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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
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History and Epidemiology
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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
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Physicochemical Properties
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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
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In the presence of moisture, phosphide is converted to gaseous PH3 (hydrogen phosphide, phosphorus trihydride), ammonia, and carbon dioxide:
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[AlP + 3H2O = Al(OH)3 + PH3
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AlP + 3HCl = AlCl3 + PH3]
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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
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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
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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
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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
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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
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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
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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
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Clinical Manifestations
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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
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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.
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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
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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
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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
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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
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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
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Toxicological Analyses.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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.