PARAQUAT

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 4,4'-BIPYRIDINIUM, 1,1'-DIMETHYL-
2) 1,1'-DIMETHYL-4,4'-BIPYRIDINIUM
3) N,N'-DIMETHYL-4,4'-BIPYRIDINIUM
4) N,N'-DIMETHYL-GAMMA,GAMMA'-DIPYRIDINIUM
5) DIMETHYL VIOLOGEN
6) GRAMOXONE S
7) METHYL VIOLOGEN
8) METHYL VIOLOGEN (2+)
9) PARAQUAT DICATION
10) PARAQUAT (CAS 1910-42-5)
11) PARAQUAT
12) PARAQUAT ION
13) PILLARQUAT (CAS 1910-42-5)
14) PRIGLONE
15) References: Lewis, 1998; Lewis, 1997; HSDB, 1999

1) AH 501
2) BIPYRIDINIUM, 1,1'-DIMETHYL-4,4'-,DICHLORIDE
3) 4,4'-BIPYRIDINIUM, 1,1'-DIMETHYL-,DICHLORIDE
4) CEKUQUAT
5) CRISQUAT
6) DEXTRONE
7) DEXTRONE X
8) DEXTRONE-X
9) DEXURON
10) N,N'-DIMETHYL-4,4'-BIPYRIDINIUM DICATION
11) N,N'-DIMETHYL-4,4'-BIPYRIDINIUM DICHLORIDE
12) N,N'-DIMETHYL-4,4'-BIPYRIDYLIUM DICHLORIDE
13) 1,1'-DIMETHYL-4,4'-BIPYRIDINIUM DICHLORIDE
14) 1,1'-DIMETHYL-4,4'-DIPYRIDINIUM-DICHLORID (GERMAN)
15) 4,4'-DIMETHYLDIPYRIDYL DICHLORIDE
16) 1,1'-DIMETHYL-4,4'-DIPYRIDYLIUM CHLORIDE
17) N,N'-DIMETHYL-4,4'-DIPYRIDYLIUM DICHLORIDE
18) N,N'-DIMETHYL-GAMMA,GAMMA'-DIPYRIDYLIUM
19) DIMETHYL VIOLOGEN CHLORIDE
20) ESGRAM
21) GOLDQUAT 276
22) GRAMIXEL
23) GRAMONOL
24) GRAMOXON
25) GRAMOXONE
26) GRAMOXONE D
27) GRAMOXONE DICHLORIDE
28) GRAMOXONE INTEON
29) GRAMOXONE S
30) GRAMOXONE W
31) GRAMURON
32) HERBAXON
33) HERBOXONE
34) METHYLVIOLOGEN
35) METHYL VIOLOGEN
36) METHYL VIOLOGEN DICHLORIDE
37) METHYL VIOLOGEN (REDUCED)
38) OK 622
39) ORTHO PARAQUAT CL
40) PARA-COL
41) paraquat (ACGIH)
42) PARAQUAT CHLORIDE
43) PARAQUAT CL
44) PARAQUAT, DICHLORIDE
45) PATHCLEAR
46) PILLARQUAT
47) PILLARXONE
48) PP148
49) SWEEP
50) TERRAKLENE
51) TOTACOL
52) TOTAL
53) TOXER TOTAL
54) VIOLOGEN, METHYL-
55) WEEDOL
56) References: Lewis, 1998; Lewis, 1997; HSDB, 1999

1) 4,4'-BIPYRIDINIUM, 1,1'-DIMETHYL-,BIS(METHYL SULFATE)
2) 1,1'-DIMETHYL-4,4'-BIPYRIDINIUM DIMETHYLSULFATE
3) 1',1'-DIMETHYL-4,4'-DIPYRIDINIUM DI(METHYL SULFATE)
4) GRAMOXONE METHYL SULFATE
5) PARAQUAT BIS(METHYL SULFATE)
6) PARAQUAT DIMETHYL SULFATE
7) PARAQUAT DIMETHYL SULPHATE
8) PARAQUAT I
9) PILLARQUAT
10) PP910
11) References: Lewis, 1998; Lewis, 1997; HSDB, 1999

1.2.1) MOLECULAR FORMULA
1) C12-H14-N2 (PARAQUAT)
2) C12-H14-N2.2Cl (PARAQUAT, DICHLORIDE SALT)
3) C12-H14-N2.2C-H3-O4-S (PARAQUAT, BIS(METHYLSULFATE)SALT)

Available Forms Sources

1) GENERAL FORMULATION

a) Paraquat is available as colorless crystals (dichloride salt) or a yellow solid (bis(methyl sulfate) salt). It is soluble in water, odorless or with a faint ammonia-like odor. Paraquat ion (active) is liberated through the application of the dichloride and bis(methyl sulfate) salts in the commercial product (Budavari, 1996; Clayton & Clayton, 1994; Lewis, 1998; Harbison, 1998).
b) Technical products are available as liquids, with concentrations ranging from 20% to 50% (Morgan, 1993).
c) Paraquat is classified as a Restricted Use Pesticide by the Environmental Protection Agency and may be used only by commercial licensed users. Exceptions to the restriction include spot weed and grass control pressurized spray formulations containing 0.44% paraquat bis(methyl sulfate) and liquid fertilizers containing 0.025%, 0.03%, or 0.04% paraquat dichloride (EPA, 1986).

1) Homeowner products with a paraquat content of 0.276% are not classified as Restricted Use Pesticides following an EPA ruling (EPA, 1988).

2) LOW CONCENTRATION FORMULATION

a) A low concentration paraquat product is available in Japan (Yoshioka et al, 1992). The new product is a mixture of 4.5% w/v paraquat ion and 4.5% w/v diquat ion.

