GLYPHOSATE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Glycine, N-(phosphonomethyl)-
2) Glyphosate
3) MON 0573
4) MON 2139
5) N-Phosphonomethyl glycine
6) N-(Phosphonomethyl)glycine
7) Molecular Formula: C3-H8-N-O5-P
8) CAS 1071-83-6
9) Herbicides, Glyphosate

1.2.1) MOLECULAR FORMULA
1) C3H8NO5P
2) HOOCCH2NHCH2PO(OH)2

Available Forms Sources

1) Glyphosate is an odorless, colorless to white crystalline powder. It is a weak acid and zwitterionic (dipolar ion) with dissociation constants (pKa) that range from less than 2 to 10.6. As a 1% solution, it has a pH of 2 (HSDB, 2004; Pohanish, 2002; Krieger, 2001).
2) Glyphosate's technical purity grade is generally greater than 90% (averaging 96% purity on a dry weight basis). The minimum purity for technical grade glyphosate is 80% (HSDB, 2004; Krieger, 2001; IPCS, 1994).
3) Glyphosate herbicides are commonly applied in spray form and primarily formulated as either a water-soluble liquid or concentrate solution, or a solution made with a water-soluble powder and other ingredients. Glyphosate herbicides also come as pressurized liquids, aerosols, emulsions, pellets/tablets, granules, powders, and microencapsulated products (Meister, 2003; Giesy et al, 2000; Krieger, 2001; EPA, 2002; Harbison, 1998).
4) Glyphosate herbicides commonly consist of water and the isopropylamine (IPA) salt form (CAS 38641-94-0) of glyphosate, or they include water, the IPA salt, plus a surfactant and other inert ingredients. Commercial herbicides may contain other glyphosate salts (trimethylsulfonium, monoammonium, and sodium) as the active ingredient (HSDB, 2004; Pohanish, 2002; Giesy et al, 2000; EPA, 2002).
5) Glyphosate formulations and their toxicity differ depending on the type and concentration of the active ingredient and/or the added surfactants. The polyoxyethylene tallowamines (e.g., polyoxyethylene amine or POEA) is a class of surfactants most commonly used in glyphosate formulations. Other glyphosate herbicide additives include sulfuric and phosphoric acid and a variety of inert materials (HSDB, 2004; Giesy et al, 2000; EPA, 2002).

1) SOURCES OF EXPOSURE

a) OCCUPATIONAL

1) Potential occupational exposure to glyphosate exists for those involved in its manufacture, as well as the formulation and application of glyphosate herbicides. Worker exposure may occur during spraying, mixing, and cleaning. Potential exposure routes include inhalation, ingestion, and/or skin contact with the chemical or with plants and soil that have been sprayed. Worker exposure may also occur during transport, storage, and disposal of this chemical (HSDB, 2004; EPA, 2002; Pohanish, 2002).

b) GENERAL POPULATION

1) The general public may be exposed to glyphosate, given its widespread use for control of terrestrial and aquatic weeds in residential and recreational areas (parks, golf courses, and reservoirs). Potential exposure routes for swimmers in treated reservoirs include dermal contact and incidental ingestion (69 FR 51301 - 51312, 2004; HSDB, 2004; Pohanish, 2002).
2) Gardeners may be exposed to glyphosate through contact with or use of a variety of commercial herbicide products containing this chemical or through contact with treated plants (HSDB, 2004).
3) Dermal and dietary exposure is possible for persons intentionally or accidentally touching or consuming food and water that have been recently sprayed (HSDB, 2004; Pohanish, 2002).

2) COMMERCIAL PRODUCTION

a) Production of glyphosate is a two-phase process. First, a mixture of glycine (50 parts), chloromethylphosphonic acid (92 parts), an aqueous solution of 50% sodium hydroxide (150 parts), and water (100 parts) are refluxed. Additional aqueous solution of 50% sodium hydroxide (50 parts) is added to maintain basic pH and refluxing is resumed. Then, the mixture is cooled and filtered before concentrated hydrochloric acid (160 parts) is added and the mixture is filtered again. Glyphosate is slowly precipitated out in the filtrate (IPCS, 1994).

3) COMMERCIAL SOURCES

a) Glyphosate-based herbicide formulations are sold under many tradenames and produced by numerous manufacturers. Glyphosate was first introduced as a commercial product in 1974. Glyphosate production and its use in commercial herbicides for agriculture continues to increase worldwide (Meister, 2003; Krieger, 2001).

1) Glyphosate is formulated into systemic herbicides that provide non-selective, post-emergent control of annual and perennial plants. The herbicide product is extensively used because of its suitability for general weed control on many food and non-food crops (forests, nurseries), on "no-till" farmland, on non-cropland (industrial, recreational, public areas), in aquaculture, and for aquatic weed control in reservoirs (HSDB, 2004; Meister, 2003; Pohanish, 2002; EPA, 2002).
2) Technical grade glyphosate (glyphosate acid, CAS 1071-83-6), as the pure chemical by itself, is not directly applied as a herbicide in the environment, nor is it included in product formulations. Rather, it is the isopropylamine (IPA) salt form of glyphosate that is formulated into most commercial products (Tsui & Chu, 2003; Krieger, 2001).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Glyphosate is a broad-spectrum systemic herbicide, and is the most widely used herbicide in the USA. It is available under a variety of trade names, including Roundup(R).
B) TOXICOLOGY: Glyphosate is an aminophosphonic analogue of the amino acid glycine. It kills plants by interfering with the synthesis of the amino acids phenylalanine, tyrosine, and tryptophan. Other chemicals added to glyphosate mixtures (eg, surfactants and diquat) are probably responsible for much of the reported toxicity.
C) EPIDEMIOLOGY: Exposure is common, severe toxicity is rare. In the United States, poison centers in the past decade have reported more than 4000 exposures per year of glyphosate-containing herbicides, of which several hundred are evaluated in a healthcare facility. However, only about 1% of these exposures were intentional ingestions, and fatalities are rare. The clinical effects described are limited to glyphosate isoprophylamine (also known as Roundup(R)) and not glyphosate-trimesium, which appears to have a different mechanism of action that may produce rapid toxicity following ingestion. Two fatal cases of intoxication have been reported within 1 hour or less of oral exposure in an adult and a child to glyphosate-trimesium
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Ingestion can cause nausea, vomiting, abdominal pain, diarrhea, slight sedation, mouth and throat pain. Eye exposure can cause conjunctivitis. Dermal exposure can cause erythema, piloerection, and contact dermatitis.
2) SEVERE TOXICITY: Oral or gastrointestinal mucosal ulceration, hypotension, mild elevations in liver enzymes, leukocytosis, metabolic acidosis, oliguric/anuric renal failure, hyperthermia, pulmonary edema, respiratory failure, ventricular dysrhythmias, coma, and seizures are rare manifestations generally only seen after deliberate ingestion. Severe toxicity resulting in death, most often following intentional exposure, has been related to hypovolemic shock followed by respiratory failure. Prolonged dermal exposure can cause burns. The development of respiratory distress, pulmonary edema, renal failure or acidosis requiring hemodialysis, and/or hyperkalemia are highly associated with poor prognosis.

0.2.4)

A) WITH POISONING/EXPOSURE

1) Irritation of the mouth and throat is possible after ingestion.
2) Conjunctivitis may occur following splash contact; nystagmus rarely occurs with systemic poisoning.

0.2.5)

A) WITH POISONING/EXPOSURE

1) Shock occurs in most severe cases. Dysrhythmias including ventricular dysrhythmias, bradycardia, and cardiac arrest, have been reported.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Life-threatening effects include pulmonary edema and aspiration pneumonitis. Irritation occurs.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Mental status changes may be seen late in the course of glyphosate poisoning.

0.2.8)

A) WITH POISONING/EXPOSURE

1) COMMON SIGNS: Nausea and vomiting; erythema of mucous membranes; epigastric pain.
2) SEVERE CASES: Hemorrhage; paralytic ileus; prolonged dehydrating diarrhea; necrosis and hemorrhage of mucous membranes.

0.2.9)

A) WITH POISONING/EXPOSURE

1) Elevated liver enzymes may be seen following toxic exposures to glyphosate.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Oliguria and anuria are primary toxic effects of severe glyphosate poisonings.

0.2.11)

A) WITH POISONING/EXPOSURE

1) Metabolic acidosis has been frequently reported following glyphosate poisonings.

0.2.12)

A) WITH POISONING/EXPOSURE

1) Hyperkalemia has been reported following toxic exposures to glyphosate.

0.2.13)

A) WITH POISONING/EXPOSURE

1) Leukocytosis may be seen following severe glyphosate ingestions. One case of acute hemolysis was reported following intravenous injection of glyphosate.

0.2.14)

A) WITH POISONING/EXPOSURE

1) Commercial glyphosate formulations have caused erythema, piloerection, and contact dermatitis. Chemical burns resulting in necrotic epidermis and eroded lesions occurred in one elderly adult.

0.2.15)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis has been reported in an self-inflicted intramuscular injection of glyphosate-surfactant herbicide.

0.2.20)

A) Skeletal alterations were observed in the offspring of rats fed glyphosate-Roundup(R) during pregnancy.

0.2.21)

A) Glyphosate has been classified as probably carcinogenic to humans (Group 2A) by IARC following a systematic review and evaluation of the scientific evidence.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) For mild or moderate symptoms, supportive care should be sufficient. This includes dilution or irrigation of oral mucosa with water or milk and antiemetics or pain medications as needed.

B) MANAGEMENT OF SEVERE TOXICITY

1) For patients with severe toxicity, anticipate the need for intubation, correction of electrolyte abnormalities, support for metabolic acidosis, hyperkalemia and renal failure, and treatment of hypotension (fluids, vasopressors if necessary) and cardiac dysrhythmias. Patients with deliberate overdose or clinical manifestations (odynophagia, drooling) should have endoscopy to evaluate for potential gastrointestinal burns.

C) DECONTAMINATION

1) PREHOSPITAL: Small amounts of water may be used for dilution after ingestion. Wash exposed skin, irrigate exposed eyes and remove contaminated clothing. Emesis is not recommended, and charcoal in general should be avoided.
2) HOSPITAL: In general, decontamination is not indicated for this overdose, but may be considered for massive overdoses that present early. Nasogastric or orogastric aspiration can be considered if the patient is awake and cooperative and if the ingestion was very large and relatively recent. There is no role for the use of lavage, whole bowel irrigation or multiple doses of charcoal.

