|TOXICOLOGY SYMPOSIA – REVIEW ARTICLE
|Year : 2015 | Volume
| Issue : 1 | Page : 15-19
Aluminum phosphide poisoning
Surjit Singh, Ashish Bhalla
Department of Internal Medicine, PGIMER, Chandigarh, India
|Date of Web Publication||19-Feb-2015|
Dr. Ashish Bhalla
Department of Internal medicine, PGIMER, Sector 12, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Over the last three decades, aluminum phosphide has emerged as an important pesticide agent being sued for self-harm in India is well as other countries. High mortality is due to severe mitochondrial dysfunction leading to disruption of cellular respiration leading to tissue hypoxia and organ dysfunction. In spite of a lot of research, no definitive anbtidote is available, and the treatment remains largely supportive.
Keywords: Aluminum phosphide poisoning, mitochondrial dysfunction, oxidative stress, phosphine toxicity
|How to cite this article:|
Singh S, Bhalla A. Aluminum phosphide poisoning. J Mahatma Gandhi Inst Med Sci 2015;20:15-9
| Introduction|| |
Pesticide poisoning is an important cause of morbidity and mortality in India.  Till 1980, aluminum phosphide (ALP) had not appeared on the scene. We recorded our first case of ALP ingestion in late 1979 and after publication of our first largest series in literature in 1985,  there has been an explosion of reports from different parts of India predominantly being northwest and central India. ,,,,, It is uncommon in other parts of India as well as in the rest of the world except Iran, Jordan and Morocco from where a few case series have been reported. ,,
Aluminum phosphide is available as greenish grey tablet of 3 g, which contains 56% ALP and 44% ammonium carbonate. Some preparations such as Sanphos contain 5% ammonium carbonate and 40% inert ingredients. It is also formulated as pellets, granules and as the dust. However, since late 90's, ALP is being marketed in India mainly as granulated powder in plastic pouches (10 g) as Celphos (Excel industries). However, 3 g tablets are still available either as imported from China or manufactured by some small producers with different brand names.
Toxicity of ALP is due to phosphine (pH 3 ), which is released when it comes in contact with moisture or hydrochloric acid. Phosphine has been reported to have the odor of decaying fish at concentrations below the Occupational Safety and Health Administration's Permissible Exposure Limit of 0.3 parts per million (ppm). However, Zaebst et al., reported that workers noticed no odor when they worked in phosphine concentrations as great as 50 ppm for several minutes with no respiratory protection.  This lack of apparent odor may be attributable to olfactory fatigue. Others have reported that phosphine has a garlic-like odor which is likely to be due to impurities such as substituted phosphines, diphosphines, methane, and most important, arsine, which has garlic-like odor.
| Clinical Features|| |
[Table 1] highlights the clinical features of aluminium phosphide poisoning. Immediately after ingestion, almost all patients develop nausea, vomiting, retrosternal burning, epigastric discomfort and in significant poisoning, hypotension and shock develops invariably in 30 min to 2 h. ,,,, Signs of sympathetic overactivity such as sweating and tachycardia are common. Several electrocardiographic abnormalities have been reported [Table 2]. Oliguria develops in approximately half of cases. Adult respiratory distress syndrome commonly develops in patients with severe hypotension. If the patient survives shock, acute renal failure and tender hepatomegaly may develop. Other complications include disseminated intravascular coagulation, intravascular hemolysis, gastrointestinal bleeding, fulminant hepatic failure, congestive cardiac failure and rarely pericarditis. Patients generally remain mentally clear though restless till cerebral anoxia due to shock supervenes, resulting in drowsiness, delirium and coma. ,,
The outcome correlates best with a number of vomits patient gets after ingestion and severity of hypotension and acidosis.  The majority of deaths occur within the first 12-24 h and are usually due to refractory hypotension and arrhythmias. Deaths after 24 h may be due to acute respiratory distress syndrome, liver failure, renal failure or other complications.  Reported findings on necropsy are congestion of liver, spleen, kidneys, adrenals, gastrointestinal tract and brain that correlated with the severity of hypotension. Histopathology does not reveal any specific changes beyond visceral congestion and patchy necrosis of the liver. 
