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Goldfrank's Toxicologic Emergencies, 10e > 112:

Darren M. Roberts

HISTORY, CLASSIFICATION, AND EPIDEMIOLOGY

An , any chemical that regulates the growth of a plant, encompasses 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 where weeds are particularly targeted. Poisoning may occur following acute (intentional or unintentional poisoning) or chronic (such as occupational) exposures. Depending on the herbicide and the characteristics of the exposure, this may lead to clinically significant poisoning, including death. This chapter focuses on the most widely used herbicides and also those associated with significant clinical toxicity. In particular, risk assessment and the management of patients with a history of acute herbicide poisoning are emphasized.

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

Herbicides are the most widely sold pesticides in the world, where 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 13% of the overall herbicide use in the United States, while 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 four of the top five used pesticides in 2007, including , , , and 2,4-dichlorophenoxyacetic acid.33

Not all herbicide exposures are clinically significant. In developed countries, most acute herbicide exposures are unintentional and the majority of patients do not require admission to 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 five deaths per year and 20 patients per year with clinical outcomes categorized as “major” that were attributed to herbicide poisoning (Chap. 136). Most deaths were due to paraquat and , 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 may also occur with unintentional (eg, storage of a herbicide in food or drink containers) or criminal exposures.

Classification

Hundreds of xenobiotics have herbicidal activity and they may be 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

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action (contact herbicides or hormone dysregulators), use (preemergence or postemergence), or their toxicity to rats (LD50). Certain xenobiotics are classified as plant growth regulators rather than herbicides, but in this chapter all are considered to be herbicides.

Table 112–1 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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TABLE 112–1. Characteristics of the Major Herbicides Categorized by Chemical Class and WHO Hazard Classification

Applications, Usage Data, WHO Clinical Effects, Potential Chemical Classa and Mechanism of Action Hazard Compounds Included Specific Treatments, and in Plants, If Knownb Classc Supportive Care

Alcohol and Broad-spectrum contact Ib Allyl alcohol (2-propen-1-ol) Local irritation, cardiotoxicity, aldehyde herbicide and acrolein (the metabolite pulmonary edema, and death. of allyl alcohol) Administer N-acetylcysteine or mesna

Amide, Fig. 112–1 Selective for grasses pre- or III Anilide derivatives: See text for anilide postemergence U Acetochlor, , derivatives. There are limited In 2007, acetochlor, dimethachlor, flufenacet, human data about the , , and mefluidide, metolachlor, nonanilide derivatives. are listed , propanil (DCPA) Lethargy or sedation among the top herbicides Nonanilide derivatives: preceded death in animals used in the United States Chlorthiamid, diphenamid exposed to chlorthiamid. Multiple mechanisms of Anilide derivatives: Behavioral changes, ataxia, action, including inhibition , clomeprop, and prostration were noted in of photosynthesis at diclosulam, flamprop, animals exposed to photosystem II and/or flumetsulam, metosulam, diphenamid. Drowsiness and inhibition of mefenacet, metazachlor, tachypnea were noted in dihydropteroate synthase pentanochlor, pretilachlor goats following acute and/or inhibition of cell Nonanilide derivatives: poisoning with napropamide division through inhibition , bromobutide, of the synthesis of very- dimethenamid, isoxaben, long-chain fatty acids napropamide, oryzalin, and/or inhibition of propyzamide, tebutam acetolactate synthase (interferes with branched amino acid synthesis) and/or inhibition of microtubule assembly Some compounds may also be included in other chemical classes, including asulam (carbamate); oryzalin (dinitroaniline); clomeprop (phenoxy); diclosulam, flumetsulam, and metosulam (triazolopyrimidines)

Aromatic acid In 2007, dicamba was the III Bispyribac causes fifth most used herbicide in U gastrointestinal irritation,

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Applications, Usage Data, WHO Clinical Effects, Potential Chemical Classa and Mechanism of Action Hazard Compounds Included Specific Treatments, and in Plants, If Knownb Classc Supportive Care

the domestic sector in the Dicamba, sedation and death (case United States 2,3,6-trichlorobenzoic acid fatality 1.8%; asystolic arrest

Dicamba is commonly (2,3,6-TBA) reported).30 Minimal toxicity coformulated with Bispyribac, chloramben from dicamba.87 Human data phenoxyacetic acid (amiben), chlorthal, are limited for the other compounds , pyriminobac, compounds, particularly Inhibits acetolactate pyrithiobac, , single-agent exposures. In synthase and/or inhibition quinmerac animals, myotonia, dyspnea, of microtubule assembly and death are reported with and/or indole acetic acid- dicamba and 2,3,6-TBA like (synthetic ) poisoning

Arsenical Unknown III Dimethylarsinic acid Chap. 89 (cacodylic acid), methylarsonic acid (MAA or MSMA)

Benzothiazole Indole acetic acid-like U Benazolin, Limited human data (synthetic auxins) and/or methabenzthiazuron inhibits photosynthesis at photosystem II

Bipyridyl Nonselective, II Paraquat, diquat See text for paraquat and postemergence, contact diquat herbicide Photosystem I electron diversion These compounds are part of a larger group of quaternary ammonium herbicides, including difenzoquat, which is also a pyrazole compounds (see below)

Carbanilate Inhibits photosynthesis at U Carbetamide, Limited human data photosystem II and/or desmedipham, inhibits mitosis or phenmedipham, propham microtubule organization

Cyclohexane Postemergence, selective III Butroxydim, , Limited human data oxime for grasses U tralkoxydim Alloxydim, cycloxydim, cyhalofop

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Applications, Usage Data, WHO Clinical Effects, Potential Chemical Classa and Mechanism of Action Hazard Compounds Included Specific Treatments, and in Plants, If Knownb Classc Supportive Care

Inhibits acetyl-CoA carboxylase (lipid biosynthesis inhibitors)

Dinitroaniline Preemergence, selective for III Fluchloralin, Pendimethalin induces mild grasses U (benefin), clinical toxicity in most cases, In 2007, and butralin, dinitramine, but gastroduodenal erosions, pendimethalin were among ethalfluralin, oryzalin, seizures, and death due to the top 10 herbicides used prodiamine, trifluralin respiratory failure are in the United States overall, reported. Limited human data while trifluralin and for the others pendimethalin were among Aniline metabolites are the top 10 used in the reported from trifluralin and domestic sector oryzalin, which may induce Inhibits microtubule methemoglobinemia and assembly hemolysis with prolonged exposures. In rats, fluchloralin induces hyperexcitability, tremors, and convulsions prior to death. Agitation, trembling, and fatigue occur in rats following lethal doses of trifluralin. Many of these compounds are poorly absorbed and may be subject to enterohepatic recycling.

