111: Fumigants

Proper use of pesticides can have a beneficial role in human health by increasing the quality and quantity of crops. Alternatively, their improper use can lead to a variety of acute and chronic poisonings.⁵⁶ Pesticide ­poisoning is a global public health problem,⁵⁴ and each year approximately 300,000 deaths occur worldwide due to pesticides.⁵³

Fumigants are nonspecific pesticides applied to kill and control rodents, nematodes, insects, weed seeds, and fungi anywhere in soil, on structures, crops, grains, and commodities.⁴⁹ They represent a diverse group of xenobiotics that are dissimilar in their chemical structures, physical properties, and mechanisms of toxicity (Tables 111–1 and 111–2). Many fumigants, particularly the halogenated solvents, have been largely abandoned because of their toxicity. In the 1987 Montreal Protocol, an international agreement was adapted to phase out ozone-depleting chemicals, such as methyl bromide, which was scheduled to be discontinued in 2005. ­Unfortunately, many agricultural companies received exemptions, as satisfactory substitutes for some of its uses have not emerged.

Since fumigants exist as solids that can release toxic gases on reacting with water (zinc phosphide, aluminum phosphide) or with acids (sodium or calcium cyanide), as liquids (ethylene dibromide, dibromochloropropane, formaldehyde) that can vaporize at ambient temperature, or as gases (methyl bromide, hydrogen cyanide, ethylene oxide), inhalation is the most common route of exposure (Table 111–1). In their gaseous forms fumigants are generally heavier than air and will stay concentrated just above the ground surface and lower floors of buildings.

Their exposure risk is enhanced by their general lack of good warning properties, non–species-selective effects, and high potency. Although chemicals from many different classes were used in the past as fumigants, only a few remain in use today in the United States. This chapter summarizes those remaining and also highlights important fumigants that are in use in developing countries.

Introduction

In addition to the organic phosphorus and organic chlorine compounds, metal phosphides (aluminum, zinc, magnesium, and calcium) have long been used as rodenticides and fumigants around the world. The metal phosphides are advantageous due to their low cost, high effectiveness in destroying harmful insects and rodents, freedom from toxic residue, and lack of adverse effect on seed viability. Phosphides are used to protect grain held in silos, in the holds of ships, and during transportation by rail. They are generally admixed with the grain at a predetermined rate at the initiation of storage.^26,56 Upon exposure to ambient moisture, the metal phosphides release phosphine gas (PH₃). Exposure to water results in rapid release highlighting the concern for their use as chemical weapons.¹⁶

History and Epidemiology

From 1900 until 1958 only 59 cases of PH₃ and metal phosphides poisoning were reported in the literature, the majority of which were unintentional. Fatal outcomes were reported in 26 of these cases.^95,105 Over the last 35 years, cases of poisoning have escalated, carrying a high mortality rate, likely related to the use of these chemicals for suicidal purposes.¹²⁰ Aluminum phosphide (AlP) poisoning is now one of the commonest causes of poisoning in agricultural societies, such as those found in India, Sri Lanka, Iran, Jordan, and Morocco.^{16,46,48,96,115,120} The incidence of phosphide poisoning is rare in Europe and North America.^100,107

Physicochemical Properties

Commercially, AlP is most widely available as a greenish-gray tablet that has a garlic odor. The tablets usually contain 3 g of AlP (56%), ammonium carbamate, and urea. Zinc phosphide (Zn₃P₂; molecular weight of 258.1 Da) is available as a dark gray powder and or quadrilateral crystals that has odor of acetylene or rotten fish. Calcium phosphide (Ca₃P₂; molecular weight of 182.2 Da) is available as a reddish-brown crystal powder.⁹

In the presence of moisture, phosphide is converted to gaseous PH₃ (hydrogen phosphide, phosphorus trihydride), ammonia, and carbon dioxide:

OR

Each AlP tablet liberates up to 1 g of PH₃. The release of PH₃ is even more vigorous after contact with an aqueous acid, such as hydrochloric acid. The residue Al(OH)₃ is nontoxic.^9,48,136 PH₃ may be flammable, and other by-products of commercial tablets (aluminum oxide and diphosphine gas) are spontaneously flammable in air.^{38,69,117,146,147}