3) NEW FORMULATION

a) A new paraquat formulation called GRAMOXONE INTEON has been created to limit toxicity following intentional or inadvertent ingestion by reducing the amount of paraquat absorbed from the gastrointestinal tract. The formulation works by the addition of a natural alginate that immediately gels when it reaches the stomach, and the amount of an emetic was also increased. This improves the efficacy of using emesis after the formulation has gelled in the stomach. In addition, magnesium sulphate (an osmotic purgative) has been added to speed the transport of any remaining product through the small intestine to minimize absorption. In an observational study, the survival rates following an INTEON ingestion were significantly better than the standard formulation (hazard ratio 0.73, 95% CI 0.60-0.89; p = 0.002). At 3 month follow-up, the number of cases alive in the INTEON group were 103 (35.6%) (n=289), as compared to 76 (25.6%) (n=297) in the standard formulation group (Wilks et al, 2008).

4) AVAILABILITY

a) Internationally, paraquat is usually available as a solution of 200 grams of paraquat ion per liter; in the USA, formulations of 2 pounds per US gallon are common (Hall, 1995).
b) Paraquat is also available as granular or solid preparations (Hall, 1995).
c) Paraquat may be formulated with other herbicides, such as (Hall, 1995):

1) Diquat
2) Monolinuron
3) Diuron
4) Simazine
5) Princip
6) Atrazine
7) Bladex
8) Lasso
9) Lexone
10) Lorox
11) Sencor

1) Paraquat is a rapidly-acting herbicide. It kills the tissues of green plants by contact action with foliage and by some amount of translocation to the xylem (Hall, 1995).
2) Paraquat can be used to control most annual weeds and grasses. It has been used on a wide variety of food and nonfood crops. It can also be applied in water to control weeds in irrigation ditchbanks (Hall, 1995).
3) Paraquat may be used as a preplant or preemergence spray on croplands. It is applied to foliage by broadcast, band, or directed spray ground-bared equipment, and can also be broadcast sprayed from aircraft (Hall, 1995).
4) PARAQUAT-TREATED MARIJUANA

a) Paraquat has been previously used to destroy illicit marijuana plants. However, even if the plants are harvested and smoked shortly after spraying, there appears to be no risk associated with paraquat. Residues as high as 2264 ppm (average 331 ppm) were found in 3.6% of confiscated marijuana in the US in 1978 (Hall, 1995).
b) The temperatures generated by smoking paraquat-contaminated marijuana inactivate the paraquat. NO cases of pulmonary injury from smoking paraquat-contaminated marijuana have been documented (Hall, 1995).

5) PARAQUAT ADULTERATED ALCOHOL

a) In Sri Lanka, illicit alcohol is brewed by fermenting and distilling a solution of cane sugar and the drink is referred to as "kasippu". During fermentation various agents are added to alter its taste and potency. These additives are used in minute quantities to increase the effects of the brew. In 2005, 50 men were exposed to this brew with 5 fatalities reported secondary to paraquat contamination. Among those that died, the most common symptoms included: fever, headache, cough, dyspnea, abdominal pain, hepatomegaly, and alterations in lung function. At autopsy, the findings were consistent with fatal acute pneumonitis secondary to paraquat exposure (Beligaswatte et al, 2008).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Paraquat is used primarily as a herbicide. The solution is usually blue-green in color. Concentrates of the solution range from 20% to 40% with dilutions of 0.1% to 0.5% typically made for herbicidal use.
B) TOXICOLOGY: Contact with mucosus membranes may lead to caustic injury. Absorption of the toxin may lead to pulmonary, hepatic, renal, and myocardial injury. Paraquat is concentrated in type I and type II pneumocytes and leads to the generation of oxygen free radicals and subsequent pulmonary fibrosis.
C) EPIDEMIOLOGY: Paraquat is used in over 120 developed and developing countries in the world due to its efficacy as a herbicide, inactivation when in contact with soil, low toxicity when handled appropriately. Paraquat is a restricted-use pesticide in the United States, thus significant exposures are rare. Exposures are most common in areas with higher availability. Intentional ingestions pose the greatest risk of severe toxicity or death. Occupational exposures are primarily dermal and rarely result in systemic toxicity.
D) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Ingestion of a 20% solution, the most commonly available concentrated solution, is expected to cause caustic injury to the oral mucosa and esophagus. Nausea and vomiting are common. The patient may develop transient renal, hepatic and respiratory impairment. Symptoms usually resolve in patients with a mild exposure. Patients with moderate toxicity can develop permanent pulmonary injury.
2) SEVERE TOXICITY: Nearly all patients that develop severe paraquat toxicity have ingested concentrated forms of the herbicide. Patients may die in the first several days due to gastrointestinal perforations or multiorgan failure. Patients that survive the early phase of toxicity involving cardiovascular, hepatic, and renal systems develop pulmonary fibrosis and subsequent death over the following 2 to 4 weeks postingestion.
3) EARLY FINDINGS may include:

a) GASTROINTESTINAL: Nausea and vomiting are present almost immediately following ingestion. Corrosive injuries to the esophagus and stomach are common and perforations may occur.
b) CARDIOVASCULAR: Patients may develop hypotension due to massive fluid losses and cardiac dysrhythmias. Prolonged QT has also been reported.
c) HEPATIC: Hepatic failure due to centrilobular necrosis progresses over the first 24 to 48 hours.
d) RENAL: Renal failure due to acute tubular necrosis progresses rapidly over the ensuing 24 hours postingestion.
e) NEUROLOGIC: Patients may develop CNS depression (eg, lethargy, coma) and seizures with severe toxicity.

4) LATE FINDINGS may include:

a) PULMONARY: The lungs are inordinately affected by paraquat toxicity due to transport of the toxin into pneumocytes. Patients develop progressive fibrosis and hypoxia over 2 to 4 weeks postingestion.

5) DERMAL EXPOSURE: High concentrations may lead to corrosive injury to the dermis (blistering). Symptoms occur rapidly and may progress for 24 hours. Systemic toxicity due to dermal exposure through intact skin is uncommon. However, prolonged exposure to concentrated solutions can lead to skin damage and subsequent systemic absorption. INHALATION EXPOSURE: Significant pulmonary toxicity from inhalational exposures has not been reported. This is likely due to the large size of the paraquat droplets when sprayed. Patients may develop upper airway irritation or ulceration due to inhalational exposure. OCULAR EXPOSURE: Significant corrosive injury may progress for 24 hours. Corneal injury and protracted opacification of the cornea may result from exposure.