Diphenylether Postemergence III , fluoroglycofen Limited human data (particularly broad leaves) U , , Contact herbicide, inhibits chlomethoxyfen, oxyfluorfen protoporphyrinogen oxidase, and/or inhibits carotenoid biosynthesis Aclonifen is also an amine compound

Halogenated Inhibit lipid synthesis U Dalapon, fluopropanate Limited human data aliphatic

Imidazolinone Inhibit acetolactate U Imazamethabenz, , Limited human data. In a synthase, interfering with imazaquin, imazethapyr small case series, imazapyr branched amino acid induced sedation, respiratory synthesis distress, metabolic acidosis,

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Applications, Usage Data, WHO Clinical Effects, Potential Chemical Classa and Mechanism of Action Hazard Compounds Included Specific Treatments, and in Plants, If Knownb Classc Supportive Care

hypotension, and hepatorenal dysfunction

Inorganic Nonselective III Sodium chlorate Nausea, vomiting, diarrhea, metabolic acidosis, kidney failure, hemolysis, methemoglobinemia, rhabdomyolysis, and disseminated intravascular coagulation. Treatment includes hemodialysis and erythrocyte and plasma transfusion. Methemoglobinemia is usually unresponsive to methylene blue (a single report suggested benefit when used within 6 hours of

exposure63) but sodium thiosulphate has been trialed

Nitrile Preemergence, selective for U Ammonium sulfamate Limited human data grasses II , ioxynil Limited human data; in Inhibits photosynthesis at U Dichlobenil animals, it uncouples photosystem II and/or oxidative phosphorylation inhibition of cell wall and induces CNS toxicity (may (cellulose) synthesis be prevented by DMPS) Commonly coformulated with phenoxyacetic acid compounds

Dinitrophenol Uncoupling (membrane Ib Dinoterb, DNOC (4,6-dinitro- Limited human data; disruption) o-cresol) methemoglobinemia is reported in animals. Dinitrophenol uncouples oxidative phosphorylation

Organic : preemergence II Butamifos, bialaphos Limited human data. phosphorus selective for grasses. III (bilanafos), anilofos, Bialaphos is metabolized to Glyphosate and U bensulide, piperophos glufosinate in plants, but in are nonselective Glufosinate humans only the metabolite postemergence herbicides Fosamine, glyphosate L-amino-4-hydroxymethyl- In 2007, glyphosate was the phosphonoyl-butyric acid has most used pesticide in the been found. Clinical effects of

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Applications, Usage Data, WHO Clinical Effects, Potential Chemical Classa and Mechanism of Action Hazard Compounds Included Specific Treatments, and in Plants, If Knownb Classc Supportive Care

United States and the poisoning include apnea, second most used in the amnesia, and metabolic domestic sector acidosis. Anilofos and Bialaphos and glufosinate bensulide are shown to inhibit glutamine inhibit acetyl cholinesterase synthetase, bensulide See text for glufosinate and inhibits lipid synthesis, and Fig. 112–5 glyphosate inhibits EPSP See text for glyphosate and synthase, which interferes Fig. 112–7; Limited human with aromatic amino acid data for fosamine synthesis

Phenoxy (Fig. 112 Postemergence, selective II Phenoxyacetic derivatives: See text for phenoxyacetic –8) for grasses III 2,4-D derivatives; similar clinical In 2007, 2,4-D was the fifth U Nonphenoxyacetic features of toxicity are noted most used herbicide in the derivatives: haloxyfop, for the chlorinated United States but the most quizalofop-P nonphenoxyacetic acid used in the domestic sector Phenoxyacetic derivatives: compounds. Mild clinical ( was fourth) MCPA, 2,4,5-T toxicity from fenoxaprop-

Inhibits acetyl-CoA Nonphenoxyacetic ethyl in acute overdose.132 carboxylase (lipid derivatives: Bromofenoxim, Limited human data on biosynthesis inhibitors; 2,4-DB, , poisoning for others. fops) or indole acetic acid- diclofop, , MCPB, Fluazifop 0.07 mg/kg was like ( growth mecoprop (MCPP), safely administered to regulators; chlorinated quizalofop, propaquizafop humans in a volunteer study compounds) Nonphenoxyacetic Clomeprop is also an amide derivatives: Clomeprop, compound fenoxaprop-ethyl

Pyrazole May relate to inhibition of II Difenzoquat Limited human data 4-hydroxyphenyl-pyruvate III Pyrazoxyfen, pyrazolynate dioxygenase or U Azimsulfuron photosystem I electron diversion (difenzoquat is also a quaternary ammonium compound)

Pyridazine Preemergence application. III Pyridate Limited human data Inhibits photosynthesis at photosystem II

Pyridazinone Inhibits photosynthesis at U Chloridazon, norflurazon Limited human data. In photosystem II or inhibits animals, chloridazon appears carotenoid biosynthesis at to interfere with

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Applications, Usage Data, WHO Clinical Effects, Potential Chemical Classa and Mechanism of Action Hazard Compounds Included Specific Treatments, and in Plants, If Knownb Classc Supportive Care

the phytoene desaturase mitochondrial function. step Respiratory distress, seizures, and paralysis precede death

Pyridine Inhibits carotenoid III Limited human data on biosynthesis at the U Diflufenican, , poisoning, but triclopyr

phytoene desaturase step , fluthiacet, appears to be low toxicity,87 and/or inhibits microtubule except for one case of acute assembly and/or indole poisoning with metabolic acetic acid-like (synthetic acidosis, coma and auxins) cardiotoxicity; yet, recovery was complete. Triclopyr 0.5 mg/kg was safely administered to humans in a volunteer study. Picloram 5 mg/kg was safely administered to humans in a volunteer study

Thiocarbamate Preemergence, selective for II EPTC, molinate, pebulate, Molinate 5 mg was orally grasses III prosulfocarb, thiobencarb, administered to volunteers. Inhibits lipid synthesis U vernolate Limited human data, Cycloate, esprocarb, triallate including effects on Tiocarbazil cholinesterase. Some compounds display variable inhibition of nicotinic receptors, esterases, and aldehyde dehydrogenase in animals. Cycloate induces neurotoxicity in rats

Triazine (Fig. 112 Mostly preemergence and II , terbumeton See text –9) nonselective III Ametryn, desmetryn, In 2007 atrazine was the U dimethametryn, simetryn second most used Atrazine, , herbicide in the United prometryn, propazine, States and was simazine, , seventh terbutryn, trietazine Inhibits photosynthesis at photosystem II

Triazinone Inhibits photosynthesis at II , Limited human data. With photosystem II III Metamitron hexazinone, rats and guinea pigs experience lethargy and

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Applications, Usage Data, WHO Clinical Effects, Potential Chemical Classa and Mechanism of Action Hazard Compounds Included Specific Treatments, and in Plants, If Knownb Classc Supportive Care

ataxia, progressing to clonic seizures prior to death, while dogs were not particularly sensitive. Goats experience sedation, lethargy, and impaired respiration with metamitron poisoning

Triazole Postemergent, U Amitrole (aminotriazole) Limited human data on nonselective single-agent exposures. Commonly coformulated Ingestion of 20 mg/kg in a with ammonium human and > 4000 mg/kg in thiocyanate. Inhibits rats did not induce symptoms lycopene cyclase; chlorophyll or carotenoid pigment inhibitor