Although PH₃ is colorless and odorless in pure form up to toxic concentrations (200 parts per million {ppm}), the presence of substituted phosphines and diphosphines imparts a decaying fish or garlic odor that is detectable at concentrations of as little as 2 ppm.^26,27,104

Toxicokinetics

Following ingestion, the most common route of exposure, metal phosphides react with acidic fluid in the gastrointestinal (GI) tract to release PH₃, which is rapidly absorbed. Phosphides may be absorbed as microscopic particles of unhydrolyzed salt and subsequently converted to PH₃. PH₃ can be absorbed from respiratory tract mucosa if inhaled. Dermal and ocular absorption occurs.⁹

There are no data on the distribution of PH₃ to tissues, but one would expect this small soluble molecule to readily reach all organs.^9,89 PH₃ is detectable in the blood and liver of decedents following ingestion.^6,32 Hypophosphite is the major degradation product in the urine, and smaller amounts of phosphate and phosphite may be identified, while PH₃ itself is exhaled.⁵⁷

Toxicodynamics

PH₃ is a protoplasmic toxin that interferes with enzymatic function and synthesis of proteins.¹²⁰ The mechanism of toxicity includes blocking the electron transport chain and oxidative phosphorylation through noncompetitive inhibition of cytochrome-c oxidase. This inhibits cellular respiration and leads to the formation of highly reactive hydroxyl radicals that cause additional damage.^17,42,123 PH₃ also inhibits catalase, induces superoxide dismutase, and reduces the glutathione (GSH) concentration. All of these effects combine to result in lipid peroxidation and protein denaturation of cell membranes, leading to widespread cellular damage and ion channel dysfunction.^30,31,34,65

PH₃ directly injures the alveolar capillary membrane in addition to producing oxidative injury, leading to acute respiratory distress syndrome (ARDS).^57,120 Although both AlP and PH₃ inhibit cholinesterase activity, this effect is unlikely to have substantial clinical relevance.^{3,84,85,94,108}

Toxic Dose

Ingestion of 1 g of ZnP can cause toxicity in humans and death has been reported after ingestion of 4 g. Ingestion of 500 mg of AlP can be fatal.¹⁰ The recommended exposure limit (REL) of PH₃ in workplace is less than 0.3 ppm as a time-weighted average (TWA) for up to 10 hours per day during a 40 hour work week, and 1 ppm as a 15-minute short-term exposure limit (STEL) that should not be exceeded at any time during a workday. The National Institute of Occupational Safety and Health has established 50 ppm as the concentration that is immediately dangerous to life or health (IDLH) for PH₃, and the concentration of 400 to 600 ppm could be lethal within 0.5 hours.^98,132 Workplace standards are not available for AlP specifically.¹³²

Clinical Manifestations

The smell of garlic or decaying fish on the breath is a common finding and can be the result of oral or inhalational poisoning with phosphides and PH₃.¹⁰⁷ The clinical manifestations are dependent on the dose, route of entry, and time since exposure⁵⁷ After ingestion, the onset of toxicity usually is slightly more rapid for AlP (10–15 minutes) than for ZnP (20–40 minutes).^56,74 In patients with mild poisoning, nausea, repeated vomiting, diarrhea, abdominal ­discomfort or pain, especially epigastric pain, and tachycardia are common clinical manifestations. In those with moderate to severe effects, GI manifestations, refractory hypotension and shock, palpitations, cardiovascular ­collapse, dysrhythmias, tachypnea, and ARDS occur early.^48,109

Restlessness, anxiety, dizziness, ataxia, numbness, paresthesias, and tremor are universally observed, but central nervous system (CNS) manifestations are not prominent until a secondary event, such as hypoxia occurs. Late and severe neurologic findings include delirium, convulsions, and coma.