0.2.20)

A) Paraquat has been shown to cross the placental barrier and adverse reproductive effects, including fetotoxicity, have been observed in humans and animals after ingestion of paraquat.

0.2.21)

A) There is no direct evidence that paraquat is a human carcinogen.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Following decontamination, supportive care is the mainstay of care. Immunosuppressive therapy (glucocorticoids and cyclophosphamide) should be administered to a patient at risk of moderate or severe pulmonary toxicity and those with symptoms consistent with moderate to severe toxicity.

B) MANAGEMENT OF SEVERE TOXICITY

1) Following decontamination, supportive care is the mainstay of care. Aggressive fluid resuscitation should aim to replace fluid losses and maintain renal blood flow in order to augment toxin elimination. Early hemoperfusion may reduce mortality. Immunosuppressive therapy (eg, cyclophosphamide, methylprednisolone and dexamethasone) should be administered to treat the acute inflammatory process associated with paraquat poisoning that can lead to lung injury and death (see IMMUNOSUPPRESSIVE THERAPY). Prolonged QT interval has been reported following paraquat exposure. In patients with QT prolongation, monitor serum electrolytes including potassium, calcium and magnesium in patients with significant overdose; correct any abnormalities.

C) DECONTAMINATION

1) PREHOSPITAL: DERMAL EXPOSURE: Remove contaminated clothing and wash thoroughly with soap and water.
2) HOSPITAL: DERMAL EXPOSURE: Remove contaminated clothing and wash thoroughly with soap and water. Care should be taken not to abrade the skin because disruption of the stratum corneum may lead to increased toxin absorption. INGESTION: Patients with a recent ingestion should receive nasogastric suction with a soft, small gauge tube in order to remove any liquid remaining in the stomach. After gastric decontamination with an NG tube, aggressive antiemetic therapy should be provided to facilitate administration of the adsorbent agent. Patients with an ingestion within the last 24 hours should be given one of the following: ACTIVATED CHARCOAL: DOSE: ADULT: 50 to 100 g; CHILD: 1 g/kg); BENTONITE CLAY (7% solution): DOSE: ADULT: 100 to 150 g; CHILD less than 12 years of age: : 2 g/kg; or FULLER'S EARTH (30% solution) DOSE: ADULT: 100 to 150 g; CHILD less than 12 years of age: 2 g/kg). AVOID: Gastric lavage is NOT recommended because of corrosive injuries imparted by the solution itself may increase the risk of iatrogenic perforation. OCULAR EXPOSURE: Copious irrigation with saline or sterile water and ophthalmology consultation.

D) AIRWAY MANAGEMENT

1) Airway support should be considered for patients with severe CNS depression or those at risk of aspiration.

E) ANTIDOTE

1) There is NO antidote available for paraquat toxicity.

F) IMMUNOSUPPRESSIVE THERAPY

1) SUMMARY: Several small studies suggest that immunosuppressive therapy can reduce the mortality rate of severe paraquat poisoning. Different strategies have been recommended.
2) PULSE THERAPY: This protocol suggests the following: ACTIVATED CHARCOAL: Gastric lavage followed by administration of 1 g/kg of activated charcoal in 250 mL of magnesium citrate in patients presenting within 24 hrs. HEMOPERFUSION: Two 8 hours courses of activated charcoal hemoperfusion within 24 hrs of paraquat ingestion. After hemoperfusion, administer IV cyclophosphamide 15 mg/kg/day in 200 mL D5NS infused over 2 hrs for 2 consecutive days. Also administer 1 g methylprednisolone in 200 mL D5NS infused over 2 hrs daily for 3 consecutive days. After the initial pulse therapy, administer dexamethasone 5 mg IV every 6 hrs until PaO2 is 80 mmHg (11.5 kPa) or greater. If PaO2 is less than 60 mmHg (8.64 kPa), repeat IV methylprednisolone 1 g in 200 mL D5NS infused over 2 hours daily for 3 consecutive days. If WBC is greater than 3000/m(3) and it has been 2 weeks since the initial pulse of cyclophosphamide, repeat IV infusion of cyclophosphamide 15 mg/kg in 200 mL D5NS infused over 2 hrs as a single dose. Then continue IV dexamethasone 5 mg every 6 hrs until PaO2 is 80 mmHg (kPa 11.5) or greater. Then reduce dexamethasone dose gradually.
3) ALTERNATIVE THERAPIES: Other treatment methods have included the following: High-dose therapy includes the same initial treatment (activated charcoal and hemoperfusion) as pulse therapy along with high-dose cyclophosphamide (5 mg/kg/d) and dexamethasone 24 mg/d for 14 days. Another method includes early decontamination and 15 mg/kg of cyclophosphamide in D5NS in 200 mL infused over 2 hrs for 2 days and methylprednisolone 1 g in 200 mL D5NS IV infused over 4 hrs and repeated for 3 consecutive days. Mesna (15 mg/kg) was also administered over 4 days to avoid side effects to cyclophosphamide.

G) HYPOTENSION

1) Treat hypotension with isotonic fluid resuscitation until the patient is felt to be euvolemic, followed by addition of vasopressors in standard doses. Cardiac dysrhythmias should be treated according to typical ACLS protocols.

H) OXYGEN THERAPY

1) In general, oxygen therapy should be withheld until the PaO2 is below 50 mmHg, because supplemental oxygen may lead to increased production of oxygen free radicals and increased pulmonary toxicity. Lung transplantation may be considered late in the course for patients with severe pulmonary injury and subsequent hypoxia after the serum paraquat concentration is zero.

I) NAUSEA AND VOMITING

1) Treatment is supportive with care to ensure replacement of gastrointestinal fluid losses. Antiemetics should be provided liberally (Ondansetron: Adult: 4 to 8 mg IV; Children: 0.15 mg/kg IV). Stress ulcer prophylaxis should be provided, since patients are likely to have corrosive injury due to the ingestion.

J) ACUTE TUBULAR NECROSIS

1) Renal injury is due to acute tubular necrosis and is largely reversible. Adequate fluid resuscitation is key to limiting secondary renal injury. Hemodialysis for oliguric renal failure is occasionally necessary as a temporizing measure until renal function improves.

