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Goldfrank's Toxicologic Emergencies, 10e > 115: Monofluoroacetate and

Fermin Barrueto, Jr. FIGURE 115–1.

HISTORY AND EPIDEMIOLOGY

Sodium monofluoroacetate (SMFA) occurs naturally in plants native to , , and South and West (eg, gifblaar {}).11 The highest concentration (8.0 mg/g) is found in the seeds of a South African plant, Dichapetalum braunii.11 In the 1940s, SMFA was released as a (CAS No. 62-74-8) and assigned the compound number 1080, which was registered as its trade name. Fluoroacetamide, a similar , is known as Compound 1081. These compounds are widely effective as against most and some .26 Both products were banned in the United States in 1972, except to protect sheep and cattle from . Collars embedded with SMFA are placed around the neck of livestock, the typical point of attack for coyotes.

Sodium monofluoroacetate is used extensively in and Australia to control the possum population and other animal species considered pests that have no natural predators. Its continued use is extremely controversial, but following a recent review of the ramifications of the use of the compound, the government of New Zealand retained both the aerosolized and collar applications. Reported cases of poisoning with SMFA are uncommon and the epidemiology is poorly understood. There have been only 65 reported cases from 1999 to 2010 with no deaths in the National Poisoning Database System of the American Association of Control Centers (Chap. 136).

TOXICOKINETICS AND TOXICODYNAMICS

Sodium monofluoroacetate is an odorless and tasteless white powder with the consistency of flour. When it is dissolved in water, it is said to have a vinegarlike taste. Sodium monofluoroacetate and fluoroacetamide (CAS No. 640-19-7) are well absorbed by the oral and inhalational routes.10,11,12,27 Detailed toxicokinetic data are lacking in , but in sheep, up to 33% of an ingested dose is excreted unchanged in the urine over 48 hours. Glucuronide and glutathione conjugates have been isolated.11 Substantial defluorination is not thought to occur in vivo. The serum half-life is estimated to be 6.6 to 13.3

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10 19 hours in sheep. Sodium monofluoroacetate has an LD50 of 0.07 mg/kg in . The oral dose thought to be lethal to humans is 2 to 10 mg/kg.3

PATHOPHYSIOLOGY

Sodium monofluoroacetate, a structural analog of acetic acid (Fig. 115–1), is an irreversible inhibitor of the tricarboxylic acid cycle (Fig. 13–3). Monofluoroacetic acid enters the mitochondria, where it is converted to monofluoroacetyl- (CoA) by acetate thiokinase. Mitochondrial is then joined with the monofluoroacetyl-CoA complex with oxaloacetate to form fluorocitrate. Fluorocitrate then covalently binds , preventing the from any further metabolic activity in the tricarboxylic acid cycle.17 Thus, fluorocitrate acts as a “suicide inhibitor” of aconitase, producing a biochemical dead end. The net toxicity caused by fluorocitrate results from the increase in tricarboxylic acid cycle substrates proximal to inhibition of aconitase and the depletion of substrates distal to the step catalyzed by aconitase. This inhibition of aconitase impairs energy production, leading to anaerobic metabolism and metabolic acidosis with an elevated lactate concentration. Additionally, other tricarboxylic acid cycle intermediates increase in concentration, contributing to the toxicity. α-Ketoglutarate depletion, caused by the lack of isocitrate, leads to glutamate depletion since α-ketoglutarate is a precursor of glutamate synthesis. Glutamate depletion leads to urea cycle disruption and ammonia accumulation. Impaired fatty acid oxidation leads to ketosis. Excess citrate binds to divalent cations such as calcium causing hypocalecmia.

FIGURE 115–1. Structural similarities among acetyl-CoA, sodium monofluoroacetate, and fluoroacetamide.

Disruption of the tricarboxylic acid and urea cycles affects every system in the human body, but the most consequential effects occur in the central nervous system and the cardiovascular system. Fluoride toxicity from enzymatic defluorination of sodium monofluoroacetate and fluoracetamide does not occur substantially in vivo and is of minor significance.

CLINICAL MANIFESTATIONS Loading [Contrib]/a11y/accessibility-menu.js

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The majority of the clinical experience with SMFA is associated with intentional self-poisoning; fluoroacetamide poisoning is presumed to have a similar presentation.9,16,18,29 Most patients develop symptoms within 6 hours after exposure. In the largest case series of 38 Taiwanese patients who ingested SMFA, 7 died.6 The most common clinical findings recorded at the time of emergency department (ED) presentation were nausea and (74%), diarrhea (29%), agitation (29%), and abdominal pain (26%).6 The mean time to presentation to the hospital was 10.9 ± 5.7 hours for those who died and 3.4 ± 0.6 hours for the survivors. All deaths occurred within 72 hours of admission to the hospital. The presence of respiratory distress or seizures was a poor prognostic indicator of death. All seven patients who died had systolic blood pressures less than 90 mm Hg on presentation to the ED, a finding noted in only 16% of the survivors.6

In a case series involving two patients, invasive hemodynamic monitoring revealed persistent low systemic vascular resistance and increased cardiac output despite adequate fluid resuscitation.7 The authors theorized that the cardiovascular response may have been triggered by ATP depletion and inhibition of gluconeogenesis.7 Anaerobic metabolism, mitochondrial inhibition, and sensitivity of the vasculature to SMFA are also confounding factors.