Following limited PH₃ inhalational exposure, patients commonly have airway irritation and breathlessness.²⁶ Other features may include dizziness, tightness in the chest, headache, nausea, vomiting, diarrhea, ataxia, numbness, paresthesias, tremor, muscle weakness, and diplopia.^48,56,132 In patients with significant inhalations, ARDS, cardiac failure, dysrhythmias, convulsions, coma, and delayed manifestations of hepatotoxicity and nephrotoxicity may also occur.^48,132

Uncommon complications of phosphides and PH₃ poisoning include gastroduodenitis, hepatitis,³⁵ ascites¹⁴ pancreatitis,¹⁴³ myocardial infarction,^72,76 acute pericarditis,²⁷ pleural effusion,¹³³ skeletal muscle damage and rhabdomyolysis,¹⁰⁹ acute tubular necrosis, adrenocortical congestion, hemorrhage and/or necrosis,⁷ and delayed esophageal stricture or tracheoesophageal fistula.^73,81,142 Hepatic and kidney failure, as well as disseminated intravascular coagulation (DIC), may occur following acute poisoning.^14,48,109

Diagnostic Testing

Initial investigations should include electrocardiography (ECG) and continuous cardiac monitoring, chest radiograph, blood glucose, blood gases, serum electrolytes, complete blood count, and liver and kidney function studies. Hypokalemia is common after oral poisoning and is probably due to vomiting, although this effect may be catecholamine related.¹⁰⁹ Magnesium concentrations may be normal,¹²⁴ increased, or decreased.^{23,25,28,29,121,122}

Hypoglycemia as a result of impaired gluconeogenesis, glycogenolysis, and possibly due to adrenal insufficiency is common and may be severe and persistent.^36,45 Hyperglycemia has also been reported.^89,90 Metabolic acidosis or mixed metabolic acidosis and respiratory alkalosis are common.¹⁰⁹ Intravascular hemolysis, methemoglobinemia, and microangiopathic hemolysis are unusual complications of phosphide poisoning.^77,118,127

ECG abnormalities are very common, but highly variable, and include rhythm disturbances, ST segment and T wave changes, and conduction defects.^25,71,128 During the first 3 to 6 hours after poisoning, sinus tachycardia is predominant, followed over the next 6 to 12 hours by ST segment and T wave changes, conduction disturbances, and dysrhythmias.^45,126 Ventricular tachycardia, ventricular fibrillation, supraventricular tachycardia, and atrial flutter/fibrillation are the most common consequential dysrhythmias.¹²⁵ Echocardiography may reveal dysfunction, dilation, and hypokinesia or akinesia of the left ventricle that typically resolves over several days.^2,15,55

Toxicological Analyses.

Chemical analysis for PH₃ in blood or urine is not recommended and is not typically helpful as PH₃ is rapidly oxidized to phosphite and hypophosphite.¹⁴⁷ Gas chromatography with a nitrogen-phosphorous detector is the most specific and sensitive test.⁹⁷ The presence of PH₃ is suggested by a positive silver nitrate test on gastric content or exhaled breath. In this test which is not clinically available and is not validated paper impregnated with silver nitrate will turn black (silver phosphate) in the presence of PH₃.⁹³

Prognosis

The mortality rate following metal phosphide ingestion is 31% to 77%.^{23, 24, and 25,116} Most of the deaths occur within 12 to 24 hours and are due to cardiovascular collapse.^5,128 After 24 hours, most of the deaths are due to refractory shock, severe acidemia, and ARDS.¹⁴⁵ Fulminant hepatic failure may develop within 72 hours after poisoning and may be another cause of death.⁷

A high Acute Physiology and Chronic Health Evaluation Score, a high Simplified Acute Physiology Score, shock, decreased level of consciousness, lack of vomiting after ingestion, acidemia, hyperglycemia, uremia, hemoconcentration, leukocytosis, and ECG abnormalities are all poor prognostic factors.^{23, 24, and 25,80,89,90,115,116,128}

Treatment

The victim of PH inhalation should immediately be removed to fresh air and supplemental oxygen should be provided as needed.^57,109 Clinical staff and other health care professionals should use universal precautions, including gloves and masks,⁹³ with the understanding that a particulate mask will not protect against PH₃. As PH₃ may be absorbed by the cutaneous route, the patient’s clothes should be removed and their skin and eyes decontaminated with water as early as possible.⁴⁸ GI decontamination may be useful if it is done within 1 to 2 hours of ingestion. The acidic content of stomach assists the conversion of phosphide to PH₃, and some have suggested the oral administration of sodium bicarbonate, but this is not supported by experimental evidence.^57,82 Potassium permanganate (1:10,000) has also been suggested in case reports as an adjunct to gastric lavage to oxidize PH₃ to nontoxic phosphate.^82,103

