178 PART THREE Classes of Toxicants
distribution and elimination of amitraz metabolites, 10 or
sensitivity of equines to decreases in colonic blood flow
caused by amitraz.1
Improper mixing of amitraz concentrates before applica-
tion on livestock or inappropriate use of amitraz products on
equines are common causes of amitraz toxicosis in large
animals, although transient depression anorexia and ataxia
sometimes occur at recommended levels.1 Amitraz toxicosis
has developed in dogs dipped in amitraz solutions at recom-
mended levels.4 Additionally, ingestion of amitraz collars is a
potential cause of toxicosis in dogs.11 Less commonly, pets or
livestock may be exposed through aerial spraying of crops,
accidental spills resulting in water or food contamination,
and malicious poisonings.
Clinical Signs. Because many formulations of amitraz
include xylene as a carrier, some of the signs resulting from
exposure to amitraz compounds may be secondary to xylene
toxicosis.12 Signs of amitraz toxicosis generally begin within 2
to 4 hours of dermal or oral exposure, although in some
cases onset of signs is delayed up to 12 hours.2,13 Clinical
signs that have been associated with amitraz toxicosis in
dogs and cats include vomiting, depression, disorientation,
ataxia, ileus, bradycardia, hypertension or hypotension,
hypothermia, coma, and seizures.14 In ruminants, salivation,
depression, anorexia, ataxia, disorientation, tremors, de-
creased milk production, and coma have been reported.14
Horses display similar neurologic signs; furthermore, they are
particularly prone to the development of ileus, with resulting
large intestinal impaction and severe colic.2,9
Death resulting from amitraz toxicosis is usually due
to profound bradycardia, CNS depression leading to res-
piratory depression, or, especially in equines, complications
of ileus (e.g., intestinal impaction with subsequent vascular
compromise, shock, and sepsis).1,9,13
Clinical Pathology. Hyperglycemia has been reported in
several species in relation to exposure to amitraz.1,6,13 Alter-
ations of serum alkaline phosphatase, albumin-globulin
ratios, serum potassium, and alanine aminotransferase have
been reported in rats in long-term amitraz feeding trials,1 but
similar alterations have not commonly been associated with
acute amitraz toxicosis in domestic animals.
Lesions. In most species few gross or histopathologic
lesions are expected in cases of amitraz toxicosis. In equines
large intestinal impaction may be seen at necropsy. Long-
term feeding studies in dogs and rats revealed only mild and
nonspecific histopathologic alterations in the liver and
adrenal gland.1
Diagnostic Testing. Amitraz can be detected in stomach
contents, urine, feces, and tissues of animals using gas
chromatography (GC)-mass spectrometry.14 In addition, the
amitraz metabolite 4-amino-3-methylbenzoic acid has been
detected in the urine of humans, although the availability of
such testing is not known.1
Treatment. The aims of treatment are to stabilize the
patient, prevent further exposure, and provide supportive
care. Yohimbine6,15 and atipamezole13 have been used in
several species to successfully reverse the bradycardia, CNS
depression, and hyperglycemia caused by amitraz toxicosis.
Atropine is contraindicated in the treatment of amitraz-
induced bradycardia, because it can potentiate both
hypertension and ileus.16 Seizures generally respond to
diazepam; a barbiturate may be used if diazepam is ineffec-
tive, although this compounds any CNS and cardiovascular
depression.
Once the animal is stable, dermal exposures can be
decontaminated by bathing the animal with a mild detergent
and water; because hypothermia is common in amitraz
toxicosis, appropriate measures should be taken to keep the
animal warm during and after bathing. When mild signs have
developed after appropriate topical use of amitraz, no further
treatment is usually necessary and signs should subside
within 24 to 72 hours.14
Emesis may be induced early in oral amitraz exposures;
because of the risk of aspiration, emesis is contraindicated in
symptomatic animals or in cases of ingestion of formulations
containing high percentages of xylene or other volatile
solvents. The decision to use activated charcoal in the face of
potential amitraz-induced ileus must be made with care.