D) AIRWAY MANAGEMENT

1) Airway management may become an issue, especially if there is any aspiration, and early intubation may be needed for patients with significant respiratory symptoms.

E) ANTIDOTE

1) There is no specific antidote for glyphosate.

F) ENHANCED ELIMINATION

1) Glyphosate is excreted rapidly in the urine. Maintaining an adequate urine output is important. Hemodialysis is effective in clearing glyphosate, and has been used infrequently in patients who develop acute renal failure after overdose (primarily to correct acidosis and hyperkalemia rather than to remove glyphosate). Hemoperfusion is not effective.

G) PATIENT DISPOSITION

1) HOME MANAGEMENT: Inadvertent or occupational exposures with minor to no symptoms can be observed at home.
2) OBSERVATION CRITERIA: Patients with intentional exposures or with more than minor symptoms should be sent to a healthcare facility for observation for 4 to 6 hours, until symptoms improve or resolve.
3) ADMISSION CRITERIA: Any patients with significant persistent symptoms should be admitted to the hospital. Four predictors of poor outcomes or mortality include respiratory distress, pulmonary edema, renal failure or acidosis requiring hemodialysis, and hyperkalemia. Any patient with any of these predictors should be admitted to the ICU. Criteria for discharge should be resolution or significant improvement of symptoms.
4) CONSULT CRITERIA: For patients with severe toxicity, potential consultants include intensivists, pulmonologists, and nephrologists. Poison centers should be called on all exposures requiring medical care. Consult a medical toxicologist for patients with severe toxicity or in whom the diagnosis is unclear.

H) PITFALLS

1) Pitfalls to management include the fact that glyphosate containing herbicides may contain many other chemicals/substances that can cause severe symptoms, especially respiratory failure and arrest and potentially renal failure as well.

I) TOXICOKINETICS

1) In experimental animals, only about 2% of dermal application are absorbed. Small amounts of an N-dealkylated metabolite, aminomethylphosphonic acid, have been detected in human urine.

J) DIFFERENTIAL DIAGNOSIS

1) Glyphosate ingestions can mimic ingestions of other surfactants or caustic substances.

0.4.3)

A) Move patient away from the toxic environment into fresh air. Appreciable inhalation exposures resulting in toxicity are unlikely due to glyphosate’s low vapor pressure.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) Local decontamination with soap and water; treat symptoms as needed.

0.4.6)

A) Evaluate for compartment syndrome and hemolysis if parenteral exposure is suspected.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPOTHERMIA: Reduced body temperature and a decrease in spontaneous activity have been reported (Matsukawa et al, 1991) Prod Info, 1979.
2) HYPERTHERMIA: Mild hyperthermia may occur with glyphosate exposure (Sampogna & Cunard, 2007; Tominack et al, 1991) and was reported in 7 of 97 adult cases (Tominack et al, 1991). Chen et al (1995) reported a fever incidence of 35% in a case series of 100 patients (Chen et al, 1995).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION may develop with large ingestions (Stella & Ryan, 2004; Menkes et al, 1991; Tominack et al, 1991) .

3.3.5)

A) WITH POISONING/EXPOSURE

1) Tachycardia (120 to 140 beats/min) was reported in a 37-year-old man who ingested 1 L of an herbicide containing 41% glyphosate and 15% polyoxyethylenamine (a surfactant) (Stella & Ryan, 2004).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

1) Irritation of the mouth and throat is possible after ingestion.
2) Conjunctivitis may occur following splash contact; nystagmus rarely occurs with systemic poisoning.

3.4.3)

A) WITH POISONING/EXPOSURE

1) SUMMARY: Severe ocular effects from glyphosate-surfactant splash contact appears to be rare. In one series of 1513 calls to poison centers, no permanent changes to the structure or function of the eyes were reported (Acquavella et al, 1999a). In this series, 21% reported no injuries, 70% had minor transient symptoms, and 2% had temporary injuries.
2) CONJUNCTIVITIS: Splash contact with commercial products has led to mild conjunctivitis, which cleared in 1 to 2 days (Personal Communication, 1984b). Acute conjunctivitis with ulceration and corneal opacity has been reported in domestic animals following local contact (Burgat et al, 1998).
3) NYSTAGMUS: Prolonged nystagmus (19 days) was reported in one case (Matsukawa et al, 1991).
4) PERIORBITAL EDEMA: Gross periorbital edema with chemosis occurred when a patient wiped Roundup(R) into eyes (Temple & Smith, 1992).

3.4.6)

A) WITH POISONING/EXPOSURE

1) MUCOSAL IRRITATION/ULCERATION: This agent is mildly irritating to mucous membranes and abraded skin. Pharyngeal erosions have been described after oral ingestions (Matteucci & Clark, 2005; Sawada et al, 1988).
2) ORAL/THROAT PAIN: INCIDENCE: Oral and throat pain: 41%; oral mucosal ulceration: 7%; dysphagia: 6%. Endoscopy in patients with ulceration showed gastritis, esophagitis, and mucosal edema, but no full thickness injury (Tominack et al, 1991). In another case series (n=131), sore throat was reported in 79.5% of ingestions (Lee et al, 2000).
3) HYPERSALIVATION may occur (Prod Info, 1979). Tominack et al (1991) reported one case of excessive salivation (Tominack et al, 1991).
4) DYSPHAGIA: Tominack et al (1991) reported a 6% incidence of dysphagia in 97 cases (Tominack et al, 1991).
5) VOICE ALTERATIONS, including a raspy sound to the voice, have been reported following irritation from inhalation (Mack, 1993).

Cardiovascular

3.5.1)

A) WITH POISONING/EXPOSURE

1) Shock occurs in most severe cases. Dysrhythmias including ventricular dysrhythmias, bradycardia, and cardiac arrest, have been reported.

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Shock occurs in most severe cases. Shock developed in 18 of 97 patients who ingested glyphosate concentrate (41% glyphosate) in one series (Tominack et al, 1991). In another series, shock developed in 7 of 100 patients following glyphosate overdoses (Chen et al, 1995).

a) Signs of hypovolemic shock (hypotension, decreased urine output) were seen in 9 fatal cases of Roundup(R) ingestion (Sawada et al, 1988) and in one 84-year-old man who ingested only 60 to 80 mL (Cheng & Cheng, 1995).
b) SURFACTANT VOLUME: In a retrospective review of 107 patients with acute glyphosate intoxication, surfactant volume had a role in the development of severe toxicity compared to the surfactant type (ingredient) in various glyphosate herbicide products. In patients that ingested surfactant volumes of 8 mL or more there was a strong association with the development of hypotension (47.1%), mental deterioration (38.6%), respiratory failure (30%), acute kidney injury (17.1%) and arrhythmia (10%). Most patients improved with no long-term sequelae; however, 2 patients died of refractory shock, metabolic acidosis and respiratory failure (Seok et al, 2011).

b) MECHANISM

1) MECHANISM: Hypovolemia has been suspected as the cause of shock, and hypotension may initially respond to hydration therapy. Recurrent hypotension refractory to fluids and vasopressors was not due to hypovolemia, as assessed by central venous pressure, hematocrit, and BUN in one series (Talbot et al, 1991).

c) INCIDENCE

1) In a series of 601 patients who developed concentrated forms of glyphosate (generally 36% w/v), transient hypotension developed in 5% of those with mild poisoning, and in 48% of the 33 patients with moderate to severe poisoning. Progressive hypotension despite inotropic support developed in all fatal cases (Roberts et al, 2010).
2) In a retrospective review of glyphosate exposures reported to the Taiwan National Poison Control Center between 1986 and 2007, 2023 (92.5%) cases of oral ingestion occurred with 146 patients deaths reported after oral exposure for a case fatality rate of 7.2%. Shock (n=85, 58.2%) and respiratory failure (n=34, 23.3%) were the most common causes of death. Further analysis showed that shock commonly presented as hypovolemia (n=40, 34.5%), cardiogenic shock (n=6, 5.2%) or undetermined cause of shock (n=70, 60.3%). Approximately half of the patients (48.4%) that developed cardiovascular-collapse events died within 1 day and 78.1% died within 3 days compared to 17.6% and 44.1%, respectively of patients that died of respiratory failure on days 1 and 3 (Chen et al, 2009).

d) CASE REPORTS

1) CASE REPORT: Cardiogenic shock was reported in 26-year-old man following a suicidal ingestion of 150 mL glyphosate-surfactant. While the patient was in shock, echocardiography revealed diffuse left ventricular hypokinesias with markedly decreased ejection fraction. Electrolyte status remained normal. Treatment with epinephrine, atropine, and calcium did not improve hemodynamics. Normalization of the QRS complex, return to sinus rhythm, and improved hemodynamic status occurred without further intervention over the next 16 hours (Lin et al, 1999).

a) The authors suggested that the cardiogenic shock was due to transient suppression of the cardiac conduction system and contractility, as opposed to intravascular hypovolemia.

2) CASE REPORTS: Intractable hypotension occurred in a 37-year-old man and a 77-year-old man who intentionally ingested 1 L and 500 mL, respectively, of an herbicide containing 41% glyphosate and 15% polyoxyethyleneamine (POEA) (Stella & Ryan, 2004).

B) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Tachycardia and palpitations have been reported Temple & Smith 1992; (Menkes et al, 1991; Tominack et al, 1991).
b) Various cardiac dysrhythmias, including ventricular dysrhythmias, bradycardia, and cardiac arrest have been reported (Stella & Ryan, 2004; Tominack et al, 1991).
c) Metabolic acidosis, abnormal chest X-ray, tachycardia, and elevated serum creatinine were highly predictive of mortality in a retrospective case series (n=58) (Lee et al, 2008).
d) SURFACTANT VOLUME: In a retrospective review of 107 patients with acute glyphosate intoxication, surfactant volume had a role in the development of severe toxicity compared to the surfactant type (ingredient) in various glyphosate herbicide products. In patients that ingested surfactant volumes of 8 mL or more there was a strong association with the development of hypotension (47.1%), mental deterioration (38.6%), respiratory failure (30%), acute kidney injury (17.1%) and arrhythmia (10%). Most patients improved with no long-term sequelae; however, 2 patients died of refractory shock, metabolic acidosis and respiratory failure (Seok et al, 2011).

3.5.3)

A) ANIMAL STUDIES

1) CARDIAC FAILURE

a) RATS: In an in-vitro study, the direct effect of Roundup(R) (glyphosate and surfactant) on isolated rat cardiac muscle was examined. Increasing doses resulted in decreased contractility and heart rate. With glyphosate application alone, contractility of cardiac muscles gradually decreased (Tai et al, 1995).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Life-threatening effects include pulmonary edema and aspiration pneumonitis. Irritation occurs.

