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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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Fumigants are applied to control rodents, nematodes, insects, weed seeds,
and fungi anywhere in the soil, structures, crop, grains, and commodities.
Many different chemical classes have been used as fumigants, but only a few
remain in use today in the United States. Most fumigants, especially many of
the halogenated solvents, were abandoned because of their toxicity. While fu-
migants exist in all three physical states, they are most commonly used in the
gaseous form, which explains why inhalation is the most common route of
exposure.

METHYL BROMIDE

History and Epidemiology

Methyl bromide (CH

3Br) was used as an anesthetic in the early 1900s, but fa-
talities halted this practice. It was employed as a fire retardant during World
War II, a role that persisted into the 1960s in Europe. Currently, its primary
role is as a fumigant.
Methyl bromide and possibly other fumigants have also escaped from fu-
migated structures to adjacent or conjoined buildings, resulting in severe ill-
ness and fatalities. Underground pipes adjoining sections of a greenhouse
have led to exposures. Fatalities have occurred when workers entered tanks
containing fumigant residues. In Europe, indoor and outdoor exposures to old
fire extinguishers have caused severe poisoning and fatalities.

Toxicokinetics

Dermal absorption of methyl bromide contributes to its toxicity. Significant in-
dividual variability exists for methyl bromide metabolism. Like methyl bro-
mide, bioactivation followed by alkylation appear to be responsible for toxicity
for the banned fumigant, ethylene bromide. The antifertility effects and toxicity
of ethylene bromide are attributed to its alkylating, mustardlike, activity.

Pathology/Pathophysiology

Methyl bromide is highly neurotoxic. Autopsy findings demonstrate symmet-
ric neuronal loss and gliosis in the inferior colliculi and the cerebellar dentate
nuclei. These lesions are reportedly similar to those of the thiamine defi-
ciency noted in Wernicke encephalopathy. The dorsal root ganglia also un-
dergo neuronal loss. The peripheral nerves showed axonal and myelin loss
with inflammatory changes. Methylation of the sulfhydryl groups of meta-
bolic enzymes is proposed as a common mechanistic pathway.

Clinical Manifestations

Exposure to high concentrations of methyl bromide lead to immediate life-
threatening toxicity, including a rapid loss of consciousness followed by sei-
zures, dysrhythmias, and death. In contrast, symptoms may be delayed for
days following low level exposure. Cardiopulmonary, hepatorenal, and neu-
rologic manifestations may develop following methyl bromide exposure, as
well as many of the other fumigants (Table 112–1).

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8
6
7

TABLE 112–1.Comparison of Clinical Effects of Fumigants

Clinical Effect

Chloropicrin

Dichloropropene

Ethylene
Dibromide

Metam
Sodium

Methyl
Bromide

Phosphine

Sulfuryl
Fluoride

Mucus membrane irritation

+ +

+

+ +

+ +

± High
concentration

+ +

± High
concentration

Dermatitis

+

+

+

+

+

Burns (frostbite)

+

+

+

+

Gastrointestinal:
Nausea, vomiting,
abdominal pain

+

+

+

+

+

+

+

Hepatic dysfunction

+

+

+ +

+

+

Chest pain

+

+

+

+

Acute lung injury

+

+

+

+

+

Cardiovascular:
Hypotension

+

+

+

+

+

+

Dysrhythmias

+

Late

+

+ +

+ +

Nephrotoxicity

+

+

+ +

+

+

Mental status

+

+

+

+

+

+

+

changes

+ = Presence; – = absence; ± = variable; ++ = very substantial.

868

PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Some individuals may initially manifest irritant symptoms of the eye, na-
sopharynx, and oropharynx, possibly related to chloropicrin, which is usually
formulated as 2% of the methyl bromide concentration. The overlap of the ir-
ritant and nonspecific symptoms of methyl bromide and chloropicrin make it
difficult to absolutely differentiate at the time of the exposure. In more severe
poisoning cases, pulmonary symptoms may begin with cough or shortness of
breath that may rapidly progress to bronchitis, pneumonitis, acute lung injury
(ALI), and hemorrhage.
Initial central nervous system symptoms can include headache, vomit-
ing, dizziness, drowsiness, euphoria, confusion, diplopia, dysmetria, dys-
arthria, and mood disorders or inappropriate affect. These may progress
to ataxia, intention tremor, fasciculations, myoclonus, delirium, seizures,
and coma.

