K: PESTICIDES

CASE STUDY 11

INTRODUCTION

HISTORY AND EPIDEMIOLOGY

Although barium is utilized in various forms in developed nations, exposure to barium salts is uncommon and clinically significant poisoning is rare. Acute, clinically relevant exposures occur most commonly following the intentional ingestion of the soluble salts found in rodenticides, insecticides, or depilatories.^10,11 Barium carbonate has an appearance similar to flour, which is reported to be responsible for most unintentional barium poisonings.^9,13

Barium salts and barium hydroxide are extensively employed in industry particularly in thermoplastics and the manufacture of synthetic fibers, soap manufacture, and in lubricants (Table 107–1). Toxicity occurs following occupational exposure to barium salts through ingestion, inhalation,³⁴ or explosion of the propellant barium styphnate.¹⁵ Despite the fact that barium sulfate is insoluble, rare cases of unintentional toxicity are reported during radiographic procedures and include complications associated with oral²⁴ and rectal administration.^14,19,22,27 Toxicity and death occurred when solutions were unintentionally contaminated with soluble contrast barium salts.²⁹

CHEMISTRY

Barium is a soft metallic element that was first isolated by Sir Humphry Davy in 1808. With an atomic weight of 137.3 Da, barium is located at number 56 in the periodic table (between cesium and lanthanum). The metal oxidizes easily when exposed to water or alcohol, has a melting point of 1,341°F (727°C) and a boiling point of 3,398°F (1,870°C). Elemental barium is not found in nature; it normally occurs as an oxide, dioxide, sulfate (barite), or carbonate (witherite). Chemically, barium resembles calcium more than it resembles any other element. Although some barium salts are naturally occurring, most used commercially are produced from the more commonly found carbonates or oxides. Barium salts are typically classified as either water soluble or insoluble, but the solubility of all barium salts increases as pH falls. The soluble salts acetate, chloride, hydroxide, oxide, nitrate, and (poly) sulfide are the most commonly associated with toxicity (Table 107–1). Barium (poly) sulfide also produces toxicity through the formation of hydrogen sulfide when ingested and exposed to gastric hydrochloric acid. Poorly soluble barium carbonate is converted by gastric acid to highly soluble barium chloride. The other insoluble barium salts such as arsenate, chromate, fluoride, oxalate, and sulfate are rarely associated with toxicity.

TOXICOKINETICS

Toxicity can result from ingestion of as little as 200 mg of a barium salt. Oral lethal doses are reported to range from 1 to 30 g of a barium salt. Occupational exposure to barium fumes of greater than 0.02 mg/m³ are associated with health effects.³⁸ Exposure to inhaled particulate insoluble barium causes pulmonary baritosis, which consists of very fine punctate and annular lesions and some slightly larger nodular lesions.³⁸

Following ingestion, 5% to 10% of soluble barium salts are absorbed,¹⁶ with the rate of absorption dependent on the degree of water solubility of the salt. The time to peak serum concentration is 2 hours.¹⁶

The toxicokinetics are characterized by a rapid redistribution phase, followed by a slow decrease of serum barium concentrations, with a reported half-life ranging between 18 and 85 hours.^16,28 Renal elimination of the absorbed dose accounts for 10% to 28% of total barium excretion, with the predominant route of fecal elimination through the gastrointestinal tract.

In published case reports of symptomatic patients, serum barium concentrations range from 3.7 to 41.1 mg/L.^{2,9,23,25,28,31,33} Death is uncommon following ingestion, but occurs most commonly in clinical settings with limited health care resources.¹³ Death from an ingestion of barium chloride was associated with the following barium concentrations at autopsy: blood, 9.9 mg/L; bile, 8.8 mg/L; urine, 6.3 mg/L; and gastric contents, 10 g/L.¹⁷

Intravasation is a rare but serious complication of radiologic studies in which barium sulfate is administered under pressure, such as a barium enema. Following a small perforation, barium sulfate leaks into the peritoneal cavity or portal venous system.²² Although sudden cardiovascular collapse occurs, it is unclear whether this is the result of venous occlusion (pulmonary embolism), overwhelming sepsis, or barium toxicity.^7,32,37 In at least one case report of intravasation, signs and symptoms were consistent with barium toxicity and elevated barium concentrations were confirmed.²⁴ Under these circumstances if hypokalemia is present, then barium toxicity can be assumed.

Additionally, intravenous administration of barium sulfate has occurred as the result of unintentional administration. Recognition followed by aspiration through a central venous catheter was associated with a good outcome.³⁰

PATHOPHYSIOLOGY

Hypokalemia is due to redistribution of potassium from the extracellular to intracellular compartment. This is thought to be due to 2 synergistic mechanisms. Barium inhibits calcium-activated potassium rectifier channels, reducing outward flow of potassium; this occurs in the context of persistent Na⁺,K⁺-ATPase pump electrogenesis leading to a shift of extracellular potassium into the cell.³

Intracellular trapping of potassium leads to depolarization and paralysis.¹⁸ Additionally, the inhibition of potassium channels increases vascular resistance and reduces blood flow^4,6 and is the likely mechanism for hypertension and metabolic acidosis with an elevated lactate concentration.

Although severe hypokalemia contributes significantly to paralysis, some authors report that muscle weakness correlates better with barium concentrations than with potassium concentrations.^25,33 This suggests a possible direct effect of barium on either skeletal muscle or neuromuscular transmission.

CLINICAL MANIFESTATIONS

Abdominal pain, nausea, vomiting, and diarrhea commonly occur within 2 hours of ingestion.¹³ Esophageal injury and hemorrhagic gastritis are also reported.^1,18

Severe hypokalemia is the cardinal feature of barium toxicity and typically occurs within 2 hours following oral or parenteral exposure. Hypokalemia is exacerbated by blood transfusions, suggesting that fresh red blood cells provide a new reservoir for K⁺ sequestration.¹⁵ Progressive hypokalemia is associated with ventricular dysrhythmias, hypotension, profound flaccid muscle weakness, and respiratory failure (Chaps. 12, 15, and 22).³

Other effects less commonly reported include hypertension, metabolic acidosis with an elevated lactate concentration, hypophosphatemia, and rhabdomyolysis.¹⁶ Altered level of consciousness, seizures,⁸ and parkinsonism with findings on magnetic resonance imaging of bilateral hyperintensity of the basal ganglia are reported.¹² It is unclear whether these latter findings are due to direct toxicity, deposition of barium, or secondary to tissue ischemia.

DIAGNOSTIC TESTING

Barium can be measured by a variety of techniques. Mass spectrometry and graphite furnace atomic absorption spectrometry can quantitate barium in blood and urine.^18,20 Serum barium concentrations are not readily available, but values greater than 0.2 mg/L are considered abnormal.⁵

Following acute exposures, patients should have serum electrolytes (particularly potassium and phosphate) measured hourly while performing continuous electrocardiographic monitoring. Creatine phosphokinase (CK), acid–base status, and kidney function should also be measured. In one case, abdominal radiography showed barium, but the sensitivity and specificity of radiography for barium poisoning is unknown.¹⁸

MANAGEMENT

Toxicologic etiologies for flaccid paralysis such as hypermagnesemia, botulism, and the administration of neuromuscular blockers should be evaluated while the serum potassium concentration is being determined. Once the hypokalemia is diagnosed, other causes of acute hypokalemia (Chap. 12) associated with paralysis such as periodic hypokalemic paralysis, toluene toxicity, and diuretic use are included in the differential diagnosis if there is no history or laboratory confirmation of barium exposure.

Patients who are asymptomatic at 6 hours following ingestion with normal potassium concentrations can be discharged. Patients with signs or symptoms of toxicity should be admitted to an intensive care unit with expectant management of respiratory compromise and cardiovascular instability.

DECONTAMINATION

Activated charcoal is unlikely to be effective. Orogastric lavage is reasonable in patients who present early after ingestion, but lavage is unlikely to provide substantial benefit in patients who are already symptomatic or who have had spontaneous emesis. Oral sodium sulfate administration theoretically prevents absorption by precipitating unabsorbed barium ions as insoluble, nontoxic barium sulfate. Oral magnesium sulfate has had similar efficacy.²¹ Early administration of oral magnesium sulfate is a reasonable intervention; the dose is 250 mg/kg for children and 30 g for adults.²³ Intravenous magnesium sulfate or sodium sulfate is not recommended because of its potential to produce acute kidney injury due to precipitation of barium in the renal tubules.^25,36

Patients in respiratory failure should receive assisted ventilation. Expeditious correction of hypokalemia is important to minimize the risk or to treat cardiac dysrhythmias. It should be anticipated that large doses of potassium replacement (400 mEq in 24 hours) will be required to correct serum potassium although as noted above repletion of potassium alone may be inadequate to improve the resting membrane potential or muscle strength¹⁸ (Chap. 12). As hypokalemia is due to intracellular sequestration of potassium, potassium supplementation increases the total body potassium load. In this situation, rebound hyperkalemia should be expected when barium is eliminated, especially in patients with acute or chronic kidney disease. Observation and serial evaluation for this clinical complication is essential.

Elimination Enhancement

If hypokalemia is unable to be corrected or if the correction of hypokalemia does not restore normal motor function and muscle strength, hemodialysis is recommended. Case reports suggest that hemodialysis for the management of severe barium toxicity is associated with rapid clinical improvement.^2,28,31,35 Additionally, in a case report, continuous veno-venous hemodiafiltration provided a clinically significant increase in measured barium elimination, stabilized serum potassium concentrations, and was associated with rapidly improved motor strength.¹⁸

Management of Intravasation

Following intravasation of oral barium sulfate patients should be admitted to an intensive care unit. Expectant management should include evaluation of intraabdominal sepsis, hemorrhage and trauma, pulmonary embolus, and barium toxicity.²² Prophylactic antibiotics use appears reasonable and serial determinations of serum potassium concentrations are warranted. Computed tomography scanning of the chest and abdomen can demonstrate both the location and extent of the barium sulfate administered.³²

SUMMARY

• Although poisoning by barium salts is rare, these salts are widely used in industry and therefore represent a substantial risk for human exposure.

• The hallmark of barium salt toxicity is rapidly developing and severe hypokalemia with attendant weakness progressing to paralysis.

• In addition to supportive care, the mainstay of treatment is rapid correction of hypokalemia.

• Hypokalemia results from an intracellular shift of potassium. As toxicity resolves and potassium redistributes into the extracellular space, cautious evaluation for the development of hyperkalemia is essential.

• Extracorporeal therapies are reasonable in cases of refractory hypokalemia.

REFERENCES

HISTORY AND EPIDEMIOLOGY

The proper use of pesticides has a beneficial role in human health by increasing the quality and quantity of crops. Alternatively, acute and chronic pesticide poisoning are significant causes of morbidity and mortality worldwide, especially in developing countries, making pesticide poisoning a global public health problem.^78,191

Fumigants are nonspecific pesticides applied to kill and control rodents, nematodes, insects, weed seeds, and fungi anywhere in soil, in structures, crops, grains, and commodities.³⁷ They represent a diverse group of pesticides that are dissimilar in their chemical structures, physical properties, and mechanisms of toxicity (Tables 108–1 and 108–2). Many fumigants, particularly the halogenated solvents, have been largely abandoned because of their toxicity. In the 1987 Montreal Protocol, an international agreement was adopted 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 methyl bromide uses have not emerged.

Because fumigants exist as solids that 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 108–1). In their gaseous forms, fumigants are generally heavier than air and will be found concentrated just above the ground surface and lower floors of buildings.

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

METAL PHOSPHIDES AND PHOSPHINE

Introduction

In addition to the organic phosphorus and organic chlorine compounds, metal phosphides (aluminum, zinc, magnesium, and calcium) have been used as rodenticides and fumigants around the world for many years. The metal phosphides are advantageous because of their low cost, high effectiveness in destroying harmful insects and rodents, freedom from toxic residue, and lack of adverse effects on seed viability. Metal 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.¹⁶³ Following 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.²⁵ Phosphine gas itself is also used in the synthesis of flame retardants, organic phosphorus compounds, pharmaceuticals, and in the production of semiconductors.¹⁷⁰

History and Epidemiology

Over the last decades, cases of PH₃ and metal phosphide poisonings have escalated, carrying a high mortality rate, likely related to the use of these chemicals for suicides.^{42,64,93,98,131,179,190,197} Unintentional poisoning as a result of negligence or ignorance are also reported.^{54,120,160,172} Aluminum phosphide (AlP) poisoning is one of the commonest causes of poisoning both in adults and children in agricultural societies and developing countries, such as India, Sri Lanka, and Iran.^{68,72,110,148,173,177} The incidence of AlP poisoning is low in developed countries;^155,160 however, PH₃ poisoning has increased in frequency as it is a by-product of the use of red phosphorus in the synthesis of methamphetamines.^33,215

Physicochemical Properties

Commercially, AlP (molecular weight of 57.95 Da) is most widely available as a greenish-gray tablet or pellet bag and granular form that has a garlic odor. The 3-g tablet usually contains AlP (56%), ammonium carbamate, and urea, which liberates PH₃ (up to 1 g), ammonia, and carbon dioxide. Each pellet (0.6 g) releases 0.2 g PH₃.