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Acute lung injury may occur following glyphosate exposure (Sampogna & Cunard, 2007; Tominack et al, 1991; Sawada & Nagai, 1987).
b) INCIDENCE: 5.3% (Sawada & Nagai, 1987); 13% (Tominack et al, 1991).
c) Pulmonary edema, acidosis, and hyperkalemia are predictors highly associated with poor outcome and mortality in a retrospective case series (n=131) (Lee et al, 2000).
d) Intractable low-pressure pulmonary edema was reported in 2 fatal cases (Talbot, 1989). Severe pulmonary edema was seen at autopsy in 2 fatal cases (Dickson et al, 1988).
e) CASE REPORT: A 69-year-old woman intentionally ingested 500 mL of glyphosate-surfactant herbicide (48% glyphosate potassium salts; Roundup Maxload (R)) and was found alert but vomiting by her spouse. Once admitted, she lost consciousness and became pulseless. Following CPR and repeated cardioversion; ventricular tachycardia was unresponsive to antiarrhythmics. Initial laboratory findings included severe hyperkalemia (potassium 10 mEq/L), normal renal function and metabolic acidosis. Treatment included percutaneous cardiopulmonary support and continuous hemodialysis which corrected the patient's elevated potassium concentration. The patient recovered following a complicated clinical course that included esophageal and gastric erosions and acute respiratory distress syndrome. The patient required intubation and mechanical ventilation for 20 days. Her serum glyphosate concentration on admission was 1625.74 mcg/mL and 18 hours later was 100.44 mcg/mL (Kamijo et al, 2012).
f) CASE REPORT: Pulmonary edema, necessitating mechanical ventilation, was reported in a 77-year-old man who intentionally ingested 500 mL of an herbicide containing 41% glyphosate and 15% polyoxyethyleneamine (a surfactant) (Stella & Ryan, 2004).

B) RESPIRATORY FAILURE

1) WITH POISONING/EXPOSURE

a) SURFACTANT VOLUME: In a retrospective review of 107 patients with acute glyphosate intoxication, surfactant volume had a role in the development of severe toxicity compared to the surfactant type (ingredient) in various glyphosate herbicide products. In patients that ingested surfactant volumes of 8 mL or more there was a strong association with the development of hypotension (47.1%), mental deterioration (38.6%), respiratory failure (30%), acute kidney injury (17.1%) and arrhythmia (10%). Most patients improved with no long-term sequelae; however, 2 patients died of refractory shock, metabolic acidosis and respiratory failure (Seok et al, 2011).
b) INCIDENCE: In a retrospective review of glyphosate exposures reported to the Taiwan National Poison Control Center between 1986 and 2007, 2023 (92.5%) cases of oral ingestion occurred with 146 deaths reported after oral exposure for a case fatality rate of 7.2%. Shock (n=85, 58.2%) and respiratory failure (n=34, 23.3%) were the most common causes of death. Further analysis showed that respiratory failure commonly presented as aspiration (n=60, 61.2%); respiratory failure of undetermined cause occurred in 31 (31.6%) patients. Acute respiratory distress syndrome (n=4, 4.1%) and pulmonary edema (n=3, 3.1%) also occurred in a small number of patients. Approximately half of the patients (48.4%) that developed cardiovascular-collapse events died within 1 day and 78.1% died within 3 days compared to 17.6% and 44.1%, respectively of patients that died of respiratory failure on days 1 and 3 (Chen et al, 2009).

C) PULMONARY ASPIRATION

1) WITH POISONING/EXPOSURE

a) The manufacturer has stated that death was often associated with aspiration pneumonitis after concurrent alcohol ingestion (Jackson, 1988).
b) INCIDENCE: 3.6% (Sawada et al, 1988); 1% (Tominack et al, 1991).
c) CASE SERIES: Cheng & Cheng (1995) reported lung infiltration with aspiration pneumonia in 2 of 28 patients following ingestions of glyphosate herbicide (Cheng & Cheng, 1995).
d) CASE SERIES: Chang et al (1999) reported aspiration pneumonia, as opposed to pulmonary edema or hypotension, to be the major cause of mortality (Chang et al, 1999).
e) Chang et al (1999) report tracheal injury with erosion and significant hypopharyngeal damage, with 6 of 11 cases experiencing damage to the aryteno-epiglottic folds; pneumonia developed in 4 of these patients. The authors concluded that injuries to the aryteno-epiglottic folds may lead to airway injury due to glyphosate toxicity and aspiration of oral secretions (Chang et al, 1999).

D) PNEUMONITIS

1) WITH POISONING/EXPOSURE

a) Pneumonitis and mild to moderate respiratory distress, with chest radiograph revealing interstitial bilateral infiltrations, has been reported in a worker with presumed inhalation exposure to Roundup(R). Signs of burns in the mucosal membranes of the pharynx and larynx were also seen on otolaryngologic examination (Carel & Pushnoy, 1999; Pushnoy et al, 1998) . The authors presumed that the patient, who worked in a small, hot room with a ventilator blowing over a bucket of parts soaked in Roundup, was exposed to a mixture of vapor and airborne droplets, with part of the toxicity due to the surfactant.

1) Goldstein et al (1999) suggested that this patient's pneumonitis was not due to Roundup(R) or any of its components. They state that this product does not become significantly airborne through vaporization, even in a poorly ventilated space.

E) IRRITATION SYMPTOM

1) WITH POISONING/EXPOSURE

a) Inhalation has produced a raspy feeling of the throat and upper respiratory tract irritation.

F) CYANOSIS

1) WITH POISONING/EXPOSURE

a) Cyanosis of lips and nailbeds may occur (Matsukawa et al, 1991).

G) BRONCHOSPASM

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Protracted bronchospasm necessitating prolonged mechanical ventilation is reported in a 55-year-old man 6 hours after the ingestion of 500 mL of Roundup(R) herbicide. Bronchospasm persisted, despite therapy with steroids and bronchodilators, and pneumomediastinum, tension pneumothorax, and subcutaneous emphysema developed by day 20. The patient died of sepsis on day 62 (Chang et al, 1999).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) Mental status changes may be seen late in the course of glyphosate poisoning.

3.7.2)

A) ALTERED MENTAL STATUS

1) WITH POISONING/EXPOSURE

a) Mental status changes have been reported in 11% to 12% of ingestions; occurs late in the course of poisoning unless coingestants are involved; may be secondary to hypoxia or hypotension (Matsukawa et al, 1991; Talbot et al, 1991; Tominack et al, 1991) .
b) SURFACTANT VOLUME: In a retrospective review of 107 patients with acute glyphosate intoxication, surfactant volume had a role in the development of severe toxicity compared to the surfactant type (ingredient) in various glyphosate herbicide products. In patients that ingested surfactant volumes of 8 mL or more there was a strong association with the development of hypotension (47.1%), mental deterioration (38.6%), respiratory failure (30%), acute kidney injury (17.1%) and arrhythmia (10%). Most patients improved with no long-term sequelae; however, 2 patients died of refractory shock, metabolic acidosis and respiratory failure (Seok et al, 2011).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea, vomiting, abdominal pain, watery diarrhea, and oral pain have been reported in cases of glyphosate ingestion (Sampogna & Cunard, 2007; Matteucci & Clark, 2005; Sawada et al, 1988).
b) Vomiting and abdominal pain were noted in almost all of 56 cases of glyphosate ingestion, with hemorrhage and paralytic ileus in severe cases (Sawada et al, 1988). Hematemesis and melena lasting several days were noted in some patients who were initially asymptomatic.
c) Vomiting persisted in 44% of cases (Tominack et al, 1991); 3 had hematemesis. Abdominal or epigastric pain was persistent in 10 cases.
d) Vomiting was reported in 2 patients following ingestion of an herbicide containing 41% glyphosate and 15% polyoxyethyleneamine (POEA) (Stella & Ryan, 2004).
e) INCIDENCE: In a series of 131 patients who ingested concentrated forms of glyphosate, nausea with or without vomiting was reported in 73.8% of patients (Lee et al, 2000). In another series of 601 patients who developed concentrated forms of glyphosate (generally 36% w/v), gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain) were reported in 83% of those with mild poisoning, 67% of patients with moderate to severe poisoning, and 79% of patients with fatal poisoning (Roberts et al, 2010).

B) ACUTE PANCREATITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An elderly man presented to the emergency department after ingesting approximately 100 mL of glyphosate-surfactant. The patient developed respiratory failure that progressed to chemical pneumonitis. He also presented with abdominal guarding and pain, and by day 5 of his hospital stay, his amylase/lipase level was elevated to 478/2406 Units/L with increased epigastric pain. A diagnosis of pancreatitis was made, and with abdominal rest (the patient was started on TPN) the patient's condition and laboratory markers improved by hospital day 10 (Hsiao et al, 2008).

C) CHEMICAL BURN

1) WITH POISONING/EXPOSURE

a) Esophageal and gastric erosions were reported in 7 cases (Sawada et al, 1988). In 9 fatal cases, necrosis and hemorrhage of the jejunum and ileum were present.
b) Seven out of 97 patients exhibited oral mucosal ulceration and one exhibited excessive salivation in a survey of glyphosate poisonings (Tominack et al, 1991).
c) Erythema of mucous membranes may occur with ingestion of diluted material.
d) CASE SERIES: The most common clinical effects in 28 patients following glyphosate ingestions included nausea, vomiting, oral ulcers, and epigastric pain. Panendoscopy showed superficial gastritis, gastric erosion, and multiple peptic ulcers in 10 of the patients (Cheng & Cheng, 1995).
e) CASE SERIES: In a series of 50 patients with glyphosate-surfactant ingestions, esophageal injury was seen in 68%, gastric injury in 72%, and duodenal injury in 16% following an endoscopic examination. No grade 3 injuries were reported. The group with grade 2 esophageal injuries had more significantly increased WBC, amount of product ingested, length of hospital stay, and occurrence of serious complications than patients with grade 1 injuries (Chang et al, 1999).
f) CASE REPORT: A 25-year-old woman was admitted with a 4 day history of fever and painful oral ulcers after intentionally ingesting glyphosate. Physical exam showed extensive oral ulcers that bled easily. By day 3, it was determined that she had ingested 100 to 150 mL of glyphosate (43.15% w/w with 95% purity and net concentration of 41% SL) after developing subcutaneous emphysema and pneumomediastinum due to esophageal perforation. Her clinical course rapidly declined requiring mechanical ventilation, inotropes and dialysis. She died 12 days after ingestion (Jyoti et al, 2014).
g) CASE REPORT: A 77-year-old man presented with vomiting and abdominal pain approximately 4 hours after ingesting 500 mL of an herbicide containing 41% glyphosate and 15% polyoxyethylenamine (a surfactant). One hour later, he developed hypotension and cardiovascular collapse. An ECG showed junctional bradycardia. Laboratory analysis revealed severe metabolic acidosis (pH 7.19, HCO3 15 mmol/L) and hyperkalemia (7.4 mmol/L). He developed pulmonary edema requiring mechanical ventilation. Despite supportive care, including hemofiltration, his metabolic acidosis and hypotension persisted, he developed anuric renal failure and a rigid abdomen, and he died 26 hours postingestion. An autopsy revealed evidence of mucosal stomach ulceration and small bowel infarction (possibly secondary to hypotension) (Stella & Ryan, 2004).

