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Goldfrank's Manual of Toxicologic Emergencies

Goldfrank's Manual of Toxicologic Emergencies

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Published by Kang Kyu Choi
Goldfrank's Manual of Toxicologic Emergencies
Goldfrank's Manual of Toxicologic Emergencies

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Published by: Kang Kyu Choi on Jul 10, 2011
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ORGANIC CHLORINE PESTICIDES

History and Epidemiology

Until the 1940s, commonly available pesticides included highly toxic arseni-
cals, mercurials, lead, sulfur, and nicotine. The organic chlorine insecticides
were developed as inexpensive, nonvolatile, environmentally stable, insecti-
cides with relatively low acute toxicity. Widespread use of these compounds
occurred from the 1940s until the mid-1970s. However, the properties that
made them effective insecticides also made them environmental hazards: slow
metabolism, lipid solubility, chemical stability, and environmental persistence.
The demonstration of dichlorodiphenyltrichloroethane (DDT) residues in hu-
mans, led to the severe restriction or total ban of DDT and most other organic
chlorines in North America and Europe. DDT is still widely used for malaria
control programs in many countries.

Toxicokinetics

The organic chlorine pesticides are grouped into four categories based on their
chemical structures and similar toxicities: (a) DDT and related analogs; (b) cy-
clodienes (the related isomers aldrin, dieldrin, and endrin, as well as heptachlor,
endosulfan) and related compounds (toxaphene, dienochlor); (c) hexachlorocy-
clohexane (lindane, the γisomer, with the commonly used misnomer γ-benzene
hexachloride); and (d) mirex and chlordecone. These compounds differ sub-
stantially, both between and within groups, with respect to toxic doses, skin ab-
sorption, fat storage, metabolism, and elimination. The signs and symptoms of
toxicity in humans, however, are remarkably similar within each group.

Absorption

All of the organic chlorine pesticides are well absorbed orally and by inhala-
tion; transdermal absorption is variable, depending on the particular com-
pound. DDT and its analogs are very poorly absorbed transdermally, unless
the pesticide is dissolved in a suitable hydrocarbon solvent. DDT has limited
volatility, so that air concentrations are usually low, and toxicity by the respi-
ratory route is unlikely. All of the cyclodienes have significant transdermal
absorption rates. Toxaphene is poorly absorbed through the skin in both acute
and chronic exposures. Lindane is well absorbed after skin application. Mirex
and chlordecone are efficiently absorbed via skin, by inhalation, and orally.

Distribution

All organic chlorines are lipophilic, a property that allows penetration to their
sites of action. The fat-to-serum ratios at equilibrium are high, in the range of
660:1 for chlordane; 220:1 for lindane; and 150:1 for dieldrin.

Metabolism

The high lipid solubility and very slow metabolic disposition of DDT, DDE
(dichlorodiphenyldichloroethylene, a metabolite of DDT), dieldrin, hep-

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110INSECTICIDES: ORGANIC CHLORINES, PYRETHRINS/PYRETHROIDS, AND DEET

849

tachlor, chlordane, mirex, and chlordecone causes significant adipose tissue
storage and increasing body burdens in chronically exposed populations. Or-
ganic chlorines that are rapidly metabolized and eliminated, such as endrin
(an isomer of dieldrin), endosulfan, lindane, methoxychlor, dienochlor, chlo-
robenzilate, dicofol, and toxaphene, tend to have less persistence in body tis-
sues, despite being highly lipid soluble.
Most organic chlorines are metabolized by the hepatic microsomal enzyme
systems by dechlorination, oxidation, most with subsequent conjugation. In ani-
mals, most organic chlorine pesticides induce the hepatic microsomal enzyme
systems. However, induction of hepatic enzymes has not been described in man,
except in rare cases of massive exposure with concomitant neurologic findings.

Elimination

The half-lives of fat-stored compounds and poorly metabolized organic chlo-
rines such as DDT and chlordecone are measured in months or years. The
elimination half-life of lindane is 21 hours in adults. The primary route of ex-
cretion of the organic chlorines is in the bile, but most also have detectable
urinary metabolites.

Mechanisms of Toxicity

The organic chlorines exert their most important effects in the central nervous
system, where they affect the neuronal membrane by either interfering with re-
polarization, by prolonging depolarization, or by impairing the maintenance of
the polarized state of the neuron. The end result is hyperexcitability of the ner-
vous system and repetitive neuronal discharges. DDT primarily affects the
axon, by causing the voltage-dependent Na+

channels to remain open after de-
polarization, allowing repetitive action potentials. The cyclodienes, toxaphene
and lindane act as γ-aminobutyric acid (GABA) antagonists.
Organic chlorines also sensitize the myocardium to endogenous catechol-
amines and predispose test animals to dysrhythmias, presumably in a fashion
similar to the chlorinated hydrocarbon solvents (Chap. 102).