There is limited evidence that activated charcoal (AC) 100 g may reduce GI absorption if the patient arrives within 1 hour after ingestion of a large amount of poison. Its routine use is not recommended as PH₃ is rapidly absorbed from the GI tract.⁸² In vitro studies suggest that lipid, mainly vegetable oils and liquid paraffin, inhibit PH₃ release from the ingested AlP.⁵¹ This approach was utilized in a single case report.¹¹⁴

Management should be rapidly initiated based on a history and clinical examination that support phosphides/PH₃ poisoning, and should not be delayed for the confirmatory diagnosis.⁵⁷ Standard supportive care to address ventilatory and vital sign abnormalities should be administered. If necessary, norepinephrine or phenylephrine should be employed. Vasopressors with greater β-receptor agonist action like dopamine and dobutamine should be used cautiously as they are prone to induce dysrhythmias.⁵⁷

As there is no known specific antidote, management remains primarily intensive monitoring and supportive treatment, to allow the toxin to be eliminated. ARDS, hypoglycemia, hypokalemia, and metabolic acidosis should be managed conventionally.^57,109

Dysrhythmias should be treated with standard antidysrhythmics. Recently, a few studies hypothesized that treatment with digoxin could have beneficial effects on myocardial contractility and blood pressure.^91,112

The benefit of hyperinsulinemia-euglycemia treatment is suggested by preliminary investigations in that insulin ­promotes energy production from carbohydrates, restores calcium flux, and improves myocardial contractility.⁵⁹ The use of an intraaortic balloon pump is reported,¹¹⁹ but the usefulness of extracorporeal life support in ­circulatory failure due to phosphides/PH₃ poisoning was not formally evaluated.¹³

N-acetylcysteine (NAC) has been shown in an experimental animal model⁸ and human study¹³⁵ to be beneficial. As the experimental and clinical evidence shows that both PH₃ and aluminum inhibit acetylcholinesterase,^3,84,85,108 pralidoxime may have a role in the management. Further studies are recommended to confirm usefulness of oximes,⁹⁴ and they are not currently recommended.

Experimental data show that hyperbaric oxygenation may improve the survival time of poisoned rats, with no change in the mortality rate.¹¹¹ Magnesium sulfate acts as a cell membrane stabilization factor and, possibly by this mechanism, reduces the incidence of fatal dysrhythmias.^28,29 Magnesiumalso has antioxidant effects and combats free radicals due to PH₃.^33,34 Although likely of low risk, the use of magnesium sulfate in phosphides/PH₃ poisoning is controversial.^57,109 Hemodialysis is not very effective in removing PH₃, although it may be useful in the setting of a patient with acute kidney failure, severe metabolic acidosis, or fluid overload.⁵⁷ As stated previously, the sole recognized approach remains intensive care monitoring and supportive treatment. All other approaches remain experimental.

History and Epidemiology

Methyl bromide was used as an anesthetic in the early 1900s, but fatalities halted this practice. Today, methyl bromide is used widely as a fumigant for all types of dry food stuffs, in grain elevators, mills, ships, warehouses, greenhouses and food-processing facilities for the control of nematodes, fungi and weeds. It is termed a structural or commodity fumigant which is a class term for the Environmental Protection Agency.

Methyl bromide is also used as a methylating chemical in manufacturing and as a low-boiling solvent for extracting oils from nuts, seeds and flowers. Methyl bromide has also been used as a refrigerant and fire retardant. Historically, poisoning incidents involving the general public were mainly associated with the methyl bromide used in fire extinguishers. Other poisoning incidents have involved unauthorized entry into buildings being fumigated with methyl bromide.^12,60

Occupational and environmental exposures to methyl bromide as a fumigant are most common. Hazardous materials incidents are reported for methyl bromide, during manufacture or as a result of use and transport,^20,106 but they are relatively uncommon in plant employees or residents living adjacent to agricultural fields where methyl bromide is applied.²⁰ Before 1955, the majority of methyl bromide poisonings resulted from chemical manufacture and filling operations. Since then, fumigation has become the major source of fatalities and fumigators, and greenhouse workers are the highest risk group. In many countries the use of methyl bromide is restricted to trained and licensed personnel.⁴⁴

Methyl bromide has a threshold limit value-time weighted average (TLV-TWA) of 5 ppm and IDLH concentration is 2000 ppm. The Occupational Safety and Health Administration (OSHA) permissible exposure limit is 20 ppm.