D) DIARRHEA

1) WITH POISONING/EXPOSURE

a) SUMMARY: Most significant ingestions of the commercial product result in diarrhea; sometimes serious enough to produce dehydration and electrolyte imbalance. Vomiting, irritation of the pharynx, and diarrhea may persist for 2 to 5 days, after ingestion of concentrate (Sampogna & Cunard, 2007; Matteucci & Clark, 2005; Personal Communication, 1984a).
b) INCIDENCE: 12% of adult cases; 1 had melena (Tominack et al, 1991). In another case series, 15% of 100 patients developed diarrhea (Chen et al, 1995).

E) RUPTURE OF COLON

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 75-year-old man developed severe hypotension and multi organ failure (acute lung injury, renal failure, in addition to hemodynamic instability) after ingesting 150 mL of glyphosate surfactant in a suicide attempt. On the 9th day of hospitalization he developed fever, abdominal distension and colonic distension, and longitudinal rupture of his descending colon with widespread peritonitis was found intraoperatively approximately 11 days after ingestion. The colonic rupture was likely secondary to ischemia from severe hypotension. The patient eventually recovered with standard care(Palli et al, 2011).

3.8.3)

A) ANIMAL STUDIES

1) IRRITATION

a) DOMESTIC ANIMALS who accidentally ingest glyphosate products experience mostly mucosal and gastrointestinal irritation with eventual depression. Of 31 recorded cases, 61% had spontaneous vomiting which occurred within a few minutes or 1 to 2 hours after ingestion. Hypersalivation in 26% was associated with oral and laryngeal mucosal inflammation. In 16% of cases, mild diarrhea was reported (Burgat et al, 1998).

Hepatic

3.9.1)

A) WITH POISONING/EXPOSURE

1) Elevated liver enzymes may be seen following toxic exposures to glyphosate.

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Elevated serum amylase, bilirubin (6/17 cases), and lactate dehydrogenase, presumably due to hemolysis, were reported in a series of Roundup(R) ingestions (Sawada et al, 1988).
b) INCIDENCE: 19% to 40% (AST up to 237 Units/L) (Talbot et al, 1991; Tominack et al, 1991) . In another case series, 27 of 84 patients presented with elevated hepatic enzyme levels (Chen et al, 1995). In yet another case series (n=131), 33.6% of patients developed hepatic abnormalities (Lee et al, 2000).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Oliguria and anuria are primary toxic effects of severe glyphosate poisonings.

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Oliguria and anuria occur in severe cases (Matteucci & Clark, 2005; Tominack et al, 1991); this may be secondary to or exacerbated by hypotension. Hematuria may be present.

1) SURFACTANT VOLUME: In a retrospective review of 107 patients with acute glyphosate intoxication, surfactant volume had a role in the development of severe toxicity compared to the surfactant type (ingredient) in various glyphosate herbicide products. In patients that ingested surfactant volumes of 8 mL or more there was a strong association with the development of hypotension (47.1%), mental deterioration (38.6%), respiratory failure (30%), acute kidney injury (17.1%) and arrhythmia (10%). Most patients improved with no long-term sequelae; however, 2 patients died of refractory shock, metabolic acidosis and respiratory failure (Seok et al, 2011).
2) INCIDENCE: 10 of 97 adult patients in one series (Tominack et al, 1991). In another case series, 18 of 88 patients presented with abnormal renal function tests following overdoses (Chen et al, 1995).
3) POSTMORTEM: Acute renal tubular necrosis was found on postmortem examination in a suicidal ingestion. Analysis for glyphosate in tissue showed a higher concentration in the kidney (3650 ppm) than in the brain (100 ppm), liver (600 ppm), and blood (100 ppm) (Menkes et al, 1991).
4) PROGNOSIS is poor for patients developing renal failure necessitating hemodialysis (Lee et al, 2000). In one case series (n=131), 3 patients developed renal failure and were given hemodialysis; all 3 died (Lee et al, 2000).
5) Metabolic acidosis, abnormal chest X-ray, tachycardia, and elevated serum creatinine were highly predictive of mortality in a retrospective case series (n=58) (Lee et al, 2008).

b) CASE REPORT: A 51-year-old man presented to the hospital with diaphoresis, dysphagia, vomiting, diarrhea, and mild chest tightness 6 hours after ingesting "4 gulps" (approximately 240 mL) of an unknown glyphosate containing product in a suicide attempt. The patient was treated with supportive care and admitted to the hospital for close cardiopulmonary observation. Approximately 12 hours after presentation, the patient developed increasing symptoms of renal failure with measured serum creatinine of 3.6 mg/dL and a urine output of 20 ml/hr. Upon further questioning, it was discovered that the patient had ingested a product that contained 18% glyphosate, 0.73% diquat, and 7% polyoxyethyleneamine (POEA). The patient's serum creatine elevated to 4.8 mg/dL by hospital day 4 and he underwent 4 hours of hemodialysis with one liter of fluid removed. The patient's condition was thought to be complicated by coingestion of an ACE inhibitor (benazepril) and NSAIDs (naproxen and aspirin), but rapidly responded to hemodialysis. After treatment, the patient's status improved and he regained renal function over a 2-week period (Sampogna & Cunard, 2007).
c) CASE REPORT: Approximately 24 hours after ingesting "4 or 5 large gulps" of a product containing 50.2% glyphosate isopropylamine and 15% polyoxyethyleneamine, a 51-year-old man experienced oliguria with elevated serum creatinine (4.9 mg/dL). Following one 4 hour course of hemodialysis, his urine output improved and his creatinine fell to 2.7 mg/dL (Matteucci & Clark, 2005).
d) CASE REPORTS: Anuric renal failure occurred in two patients who ingested 1 liter and 500 mL, respectively, of an herbicide containing 41% glyphosate and 15% polyoxyethyleneamine (a surfactant). Despite aggressive supportive measures, both patients died within 2 days postingestion (Stella & Ryan, 2004).

Acid-Base

3.11.1)

A) WITH POISONING/EXPOSURE

1) Metabolic acidosis has been frequently reported following glyphosate poisonings.

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis and leukocytosis are the most common laboratory findings following ingestions (Lee et al, 2000).
b) Metabolic acidosis was reported in 78% of fatalities (Tominack et al, 1991). Acidosis may be severe (Matsukawa et al, 1991).
c) Pulmonary edema, acidosis, and hyperkalemia were highly associated with poor outcome and mortality in a retrospective case series (n=131) (Lee et al, 2000).
d) Metabolic acidosis, abnormal chest x-ray, tachycardia, and elevated serum creatinine were highly predictive of mortality in a retrospective case series (n=58) (Lee et al, 2008).
e) CASE REPORTS: Two patients developed metabolic acidosis refractory to supportive measures following intentional ingestion of an herbicide containing 41% glyphosate and 15% polyoxyethyleneamine (POEA) (Stella & Ryan, 2004).

1) The first patient was a 37-year-old man who ingested approximately 1 liter of the herbicide and presented with vomiting and a sore throat. The patient's pulse rate was 120 BPM and an ECG demonstrated broad complex regular tachycardia (heart rate of 140 BPM). Laboratory analysis revealed metabolic acidosis (pH 7.25, HCO3 13 mmol/L), hyperkalemia (8.2 mmol/L), and leukocytosis. The patient became hypoxic, requiring mechanical ventilation. Despite aggressive supportive measures, including hemodialysis, the patient's metabolic acidosis persisted, he developed renal impairment progressing to anuric renal failure and intractable hypotension, and he died approximately 2 days postingestion.
2) The second patient was a 77-year-old man who presented with vomiting and abdominal pain approximately 4 hours after ingesting 500 mL of the herbicide. One hour later, he developed hypotension and cardiovascular collapse. An ECG showed junctional bradycardia. Laboratory analysis revealed severe metabolic acidosis (pH 7.19, HCO3 15 mmol/L) and hyperkalemia (7.4 mmol/L). He developed pulmonary edema requiring mechanical ventilation. Despite supportive care, including hemofiltration, his metabolic acidosis and hypotension persisted, he developed anuric renal failure and a rigid abdomen, and he died 26 hours postingestion.

Hematologic

3.13.1)

A) WITH POISONING/EXPOSURE

1) Leukocytosis may be seen following severe glyphosate ingestions. One case of acute hemolysis was reported following intravenous injection of glyphosate.

3.13.2)

A) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) Leukocytosis is a common laboratory finding following glyphosate herbicide ingestions (Stella & Ryan, 2004; Lee et al, 2000).
b) CASE SERIES: White blood cell counts were greater than 10,000/mm(3) in 11 of 14 patients in whom this was measured in one series (Tominack et al, 1991) and in 48 of 93 cases in another series. The incidence was related to clinical severity in the latter series, occurring in 30% of asymptomatic cases, 53% of mild cases, 65% of moderate cases, and 71% of severe cases (Talbot et al, 1991).
c) CASE REPORT: Leukocytosis was first noted 12 days after ingestion in one case, continuing for 3 weeks; no infectious etiology was proven (Menkes et al, 1991).

B) HEMOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 22-year-old man survived after self-injecting approximately 250 mL of diluted glyphosate-surfactant herbicide in a suicide attempt. The patient presented with mild metabolic acidosis and acute hemolysis, which required plasmapheresis and blood transfusions. He made a full recovery 4 days later (Wu et al, 2006).

Dermatologic

3.14.1)

A) WITH POISONING/EXPOSURE

1) Commercial glyphosate formulations have caused erythema, piloerection, and contact dermatitis. Chemical burns resulting in necrotic epidermis and eroded lesions occurred in one elderly adult.