Drug Interactions

There are theoretical consequences of liver enzyme induction, such as en-
hanced metabolism of therapeutic drugs and/or reduced efficacy.

Clinical Manifestations

Acute Exposure

In sufficient doses, organic chlorines lower the seizure threshold (DDT and
related sodium channel xenobiotics) or remove inhibitory influences (antago-
nism to GABA effects) and produce CNS stimulation, with resultant seizures,
respiratory failure, and death. After DDT exposure, tremor may be the only
initial manifestation. Nausea; vomiting; hyperesthesias of the mouth and
face; paresthesias of face, tongue, and extremities; headache; dizziness; my-
oclonus; leg weakness; agitation; and confusion may subsequently occur.
Seizures only occur after very high exposures, usually only after ingesting
large amounts. Single, acute, oral doses of 10 mg/kg or more of DDT are usu-
ally necessary to produce symptoms. However, with lindane, the cyclodienes,
and toxaphene, there often are no prodromal signs or symptoms, and more of-
ten than not, the first manifestation of toxicity is a generalized seizure. If sei-

850

PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

zures develop, they often occur within 1–2 hours of ingestion when the stom-
ach is empty, but may be delayed as much as 5–6 hours when the ingestion
follows a substantial meal.
The cyclodienes are notable for their propensity to cause seizures that may
recur for several days following an acute exposure. If the seizures are brief
and hypoxia has not occurred, recovery is usually complete. Hyperthermia
secondary to central mechanisms or increased muscle activity is common.

Lindane: Specific Risks

Patients are at risk for developing central nervous system toxicity from im-
proper topical therapeutic use such as exceeding recommended application
times or amounts, repeated applications, application following hot baths, and
use of occlusive dressings or clothing after application. Toxicity also occurs
after unintentional oral ingestion of topical preparations. Young children ap-
pear at greatest risk, possibly because of greater skin permeability, increased
ratio of body surface area to mass, or immature liver enzymes.

Chronic Exposure

Chlordecone, unlike the other organic chlorines, produces an insidious pic-
ture of chronic toxicity related to its extremely long persistence in the body.
The clinical syndrome consists of a prominent tremor of the hands, a fine
tremor of the head, and trembling of the entire body. Other findings include
weakness, opsoclonus (rapid, irregular, dysrhythmic ocular movements),
ataxia, mental status changes, rash, weight loss, and elevated liver enzymes.

Diagnostic Testing

The history of exposure to an organic chlorine pesticide is the most critical
piece of information. Toxaphene, a chlorinated pinene, has a mild turpentine-
like odor, and endosulfan has a unique, “rotten egg,” sulfur odor.
Gas chromatography can detect organic chlorine pesticides in serum, adi-
pose tissue, and urine. Laboratory evaluation will not alter the course of
management, as these blood tests are not available on an emergent basis. At
present, there are no data correlating health effects and tissue concentra-
tions. Most humans studied have measurable concentrations of DDT in adi-
pose tissue. Serum lindane levels document exposure, and most laboratories
report toxic ranges. Lindane-exposed workers with chronic neurologic
symptoms showed blood lindane concentrations of 0.02 mg/L. A limited se-
ries of patients with acute lindane ingestion suggests that a serum concentra-
tion of 0.12 mg/L correlates with sedation, and that 0.2 mg/L is associated
with seizures and coma.

Management

As with any patient who presents with an altered mental status, assessment and
stabilization of the airway is necessary, followed by administration of dextrose
and thiamine as indicated. Skin decontamination is essential, especially in the
case of topical lindane. Clothing should be removed and placed in a plastic bag
and the skin washed with soap and water. Healthcare providers should be pro-
tected with rubber gloves and aprons. Because these pesticides are almost in-
variably liquids, a nasogastric tube can be used to suction and lavage the gastric
contents, if clinically indicated. This is most appropriate only with a very recent
ingestion (Chap. 8). Because the organic chlorines are all neurotoxins, the risk

110INSECTICIDES: ORGANIC CHLORINES, PYRETHRINS/PYRETHROIDS, AND DEET

851

of complications associated with seizures probably outweighs the risk of any of
the GI decontamination strategies once toxicity is evident.
Seizures should be controlled with a benzodiazepine followed by pentobar-
bital or a propofol infusion and neuromuscular blockade, if necessary. Pheny-
toin is much less effective in these cases, particularly with the GABA-chloride
ionophore antagonists lindane, toxaphene, and the cyclodienes. Hyperthermia
should be managed aggressively with external cooling. Cholestyramine, at a
dosage of 16 g/d in divided doses, should be administered to all patients symp-
tomatic from chlordecone, and possibly other organic chlorines.