Methyl bromide is a colorless gas at room temperature and standard pressure. It is three times heavier than air. It is odorless except at high concentrations when it has a burning taste and a sweet chloroformlike smell. Commercially it is available as a liquefied gas. The formulations also may contain chloropicrin or amyl acetate as a warning agent.

Toxicokinetics

Inhalation is the primary route of exposure, although methyl bromide is rapidly absorbed through the dermal and oral routes. After absorption, methyl bromide or metabolites are rapidly distributed to many tissues, including the lungs, adrenals, kidneys, liver, brain, testis, and fat. The major organs of distribution observed immediately after exposure includes fat, lungs, liver, adrenals, and kidneys.

The metabolism of methyl bromide has not been completely elucidated. Methyl bromide is partially converted to inorganic bromide in man and bromide concentrations in blood and target organs increase after exposure to methyl bromide.^12,64 It is metabolized to methyl glutathione by the enzyme glutathione S-transferase (GST) and is then converted into the neurotoxic metabolites of methanethiol and formaldehyde.⁷⁹

Depending on the route of exposure, 16% to 40% is eliminated as metabolized methyl bromide in the urine and only 4% to 20% is eliminated in the expired air as parent compound. Biliary excretion accounts for about 46% of the elimination, generally within 24 hours following oral exposure.^4,87,88 Methyl bromide is hydrolyzed and produces methanol and hydrobromic acid in animal models.

Toxicodynamics

The mode of action of methyl bromide is still not understood. Several mechanisms of toxicity are postulated, including the direct cytotoxic effect of the intact methyl bromide molecule or toxicity due to one of its metabolites.

Methyl bromide is a potent alkylating agent with high affinity for sulfhydryl and amino groups. It reacts in vitro with a number of sulfhydryl-containing enzymes and causes irreversible inhibition of microsomal metabolism.^12,50,129

It binds to amine groups in amino acids, interfering with protein synthesis and function. Also it may methylate many other cellular components such as GSH, proteins, DNA, and RNA.¹³⁰ The methanethiol and formaldehyde metabolites may have a role in neurologic and visual changes. The bromide ion concentrations are insufficient to explain methyl bromide toxicity.

Clinical Manifestations

Inhalation of more than 10,000 ppm for more than a few minutes may cause death.⁶⁰ Severe poisoning may result in tremor, convulsion, rapid loss of consciousness, dysrhythmias, and death. Convulsions generally occur in fatal cases, but ARDS leading to respiratory failure or cardiovascular collapse is the leading cause of death. Pulmonary symptoms begin with cough or shortness of breath that may rapidly progress to bronchitis, pneumonitis, and ARDS.⁶³ By contrast, following low concentration exposure, a characteristic delay of up to 48 hours in the onset of symptoms is expected. Headache, dizziness, abdominal pain, nausea, vomiting, chest pain, and difficulty breathing are the manifestations of mild to moderate exposure. Some individuals may initially manifest irritant symptoms of the eye, nasopharynx, and oropharynx, which may be misdiagnosed as influenza or another viral illness. Visual disturbances such as blurred or double vision may also appear.^22,49

The neurologic effects of methyl bromide poisoning are the most consequential and may occur without antecedent irritant effects. Initial CNS signs and symptoms that may manifest in the first few hours after exposure include headache, dizziness, numbness, drowsiness, euphoria, confusion, diplopia, dysmetria, dysarthria, agitation and mood disorders, or inappropriate affect. Those that may progress rapidly in the first day or manifest over the next few days include ataxia, intention tremor, fasciculation, myoclonus, delirium, seizures, and coma.^39,40

Methyl bromide can also cause skin lesions, including severe irritation, erythema, corrosive skin injury, blisters, and vesicles predominantly in moist areas or pressure points such as groin, axilla and wrist.¹⁴⁸ Liver and kidney damage have also been described.^12,60