3.14.2)

A) PILOERECTION

1) WITH POISONING/EXPOSURE

a) Piloerection was seen in early studies (Prod Info, 1979).

B) DERMATITIS

1) WITH POISONING/EXPOSURE

a) Dermatitis resembling sunburn has been seen when the material has been in contact with skin for more than 30 minutes.

1) No systemic symptoms have been seen due to absorption via intact or abraded skin (Personal Communication, 1984a). Erythema was noted in 1 of 23 subjects after single application of Roundup(R) to unabraded skin, and in 10 of 10 subjects after application to abraded skin (Maibach, 1986).

b) Contact dermatitis has been reported in agricultural workers chronically exposed to the commercial formulation (Moses, 1989a; CDFA, 1984).
c) CASE REPORT: A 54-year-old man developed disseminated skin lesions and blisters after accidentally spraying himself with glyphosate(Barbosa et al, 2001).

C) CHEMICAL BURN

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 78-year-old woman developed extensive chemical burns on her lower trunk and legs after direct contact (knee area) and her clothing inadvertently came in contact with glyphosate (which she continued to wear for several hours after exposure). Within 24 hours of exposure, diffuse erythematous macules and areas of erosion appeared on the posterior and anterior aspects of the legs, lower trunk, and knees. Bullae was present within the erythematous areas, but ruptured revealing large areas of necrotic epidermis and extensive erosion. Following supportive care, which included wet dressings, topical steroid therapy, and systemic antibiotics, the patient began to improve within 1 week, with complete resolution within 4 weeks (Amerio et al, 2004).

Musculoskeletal

3.15.1)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis has been reported in an self-inflicted intramuscular injection of glyphosate-surfactant herbicide.

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis was reported in a 42-year-old woman after she injected 6 mL of glyphosate into the muscles of her left lateral aspect of the elbow 15 hours prior to presentation to hospital. The patient developed an elevated creatine phosphokinase of 1743 IU/L and C-reactive protein of 12.3 mg/L. She was treated with alkaline diuresis and her CPK decreased to 1289 IU/L the following day. Swelling of the injected muscles of her left arm showed continued improvement and the patient was discharged 4 days after event (Weng et al, 2008).

Reproductive

3.20.1)

A) Skeletal alterations were observed in the offspring of rats fed glyphosate-Roundup(R) during pregnancy.

3.20.2)

A) ANIMAL STUDIES

1) SKELETAL MALFORMATION

a) Skeletal alterations were observed in the offspring of rats (n=60) fed glyphosate-Roundup(R) from day 6 to 15 of pregnancy. The percentage of altered fetuses was 15.4% in the controls, 33.1% in the 500 mg/kg group, 42.0% in the 750 mg/kg group, and 57.3% in the 1000 mg/kg group. The most frequent skeletal malformations observed were enlarged fontanel and incomplete skull ossification. Fifty percent of the dams treated with 1000 mg/kg glyphosate died between day 7 and 14 of pregnancy(Dallegrave et al, 2003).

2) UROGENITAL ABNORMALITY

a) Developmental abnormalities of the urogenital system have been observed in mammals(RTECS, 2004).

3) LACK OF EFFECT

a) Glyphosate did not produce adverse reproductive effects or birth defects in two multigeneration rat reproduction studies. Polyoxyethyleneamine (POEA) administered at doses of 15 to 300 mg/kg to rats on gestation days 6 through 15 did not produce fetal changes(Williams et al, 2000).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS1071-83-6 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Glyphosate
b) Carcinogen Rating: 2A

1) The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

3.21.2)

A) Glyphosate has been classified as probably carcinogenic to humans (Group 2A) by IARC following a systematic review and evaluation of the scientific evidence.

3.21.3)

A) SUMMARY

1) The International Agency for Research on Cancer (IARC) has determined that glyphosate is probably carcinogenic to humans (Group 2A) after a systematic review and evaluation of the scientific evidence by the Working group made up of 17 experts from 11 countries (International Agency for Research on Cancer, 2015).
2) Glyphosate has been detected in air during spraying, in water, and in food. There is limited evidence in humans for carcinogenicity of glyphosate. In case-control studies of occupational exposure in the US, Canada and Sweden there has been an increased risk for non-Hodgkin lymphoma that persisted after adjusting for other pesticide exposures. However, the Agricultural Health Study cohort did not show a significantly increased risk of non-Hodgkin lymphoma (Guyton et al, 2015).

3.21.4)

A) LACK OF EFFECT

1) Earlier research showed that glyphosate was not carcinogenic following chronic exposure in mice and rats (Williams et al, 2000).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Serum and urine glyphosate concentrations can be measured but are not clinically useful in guiding therapy or readily available.
B) Obtain a CBC, serum creatinine, BUN, liver enzymes, serum electrolytes, arterial blood gases, urinalysis and chest x-ray in symptomatic patients.
C) Initiate ECG and continuous cardiac monitoring and pulse oximetry on patients with significant symptoms.
D) Consider endoscopy for patients with suspected caustic gastrointestinal injuries (large volume/deliberate ingestion, or symptoms such as odynophagia, drooling).

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor serum creatinine, BUN, liver function tests, and serum electrolytes in symptomatic patients.

B) HEMATOLOGIC

1) Monitor CBC in symptomatic patients.

C) ACID/BASE

1) Monitor arterial blood gases in symptomatic patients.

4.1.3)

A) URINALYSIS

1) Monitor urine output and perform urinalysis in symptomatic patients.

4.1.4)

A) OTHER

1) MONITORING

a) Pulmonary artery catheterization may be useful for patients with shock that does not respond to standard treatments.

Radiographic Studies

1) Obtain a chest radiograph in symptomatic patients.

Methods

1) Glyphosate and its major plant metabolite, aminomethylphosphonic acid (AMPA), N-methylaminomethylphosphonic (MAMPA), and methylphosphonic (MPA) acids have been measured by gas chromatography (Kudzin et al, 2002; Deyrup et al, 1985), high-performance liquid chromatography (HPLC) (Cowell et al, 1986; Moye et al, 1983; Powell et al, 1990; Talbot et al, 1995; Roseboom & Berkhoff, 1982), gas chromatography/mass spectrometry (GC-MS) (Kudzin et al, 2002; Kageura et al, 1988), and nuclear magnetic resonance spectroscopy (NMR) (Kudzin et al, 2002; Dickson et al, 1988).
2) None of these methods are readily available for clinical use.

Treatment

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Any patients with significant persistent symptoms should be admitted to the hospital. Four predictors for poor outcomes or mortality include respiratory distress, pulmonary edema, renal failure or acidosis requiring hemodialysis, and hyperkalemia. Any patient with any of these predictors should be admitted to the ICU. Criteria for discharge should be resolution or significant improvement of symptoms (Lee et al, 2008).
B) Patients that exhibit more than mild transient symptoms following ingestion should be monitored for a minimum of 12 hours (Stella & Ryan, 2004).

6.3.1.2) HOME CRITERIA/ORAL

A) Inadvertent or occupational exposures with minor to no symptoms can be observed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) For patients with severe toxicity, potential consultants include intensivists, pulmonologists, and nephrologists. Poison centers should be called on all exposures requiring medical care. Consult a medical toxicologist for patients with severe toxicity or in whom the diagnosis is unclear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with intentional exposures or with more than minor symptoms should be sent to a healthcare facility for observation for 4 to 6 hours, until symptoms improve or resolve.

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Small amounts of water may be used for dilution after ingestion. Wash exposed skin, irrigate exposed eyes and remove contaminated clothing. Activated charcoal in general should be avoided.

6.5.2)

A) SUMMARY: In general, decontamination is not indicated for this overdose, but may be considered for massive overdoses that present early. Nasogastric or orogastric aspiration can be considered if the patient is awake and cooperative and if the ingestion was very large and relatively recent. There is no role for the use of lavage, whole bowel irrigation or multiple doses of charcoal.
B) EMESIS/NOT RECOMMENDED

1) Emesis is not recommended, although spontaneous vomiting may occur. The concentrated solution (41% glyphosate) may cause esophageal erosion; it is not known if lower concentrations are less irritating or if the surfactant is an irritant.

C) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) MONITORING OF PATIENT

1) Serum and urine glyphosate concentrations can be measured, but are not clinically useful in guiding therapy or readily available.
2) Obtain a CBC, serum creatinine, BUN, liver enzymes, serum electrolytes, arterial blood gases, urinalysis and chest x-ray in symptomatic patients.
3) Initiate ECG and continuous cardiac monitoring and pulse oximetry on patients with significant symptoms.
4) Consider endoscopy for patients with suspected caustic gastrointestinal injuries (large volume/deliberate ingestion, or symptoms such as odynophagia, drooling).

B) SUPPORT

1) Monitor vital signs. Hypovolemic shock and respiratory failure have been observed following significant oral toxicity.

C) IRRIGATION

1) Irrigate the mouth with water rinses.

D) DILUTION

1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).

E) ENDOSCOPIC PROCEDURE

1) Endoscopy has been used to evaluate mucosal corrosive injuries following glyphosate-surfactant ingestions. In one series (n=50), no grade 3 injuries were found. Grade 2 injuries were reported, with the severity of injury correlating with prognostic indicators (Chang et al, 1999). Information regarding the use of endoscopy, corticosteroids or surgery in the setting of concentrated glyphosate-surfactant ingestion is limited. The following information is derived from experience with other corrosives. Consider endoscopy in patients with signs or symptoms of mucous membrane irritation following ingestion.
2) SUMMARY: Obtain consultation concerning endoscopy as soon as possible, and perform endoscopy within the first 24 hours when indicated.
3) INDICATIONS: Endoscopy should be performed in adults with a history of deliberate ingestion, adults with any signs or symptoms attributable to inadvertent ingestion, and in children with stridor, vomiting, or drooling after unintentional ingestion (Crain et al, 1984). Endoscopy should also be performed in children with dysphagia or refusal to swallow, significant oral burns, or abdominal pain after unintentional ingestion (Gaudreault et al, 1983; Nuutinen et al, 1994). Children and adults who are asymptomatic after accidental ingestion do not require endoscopy (Gupta et al, 2001; Lamireau et al, 2001; Gorman et al, 1992).
4) RISKS: Numerous large case series attest to the relative safety and utility of early endoscopy in the management of caustic ingestion.

a) REFERENCES: (Dogan et al, 2006; Symbas et al, 1983; Crain et al, 1984a; Gaudreault et al, 1983a; Schild, 1985; Moazam et al, 1987; Sugawa & Lucas, 1989; Previtera et al, 1990; Zargar et al, 1991; Vergauwen et al, 1991; Gorman et al, 1992)

5) The risk of perforation during endoscopy is minimized by (Zargar et al, 1991):

a) Advancing across the cricopharynx under direct vision
b) Gently advancing with minimal air insufflation
c) Never retroverting or retroflexing the endoscope
d) Using a pediatric flexible endoscope
e) Using extreme caution in advancing beyond burn lesion areas
f) Most authors recommend endoscopy within the first 24 hours of injury, not advancing the endoscope beyond areas of severe esophageal burns, and avoiding endoscopy during the subacute phase of healing when tissue slough increases the risk of perforation (5 to 15 days after ingestion) (Zargar et al, 1991).