| Pathophysiology|| |
The exact mechanism by which phosphine acts is not clear. Nakakita et al.  found that oxygen uptake in isolated rat liver mitochondria was inhibited by it. It inhibited adenosine diphosphate uncoupler, and ion stimulated respiration, but exact target site was not identified. In a later detailed study  it was found to be strong inhibitor of mitochondrial respiration in active state (state-3) then in resting state (state-4) in mouse liver, housefly flight muscles, granry weevils and beef heart. It was found to inhibit uncoupled site and ion pumping state affecting pyruvate, malate, succinate, glycerophosphate and ascorbate cytochrome substrates. The effect was maximum on liver mitochondria while that on beef heart was of the intermediate nature. This inhibition could not be reversed by uncouplers suggesting that it is due to direct an effect on electron transport which is an important electrochemical link between respiration and phosphorylation in mitochondria. The spectral and dichroisim studies revealed an interaction with heme moiety of cytochrome oxidase (cytochrome-C) but is yet to be determined whether it interacts with either cytochrome a or a3 or both. In a study  involving three species of stored beetles, insect catalase and not cytochrome-C-oxidase system was found to be inhibited. In a recent experimental study where parameters of energy metabolism and oxidative stress were measured in rat brain and liver, following administration of ALP in LD50 dose that is, 10 mg/kg body weight, it was found that cytochrome-C oxidase activity in platelets was inhibited with decrease being in a concentration dependent manner. The adenosine triphosphate (ATP) synthesis was found to be decreased with a marked decrease in ATP levels in both liver and brain. The activity of succinic dehydrogenase and NADH dehydrogenase was markedly lower along with depletion of glycogen content in liver and activity of glycolytic enzyme was found to be increased in it. The activity of G-6PD was decreased in both organs. The results suggest that inhibition of cytochrome oxidase disturbs electron transport, leading to impaired energy metabolism. , In a recent study, cytochrome-C-oxidase activity in platelets of 26 patients with severe ALP poisoning was found to be inhibited by >50% (P < 0.001) as compared to healthy controls as well as those in shock due to other causes like sepsis, massive bleed and myocardial infarction.  The exact mechanism by which phosphine acts as a cellular toxin, however, is still not clear and more studies are required.
The following alone or in combination would help in the diagnosis:
- History of ingestion.
- Symptoms and signs compatible with ALP ingestion are mainly vomiting with vomitus smelling like decaying fish or garlic, severe hypotension or shock, metabolic acidosis and abnormalities in cardiac rate or rhythm.
- The diagnosis of ALP ingestion can be confirmed by detecting phosphine in exhaled air or in stomach aspirate by silver nitrate. This test is based on heating diluted gastric contents in a flask and exposing a strip of filter paper impregnated with freshly prepared silver nitrate near the mouth of the flask. The presence of phosphine turns the paper black.  The test can also be performed by holding the silver nitrate paper as a mask for the patient to breathe into. However, the breath test is not reliable. A false negative result may occur in patients being given oxygen as phosphine may get converted to phosphorus pentoxide. A false positive result may occur if there is hydrogen sulfide in the air.
- The phosphine in breath can also be detected using phosphine detector tubes.
- For spot sampling of phosphine in air, detector tubes and bulbs are available commercially. However, the most specific and sensitive is gas chromatography which can detect minute amounts of phosphine in air. 
Early recognition and management of the poisoning is essential. Induction of emesis is contraindicated though spontaneous vomiting often occurs. Gastric lavage should be considered if the procedure can be performed by experienced staff within 1 h of ingestion. However, there is no evidence that gastric lavage improves outcome in poisoned patients, and it can be associated with complications including aspiration, hypoxia and tachycardia. Gastric lavage should only be carried out in an obtunded patient if the airway can be adequately protected to avoid aspiration into the lungs. Gastric lavage is generally be followed by intragastric administration of a slurry of activated charcoal adult 50-100 g; infant 1 g/kg; child 1-12 years, 25-50 g. However, no studies are available in literature that show that it benefits patients.
Patients who have ingested ALP, insertion of a nasogastric or orogastric tube may release phosphine, presenting a potential toxic hazard to staff caring for the patient. In addition, phosphine may auto ignite. Vomitus may also be hazardous because of phosphine emission. Staff attending the patient should take appropriate protective measures to prevent contamination. However, iatrogenic poisoning in handlers has not been reported in care givers in India despite thousands of cases having been managed in hospitals with varying facilities  and only single case of auto ignition has been reported. 