Most patients who develop seizures or coma will not survive, and in the few survivors recovery typically may take months. Permanent sequelae such as neuropsychiatric impairment, ataxia, muscular weakness, irritability, blurred vision, myoclonus, and electroencephalographic (EEG) disturbances are frequent.^19,137

Diagnostic Testing

The standard laboratory evaluations such as a complete blood count, serum electrolytes, blood urea nitrogen (BUN) creatinine, ammonia concentration, blood gases, urinalysis, hepatic enzymes, chest radiography, ECG, and EEG should be obtained after an acute exposure. Hemoglobin adducts are used as a biologic index for exposure to methyl bromide.⁷⁰ Hemoglobin adducts have a life span of about 2 months, so workers who have only intermittent exposure to methyl bromide may benefit from testing.

Although a serum bromide concentration may help confirm the diagnosis, it is not readily available in most laboratories. Furthermore, it does not always correlate with the severity of the exposure and does not facilitate clinical management. Serum bromide concentrations may also remain elevated for a week or more following an acute exposure.⁶⁶

The findings on magnetic resonance imaging following methyl bromide intoxication are symmetric T2 signal abnormalities in posterior putamen, subthalamic nuclei, restiform bodies, vestibular nuclei, inferior colliculi, and periaqueductal gray matter and also symmetric involvement of inferior colliculi and periaqueductal gray, as well as dentate nuclei, dorsal pons, and inferior olives.⁴⁷

Treatment

Rescue and decontamination should be performed only by personnel wearing personal protective equipment. In patients with respiratory and cardiac arrest, cardiopulmonary resuscitation should be initiated immediately if it is safe to perform. Following inhalation, the patient should be safely removed from the exposure site. The outer clothing should be removed carefully, as methyl bromide may adhere to clothing, including rubber and leather, and the affected skin should be washed with soap and water. Decontamination includes irrigation of the eyes with copious amounts of 0.9% NaCl solution or water. It is also reasonable to administer at least one dose of oral AC following ingestion, although there is no supporting documentation for any benefit. Medical management should proceed as it would for any hazardous materials event (Chap. 131).

Management is primarily general and supportive care, and may require intensive care unit management of coma, seizures, ARDS, hepatic and kidney failure. Administer supplemental oxygen and treat bronchospasm, ARDS, and seizures. Seizures are common and difficult to control with traditional anticonvulsants such as benzodiazepines and phenytoin. Pentobarbital, high-dose thiopental, and propofol have been required in many cases.⁶⁶ All exposed patients should be monitored for a minimum of 24 to 48 hours to detect delayed symptoms, especially ARDS.

Although British anti-Lewisite (dimercaprol) has been used for the treatment of methyl bromide poisoning, its effectiveness is only reported in less severely affected patients.⁶⁰ The usage of NAC is not studied in controlled prospective trials, but its effectiveness is reported in mild to moderate poisonings.⁶⁶

There are no data indicating the benefit of alkalinization or hemoperfusion. Hemodialysis can rapidly clear serum bromide, but tissue injury following exposure occurs as the bromide is released into the serum, suggesting that the methylation of neuronal proteins has already occurred and the neurologic injury occurs. Posthemodialysis neurologic improvement is reported, but severe disabilities may remain. There is little evidence to support routine hemodialysis. There is little evidence to support these experimental approaches.

History and Epidemiology

1,3-Dichloropropene is a volatile chlorinated aliphatic hydrocarbon that was introduced in 1945 and is primarily used as a soil fumigant for nematodes. Its use escalated after the restriction of ethylene dibromide, methyl bromide, and dibromochloropropane in 1956. The current formulation contains dichloropropene in soybean oil.¹³⁸

Exposures are reported during production, application, and ingestion, most commonly in occupational settings where formulations are manufactured or applied. Unintentional releases during transport resulted in several poisonings.⁸³ The OSHA standard TLV-TWA for dermal exposure is 1 ppm.⁷⁸

Toxicokinetics

Dichloropropene is rapidly absorbed by the oral, inhalational, and dermal routes. Oral exposure is theoretically possible through contaminated groundwater, but this has not been reported in humans.¹³² Inhalation is the primary route of human exposure and dichloropropene is rapidly absorbed from the lungs.^18,140