Zinc phosphide (Zn₃P₂; molecular weight of 258.1 Da) is available as a dark-gray powder or as quadrilateral crystals that have an odor of acetylene or rotten fish. Calcium phosphide (Ca₃P₂; molecular weight of 182.2 Da) is available as a reddish-brown crystal powder. Magnesium phosphide (Mg₃P₂; molecular weight of 134.8 Da) is a white crystalline solid.^15,143

In the presence of moisture or acid, metal phosphides are converted to PH₃ (hydrogen phosphide, phosphorus trihydride, molecular weight of 34 Da):

or

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.^15,170 Phosphine gas is flammable, and other by-products of commercial tablets (diphosphine gas) are spontaneously flammable in air concentrations above the lower explosive limit (LEL) of 1.8% v/v.^{100,130,175,201,214,216} In aqueous solutions, PH₃ produces phosphinic, phosphonic and phosphoric acids, which are all corrosive and produce exothermic reactions.^130,170

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.^159,163,170

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. Metal phosphides may be absorbed as microscopic particles of unhydrolyzed salt and subsequently converted to PH₃. Phosphine gas is also absorbed from respiratory tract mucosa if inhaled. Dermal absorption is insignificant.¹⁵

There are no data about distribution of PH₃ in humans, but it would be expected that as a small soluble molecule PH₃ is widely distributed.^15,163 Its half-life ranges from 5 to 24 hours based on various factors.²⁰⁹ Phosphine gas is detectable in the blood of severely poisoned patients and is also found in the kidney, brain, and liver of decedents following ingestion.^11,49 In vitro studies demonstrated that PH₃ interacts irreversibly with free hemoglobin and hemoglobin in intact erythrocytes (rat and human) that results in the production of Heinz bodies and hemichromes, which are methemoglobin derivatives.^40,161 Rare clinical presentations such as intravascular hemolysis and methemoglobinemia support the involvement of erythrocytes in the biotransformation of PH₃ in humans.¹⁶³

Phosphate, hypophosphite, and phosphite are identified in the urine, whereas PH₃ itself is exhaled.^81,163

Toxicodynamics

The toxicity of metal phosphides is due to PH₃ release. Phosphine gas is a protoplasmic toxin. The mechanisms of toxicity include blocking the electron transport chain and oxidative phosphorylation through noncompetitive inhibition of cytochrome-c oxidase.^9,182 Phosphine gas decreases the activities of mitochondrial complexes I, II, IV, V. This inhibits cellular respiration and ATP production and leads to the formation of highly reactive hydroxyl radicals that cause additional damage.^{10,26,59,60,102,170,182,185} Phosphine gas also inhibits catalase, induces superoxide dismutase, and reduces the glutathione (GSH) concentration. All of these effects combine to result in lipid peroxidation, protein denaturation of cell membranes, and DNA damage, leading to widespread cellular damage and ion channel dysfunction.^{10,47,48,50,60,82,94,102,109,170,185,200,203}

Because PH₃ is corrosive, it directly injures the alveolar capillary membrane in addition to producing oxidative injury, leading to an acute respiratory distress syndrome (ARDS).^81,179 Although both AlP and PH₃ inhibit cholinesterase activity, this effect is unlikely to have substantial clinical relevance.^{6,127,128,142,162}

Toxic Dose

Ingestion of 1 g of zinc phosphide can causes toxicity in humans, and death is reported after ingestion of 4 g. Ingestion of 500 mg of AlP can be fatal.¹⁶ The recommended exposure limit (REL) of PH₃ in the 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 established 50 ppm as the concentration that is immediately dangerous to life or health (IDLH) for PH₃.^153,196 Workplace standards are not available for AlP specifically.¹⁹⁶

Clinical Manifestations

The smell of garlic or decaying fish on the breath is a common finding and results from oral or inhalational poisoning with metal phosphides and PH₃.¹⁶⁰ The clinical manifestations are dependent on the dose, route of entry, and time since exposure.⁸¹ After ingestion, the onset of toxicity usually is slightly more rapid for AlP (10–15 minutes) than for zinc phosphide (20–40 minutes).^80,108 In patients with mild poisoning, nausea, repeated vomiting, thirst, diarrhea, abdominal discomfort or pain, especially epigastric pain, and tachycardia are common clinical manifestations. In those with moderate to severe effects, palpitations, tachypnea, GI manifestations, dysrhythmias, ARDS, hypotension, shock, and cardiovascular collapse, occur rapidly.^{72,93,98,106,109,110,131,146,163,177,197}

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.^93,110,197 Late and severe neurologic findings include delirium, convulsions, ischemic/hemorrhagic stroke and coma.^1,27,55

Following limited PH₃ inhalational exposure, patients commonly have airway irritation and breathlessness.¹⁷⁰ Other features include chest tightness, tachycardia, headache, nausea, vomiting, diarrhea, numbness, muscle weakness, and diplopia.^72,80,196

Uncommon complications of metal phosphides and PH₃ poisoning include gastroduodenitis, hepatitis,⁵¹ ascites,²² pancreatitis,²¹¹ myocardial infarction,^104,111 acute pericarditis,⁴⁴ pleural effusion,^67,198 rhabdomyolysis,¹⁶³ acute tubular necrosis, adrenocortical congestion, hemorrhage and/or necrosis,¹² and delayed esophageal stricture or tracheoesophageal fistulas.^{23,105,113,123,152,210} Liver and kidney failure, as well as disseminated intravascular coagulation (DIC), are also rarely reported following acute poisoning.^{22,54,72,163,196}

Diagnostic Testing

Initial investigations should include electrocardiography (ECG) and continuous cardiac monitoring, chest radiograph, blood glucose, blood gases, serum electrolytes, complete blood count (CBC), liver, and kidney function studies.

Hypokalemia is common after oral poisoning.^98,131,163 Magnesium concentrations are reported as normal, increased, or decreased.^{10,41,43,45,46,180,181,183,197} Hypoglycemia as a result of impaired gluconeogenesis, glycogenolysis, and possibly due to adrenal insufficiency is common and at times severe and persistent.^{52,66,107,137} Hyperglycemia and metabolic acidosis are also reported.^{93,134,135,177,197} Hemolysis, methemoglobinemia, leukopenia, and hyperbilirubinemia are unusual complications of metal phosphides poisonings.^{112,116,146,156,170,176,188,193}

Electrocardiographic abnormalities are very common, but highly variable, and include rhythm disturbances, ST segment and T wave changes, QRS complex widening, and conduction defects that revert to a normal pattern within several days.^{43,103,170,179,189} 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.¹⁸⁷ Ventricular tachycardia, ventricular fibrillation, supraventricular tachycardia, and atrial flutter/fibrillation are the most common consequential dysrhythmias.¹⁸⁴ Echocardiography typically reveals cardiac dysfunction, dilation, and hypokinesia or akinesia of the left ventricle that typically resolves over several days.^5,24,25,79

Chest radiography shows diffuse infiltration, pulmonary edema, ARDS, and atelectasis.^143,170 As aluminum and PH₃ both inhibit cholinesterase,^{6,127,128,162} measurement of cholinesterase activity in the presence of cholinergic findings is recommended.¹¹⁰

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.^15,81,163 The presence of PH₃ is suggested by a positive silver nitrate test on gastric contents or exhaled breath. In this test, which is a simple and sensitive method to detect PH₃, paper impregnated with silver nitrate will turn black (silver phosphide) in the presence of PH₃.¹⁴¹ The detection limit of the test is 0.05 ppm for PH₃.

The ammonium molybdate test is another chemical method that is used for the qualitative or quantitative analysis of phosphorus, PH₃, and phosphides in the stomach contents and postmortem samples. Formation of canary yellow precipitates confirms the presence of PH₃ or phosphides.^65,114

Headspace gas chromatographic with a nitrogen-phosphorous detector (HS-GC/NPD) is a specific and sensitive test for PH₃ or phosphides.¹⁴⁹ Headspace gas chromatography coupled with mass spectrometry (HS-GC-MS) was described for the analysis of the PH₃ metabolites in biological samples. The detection limit of this method for PH₃ is 0.2 mcg/mL.²¹⁷ Unfortunately, none of these tests are available in a time frame to permit their clinical utility.

Prognosis

The mortality rate following ingestion of metal phosphides is reportedly 31% to 77%.^{41-43,63,98,109,121,131,174,177,197} Most of the deaths occur within 12 to 24 hours and are due to cardiovascular collapse.^8,189 After 24 hours, most of the deaths are due to refractory shock, severe acidemia, and ARDS.²¹³ Fulminant hepatic failure develops within 72 hours after poisoning and is another cause of delayed death.¹²

In some studies of acute AlP poisoning, vomiting after ingestion was significantly more common in survivors. Nonsurvivors ingested significantly higher doses of AlP and had greater delays from exposure to treatment initiation. In nonsurvivors blood pressure and level of consciousness were significantly altered on admission.^{93,173,177,197} The Acute Physiology and Chronic Health Evaluation (APACHE) Score and Simplified Acute Physiology Score (SAPS) are significantly higher in nonsurvivors than survivors.^98,131,174

Metabolic acidosis with an elevated lactate concentration is an index of severity of AlP poisoning. It was demonstrated that there is significant correlation between blood lactate concentration and time of death in the nonsurvivors. Also, derived from this study, the line of best fit connecting the blood lactate concentration of 5.4 mmol/L at 4 hours and 2.8 mmol/L at 24 hours post ingestion was used to predict the likelihood of death.⁶³

Treatment

The victim should immediately be removed from the area of exposure to fresh air, and supplemental oxygen should be provided as needed.^81,163 Clinical staff and other health care professionals should use universal precautions, including gloves, goggles, N95 respirators and other PPE as indicated (Special Considerations: SC2),¹⁴¹ with the understanding that a particulate mask will not protect against PH₃. Staff should also be aware of the risk for spontaneous ignition.^175,214 As PH₃ is absorbed cutaneously, the patient’s clothes should be removed and the skin and eyes decontaminated with water as early as possible.⁷²

In oral exposure, gastric emptying is reasonable if it is done within a few hours of ingestion and significant emesis has not already occurred (Chap. 5). The acidic content of stomach facilitates the conversion of metal phosphides to PH_3. As a result, some authors suggest the oral administration of sodium bicarbonate (88 mEq), but this is not supported by clinical trials, and therefore not recommended at this time.^{4,81,82,84,93,110,124,200} Potassium permanganate (KMnO₄) (1:10,000) was used as an adjunct to gastric lavage to oxidize PH₃ to nontoxic phosphate.^{4,82,84,93,124,158,197,200} Neither this approach nor the use of boric acid¹⁸⁶ is recommended because of multiple associated risks and no proven benefit.¹⁴⁰

There is limited evidence that activated charcoal (AC) (Chap. 5 and Antidotes in Depth: A1) fails to reduces GI absorption even if administered rapidly following ingestion.^84,93,110 Its use is therefore not routinely recommended.¹²⁴

In vitro studies suggest that lipid, mainly vegetable oils and liquid paraffin, inhibit PH₃ release from the ingested AlP.^{4,76,93,165,171,187} Unfortunately, aspiration is a significant risk with oil ingestion and these data are too premature to recommend the routine use of oils at this time.

Management should be rapidly initiated based on a history and clinical examination that support metal phosphides or PH₃ poisoning, and should not be delayed for a confirmatory diagnosis.⁸¹ Standard supportive care to address ventilatory and vital sign abnormalities should be administered. If necessary, norepinephrine or phenylephrine are recommended.^81,84

As there is no known specific antidote, management remains primarily intensive monitoring and supportive treatment, to allow sufficient time for the poison to be eliminated. Hypoglycemia, hypokalemia, and ARDS, should be managed conventionally.^81,84,163 Aggressive correction of severe acidemia in acute AlP poisoning with IV sodium bicarbonate theoretically improves the outcome,^84,106,125 and is reasonable as long as the sodium load can be tolerated.

In view of the role of oxidative stress in toxicity from metal phosphides or PH₃, antioxidants such as N-acetylcysteine (NAC), vitamin C, vitamin E, magnesium, melatonin, and methylene blue were investigated both in experimental and clinical studies.^38,50

The beneficial effects of NAC in animal studies are variable.^13,71 In a human study, NAC administration at a dose of 140 mg/kg IV infusion as a loading dose and 70 mg/kg IV infusion every 4 hours up to 17 doses significantly decreased the plasma malondialdehyde (MDA) concentration as a biomarker of lipid peroxidation, the duration of hospitalization, and rate of intubation. In that study, the mortality rate in NAC treatment and control groups were 36% and 60%, respectively.²⁰⁰ In another clinical study, NAC administration significantly decreased the mortality rate and increased the duration of survival in fatal cases in the treatment group.³ For these reasons, we recommend the utilization of NAC at these doses (Antidotes in Depth: A3).

Administration of vitamin E (alpha tocopherol) at a dose of 400 mg IM, every 12 hours for 72 hours in a human study, significantly decreased the plasma MDA concentration and the necessity for, and duration of, intubation and mechanical ventilation. This treatment also significantly decreased the mortality rate from 50% in control group to 15% in treatment group.⁸² Given these encouraging results and limited safety concerns, it is reasonable to administer vitamin E in cases of life-threating toxicity, if it is available.

In a limited study, the use of oral liothyronine with a dose of 50 mcg in the first 6 hours of poisoning as an adjuvant therapy in acute AlP poisoning was suggested to decrease lipid peroxidation and improve systolic blood pressure and arterial blood pH.⁷³ There is inadequate evidence to recommend routine utilization at this time.

The use of magnesium sulfate (MgSO₄) in metal phosphides or PH₃ poisoning remains controversial and unsubstantiated.^81,163,183 Because of the low risk of the use of MgSO₄ in metal phosphides or PH₃ poisoning and the recent study showing its usefulness,¹⁷⁷ it is reasonable to utilize MgSO₄ utilization at standard intravenous doses.⁸⁴ Dysrhythmias should be treated with standard antidysrhythmics.^{84,102,136,166}

The benefit of highdose insulin (HDI) treatment (Antidotes in Depth: A21) is suggested by preliminary investigations in that insulin promotes energy production from carbohydrates, restores calcium flux, and improves myocardial contractility.⁸⁵ There is inadequate evidence to routinely recommend this intervention; however, in cases of refractory shock, a trial of HDI is reasonable.

The use of an intraaortic balloon pump in circulatory failure due to acute AlP poisoning is reported.^{21,61,138,178} It is only recommended following failure of all other procedures.

Clinical studies showed the beneficial effects of venoarterial extracorporeal membrane oxygenation (VA-ECMO) with regard to improvement of short-term survival patients with acute AlP poisoning. If available, VA-ECMO is recommended in the management of a subset of acute AlP-poisoned patients with severe left ventricular dysfunction (LV ejection fraction ≤35%), refractory cardiogenic shock, and severe acidemia (pH ≤7) who do not respond to conventional treatment.^{61,86,139,144,145}

One study reported the beneficial effect of IV administration of lipid emulsion (20%) at a dose of 10 mL/hour in 2 cases with AlP poisoning.¹⁹ Given the lack of beneficial evidence for intravenous lipid emulsion (ILE) in oral overdoses, its complication rate, and its ability to interfere with ECMO, we recommend not to use ILE in this setting unless there are no other options in cardiac resuscitation available (Antidotes in Depth: A23). High-dose l-carnitine (1 g 3 times a day for 10 days) was given as an essential cofactor in fatty acid metabolism.⁶¹

Because the experimental and clinical evidence shows that both PH₃ and aluminum inhibit acetylcholinesterase,^{6,127,128,162} atropine and pralidoxime have theoretical roles in management.¹¹⁰ Further studies are recommended to confirm usefulness of oximes.¹⁴² Neither atropine nor oximes are routinely recommended at this time.