Triazolone Inhibits acetolactate U Flucarbazone Limited human data synthase

Triazolopyrimidine Inhibits acetolactate U Diclosulam, flumetsulam, Limited human data. Asthma synthase. These herbicides metosulam is reported from occupational are also amide compounds exposures to flumetsulam

Uracil Mostly preemergence. U Bromacil, lenacil, terbacil Limited human data Inhibit photosynthesis at photosystem II

Urea Both pre- and III Isoproturon, isouron, Limited human data. Some postemergence U herbicides are Inhibits acetolactate Bensulfuron, metabolized to aniline synthase (interferes with chlorbromuron, compounds, which induce branched amino acid chlorimuron, chlorotoluron, methemoglobinemia and synthesis) and/or inhibits cinosulfuron, hemolysis (similar to photosynthesis at cyclosulfamuron, daimuron, propanil, see text). Given the photosystem II and/or dimefuron, diuron, fenuron, limited experience in treating inhibition of carotenoid fluometuron, , poisonings with urea biosynthesis methyldymron, herbicides, it is reasonable to metobromuron, metoxuron, apply treatments described metsulfuron, , for amide herbicide poisoning neburon, nicosulfuron, (see text); success with primisulfuron, methylene blue has been pyrazosulfuron, rimsulfuron, reported. Wheeze is reported siduron, sulfometuron,

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Applications, Usage Data, WHO Clinical Effects, Potential Chemical Classa and Mechanism of Action Hazard Compounds Included Specific Treatments, and in Plants, If Knownb Classc Supportive Care

thifensulfuron, triasulfuron, from occupational exposures tribenuron, triflusulfuron to chlorimuron Animal studies suggest that isoproturon causes CNS depression and tebuthiuron causes lethargy, ataxia, and anorexia

Miscellaneous : may be II Clomazone, endothal Limited human data; in one coformulated with propanil III Bentazone, quinoclamine case vomiting and gastric and Clomazone and fluridone: U Benfuresate, cinmethylin, pulmonary hemorrhage chlorophyll or carotenoid ethofumesate, fluridone, preceded death. Animal pigment inhibitor flurochloridone, oxadiazon studies suggest that Bentazone: pre- and clomazone inhibits postemergence for control acetylcholinesterase and of broadleaf plants. Inhibit endothal induces lethargy, photosynthesis respiratory, and hepatic Fluridone: chlorophyll or dysfunction. In vitro, carotenoid pigment clomazone induces oxidative inhibitor stress and inhibits acetylecholinesterase Bentazone: gastrointestinal irritation, hepatic failure, acute kidney injury, dyspnea, muscle rigidity, confusion, death Limited human data

aMany of these classes can be further subclassified on the basis of chemical structure; however, the relationship between structure and clinical effects is not adequately described. The classification listed here is adapted from http://www.alanwood.net/pesticides/class_herbicides.html. Accessed December 9, 2012.

b The mechanism by which a number of herbicides regulate plant growth is not fully described. The mechanisms listed here are adapted from http://www.plantprotection.org/HRAC/MOA.html. (Accessed December 9, 2012) and http://www.ces.purdue.edu/extmedia/WS/WS- 23-W.html (Accessed December 9, 2012).

c WHO Hazard Classification scale for oral liquid exposures of the technical grade ingredient based on rat LD50 (mg/kg body weight): Ia = “extremely hazardous,” < 20 mg/kg; Ib = “highly hazardous,” 20–200 mg/kg; II = “moderately hazardous,” 200–2000 mg/kg; III = “slightly hazardous,” > 2000 mg/kg; and U = “technical grade active ingredients of pesticides unlikely to present acute hazard in normal use.”

CNS = central nervous system; WHO = World Health Organization.

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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 can vary among studies in the same type of animal, and between different species. For example, in the

83 case of paraquat the LD50 in rats, monkeys, and guinea pigs is reported as 125 mg/kg, 50 mg/kg, and 25 mg/kg, respectively. 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 may contribute to the overall toxicity.

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

Contribution of Coformulations

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

The most widely discussed example of a coformulant dominating the toxicity of an herbicide product is that of glyphosate-

containing products, which is discussed below. Another example is imazapyr, which has an LD50 in rats of 1500 mg/kg intraperitoneally (IP) compared with 262 mg/kg IP when administered as the product Arsenal. This difference is attributed to

the surfactant nonylphenol ethoxylate used in this product, which has an LD50 of 75 mg/kg IP. In vitro studies with a number

of formulations demonstrate increased cardiovascular toxicity compared with the technical herbicides.13 Similarly, coformulants increase the in vitro toxicity from phenoxyacetic acid derivatives and glufosinate.

Impurities may also be generated during manufacture or storage of the herbicide formulation, which can contribute to toxicity. For example, phenolic byproducts from the manufacture of phenoxyacetic acid herbicides may be found as impurities in commercial formulations. Some proprietary products contain a combination of herbicidal compounds that probably have additive effects, further complicating the risk assessment of an acute exposure.

Epidemiology

The incidence of poisoning with individual herbicides depends on their availability. Availability is associated with local marketing practices and is reflected in sales in the domestic sector. For example, paraquat poisonings are now rare in the United States, while the incidence of glyphosate poisoning has increased. Similarly, after paraquat was banned in Japan in the late 1980s there was an increase in the number of glufosinate poisonings.

Herbicide poisoning is a major issue in developing countries of the Asia-Pacific region where subsistence farming is common and herbicide use is relatively high. By contrast, the incidence of severe herbicide poisoning is less in developed countries because the population is concentrated in urban areas where access is limited to lower toxicity herbicides that are sold in smaller volumes as diluted formulations intended for household use (Chaps. 113 and 137).

Regulatory and Considerations

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

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The toxicity of herbicides varies among individual xenobiotics, but as a group, they appear to be intrinsically more toxic than medications when ingested with suicidal intent. Restrictions of the availability and formulation of toxic herbicides by regulatory authorities may improve outcomes from herbicide poisoning. For example, in the context of self-poisoning, the replacement of highly toxic pesticides with less toxic compounds can decrease the overall mortality97 without altering agricultural outputs.72 Prospective cohort studies have been 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, 10.7%99; and paraquat, 50% to 70%.128 This information is of interest to regulatory authorities in their control of the marketing, sales, and formulation of herbicides.

Regulatory bodies must also consider 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 can occur when the herbicide is rapidly inactivated or binds strongly to soil components. For example, paraquat and glyphosate are inactivated when they contact soil, which is favorable because they remain in the region of application. By contrast, atrazine is more mobile, allowing it to leach into groundwater and migrate great distances. While the concentration of atrazine at distant sites is low, there is concern that it has the potential to alter the growth and development of nontarget plants and animals.104

GENERAL COMMENTS FOR THE MANAGEMENT OF ACUTE HERBICIDE POISONING

Diagnosis

Herbicide poisoning is diagnosed following a specific history or other evidence of exposure (such as an empty 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 due to variability in salts, concentrations, and coformulants. Further, in some cases it is also necessary to determine the specific type of a brand; for example, the product called Roundup contains glyphosate but it is sold in different formulations worldwide within market sectors.