The initial neurologic manifestations consist of agitation and confusion with progression to seizures. Neurologic sequelae such as cerebellar dysfunction may be permanent.30,15 One report describes a 15 year- old girl who survived an initial exposure to SMFA but later developed cerebellar dysfunction and cerebral atrophy, demonstrated by computed tomography.30 QT interval prolongation, premature ventricular contractions, ventricular fibrillation, ventricular tachycardia, and other dysrhythmias are documented.6 SMFA has negative inotropic effects, except in one case report that described episodic hypertension.25 associated with severe poisoning are seizures, respiratory distress, and .

DIAGNOSTIC TESTING

The presence of SMFA and fluoroacetamide can be confirmed in the blood and urine with gas chromatography–mass spectrometry and thin-layer chromatography.1,5,20 Simultaneous analysis for other that can induce seizures, for example, fluoroacetamide and “tetramine,” has been performed by gas chromatography in China, where exposure to these xenobiotics is more probable.2,4,31 Like tetramine, SMFA is considered a potential weapon of mass destruction.13 An elevated serum citrate concentration has been proposed as a useful marker for exposure to SMFA.4 However, none of these studies can be performed in a clinically relevant period. A combination of history, signs, symptoms, and common laboratory tests can assist with the diagnosis.

Hypokalemia, anion gap metabolic acidosis, and an elevated creatinine concentration8 are associated with 6 severeLoading poisoning[Contrib]/a11y/accessibility-menu.js but are very nonspecific. The predominant electrolyte abnormality will be hypocalcemia,

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although hypokalemia can result from acute kidney injury and gastrointestinal losses. Creatinine, liver enzyme, and bilirubin concentrations may also be elevated as a result of multisystem organ toxicity. Ketones may be present in urine and serum. A complete blood cell count may reveal leukocytosis. An electrocardiogram is valuable in the diagnosis of SMFA exposure; a prolonged QT interval, atrial fibrillation with a rapid ventricular response, ventricular tachycardia, and other dysrhythmias may be present.6,28 An initial computed tomography scan of the brain may be normal, but subsequent scans may reveal cerebral atrophy.30 Diffusion weighted magnetic resonance imaging (MRI) has shown reversible symmetric high signal intensity in the cerebellar peduncles, corpus callosum, internal capsules, and corona radiata in an SMFA poisoned patient with a sublethal ingestion. MRIs were performed on the day of ingestion and 7 days later.15 Brain single photon emission computed tomogram (SPECT) was also normal 14 days later.

TREATMENT

Initial decontamination should include removal of clothes and cleansing of skin with soap and water. Because there is no proven for SMFA or fluoroacetamide poisoning, orogastric lavage should be considered for exposed patients who present to the ED prior to significant emesis. Appropriate patients should receive 1 g/kg of activated charcoal (AC) orally. A study showed that colestipol is more effective than AC in binding SMFA.21 By extension, it seems reasonable to consider the use of colestipol, if available, for the treatment of life-threatening exposures in humans, although there are no human data to support this therapy. A suggested initial dose would be 5 g.

In a model, glycerol monoacetate (monacetin) at a dose of 0.5 mL/kg every 30 minutes prolonged survival. In this context, monacetin functions as an acetate donor for ultimate incorporation into citrate in place of fluoroacetate.29 Both ethanol and glycerol monoacetate are converted to acetyl-CoA and compete with monofluoroacetyl-CoA for binding of citrate synthase. This may prevent the “suicide-inhibition” of aconitase, subsequent increase in citrate, and the formation of the toxic metabolite fluorocitrate.29 Availability of monacetin for human use is limited, and appropriate human dosing is unknown.

Ethanol has been used in human cases, although the appropriate dose is unknown and there is not enough evidence to support its use as a single antidote.6,7,24 A reasonable therapeutic dose is the amount of ethanol required to obtain and sustain an ethanol serum concentration of 100 mg/dL ( in Depth: A31). One intriguing case report involves a patient who ingested 240 mg of SMFA (typically a ) mixed with a Taiwanese wine (30% ethanol) and survived.6 It is possible that the ethanol decreased or delayed the toxicity of SMFA.

