for urine
pH manipulation and the administration of substantial
amounts of intravenous fluid in an already compromised
patient.
ACKNOWLEDGEMENT
Presented as 3 separate Keynote lectures at the XIX Interna-
tional Congress of the European Association of Poisons Centres
and Clinical Toxicologists, June 1999, Dublin, Ireland.
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