Depending on local laboratory resources it may be possible to confirm the diagnosis with a specific assay, such as paraquat and glufosinate, but these are not usually available in a clinically meaningful timeframe.

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

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

Initial Management

An accurate risk assessment is necessary for the proper triage and subsequent management of patients with acute herbicide poisoning. Risk assessment involves consideration of the dose ingested, time since ingestion, clinical features, patient factors, and availability of medical facilities. All intentional exposures should be considered 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 a health care facility.

For many herbicides the initial management of an acute poisoning follows standard guidelines. All patients should receive prompt resuscitation emphasizing the airway, breathing, and circulation. Gastrointestinal toxicity, such as nausea, vomiting,

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and diarrhea, is common, leading to salt and water depletion that requires the administration of antiemetics and intravenous fluids.

Gastrointestinal decontamination may decrease absorption of the herbicide from the gut, reducing systemic exposure. Gastric lavage is generally not recommended in acute poisoning because patients usually present too late or have self- decontaminated from vomiting and diarrhea. Lavage has been used by some practitioners for patients presenting shortly after an ingestion of a liquid formulation for which treatment options are limited. Depending on the procedure used, this treatment may cause harm and should only be conducted by an experienced clinician when the airway is protected. Ingestion of a corrosive product is a relative contraindication. Oral activated charcoal may be given if the patient presents within 1 to 2 hours of ingestion of an herbicide known to cause significant poisoning. In the case of some herbicides there is prolonged absorption (eg, propanil, MCPA), so later administration of activated charcoal may be reasonable.

Specific antidotes are available for only a few herbicides, which reflect their ill defined mechanisms of toxicity.

Extracorporeal techniques, including hemoperfusion and hemodialysis, may decrease the systemic exposure by increasing the rate of elimination. The role of these treatments is discussed below for each pesticide.

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

Laboratory investigations may be 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 where possible. Respiratory distress and hypoxia with focal respiratory crackles soon after presentation are likely to result from aspiration pneumonitis, which can be confirmed on chest radiography.

Patients with a history of acute ingestion should be observed for a minimum of 6 hours. Patients with a history of intentional ingestion and gastrointestinal symptoms should be observed for at least 24 hours depending on the herbicide given that clinical toxicity may progress or be delayed in some cases.

Occupational and Secondary Exposures (Including Nosocomial Poisoning)

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

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

Amide Compounds, Particularly Anilide Derivatives

Anilide compounds are the most widely used amide herbicides, of which propanil (3′4′-dichloropropionanilide {DCPA}), alachlor (2-chloro-2′,6′-diethyl-N-methoxymethylacetanilide), and butachlor (N-butoxymethyl-2-chloro-2′,6′ -diethylacetanilide) are particularly common. Other amide herbicides and available toxicity data are listed in Table 112–1. In 2007, acetochlor, propanil, metolachlor, and dimethenamid were among the top herbicides used 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. 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

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of less than 3% for butachlor, metachlor, and alachlor. Poor outcomes may reflect the inadequacies of current treatment regimens.

Pharmacology

Most of the clinical manifestations of propanil poisoning are mediated by its metabolites. 3,4-Dichlorophenylhydroxylamine is the most toxic metabolite and it directly induces methemoglobinemia and hemolysis in a dose-related manner. 3,4-Dichlorophenylhydroxylamine is cooxidized with oxyhemoglobin (Fe2+) in erythrocytes to produce methemoglobin (Fe3+; Chap. 127).

However, toxicity may not be solely attributed 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 may contribute to clinical outcomes. Rats show signs of toxicity despite inhibition of the hydrolytic enzymes that metabolize propanil (Fig. 112–1) and in the absence of methemoglobinemia, supporting direct toxicity from propanil itself.115 Coformulants may also contribute.

FIGURE 112–1. Structures of common anilide compounds and the bioconversion of propanil.

The hydroxylamine metabolite depletes glutathione, which may induce toxicity, although this is not consistently reported. Other possible toxicities from the of propanil include nephrotoxicity, lipoperoxidation, myelotoxicity, and immune dysfunction; the significance of these toxicities is poorly defined.

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

Pharmacokinetics and Toxicokinetics

Absorption is rapid in animals, with a peak serum concentration expected one hour postingestion. The volume of distribution (Vd) of propanil has not been determined, 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 where uptake and distribution of propanil were noted to be extensive. Anilide compounds interact with adenosine triphosphate (ATP)-binding cassette transporters, which may also influence the kinetics.

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Anilide compounds undergo sequential metabolic reactions that produce toxic xenobiotics (Fig. 112–1). 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 isoenzyme has not been determined. N-hydroxylation of 3,4-dichloroaniline produces the hydroxylamine compound that induces hemolysis and methemoglobinemia, which are the most obvious manifestations of propanil poisoning.76,77,115

These bioactivation reactions appear to be fairly rapid, whereas 3,4-dichloroaniline and methemoglobin are formed within 2

to 3 hours of parenteral administration of propanil to animals. The hydroxylation of 3,4-dichloroaniline may be 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.

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, which varies with dose, and cytochrome P450 activity (Chap. 127).

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 may reflect 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 while in a fatal case the concentration of 3,4-dichloroaniline continued to increase until at least 30 hours postingestion.99 By 36 hours postingestion the concentration of 3,4-dichloroaniline is low in survivors, so clinical toxicity is unlikely to increase beyond this time.99

Pathophysiology

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

Clinical Manifestations

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

Alachlor, metachlor, and butachlor appear to be 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

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cardiac dysrhythmias; hypotension and coma preceded death.71,112 Methemoglobinemia was not reported in these studies. Hepatic dysfunction was reported following dermal occupational exposure to butachlor.

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

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

Diagnostic Testing

Patients with a history of propanil poisoning should be investigated for the presence of methemoglobinemia (Chap. 127).

While the concentrations of propanil and 3,4-dichloroaniline appear to 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 has not been validated. Further, the relationship between concentration and outcomes may depend on patient comorbidities.

Management

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

Routine clinical observations are sufficient to detect signs of poisoning, in particular, sedation and clinical cyanosis. Until more data are available it seems reasonable to focus treatment on reversal of methemoglobinemia. There is sufficient time to initiate specific treatments in propanil poisoning given that clinical signs of poisoning are noted early postingestion, yet the time to death is usually greater than 24 hours. 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 empirical.

Resuscitation and Supportive Care.

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

Hemoglobin concentrations should be monitored to detect hemolysis, and folate supplementation may be necessary during the recovery phase if anemia is significant.

Gastrointestinal Decontamination.

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

Extracorporeal Removal.