Cutaneous lesions include erythema, vesicles, and bullae. Chronic expo-
sure to methyl bromide is associated with hepatotoxicity and nephrotoxicity.

Diagnostic Testing

Although a serum bromide concentration does not facilitate the clinical man-
agement, an elevated concentration might help to confirm the diagnosis.
Other standard laboratory tests should be obtained based on clinical needs.
An elevated serum bromide concentration may cause a false elevation in se-
rum chloride, when assayed using an ion selective electrode meter.

Treatment

Treatment for methyl bromide poisoning relies on general and supportive
care. Decontamination should include the removal of clothing, as methyl bro-
mide may bind to clothing, including rubber and leather. Irrigation of the eyes
with saline and skin decontamination with soap and water should be per-
formed. Because of the systemic toxicity of the halogenated fumigants, it is
reasonable to administer at least one dose of oral activated charcoal following
ingestion.

Seizures are common and difficult to control with traditional anticonvul-
sants such as benzodiazepines and phenytoin. Many cases have required pen-
tobarbital coma and neuromuscular paralysis.

Prognosis

Most patients who develop seizures and coma will not survive. The few sur-
vivors of methyl bromide exposure described in the literature frequently have
neuropsychiatric sequelae. Although improvement may occur over time, re-
covery is often incomplete.

DICHLOROPROPENE

Dichloropropene was introduced in 1945 and is primarily used as a soil fumi-
gant for nematodes.

Occupational Exposure

Chronic subclinical changes have been reported in soil fumigators using
dichloropropene in the Dutch flower bulb occupations. Various lymphomas
are reported in firemen after dichloropropene exposure.

112METHYL BROMIDE AND OTHER FUMIGANTS

869

Toxicokinetics

The metabolism of dichloropropene likely resembles that of other chlorinated
hydrocarbon solvents such as carbon tetrachloride and chloroform. The dose
and route correlate with toxicity and outcome in rodent models. At 100 mg/
kg in mice, hepatotoxicity occurs by the intraperitoneal route, but not after
oral gavage. Hepatic failure and death was caused by intraperitoneal adminis-
tration of 700 mg/kg. The inhalational route is the primary method of toxicity
for dichloropropene. In a human volunteer study, dermal absorption of
dichloropropene was only 2–5% of inhalational absorption.

Clinical Manifestations

There are a few reports of systemic dichloropropene toxicity. Tachycardia,
tachypnea, hypotension, sweating, abdominal pain, and hematochezia occur
rapidly after ingestion. Rhabdomyolysis, metabolic acidosis, hyperglycemia,
and acute respiratory distress syndrome (ARDS) may also occur. Inhalation
produces headache, neck pain, nausea, and dyspnea. Contact dermatitis may
develop and healing leads to pigmented lesions.

Diagnostic Testing

Hepatic and renal function should be monitored following acute poisoning.
No additional tests are recommended beyond those needed for supportive
care.

Management

The patient’s clothes should be removed and bagged to avoid continued inha-
lational and dermal exposure of the patient and the healthcare worker. If in-
gestion occurs, one dose of activated charcoal should be administered. There
are no data to support specific therapies beyond supportive care.

PHOSPHIDES

Phosphides are usually found as powders or pellets, usually in the form of
zinc or aluminum phosphide (Zn

3P

2and AlP, respectively). Phosphine gas

(PH

3) is formed from phosphides after contact with water, particularly if
acidic. Phosphide tablets are often placed in grain stores, such as ships, al-
lowing the phosphine to be released once the storage sites are sealed.
Many reports of serious phosphide poisoning, including fatalities, originate
from India and other developing countries. The consumption of aluminum
phosphide is a common choice for suicide in India. Clandestine methamphet-
amine laboratories that use the ephedrine–hydriodic acid–red phosphorus man-
ufacturing method may generate phosphine gas at high reaction temperatures.
Fatalities are reported, and first responders have also been exposed to high
phosphine concentrations.

