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HISTORY, CLASSIFICATION, AND EPIDEMIOLOGY
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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Contribution of Coformulations
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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.
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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.
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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.
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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.
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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).
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Regulatory Considerations
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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.
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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.
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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
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GENERAL COMMENTS FOR THE MANAGEMENT OF ACUTE HERBICIDE POISONING
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Occupational and Secondary Exposures (Including Nosocomial Poisoning)
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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.
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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.
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Amide Compounds, Particularly Anilide Derivatives
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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.
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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+).
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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.
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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.
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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.
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Pharmacokinetics and Toxicokinetics
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Absorption is rapid in animals, with a peak serum concentration expected one hour postingestion. The volume of distribution (Vd) of propanil is not defined, but is expected to be large given that both propanil and 3,4-dichloroaniline are highly lipid soluble. This Vd is consistent with data in the channel catfish in which uptake and distribution of propanil were noted to be extensive.
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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 (Km = 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
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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 (Km = 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.
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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).
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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
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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.
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Clinical Manifestations
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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%.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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Resuscitation and Supportive Care
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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.
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Gastrointestinal Decontamination
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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.
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Extracorporeal Removal
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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).
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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.
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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.
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BIPYRIDYL COMPOUNDS, PARAQUAT AND DIQUAT
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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.
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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
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Supplemental oxygen probably increases the generation of reactive oxygen species.
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Pharmacokinetics and Toxicokinetics
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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.
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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
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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.
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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
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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.
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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
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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.
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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.
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Clinical Manifestations
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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.
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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
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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.
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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
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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.
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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
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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.
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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
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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).
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Resuscitation and Supportive Care
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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.
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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.
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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.
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Gastrointestinal Decontamination
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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
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Extracorporeal Removal
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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.
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Treatment Recommendations
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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.
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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.
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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.
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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.
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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
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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
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Cellular toxicity appears to be persistent; for example, mouse studies note that effects persists beyond 2 weeks after an acute exposure.
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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
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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
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Pharmacokinetics and Toxicokinetics
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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.
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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.
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Glufosinate does not appear to bind to plasma proteins to a significant extent. The Vd 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
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Glufosinate is subject to minimal metabolism and the majority of the bioavailable dose of glufosinate is excreted unchanged in urine.
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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
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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.
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Clinical Manifestations
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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
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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
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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.
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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.
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Resuscitation and Supportive Care
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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.
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Gastrointestinal Decontamination
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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.
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Extracorporeal Removal
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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.
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Specific antidotes are not available. Benzodiazepines should be first-line therapy for seizures.
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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.
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Glyphosate inhibits 5-enolpyruvylshikimate-3-phosphate synthase in plants, which interferes with their aromatic amino acid synthesis; this enzyme is not present in humans.
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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.
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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
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Pharmacokinetics and Toxicokinetics
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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
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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.
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Clinical Manifestations
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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
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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
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Intravenous self-administration of glyphosate-containing herbicide caused hemolysis in one patient, and intramuscular self-administration caused rhabdomyolysis in another.
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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
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Respiratory, ocular, and dermal effects occur following occupational use of these preparations but are usually of minor severity.
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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.
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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.
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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.
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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
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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.
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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.
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Resuscitation and Supportive Care
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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.
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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.
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Gastrointestinal Decontamination
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No data exist to support the role of gastrointestinal decontamination in acute poisoning with glyphosate-containing herbicides beyond the usual recommendations discussed above.
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Extracorporeal Removal
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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.
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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.
++
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 Vd 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 (pKa 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.
++
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.
++
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.