K) SEIZURES

1) Seizures should be treated with benzodiazepines.

L) ENHANCED ELIMINATION

1) Hemoperfusion may increase survival if initiated early (ideally within 5 hours), based on data from retrospective studies. Both hemoperfusion and hemodialysis have been shown to increase paraquat clearance. Hemoperfusion is the preferred method of extracorporeal elimination, if available.

M) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with dermal exposures involving a small body surface area to intact skin that do not have local symptoms or mucous membrane involvement can be managed at home with simple soap and water decontamination.
2) OBSERVATION CRITERIA: Patients with dermal, "lick", "sip" or "taste" exposures can be observed for 6 hours and evaluated for evidence of caustic injuries.
3) ADMISSION CRITERIA: Any patient with an intentional ingestion should be admitted to the hospital for monitoring. Patients with corrosive injury or other systemic toxicity should be admitted.
4) CONSULT CRITERIA: A toxicologist should be consulted for all ingestions and all dermal exposures involving more than minimal body surface area. Appropriate medical subspecialties should be consulted to aid in the support of specific organ dysfunction due to toxicity.

N) PITFALLS

1) Failure to consider decontamination early in patients with ingestion can lead to significant absorption and progression of toxicity with no effective treatment. Failure to provide immunosuppressant therapy may lead to increased pulmonary toxicity.

O) TOXICOKINETICS

1) Following an ingestion, absorption is rapid and peak serum paraquat concentrations occur within 2 hours. Paraquat is cleared primarily through the kidneys within the first 12 to 24 hours. Dermal absorption through intact skin is minimal. Mucous membrane and ocular exposures may lead to minimal systemic absorption though local tissue damage may be significant.

P) DIFFERENTIAL DIAGNOSIS

1) Ingestion of other herbicide products, such as glyphosate, should be considered because they may lead to similar cardiovascular toxicity though pulmonary and renal impairment are uncommon. Other inhalational exposures leading to chemical pneumonitis should be considered in patients presenting with pulmonary toxicity since this is a later finding in paraquat toxicity. Primary medical etiologies of pulmonary fibrosis should be considered if there is not a history of paraquat ingestion.

0.4.3)

A) There have been no substantiated cases of paraquat poisoning due to inhalation of "fumes." Inhalation of spray mist does occur, but the droplets are usually large and deposit in the upper respiratory tract where they cause local irritant effects. Although pulmonary toxicity has not been reported after inhalation exposure, supplemental oxygen should be avoided unless significant hypoxia develops.

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) 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. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
2) Paraquat is well absorbed through abraded or injured skin; fatalities following skin exposure have occurred. Medical personnel must take precautions so as not to become contaminated.

Range Of Toxicity

1) MILD TOXICITY: Ingestion of less than 20 mg paraquat ion per kg body weight (less than 7.5 mL of 20% [w/v] paraquat concentrate): No symptoms or mild GI effects; recovery likely.
2) MODERATE to SEVERE TOXICITY: 20 to 40 mg paraquat ion per kg body weight (7.5 to 15 mL of 20% [w/v] paraquat concentrate): Pulmonary fibroplasia develops. Death occurs in most cases, but may be delayed 2 to 3 weeks.
3) FATAL: Greater than 40 mg paraquat ion per kg body weight (more than 15 mL of 20% [w/v] paraquat concentrate): Multiple organ failure occurs; toxicity progresses rapidly. Mortality is essentially 100% in 1 to 7 days.
4) SURVIVAL CURVES for patients that ingested paraquat have been developed based upon serum paraquat concentrations and hours since the ingestion. They are useful for prognosis only.

Clinical Effects

Summary Of Exposure

4) LATE FINDINGS may include:

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) CASE SERIES: In a retrospective study of 103 patients with acute paraquat poisoning, hypothermia (less than 36.5 degrees C) was found to be an independent risk factor associated with a higher mortality rate (Chang et al, 2008). Of the non-survivors, 25 (35.7%) had developed hypothermia, as compared to 3 (9.1%) in the survivor group.

3.3.4)

A) Hypotension may develop (HSDB , 1999).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) OPACIFICATION: Protracted opacification of the cornea from paraquat splashed in the eye may occur (Grant, 1993; Morgan, 1993).
2) The severity of eye injuries from splashes seems to be related to surfactants contained in commercial preparations rather than paraquat itself (Grant, 1993).
3) IRRITATION: Concentrated paraquat may cause severe eye irritation, reaching its maximum in 12 to 24 hours. Extensive loss of superficial areas of the corneal and conjunctival epithelium may occur (Grant, 1993; Harbison, 1998). Healing, although slow, is usually complete if given medical care.

a) CASE REPORTS: Two cases of progressive eye irritation with punctate keratopathy and delayed corneal epithelial defects were reported after eye exposure to the herbicide Preeglox-L (5% paraquat, 7% diquat, 3.2% polyoxyethylene; pH 4.0). The eyes had been immediately irrigated with water after the accidents and medical care had been initiated within 1 or 2 days (Nirei et al, 1993).

3.4.5)

A) WITH POISONING/EXPOSURE

1) EPISTAXIS may occur from local deposition and from prolonged inhalation of paraquat droplets in the upper respiratory tract (Pond, 1990; Baselt, 1997; Morgan, 1993).

3.4.6)

A) WITH POISONING/EXPOSURE

1) SORE THROAT: Local deposition of paraquat droplets may produce a sore throat (Morgan, 1993).
2) IRRITATION: Upper respiratory tract irritation and sore throat have been described in chronically exposed workers (Popendorf et al, 1985).

Cardiovascular

3.5.2)

A) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) Tachycardia, hypotension, and cardiorespiratory arrest may occur with large ingestions (HSDB , 1999).
b) A prospective observational study of 43 patients with paraquat poisoning to evaluate the effects on hemodynamics and oxygen metabolism for the first 96 hours after admission. Patients were divided into three groups based on the severity index of paraquat poisoning (SIPP = serum level on presentation in mg/l multiplied by the time since ingestion in hours). All patients with an SIPP of more than 50 died within 125 hours of ingestion of circulatory failure. These patients had lower cardiac index, decreased left ventricular stroke work index, decreased systemic vascular resistance, and increased oxygen extraction ratio.