Toxicokinetics and Pathophysiology

Inhalation of phosphine gas results in nearly instant toxicity. Phosphides pro-
duce toxicity rapidly, generally within 30 minutes of ingestion, and death
may follow in less than 6 hours. The ingestion of fresh, unopened tablets con-
sistently results in toxicity, and ingestions larger than 500 mg are often fatal.

870

PART C THE CLINICAL BASIS OF MEDICAL TOXICOLOGY

Phosphine disrupts mitochondrial function by blocking cytochrome-c oxi-
dase. In addition to producing energy failure in cells, free radical generation
increases resulting in lipid peroxidation.

Clinical Manifestations

Phosphides are potent gastric irritants; profuse vomiting and abdominal pain
are often the first symptoms. Respiratory signs and symptoms include tach-
ypnea, hyperpnea, dyspnea, cough, and chest tightness that may progress to
acute lung injury over days. Tachycardia, hypotension and dysrhythmias may
develop. Phosphine-induced dysrhythmias include atrial fibrillation and flut-
ter, heart block, and ventricular tachycardia and fibrillation. Central nervous
system toxicity includes coma, seizures, and delirium.

Diagnostic Testing

Phosphine tissue concentrations are not routinely available.

Management

Patients who ingest phosphine frequently vomit from the irritant effects of
phosphine. Theoretically, off-gassing from emesis may expose healthcare
workers to phosphine fumes. The emesis should be placed in sealed contain-
ers and disposed of properly, as wet phosphides will continue to generate
phosphine gas. Vomiting makes activated charcoal administration difficult
and raises the risk of aspiration. Because it is unknown to what extent acti-
vated charcoal binds phosphides and what the likely effectiveness of gastric
evacuation by emesis is, administration of oral activated charcoal is probably
unnecessary.

Comprehensive supportive care is recommended. Dilution with bicarbon-
ate solution has been recommended, as bicarbonate is believed to decrease
the gastric hydrochloric acid concentration which assists in the conversion of
phosphides to phosphine gas.

SULFURYL FLUORIDE

History and Epidemiology

Sulfuryl fluoride is used as a structural fumigant insecticide, to control wood-
boring insects such as termites in homes. Structure or tent fumigation is per-
formed by completely enclosing a house or other structure in plastic or a tar-
paulin; the sulfuryl fluoride is pumped in as a compressed gas. Chloropicrin
may be added as a warning agent.

Toxicokinetics and Pathophysiology

Little is known about the toxicokinetics of sulfuryl fluoride in humans. The
mechanism of toxicity is not understood. The measurable fluoride concentra-
tions in patients suggest that the release of fluoride may be a major patho-
physiologic mechanism.

Clinical Manifestations

Case reports of sulfuryl fluoride exposure describe acute and subacute
courses that have many similarities to methyl bromide. Initial symptoms may

112METHYL BROMIDE AND OTHER FUMIGANTS

871

be gastrointestinal, including nausea, vomiting, diarrhea, and abdominal pain,
or respiratory, including cough and dyspnea. Irritation of mucosal surfaces
may produce salivation, lacrimation with conjunctivitis, and nasopharyngitis.
Severe exposures affect the cardiopulmonary and nervous systems.

Diagnostic Testing

Patients with sulfuryl fluoride exposure require frequent monitoring of serum cal-
cium concentrations, as calcium complexes with fluoride ions (Chap. 101). Con-
tinuous cardiac monitoring should follow the QTc interval, as hypocalcemia may
precipitate dysrhythmias. Serum fluoride concentrations, while not helpful for the
acute management, may help with confirmatory diagnostic testing.

Management

After removal from the scene to fresh air, the patient should be disrobed to
avoid the possibility of off-gassing of any sulfuryl fluoride gas. Aggressive
treatment of hypocalcemia may be needed. Patients should have ECGs per-
formed and be attached to continuous cardiac monitoring for QTc prolonga-
tion (Chap. 101). Similar to methyl bromide, supportive care may be needed
for the seizures, dysrhythmias, and management of bronchospasm and ALI.

METAM SODIUM

Metam sodium, which breaks down into methyl isothiocyanate, is a potent
sensitizer. It is among the more common causes of occupational exposure to
fumigants. Exposed individuals develop irritant-induced asthma or reactive
airways disease syndrome (RADS) and dermatitis.

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