The management continues to be unsatisfactory as there is no specific antidote and remains supportive only. The factors, which have been found to correlate best with outcome are numbers of vomits patient has after ingestion and severity of shock and acidosis. The main factor which guides the management is the treatment of shock/hypo tension with appropriate measures. Intravenous fluids should be administered as leakage of fluids from intravascular to the extravascular space occurs as a result of capillary dysfunction.  However, central venous pressure is generally high in them. In eleven intensively monitored patients, global hypokinesia of left ventricle with decreased ejection fraction was observed but administration of large quantities of fluids quantities administered to combat this did not make any significant difference in the outcome.  The administration of fluids can be combined with dopamine/dobutamin infusion to maintain systolic blood pressure above 80 mmHg.
Magnesium sulfate, a membrane stabilizer can reverse arrhythmias and has been used. Though arrhythmias improve, mortality does not decline. In severe cases compromised, adrenal function has been reported.  Though corticosteroids have been administered, outcome remains poor.
There is experimental evidence to suggest that pretreatment with N-acetylcysteine (NAC) and melatonin helps in improving outcome in animal, , However, the results in humans are inconsistent. An Iranian study has shown a significant benefit of starting NAC in poisoned patients  but our experience in severely poisoned patients has not been encouraging.  Since there is no concrete evidence of its role, NAC cannot be recommended for treatment of ALP poisoning as of now. Some other drugs which are known to protect mitochondrial oxidative phosphorylation such as hydroxycobalamine and Vitamin C appear promising but have not yet been tried. Supportive therapy in the form of intra-aortic balloon pumps and extracorporeal membrane oxygenation have been tried in severely ill patients with variable results. 
In survivors, diffuse capillary leak syndrome  and long-term esophageal complications like strictures and trachea esophageal fistula have been reported. 
An important preventive measures lies in better regulated supply of ALP which otherwise is an excellent and safe fumigant as it leaves little residue on grain. Legislative and administrative measures have been suggested to restrict and modify its supply in India. Unfortunately, there has been a failure in their application except largest producer of it in India has started marketing it as granulated powder in 10 g plastic pouches. In our retrospective analysis, we have observed that though number of cases due to ALP have continued to increase, a consistent decline in mortality was observed from year 2000 onwards since when bulk of ALP available in market has been in form of granulated powder in plastic pouch in pouch. These pouches could have led to a decreased severity of poisoning as ALP gets exposed to atmospheric moisture leading to escape of phosphine during opening of these pouches to swallow ALP granules. 
| References|| |
Murali R, Bhalla A, Singh D, Singh S. Acute pesticide poisoning: 15 years experience of a large North-West Indian hospital. Clin Toxicol (Phila) 2009;47:35-8.
Singh S, Dilawari JB, Vashist R, Malhotra HS, Sharma BK. Aluminium phosphide ingestion. Br Med J (Clin Res Ed) 1985;290:1110-1.
Siwach SB, Yadav DR, Arora B, Dalal S, Jagdish. Acute aluminum phosphide poisoning - An epidemiological, clinical and histo-pathological study. J Assoc Physicians India 1988;36:594-6.
Chugh SN, Chugh K, Ram S, Malhotra KC. Electrocardiographic abnormalities in aluminium phosphide poisoning with special reference to its incidence, pathogenesis, mortality and histopathology. J Indian Med Assoc 1991;89:32-5.
Khosla SN, Chugh SN, Nand N, Saini RS. Systemic involvement in aluminium phosphide poisoning (a report of 10 cases). J Assoc Physicians India 1986;34:227-30.
Bajaj R, Wasir HS, Aggarwal R. Aluminium phospide poisoning clinical toxicity and outcome in eleven intensively monitored patients. Natl Med J India 1988;1:270-4.
Katira R, Elhence GP, Mehrotra ML, Srivastava SS, Mitra A, Agarwala R, et al.
A study of aluminum phosphide (AlP) poisoning with special reference to electrocardiographic changes. J Assoc Physicians India 1990;38:471-3.
Moghadamnia AA, Abdollahi M. An epidemiological study of poisoning in northern Islamic Republic of Iran. East Mediterr Health J 2002;8:88-94.
Abder-Rahman HA, Battah AH, Ibraheem YM, Shomaf MS, el-Batainch N. Aluminum phosphide fatalities, new local experience. Med Sci Law 2000;40:164-8.