Treatment with combined hemodialysis and hemoperfusion was associated with a propanil elimination half-life of one hour, although clearance was not directly measured.86 However, half-lives as short as one hour have been reported in patients who have not received this treatment,99 so its efficacy remains unknown. Exchange transfusion has the potential to decrease the concentration of propanil and free hemoglobin, while replacing reduced hemoglobin and hemolyzed erythrocytes. However, the function of transfused erythrocytes is temporarily impaired posttransfusion because of depletion of 2,3-bisphosphoglycerate during storage. Further, transfusion reactions such as acute respiratory distress syndrome may occur, which is of concern 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 (Chap. 10).

Antidotes.

Antidotes are largely used for the treatment of methemoglobinemia. Methylene blue (Antidotes in Depth: A41) is considered 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 may be prevented by administration of methylene blue as a constant infusion.

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

BIPYRIDYL COMPOUNDS, PARAQUAT AND DIQUAT

Bipyridyl compounds are nonselective contact herbicides. The most widely used is paraquat (1,1′-dimethyl-4,4′ -bipyridinium), but diquat (1,1′-ethylene-2,2′-bipyridyldiylium) is also commonly used (Fig. 112–2). 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 may be coformulated with paraquat (allowing a lower concentration of paraquat) or used as an alternative in countries where paraquat is severely restricted. Because more data are available on paraquat than diquat, much of the following discussion and information relates particularly to paraquat.

FIGURE 112–2. Structures of paraquat and diquat.

Pharmacology

Paraquat and diquat formulations are highly irritating and often corrosive, causing direct injury. Paraquat induces intracellular toxicity by the generation of reactive oxygen species that nonspecifically damage the lipid membrane of cells,

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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. 112–3). 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 as long as 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.18,22

FIGURE 112–3. Toxicology of paraquat (PQT) and proposed mechanisms of action of potential treatments. Antioxidants include vitamins C and E and glutathione donors (particularly N-acetylcysteine, S-carboxymethylcysteine). PQT• = paraquat radical; NO• = nitric oxide; ONOO– = peroxynitrite; OH• = hydroxyl radical.

Supplemental oxygen probably increases the generation of reactive oxygen species.

Pharmacokinetics and Toxicokinetics

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

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The oral bioavailability of paraquat varies among animal species, but overall it is low (< 10%). The 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 allows sufficient paraquat to be absorbed for significant poisoning to occur. Absorption is rapid and the peak concentration occurs within one hour. Coingestion of food may decrease the absorption of paraquat. Recently, paraquat was reformulated with an increased 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 it may not have been sustained.128

Paraquat binds minimally to plasma proteins. Paraquat and diquat rapidly distribute to all tissues where they accumulate but may 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; this may be delayed in the context of kidney impairment.5 Paraquat slowly redistributes from the lungs into the systemic circulation as the plasma concentration falls, which may reflect impaired pneumocyte function from acute respiratory distress syndrome. By contrast, diquat uptake occurs to a limited extent.

Paraquat and diquat are not metabolized and 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 Its clearance initially exceeds that of creatinine because of active secretion and also through increased renal blood flow.12 Renal clearance may be reduced by exogenous compounds or an acidic urine pH.12 Impaired kidney function is commonly reported with paraquat and diquat poisoning, 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 In animals, the terminal elimination half-life of paraquat is more than 50 hours.84

Pathophysiology

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

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

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

Necrosis of the gastrointestinal tract limits intake 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 may lead to irreversible organ injury and death.

Clinical Manifestations

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

Most ingestions of bipyridyl compounds induce poisoning, where ingestion of as little as 5 mL of paraquat 20% wt/vol can cause death in more than 50% of cases. 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 pseudodiphtheria117) and ulceration are prominent symptoms that occur within 12 hours. Oromucosal injury has been observed following brief oral exposures without swallowing. Dysphagia and odynophagia follow larger exposures and may progress to esophageal rupture, mediastinitis, subcutaneous emphysema, and pneumothorax, which are preterminal events. Death is more likely in those patients who experience a peripheral burning sensation.29

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

By contrast, acute lung injury 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 may be followed by progressive pulmonary fibrosis and death weeks or months postingestion. Varying degrees of acute kidney injury and hepatic dysfunction can also occur.6,48 Acute kidney injury peaks around 5 days postingestion and resolves within 3 weeks in survivors.54 Paraquat-induced pulmonary injury can resolve to near-normal function over months to years in survivors.66

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

Ingestion of the adjuvant for Gramoxone Inteon can induce minor gastrointestinal symptoms, an elevated serum osmolar gap and metabolic acidosis with hyperlactatemia, but outcomes are favorable.80

Diagnostic Testing

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

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

Given that outcomes from paraquat poisoning are generally poor, diagnostic tests may help differentiate patients who may survive from those in whom death is almost certain. The dose of paraquat is a well-established predictor of death, although this information may not be accurately known at the time of admission. Investigations in patients with acute paraquat

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poisoning have attempted to determine the severity of poisoning and better define prognosis. Unfortunately, few have been validated so their predictive ability is unconfirmed. A range of prognostic tests has been reviewed24 and a selection of these are discussed below.

Quantitative analysis of the concentration of paraquat in plasma is useful for prognostication, and a number of similar nomograms have been developed to assist with this process (Fig. 112–4). 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) can also be 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.

(A) Compilation of three nomograms proposed by Proudfoot et al,94 Scherrmann et al,108 and Jones et al.52

(B) Hart paraquat nomogram.36 In A, concentrations below lines predict survival. In B, lines link concentrations of equal probability of survival. (Reproduced with permission from Eddleston M, Wilks MF, Buckley NA. Prospects for treatment of paraquat-induced lung fibrosis with immunosuppressive drugs and the need for better prediction of outcome: a systematic review, QJM 2003;96(11):809–824.)

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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, kidney function, and liver function tests.24 Various specific changes have been proposed to predict death (eg, metabolic acidosis with hyperlactatemia), but few have been validated. In general, any abnormal result raises the suspicion of a significant poisoning.

A raised admission creatinine concentration predicts death but is neither sensitive nor specific, although the higher the creatinine concentration, the higher the risk of death.31,54,58,102

The rate of increase in creatinine concentration is a simple and practical test to predict prognosis. An increase less than 0.03 mg/dL/h (3 µmol/L/h) over 5 hours predicts survival,95 or greater than 0.05 mg/dL/h (4.3 µmol/L/h) over 12 hours (sensitivity 100%, specificity 85%, likelihood ratio 7) predicts death.102 A similar relationship was noted for cystatin C, where 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 the rate of increase can be 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 likely to 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.

Management

Because death can occur following 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 can be conducted.

Many medical interventions have been 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.

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. The literature is complicated by case reports describing survival in patients who were administered one or a combination of therapies, despite apparently poor prognosis. Various other treatments have been studied in animals including pirfenidone, complement inhibition, p-sulfonatocalix-[4]arene, dimercaptopropane sulfonate, ambroxol, and selenium, but human data are lacking.

The choice of which interventions should be administered to a patient is best made on a case-by-case basis by the treating physician in consultation with relevant resources. Detailed discussion with the patient and relatives early in the presentation is recommended to determine their preference for treatment modalities in the context of the estimated prognosis (see above). 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. Treatments that reduce the exposure to paraquat by either reducing absorption or increasing clearance must be initiated promptly. In contrast, active treatment seems unlikely to be of assistance to patients in whom this test is strongly positive, or those with evolving multiorgan dysfunction. Instead, palliation should be the priority, including oxygen for hypoxia and morphine for dyspnea and oropharyngeal and abdominal pain.