1) Only one of 13 patients with an SIPP of 10 to 50 survived, the rest died between 115 and 960 hours after ingestion of respiratory failure. This group had increased cardiac index, initially increased left ventricular stroke work index, decreased systemic vascular resistance, increased oxygen delivery index and oxygen consumption index, and increasing oxygen extraction ratio. All patients with an SIPP of less than 10 survived (Yamamoto et al, 2000).

c) RISK FACTOR FOR DEATH AND ORGAN FAILURE: Cardiac arrest is the main cause of death during the first 2 to 3 days of exposure to paraquat. Other critical complications causing death include respiratory failure and renal failure. In one study, 41 patients with acute paraquat poisoning were evaluated to determine risk factors for death and organ failure. Overall, respiratory failure, hepatic dysfunction, and acute kidney injury developed in 26, 19, and 35 patients, respectively. Twenty-one patients developed respiratory failure and died despite supportive care. The main significant independent risk factors predicting mortality included the amount of paraquat ingested, paraquat plasma concentrations, and the time to a negative urine dithionite test. The main significant independent risk factors predicting organ dysfunction included the amount of paraquat ingested and the time to a negative urine dithionite test. It was concluded that the time to a negative urine dithionite test was a reliable marker for predicting mortality and/or essential organ failure in patients with acute paraquat poisoning, who survive 72 hours (Seok et al, 2012).

B) PROLONGED QT INTERVAL

1) WITH POISONING/EXPOSURE

a) In a retrospective study, the prognostic value of QTc prolongation in severely paraquat-poisoned patients was evaluated. Overall, 53 non-survivors and 7 survivors were included in the study. QTc intervals ranged from 0.35 to 0.48 seconds and 0.32 to 0.63 seconds in the survivor and non-survivor groups, respectively. One (14.3%) survivor and 32 (60.4%) non-survivors had a QTc of 0.45 seconds or higher, with a median survival time of 26 hours; 50% of these patients died within 1 day. QTc of less than 0.45 seconds was observed in 6 (85.7%) survivors and 21 (39.6%) non-survivors, with a median survival time of 95 hours. It was concluded that QTc prolongation can be a useful prognostic factor for predicting the severity of poisoning and mortality risk in acute paraquat-poisoned patients. In addition, QTc prolongation of greater than 45 msec predicted mortality regardless of potassium concentration (Lin et al, 2014).

3.5.3)

A) ANIMAL STUDIES

1) HYPERTENSION

a) To determine whether paraquat-induced lipidic peroxidation (LP) provokes changes in blood pressure, groups of adult male Wistar rats were studied 2 and 12 hours after intraperitoneal administration of paraquat 35 mg/kg. LP was evaluated by monitoring thiobarbituric acid reactive substances (TBARS) in the lungs, kidneys and liver and validated by a group treated with an antioxidant, superoxide dismutase (CnZnSOD 50,000 IU/kg). For rats studied 2 hours after paraquat administration, TBARS levels were significantly higher in the kidneys, compared with controls. Systolic and diastolic blood pressure were significantly higher and heart rate significantly lower than basal levels at 2 and 12 hours. The group treated with paraquat and CnZnSOD had significantly lower levels of TBARS; mean arterial pressure and heart rate did not differ from controls (Oliveira et al, 2005).

Respiratory

3.6.2)

A) FIBROSIS OF LUNG

1) WITH POISONING/EXPOSURE

a) The patient's prognosis depends on the severity of lung injury. Lung damage may begin within hours of ingestion, and may become more apparent after several days (Honore et al, 1994). Progressive pulmonary fibrosis, commonly delayed 3 to 14 days, often is the cause of death or results in severe disability in survivors (LoSasso et al, 2002; Bismuth, 1995).
b) Type I and type II pneumocytes selectively accumulate paraquat. Biotransformation processes within these cells are believed to result in the generation of free radicals which may cause lipid peroxidation and cell injury. Cell wall injury causes mononuclear macrophage activation and, eventually, pulmonary fibrosis (Honore et al, 1994).
c) CASE SERIES

1) In long-term follow-up of 27 patients who had ingested paraquat (estimated average amount 0.4 +/- 0.22 g), high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) were used to determine sequential changes of paraquat-induced pulmonary damage. Patients were divided into a normal (n=14) and an abnormal (n=13) group. HRCT findings showed that pulmonary manifestations follow a characteristic time course, beginning with diffuse ground-glass opacity (peaking on day 7 postingestion), increased consolidation and evolving into pulmonary fibrosis (between 2 weeks and 1 month) with partial reversibility (for up to 6 months). FVC, FEV1, and diffusing capacity all improved slightly at 1 and 6.5 months (Huh et al, 2006).
2) Yamamoto et al (2000) performed a prospective observational study of 43 patients with paraquat poisoning to evaluate the effects on hemodynamics and oxygen metabolism for the first 96 hours after admission. Patients were divided into 3 groups based on the severity index of paraquat poisoning (SIPP = serum level on presentation in mg/L multiplied by the time since ingestion in hours). All patients with an SIPP of more than 50 died within 125 hours of ingestion of circulatory failure. These patients had a lower cardiac index, decreased left ventricular stroke work index, decreased systemic vascular resistance, and increased oxygen extraction ratio (Yamamoto et al, 2000).

a) Only one of 13 patients with an SIPP of 10 to 50 survived, the rest died between 115 and 960 hours after ingestion of respiratory failure. This group had an increased cardiac index, initially increased left ventricular stroke work index, decreased systemic vascular resistance, increased oxygen delivery index and oxygen consumption index, and increasing oxygen extraction ratio. All patients with an SIPP of less than 10 survived (Yamamoto et al, 2000).