In another experimental study, the protective role of iron sucrose as an electron receiver was shown potentially be a competitor with mitochondrial respiratory chain complexes.¹⁸⁵ Once again these data are too preliminary to recommend the use of this approach.

Experimental data suggest that hyperbaric oxygenation (HBO) improves the survival time of poisoned rats, with no change in the mortality rate.¹⁶⁴ There is inadequate evidence to recommend the use of HBO for this toxin.

Hemodialysis is not very effective in removing PH₃^83,151 but is recommended in patients with acute kidney failure, severe metabolic acidemia, or fluid overload.^61,81

The sole recognized approach remains intensive care monitoring and supportive treatment.

METHYL BROMIDE

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 also used as an insecticide, fire extinguisher, and refrigerant, although its domestic use was banned in 1987. 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. It is termed a structural or commodity fumigant, which is a class term from the Environmental Protection Agency.

Historically, poisonings involving the general public were mainly associated with the methyl bromide used in fire extinguishers. Other poisoning involved unauthorized entry into buildings being fumigated with methyl bromide.^20,87,117

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,^28,32,69 but they are relatively uncommon in plant employees or residents living adjacent to agricultural fields where methyl bromide is applied.^32,36 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.⁶²

Methyl bromide has a threshold limit value–time weighted average (TLV-TWA) of 5 ppm and the IDLH concentration is 2,000 ppm. The Occupational Safety and Health Administration (OSHA) permissible exposure limit is 20 ppm.

Methyl bromide (CH₃Br) is a halogenated aliphatic hydrocarbon. It is a colorless gas at room temperature and standard pressure.³⁴ It is 3 times heavier than air. It is odorless except at high concentrations, when it has a burning taste and sweet, chloroformlike smell. Commercially, it is available as a liquefied gas. Some formulations also 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 is not 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.^20,36 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.¹¹⁹

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.^7,132,133 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.^20,75,192 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.^31,194 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 is sufficient to cause death.⁸⁷ Severe poisoning produces 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 rapidly progresses to bronchitis, pneumonitis, and ARDS.⁹¹ In contrast, following low concentration exposure, a characteristic delay of up to 48 hours in the onset of manifestations is expected. Headache, dizziness, abdominal pain, nausea, vomiting, chest pain, and difficulty breathing are the manifestations of mild to moderate exposure. Some individuals initially manifest irritant symptoms of the eye, nasopharynx, and oropharynx, which are misdiagnosed as influenza or another viral illness. Visual disturbances such as blurred or double vision are also reported.^39,74

The neurologic effects of methyl bromide poisoning are the most consequential and often occur without antecedent irritant effects. Initial CNS signs and symptoms that 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 findings progress rapidly in the first day or manifest over the next few days include ataxia, intention tremor, fasciculation, myoclonus, delirium, seizures, and coma.^14,34,56-58

Methyl bromide also causes severe irritation, erythema, corrosive skin injury, blisters, and vesicles predominantly in moist areas or pressure points such as groin, axilla and wrist.^92,218 Liver and kidney damage are also described.^20,87

Most patients who develop seizures or coma will not survive, and in those who survive, recovery typically takes months. Permanent sequelae such as neuropsychiatric impairment, ataxia, muscular weakness, irritability, blurred vision, myoclonus, and electroencephalographic (EEG) disturbances are frequent.^30,204

Diagnostic Testing

The standard laboratory evaluations such as CBC, serum electrolytes, blood urea nitrogen (BUN), creatinine, ammonia concentration, blood gases, urinalysis, hepatic enzymes, chest radiography, and ECG, should be obtained after an acute exposure.

Although a serum bromide concentration will help to 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 are reported to remain elevated for a week or more following an acute exposure.⁹⁵ Hemoglobin adducts are used as a biologic index for exposure to methyl bromide.¹⁰¹ Hemoglobin adducts have a life span of about 2 months, so workers who even have only intermittent exposure to methyl bromide benefit from testing.

The findings on magnetic resonance imaging following methyl bromide toxicity 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.⁷⁰

Treatment

The poisoned or exposed individual should be immediately removed from the area of exposure to fresh air. 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 when it is safe to perform. The clothing should be removed carefully, as methyl bromide adheres to clothing, including rubber and leather, and placed in plastic bags and disposed appropriately. The affected skin should be washed with soap and water. Decontamination includes irrigation of the eyes with copious amounts of 0.9% sodium chloride 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. 132).

Management is primarily general and supportive care, and often requires intensive care unit management of coma, seizures, ARDS, and 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. Pentobarbital, high-dose thiopental, and propofol are required in many cases.⁹⁵ All exposed patients should be monitored for a minimum of 24 to 48 hours to detect delayed effects, especially ARDS.

Although dimercaprol was used for the treatment of methyl bromide poisoning, its effectiveness is only reported in less severely affected patients⁸⁷ and there is inadequate evidence to support the use of dimercaprol. The use of NAC is not studied in controlled prospective trials, but its effectiveness is reported in mild to moderate poisonings.⁹⁵ For this reason and the benignity of NAC, we recommend the utilization of NAC at standard doses.

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 and neurologic injury has already occurred. Post hemodialysis, neurologic improvement is reported, but severe disabilities typically remain. Thus, there is inadequate evidence to support the use of hemodialysis.

DICHLOROPROPENE

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 solubilized in soybean oil.²⁰⁵

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.¹²⁶ The OSHA standard TLV-TWA for dermal exposure is 1 ppm.¹¹⁸

Toxicokinetics

Dichloropropene is rapidly absorbed by the oral, inhalational, and dermal routes. Oral exposure is theoretically possible through contaminated groundwater, but this is not reported in humans. Inhalation is the primary route of human exposure and dichloropropene is rapidly absorbed from the lungs.^29,207

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.¹⁸

The metabolism of dichloropropene is similar to that of other chlorinated hydrocarbon solvents such as carbon tetrachloride and chloroform (Chap. 105). In humans, dichloropropene is metabolized in liver via oxidation in a phase I biotransformation,^17,129,195 which is catalyzed by CYP2E1⁷⁷ and then glutathione-dependent biotransformation.^29,207,212 Toxicity is proposed to result from metabolism via an electrophilic epoxide intermediate.²⁰⁸ Most of the glutathione-conjugated form of dichloropropene is eliminated by the kidneys, and smaller amounts are eliminated in the feces.^53,96,205

Toxicodynamics

Human and animal health effects 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 is more than one mechanistic pathway in humans.

Glutathione depletion is documented in the rat model. The dose and route of dichloropene correlated with toxicity and outcome in rodent models. At 100 mg/kg in mice, hepatotoxicity occurred by the intraperitoneal route, but not after oral gavage. At 700 mg/kg administered by the intraperitoneal route, hepatic failure and death resulted.¹⁷ 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.¹⁹⁹

Clinical Manifestations

Signs and symptoms of acute oral or inhalational exposure include nausea, vomiting, bloody diarrhea, pancreatitis, hepatotoxicity, tachycardia and hypotension,⁹⁰ dyspnea,⁹⁷ ARDS,⁹⁰ CNS depression,¹²⁶ acute kidney injury (acute tubular necrosis),⁹⁰ and muscle pain and weakness.¹²⁶ Coagulopathy and thrombocytopenia, hyperglycemia, severe metabolic acidosis,⁹⁰ and intravascular fluid depletion secondary to hemorrhage are reported. Dermal manifestations include contact hypersensitivity,^87,205,206 erythema,¹²⁶ and profuse sweating.⁹⁰ Mucous membrane irritation including erythema, edema, and irritation of the eyes, ears, nose, and throat occurs.^126,205 Concentrations above 1,000 ppm cause lacrimation.² Hematologic malignancies including lymphoma and histiocytic lymphoma were reported after prolonged (6 years) dichloropropene exposure.¹²⁶

Radiographic abnormalities typically lag behind clinical signs. It may take up to 8 hours before abnormalities appear on chest radiography, even in symptomatic patients.⁹⁰

Weight loss, hyperemia and superficial ulcerations of the nasal mucosa, inflammation of the pharynx, bleeding from swollen gums,¹²⁶ hepatic aminotransferase elevations, and kidney function abnormalities²⁹ are reported after chronic exposure to dichloropropene.

Diagnostic Testing

Liver and kidney function should be monitored following acute poisoning.⁹⁰ No additional or specific tests are recommended beyond those needed for supportive care. Biomonitoring for exposure to dichloropropene is under development.²⁹ Hepatic gamma-glutamyl transpeptidase (GGT) 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.²⁹

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 professionals. Symptomatic and supportive care should be provided as for methyl bromide. Following ingestion, oral AC is reasonable, but there is no proven value. Orogastric lavage is also reasonable in a patient presenting shortly following ingestion. Exposed eyes should be irrigated with copious amounts of water or 0.9% sodium chloride solution for at least 15 minutes, and exposed skin should be similarly washed with soap.¹¹⁵

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.

SULFURYL FLUORIDE

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,^147,157 and Washington, a 5-year review of fumigant illness did not contain any reports of sulfuryl fluoride toxicity.³²

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.¹⁵⁴

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.¹⁶⁸ 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 is of major pathophysiologic consequence.¹⁵⁷ Fluoride complexes with calcium and magnesium, resulting in hypocalcemia and hypomagnesemia (Chap. 104).⁸⁸

Clinical Manifestations

Case reports of sulfuryl fluoride exposure describe acute and subacute clinical courses that share many similarities to methyl bromide poisoning. Initial manifestations, especially in limited exposures, include nausea, vomiting, diarrhea, abdominal pain, cough, and dyspnea. Irritation of mucosal surfaces produces salivation and nasopharyngitis, lacrimation, and conjunctival injection. Central nervous system manifestations include paresthesias, irritability, agitation, tetany, refractory seizures, and coma. Finally, fluoride toxicity results in profound shock, cardiac dysrhythmias, wide QRS complexes, prolongation of the QT interval, torsade de pointes, hyperkalemia, and ARDS (Chap. 104).^157,167

Memory and dexterity testing were abnormal in structural fumigation workers exposed to both methyl bromide and sulfuryl fluoride.³⁵

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 complex 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 should be expected (Antidotes in Depth: A32). Similar to the management of methyl bromide, intensive care is often required for seizures, dysrhythmias, bronchospasm, and ARDS. As the fluoride ion is excreted in the urine, fluid resuscitation is recommended to maintain a steady urine output.²⁰²

METHYL IODIDE

Iodomethane or methyl iodide is a monohalomethane and mainly used as a chemical reagent in the manufacturing of different pharmaceuticals and pesticides.^89,169 It is proposed as a fumigant to replace methyl bromide.

Human poisoning with methyl iodide is rare. Recently there are reports of dermal exposure with severe burns, respiratory insufficiency, and delayed neuropsychiatric sequel. Cerebellar and Parkinson findings followed by the development of cognitive impairment and the late appearance of psychiatric disturbances (personality change) are reported.^{89,99,122,150,169}

There is no antidote for the treatment of methyl iodide poisoning. Successful treatment requires early diagnosis and cessation of exposure. It is difficult to distinguish the neurotoxic syndromes due to methyl iodide poisoning from other neurodegenerative conditions, infectious processes, and psychiatric disorders, especially when there is a lag time between exposure and onset of clinical manifestations.¹²²

SUMMARY

• Exposure to fumigants follow inhalation, dermal exposure, or ingestion depending on the specific fumigant and the physical state.

• The fumigants are associated with multiorgan failure and, following acute exposure, adversely affect the cardiovascular, respiratory, 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.

• First-responder protection from inhalation is important to prevent poisoning for these health care workers.

Acknowledgment

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

REFERENCES

HISTORY, CLASSIFICATION, AND EPIDEMIOLOGY

Herbicides, defined as any chemical that regulates the growth of a plant, encompass a large number of xenobiotics of varying characteristics. Herbicides are used around the world for the destruction of plants in the home environment and also in agriculture in which weeds are particularly targeted. Poisoning follows acute (intentional or unintentional poisoning) or chronic (such as occupational) exposures. Depending on the herbicide and the characteristics of the exposure, this may lead to clinically significant poisoning, including death. This chapter focuses on the most widely used herbicides and also those associated with significant clinical toxicity. In particular, risk assessment and the management of patients with a history of acute herbicide poisoning are emphasized.

Prior to the 1940s, the main method of weed control and field clearance was manual labor, which was time consuming and expensive. A range of xenobiotics were tested, including metals and inorganic compounds; however, their efficacy was limited. The first herbicide marketed was 2,4-dichlorphenoxyacetic acid (2,4-D) during the 1940s, followed by other phenoxy acid compounds. Paraquat was marketed in the early 1960s, followed by dicamba later that decade. The development of new herbicides is an active area of research and new herbicides and formulations are frequently released into the market. This includes a number of novel structural compounds for which clinical toxicology data are unavailable. Hundreds of xenobiotics are classified as herbicides and a much larger number of commercial preparations are marketed. Some commercial preparations contain more than one herbicide to potentiate plant destruction. From another perspective, crops are being developed that are resistant to particular herbicides to maximize the selective destruction of weeds without reducing crop production.

Herbicides are the most widely sold pesticides in the world; in 2007 they accounted for approximately 40% of the total world pesticide market and 48% of the pesticide market in the United States. Home and garden domestic use accounts for 7% of the overall herbicide use in the United States, whereas the remainder is used in agriculture, government (eg, vegetation control on highways and railways), and industry. In each of the US market sectors, herbicides were 4 of the top 5 used pesticides in 2012, including glyphosate, atrazine, metolachlor-S, and 2,4-D.³³

Not all herbicide exposures are clinically significant. In developed countries, most acute herbicide exposures are unintentional and the majority of patients do not require admission to a hospital. The National Poisoning Database System (NPDS) of the American Association of Poison Control Centers (AAPCC) describes approximately 10,000 herbicide exposures each year. Over the last 12 years, there were approximately 5 deaths per year and 20 patients per year with clinical outcomes categorized as “major” that were attributed to herbicide poisoning (Chap. 130). Most deaths were due to paraquat and diquat, although recently glyphosate and phenoxy acid compounds are more commonly implicated. Cases of severe poisoning that required hospitalization usually followed intentional self-poisoning. Significant toxicity including death also occurs with unintentional (eg, storage of an herbicide in food or drink containers) or criminal exposures.

Classification

Hundreds of xenobiotics have herbicidal activity and they are subclassified by a number of methods. Most commonly they are categorized in terms of their spectrum of activity (selective or nonselective), chemical structure, mechanism of action (contact herbicides or hormone dysregulators), use (preemergence or postemergence), or their toxicity to rats such as the amount of that xenobiotic killing 50% of exposed animals (LD₅₀). Certain xenobiotics are classified as plant growth regulators rather than herbicides, but in this chapter all are considered to be herbicides.