Serial pulse oximetry measurements and chest radiographs will demonstrate development 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 Patients developing acute kidney injury should receive hemodialysis or hemofiltration per usual guidelines if active treatment is to be pursued, and these treatments may also enhance elimination of herbicide if commenced promptly (see below).

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Resuscitation and Supportive Care.

All patients should receive prompt routine resuscitation and close observation. Oxygen should be administered to patients for palliation only 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 can theoretically hasten the progression of injury. Intravenous fluids should be administered to patients who are volume depleted from poor intake, diarrhea, or third- space shifts, as this may reduce the extent of acute kidney injury and promote renal clearance of paraquat. Care is required with volume resuscitation in the context of acute kidney injury to prevent fluid overload. Electrolyte abnormalities may also occur and these should be corrected as required.

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

Gastrointestinal Decontamination.

Paraquat is coformulated with an emetic so self-decontamination may have occurred by the time of presentation to hospital. Fuller’s Earth and activated charcoal have been advocated to decrease absorption of paraquat. Both adsorb paraquat to a similar extent but Fuller’s Earth is of limited supply.4 However, paraquat is rapidly absorbed so decontamination should be commenced within a few hours of ingestion. Gastric lavage has not been shown to improve outcomes and may even be harmful if administered to patients ingesting less than 30 mL.127

Extracorporeal Removal.

Extracorporeal techniques, including charcoal hemoperfusion, plasmapheresis, and hemodialysis/filtration, have been studied to decrease the systemic exposure by increasing the rate of elimination. 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 clearance is maximized when treatment is initiated within the first couple of hours because the plasma concentration is high.39 Further, given that paraquat rapidly distributes from the circulation, prompt treatment is necessary to limit the uptake into pulmonary and other tissues.89

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

Past experience suggested that extracorporeal treatments do not sufficiently improve mortality in humans, particularly when the concentration is greater than 3 mg/L.35 Hemoperfusion followed by continuous venovenous hemofiltration may prolong the time to death compared with hemoperfusion alone without changing the overall mortality in a randomized, controlled trial. All patients in this study also received high-dose dexamethasone and ascorbic acid.57 However, increasing publications from eastern Asia suggest a clinical benefit from these therapies if commenced early but confirmatory data would be of interest.

Extracorporeal techniques may also induce harm because of the requirement for central venous access, metabolic disequilibrium, or increased clearance of antidotes. Therefore, their use requires careful consideration on a case-by-case basis.

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Antidotes.

A large number of potential antidotes have been studied in the treatment of acute paraquat poisoning. They attempt to counteract the effects of paraquat by targeting various steps in the pathogenesis of organ dysfunction or to alter cellular uptake (Fig. 112–3). Unfortunately, none of these antidotes are proven to reduce mortality. Some of the interventions that decrease paraquat exposure by decreasing absorption126 or increasing elimination57 were shown to prolong the time to death. Therefore, combining these treatments with effective antidotes in a multimodal approach to treatment may reduce mortality. The combination (if any) that will improve outcomes is not known, more research is required to determine the role of the various proposed antidotes in routine clinical care.

Immunosuppression with corticosteroids (dexamethasone or methylprednisolone) and cyclophosphamide are the most extensively studied antidotes in humans. Early randomized controlled trial data (three trials, n = 164 patients) suggested a benefit from these treatments but due to 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, this immunosuppressive regimen is not currently recommended.

Generation of reactive oxygen species is an important step in the pathogenesis of paraquat poisoning (Fig. 112–3). This leads to cytotoxicity, the extent of which depends on the concentration of paraquat at the cellular level and the efficiency of endogenous protective mechanisms. Scavenger defense mechanisms against reactive oxygen species include antioxidants 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) to patients did not improve outcomes in every human or animal study. Poor intracellular penetration to the site of redox cycling may limit the effect of some compounds. Potentially, vitamin C might increase oxidative toxicity.22 Typical doses that have also been used in patients with acute poisoning include: vitamin E 300 mg orally twice daily, vitamin C 25 mg/kg/day or 3 g/day for 7 days, and N-acetylcysteine 150 mg/kg over 3 hours as a loading dose followed by 500 mg/kg/day by continuous infusion. The scavenging agents superoxide dismutase and amifostine and the iron chelator deferoxamine have also been studied, but results were not encouraging.

Some treatments may influence the toxicokinetics of paraquat at the cellular level. Xenobiotics that decrease the uptake of paraquat into pneumocytes have been studied such as putrescine, spermidine, and deferoxamine, but their effect is limited and they do not alter efflux. Corticosteroids, particularly dexamethasone and methylprednisolone, have been shown in animal models to induce p-glycoprotein, which increases the cellular efflux and excretion of paraquat.

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 in Sri Lanka 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.

Treatment Recommendations.

Most clinical studies have not demonstrated favorable outcomes, in contrast to animal studies, which may reflect higher toxicity or delayed institution of therapy. Studies reporting a delayed time to death suggest a possible effect, prompting further research into dose-response and the effect of combination therapy. Active treatment, particularly with invasive modalities such as hemoperfusion/dialysis is anticipated to interfere with end-of-life care. Based on these principles, our recommendations favor intervention where there may be a hope of recovery, while limiting therapeutics desperation. The

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prognosis in patients presenting more than 12 hours after ingesting 50 mL or more of paraquat 20% wt/vol, those with a positive plasma dithionite test, or those with a SIPP greater than 50 is so poor that treatment should focus on symptom control and end-of-life support and palliation. The prognosis in patients presenting within 6 hours of ingesting less than 50 mL of paraquat, those with a faint-positive dithionite test, or those with a SIPP less than 50 is also poor but prompt multimodal treatment with volume resuscitation, oral activated charcoal (or Fuller’s earth), hemoperfusion or hemodialysis, intravenous corticosteroids, acetylsalicylate, acetylcysteine, deferoxamine, and vitamin E can be commenced. It cannot be over-emphasized that any potential benefit of these treatments 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 timeframe. Other exposures not yet mentioned are associated with poor prognosis and unlikely to respond to treatment. However, if resources are available and psychosocial 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.

GLUFOSINATE

Glufosinate ({2RS}-2-amino-4-{hydroxy(methyl)phosphinoyl}butyric acid; Fig. 112–5) is a nonselective herbicide used predominantly in Japan, which is where most cases of acute poisoning are reported; however, use is increasing in other parts of Asia. 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

FIGURE 112–5. Structure of glufosinate.

Pharmacology

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

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

The extent to which the surfactant contributes to clinical toxicity has not been 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 observed in a single case report of glufosinate ammonium poisoning.70

Pharmacokinetics and Toxicokinetics

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

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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.