d) CASE REPORTS

1) A 16-year-old teenager lived on a farm with his family and developed progressive respiratory distress requiring mechanical ventilation. A CT scan of the chest on day 8 showed diffuse parenchymal lung disease and pneumomediastinum. High frequency oscillation and use of nitric oxide was needed to improve gas exchange. On day 18, the patient was transferred for extracorporeal membrane oxygenation and possible lung transplantation. However, the patient developed pulmonary hemorrhage and persistent thoracic bleeding and multiorgan failure occurred. Neuro status deteriorated and the decision was made to withdraw care and the patient died on day 44. Although no deliberate or inadvertent ingestion could be determined by history, the patient had a positive urine paraquat level of 0.07 mcg/mL (normal less than 0.01 mcg/mL) 18 days after the initial onset of symptoms; serum paraquat concentration was below detection thresholds (LoSasso et al, 2002).
2) Approximately 4 weeks after drinking 50 mL of 25% paraquat, a 33-year-old man presented with acute-onset hepatitis, renal failure, and lung fibrosis. His initial chest radiograph showed reticular infiltration in bilateral lung fields. Chest CT scan revealed severe thickening at interlobular septum and peribronchovascular bundle. Lung biopsy revealed aggregates of hemosiderin-laden macrophages in the interstitium and alveolar spaces. Marked lymphocytes and mild interstitial fibrosis were observed at lung tissue. Following treatment with intravenous cyclophosphamide and methylprednisolone pulse therapy, he gradually recovered; however, he had persistent mild lung fibrosis (Huang et al, 2005).
3) A 23-year-old man presented to a local ED after inadvertently ingesting a mouthful of paraquat 20% (about 6 to 10 g). He immediately induced vomiting after ingestion. On admission, his paraquat concentrations in serum and urine were 2.12 mg/L and 350 mg/L, respectively, indicating a lethal dose. Despite decontamination with a gastric lavage and activated charcoal, he developed acute non-oliguric kidney injury within 48 hours and was transferred to a tertiary care center. His physical examination showed mild jaundice and swelling and redness of the throat while his laryngoscopy revealed redness and necroses of the hypopharynx, epiglottis, and vocal cords. Laboratory results revealed elevated liver enzymes, mildly elevated inflammatory markers and acute kidney injury. He underwent hemodialysis and received IV methylprednisolone and cyclophosphamide to delay the development of pulmonary fibrosis. In addition, he received tamoxifen (3 x 20 mg orally) due to its antiproliferative and anti-inflammatory effects in retroperitoneal fibrosis. About 72 hours postingestion, his condition deteriorated and he developed respiratory failure, necessitating oxygen supplementation. On day 9, invasive ventilation was required due to the progression of pulmonary fibrosis. He was placed on a high urgency lung transplantation list; however, his condition continued to deteriorate with the onset of systemic inflammatory response syndrome. On day 12, an extracorporeal membrane oxygenation (ECMO) was implemented, but despite further supportive care, he developed hemodynamic instability and septic multiorgan dysfunction with kidney, liver, and hemodynamic failure. The patient died 32 days postingestion from cardiac failure with pulseless electrical activity (Bertram et al, 2013).

B) ACUTE RESPIRATORY FAILURE

1) WITH POISONING/EXPOSURE

a) Respiratory failure due to severe impairment of gas exchange may occur following ingestion of large amounts of paraquat (Morgan, 1993).
b) RISK FACTOR FOR DEATH AND ORGAN FAILURE: Cardiac arrest is the main cause of death during the first 2 to 3 days of exposure to paraquat. Other critical complications causing death include respiratory failure and renal failure. In one study, 41 patients with acute paraquat poisoning were evaluated to determine risk factors for death and organ failure. Overall, respiratory failure, hepatic dysfunction, and acute kidney injury developed in 26, 19, and 35 patients, respectively. Twenty-one patients developed respiratory failure and died despite supportive care. The main significant independent risk factors predicting mortality included the amount of paraquat ingested, paraquat plasma concentrations, and the time to a negative urine dithionite test. The main significant independent risk factors predicting organ dysfunction included the amount of paraquat ingested and the time to a negative urine dithionite test. It was concluded that the time to a negative urine dithionite test was a reliable marker for predicting mortality and/or essential organ failure in patients with acute paraquat poisoning, who survive 72 hours (Seok et al, 2012).

C) PULMONARY HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) Pulmonary hemorrhage may be detected upon histological examinations. Alveolar epithelial injury was reported with subsequent development of multiorgan failure (Harsanyi et al, 1987).
b) HEMORRHAGIC PULMONARY EDEMA: Dyspnea, cough, and hemoptysis are early manifestations of hemorrhagic pulmonary edema (Pond, 1990).

D) PNEUMOTHORAX

1) WITH POISONING/EXPOSURE

a) Pneumothorax, pneumopericardium and subcutaneous emphysema may develop in patients with paraquat induced lung injury (Ruiz-Bailen et al, 2001; Daisley & Simmons, 1999).

E) MEDIASTINAL EMPHYSEMA

1) WITH POISONING/EXPOSURE

a) A prospective cohort study evaluated the occurrence of pneumomediastinum (PM) in patients with oral paraquat intoxication and its prognostic value for predicting mortality. Overall, 16 (21.3%) of 75 enrolled patients with paraquat intoxication developed PM, with only one patient surviving until the follow-up ended. Thirteen patients developed PM within 3 days of paraquat ingestion, with subcutaneous emphysema in 8 patients and pneumothorax in 2 patients. Although both groups had similar paraquat concentration, symptoms, and amount of paraquat ingested, patients with PM were younger, had higher score of Acute Physiology and Chronic health Evaluation and Sequential Organ Failure Assessment, and a higher incidence of acute renal failure (100% vs 55.9%), toxic hepatitis (68.8% vs 32.2%), and respiratory insufficiency (81.2% vs 39%). It was also determined that the estimated amount of paraquat ingestion and PM were independent predictors of 90-day death (93.8% of patients with PM vs 40.7% of those without PM) or 5-day death (81.2% of patients with PM vs 28.8% of those without PM). It was concluded that early occurrence of PM within 8 days, is a specific predictor of mortality in paraquat poisoning (Zhou et al, 2015).
b) CASE REPORT: A 20-year-old man developed pneumothorax (35%), pneumomediastinum, pneumopericardium and subcutaneous emphysema after ingesting paraquat. Bronchoscopy revealed friable and hyperemic tracheal mucosa, necrotic ulcers of the trachea and bronchial tree, and a necrotic lesion overlying a rupture in the posterior tracheal wall (Ruiz-Bailen et al, 2001).