Table 109–1 lists the extensive range of herbicides in current use.⁴⁹ By convention, they are subclassified according to their chemical class and their World Health Organization (WHO) hazard classification. Unfortunately, the utility of these (or any other) methods of classification to predict the hazard to humans with self-poisoning is not proven.

The WHO categorizes pesticides by their LD₅₀. This system does not consider morbidity or the effect of treatments. Further, the calculated LD₅₀ varies among studies in the same type of animal, and between different species. For example, in the case of paraquat, the LD₅₀ in rats, monkeys, and guinea pigs is reported as 125, 50, and 25 mg/kg, respectively.⁸³ It should be emphasized that the intended application of the WHO hazard classification was for the risk assessment following occupational exposures to operators using the product as intended. Furthermore, the LD₅₀ is determined by using the pure herbicide compound, whereas human poisoning follows exposure to proprietary formulations that also contain coformulants, and these often contribute to the overall toxicity. Preparations that decrease human toxicity without compromising herbicidal activity are also being developed, for example, paraquat containing lysine salicylate.

Herbicides within a single chemical class can manifest different clinical toxicity; for example, glyphosate is an organic phosphorus compound that does not inhibit acetylcholinesterase, which contrasts with insecticides of a similar structure. The mechanism of action of herbicides in plants usually differs from the mechanism of toxicity in humans; indeed, for some herbicides the mechanism of human toxicity is poorly described.

Contribution of Coformulations

Commercial herbicide formulations are identified by their active ingredients but they almost always contain coformulants that often contribute to clinical toxicity. Hydrocarbon-based solvents and surfactants improve the contact of the herbicide with the plant and enhance penetration. Coformulants are generally considered “inactive” or “inert” because they lack herbicidal activity; however, increasingly their contribution to the human toxicity of a formulation is being appreciated.

The most widely discussed example of a coformulant dominating the toxicity of an herbicide product is that of glyphosate-containing products, which is discussed below. Another example is imazapyr, which has an LD₅₀ in rats of 1,500 mg/kg intraperitoneally (IP) compared with 262 mg/kg IP when administered as the product Arsenal. This difference is attributed to the surfactant nonylphenol ethoxylate used in this product, which has an LD₅₀ of 75 mg/kg IP. In vitro studies with a number of formulations demonstrate increased cardiovascular toxicity compared with the technical herbicides.¹³ Similarly, coformulants increase the in vitro toxicity from phenoxyacetic acid derivatives and glufosinate.

Impurities generated during manufacture or storage of the herbicide formulation also contribute to toxicity. For example, phenolic by-products from the manufacture of phenoxyacetic acid herbicides are reported in commercial formulations. Some proprietary products contain a combination of herbicidal compounds that probably have additive effects, further complicating the risk assessment of an acute exposure.

Epidemiology

The incidence of poisoning with individual herbicides depends on their availability. Availability is associated with local marketing practices and is reflected in sales in the domestic sector. For example, paraquat poisonings are now comparatively rare in the United States (it remains the 23rd most commonly used pesticide in the United States³³), whereas the incidence of glyphosate poisoning has increased. Similarly, after paraquat was banned in Japan (late 1980s) and Korea (2012), there was an increase in the number of glufosinate poisonings.

Herbicide poisoning is a major issue in developing countries of the Asia-Pacific region where subsistence farming is common and herbicide use is relatively high. By contrast, the incidence of severe herbicide poisoning is less in developed countries because the population is concentrated in urban areas where access is limited to lower-toxicity herbicides that are sold in smaller volumes as diluted formulations intended for household use (Chaps. 110 and 136).

Regulatory Considerations

When properly used, most herbicide formulations have a low toxic potential for applicators because they are poorly absorbed across the skin and respiratory membranes. When inappropriately used, in particular when there is enteral (or rarely parenteral) exposure, toxicity is more pronounced.

The toxicity on herbicides varies among individual xenobiotics and many are intrinsically more toxic than medications when ingested with suicidal intent. Restrictions of the availability and formulation of toxic herbicides by regulatory authorities improve outcomes from herbicide poisoning. For example, in the context of self-poisoning, in Sri Lanka the replacement of highly toxic pesticides with less toxic compounds decreased the overall mortality⁹⁷ without altering agricultural outputs.⁷² Prospective cohort studies are useful for estimating the case fatality of individual herbicides in the context of intentional self-poisoning, particularly when encountered in the same clinical environment. For example, in Sri Lanka the following herbicide case fatalities are reported: fenoxaprop-P-ethyl, 0%;¹³² bispyribac, 1.8%;³⁰ glyphosate, 3.2%;¹⁰⁰ 4-chloro-2-methylphenoxyacetic acid (MCPA), 4.4%;⁹⁸ propanil, 3.1% to 10.7%;⁹⁹ and paraquat, 50% to 70%.¹²⁸ This information is of interest to regulatory authorities in their control of the marketing, sales, and formulation of herbicides.

Regulatory bodies must also evaluate other factors, including the cost and efficacy of herbicides and their fate in the environment. An ideal herbicide is one that is selective for the target plant and does not migrate far from the site of application. Selective targeting occurs when the herbicide is rapidly inactivated or binds strongly to soil components. For example, paraquat and glyphosate are inactivated when they contact soil, which is favorable because they remain in the region of application. By contrast, atrazine is more mobile, allowing it to leach into groundwater and migrate great distances. While the concentration of atrazine at distant sites is low, there is concern that it has the potential to alter the growth and development of nontarget plants and animals.¹⁰⁴

GENERAL COMMENTS FOR THE MANAGEMENT OF ACUTE HERBICIDE POISONING

Diagnosis

Herbicide poisoning is diagnosed following a specific history or other evidence of exposure (such as an empty or partially used bottle) and associated clinical symptoms. A detailed history, including the type of herbicide, amount, time since poisoning, and symptoms, is essential. It is necessary to determine the actual brand in many cases because of variability in salts, concentrations, and coformulants. Furthermore, in some cases it is also necessary to determine the specific type of a brand; for example, the product called Roundup contains glyphosate but it is sold in different formulations worldwide within market sectors.

Depending on local laboratory resources, the diagnosis is confirmed using a specific assay, such as paraquat and glufosinate, but these are not usually available in a clinically meaningful time frame.

The low incidence of herbicide poisoning in some regions often means that it is not considered in the differential diagnosis when a history is not available. Therefore, a high index of suspicion is necessary and clinicians should be familiar with the features of herbicide poisoning.

The pathophysiology of acute herbicide poisoning, and therefore the clinical manifestations, vary between individual compounds. Some herbicides induce multisystem toxicity due to interactions with a number of physiologic systems. The mechanism of toxicity and pathophysiological changes in humans are discussed below for each herbicide individually.

Initial Management

An accurate risk assessment is necessary for the proper triage and subsequent management of patients with acute herbicide poisoning. Risk assessment involves an understanding of the dose ingested, time since ingestion, clinical features, patient factors, and availability of medical facilities. All intentional exposures should be assumed significant. If a patient presents to a facility that is unable to provide sufficient medical and nursing care or does not have ready access to necessary antidotes, then arrangements should be made to rapidly and safely transport the patient to an appropriate health care facility.

For many herbicides, the initial management of an acute poisoning follows standard guidelines. All patients should receive prompt resuscitation emphasizing the airway, breathing, and circulation. Gastrointestinal toxicity, such as nausea, vomiting, and diarrhea, is common, leading to salt and water depletion that requires the administration of antiemetics and intravenous fluids.

Gastrointestinal decontamination decreases absorption of the herbicide from the gut, reducing systemic exposure. We generally recommend not to perform gastric lavage in acute poisoning because patients usually present too late or have self-decontaminated from vomiting and diarrhea. However, gastric lavage is reasonable for patients presenting shortly after an ingestion of a liquid formulation for which treatment options are limited. Ingestion of a corrosive product is a relative contraindication. Depending on the procedure used, this treatment is potentially harmful and should only be conducted by an experienced clinician when the airway is protected. Oral activated charcoal is recommended if the patient presents within 1 to 2 hours of ingestion of an herbicide known to cause significant poisoning. In the case of herbicides with prolonged absorption (eg, propanil, MCPA), later administration of activated charcoal is reasonable. Specific antidotes are available for only a few herbicides, which reflect their ill-defined mechanisms of toxicity. Extracorporeal techniques, including hemoperfusion and hemodialysis, decrease the systemic exposure by increasing the rate of elimination. The role of these treatments is discussed below for each pesticide.

Dermal decontamination is recommended if the patient has incurred cutaneous exposure. The patient should be washed with soap and water, and contaminated clothes, shoes, and leather materials should be removed and safely discarded.

Laboratory investigations are useful for determining the evolution of organ toxicity, including serial measurement of liver and kidney function, electrolytes, and acid–base status. Abnormalities should be corrected when possible. Respiratory distress and hypoxia with focal respiratory crackles soon after presentation are likely to result from aspiration pneumonitis, which should be confirmed on chest radiography.

We recommend a minimum of 6 hours of observation for patients with a history of acute ingestion, unless otherwise stated below. For patients with a history of intentional ingestion and gastrointestinal symptoms, we recommend at least 24 hours of observation depending on the herbicide, given that clinical toxicity will progress or be delayed in some cases.

Occupational and Secondary Exposures (Including Nosocomial Poisoning)

Concern has been expressed regarding the risk of nosocomial poisoning to staff and family members who are exposed to patients with acute herbicide poisoning. However, the risk to health care staff providing clinical care is low compared with other occupations, such as agricultural workers in whom acute toxicity is rarely observed. Universal precautions using nitrile gloves are recommended to provide sufficient protection for staff members.

Few cases of secondary poisoning, if any, are confirmed, and effects in these potentially exposed individuals were generally mild, such as nausea, dizziness, weakness, and headaches, probably relating to inhalation of the hydrocarbon solvent. These symptoms usually resolve after exposure to fresh air. Biomarkers for monitoring occupational exposures, as in the case of pesticide applicators, are outside the scope of this chapter.

Amide Compounds, Particularly Anilide Derivatives

Anilide compounds are the most widely used amide herbicides, of which propanil (3′4′-dichloropropionanilide {DCPA}), alachlor (2-chloro-2′,6′-diethyl-N-methoxymethylacetanilide), and butachlor (N-butoxymethyl-2-chloro-2′,6′-diethylacetanilide) are particularly common. Other amide herbicides and available toxicity data are listed in Table 109–1. In 2012, acetochlor, propanil, metolachlor, and metolachlor-S were among the most commonly used herbicides in the United States.³³ Anilide compounds are selective herbicides used mostly in rice cultivation in many parts of the world. Acute self-poisoning is reported particularly in Asia where subsistence farming is common. Toxicity data are limited for most compounds, except for propanil, butachlor, metachlor, and alachlor. The case fatality of propanil exceeds 10%, compared with a combined mortality of less than 3% for butachlor, metachlor, and alachlor in case series from Asia.

Pharmacology

Most of the clinical manifestations of propanil poisoning are mediated by its metabolites. 3,4-Dichlorophenylhydroxylamine is the most toxic metabolite and it directly induces methemoglobinemia and hemolysis in a dose-related manner. 3,4-Dichlorophenylhydroxylamine is cooxidized with oxyhemoglobin (Fe²⁺) in erythrocytes to produce methemoglobin (Fe³⁺).

However, toxicity is not solely due to methemoglobinemia. Isolated methemoglobin levels exceeding 50% are usually required for fatal outcomes, but fatal propanil poisoning is reported with methemoglobin levels as low as 40%.^{17,86,129,130} Therefore, other toxic mechanisms must contribute to clinical outcomes. Rats show signs of toxicity despite inhibition of the hydrolytic enzymes that metabolize propanil (Fig. 109–1) and in the absence of methemoglobinemia, supporting direct toxicity from propanil itself.¹¹⁵ Dose-dependent kidney and liver cytotoxicity are noted in mice with chronic dosing. Coformulants may also contribute.

The hydroxylamine metabolite depletes glutathione, although this is not consistently reported. Other possible toxicities from the metabolism of propanil include nephrotoxicity, lipid peroxidation, myelotoxicity, and immune dysfunction; the significance of these toxicities is poorly defined.

Para-hydroxylated aniline and other compounds are products of alachlor, butachlor, and acetochlor (2-chloro-N-ethoxymethyl-6′-ethylacet-o-toluidide) metabolism and reduces glutathione and induce hepatotoxicity or cancer, particularly in rats.

Pharmacokinetics and Toxicokinetics

Absorption is rapid in animals, with a peak serum concentration expected one hour postingestion. The volume of distribution (V_d) of propanil is not defined, but is expected to be large given that both propanil and 3,4-dichloroaniline are highly lipid soluble. This V_d is consistent with data in the channel catfish in which uptake and distribution of propanil were noted to be extensive.

Anilide compounds undergo sequential metabolic reactions that produce toxic xenobiotics (Fig. 109–1). The first reaction is hydrolysis of the anilide to an aniline compound. This reaction is catalyzed by an esterase known as arylamidase, which has a high capacity in humans compared to rats (K_m = 473 µM and 271 µM, respectively) and sometimes by the cytochrome P450 system. Examples include the bioconversion of propanil to 3,4-dichloroaniline and also conversion of alachlor and butachlor to 2,6-diethylaniline. These aniline intermediates are then oxidized by cytochrome P450, although the responsible enzyme is not defined. N-Hydroxylation of 3,4-dichloroaniline produces the hydroxylamine compound that induces hemolysis and methemoglobinemia, which are the most obvious manifestations of propanil poisoning.^76,77,115

These bioactivation reactions appear to be fairly rapid, whereas 3,4-dichloroaniline and methemoglobin are formed within 2 to 3 hours of parenteral administration of propanil to animals. The hydroxylation of 3,4-dichloroaniline is saturable (K_m = 120 µM in rats) and slower than arylamidase, leading to a prolonged elimination of 3,4-dichloroaniline following large exposures. In the case of alachlor, butachlor, and acetochlor, parahydroxylated aniline compounds are produced, which appear to be carcinogens in rats.

These metabolic reactions are similar to those of dapsone, which are well characterized: the severity of methemoglobinemia relates to the amount of the dapsone hydroxylamine, metabolite, which varies with dose, and cytochrome P450 activity (Chap. 124).