Activated charcoal adsorbs amitraz, but if ileus develops
before the charcoal has passed, the amitraz may eventually
be released from the charcoal and be available for ab-
sorption. In addition, if intestinal surgery becomes necessary,
activated charcoal in the gastrointestinal tract may com-
plicate matters. Saline cathartics are recommended whether
or not activated charcoal is used.14 Surgery to remove
ingested amitraz collar pieces may be required.
General supportive care includes maintenance of normal
body temperature, intravenous (IV) fluid therapy for cardio-
vascular support, and maintenance of normal gastrointestinal
motility.
Prognosis. With prompt and appropriate treatment, the
prognosis in most cases of amitraz toxicosis is good.13 The
prognosis for comatose, seizuring, or moribund animals, or
for equines exhibiting evidence of ileus must be considered
guarded.
Prevention and Control. Proper mixing and adminis-
tration of amitraz per label directions minimize the risk of
toxicosis. Amitraz collars should be fitted properly and any
excess collar length should be cut off to minimize the risk of
the collar being chewed or ingested.
ANTICHOLINESTERASE INSECTICIDES
Gavin L. Meerdink
Synonyms. Besides the widespread use of anticholin-
esterases for insect control, some have been developed for
chemical warfare and are referred to as “nerve gases.”
Sources. Organophosphorus (OP) and carbamate insec-
ticides have been in common use in agriculture, gardens,
Chapter 21 Insecticides and Molluscicides
and homes since the 1970s. Not all of these are cholin-
esterase inhibitors; some formulations are used as herbicides
or fungicides. Insecticides can be in spray, powder, or gran-
ule form.
Aerial spraying can be circumstantially associated with
animal illness. Spray dispersion is a function of droplet size
and wind velocity. Amounts hazardous to animal health are
not likely to be distributed long distances by this method.
Most OP insecticides (except dichlorvos) have comparatively
low volatility.1
Other potential sources can come from medications.
Certain members of this class of compounds are used as
therapeutic agents, such as deworming products for animals.
Some that cross the blood-brain barrier have been proposed
for the treatment of Alzheimer’s disease. 2
Toxicokinetics. Most of the agents are absorbed readily by
any route. The rate is influenced by lipid solubility and
formulation. The agents undergo oxidation and hydrolysis by
esterases, namely carboxylesterases and paraoxonases, that
are found in the plasma and liver.2 A variety of conjugation
reactions follow primary metabolic processes. Excretion is via
urine and feces. Most OPs are excreted as hydrolysis
products in the urine.1,2 The rate of metabolism and excre-
tion may be reduced by the inhibition of esters by the
insecticide.3
Many of the OPs, specifically the phosphorothioate and
phosphorodithioate compounds, contain a sulfur attached
by double bond to the phosphorus. The sulfur is exchanged
for oxygen by cytochrome P-450 metabolism in the hepato-
cyte. This “lethal synthesis,” oxygen for sulfur substitution,
accounts for the full potential efficacy as an insecticide.1,2
Mechanism of Action. Acetylcholine transfers impulses at
cholinergic nerve synapses and at neuromuscular junctions.
Acetylcholine is catabolized (in 0.1 msec) by acetylcholin-
esterase, or other cholinesterases (ChE), to acetic acid and
choline. OP and carbamate insecticides produce their toxic
effects by binding with ChE enzymes, thereby inhibiting the
catabolism of the acetylcholine. Poisoning is caused by
overstimulation of the end organ as a result of the ac-
cumulation of acetylcholine. Death results primarily from
respiratory failure, often with a cardiovascular component.1-3
Like acetylcholine, OP and carbamate insecticides share a
structural compatibility with acetylcholinesterase and other
ChE and readily bind to at least one of three sites of the ChE
enzymes. The more structurally suited relative to binding, the
higher the affinity and the more effective the insecticide is in
producing the anticholinergic effect. OPs in general have
higher affinity for the enzyme sites than do the carbamates.
Therefore, OPs are often referred to as “irreversible” in-
hibitors and carbamates as “reversible” inhibitors of ChE
because they can spontaneously dislodge from the enzyme.
This distinction is not absolute and cannot be used as a strict
separation of the two insecticide groups.2,4 The stability of
the OP-ChE enzyme bond is enhanced through “aging,”
which is caused by the loss of one of the alkyl groups.2
Toxicity and Risk Factors. Errors in use, mixing, or
storage of unused materials are common reasons for animal
179
exposures that result in poisoning. Given the high toxicity of
several of these agents, animals have been poisoned by
licking empty bags. The color or odor of some insecticides
may aid in identification by owners but does not seem to
deter ingestion by animals.