F) INJURY OF TRACHEA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 20-year-old man developed pneumothorax (35%), pneumomediastinum, pneumopericardium and subcutaneous emphysema after ingesting paraquat. Bronchoscopy revealed friable and hyperemic tracheal mucosa, necrotic ulcers of the trachea and bronchial tree, and a necrotic lesion overlying a rupture in the posterior tracheal wall (Ruiz-Bailen et al, 2001).

G) SEQUELA

1) WITH POISONING/EXPOSURE

a) LUNG FUNCTION IMPROVEMENT: Acute paraquat poisoning survivors may have progressive improvement in lung function (Lee et al, 1995; Bismuth & Hall, 1995; Lin et al, 1995).
b) In long-term follow-up of 27 patients who had ingested paraquat (estimated average amount 0.4 +/- 0.22 g), high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) were used to determine sequential changes of paraquat-induced pulmonary damage. Patients were divided into a normal (n=14) and an abnormal (n=13) group. HRCT findings showed that pulmonary manifestations follow a characteristic time course, beginning with diffuse ground-glass opacity (peaking on day 7 postingestion), increased consolidation and evolving into pulmonary fibrosis (between 2 weeks and 1 month) with partial reversibility (for up to 6 months). When compared with the PFT results, FVC, FEV1, and diffusing capacity all improved slightly at 1 and 6.5 months (Huh et al, 2006).
c) Yamashita et al (2000) performed a study of lung function in 12 survivors of paraquat poisoning with PFT evaluations performed at 3.7 weeks and 3.4 years after exposure. The tests performed 3.4 years after exposure revealed decreased total lung capacity (81% of predicted). Vital capacity was also decreased compared to the 3.7 week evaluation, but remained within the normal range. The authors suggest that survivors of acute paraquat poisoning may be left with residual restrictive pulmonary dysfunction (Yamashita et al, 2000).
d) The patient's prognosis depends on the severity of lung injury. Lung damage may begin within hours of ingestion, and may become more apparent after several days (Honore et al, 1994). Progressive pulmonary fibrosis, commonly delayed 3 to 14 days, often is the cause of death or results in severe disability in survivors (LoSasso et al, 2002; Bismuth, 1995).

Neurologic

3.7.2)

A) EXTRAPYRAMIDAL DISEASE

1) WITH POISONING/EXPOSURE

a) Because of the similarity of paraquat to N-methyl-4-phenyltetrahydropyridine, a Parkinsonism inducer, 7 patients with paraquat exposure (3 dermal, 4 oral) were tested for Parkinsonism. Paraquat did NOT induce Parkinsonism in these patients (Zilker et al, 1988).

B) COMA

1) WITH POISONING/EXPOSURE

a) Coma and seizures may develop after paraquat exposure (Tominack & Pond, 2002).

C) CEREBRAL EDEMA

1) WITH POISONING/EXPOSURE

a) Two mechanisms have been reported for development of brain damage after paraquat poisoning. Direct toxic effects on cerebral blood vessels and indirect effects due to prolonged hypoxia have been reported. Evidence of astrocytic gliosis is more predominant in patients surviving longer than 5 days (Hughes, 1988).
b) Cerebral edema may be found at autopsy (Daisley & Simmons, 1999).

3.7.3)

A) ANIMAL STUDIES

1) ANIMAL STUDIES

a) Experimental animals that were exposed to extremely high doses of paraquat showed signs of neurological disturbances, such as decreased motor activity, lack of coordination, ataxia, and dragging of their hind limbs (Clayton & Clayton, 1994).

Gastrointestinal

3.8.2)

A) ULCER OF ESOPHAGUS

1) WITH POISONING/EXPOSURE

a) Early effects of ingestion include chemical irritation and swelling, edema and ulceration of the mouth, pharynx, esophagus (with possible rupture), stomach and intestines, due to paraquat's corrosive effect on mucosal linings (Bismuth, 1995; Pond, 1990; Morgan, 1993; Daisley & Simmons, 1999; Singh et al, 1999).
b) Immediate irritation of the gut often occurs, with the development of abdominal pain, nausea, vomiting, and diarrhea (Liao & Hung, 2002; Papanikolaou et al, 2001; Bismuth, 1995; Pond, 1990). Patients who develop gut lesions generally have a poor prognosis (Honore et al, 1994; Harbison, 1998; Singh et al, 1999; Kalabalikis et al, 2001).
c) CASE REPORT: A 21-year-old woman, 27 weeks pregnant, developed nausea, vomiting, mild oral mucosa pain, and hematemesis 2 hours after drinking one-third of a bowl (about 40 mL) of paraquat solution (24% solution of 1,1'-dimethyl-4,4'-bipyridylium dichloride; about 168 mg/kg paraquat ion) in a suicide attempt. The urine dithionate test revealed dark blue color. Following supportive therapy, she recovered and delivered a healthy girl baby 14 weeks after exposure (Jenq et al, 2005).