Propanil displays nonlinear toxicokinetics in humans with prolonged absorption continuing for approximately 10 hours following ingestion. Bioconversion to 3,4-dichloroaniline occurs largely within 6 hours, although it is particularly variable, which reflects interindividual differences in esterase activity, dose, or coexposure to cholinesterase inhibitors.⁹⁹ The median apparent elimination half-life of propanil is 3.2 hours compared with 3,4-dichloroaniline, which has a highly variable elimination profile. In general, the concentration of 3,4-dichloroaniline exceeds that of propanil and remains elevated for a longer period.⁹⁹ In a case of coingestion of carbaryl, the peak 3,4-dichloroaniline concentration was observed at 24 hours,⁴² whereas in a fatal case the concentration of 3,4-dichloroaniline continued to increase until at least 30 hours postingestion.⁹⁹ By 36 hours postingestion, the concentration of 3,4-dichloroaniline is low in survivors, so clinical toxicity is unlikely to increase beyond this time.⁹⁹

Pathophysiology

The predominant clinical manifestation in acute poisoning is methemoglobinemia. Methemoglobin is unable to bind and transport oxygen, inducing a relative hypoxia at the cellular level despite adequate dissolved arterial oxygen content. This leads to end-organ dysfunction, including central nervous system depression, hypotension, and acidemia. Because the plasma concentration of 3,4-dichloroaniline remains elevated, the potential production of methemoglobin persists for a protracted period of time.^42,86,129 Sedation due to the direct effect of propanil or a hydrocarbon coformulant solvent causes hypoventilation, which contributes to cellular hypoxia. Failure to correct these abnormalities may lead to irreversible injury and death.

Clinical Manifestations

Methemoglobinemia, hemolysis and anemia, coma, and death are reported following acute propanil poisoning. These occur in the clinical context of cyanosis, acidemia, and progressive end-organ dysfunction. A case fatality as high as 10.7% is reported and the median time to death was 36 hours. Patients who die tend to be older with a depressed Glasgow Coma Scale score and elevated concentration of propanil. Nausea, vomiting, diarrhea, tachycardia, dizziness, and confusion are also reported in patients who do not develop severe poisoning.⁹⁹ However, with earlier recognition and improved use of methylene blue and a color chart for categorizing severity of methemoglobinemia, mortality decreased to 3.1%.

Alachlor, metachlor, and butachlor are less toxic than propanil, with a case fatality less than 3% with self-poisoning.^71,112 The manifestations of acute poisoning are usually mild, including gastrointestinal symptoms, agitation, dyspnea, and abnormal liver enzymes.^71,112 Major symptoms include seizures, rhabdomyolysis, acidemia, kidney failure, and cardiac dysrhythmias; hypotension and coma preceded death.^71,112 Methemoglobinemia was not reported in these studies. Hepatic dysfunction was reported following dermal occupational exposure to butachlor.

Cyanosis was reported following acute ingestion of mefenacet (2-benzothiazol-2-yloxy-N-methylacetanilide) and imazosulfuron (1-{2-chloroimidazo-(1,2-a) pyridin-3-ylsulfonyl}-3-{4,6-dimethoxypyrimidin-2-yl}urea) in the context of normal cooximetry. This was attributed to formation of a green pigment (green-colored urine was also reported), and no other symptoms of toxicity were observed.¹¹⁴

Acute metolachlor (2-chloro-N-{6-ethyl-o-tolyl}-N-{(1RS)-2-methoxy-1-methylethyl}acetamide) poisoning in goats induced predominantly neuromuscular symptoms, including tremors, ataxia, and myoclonus, which progressed rapidly to death. Kidney and hepatocellular toxicity were also noted. Acute acetochlor exposures in rats induced methemoglobinemia and hepatocellular toxicity.

Diagnostic Testing

Patients with a history of propanil poisoning should be investigated for the presence of methemoglobinemia (Chap. 124). In the absence of co-oximetry, simple color charts can be used to support the diagnosis and severity of methemoglobinemia and to direct the use of antidotes at the bedside.

While the concentrations of propanil and 3,4-dichloroaniline reflect clinical outcomes, this relationship is less marked for 3,4-dichloroaniline during the first 6 hours, which probably relates to the time for bioconversion from propanil.⁹⁹ However, propanil and 3,4-dichloroaniline assays are not commercially available and this observation was not validated. Further, the relationship between concentration and outcomes may depend on patient comorbidities.

Management

The minimum toxic dose has not been determined and the potential for severe poisoning and death is high, so all patients with amide herbicide ingestions should be treated as significant and monitored for a minimum of 12 hours. Patients with symptomatic ingestions should be treated cautiously, including continuous monitoring for 24 to 48 hours, preferably in an intensive care unit.

Routine clinical observations are sufficient to detect signs of poisoning, in particular sedation and cyanosis, which are noted early postingestion. The time to death is usually greater than 24 hours so there is an opportunity to initiate treatment. There are no controlled clinical or laboratory data available on the effect of any specific treatment in acute symptomatic propanil poisoning, so management is largely focused on reversal of methemoglobinemia and supportive care.

Resuscitation and Supportive Care

Prompt resuscitation and close observation are required in all patients. Patients should be monitored clinically including pulse oximetry, and receive supportive care including supplemental oxygen, intravenous fluids, and ventilatory and hemodynamic support as required. In the absence of cooximetry analysis, significant methemoglobinemia should be suspected when cyanosis does not correct with high-flow oxygen and ventilatory support. Bedside visual assessment, using blood added to absorbent paper, is an accurate method to quantify the degree of methemoglobinemia.¹¹³ Euglycemia should be ensured since adequate glucose concentrations are required for reversal of methemoglobin. Hemoglobin concentrations should be monitored to detect hemolysis, and folate supplementation is recommended during the recovery phase if anemia is significant.

Gastrointestinal Decontamination

Toxicokinetic studies of propanil demonstrate a prolonged absorption phase, so it is reasonable to administer activated charcoal to the patient a number of hours postingestion.

Extracorporeal Removal

Data are extremely limited and based on a single report it does not have a role in routine care. A report of combined hemodialysis and hemoperfusion noted a propanil elimination half-life of one hour,⁸⁶ but similar half-lives are reported in patients who have not received this treatment.⁹⁹ Exchange transfusion has the potential to decrease the concentration of propanil and free hemoglobin, while replacing reduced hemoglobin and hemolyzed erythrocytes. Exchange transfusion may be particularly useful in the treatment of patients who also have glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, the function of transfused erythrocytes is temporarily impaired posttransfusion because of depletion of 2,3-bisphosphoglycerate and G6PD during storage. Further, transfusion reactions such as acute respiratory distress syndrome (ARDS) are a concern, particularly when oxygenation is already impaired. In the absence of controlled studies, the role of such treatments in the routine management of acute propanil poisoning is poorly defined and cannot be recommended at this time (Chap. 6).

Antidotes

Methylene blue (Antidotes in Depth: A43) is the first-line treatment for methemoglobinemia. Methylene blue has a half-life of 5 hours, which is commonly shorter than that of 3,4-dichloroaniline, so rebound poisoning (ie, an increase in methemoglobin following an initial recovery postadministration of methylene blue) is anticipated and has been observed with a bolus regimen. This is prevented by administration of methylene blue as a constant infusion.

Other potential treatments for methemoglobinemia from propanil include toluidine blue, N-acetylcysteine, ascorbic acid, and cimetidine, but no clinical studies have assessed the role of these potential antidotes in the management of propanil poisoning.

BIPYRIDYL COMPOUNDS, PARAQUAT AND DIQUAT

Bipyridyl compounds are nonselective contact herbicides. The most widely used is paraquat (1,1′-dimethyl-4,4′-bipyridinium), but diquat (1,1′-ethylene-2,2′-bipyridyldiylium) is also commonly used (Fig. 109–2). Paraquat is one of the most toxic pesticides available. Ingestion of as little as 10 to 20 mL of the 20% wt/vol solution is sufficient to cause death. Overall, the mortality rate varies between 50% and 90%; however, in cases of intentional self-poisoning with concentrated formulations, mortality approaches 100%. An increasing number of countries are banning the sale of paraquat in view of its high toxicity. Diquat is less toxic than paraquat, so it is frequently coformulated with paraquat (allowing a lower concentration of paraquat) or used as an alternative in countries where paraquat is severely restricted. Nevertheless, deaths are still reported from intentional and unintentional diquat poisoning in the United States. Because more data are available on paraquat than diquat, much of the following discussion and information relates particularly to paraquat.

Pharmacology

Paraquat and diquat formulations are highly irritating and often corrosive, causing direct injury. They induce intracellular toxicity by the generation of reactive oxygen species that nonspecifically damage the lipid membrane of cells, inducing cellular injury and death. Once paraquat enters the intracellular space it is oxidized to the paraquat radical. This radical is subsequently reduced by diaphorase in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) to re-form the parent paraquat compound and superoxide radical, a reactive oxygen species. This process is known as redox cycling (Fig. 109–3). The superoxide radical is susceptible to further reactions by other intracellular processes, leading to formation of other reactive oxygen species, including hydroxyl radicals and peroxynitrite. Reactive oxygen species are potent cytotoxics. Paraquat redox cycling continues if NADPH and oxygen are available. Depletion of NADPH prevents recycling of glutathione and interferes with other intracellular processes, including energy production and active transporters, exacerbating toxicity. Intracellular protective mechanisms, such as glutathione, superoxide dismutase, and catalase, are overwhelmed or depleted following large exposures. Taken together, these cytotoxic reactions induce cellular necrosis, which is followed by an influx of neutrophils and macrophages. The reactions contribute to the inflammatory response and promote fibrosis and destruction of normal tissue architecture over a number of days.^2,18

Supplemental oxygen probably increases the generation of reactive oxygen species.

Pharmacokinetics and Toxicokinetics

Absorption is limited following dermal exposures, although prolonged exposures (at least several hours) to concentrated formulations degrades the epithelial barrier, allowing some systemic absorption. Absorption across the respiratory epithelium is limited.

The oral bioavailability of paraquat in humans is estimated to be less than 5%,¹⁶ yet an oral exposure of as little as 10 mL of the 20% wt/vol formulation is sufficient for significant poisoning to occur. Absorption is rapid and the peak concentration occurs within one hour. The peak parquat plasma concentration correlates with the amount ingested. Paraquat was reformulated with an emetic along with an alginate (Gramoxone Inteon) that formed a gelatinous mixture on contact with gastric acid, limiting release of the paraquat into the stomach. This formulation reduced paraquat absorption in animals³⁷ and initially appeared to improve outcomes from self-poisoning in humans (mortality of 64% compared with 74% with the standard preparation),¹²⁶ but this observation was not sustained.¹²⁸

Paraquat binds minimally to plasma proteins. Paraquat and diquat rapidly distribute to all tissues and then redistribute back to the central circulation.⁸⁴ In humans, the distribution half-life is approximately 5 hours. Paraquat is taken up by alveolar cells through an active energy-dependent polyamine transporter. Paraquat accumulates in alveolar cells, peaking at around 6 hours postingestion in patients with normal kidney function, but later in the context of kidney impairment.⁵ Paraquat slowly redistributes from the lungs into the systemic circulation as the plasma concentration falls. By contrast, diquat uptake occurs to a limited extent.

Paraquat and diquat are not metabolized. Elimination is primarily renal with more than 90% of a dose being excreted within the first 24 hours of poisoning if kidney function is maintained.⁴⁵ Systemic clearance initially exceeds that of GFR because of active secretion.¹² Impaired kidney function commonly occurs with paraquat and diquat poisoning, particularly beyond 24 to 48 hours postingestion, which decreases excretion and potentiates poisoning. Elimination is prolonged in this setting with a terminal half-life of around 80 hours in humans.⁴⁵ Paraquat is detected in the urine of surviving patients beyond 30 days despite plasma concentrations being quite low 48 hours postingestion.³

Pathophysiology

Paraquat and diquat induce nonspecific cellular necrosis. Lung and kidney injuries are prominent in acute paraquat poisoning because of the high concentrations found in these cells.

Acute pneumonitis and hemorrhage, followed by ongoing inflammation and progressive pulmonary fibrosis, reduces oxygen diffusion and induces dyspnea and hypoxia, which interferes with normal cellular function.²²

Paraquat induces acute tubular necrosis due to direct toxicity to the proximal tubule in particular, and to a lesser degree distal structures. Other factors contributing to the development of acute kidney injury include hypoperfusion from hypovolemia and/or hypotension and direct glomerular injury. Varying degrees of oliguria, proteinuria, hematuria, and glycosuria are reported.¹² Acute kidney injury interferes with normal fluid and electrolyte homeostasis, as well as interfering with paraquat elimination, which promotes systemic toxicity.

Necrosis of the gastrointestinal tract limits absorption and causes fluid shifts that contribute to hypotension induced by direct vascular toxicity. Hypotension impairs tissue perfusion and if uncorrected progresses to irreversible shock. Failure to correct these abnormalities leads to irreversible organ injury and death.

Clinical Manifestations

Topical exposures induce painful irritation to the eyes (including formation of a conjunctival pseudomembrane) and skin, progressing to ulceration or desquamation depending on the concentration of the solution, duration of exposure, and adequacy of decontamination. Intravenous administration induces severe poisoning from small exposures.

Most ingestions of bipyridyl compounds induce poisoning, in which ingestion of as little as 5 mL of paraquat 20% wt/vol causes death in more than 50% of cases. Outcomes are more favorable in pediatric patients because of the higher proportion with unintentional poisoning. Gastrointestinal toxicity occurs early, including nausea, vomiting, and abdominal and oral pain. Diarrhea, ileus, and pancreatitis are also reported. Necrosis of mucous membranes, occasionally referred to as pseudodiphtheria,¹¹⁷ and ulceration are prominent findings that occur within 12 hours. Oromucosal injury without systemic features is observed following brief oral exposures without swallowing. Dysphagia and odynophagia follow larger exposures and progress to esophageal rupture, pneumomediastinum and mediastinitis, subcutaneous emphysema, and pneumothorax, which are usually preterminal events. Death is more likely in those patients who experience a peripheral burning sensation.²⁹

Respiratory symptoms are prominent in patients with paraquat poisoning, including acute respiratory distress syndrome manifesting as dyspnea, hypoxia, and increased work of breathing. Ingestions of greater than 50 mL of 20% wt/vol formulation causes multiorgan dysfunction with rapid onset of death within days of ingestion in most patients. Features include hypotension, acute kidney and liver injury, severe diarrhea, and hemolytic anemia.