Akkaoui M, Achour S, Abidi K, Himdi B, Madani A, Zeggwagh AA, et al
. Reversible myocardial injury associated with aluminum phosphide poisoning. Clin Toxicol (Phila) 2007;45:728-31.
Zaebst DD, Blade LM, Burroughs GE, Morelli-Schroth P, Woodfin WJ. Phosphine exposures in grain elevators during fumigation with aluminium phosphide. Appl Ind Hyg 1988;3:146-54.
Singh S, Singh D, Wig N, Jit I, Sharma BK. Aluminum phosphide ingestion - A clinico-pathologic study. J Toxicol Clin Toxicol 1996;34:703-6.
Gupta S, Ahlawat SK. Aluminum phosphide poisoning - A review. J Toxicol Clin Toxicol 1995;33:19-24.
Nakakita H, Katsumata Y, Ozawa T. The effect of phosphine on respiration of rat liver mitochondria. J Biochem 1971;69: 589-93.
Chefurka W, Kashi KP, Bond EJ. The effect of phosphine on electron transport in mitrochondria. Pestic Biochem Physiol 1976;6:65-84.
Price NR, Dance SJ. Some biochemical aspects of phosphine action and resistance in three species of stored product beetles. Comp Biochem Physiol C 1983;76:277-81.
Dua R, Gill KD. Effect of aluminium phosphide exposure on kinetic properties of cytochrome oxidase and mitochondrial energy metabolism in rat brain. Biochim Biophys Acta 2004;1674:4-11.
Dua R, Gill KD. Aluminium phosphide exposure: Implications on rat brain lipid peroxidation and antioxidant defence system. Pharmacol Toxicol 2001;89:315-9.
Singh S, Bhalla A, Verma SK, Kaur A, Gill K. Cytochrome-c oxidase inhibition in 26 aluminum phosphide poisoned patients. Clin Toxicol (Phila) 2006;44:155-8.
Chugh SN, Ram S, Chugh K, Malhotra KC. Spot diagnosis of aluminium phosphide ingestion: An application of a simple test. J Assoc Physicians India 1989;37:219-20.
Vins Jansen A, Thrane KE. Gas chromatographic determination of phosphine in ambient air. Analysis 1978;103:1195-8.
Christophers AJ, Singh S, Goddard DG. Dangerous bodies: A case of fatal aluminium phosphide poisoning. Med J Aust 2002;176:403.
Yadav J, Athawal BK, Dubey BP, Yadav VK. Spontaneous ignition in case of celphos poisoning. Am J Forensic Med Pathol 2007;28:353-5.
Chugh SN, Ram S, Sharma A, Arora BB, Saini AS, Malhotra KC. Adrenocortical involvement in aluminium phosphide poisoning. Indian J Med Res 1989;90:289-94.
Azad A, Lall SB, Mittra S. Effect of N-acetylcysteine and L-NAME on aluminium phosphide induced cardiovascular toxicity in rats. Acta Pharmacol Sin 2001;22:298-304.
Hsu C, Han B, Liu M, Yeh C, Casida JE. Phosphine-induced oxidative damage in rats: Attenuation by melatonin. Free Radic Biol Med 2000;28:636-42.
Tehrani H, Halvaie Z, Shadnia S, Soltaninejad K, Abdollahi M. Protective effects of N-acetylcysteine on aluminum phosphide-induced oxidative stress in acute human poisoning. Clin Toxicol (Phila) 2013;51:23-8.
Bhalla A, Nath J, Singh S, Malhotra S, Sharma N. A Randomized Trial of N Acetyl Cystine in Patients with Established Severe Aluminium Phosphide Poisoning. Presented at 9 th
Congress of APAMT Held at Vietnam from 17 th
November 2010, Hanoi, Vietnam.
Siddaiah L, Adhyapak S, Jaydev S, Shetty G, Varghese K, Patil C, et al.
Intra-aortic balloon pump in toxic myocarditis due to aluminum phosphide poisoning. J Med Toxicol 2009;5:80-3.
Bhalla A, Mahi S, Sharma N, Singh S. Polyserositis: An unusual complication of aluminium phosphide poisoning. Asia Pac J Med Toxicol 2012;1:14-7.
Jain RK, Gouda NB, Sharma VK, Dubey TN, Shende A, Malik R, et al.
Esophageal complications following aluminium phosphide ingestion: An emerging issue among survivors of poisoning. Dysphagia 2010;25:271-6.
[Table 1], [Table 2]
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