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 to the central nervous system, and in a case of acute poisoning the cerebrospinal fluid concentration was one-third the serum concentration 27 hours postingestion. The rate of distribution to the cerebrospinal fluid has not been characterized, but it is theorized that glufosinate might distribute to the central nervous system slowly (perhaps due to active transporters) where it accumulates, which is why the onset of respiratory depression is delayed.44 This theory was not supported in a case where glufosinate was not detected in the cerebrospinal fluid 6 hours after a seizure that occurred 30 hours postingestion.121 Indeed, seizures have occurred in some patients after glufosinate was no longer detectable in the blood.124 Seizures occur 3 hours postadministration of intracerebral glufosinate in rats, which further challenges the theory that distribution kinetics influence the delayed onset of seizures in humans.34

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

The elimination half-life is 4 hours in rats, while 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 where the elimination profile appeared biphasic with a distribution half-life of 2 to 4 hours and a terminal elimination of 10 to 18 hours.38,41,118

Pathophysiology

It is not known whether the manifestations of glufosinate poisoning represent a primary (toxic) or secondary (downstream) effect. The most important manifestations are neurological, 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 may lead to irreversible cellular injury and death.

Clinical Manifestations

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

Other manifestations include cardiac dysrhythmias, fever, amnesia (antegrade and retrograde), diabetes insipidus, and rhabdomyolysis. Refractory hypotension may be preterminal.60,73,74

Diagnostic Testing

Glufosinate poisoning is diagnosed clinically in the context of a history of exposure. Glufosinate assays are available for clinical use in Japan and a nomogram was developed for predicting clinical outcomes (Fig. 112–6).40 Clinical chemistry assays including kidney function, blood gases, electrolytes, creatine kinase, and ammonia concentrations may support clinical management. Metabolic acidosis is more common with severe poisoning.74 The ammonia concentration is not often

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markedly elevated or does not consistently correlate with clinical outcomes. If serial measurements identify an increasing concentration this may suggest increased risk of neurotoxicity.34,60,73

FIGURE 112–6. Glufosinate nomogram as described by Hori et al.40 Concentrations above the line are associated with more severe poisoning.

Management

Although toxicity appears to be dose dependent, 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 can be delayed. Prior to discharge, each patient should be carefully screened to identify those with memory deficits.

Resuscitation and Supportive Care.

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

Gastrointestinal Decontamination.

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

Extracorporeal Removal.

Hemodialysis and hemoperfusion have been used in the management of acute glufosinate poisoning. Hemodialysis appears to be superior to hemoperfusion in terms of extraction of glufosinate from whole blood in vitro, with an extraction ratio of 80%. However, the clearance by hemodialysis is less than 60% of renal clearance in patients with normal kidney function. Prompt hemodialysis in patients decreases the concentration of glufosinate and probably ammonia but 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 consider these treatments in patients with severe poisoning and also in those with impaired kidney function.

Antidotes.

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Specific antidotes are not available. Rat studies did not demonstrate benefit with the use of atropine and pralidoxime. Ethanol coingestion appears to be protective. Benzodiazepines should be first-line therapy for seizures.

GLYPHOSATE

Glyphosate (N-{phosphonomethyl}glycine; Fig. 112–7) 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 2007, 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 may differ with respect to their toxicity profile.

FIGURE 112–7. Structure of glyphosate.

Pharmacology

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

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

Experimentally, there is minimal (if any) mammalian toxicity from glyphosate itself. Glyphosate is categorized as WHO class 49 “U” (unlikely to present acute hazard in normal use; LD50 > 4000 mg/kg). Surfactant coformulants are considered the more

toxic component in glyphosate-containing herbicides. Polyoxyethyleneamine (tallow amine; LD50 equal to 1200 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 may also contribute to toxicity. Isopropylamine has a rat LD50 of 111 to 820

mg/kg, decreases vascular resistance, and may either increase or decrease cardiac contractility and rate.50,93

Pharmacokinetics and Toxicokinetics

The kinetics of the surfactant has not been 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

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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 model82). Glyphosate has an elimination half-life that is less than 4 hours and is excreted unchanged in the urine.7,9,43,100,125

Pathophysiology

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

Clinical Manifestations

Abdominal pain with nausea, vomiting, and/or diarrhea are the most common manifestations of acute poisoning. These may be mild and self-resolving, but in patients with severe poisoning there may be inflammation, ulceration, or infarction. Severe diarrhea and recurrent vomiting may induce dehydration. Gastrointestinal burns and necrosis occur with high doses of concentrated formulations and may be associated with hemorrhage. Extensive erosion of the upper gastrointestinal tract is associated with more severe systemic poisoning and a prolonged hospitalization.14,15,47,79,100

Severe poisoning manifests as multiorgan failure, including hypotension, cardiac dysrhythmias, kidney and liver dysfunction, hyperkalemia, pancreatitis, pulmonary edema or pneumonitis, altered level of consciousness including encephalopathy, and metabolic acidosis. These effects may be transient or severe, progressing over 12 to 72 hours to resistant shock, respiratory failure, and death. The mechanism of hypotension may relate to both hypovolemia (fluids shifts and increased losses) and/or direct cardiotoxicity.7,15,65,69,79,100,111,120

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

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

Respiratory, ocular, and dermal symptoms may occur following occupational use of these preparations but are usually of minor severity. Significant skin reactions from topical exposure are also reported.

Diagnostic Testing

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

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A number of clinical criteria for the classification of severity are suggested, but none have been validated.7,100,120,122 There are no readily available specific clinical investigations to guide management or estimate prognosis in acute poisoning. Higher glyphosate plasma concentrations are associated with more severe poisoning; for example concentrations greater than 734 mg/L predicted death in one study,100 while a review noted that severe poisoning is associated with concentrations greater than 1000 mg/L.7 These concentrations probably reflect the amount of exposure, since glyphosate is minimally toxic. However, quantitative glyphosate assays are not routinely available for clinical use.

Targeted laboratory and radiological investigations should be conducted in patients demonstrating anything more than mild gastrointestinal symptoms. Pulse oximetry and blood gas measurements may be useful for detection of metabolic disequilibria and respiratory impairment. Electrolytes should be measured early because some formulations contain glyphosate as a potassium salt and severe hyperkalemia is reported.

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

Endoscopy can diagnose erosions or ulceration following exposures to the concentrated formulation. However, this procedure may be complicated by perforation and may not change management, so its use requires careful consideration.

Management

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

Resuscitation and Supportive Care.

All patients should receive prompt resuscitation, close observation, and routine supportive care; other treatments are largely empiric. The airway is usually maintained but respiratory failure and respiratory distress 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 should be used. Other investigations such as echocardiography, central venous pressure, or pulmonary artery catheter may also guide management, if available.

Biochemical and acid–base abnormalities, such as hyperkalemia, should be corrected where possible. The contribution of uncoupling of oxidative phosphorylation to clinical toxicity and death has been proposed, but no specific treatment is available if this develops. 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, may be 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.

Gastrointestinal Decontamination.

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

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Extracorporeal Removal.