In a mouse model, use of a combination of calcium salts, sodium succinate, and α-ketoglutarate improved survival.22 The rationale of using these antidotes is to provide tricarboxylic acid cycle intermediates distal to the inhibited aconitase in an attempt to improve energy production. These antidotes were not effective

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unless calcium was coadministered, emphasizing the importance of replenishing electrolytes, particularly the divalent cations that are chelated by citrate.14,28,23

If a patient develops hypotension and shock, rapid administration of intravenous 0.9% NaCl should be followed by a vasopressor, such as norepinephrine or vasopressin. Supportive care, correction of electrolyte abnormalities (especially calcium and potassium), ethanol infusion, and monitoring for dysrhythmias (prolonged QT interval) and seizures are the practical mainstays of treatment.

SUMMARY

Sodium monofluoroacetate and fluoroacetamide are potent that inhibit the tricarboxylic acid cycle, disrupting cellular energy production.

Patients who are exposed to SMFA typically present with nausea, vomiting, agitation, and abdominal pain, which may be followed by hypotension, respiratory distress, shock, seizures, and death.

Lactate accumulation, hypokalemia, hypocalcemia, metabolic acidosis, and elevation of serum creatinine also occur.

Treatment of SMFA and fluoroacetamide poisoning largely involves replenishing electrolytes, correcting hypotension with intravenous fluids and vasopressors if necessary, monitoring for dysrhythmias, and treating seizures.

Ethanol, although not well studied as an antidote, is relatively familiar, readily available, and can be administered safely. The efficacies of other experimental antidotes are unknown.

References

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2. Barrueto F Jr, Furdyna PM, Hoffman RS et al.: Status epilepticus from an illegally imported Chinese rodenticide: “tetramine.”J Toxicol Clin Toxicol. 2003;41:991–994. CrossRef [PubMed: 14705847]

3. Beasley M: Guidelines for the safe use of sodium fluoroacetate (1080). New Zealand Occupational Safety & Health Service, August 2002.

4. Bosakowski T, Levin AA: Serum citrate as a peripheral indicator of fluoroacetate and fluorocitrate toxicity in and dogs. Toxicol Appl Pharmacol. 1986;85:428–436. CrossRef [PubMed: 3764925] Loading [Contrib]/a11y/accessibility-menu.js

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5. Cai X, Zhang D, Ju H et al.: Fast detection of fluoroacetamide in body fluid using gas chromatography- mass spectrometry after solid-phase microextraction. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;802:239–245. CrossRef [PubMed: 15018783]

6. Chi CH, Chen KW, Chan SH et al.: Clinical presentation and prognostic factors in sodium monofluoroacetate intoxication. J Toxicol Clin Toxicol. 1996;34:707–712. CrossRef [PubMed: 8941201]

7. Chi CH, Lin TK, Chen KW: Hemodynamic abnormalities in sodium monofluoroacetate intoxication. Hum Exp Toxicol. 1999;18:351–353. CrossRef [PubMed: 10413241]

8. Chung HM: Acute renal failure caused by acute monofluoroacetate poisoning. Vet Hum Toxicol. 1984;26 (suppl 2):29–32. [PubMed: 6523725]

9. Deng HY, Gao Y, Li YJ: Management of severe fluoroacetamide poisoning with hemoperfusion in children. Zhongguo Dang Dai Er Ke Za Zhi. 2007;9:253–254. [PubMed: 17582269]

10. Eason CT, Gooneratne R, Fitzgerald H et al.: Persistence of sodium monofluoroacetate in livestock animals and risk to humans. Hum Exp Toxicol. 1994;13:119–122. CrossRef [PubMed: 7908808]

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12. Eason CT, Turck P: A 90-day toxicological evaluation of Compound 1080 (sodium monofluoroacetate) in Sprague-Dawley rats. Toxicol Sci. 2002;69:439–447. CrossRef [PubMed: 12377993]

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15. Im TH, Yi HJ: The utility of early brain imaging (diffusion magnetic resonance and single photon emission computed tomography scan) in assessing the course of acute sodium monofluoracetate

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intoxication. J Trauma. 2009;66:E72–E74. CrossRef [PubMed: 19509606]

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18. Lin J, Jiang C, Ou J, Xia G: Acute fluoroacetamide poisoning with main damage to the . Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2002;20:344–346. [PubMed: 14694721]

19. Meenken D, Booth LH: The risk to dogs of poisoning from sodium monofluoroacetate (1080) residues in possum (Trichosurus vulpecula). New Zealand J Agric Res. 1997;40:573–576. CrossRef

20. Minnaar PP, Swan GE, McCrindle RI et al.: A high-performance liquid chromatographic method for the determination of monofluoroacetate. J Chromatogr Sci. 2000;38:16–20. CrossRef [PubMed: 10654787]

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26. Sherley M: The traditional categories of fluoroacetate poisoning signs and symptoms belie substantial underlying similarities. Toxicol Lett. 2004;151:399–406. CrossRef [PubMed: 15261984]

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