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112: Herbicides Page 1 of 47 Goldfrank's Toxicologic Emergencies, 10e > 112: Herbicides Darren M. Roberts HISTORY, CLASSIFICATION, AND EPIDEMIOLOGY An herbicide, 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 agriculture 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. Paraquat was marketed in the early 1960s, followed by dicamba later that decade. The development of new herbicides is an active area of research and new herbicides and formulations are frequently released into the market. This includes a number of novel structural compounds for which clinical toxicology data are unavailable. Hundreds of xenobiotics are classified as herbicides and a much larger number of commercial preparations are marketed. Some commercial preparations contain more than one herbicide to potentiate plant destruction. From another perspective, crops are being developed that are resistant to particular herbicides to maximize the selective destruction of weeds without reducing crop production. Herbicides are the most widely sold pesticides in the world, 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 glyphosate, atrazine, acetochlor, 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 diquat, although recently glyphosate and phenoxy acid compounds are more commonly implicated. Cases of severe poisoning that required hospitalization usually followed intentional self-poisoning. Significant toxicity 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 https://accessemergencymedicine.mhmedical.com/content.aspx?bookid=1163&sectionid=6... 9/3/2018 Page 2 of 47 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. https://accessemergencymedicine.mhmedical.com/content.aspx?bookid=1163&sectionid=6... 9/3/2018 Page 3 of 47 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, alachlor, derivatives. There are limited In 2007, acetochlor, dimethachlor, flufenacet, human data about the propanil, metolachlor, and mefluidide, metolachlor, nonanilide derivatives. dimethenamid are listed propachlor, 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 Butachlor, 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 Asulam, 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, https://accessemergencymedicine.mhmedical.com/content.aspx?bookid=1163&sectionid=6... 9/3/2018 Page 4 of 47 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 clopyralid, pyriminobac, compounds, particularly Inhibits acetolactate pyrithiobac, quinclorac, 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 auxins) 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, sethoxydim, Limited human data oxime for grasses U tralkoxydim Alloxydim, cycloxydim, cyhalofop https://accessemergencymedicine.mhmedical.com/content.aspx?bookid=1163&sectionid=6... 9/3/2018 Page 5 of 47 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 Pendimethalin induces mild grasses U Benfluralin (benefin), clinical toxicity in most cases, In 2007, trifluralin 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
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