++
All patients with significant poisonings, particularly those with symptomatic oral ingestions, should be treated cautiously, including continuous monitoring for 24 to 48 hours preferably in an intensive care unit. Initial mild toxicity such as gastrointestinal symptoms with normal vital signs and level of consciousness does not preclude subsequent severe toxicity and death.98
++
Animal studies suggest that phenoxy herbicide toxicity increases when elimination is impaired. Empirically, this supports the use of treatments that reduce exposure by either decreasing absorption or increasing elimination. Unfortunately, there is insufficient evidence to recommend specific interventions in patients with acute phenoxy herbicide poisoning. However, an adequate urine output (>1 mL/kg/h) optimizes the renal excretion of phenoxy herbicides as well as decreasing renal toxicity from rhabdomyolysis. Because signs consistent with uncoupling of oxidative phosphorylation are associated with a poor outcome, when present more advanced treatments such as hemodialysis should be used.8,98
+++
Resuscitation and Supportive Care
++
All patients should receive routine resuscitation, close observation, and supportive care. It is reasonable to correct electrolyte abnormalities, and acidemia as acidemia promotes the distribution of weak acids and increases the intracellular concentration.
+++
Gastrointestinal Decontamination
++
Gastrointestinal decontamination is recommended to patients per the guidelines listed in Chap. 5. However, administration of activated charcoal beyond the usual time frame is reasonable given that absorption appears to be saturable.
+++
Extracorporeal Removal
++
Urgent hemodialysis is recommended in patients with severe poisoning. Because phenoxy compounds are small and water soluble, and subject to saturable protein binding with large exposures (increasing the free concentration), they are likely to be cleared by extracorporeal techniques. Extracorporeal elimination using resin hemoperfusion, hemodialysis, or plasmapheresis was studied in a few cases, with clearances approaching 75 mL/min.
++
There are no specific antidotes for phenoxy herbicides, but sodium bicarbonate or other alkalinizing agents favorably alter the kinetics of phenoxy herbicides.
++
Data from animal studies and case reports suggest that urinary alkalinization increases the elimination of phenoxy herbicides due to “ion trapping.” For example, renal 2,4-D clearance was increased from 5.1 to 63 mL/min when urine pH increased from 5.0 to 8.0.91 Compared with a total clearance of approximately 30 mL/minute or less in volunteer studies,56,105 this increase in renal clearance is potentially significant. Prospective, randomized studies are required to confirm the efficacy of urinary alkalinization in humans. Plasma alkalinization theoretically limits the distribution of phenoxy compounds from the central circulation by “ion trapping.”
++
It is reasonable to alkalinize the urine to a pH greater than 7.5 in patients who are symptomatic, particularly if there are features of uncoupling of oxidative phosphorylation or metabolic acidosis. Alkalinization is rarely associated with adverse effects when administered to patients with care and close observation (Antidotes in Depth: A5).
+++
TRIAZINE COMPOUNDS, INCLUDING ATRAZINE
++
The 1,3,5-triazine or s-triazine compound (Fig. 109–9) is central to a large number of compounds, including herbicides, other pesticides (eg, cyromazine), resins (eg, melamine), explosives (RDX or C-4), and antiinfectives. Triazine herbicides are widely used, and in 2012 atrazine was the second most used pesticide in the United States.33 However, cases of acute poisoning are infrequent. Other herbicides included in this group are listed in Table 109–1. These selective herbicides are used pre- or post-emergence for weed control.
++
++
The safety of atrazine from an environmental health perspective is debated because of its persistence and propensity to spread across water systems and potential toxicity from chronic exposure. This led to restrictions on the use of triazine compounds in the European Union.
++
The mechanism of toxicity is not fully determined, although it might relate to uncoupling of oxidative phosphorylation. Atrazine is a direct arteriolar vasodilator. Some metabolites of atrazine, particularly those remaining chlorinated, are thought to retain biologic activity.2 Similarly, clinical features of prometryn poisoning resolved posthemodialysis despite persistence of the parent herbicide, suggesting that toxic metabolites or coformulants were eliminated.11
+++
Pharmacokinetics and Toxicokinetics
++
Approximately 60% of an oral atrazine dose is absorbed in rats and the concentration peaks beyond 3 hours.78 The absorption phase of triazine compounds appears to be prolonged in humans in which the serum or plasma concentration continues to increase during treatment with hemodialysis.11,88 Atrazine is rapidly dealkylated to a metabolite that binds strongly to hemoglobin and plasma proteins, allowing it to be detected in the blood for months. Metabolites are excreted in the urine, and around 25% of them are conjugated to glutathione.78
++
The metabolism of atrazine has been studied in humans following occupational exposures, and animals, and a range of metabolites are described, in particular glutathione conjugates. Other metabolic products from dealkylation and oxidation are also present.