By contrast, ARDS is less marked with diquat ingestion or following smaller exposures of paraquat (<15–20 mL of 20% wt/vol formulations). In the case of paraquat, the acute respiratory impairment is often followed by progressive pulmonary fibrosis and death weeks or months postingestion. Varying degrees of acute kidney injury and hepatic dysfunction occur.^6,48 Acute kidney injury peaks around 5 days postingestion and resolves within 3 weeks in survivors.⁵⁴ Paraquat-induced pulmonary injury is reported to resolve to near-normal function over months to years in survivors.⁶⁶

Diquat does not concentrate in the pneumocytes as readily as paraquat. Therefore, if the patient survives the multiorgan dysfunction, pulmonary fibrosis is less likely to occur.¹³¹ Seizures are reported with diquat poisoning and uncommonly with paraquat.

Ingestion of the adjuvant for Gramoxone Inteon (20% methanol, 20% sodium lignosulfonate, 10% alkylaryl polyoxyethylene ether) induces minor gastrointestinal adverse effects, an elevated serum osmolar gap, and metabolic acidosis with hyperlactatemia, but outcomes are favorable.⁸⁰

Diagnostic Testing

Paraquat poisoning is diagnosed when there is a history of exposure and the recognized clinical features, so a high index of clinical suspicion is required. Differential diagnoses include other caustic exposures, sepsis, or other cellular poisons such as phosphine, colchicine, or iron.

The presence of a bipyridyl compound in blood confirms exposure but availability of these assays is increasingly limited. The urinary dithionite test is a simple and quick method for confirming (or excluding) paraquat and diquat poisoning. Various methods are reported, including the addition of 1 g of sodium bicarbonate and 1 g of sodium dithionite, or 1 to 2 mL of 1% sodium dithionite in 1 to 2 M sodium hydroxide, to 10 mL of urine. A color change (blue for paraquat and green for diquat) confirms ingestion—the darker the color, the higher the concentration.^3,58,103 If the test is negative on urine beyond 6 hours after ingestion, a large exposure is unlikely, but repeat testing should be conducted over 24 hours. When the dithionite test is conducted on plasma (eg, add 200 µL of 1% sodium dithionite in 2 M sodium hydroxide to 2 mL plasma from the patient), a positive result is specific for death, but a negative test does not exclude severe poisoning or death.⁵⁸

Given that outcomes from paraquat poisoning are generally poor, diagnostic tests help differentiate patients who are likely to survive compared to those in whom death is almost certain. The dose of paraquat is a well-established predictor of death, although this information often is not accurately known at the time of admission. Investigations in patients with acute paraquat poisoning have attempted to determine the severity of poisoning and better define prognosis. Unfortunately, few are validated so their predictive ability is unconfirmed. A range of prognostic tests has been reviewed²⁴ and a selection of these are discussed below.

Quantitative analysis of the concentration of paraquat in plasma is useful for prognostication, and a number of similar nomograms have been developed to assist with this process (eg, Fig. 109–4). The paraquat concentration must be interpreted relative to the time since ingestion, and each method performs similarly.¹¹⁰ The Severity Index of Paraquat Poisoning (SIPP) is also calculated with this information, by multiplying the plasma concentration (mg/L) by the time since ingestion (hours). Here, SIPP less than 10 predicts survival, SIPP 10 to 50 predicts death from lung fibrosis, and SIPP more than 50 predicts death from circulatory failure.¹⁰⁷ Determination of the concentration of paraquat in the urine of exposed patients also predicts outcomes. Barriers to the use of these methods include the limited availability of quantitative paraquat assays (leading to a long turnaround time) and the accuracy of the time of ingestion.

Other methods for predicting outcomes from paraquat poisoning have used combinations of simple laboratory tests, including blood gas analysis, complete blood count, electrolytes, uric acid, pancreatitis, kidney function, and liver function tests.²⁴ Various specific changes are proposed to predict death (eg, metabolic acidosis with an elevated lactate concentration) and increasingly complicated algorithms are being developed, but few are validated. In general, any abnormal result raises the suspicion of a significant poisoning and serial testing is warranted.

An elevated admission creatinine concentration or albuminuria predicts death but is neither sensitive nor specific, although the higher the creatinine concentration, the higher the risk of death.^31,54,58,102

The rate of increase in creatinine concentration is a simple and practical test to predict prognosis. An increase less than 0.03 mg/dL/h (3 µmol/L/h) over 5 hours predicts survival,⁹⁵ or greater than 0.05 mg/dL/h (4.3 µmol/L/h) over 12 hours (sensitivity 100%, specificity 85%, likelihood ratio 7) predicts death.¹⁰² A similar relationship was noted for cystatin C, in which a rate of increase in cystatin C greater than 0.009 mg/L/h over 6 hours (sensitivity 100%, specificity 91%, likelihood ratio 11) predicted death.¹⁰² This method of prognostication is advantageous because it is determined irrespective of the time of poisoning. Paraquat and diquat interfere with creatinine assays using the Jaffe method, but this is mostly an issue with concentrations exceeding 100 mg/L, which are rarely observed and would be associated with severe clinical toxicity.⁹² Other biomarkers of kidney function have been explored but their role in clinical management is not confirmed, nor did they improve on existing methods.

Computed tomography provides prognostic information based on the proportion of lung with ground-glass opacification. For example, ground-glass opacities in 11% to 12% of lung within 4 to 6 days postingestion predicted death in two studies, but in another less than 20% predicted survival and greater than 40% predicted death. Progression of consolidation, fibrosis, and pleural effusion over 2 to 3 days are also strong indicators of poor prognosis.

Management

Because death follows ingestion of as little as 5 mL of the 20% wt/vol paraquat, all exposures should be treated as potentially life threatening. Patients suspected of ingesting paraquat should be observed in hospital for at least 6 hours postingestion or until a urinary dithionite test is conducted.

Many medical interventions are proposed for the treatment of patients with acute paraquat poisoning but data supporting their efficacy are lacking. Dose–response studies for most of these interventions are also unavailable, and although cell-based and animal studies provide insights into the dose–response, this does not readily translate to human therapeutics.

Given the high likelihood of death from acute paraquat poisoning, many publications report concurrent administration of a number of therapies in the hope of a benefit, including activated charcoal, acetylcysteine, vitamins C and E, immunosuppressants, and hemodialysis and/or hemoperfusion. Xuebijing (a preparation made from 5 traditional Chinese medicines reported to have antiinflammatory properties) and ulinastatin are used in some hospitals in China and supported by animal studies. The literature is complicated by case reports describing survival in patients who were administered one or a combination of these and other therapies, despite apparently poor prognosis. Various other treatments have been studied in animals including pirfenidone, complement inhibition, sivelestat, bosentan, p-sulfonatocalix-[4]arene, dimercaptopropane sulfonate, ambroxol, sucralfate, bone marrow mesenchymal stem cell transplantation and selenium, but human data are lacking. We have no evidence to recommend treatment with any of these regimens.

The choice of which interventions should be administered to a patient is made on a case-by-case basis by the treating physician in consultation with relevant resources. In the context of the anticipated prognosis (see above), detailed discussion with the patient and relatives early in the presentation is recommended to determine their preference for treatment. In general, a comprehensive treatment regimen is reasonable in patients who present very early (within 2 hours of poisoning) or those with a faintly positive dithionite urinary test. Here, treatments that reduce the exposure to paraquat by either reducing absorption or increasing clearance must be initiated promptly. In contrast, active treatment is not recommended in patients in whom this test is strongly positive, or those with hemodynamic compromise or evolving lung injury. Instead, palliation should be the priority, including supplemental oxygen for hypoxia and morphine for dyspnea and oropharyngeal and abdominal pain.

Serial pulse oximetry measurements and chest radiographs will demonstrate onset and progression of lung injury. Lung transplantation has been tried in patients with delayed respiratory failure, but it was largely unsuccessful because of the prolonged elimination half-life of paraquat.⁶ However, successful lung transplantation was reported when performed 56 days postpoisoning after 12 days of extracorporeal membrane oxygenation therapy. Patients developing acute kidney injury should receive hemodialysis or hemofiltration per usual guidelines if active treatment is to be pursued, and these treatments also enhance elimination of herbicide if commenced promptly (see below).

Resuscitation and Supportive Care

All patients should receive prompt routine resuscitation and close observation. Supplemental oxygen should only be administered to patients for palliation when there is confirmed hypoxia and/or prognosis is extremely poor. Although controlled hypoxia does not prevent the development of pulmonary injury, unnecessary supplemental oxygen theoretically hastens the progression of injury. In patients with established lung injury, ventilatory support is reasonable to improve oxygenation and reduce dyspnea.

Intravenous fluids should be administered to patients who are volume depleted from reduced intake, diarrhea, or third-space shifts, as this reduces the severity of acute kidney injury and promotes renal clearance of paraquat. Care is required with volume resuscitation in the context of acute kidney injury to prevent fluid overload. Electrolyte abnormalities should be corrected as required.

Ongoing management includes regular clinical observations including urine output quantification, daily routine laboratory tests (or more frequently if clinically indicated) in patients receiving active treatment and supportive care. Analgesia for oral and abdominal pain should be administered as required, including intravenous opioids, such as morphine, and possibly topical anesthetics, such as lidocaine. Plain radiographs or a CT of the chest provide information on lung and esophageal injury, which may be prognostic as noted above.

Gastrointestinal Decontamination

Activated charcoal is recommended for all patients presumed to have ingested paraquat as soon as possible, within 2 hours of exposure. Paraquat is coformulated with an emetic so a degree of self-decontamination frequently occurs by the time of presentation to hospital. Fuller’s Earth and activated charcoal decrease absorption of paraquat to a similar extent but Fuller’s Earth is in limited supply.⁴ Because paraquat is rapidly absorbed, decontamination must be commenced within a few hours of ingestion to be useful. Gastric lavage is not shown to improve outcomes overall.¹²⁷

Extracorporeal Removal

Extracorporeal techniques, in particular hemoperfusion and hemodialysis, increase the elimination of paraquat, which decreases the systemic exposure, and potentially toxicity. Although published data regarding the efficacy of these treatments are contradictory or limited, extracorporeal treatments are recommended in cases of large exposures if the treatment can be initiated within a few hours of ingestion.

Paraquat clearance by hemoperfusion is similar to endogenous clearance but exceeds it when there is impaired kidney function.^53,67 Hemoperfusion is more efficient than hemodialysis, and elimination is maximized when treatment is initiated within the first couple of hours because the plasma concentration is high.³⁹ Further, given that paraquat rapidly distributes from the circulation, prompt treatment is necessary to limit the uptake into pulmonary and other tissues.⁸⁹

Experimentally, hemoperfusion reduces mortality in dogs only when it is commenced within a few hours of poisoning, and repeated treatments did not significantly increase clearance.⁸⁹ Other animal studies have suggested benefits from hemoperfusion when performed within one hour, including a decrease in paraquat exposure, less end-organ damage and a reduction in inflammatory cytokines, but no mortality benefit.

Past experience suggested that extracorporeal treatments do not sufficiently improve mortality in humans, particularly when the concentration is greater than 3 mg/L.³⁵ Hemoperfusion followed by continuous venovenous hemofiltration prolonged the time to death compared with hemoperfusion alone without changing the overall mortality in nonrandomized studies and a meta-analysis that included three randomized controlled trials (n = 290 patients). However, increasing publications from eastern Asia suggest a clinical benefit from these therapies if commenced early, within 4 to 6 hours of ingestion and possibly with repeat treatment or with concurrent hemodialysis.

The risk of harm from extracorporeal techniques reflects the requirement for central venous access, metabolic disequilibrium, or increased clearance of antidotes, although such risks are low.

Antidotes

A large number of potential antidotes are under study in the treatment of acute paraquat poisoning. The combination of antidotes (if any) that will improve outcomes is not known, so it is not possible to recommend specific antidotes or dosages in routine clinical care.

Antidotes attempt to counteract the effects of paraquat by targeting various steps in the pathogenesis of organ dysfunction or to alter cellular uptake (Fig. 109–3). Unfortunately, despite their potential promise in animal studies, none of these antidotes are proven to reduce mortality in humans. Some of the interventions that decrease paraquat exposure by decreasing absorption¹²⁶ or increasing elimination⁵⁷ were shown to prolong the time to death. Therefore, clinicians commonly combine these treatments as part of a multimodal approach in the hope that it will reduce mortality. There are insufficient published data to support this approach, but in view of the high mortality from paraquat this approach is not generally considered to add to patient’s risk. Therefore, such a multimodal approach to treatment may be reasonable in certain cases, such as early presentations of less than 50 mL of 20% wt/vol formulations when extracorporeal treatments are also available. Examples of specific potential antidotes are detailed here.

Immunosuppression with corticosteroids (dexamethasone or methylprednisolone) and cyclophosphamide are the most extensively studied antidotes in humans. Early randomized controlled trial data (3 trials, n = 164 patients) suggested a benefit from these treatments but because of limitations in study design these results were not considered conclusive.⁶⁸ This was followed by a larger randomized controlled trial (n = 298) that reported no mortality benefit from high-dose immunosuppression (cyclophosphamide, methylprednisolone, dexamethasone) in patients with acute paraquat poisoning.²⁸ Therefore, although nonrandomized studies support a potential benefit, this immunosuppressive regimen is not recommended.

Generation of reactive oxygen species is an important step in the pathogenesis of paraquat poisoning (Fig. 109–3). This leads to cytotoxicity, the extent of which depends on the concentration of paraquat and the efficiency of endogenous protective mechanisms such as vitamin C (ascorbic acid), vitamin E (α-tocopherol), and glutathione. Administration of these vitamins and/or a glutathione donator (eg, N-acetylcysteine, S-carboxymethylcysteine, captopril) or other scavenging agents such as superoxide dismutase and amifostine and deferoxamine is not routinely recommended because they are not proven to be beneficial, and potentially vitamin C might increase oxidative toxicity.²²

Some treatments influence the toxicokinetics of paraquat at the cellular level. Xenobiotics that decrease the uptake of paraquat into pneumocytes were studied such as putrescine, spermidine, and deferoxamine, but their effect is limited and they do not alter efflux. Corticosteroids, particularly dexamethasone and methylprednisolone, were shown in animal models to induce P-glycoprotein, which increases the cellular efflux and excretion of paraquat although data regarding the extent to which paraquat is a substrate for P-glycoprotein are conflicting. Therefore, these treatments are not routinely recommended.