Pyrethrins and Pyrethroids

The pyrethrins are the active extracts from the flower Chrysanthemum ciner-

ariaefolium.Pyrethrum, the first pyrethrin identified, consists of 6 esters de-
rived from chrysanthemic acid and pyrethric acid. When applied properly,
they have essentially no systemic mammalian toxicity because of their rapid
hydrolysis. Pyrethrins break down rapidly in light and in water, and therefore
have no environmental persistence or bioaccumulation.
The pyrethroids are the synthetic derivatives of the natural pyrethrins. They
were developed in an effort to produce more environmentally stable products.
There are more than 1000 pyrethroids, of which 6–10 are in widespread use to-
day. These insecticides have a rapid paralytic effect (“knock down”) on insects.
The classification of pyrethroids is based on their structure, their clinical mani-
festations in mammalian poisoning, as well as their actions on insect nerve
preparations and their insecticidal activity. Type I pyrethroids have a simple es-
ter bond at the central linkage without αcyano group. The type II pyrethroids
have αcyano group at the αcarbon of this ester linkage. The αcyano group
greatly enhances neurotoxicity of the type II pyrethroids and they are generally
considered more potent and toxic than the type I pyrethroids (Table 110–1).

Toxicokinetics

Absorption

The oral toxicity of pyrethrins in mammals is extremely low, because they are
so readily hydrolyzed into inactive compounds. Their dermal toxicity is even
lower, owing to their slow penetration and rapid metabolism. The pyrethroids
are more stable than the natural pyrethrins, and systemic toxicity occurs follow-
ing ingestion. Direct absorption of pyrethroids through the skin to the periph-
eral sensory nerves occurs. The pyrethroids are also absorbed via inhalation,
but not to a clinically significant degree.

Distribution

The pyrethroids and pyrethrins are lipophilic and as such are rapidly distrib-
uted to the central nervous system.

Metabolism

The pyrethroids are readily metabolized in animals and humans by hydrolases
and the cytochrome P450-dependent microsomal system. The metabolites are
of lower toxicity than the parent compounds. Piperonyl butoxide, a P450 inhib-
itor, enhances the potency of pyrethroids. It is often added to insecticide prepa-
rations to ensure lethality, as the initial “knock down” effect of a pyrethroid
alone is not always lethal to the insect.

8
5
2
TABLE 110-1.Synthetic Pyrethroids in Common Use
Pyrethroid
Class

Generic Name, CAS #

Brand Names

Generation of Pyrethroid, Dates
Introduced (If Available)

Type I

Allethrin 584-79-2

Pynamin

1st generation; First synthetic pyrethroid, 1949

Bioallethrin 584-79-2

D-trans

2nd generation, 1969: trans isomer of allethrin

Dimethrin 70-38-2

Dimetrin

Phenothrin 26002-80-2

Fenothrin, Forte, Sumithrin

2nd generation, 1973

Resmethrin 10453-86-8

Benzofluroline, Chrysron, Crossfire, Premgard,
Pynosect, Pyretherm, Synthrin

2nd generation, 1967; 20× strength of pyrethrum

Bioresmethrin 28434-01-7

2nd generation, 1967; 50× strength of pyrethrum,
isomer of resmethrin

Tetramethrin 7696-12-0

Neo-Pynamin

2nd generation, 1965

Permethrin 52645-53-1

Ambush, Biomist, Dragnet, Ectiban, Elimite, Ipi-
tox, Ketokill, Nix, Outflank, Perigen, Permasect,
Persect, Pertox, Pounce, Pramex, etc

3rd generation, 1972; Effective topical scabicide &
miticide, low toxicity

Bifenthrin 82657-04-3

Capture, Talstar

4th generation

Prallethrin 23031-36-9

SF, Etoc

4th generation

Imiprothrin 72963-72-5

Multicide, Pralle, Raid Ant & Roach

4th generation; 1998

Type II

Fenvalerate 51630-58-1

Belmark, Evercide, Extrin, Fenkill, Sanmarton,
Sumicidin, Sumifly, Sumipower, Sumitox, Tribute

3rd generation, 1973

Acrinathrin 103833-18-7

Rufast

4th generation

Cyfluthrin 68359-37-5

Baythroid, Bulldock, Cyfoxylate, Eulan SP, Solfac,
Tempo 2

4th generation

Cyhalothrin 91465-08-6

Demand, Karate, Ninja 10WP, Scimitar, Warrior

4th generation

8
5
3

Cypermethrin 52315-07-8

Ammo, Barricade, CCN52, Cymbush, Cympera-
tor, Cynoff, Cypercopal; Cyperkill, Cyrux, Demon,
Flectron, KafilSuper, Ripcord, Siperin, others

4th generation

Deltamethrin 52918-63-5

Butoflin, Butox, Crackdown, Decis, DeltaDust,
DeltaGard, Deltex, K-Othrine, Striker, Suspend