Patients who received hemodialysis have survived severe poisoning; however, other patients have died despite this treatment. Plasmapheresis has also been studied but clearances were not determined. Early initiation of any of these treatments may be required for best results. The role of extracorporeal removal in routine care is not known given that there are limited quantitative data reporting direct clearances, and uncertainty regarding what compound to measure.

Antidotes.

No specific antidote has been 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), MCPA, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T; no longer available), and mecoprop (MCPP; 2-{4-chloro-2-methylphenoxy}propionic acid; Fig. 112–8). Other phenoxy herbicides and available toxicity data are listed in Table 112–1. In 2007, 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 fourth most commonly used in the domestic sector).33

FIGURE 112–8. Structures of common phenoxy herbicides.

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 the contaminant dioxin (2,3,7,8-tetrachlorodibenzodioxin), which was a byproduct of the manufacture of phenoxy herbicides. Dioxin is a persistent organic pollutant that is alleged to induce chronic health conditions and cancer, although this has been debated. This chapter discusses only the outcomes of acute exposures to phenoxy herbicides.

Pharmacology

The mechanism of toxicity of phenoxy compounds is not well described. The formulation is irritating or corrosive, 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 may reflect the contribution of coformulants such as 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 kidney injury from 2,4-D is observed in rats.

Uncoupling of oxidative phosphorylation also may contribute to the development of severe clinical toxicity. Phenoxyacetic derivatives demonstrate concentration-dependent uncoupling of rat mitochondria in vitro, although the specific process that

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is disrupted is not sufficiently described.10,133 Features of uncoupling of oxidative phosphorylation were observed antemortem in clinical studies of patients with large 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 may contribute 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 have shown 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 order1; however, the time to peak concentration may be delayed with increasing doses, which may suggest saturable absorption (this 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 may increase the Vd and prolong 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 flow 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, which may explain the persistence of clinical toxicity and why death may occur a number of days postingestion of a phenoxyacetic herbicide.98,101

Alterations in blood pH may also change tissue distribution because phenoxyacetic herbicides are weak acids (pKa ∼ 3). Here, acidemia increases the proportion that is nonionized, and therefore lipophilic, which increases tissue binding and distribution. This has been observed in vitro and is similar to that observed for salicylates (Chap. 39). 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 may reflect a discordance between plasma (measured) and intracellular (eg, mitochondrial) concentrations.

Pathophysiology

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Direct injury to the gastrointestinal tract may cause 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 may be caused by chemicals that disrupt mitochondrial function, and causes inefficiency in energy production. At a cellular level it describes an increase in oxygen consumption and heat production out of proportion to the generation of ATP due to mitochondrial dysfunction. Varying degrees of uncoupling of oxidative phosphorylation may 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 lactic 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

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, kidney toxicity, 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 who died, which may be consistent with increased mitochondrial respiration from mild uncoupling. More severe poisoning may be 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 potentially 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 in Sri Lanka demonstrated minor toxicity in greater than 80% of patients and a mortality of 4.4% (eight 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 it may relate to uncoupling of oxidative phosphorylation or other metabolic dysfunction including acute kidney injury, as discussed above.

Diagnostic Testing

Commercial assays for the specific measurement of phenoxy herbicides are not available to assist in the diagnosis of acute poisoning. Further, their role in the management of acute poisoning is not confirmed because the relationship between plasma phenoxy herbicide concentration and clinical toxicity appears to be poor.98 Sedation is reported with a plasma phenoxy concentration above 80 mg/L,96 while 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 a number of days and resolved when the MCPA plasma concentration was less than 100 mg/L.109 By contrast, death has been reported following MCPA poisoning at plasma concentrations as low as 107 mg/L to 230 mg/L.51,90,98

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Monitoring of electrolytes, kidney function, pulse oximetry, and blood gases is recommended to detect progression of organ toxicity. Hypoalbuminemia may predispose to severe poisoning.101 Creatine kinase should be determined since rhabdomyolysis may occur following acute poisoning. Urinalysis might be useful for identifying myoglobinuria. There are insufficient data describing the role of these measurements for prognostication.

Management

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 (eg, gastrointestinal symptoms but normal vital signs and level of consciousness at presentation) 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) may optimize the renal excretion of phenoxy herbicides as well as decreasing renal toxicity from rhabdomyolysis. Since signs consistent with uncoupling of oxidative phosphorylation are likely to be associated with a poor outcome, more advanced treatments such as hemodialysis can be considered in these patients.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 given that this may promote the distribution of weak acids and increase the intracellular concentration.

Gastrointestinal Decontamination.

Gastrointestinal decontamination can be administered to patients per the guidelines listed in Chap. 8. However, administration of activated charcoal beyond the usual time frame is reasonable given that absorption appears to be saturable.

Extracorporeal Removal.

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 has been studied in a few cases, with clearances approaching 75 mL/minute. Hemodialysis should be considered in patients with severe poisoning if facilities are available.

Antidotes.

There are no specific antidotes for phenoxy herbicides, but sodium bicarbonate or other alkalinizing agents may have a role in management by altering the kinetics of phenoxy herbicides.

Data from animal studies and case reports suggest that urinary alkalinization increases the elimination of phenoxy herbicides. Increases in urinary pH increase clearance due to “ion trapping” of the phenoxy herbicide. For example, renal 2,4-D clearance was increased from 5.1 mL/minute to 63 mL/minute 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 has the potential to be clinically significant. Prospective, randomized studies are required to confirm the efficacy of urinary alkalinization in humans.

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Plasma alkalinization may also limit the distribution of phenoxy compounds from the central circulation by “ion trapping.”

It is reasonable to consider plasma and urinary (urine pH > 7.5) alkalinization 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. 112–9) 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 2007 atrazine and simazine were among the 25 most used pesticides in the United States.33 However, cases of acute poisoning are infrequent. Other herbicides included in this group are listed in Table 112–1. These selective herbicides may be used pre- or postemergence for weed control.

FIGURE 112–9. Structures of common triazine herbicides.

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.

Pharmacology

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 some biologic activity.2 Similarly, clinical features of prometryn poisoning resolved posthemodialysis despite persistence of the parent herbicide, suggesting that toxic metabolites 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 where 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 those derived from glutathione conjugation. Other metabolic products as a result of 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

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There are limited cases of triazine herbicide poisoning. Vomiting, depressed level of consciousness, tachycardia, hypertension, acute kidney injury, and metabolic acidosis with 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 112–1), and other toxic compounds. 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

Diagnostic Testing

In a single case report, clinical toxicity did not directly relate to the concentration of prometryn, but the relationship to the concentration of metabolites has not been determined.11 Routine biochemistry and blood gases are useful for monitoring for the development of systemic toxicity.

Management

Few publications of triazine herbicide poisoning are available to guide 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 reasonable.

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, which might reflect ongoing absorption. 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

Antidotes.

No antidotes are available for the treatment of triazine herbicide poisoning.

SUMMARY

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.

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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.

Acknowledgment

Rebecca L. Tominack, MD, and Susan M. Pond, MD, contributed to this chapter in previous editions.

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