Salicylates are proposed to inhibit multiple steps in the pathogenesis of paraquat poisoning, including decreasing production of reactive oxygen species, inhibition of NF-κB, antithrombotic effects, and chelation of paraquat.^20,21 Sodium salicylate 200 mg/kg decreased reactive oxygen species production and inflammation and improved survival in rats.²⁰ Similarly, lysine acetylsalicylate 200 mg/kg improved survival in rats in a dose-finding study.^23,46 A small pilot study noted a delayed time to death in patients receiving intravenous acetylsalicylic acid. Other antidotes and treatments have also been proposed, but less information regarding their effects is available. Therefore, these treatments are not routinely recommended.

Treatment Recommendations

Most clinical studies have not demonstrated favorable outcomes, in contrast to animal studies. This reflects larger poisonings, increased sensitivity or delayed institution of therapy in human reports. Because some studies report a delayed time to death in patients who receive an intervention, this has suggested a possible effect and prompted further research into dose–response and the effect of combination therapy. In patients with a poor prognosis, active treatment, particularly with invasive modalities such as hemoperfusion/dialysis, will interfere with end-of-life care. Based on these principles, our recommendations favor intervention when there is a hope of recovery, while avoiding unfounded experimental technologies.

The prognosis in patients presenting more than 12 hours after ingesting 50 mL or more of paraquat 20% wt/vol, those with a positive plasma dithionite test, or those with a SIPP greater than 50 is so poor that treatment should focus on symptom control and end-of-life support and palliation.

The prognosis in patients presenting within 6 hours of ingesting less than 50 mL of paraquat, those with a faint-positive dithionite test, or those with a SIPP less than 50 is also poor, but prompt multimodal treatment with volume resuscitation, oral activated charcoal (or Fuller’s Earth), hemoperfusion or hemodialysis, intravenous corticosteroids, acetylsalicylate, N- acetylcysteine, deferoxamine, and vitamin E can be considered on a case-by-case basis. It cannot be overemphasized that potential benefits of these treatments (if any) is time-critical so they must be commenced immediately. If any of these treatments are not available at the initial treatment center it is reasonable to transfer the patient to a center that can provide them within the stated time frame. Excluding dermal exposures, other exposures not yet mentioned are associated with poor prognosis and unlikely to respond to treatment. However, if resources are available and psychosocial or cultural factors support aggressive treatment then the previous-mentioned treatment regimen can be attempted (but a benefit is not anticipated). In particular, it is not recommended that such patients be transferred to another center to receive active treatment.

It is unfortunate that paraquat is so inexpensive and effective as an herbicide when outcomes from unintentional and intentional poisoning are so devastating despite maximal medical treatment. Ultimately, the key focus to reducing deaths from paraquat poisoning is to ban its sale (or at least highly restrict its availability to commercial operators), which is supported by outcome data from a number of countries.

GLUFOSINATE

Glufosinate (Fig. 109–5) is a nonselective herbicide used predominantly in Japan and Korea, but it is the 25th most commonly used pesticide in the United States.³³ Commercial preparations contain 14% to 30% glufosinate as the ammonium or sodium salt, with anionic surfactants. Case fatalities between 6.1% and 17.7% are reported from glufosinate poisoning, and increasing age is a risk factor.⁷⁴

Pharmacology

Glufosinate is neurotoxic, although the specific mechanism is incompletely described. Because it is structurally similar to glutamate, studies have explored whether it interferes with glutamate networks in the central nervous system. Studies in rats demonstrate both agonism and antagonism to glutamate receptors and no effect on other receptors in the brain.³⁴ Glufosinate also interferes with glutamine synthetase activity, which induces hyperammonemia. Ammonia concentrations were not markedly altered in rats,³⁴ but hyperammonemia is observed following self-poisoning.^34,60,73,124

Cellular toxicity appears to be persistent; for example, mouse studies note that effects persists beyond 2 weeks after an acute exposure.

Glufosinate was not found to inhibit cholinesterase enzymes in rat studies,³⁴ although this is reported in humans on occasion, including one case in which it decreased to 40% of the lower limit of normal with subsequent recovery.¹²⁴

The extent to which the surfactant contributes to clinical toxicity is not confirmed. Rat studies suggest that hemodynamic changes due to glufosinate ammonium formulations are entirely caused by the surfactant component rather than glufosinate itself.⁵⁹ Surfactants may also cause uncoupling of oxidative phosphorylation, although this was not demonstrated in the study of a single case of glufosinate ammonium poisoning.⁷⁰

Pharmacokinetics and Toxicokinetics

Kinetic analysis of glufosinate is limited to animal studies and a few human case reports. Minor differences in kinetics of the D- and L-glufosinate enantiomers are observed between patients, the clinical implications of which are not known.

The peak concentration is observed 1 hour postingestion in mice administered the formulated product, and less than 15% of a dose is absorbed by rats.

Glufosinate does not appear to bind to plasma proteins to a significant extent. The V_d was calculated to be 1.44 L/kg in a case of acute poisoning by assuming that the renal excretion of glufosinate is similar to animals.³⁸ Glufosinate distributes into the central nervous system, but the rate of distribution to the cerebrospinal fluid has not been characterized. It is theorized that glufosinate distributes into the central nervous system, slowly, perhaps due to active transporters, where it accumulates, which is why the onset of respiratory depression is delayed.⁴⁴ Indeed, seizures have occurred in some patients after glufosinate was no longer detectable in the blood.¹²⁴ However, this theory was not supported in a case in which glufosinate was not detected in the cerebrospinal fluid 6 hours after a seizure that occurred 30 hours postingestion.¹²¹ Yet in another case of acute poisoning, the cerebrospinal fluid concentration was one-third the serum concentration 27 hours postingestion. Seizures occur 3 hours after the administration of intracerebral glufosinate in rats, which further challenges the theory that distribution kinetics influence the delayed onset of seizures in humans.³⁴

Glufosinate is subject to minimal metabolism and the majority of the bioavailable dose of glufosinate is excreted unchanged in urine.

The elimination half-life is 4 hours in rats, whereas in rabbits elimination is biphasic with a terminal elimination half-life of 1.9 hours, which is not dose dependent. Kinetic data in humans are limited to a small number of cases of acute intentional poisoning in which the elimination profile appeared biphasic with a distribution half-life of 2 to 4 hours and a terminal elimination of 10 to 18 hours.^38,41,118

Pathophysiology

It is not known whether the manifestations of glufosinate poisoning represent a primary (toxic) or secondary (downstream) effect. The most important manifestations are neurologic, with respiratory impairment that reduces oxygen delivery and subsequently compromises cellular function. Hypotension also impairs tissue perfusion and if uncorrected progresses to shock. Failure to correct these abnormalities leads to irreversible cellular injury and death.

Clinical Manifestations

Nausea and vomiting are early features of acute poisoning. An altered level of consciousness precedes severe neurotoxicity, which occurs between 4 and 50 hours postingestion, but usually within 24 hours, and includes seizures and central respiratory failure requiring ventilatory support.^60,73,74 These toxicities often persist for a number of days. In rats, following the intraperitoneal administration of glufosinate, the onset of seizures is also delayed by a number of hours and the time to onset decreases in a dose-dependent manner.⁷⁵

Other manifestations of acute poisoning include cardiac dysrhythmias, fever, amnesia (both antegrade and retrograde), diabetes insipidus, and rhabdomyolysis. Refractory hypotension is often preterminal.^60,73,74

Diagnostic Testing

Glufosinate poisoning is diagnosed clinically in the context of a history of exposure. Glufosinate assays are available for clinical use in Japan and a nomogram was developed for predicting clinical outcomes (Fig. 109–6).⁴⁰ Clinical chemistry assays including kidney function, blood gases, electrolytes, creatine kinase, and ammonia concentrations support clinical management. Metabolic acidosis is more common with severe poisoning.⁷⁴ The ammonia concentration peaks 24 to 48 hours postingestion and increasing concentrations suggest an increased risk of neurotoxicity.^34,60,73 An increase in serum S100B protein precedes the onset of neurotoxicity.

Management

Toxicity is not consistently dose-dependent and severe symptoms are reported following unintentional ingestion, so all patients with oral exposures should be carefully monitored. Patients with confirmed exposures should be monitored for a minimum of 48 hours because the onset of clinical toxicity is often delayed. Prior to discharge, each patient should be carefully screened to identify those with cognitive impairment.

Resuscitation and Supportive Care

Routine resuscitation, close observation, and supportive care are required. Careful monitoring for the onset of respiratory failure is necessary and early intubation and ventilation is recommended in symptomatic patients. Given that glufosinate and metabolites are primarily renally cleared, intravenous fluids to maintain a consistent urine output is reasonable. Seizures should be treated in a standard manner initially with benzodiazepines as first-line therapy, which was effective in animal studies. Biochemical and acid–base abnormalities should be corrected as per usual care.

Gastrointestinal Decontamination

In most reports of glufosinate poisoning, gastric lavage and activated charcoal were administered, but it is not possible to determine whether these interventions improved clinical outcomes. The high incidence of both seizures and respiratory failure from glufosinate poisoning are relative contraindications to the administration of activated charcoal to patients with an unprotected airway.

Extracorporeal Removal

Hemodialysis and hemoperfusion were both used and hemodialysis was superior in terms of extraction of glufosinate from whole blood in vitro, with an extraction ratio of 80%. The clearance by hemodialysis is less than 60% of renal clearance in patients with normal kidney function. Although prompt hemodialysis in patients promotes a decrease in the concentration of glufosinate and probably ammonia, it is not known if this prevents the occurrence of neurotoxicity such as seizures, so its role in routine management is poorly defined. It is reasonable to administer these treatments in patients with severe poisoning and also in those with impaired kidney function.

Antidotes

Specific antidotes are not available. Benzodiazepines should be first-line therapy for seizures.

GLYPHOSATE

Glyphosate (Fig. 109–7) is a nonselective postemergence herbicide. It is used extensively worldwide, most commonly as the isopropylamine salt but also a potassium salt. Glyphosate-containing herbicides are available in various formulations: 1% to 5% glyphosate (ready to use) or 30% to 50% (concentrate requiring dilution before use). In 2012, glyphosate was the most frequently used herbicide in the United States and the second most commonly used herbicide in the domestic sector.³³ Products containing glyphosate trimesium are less widely used and differ with respect to their toxicity profile. Glyphosate is banned in some countries because of data suggesting that it is a carcinogen. However, this topic is extensively debated, and in March 2017 the EPA concluded that glyphosate is not likely to be carcinogenic to humans.

Pharmacology

Glyphosate inhibits 5-enolpyruvylshikimate-3-phosphate synthase in plants, which interferes with their aromatic amino acid synthesis; this enzyme is not present in humans.

The mechanism of toxicity of glyphosate-containing herbicides to humans is not adequately described. The formulation is irritating and high concentrations are corrosive, causing direct injury to the gastrointestinal tract. Despite being an organic phosphorus compound, glyphosate does not inhibit acetylcholinesterase. Patients with severe poisoning manifest multisystem effects, suggesting that the formulation is either nonspecific in its action or that it interferes with a physiologic process common to a number of systems. Proposed mechanisms include disruption of cellular membranes and uncoupling of oxidative phosphorylation, which are interrelated. Indeed, the mechanism of toxicity varies between different glyphosate salts. In 2 cases of glyphosate trimesium poisoning, cardiopulmonary arrest occurred within minutes of ingestion.^81,116 Because this is not reported from glyphosate isopropylamine, it is possible that these products differ in the mechanism of toxicity.

Experimentally, there is minimal (if any) mammalian toxicity from glyphosate itself. Glyphosate is categorized as WHO class “U” (unlikely to present acute hazard in normal use; the dose of a xenobiotic predicted to kill 50% of exposed animals LD₅₀ > 4,000 mg/kg).⁴⁹ Surfactant coformulants are likely the more toxic component in glyphosate-containing herbicides. Polyoxyethyleneamine (tallow amine; LD₅₀ equal to 1,200 mg/kg) is the most common surfactant formulated in these products, but others are also used. Systemic exposure to surfactants induces hypotension, which is primarily due to direct effects on the heart and blood vessels.¹³ Surfactants directly disrupt cellular and subcellular membranes, including those of mitochondria, which has the potential to lead to systemic symptoms.³² Coformulated potassium and isopropylamine contribute to toxicity. Isopropylamine has a rat LD₅₀ of 111 to 820 mg/kg, decreases vascular resistance, and either increases or decreases cardiac contractility and rate.^50,93

Pharmacokinetics and Toxicokinetics

The kinetics of the surfactant are not described. The relevance of the kinetics of glyphosate is questioned because its contribution to clinical toxicology is minimal; however, it is summarized here for completeness. Glyphosate does not penetrate the skin to a significant extent. Up to 40% of an oral dose is absorbed in rats, although this could increase when ingested as a concentrated solution with injury to the gastrointestinal epithelium. The peak glyphosate plasma concentration occurs within 2 hours of ingestion and distribution appears to be limited. Glyphosate does not readily cross the placenta according to an ex vivo model.⁸² Glyphosate has an elimination half-life of less than 4 hours and is excreted unchanged in the urine.^{7,9,43,100,125}

Pathophysiology

It is not known whether the manifestations of glyphosate poisoning represent a primary (toxic) or secondary (downstream) effect. Disruptions of oxidative phosphorylation globally impair normal cellular function as a result of limited energy supply (discussed further with the pathophysiology of phenoxy herbicides). Similarly, direct toxicity to cell membranes (including those of the mitochondria) interferes with normal cellular processes such as ion channels. Both disruptions induce multiorgan toxicity. Hypotension and dysrhythmias impair tissue perfusion, and liver and kidney injuries induce metabolic disequilibria and acidemia, which impair normal physiologic processes. Pulmonary toxicity induces hypoxia, which further compromises normal cellular functioning. Failure to correct these abnormalities leads to irreversible cellular toxicity and death.

Clinical Manifestations

Abdominal pain with nausea, vomiting, and/or diarrhea are the most common manifestations of acute poisoning. These are mild and self-resolving except in patients with severe poisoning due to inflammation, ulceration, or infarction of the gut wall. Severe diarrhea and recurrent vomiting result in dehydration. Gastrointestinal burns and necrosis occur with high doses of concentrated formulations and are associated with hemorrhage. Extensive erosion of the upper gastrointestinal tract is associated with more severe systemic poisoning and prolonged hospitalizations.^{14,15,47,79,100}

Severe poisoning manifests as multiorgan failure, including hypotension, cardiac dysrhythmias, kidney and liver dysfunction, hyperkalemia, pancreatitis, pulmonary edema or pneumonitis, altered level of consciousness including encephalopathy, seizures, and metabolic acidosis. These effects range from transient to severe, progressing over 12 to 72 hours to resistant shock, respiratory failure, and death. Hypotension relates to both hypovolemia (fluids shifts and increased losses) and/or direct cardiovascular toxicity.^{7,15,65,69,79,100,111,120}

Intravenous self-administration of glyphosate-containing herbicide caused hemolysis in one patient, and intramuscular self-administration caused rhabdomyolysis in another.