6) GRADING

a) Several scales for grading caustic injury exist. The likelihood of complications such as strictures, obstruction, bleeding, and perforation is related to the severity of the initial burn (Zargar et al, 1991):
b) Grade 0 - Normal examination
c) Grade 1 - Edema and hyperemia of the mucosa; strictures unlikely.
d) Grade 2A - Friability, hemorrhages, erosions, blisters, whitish membranes, exudates and superficial ulcerations; strictures unlikely.
e) Grade 2B - Grade 2A plus deep discreet or circumferential ulceration; strictures may develop.
f) Grade 3A - Multiple ulcerations and small scattered areas of necrosis; strictures are common, complications such as perforation, fistula formation or gastrointestinal bleeding may occur.
g) Grade 3B - Extensive necrosis through visceral wall; strictures are common, complications such as perforation, fistula formation, or gastrointestinal bleeding are more likely than with 3A.

7) FOLLOW UP - If burns are found, follow 10 to 20 days later with barium swallow or esophagram.
8) SCINTIGRAPHY - Scans utilizing radioisotope labelled sucralfate (technetium 99m) were performed in 22 patients with caustic ingestion and compared with endoscopy for the detection of esophageal burns. Two patients had minimal residual isotope activity on scanning but normal endoscopy and two patients had normal activity on scan but very mild erythema on endoscopy. Overall the radiolabeled sucralfate scan had a sensitivity of 100%, specificity of 81%, positive predictive value of 84% and negative predictive value of 100% for detecting clinically significant burns in this population (Millar et al, 2001). This may represent an alternative to endoscopy, particularly in young children, as no sedation is required for this procedure. Further study is required.
9) MINIPROBE ULTRASONOGRAPHY - was performed in 11 patients with corrosive ingestion . Findings were categorized as grade 0 (distinct muscular layers without thickening, grade I (distinct muscular layers with thickening), grade II (obscured muscular layers with indistinct margins) and grade III (muscular layers that could not be differentiated). Findings were further categorized as to whether the worst appearing image involved part of the circumference (type a) or the whole circumference (type b). Strictures did not develop in patients with grade 0 (5 patients) or grade I (4 patients) lesions. Transient stricture formation developed in the only patient with grade IIa lesions, and stricture requiring repeated dilatation developed in the only patient with grade IIIb lesions (Kamijo et al, 2004).

F) CORTICOSTEROID

1) CORROSIVE INGESTION/SUMMARY: The use of corticosteroids for the treatment of caustic ingestion is controversial. Most animal studies have involved alkali-induced injury (Haller & Bachman, 1964; Saedi et al, 1973). Most human studies have been retrospective and generally involve more alkali than acid-induced injury and small numbers of patients with documented second or third degree mucosal injury.
2) FIRST DEGREE BURNS: These burns generally heal well and rarely result in stricture formation (Zargar et al, 1989; Howell et al, 1992). Corticosteroids are generally not beneficial in these patients (Howell et al, 1992).
3) SECOND DEGREE BURNS: Some authors recommend corticosteroid treatment to prevent stricture formation in patients with a second degree, deep-partial thickness burn (Howell et al, 1992). However, no well controlled human study has documented efficacy. Corticosteroids are generally not beneficial in patients with a second degree, superficial-partial thickness burn (Caravati, 2004; Howell et al, 1992).
4) THIRD DEGREE BURNS: Some authors have recommended steroids in this group as well (Howell et al, 1992). A high percentage of patients with third degree burns go on to develop strictures with or without corticosteroid therapy and the risk of infection and perforation may be increased by corticosteroid use. Most authors feel that the risk outweighs any potential benefit and routine use is not recommended (Boukthir et al, 2004; Oakes et al, 1982; Pelclova & Navratil, 2005).
5) CONTRAINDICATIONS: Include active gastrointestinal bleeding and evidence of gastric or esophageal perforation. Corticosteroids are thought to be ineffective if initiated more than 48 hours after a burn (Howell, 1987).
6) DOSE: Administer daily oral doses of 0.1 milligram/kilogram of dexamethasone or 1 to 2 milligrams/kilogram of prednisone. Continue therapy for a total of 3 weeks and then taper (Haller et al, 1971; Marshall, 1979). An alternative regimen in children is intravenous prednisolone 2 milligrams/kilogram/day followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks then tapered (Anderson et al, 1990).
7) ANTIBIOTICS: Animal studies suggest that the addition of antibiotics can prevent the infectious complications associated with corticosteroid use in the setting of caustic burns. Antibiotics are recommended if corticosteroids are used or if perforation or infection is suspected. Agents that cover anaerobes and oral flora such as penicillin, ampicillin, or clindamycin are appropriate (Rosenberg et al, 1953).
8) STUDIES

a) ANIMAL

1) Some animal studies have suggested that corticosteroid therapy may reduce the incidence of stricture formation after severe alkaline corrosive injury (Haller & Bachman, 1964; Saedi et al, 1973a).
2) Animals treated with steroids and antibiotics appear to do better than animals treated with steroids alone (Haller & Bachman, 1964).
3) Other studies have shown no evidence of reduced stricture formation in steroid treated animals (Reyes et al, 1974). An increased rate of esophageal perforation related to steroid treatment has been found in animal studies (Knox et al, 1967).

b) HUMAN

1) Most human studies have been retrospective and/or uncontrolled and generally involve small numbers of patients with documented second or third degree mucosal injury. No study has proven a reduced incidence of stricture formation from steroid use in human caustic ingestions (Haller et al, 1971; Hawkins et al, 1980; Yarington & Heatly, 1963; Adam & Brick, 1982).
2) META ANALYSIS

a) Howell et al (1992), analyzed reports concerning 361 patients with corrosive esophageal injury published in the English language literature since 1956 (10 retrospective and 3 prospective studies). No patients with first degree burns developed strictures. Of 228 patients with second or third degree burns treated with corticosteroids and antibiotics, 54 (24%) developed strictures. Of 25 patients with similar burn severity treated without steroids or antibiotics, 13 (52%) developed strictures (Howell et al, 1992).
b) Another meta-analysis of 10 studies found that in patients with second degree esophageal burns from caustics, the overall rate of stricture formation was 14.8% in patients who received corticosteroids compared with 36% in patients who did not receive corticosteroids (LoVecchio et al, 1996).
c) Another study combined results of 10 papers evaluating therapy for corrosive esophageal injury in humans published between January 1991 and June 2004. There were a total of 572 patients, all patients received corticosteroids in 6 studies, in 2 studies no patients received steroids, and in 2 studies, treatment with and without corticosteroids was compared. Of 109 patients with grade 2 esophageal burns who were treated with corticosteroids, 15 (13.8%) developed strictures, compared with 2 of 32 (6.3%) patients with second degree burns who did not receive steroids (Pelclova & Navratil, 2005).

3) Smaller studies have questioned the value of steroids (Ferguson et al, 1989; Anderson et al, 1990), thus they should be used with caution.
4) Ferguson et al (1989) retrospectively compared 10 patients who did not receive antibiotics or steroids with 31 patients who received both antibiotics and steroids in a study of caustic ingestion and found no difference in the incidence of esophageal stricture between the two groups (Ferguson et al, 1989).
5) A randomized, controlled, prospective clinical trial involving 60 children with lye or acid induced esophageal injury did not find an effect of corticosteroids on the incidence of stricture formation (Anderson et al, 1990).

a) These 60 children were among 131 patients who were managed and followed-up for ingestion of caustic material from 1971 through 1988; 88% of them were between 1 and 3 years old (Anderson et al, 1990).
b) All patients underwent rigid esophagoscopy after being randomized to receive either no steroids or a course consisting initially of intravenous prednisolone (2 milligrams/kilogram per day) followed by 2.5 milligrams/kilogram/day of oral prednisone for a total of 3 weeks prior to tapering and discontinuation (Anderson et al, 1990).
c) Six (19%), 15 (48%), and 10 (32%) of those in the treatment group had first, second and third degree esophageal burns, respectively. In contrast, 13 (45%), 5 (17%), and 11 (38%) of the control group had the same levels of injury (Anderson et al, 1990).
d) Ten (32%) of those receiving steroids and 11 (38%) of the control group developed strictures. Four (13%) of those receiving steroids and 7 (24%) of the control group required esophageal replacement. All but 1 of the 21 children who developed strictures had severe circumferential burns on initial esophagoscopy (Anderson et al, 1990).
e) Because of the small numbers of patients in this study, it lacked the power to reliably detect meaningful differences in outcome between the treatment groups (Anderson et al, 1990).

6) ADVERSE EFFECTS

a) The use of corticosteroids in the treatment of caustic ingestion in humans has been associated with gastric perforation (Cleveland et al, 1963) and fatal pulmonary embolism (Aceto et al, 1970).

G) SURGICAL PROCEDURE

1) SUMMARY: Initially if severe esophageal burns are found a string may be placed in the stomach to facilitate later dilation. Insertion of a specialized nasogastric tube after confirmation of a circumferential burn may prevent strictures. Dilation is indicated after 2 to 4 weeks if strictures are confirmed. If dilation is unsuccessful colonic intraposition or gastric tube placement may be needed. Early laparotomy should be considered in patients with evidence of severe esophageal or gastric burns on endoscopy.
2) STRING - If a second degree or circumferential burn of the esophagus is found a string may be placed in the stomach to avoid false channel and to provide a guide for later dilation procedures (Gandhi et al, 1989).
3) STENT - The insertion of a specialized nasogastric tube or stent immediately after endoscopically proven deep circumferential burns is preferred by some surgeons to prevent stricture formation (Mills et al, 1978; (Wijburg et al, 1985; Coln & Chang, 1986).

a) STUDY - In a study of 11 children with deep circumferential esophageal burns after caustic ingestion, insertion of a silicone rubber nasogastric tube for 5 to 6 weeks without steroids or antibiotics was associated with stricture formation in only one case (Wijburg et al, 1989).