No human data describe systemic distribution, but animal studies show that tissue concentrations after dichloropropene ingestion were highest in the stomach, followed by the blood, bone, brain, heart, kidneys, liver, bladder, skin, skeletal muscle, spleen, ovaries, testes, and fat.⁴¹

The metabolism of dichloropropene is similar to that of other chlorinated hydrocarbon solvents such as carbon tetrachloride and chloroform (Chap. 108). In humans, dichloropropene is metabolized in liver via oxidation in a phase I biotransformation,^86,92,131 which is catalyzed by cytochrome P450 (CYP2E1)⁵² and then glutathione dependent biotransformation.^{18,102,140,141} Toxicity may result from metabolism via an electrophilic epoxide intermediate.¹⁴⁴

Most of the glutathione-conjugated form of dichloropropene is eliminated by the kidneys and smaller amounts are eliminated in the feces.^37,67,138

Toxicodynamics

Human and animal health effects may include damage to the liver, kidney, lung, CNS, myocardium, GI tract, skin, and mucous membranes. The exact mechanisms of toxicity are not clear, but data suggest that there may be more than one mechanistic pathway in humans.

GSH depletion has been documented in the rat model.⁵⁸ The dose and route correlated with toxicity and outcome in rodent models of dichloropropene toxicity. At 100 mg/kg in mice, hepatotoxicity occurs by the intraperitoneal route, but not after oral gavage. At 700 mg/kg administered by the intraperitoneal route, hepatic failure and death result.¹¹ The higher dose correlated with a 130 fold increase in dichloropropene epoxide formation. Interestingly, in a rat hepatocyte model, pretreatment with the antioxidant, α-tocopherol, prevented cell death.¹³⁴

Clinical Manifestations

Signs and symptoms of acute oral or inhalational exposure include nausea, vomiting, bloody diarrhea, pancreatitis, hepatotoxicity, tachycardia and hypotension,⁶² dyspnea,⁶⁸ ARDS,⁶² CNS depression,⁸³ acute kidney injury (acute tubular necrosis),⁶² and muscle pain and weakness.⁸³ Coagulopathy and thrombocytopenia, hyperglycemia, severe metabolic acidosis,⁶² and intravascular fluid depletion secondary to hemorrhage are reported. Dermal manifestations include contact hypersensitivity,^60,138,139 erythema,⁸³ and profuse sweating.⁶² Mucous membrane irritation including erythema, edema, and irritation of the eyes, ears, nose, and throat occurs.^83,138 Concentrations above 1000 ppm cause lacrimation.¹ Hematologic malignancies including lymphoma and histiocytic lymphoma were reported after prolonged (6 years) dichloropropene exposure.⁸³

Radiographic abnormalities typically lag behind clinical signs. It may take up to 8 hours before abnormalities appear on chest radiography, even in symptomatic patients.⁶²

Weight loss, hyperemia and superficial ulcerations of the nasal mucosa, inflammation of the pharynx, bleeding from swollen gums,⁸³ liver aminotransferase elevations, and renal function abnormalities¹⁸ are reported after chronic exposure to dichloropropene.

Diagnostic Testing

Liver and kidney function should be monitored following acute poisoning.⁶² No additional or specific tests are recommended beyond those needed for supportive care. Biomonitoring for exposure to dichloropropene is under development.¹⁸ Hepatic γ-glutamyl transpeptidase concentrations are increased in fumigators, but the increase is not statistically significant. However, this finding suggests hepatic enzyme induction. In fumigators, erythrocyte GST and GSH concentrations decreased with increased serum creatinine concentrations and increased urine concentrations of albumin and retinol-binding protein when compared with controls.¹⁸

Treatment

Because of the volatility of dichloropropene, caution should be used to avoid continued inhalational and dermal exposure for both the patient and the health care professional. Symptomatic and supportive care should be provided as for methyl bromide. Following ingestion, oral AC can be administered, but there is no proven value. Orogastric lavage may be appropriate in a patient presenting shortly following ingestion. Exposed eyes should be irrigated with copious amounts of water or 0.9% NaCl solution for at least 15 minutes, and exposed skin should be similarly washed with soap.