Although these two groups of insecticides include some of
the most toxic products ever marketed (e.g., LD50 of less than
1 mg/kg body weight), the range of toxicity is wide. Con-
sideration of the formula concentration or conditions of use
is likely a more important factor for the clinician in deciding
the likelihood of poisoning. Listings of toxicities for these
insecticides can be found in product data sheets and other
publications (e.g., Farm Chemicals Handbook5). Young ani-
mals are poisoned by a lower dose of these agents because
of immature development of the hydrolyzing enzyme
systems.
Repeated exposure, as might occur with grazing of con-
taminated pastures or frequent spraying, can be a clinical
concern. Most agents from these two groups are metab-
olized rapidly and excreted within a few days, whereas ChE
regeneration requires approximately 2 weeks. Thus, the
additive enzyme inhibition is clinically more significant than
accumulation of the insecticide in the body.
When a pour-on product containing chlorpyrifos was
found to produce unexpected effects in dairy bulls, the label
was changed to restrict its use on dairy breeds of any age
and bulls of any breed older than 8 months of age. Cholin-
esterase depression was demonstrated in blood and brain
tissues. Heavier, aggressive, older bulls were reported to be
more sensitive to chlorpyrifos. This was associated with
higher circulating testosterone concentrations.6
Clinical Signs. Clinical signs from an excess of these
agents result from the overstimulation of the cholinergic
nervous system, skeletal muscles, and, to a lesser degree, the
CNS. Clinical signs of acute poisoning can occur within
30 minutes, usually within 6 hours, and certainly within
12 hours after exposure. Dermal exposure can result in signs
of intoxication within a few hours but may be delayed a few
days depending on the rate of absorption.
The duration from the onset of clinical signs to death may
be a few minutes to several hours. Sudden collapse and
apparent suffocation, occasionally with epistaxis, has been
observed from large oral doses. Lesser doses or repeated
exposures can result in anorexia, lethargy, and diarrhea of
several days’ duration.
The progression of clinical signs with acute poisoning
often begins with an appearance of apprehension or un-
easiness. Evidence of abdominal discomfort with a tucked
posture and foot stomping or kicking might be observed.
Salivation and lacrimation become more copious and can be
accompanied by frequent urination and defecation (collec-
tively known as the SLUD signs). Initial fine muscle tremors
become more generalized and pronounced, leading to
stiffened, jerky movements with ataxia. Dyspnea from
increased bronchial secretions and presumably broncho-
constriction becomes pronounced. Convulsive seizures may
occur before coma, respiratory depression, and death. Clonic
seizures are more often observed in small animals than in
ruminants.
180 PART THREE Classes of Toxicants
The term intermediate syndrome has been applied to
clinical signs of apparent muscular weakness that occur
several days after exposure and that are accompanied by
persistent low blood ChE activity. OPs with high lipid
solubility and prolonged metabolism from system (cardio-
vascular, hepatic, or renal) impairment are thought to be
involved.7 A common example is a syndrome in cats that
exhibit anorexia, profound weakness, and depression fol-
lowing exposure to chlorpyrifos.
A delayed neuropathy syndrome referred to as “Ginger
Jake” paralysis arose during the days of prohibition when
Jamaican ginger extract contaminated with triorthocresyl
phosphate (TOCP) was consumed in place of alcohol. Tri-
arylphosphates, of which TOCP is an example, and certain
fluorine-containing alkylorganophosphorus compounds are
capable of inducing delayed neurotoxicosis. At least 1 week
to approximately 1 month after ingestion of the toxic agent,
evidence of sensation deficits or pain leads to weakness and
ataxia. Eventually, paralysis changes from flaccid to spastic.
Any recovery is slow and usually incomplete. Toxicity is not
related to inhibition of ChEs, but another esterase, referred
to as a neurotoxic esterase, is inhibited. Systemic effects
appear limited to the nervous system and include axon and
myelin sheath lesions.1,2
Clinical Pathology. Although results are inconsistent,
decreased serum potassium and increased serum mag-
nesium have been reported with poisoning. 8 Consistent
changes in clinical pathologic parameters do not occur and
likely are related to secondary tissue and metabolic changes.