4) DILATION - Dilation should be performed at 1 to 4 week intervals when stricture is present(Gundogdu et al, 1992). Repeated dilation may be required over many months to years in some patients. Successful dilation of gastric antral strictures has also been reported (Hogan & Polter, 1986; Treem et al, 1987).
5) COLONIC REPLACEMENT - Intraposition of colon may be necessary if dilation fails to provide an adequate sized esophagus (Chiene et al, 1974; Little et al, 1988; Huy & Celerier, 1988).
6) LAPAROTOMY/LAPAROSCOPY - Several authors advocate laparotomy or laparoscopy in patients with endoscopic evidence of severe esophageal or gastric burns to evaluate for the presence of transmural gastric or esophageal necrosis (Cattan et al, 2000; Estrera et al, 1986; Meredith et al, 1988; Wu & Lai, 1993).

a) STUDY - In a retrospective study of patients with extensive transmural esophageal necrosis after caustic ingestion, all 4 patients treated in the conventional manner (esophagoscopy, steroids, antibiotics, and repeated evaluation for the occurrence of esophagogastric necrosis and perforation) died while all 3 patients treated with early laparotomy and immediate esophagogastric resection survived (Estrera et al, 1986).

H) FLUID/ELECTROLYTE BALANCE REGULATION

1) Vomiting and diarrhea may be prolonged with large ingestions, resulting in fluid and electrolyte loss. Monitor and replace as necessary. Massive amounts of intravenous fluids may be required (Sawada et al, 1988).

I) ACUTE LUNG INJURY

1) For large ingestions respiratory support may be critical. Severe pulmonary edema has been reported in fatal cases.
2) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
3) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

4) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
5) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
6) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
7) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
8) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

J) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

4) DOBUTAMINE

a) DOSE: ADULT: Infuse at 5 to 10 micrograms/kilogram/minute IV. PEDIATRIC: Infuse at 2 to 20 micrograms/kilogram/minute IV or intraosseous, titrated to desired effect (Peberdy et al, 2010; Kleinman et al, 2010).
b) CAUTION: Decrease infusion rate if ventricular ectopy develops (Prod Info dobutamine HCl 5% dextrose intravenous injection, 2012).

K) ACIDOSIS

1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
2) Repeat doses of no more than one-half the original amount may be given no more often than every 10 minutes if required (American Heart Association, 1987). Increase minute ventilation in intubated patients.

L) FAT EMULSION

1) SUMMARY: Fat emulsion therapy was used successfully in an adult that developed cardiovascular toxicity after glyphosate-surfactant induced cardiovascular collapse (You et al, 2012).
2) CASE REPORT: A 65-year-old man was admitted with an altered mental status after intentionally ingesting 150 mL of glyphosate-surfactant. He collapsed en route to the hospital and cardiopulmonary resuscitation was performed and spontaneous circulation occurred 19 minutes later. He was hypotensive (70/40 mm Hg) with respirations assisted by mechanical ventilation. An ECG and echocardiogram showed accelerated idioventricular rhythm and global akinesis with an ejection fraction of 30%. A blood gas was consistent with lactic acidosis. Initially, the patient was treated with norepinephrine (128 mcg/min) for 2 hours with no improvement in his cardiac status (systolic BP 50 mm Hg; heart rate 74 beats/min). He was then given a 1.5 mL/kg bolus of 20% intralipids and his heart rate (77 beats/min) and blood pressures (90/30 mm Hg) immediately improved. The bolus was followed by a continuous infusion of 20% intralipids (0.25 mL/kg) for more than 20 minutes. The patient gradually improved but his clinical course was complicated by anuresis requiring continuous renal replacement therapy for 7 days. He was discharged to home with no major sequelae (You et al, 2012).

M) EXPERIMENTAL THERAPY

1) EXTRACORPOREAL MEMBRANE OXYGENATION

a) CASE REPORT: A 47-year-old man intentionally ingested 100 mL of glyphosate-surfactant (41% glyphosate isopropylamine and 15% polyoxyethyleneamine (a common surfactant)) about 1.5 hours prior to admission. His initial symptoms included drowsiness, vomiting and diaphoresis, oral ulcers, excessive salivation and diffuse crackles were also observed. An initial ECG showed a widened QRS with a duration of 134 ms and a prolonged QTc of 550 ms. Within an hour the patient was hypotensive, comatose and developed respiratory failure with a mixed metabolic and respiratory acidosis. Early treatment included intubation and mechanical ventilation. Once intubated the patient developed sustained ventricular tachycardia that was treated with lidocaine. Sodium bicarbonate was also added for persistent metabolic acidosis. Because of a lack of response to inotropic agents (dopamine and norepinephrine), extracorporeal membrane oxygenation was added about 3 hours after admission along with continuous veno-venous hemodialysis (CVVH). His cardiovascular function improved within 24 hours and ECMO and CVVH were successfully withdrawn within 2 and 4 days, respectively. The patient continued to improve and he was extubated on day 7 and transferred to a medical floor on day 8 (Chan et al, 2016).

N) TELEPHONE CONSULTATION

1) The National Pesticide Information Center (NPIC) is a cooperative effort of Oregon State University and the US EPA. NPIC provides consultation to poison centers and other health care professionals for the management of pesticide poisoning. Calls regarding emergency cases requiring immediate medical response will be transferred to the Oregon Poison Center.

a) NPIC contact information: phone: 1-800-858-7378. email: npic@ace.orst.edu Hours: 8 AM to 12 PM Pacific time Monday through Friday, excluding holidays.

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
D) Nasal irrigation with normal saline solution may help alleviate nasal irritation.
E) Appreciable inhalation exposures, resulting in toxicity, are unlikely, due to glyphosate's low vapor pressure (Acquavella et al, 1999).

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).

Enhanced Elimination

1) Glyphosate is excreted rapidly in the urine. Maintaining an adequate urine output is important as the clearance of glyphosate by the kidney (52.9 mL/minute) was as good as by hemodialysis (52.5 mL/minute); both of which were superior to hemoperfusion (6.4 mL/minute) (Hiraiwa et al, 1990).

1) Hemodialysis may be indicated in patients with renal failure. Tsuda et al (1989) have found hemodialysis more effective than direct hemoperfusion for removal of glyphosate from blood (Garlich et al, 2014; Tsuda et al, 1989).
2) CASE REPORT: An adult intentionally ingested a 41% solution of glyphosate isopropylamine in POEA surfactant and was found obtunded with respiratory depression requiring immediate intubation and mechanical ventilation. Laboratory studies showed hyperkalemia (potassium 7.8 mEq/L), acute renal failure (creatinine 3.3 mg/dL) and acidosis (pH 7.11, lactate 7.5 mmol/L). Initial treatment included, IV fluids, sodium bicarbonate, insulin and sodium polystyrene sulfonate. However, hemodialysis was added 16 hours after ingestion for refractory hyperkalemia and acidosis for 2.5 hours. Following hemodialysis, laboratory values improved significantly (potassium 4.4 mEq/L, creatinine 2.1 mg/dL, BUN 23 mg/dL, pH 7.5 and lactate 1.6 mmol/L). Within one week, his laboratory values had returned to normal (Garlich et al, 2014)
3) CASE REPORTS: Two cases of intentional glyphosate ingestion with severe poisoning survived with supportive care that included hemodialysis. Both patients rapidly developed anuric renal failure and were treated with early hemodialysis. Dialysis clearance of glyphosate was not determined.

a) Case 1 had persistent hyperkalemia with ECG changes, acute renal failure, and was hemodynamically unstable despite pressor therapy following a 300 mL ingestion of Roundup(R) (glyphosate 41%). One hour after the initiation of hemodialysis, the patient became hemodynamically stable, and 17 hours later the patient converted to a sinus rhythm and urine output improved. The patient made a favorable recovery with no sequelae.
b) Case 2 underwent hemodialysis due to refractory metabolic acidosis following a 200 mL ingestion of Roundup(R). After hemodialysis, the patient's hemodynamics improved, urine output increased, and the metabolic acidosis resolved. A full recovery was seen 7 days after admission.

1) In an in-vitro experiment evaluating the elimination of glyphosate by direct hemoperfusion (DHP) or hemodialysis (HD), measured serum glyphosate concentrations showed insignificant decreases by DHP. However, marked decreases were shown when glyphosate was removed by HD. The authors concluded that HD is most effective for glyphosate removal from serum (Tsuda et al, 1989). However, since the volume of distribution of glyphosate is unknown, it is unclear how much of the total body burden of glyphosate can be removed by extracorporeal methods.
2) Tominack (1999) reported that hemodialysis, as well as resin hemoperfusion are effective for removal of glyphosate from blood, but activated charcoal hemoperfusion was NOT effective (Tominack, 1999).

Life Support

Abstracts

Case Reports

1) ROUTE OF EXPOSURE

a) ORAL

1) A 41-year-old man ingested 500 mL of a glyphosate-surfactant herbicide (851 mg/kg glyphosate). He exhibited severe dyspnea related to presumed aspiration, abdominal pain, and vomiting upon admission to the intensive care unit 3 to 4 hours postingestion. Gastric endoscopy showed erosions of the esophagus, stomach, and duodenum. Cardiovascular collapse occurred 5 hours postingestion. Treatment included dobutamine for 24 hours, mechanical ventilation, and antibiotics for lung injury for 2 weeks. The patient was discharged from the ICU 2 weeks postingestion (Bedry et al, 1993).
2) A 43 year-old woman, who ingested up to 250 mL of Roundup(R), was discovered semiconscious with vomitus 2 to 3 hours postingestion. Presenting signs on admission to the emergency department included mydriasis, hypotension, metabolic acidosis, and hyperkalemia. Treatment during the first 10 hours included intravenous hydration, sodium bicarbonate, and insulin. Her condition deteriorated, and she became severely hypotensive, hyperkalemic, and anuric. Respiratory and cardiac arrest occurred. Postmortem examination revealed acute pulmonary edema and acute renal tubular necrosis (Temple & Smith, 1992).
3) GLYPHOSATE-TRIMESIUM FORMULATION: Based on limited case reports, the formulation containing glyphosate-trimesium appears to have a different mechanism of action that may produce rapid toxicity following ingestion. Two fatal cases of intoxication have been reported within 1 hour or less of oral exposure to glyphosate-trimesium in an adult (approximately 150 mL ingested) and a 6-year-old boy (Sorensen & Gregersen, 1999).

b) OCULAR

1) A male adult accidentally rubbed Roundup(R) concentrate into his eye. Gross periorbital edema with chemosis of the eye developed in conjunction with tachycardia, palpitations, and hypertension. Treatment with intramuscular promethazine resolved the symptoms within 24 hours (Temple & Smith, 1992).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) The following fatal prognostic indicators were derived from several studies on glyphosate-surfactant intoxication in Taiwan. The surfactant commonly used in Taiwan is polyoxyethyleneamine. It is also reportedly the most commonly used surfactant worldwide (Chan et al, 2016):

1) Age greater than 40 years;
2) Large ingestion (greater than 200 mL);
3) Clinical findings include: an elevated creatinine, acidosis, hyperkalemia, tachycardia, and respiratory failure requiring intubation.