4th generation

Esfenvalerate 66230-04-4

Asana, Asana-XL, Sumi-alpha

4th generation

Fenpropathrin 39515-41-8

Danitol, Herald, Meothrin, Rody

4th generation, 1989

Flucythrinate 70124-77-5

AASTAR, Cybolt, Fluent, Payoff

4th generation

Fluvalinate 102851-06-9

Evict, Fireban, Force, Mavrik, Raze, Yardex

4th generation

Tefluthrin 19538-32-2

Demand, Force, Karate, Scimitar

4th generation

Tralomethrin 66841-25-6

Dethmor, SAGA, Scout, Scout X-tra, Tralex

4th generation

854

PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Elimination

There is no evidence that the pyrethroids undergo enterohepatic recirculation.
Parent compounds, as well as metabolites of the pyrethroids, are found in the
urine.

Pathophysiology

Like DDT, pyrethrins and pyrethroids prolong the activation of the voltage-depen-
dent sodium channel by binding to it in the open state, causing a prolonged depo-
larization (Chap. 14). This effect on voltage-sensitive sodium channels is respon-
sible for the insecticidal activity, as well as the toxicity of the pyrethroids to
nontarget species. Type II pyrethroids are more potent, and lead to significant af-
ter-potentials and eventual nerve conduction block. Additionally, pyrethroids
block voltage-sensitive chloride channels, which may enhance CNS toxicity.

Clinical Manifestations

Most cases of toxicity associated with the pyrethrins are the result of allergic reac-
tions. At highest risk are patients who are sensitive to ragweed pollen. The syn-
thetic pyrethroids generally do not induce allergic reactions. The type I pyrethroids
are unlikely to cause systemic toxicity in humans. The type II pyrethroids cause
paresthesias, salivation, nausea, vomiting, dizziness, fasciculations, altered mental
status, coma, seizures, and acute lung injury. Many of the findings resemble or-
ganic phosphorus compound overdose. Most exposures are dermal, and local
symptoms predominate in the majority of cases. The predominant feature is local
paraesthesias in the areas of contact. Ocular contact causes more severe symp-
toms, including immediate pain, lacrimation, photophobia, and conjunctivitis.

Treatment

Initial treatment should be directed toward skin decontamination, as most
poisonings occur from exposures by this route. Patients with large oral inges-
tions of a type II pyrethroid should be treated with a single, standard dose of
activated charcoal, unless the diluent of the pyrethroid contains a petroleum
solvent. Contact dermatitis and acute systemic allergic reactions should be
treated in the usual manner, using antihistamines, corticosteroids and β-adre-
nergic agonists as clinically indicated.
Treatment of systemic toxicity is entirely supportive and symptomatic, be-
cause no specific antidote exists. Benzodiazepines should be used for tremor
and seizures.

DEET

The topical insect repellant, N,N-diethyl-3-methylbenzamide (DEET, former no-
menclatureN,N-diethyl-m-toluamide), was patented by the US Army in 1946,
and commercially marketed in the United States since 1956 as a mosquito repel-
lant. The U.S. Environmental Protection Agency (EPA) estimates that 38% of the
U.S. population uses DEET each year. DEET can be purchased in multiple for-
mulations without prescription in concentrations ranging from 5–100%.

Toxicokinetics

DEET is extensively absorbed via the gastrointestinal tract. Skin absorption
is significant, depending on the vehicle and the concentration. The volume of

110INSECTICIDES: ORGANIC CHLORINES, PYRETHRINS/PYRETHROIDS, AND DEET

855

distribution is large, in the range of 2.7–6.21 L/kg in animal studies. DEET is
extensively metabolized by oxidation and hydroxylation by the hepatic mi-
crosomal enzymes, primarily by the isozymes CYP2B6, CYP3A4,CYP2C19,
and CYP2A6. DEET is excreted in the urine within 12 hours, mainly as me-
tabolites, with 15% or less appearing as the parent compound.

Pathophysiology

The exact mechanism of DEET toxicity is unknown.

Clinical Manifestations

Most calls to poison control centers regarding DEET exposures involve mi-
nor or no symptoms, and symptomatic exposures occur primarily when
DEET is sprayed in the eyes or inhaled. A recent review of adverse reactions
to DEET showed 26 cases had major morbidity including encephalopathy,
ataxia, convulsions, respiratory failure, hypotension, anaphylaxis, or death,
particularly after ingestion or dermal exposure to large amounts. These ad-
verse reactions occurred mainly in children, and most involved prolonged use
and dosages exceeding recommendations.

Treatment

Most symptoms resolve without treatment and the majority of patients with
serious toxicity recover fully with supportive care. In cases of dermal expo-
sures, skin decontamination should be a priority to prevent further absorp-
tion. Patients with intentional oral ingestions should receive a single dose of
activated charcoal if clinically indicated. Seizures should be treated as dis-
cussed above.

856

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