There are no data to support specific therapies beyond supportive care, although the use of antioxidant therapy and NAC warrants further study. The patients should be monitored for at least 24 hours after exposure.

History and Epidemiology

Sulfuryl fluoride has been used since 1957 as a structural fumigant insecticide to control wood boring insects such as termites in homes. Structure or tent fumigation is performed by completely enclosing a house or other structure in plastic or a tarpaulin, and then sulfuryl fluoride is pumped in as a compressed gas. Chloropicrin is typically added as a warning agent. Although sulfuryl fluoride is commonly used in Florida, California,¹⁰¹ and Washington, a 5-year review of fumigant illness did not contain any reports of sulfuryl fluoride toxicity.²⁰

Toxicokinetics and Toxicodynamics

Sulfuryl fluoride gas is colorless, odorless, and heavier than air. The TLV-TWA for sulfuryl fluoride is 5 ppm; TLV-STEL is 10 ppm; IDLH is 200 ppm.⁹⁹

Little is known about the toxicokinetics of sulfuryl fluoride in humans and the exact mechanism of toxicity is not understood. The respiratory, central nervous, and cardiovascular systems are the primary target organ systems.⁴³ The measurable fluoride concentrations in patients with sulfuryl fluoride poisoning and the development of fluorosis in models of chronic, low concentration exposures suggest that the release of fluoride may be of major pathophysiologic consequence.¹⁰¹ Fluoride complexes with calcium and magnesium, resulting in hypocalcemia and hypomagnesemia (Chap. 107).⁶¹

Clinical Manifestations

Case reports of sulfuryl fluoride exposure describe acute and subacute clinical courses that share many similarities to methyl bromide poisoning. Initial symptoms, especially in limited exposures, may include nausea, vomiting, diarrhea, abdominal pain, cough, and dyspnea. Irritation of mucosal surfaces may produce salivation and nasopharyngitis, lacrimation, and conjunctival injection. CNS manifestations include paresthesias, irritability, agitation, tetany, refractory seizures, and coma. Finally, fluoride toxicity may result in profound shock, cardiac dysrhythmias, wide QRS complexes, prolongation of the QT interval, torsade de pointes, hyperkalemia, and ARDS (Chap. 107).^101,113

Memory and dexterity testing were abnormal in structural fumigation workers exposed to both methyl bromide and sulfuryl fluoride.²¹

Diagnostic Testing

Patients with sulfuryl fluoride exposure require monitoring of serum calcium, magnesium, and potassium concentrations. Patients should have an ECG performed and be attached to continuous cardiac monitoring to observe for QRS widening, QT interval prolongation, and dysrhythmias. Serum fluoride concentrations, although not helpful for acute manage­ment, may help as a confirmatory diagnostic test.

Treatment

In patients with inhalational exposure, after removal from the scene to fresh air, the patients should be partially disrobed to avoid further exposure to any liberated sulfuryl fluoride gas.

In treating sulfuryl fluoride poisoning, aggressive treatment of hypocalcemia with calcium gluconate or calcium chloride may be needed (Antidotes in Depth: A29). Similar to the management of methyl bromide, supportive care may be needed for the seizures, dysrhythmias, bronchospasm, and ARDS. As the fluoride ion is excreted in the urine, fluid resuscitation may be needed to maintain a steady urine output.¹¹⁰

Iodomethane or methyl iodide is currently under review by the US Environmental Protection Agency. It is proposed as a fumigant to replace methyl bromide. However, several reports from Europe suggest that the toxicity of methyl iodide may be similar to that of methyl bromide.^39,67 A recent report describes dermal exposure with severe burns and delayed neuropsychiatric sequel, similar to that associated with methyl bromide exposures.²¹

• Exposure to fumigants may be through ingestion or inhalation depending on the specific fumigant and the physical state.

• The fumigants are associated with multisystem organ failure and, following acute exposure, adversely affect both the cardiovascular and central nervous systems.

• Treatment involves removal from exposure and removal of outer clothing. Dermal decontamination is not generally needed given the volatile nature of most fumigants.

• Staff and patient protection from inhalation is important to prevent iatrogenic toxicity.

Acknowledgment

Keith K. Burkhart, MD, contributed to this chapter in previous editions.

References