1) The mean amount of concentrated Roundup(R) (40% glyphosate) ingested in 9 fatal cases was 206 mL (Sawada et al, 1988). These cases were all deliberate suicidal ingestion.
2) CASE REPORT: A 37-year-old woman died after ingesting approximately 500 mL of glyphosate as Roundup(R) (the formulation contained 41% glyphosate as the isopropylamine salt and 15% polyoxyethylene amine as a surfactant). At autopsy, there was evidence of gastrointestinal hemorrhage, pulmonary and brain edema and liver toxicity. A toxicology screen was negative (Sribanditmongkol et al, 2012).
3) CASE REPORT: A 25-year-old woman was admitted with a 4 day history of fever and painful oral ulcers after intentionally ingesting glyphosate. Physical exam showed extensive oral ulcers that bled easily. By day 3, it was determined that she had ingested 100 to 150 mL of glyphosate (43.15% w/w with 95% purity and net concentration of 41% SL) after developing subcutaneous emphysema and pneumomediastinum due to esophageal perforation. Her clinical course rapidly declined requiring mechanical ventilation, inotropes and dialysis. She died 12 days after ingestion (Jyoti et al, 2014).
4) Ingestion of approximately 50 mL of a glyphosate-trimesium herbicide formulation by a 6-year-old boy resulted in death within minutes. A 34-year-old woman who ingested approximately 150 mL of a glyphosate-trimesium herbicide also died quickly. Findings on postmortem examination included pulmonary edema, erosion of gastric mucous membranes, cerebral edema, and dilated right atrium and ventricle of the heart (Sorensen & Gregersen, 1999).
5) MORTALITY

a) CASE FATALITY RATE: The fatality rate in 67 cases of Roundup(R) poisoning was 7.5%, and the average dose was 184 +/- 70 mL (range 85 to 200 mL). All fatal cases were suicidal ingestions. Ingestion of larger, nonfatal doses (500 mL) was reported for some patients (Talbot et al, 1991).
b) In a series of 97 adult ingestion cases (ages 12 to 77), mortality was 17%. Most (88%) were suicidal attempts (Tominack et al, 1991).
c) In a series of 22 adult suicidal ingestion cases, 4 patients (18%) died (Sheu et al, 1998).
d) In a retrospective case series (n=131) of glyphosate-surfactant poisonings, patients that ingested greater than 200 mL were at increased risk of death (Lee et al, 2000).
e) In a series of 601 glyphosate ingestions there were 19 fatalities. Fatal cases had ingested 75 mo to 350 ml concentrated glyphosate (generally 36% w/v) (Roberts et al, 2010).

Maximum Tolerated Exposure

1) No deaths occurred with a history of ingestion of less than 150 mL concentrate or in patients less than 40 years of age (Tominack et al, 1991).
2) The manufacturer reports that ingestions of 1 to 8 ounces (30 to 240 mL) of concentrate resulted in vomiting and diarrhea of 2 to 5 days duration, but no other symptoms. Sawada et al (1988) reported that 47 patients who ingested a mean of 104 mL developed significant symptoms (co-ingestants not reported) (Sawada et al, 1988).
3) A 69-year-old woman intentionally ingested 500 mL of glyphosate-surfactant herbicide (48% glyphosate potassium salts; Roundup Maxload (R)) and was found alert but vomiting by her spouse. Once admitted, she lost consciousness and became pulseless. Following CPR and repeated cardioversion; ventricular tachycardia was unresponsive to antiarrhythmics. Initial laboratory findings included severe hyperkalemia (potassium 10 mEq/L), normal renal function and metabolic acidosis. Treatment included percutaneous cardiopulmonary support and continuous hemodialysis which corrected the patient's elevated potassium concentration. The patient recovered following a complicated clinical course that included esophageal and gastric erosions and acute respiratory distress syndrome. The patient required intubation and mechanical ventilation for 20 days. Her serum glyphosate concentration on admission was 1625.74 mcg/mL and 18 hours later was 100.44 mcg/mL (Kamijo et al, 2012).
4) A 51-year-old man developed multiorgan system damage, including acute renal failure with oliguria and severe hypoxia, 12 hours after ingesting "4 gulps" (approximately 240 mL) of a product that contained 18% glyphosate, 0.73% diquat, and 7% polyoxyethyleneamine (POEA). After supportive therapy, including 4 hours of hemodialysis, the patient's status improved and he gradually regained renal function (Sampogna & Cunard, 2007).

1) CASE REPORT: A 22-year-old man survived after self-injecting approximately 250 mL of diluted glyphosate-surfactant herbicide in a suicide attempt. The patient presented with mild metabolic acidosis and acute hemolysis, which required plasmapheresis and blood transfusions. He made a full recovery 4 days later (Wu et al, 2006).

1) In a retrospective review of 107 patients with acute glyphosate intoxication, surfactant volume had a role in the development of severe toxicity compared to the surfactant type (ingredient) in various glyphosate herbicide products. In patients that ingested surfactant volumes of 8 mL or more there was a strong association with the development of hypotension (47.1%), mental deterioration (38.6%), respiratory failure (30%), acute kidney injury (17.1%) and arrhythmia (10%). Most patients improved with no long-term sequelae; however, 2 patients died of refractory shock, metabolic acidosis and respiratory failure (Seok et al, 2011).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) Survivors in whom plasma glyphosate levels were measured had levels of 4.97 mg/mL about 2 hours after ingestion of 100 mL (Kawamura et al, 1987), 69.2 parts per million about 7 hours after ingestion of 50 mL (Iwata et al, 1988), and 600 parts per million about 1 hour after ingestion of 80 mL (Hiraiwa et al, 1990).
b) Plasma levels were undetectable by the second day (Kawamura et al, 1987; Hiraiwa et al, 1990) and 0.4 to 1 mg/mL in autopsy cases where death occurred about 6 hours after ingestion of 200 to 250 mL (Dickson et al, 1988; Kageura et al, 1988).
c) Severe poisonings were associated with plasma levels greater than 1,000 parts per million. In two patients who had ingested greater than 200 mL, peaks were reached in 4 hours, which then rapidly declined to almost undetectable levels by 12 hours. Rebound peaks were not detected during the following 5 days. Urine levels were significant on the first day and then almost undetectable by the second day (Talbot et al, 1995).
d) In a series of 601 patients with acute glyphosate overdose, including 19 fatalities, blood samples were analyzed for glyphosate in 216 patients. A glyphosate plasma concentration above 734 micrograms/mL was the best predictor of death, with a likelihood ratio of 106 (Roberts et al, 2010).

Workplace Standards

1) Not Listed

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): D ; Listed as: Glyphosate

a) D : Not classifiable as to human carcinogenicity.

3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2A ; Listed as: Glyphosate

a) 2A : The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (ORAL)HUMAN:

1) >5,000 mg/kg - Acute human oral toxicity (Category IV) (69 FR 51301 - 51312, 2004)

B) LD50- (SKIN)HUMAN:

1) >5,000 mg/kg - Acute human skin (dermal) toxicity (Category IV) (69 FR 51301 - 51312, 2004)

C) LD50- (INTRAPERITONEAL)MOUSE:

1) 130 mg/kg - convulsions, respiratory increase, increased body temperature (RTECS, 2004)

D) LD50- (ORAL)MOUSE:

1) 1,568 mg/kg - convulsions, respiratory increase, increased body temperature (RTECS, 2004)

E) LD50- (INTRAPERITONEAL)RAT:

1) 235 mg/kg - convulsions, respiratory increase, increased body temperature (RTECS, 2004)

F) LD50- (ORAL)RAT:

1) 4,873 mg/kg - convulsions, respiratory increase, increased body temperature (RTECS, 2004)

G) LD50- (ORAL)RAT:

1) 5,000 mg/kg (RTECS, 2004)

7.7.2)

A) LOAEL- (ORAL)MOUSE:

1) 4,500 mg/kg/D for 90D - male and female mice; weight gain decrease (69 FR 51301 - 51312, 2004)

B) LOAEL- (INHALATION)RAT:

1) >0.36 mg/L for 28D - highest dose tested in rats (same dose as NOAEL) - exposure duration: 6H/D and 5D/W for 4W (69 FR 51301 - 51312, 2004)

C) LOAEL- (ORAL)RAT:

1) 50 mg/kg/D for 90D - males and female rats; increased phosphorous and potassium levels (69 FR 51301 - 51312, 2004)

D) NOAEL- (ORAL)HUMAN:

1) For technical grade glyphosate, EPA's short and intermediate term oral exposure NOAEL for humans is 175 mg/kg/D (69 FR 51301 - 51312, 2004).

E) UNASSIGNED- (ORAL)HUMAN:

1) For technical grade glyphosate, EPA's chronic Reference Dose (RfD) for humans is 1.75 mg/kg/D (69 FR 51301 - 51312, 2004).

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) Glyphosate is a noncholinesterase inhibiting organophosphorus herbicide (Temple & Smith, 1992).
2) Glyphosate inhibits the shikimate metabolic pathway in plants. This pathway is not present in mammals (Adam et al, 1997; Williams et al, 2000). Weed growth is inhibited by glyphosate's ability to inhibit the enolpyruvylskimate phosphate synthase enzyme in this plant pathway. Blockade of this pathway prevents the biosyntheses of chorismate, which is a necessary intermediate for the synthesis of phenylalanine, tyrosine, and tryptophan. Glyphosate's herbicidal action is manifested by direct contact with the plant. Root system entry is negligible (Williams et al, 2000).

1) The polyoxyethyleneamine surfactant in Roundup(R) was thought to be responsible for the toxicity seen in 56 cases of ingestion (Sawada et al, 1988; Moses, 1989).
2) Intravenous injection of glyphosate, surfactant, and Roundup(R) in beagle dogs suggested that cardiac depression caused by Roundup(R) was mainly due to the surfactant (Tai et al, 1990).

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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