Lesions. Pulmonary edema often is evident at necropsy.
Severity varies and is not useful as a diagnostic determinant.
Salivation, tracheal fluid, diarrhea, and other signs of cho-
linergic stimulation might be observed.
Diagnostic Testing. Confirmation of OP or carbamate
insecticide poisoning includes (1) detection of the insecticide
in ingesta or tissues, (2) demonstration of the adverse
biological effect, that is, ChE inhibition, and (3) clinical signs
and history consistent with this poisoning.
Specimens for diagnostic submission from the clinical
patient should include whole blood for ChE activity deter-
mination and vomitus, urine, and suspect material for iden-
tification of the agent. Postmortem samples should also
contain brain, eyes (retina), liver, and stomach contents.
These samples should be submitted chilled (eyes, in par-
ticular, should not be frozen to prevent destruction of the
retina). An entire brain or hemisphere should be submitted
because ChE activity is associated with nuclei and is not
homogeneous throughout the tissue. Sections of appropriate
tissues for histology should also be saved in 10% formalin
for thorough diagnostic investigation.
Treatment. Poisoning by these agents progresses rapidly;
treatment must be instituted as soon as possible. Artificial
respiration may be successful in maintaining the animal
while waiting for the return of sufficient muscular activity.
Respiratory failure is the principal cause of death from these
insecticides.
Atropine blocks the effects of the excess acetylcholine at
the neuromuscular junction. It can control the muscarinic
signs, but not the nicotinic signs. Therapeutic response is
expected from a dose of 0.25 to 1 mg/kg of atropine. To
shorten the response time, about one fourth of the dose can
be administered intravenously. The dose should be adjusted
by assessing the degree of atropinization, that is, secretion
production and heart rate.
Because relapses are common, repeated atropine ad-
ministration may be necessary to control the return of clinical
signs (usually every 2 to 4 hours). The response to atropine
becomes less apparent with each successive treatment.
Dosages must be monitored judiciously to prevent over-
treatment, especially when treatment is prolonged. Horses
are particularly prone to develop ileus from atropine, so no
more than a total dose of 65 mg is advised for the average
horse.
Activated charcoal is given orally to bind insecticide in the
alimentary tract to prevent absorption. This addition to the
treatment regimen is beneficial, particularly for ruminants
with their large rumen stores, and should be administered as
soon as the animal’s condition is stabilized.
Oximes, such as pralidoxime Cl, dissociate the insecticide-
ChE bond and attach to the insecticide, which allows for
reactivation of the ChE enzyme. Because the bond between
OPs (but not carbamates) and ChE becomes stronger with
time, the efficacy of oximes is better within 24 hours after
exposure. The affinity between ChE and carbamates is less
than that for OPs; therefore, oximes are not recommended
for carbamate insecticide poisoning.2 Excessive doses of the
oximes are contraindicated because these drugs have the
molecular capability to inhibit ChE themselves.
Animals with dermal exposure should be washed as
quickly as possible with soap and water to prevent further
absorption. Other therapeutic measures include diazepam
(Valium, Roche Laboratories, Nutley, N.J.), which has been
used in addition to atropine or the atropine-oxime com-
bination, and appears to prevent some central effects of
accumulated acetylcholine and the bradycardia produced by
anticholinergics.9 Diphenhydramine (Benadryl, Park, Davis &
Co., Morris Plains, N.J.) can block effects of nicotine receptor
overstimulation and prevent paralysis in dogs.10
Drugs that interfere with ChE activity such as morphine,
physostigmine, phenothiazine tranquilizers, pyridostigmine,
neostigmine, and succinylcholine are contraindicated.11
Prognosis. If the dose of anticholinesterase insecticide is
not overwhelming and the animal responds to treatment, the
prognosis is favorable.
DIETHYLTOLUAMIDE
David Dorman
Synonyms. Diethyltoluamide (DEET) is the common name
for N,N-diethyl-m-toluamide, a multipurpose insect repellent
registered for direct application to human skin, clothing, and
household pets. The most commonly used insect repellent is