A large prospective study reported a case fatality of 3.2% in patients presenting to rural hospitals in Asia in which resources are limited,¹⁰⁰ but mortality reported in other studies varied from 2% to 30%.¹⁵ These differences in outcomes likely reflect differences in timely access to health care services, available medical facilities, variability in glyphosate formulations, or selection bias related to case-referral. Proposed risk factors for death include a large exposure, delayed presentation to hospital, elevated glyphosate concentration, and increasing age.^{15,79,100,111}

Respiratory, ocular, and dermal effects occur following occupational use of these preparations but are usually of minor severity.

Diagnostic Testing

Acute poisoning with a glyphosate-containing herbicide is diagnosed on the basis of a history of exposure and clinical findings. The differential diagnoses are wide, including any xenobiotic or medical condition associated with gastrointestinal effects and progressive multisystem toxicity.

A number of clinical criteria for the classification of severity are suggested, but none are validated.^{7,100,120,122} There are no readily available specific clinical investigations to guide management or estimate prognosis in acute poisoning. Higher plasma glyphosate concentrations are associated with more severe poisoning, for example concentrations greater than 734 mg/L predicted death in one study.¹⁰⁰ A review noted that severe poisoning is associated with concentrations greater than 1,000 mg/L.⁷ These concentrations probably reflect the amount of exposure, because glyphosate is minimally toxic. Quantitative glyphosate assays are not routinely available for clinical use.

Targeted laboratory and radiologic investigations should be conducted in patients demonstrating anything more than mild gastrointestinal symptoms. Pulse oximetry and blood gas measurements detect metabolic disequilibria and respiratory impairment. Electrolytes should be measured early because some formulations contain glyphosate as a potassium salt and severe hyperkalemia and electrocardiographic changes are reported.

Patients who develop marked nonspecific organ toxicity (eg, acute kidney injury, pulmonary edema, metabolic acidosis (including an elevated lactate concentration, sedation, dysrhythmias, hypotension) are more likely to die.^{15,62,64,79,100}

Endoscopy identifies erosions or ulceration following exposures to the concentrated formulation, although this will not prompt a change in management. Further, endoscopy of an inflamed viscus presents a risk of perforation.

Management

Retrospective studies suggest a correlation between ingestion, severity of poisoning, and death.^{64,100,106,122} All patients except for those with trivial exposures should be observed for a minimum of 6 hours. In particular, patients presenting with intentional self-poisoning or ingestion of a concentrated formulation must be carefully monitored. If gastrointestinal symptoms are noted then the patient should be observed for a minimum of 24 hours given that clinical toxicity may progress. Because the toxicity of individual surfactants was not determined, treatment does not vary depending on specific coformulants.

Resuscitation and Supportive Care

All patients should receive prompt resuscitation, close observation, and routine supportive care; other treatments are largely empiric. The airway is usually maintained but respiratory distress and failure occur, which require supplemental oxygen and possibly mechanical ventilation. The optimal management of hypotension is complicated because its etiology is potentially related to hypovolemia, negative inotropy, and/or reduced vascular resistance. A detailed clinical review is required, followed by cautious administration of intravenous fluids to the patient. If the response to prompt administration of 20 to 30 mL/kg intravenous fluid to the patient is insufficient or there is increasing pulmonary congestion, then vasopressors are recommended. Other investigations such as echocardiography and central venous pressure will guide management, if available.

Biochemical and acid–base abnormalities, such as hyperkalemia, should be corrected where possible. The contribution of uncoupling of oxidative phosphorylation to clinical toxicity and death is proposed, but no specific treatment is available. In the context of acute poisoning with glyphosate-containing herbicides, signs suggestive of uncoupling of oxidative phosphorylation, such as hyperthermia, metabolic acidosis with elevated lactate concentration, and hypoglycemia, often represent a preterminal event. Hemodialysis or hemofiltration should be administered to patients developing acute kidney injury per usual guidelines if active treatment is to be pursued. Survival is reported with severe glyphosate poisoning (respiratory failure, persistent ventricular tachycardia and shock refractory to inotropes, and acidemia) using extracorporeal membrane oxygenation therapy.

Gastrointestinal Decontamination

No data exist to support the role of gastrointestinal decontamination in acute poisoning with glyphosate-containing herbicides beyond the usual recommendations discussed above.

Extracorporeal Removal

The role of extracorporeal removal in routine care is not known, but we recommend using it in patients with severe poisoning. Patients who received hemodialysis have survived severe poisoning; however, other patients have died despite this treatment. There are limited quantitative data reporting direct clearances, and uncertainty regarding which compound to measure.

Antidotes

No specific antidotes are proposed or tested for the treatment of acute poisoning with glyphosate-containing herbicides, which relates in part to the unknown mechanism of toxicity.

PHENOXY HERBICIDES (PHENOXYACETIC DERIVATIVES), INCLUDING 2,4-D AND MCPA

Phenoxy compounds are selective herbicides that are widely used in both developing and developed countries. A large number of compounds are included in this category; however, the most widely used are the phenoxyacetic derivatives. This includes 2,4-dichlorophenoxyacetic acid (2,4-D), 4-chloro-2-methylphenoxyacetic acid (MCPA), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T; no longer available), and mecoprop (MCPP; 2-{4-chloro-2-methylphenoxy}propionic acid; Fig. 109–8). Other phenoxy herbicides and available toxicity data are listed in Table 109–1. In 2012, 2,4-D was the fifth most commonly used herbicide in the United States but the most commonly used herbicide in the domestic sector (MCPP was third and MCPA the ninth most commonly used in the domestic sector).³³

Agent Orange, a defoliant popularly used during the Vietnam War, was composed of an equal mixture of 2,4-D and 2,4,5-T. This product also contained contaminant dioxins, in particular 2,3,7,8-tetrachlorodibenzodioxin which was a by-product of the manufacture of phenoxy herbicides. This dioxin is a persistent organic pollutant that is alleged to induce chronic health conditions and cancer, although this is debated. This chapter discusses only the outcomes of acute exposures to phenoxy herbicides.

Pharmacology

The mechanism of toxicity of phenoxy compounds is not well described. The formulation is irritating or caustic, causing direct injury to the gastrointestinal tract. Patients with severe poisoning manifest multisystem effects, suggesting that the formulation is either nonspecific in its action or that it interferes with a physiological process common to a number of systems. As with other herbicide preparations, this reflects the uncertain contributions of coformulants such as bromoxynil, ioxynil or surfactants.

In rats, high plasma concentrations of MCPA damage cell membranes and induce toxicity, but the correlation between plasma concentrations, membrane damage, and toxicity is poor. Dose-dependent acute kidney injury from 2,4-D is observed in rats.

Uncoupling of oxidative phosphorylation also contributes to the development of severe clinical toxicity. Phenoxyacetic derivatives demonstrate concentration-dependent uncoupling of rat mitochondria in vitro, although the specific process that is disrupted is not sufficiently described.^10,133 Features of uncoupling of oxidative phosphorylation were observed antemortem in clinical studies of patients with large phenoxy herbicide exposures.⁹⁸

Phenoxy acid compounds inhibit the voltage-gated chloride channel (CLC-1) in skeletal muscles, which is thought to contribute to the neuromuscular toxicity of these compounds. Dysfunction of CLC-1 induces myotonia due to hyperpolarization of the cell membrane. Other CLC channels are important for normal renal physiology. There are differences in the degree of inhibition between individual phenoxy acid compounds, which likely contributes to the variability in animal LD₅₀ and possibly clinical features.

Other possible mechanisms of toxicity relate to their similarity to acetic acid, interfering with the utilization of acetylcoenzyme A (acetyl-CoA), or action as a false messenger at cholinergic receptors.⁸

Pharmacokinetics and Toxicokinetics

Animal studies and human case reports demonstrate nonlinear kinetics for the phenoxy herbicide compounds. Dose-dependent changes in absorption, protein binding, and clearance all occur, and each will influence the concentration-time profile.

Absorption is usually first order;¹ however, the time to peak concentration is delayed with increasing doses, which suggests saturable absorption and is supported by cell culture studies that demonstrate active absorption of these herbicides by a hydrogen ion-linked monocarboxylic acid transporter.^{55,61,101,123}

As the dose of MCPA increases, there is a change in the semilogarithmic plasma concentration–time profile from linear to a biphasic convex profile. The inflection of this elimination curve in rats is approximately 200 mg/L,^{25,26,101,123} which appears to reflect saturation of albumin binding. As the plasma concentration exceeds this point, the proportion of herbicide that is free (unbound) increases.¹⁰¹ This increases the V_d and prolongs the apparent plasma elimination half-life.

Another contributing mechanism to the observed biphasic convex concentration-time profile is saturation of renal clearance for which there is some interspecies variability. Dose-dependent renal clearance is attributed to saturation of an active transport process or direct nephrotoxicity. Renal clearance also varies with urine production because of reabsorption from the distal tubule.

Similar to data from animal studies, the semilogarithmic plasma concentration–time curve of phenoxy herbicides in humans with acute poisoning is generally convex, with an apparent inflection from a longer (but highly variable) to shorter elimination half-life between 200 and 300 mg/L. The elimination half-lives are prolonged, contributing to the persistence of clinical toxicity and occurrence of death a number of days postingestion of a phenoxyacetic herbicide.^98,101

Alterations in blood pH theoretically change tissue distribution because phenoxyacetic herbicides are weak acids (pK_a approximately 3). Here, acidemia increases the proportion that is nonionized, and therefore lipophilic, which increases tissue binding and distribution. This is observed in vitro and is similar to that observed for salicylates (Chap. 37). Similarly, an alkaline plasma pH is expected to decrease tissue (and probably receptor) binding and increase plasma concentrations.

Experience with acute human poisonings noted a poor correlation between plasma concentrations and peak toxicity.⁹⁸ This probably reflects a discordance between plasma (measured) and intracellular (eg, mitochondrial) concentrations.

Pathophysiology

Direct injury to the gastrointestinal tract causes vomiting and diarrhea, which induces hypovolemia and electrolyte abnormalities.⁸ Nonspecific cellular toxicity and uncoupling of oxidative phosphorylation interfere with normal function of ion channels and other cellular functions, preventing normal physiological processes.

Uncoupling of oxidative phosphorylation disrupts mitochondrial function, and causes inefficiency in energy production. Here, there is an increase in heat production out of proportion to the generation of ATP. Varying degrees of uncoupling of oxidative phosphorylation occur. The initial physiological response to uncoupling is to increase mitochondrial respiration to maintain the supply of ATP, which increases heat production and respiratory rate. As ATP falls there is an increase in glycolysis, causing hypoglycemia and metabolic acidosis with an elevated lactate concentration. If the mitochondrial defect persists then there will be hyperthermia and insufficient ATP for essential cellular functions, including active transport pumps such as Na⁺,K⁺-ATPase. This is followed by a loss of cellular ionic and volume regulation, which if persistent, is irreversible and cell death occurs. Because mitochondria are the primary supplier of ATP for most physiologic systems, uncoupling of oxidative phosphorylation is expected to induce multisystem toxicity.

Clinical Manifestations

Severe toxicity is more commonly reported in patients ingesting herbicide preparations containing both a phenoxy acid derivative with bromoxynil or ioxynil.

Vomiting, myotonia, confirmed on electromyography, and miosis are prominent features of 2,4-D poisoning in dogs. Severity varies in a dose-dependent manner, peaking 12 to 24 hours postingestion and persisting for a number of days.

Gastrointestinal toxicity including nausea, vomiting, abdominal or throat pain, and diarrhea are common. Other clinical features include neuromuscular findings (myalgia, rhabdomyolysis, weakness, myopathy, myotonia, and fasciculations), central nervous system effects (agitation, sedation, confusion, miosis), tachycardia, hypotension, acute kidney injury, and hypocalcemia. In some patients, these effects persist for a number of days.⁹⁸

Tachypnea with respiratory alkalosis occurs in patients with phenoxy herbicide poisoning, some of whom died, which is consistent with increased mitochondrial respiration from mild uncoupling. More severe poisoning is characterized by metabolic acidosis, hyperventilation, hyperthermia, elevated creatine kinase, generalized muscle rigidity, progressive hypotension, pulseless electrical activity, or asystole.^8,19,85,98

The mortality from acute phenoxy herbicide poisoning is high. A systematic review of all acute phenoxy herbicide poisoning described severe clinical toxicity in most patients, including death in one-third of the cases.⁸ Subsequently, a prospective study of MCPA exposures demonstrated minor toxicity in greater than 80% of patients and a mortality of 4.4% (8 of 181 patients).⁹⁸ When death occurs, it is usually delayed by 24 to 48 hours postingestion and results from cardiorespiratory arrest. The exact mechanism of death is inadequately described, but appears to relate to uncoupling of oxidative phosphorylation or other metabolic dysfunction including acute kidney injury, as discussed above.

Diagnostic Testing

Commercial assays for the specific measurement of phenoxy herbicides are not available to assist in the diagnosis of acute poisoning. Further, their role in the management of acute poisoning is not confirmed because the relationship between plasma phenoxy herbicide concentration and clinical toxicity appears to be poor.⁹⁸ Sedation is reported with a plasma phenoxy concentration above 80 mg/L,⁹⁶ whereas concentrations more than 500 mg/L are associated with severe toxicity.²⁷ A patient survived severe MCPA poisoning (hypotension and limb myotonia) with a plasma concentration of 546 mg/L. The myotonia persisted for days and resolved when the MCPA plasma concentration was less than 100 mg/L.¹⁰⁹ By contrast, death following MCPA poisoning is reported at plasma concentrations as low as 107 mg/L to 230 mg/L.^51,90,98

Monitoring of electrolytes, kidney function, pulse oximetry, and blood gases is recommended to detect progression of organ toxicity. Hypoalbuminemia predisposes to severe poisoning.¹⁰¹ Creatine kinase should be determined because rhabdomyolysis is reported following acute poisoning. Urinalysis will identify myoglobinuria. There are insufficient data describing the role of these measurements for prognostication.