++
Dermal absorption of atrazine is incomplete but increases with exposure to the proprietary formulation. Atrazine metabolites are readily measured in the urine of atrazine applicators.
+++
Clinical Manifestations
++
There are limited cases of triazine herbicide poisoning. Vomiting, depressed levels of consciousness, tachycardia, hypertension, acute kidney injury, and metabolic acidosis with an elevated lactate concentration were described in a patient with acute prometryn and ethanol poisoning.11 Similar clinical signs, in addition to hypotension with a low peripheral vascular resistance, were noted in a case of poisoning with atrazine, amitrole (Table 109–1), ethylene glycol, and formaldehyde. This was followed by progressive multiorgan dysfunction and death due to refractory shock 3 days later.88 Death following acute ametryn poisoning (coformulated with xylene and cyclohexanone) is reported, but the mechanism of death was not apparent.119
++
In a single case report, clinical toxicity did not directly relate to the concentration of prometryn, but the relationship to the concentration of metabolites was not determined.11 Routine biochemistry and blood gases are useful for monitoring for the development of systemic toxicity.
++
The limited number of publications of triazine herbicide poisoning are inadequate to guide specific management of patients with acute triazine poisoning.
+++
Resuscitation and Supportive Care
++
Routine resuscitation, close observation, and supportive care should be provided to all patients. Ventilatory support and correction of hypotension and metabolic disequilibria are appropriate.
+++
Gastrointestinal Decontamination
++
It is reasonable to administer activated charcoal to patients beyond one hour because of the slow absorption of these compounds.
+++
Extracorporeal Removal
++
Hemodialysis corrected metabolic acidosis in a case of prometryn poisoning without decreasing the serum concentration of prometryn. In the absence of direct measurements of clearance, the efficacy of hemodialysis in removing prometryn cannot be determined, but is probably limited.11 Hemodialysis clearance of atrazine was 250 mL/minute (extraction ratio 76%), but only 0.1% of the dose was removed after 4 hours of treatment. Further, similar to the previous case, atrazine concentrations continued to increase during the treatment.88
++
No antidotes are available for the treatment of triazine herbicide poisoning.
++
A large number of heterogeneous xenobiotics are classified as herbicides; the toxicity in humans is not completely described for many of these xenobiotics.
Coformulants, such as surfactants and solvents, probably contribute to clinical toxicity in commercial preparations.
Many herbicides induce multisystem toxicity for which treatments are often unsatisfactory, although some compounds induce organ-specific toxicity.
All patients with acute intentional poisoning should be carefully observed for the development of poisoning.
The priorities of treatment include prompt resuscitation, consideration of antidotes, a detailed history, ongoing monitoring, and supportive care.
More research is required to better define the clinical syndromes associated with herbicide poisoning, the toxicokinetics of relevant compounds, and the efficacy of treatments including antidotes.
Prospective case series are useful for describing the toxicity of herbicides in humans. These guide clinicians in the management of poisoning, and also inform regulatory agencies regarding the relative toxicity of different herbicides, which prompt actions that reduce risk to human health.
Regulatory agencies should monitor data research describing outcomes from unintentional and intentional self-poisoning, and actively ban or severely restrict the availability of highly toxic herbicides, in particular those for which an antidote is not available.
++
Acknowledgment
++
Rebecca L. Tominack, MD, and Susan M. Pond, MD, contributed to this chapter in previous editions.
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