B) PANCREATIC SYMPTOM

1) WITH POISONING/EXPOSURE

a) Pancreatitis may develop in some cases of acute paraquat poisoning, and can cause severe abdominal pain (Morgan, 1993).
b) In a study of 177 patients with acute paraquat poisoning and positive urine paraquat tests, 122 (70.62%) patients had normal serum amylase levels (less than 220 Units/L), 27 (15.25%) patients had mildly elevated amylase levels (220 to 660 Units/L), and 25 (14.13%) patients had elevated amylase levels (greater than 660 Units/L). Overall, 67 of 177 patients died. All patients in the elevated group died compared with 17% of patients in the normal group (p less than 0.001). It is concluded that pancreatic injury is a poor prognostic marker after an acute paraquat poisoning (Li, 2015).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) WITH POISONING/EXPOSURE

a) Within the first 24 to 96 hours indications of liver injury commonly appear, which are reversible (Hong et al, 2000; Singh et al, 1999). Bilirubin is generally more significantly elevated than transaminase levels (Hong et al, 2000; Singh et al, 1999).
b) CASE REPORT: Liver injury, confirmed by biopsy, was reported in a 44-year-old woman who survived an ingestion, but continued to use paraquat occupationally for one and half more years (Yang et al, 1987c).
c) CASE REPORT: A 21-year-old woman, 27 weeks pregnant, developed elevated ALT (62 Units/L (on day 1; normal range 0-37)) after drinking one-third of a bowl (about 40 mL) of paraquat solution (24% solution of 1,1'-dimethyl-4,4'-bipyridylium dichloride; about 168 mg/kg paraquat ion) in a suicide attempt. Following supportive therapy, she recovered and delivered a healthy girl baby 14 weeks after exposure (Jenq et al, 2005).

B) JAUNDICE

1) WITH POISONING/EXPOSURE

a) Although hepatic injury from exposure to paraquat may be sufficiently severe to cause jaundice, clinical outcome is generally not determined by hepatotoxic effects (Morgan, 1993).

C) CHOLESTASIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 25-year-old man developed prolonged cholestasis (persisting more than 2 years after exposure) after occupational dermal exposure to paraquat (Bataller et al, 2000).

D) TOXIC HEPATITIS

1) WITH POISONING/EXPOSURE

a) Approximately 4 weeks after drinking 50 mL of 25% paraquat, a 33-year-old man presented with acute-onset hepatitis (serum alanine aminotransferase 456 Units/L, total bilirubin 7.3 mg/dL, direct bilirubin 4.7 mg/dL), renal failure, and lung fibrosis. Following treatment with intravenous cyclophosphamide and methylprednisolone pulse therapy, he gradually recovered; however, he had persistent mild lung fibrosis (Huang et al, 2005).
b) In a retrospective observational study, 87 (46.5%) of the 187 patients with intentional paraquat ingestion developed hepatitis with symptoms starting within 6.7 +/- 6.2 days of exposure. Laboratory results revealed elevated transaminases and total bilirubin, with levels peaking at 9.5 +/- 8.8 days and resolving within 17.3 +/- 9.8 days of paraquat exposure. Overall, these patients were younger (39.7 +/- 13.7 vs 44.2 +/- 16.6 year old; p=0.046), suffered from greater incidences of acute respiratory failure (63.2% vs 48%, p=0.037) and acute renal failure (75.9% vs 56%; p=0.004), and had a longer period of hospitalization (16.2 +/- 14.6 vs 11.2 +/- 16.2 days; p=0.012) when compared with patients without hepatitis; however, no difference in mortality rates were observed between these 2 groups (56.3% vs 53%; p=0.649) (Yang et al, 2012).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Within the first 24 to 96 hours, indications of renal injury (proteinuria, pyuria, azotemia and hematuria) commonly appear. The renal lesion may progress to acute tubular necrosis, as indicated by oliguria/anuria (Bismuth, 1995; Pond, 1990; Morgan, 1993; Hong et al, 2000; Singh et al, 1999).
b) Despite initial paraquat-induced, acute renal failure, glomerular filtration rate improved in two patients with paraquat poisoning. These patients survived for three weeks (Zenz, 1994).
c) INCIDENCE: In a study of 278 patients with acute paraquat toxicity, an initial serum creatinine (Cr) of greater than 1.2 mg/dL was a significant predictor of mortality (odds ratio 9.00, 95% CI, P < 0.01). Overall, survival rates were higher among patients with an initially lower serum Cr (60% {108/180}), as compared to patients with an initially higher Cr (14.28% {14/98}). Of those in the initial Cr less than 1.2 mg/dL group, the estimated amount of paraquat ingested was 45.84 mL {+/- 61.22}, as compared to 98.16 mL {+/- 92.55) in patients in the initial Cr greater than 1.2 mg/dL group. The risk of acute renal injury was also evaluated with the incidence being 51.4% among 173 individuals in the initial Cr less than 1.2 mg/dL group, while the incidence of failure among this group was 34.7%. Among the 13 survivors in the failure group, that average serum Cr level peaked (4.38 mg/dL) at 5 days with acute renal failure present. Complete resolution of symptoms was observed within 3 weeks (Kim et al, 2009). In this study, the amount of paraquat ingested was found to be the most important factor in the development of acute renal injury.
d) CASE REPORT/MINOR TOXICITY: In Sri Lanka, a 25-year-old man intentionally ingested 35 mL of paraquat (the principal compound (Inteon(R) formulation) and developed acute renal failure (serum creatinine peaked at 5.6 mg/dL with oliguria), which resolved with conservative therapy. No other systemic effects were observed; radiology and arterial blood gases were normal. Follow-up at 3 months showed no evidence of permanent sequelae (Mettananda et al, 2008). The authors suggested that the relatively minor toxic effects observed with this patient, despite systemic absorption, were possibly related to a reformulation of paraquat (ie, Inteon(R) technology; an alginate is added that converts it to a gel in the stomach and acts as a purgative).
e) CASE SERIES: In a retrospective study of 103 patients with acute paraquat poisoning, acute renal failure (Cr greater than 1.8 mg/dL) was found to be an independent risk factor associated with a higher mortality rate (Chang et al, 2008). Of the non-survivors, 18 (25.7%) had developed acute renal failure with no reports of acute renal failure in the survivor group.
f) Approximately 4 weeks after drinking 50 mL of 25% paraquat, a 33-year-old man presented with acute-onset hepatitis, renal failure (serum creatinine level 6.5 mg/dL; mild microscopic hematuria), and lung fibrosis. Following treatment with intravenous cyclophosphamide and methylprednisolone pulse therapy, he gradually recovered; however, he had persistent mild lung fibrosis (Huang et al, 2005).
g) A 23-year-old man presented to a local ED after inadvertently ingesting a mouthful of paraquat 20% (about 6 to 10 g). He immediately induced vomiting after ingestion. On admission, his paraquat concentrations in serum and urine were 2.12 mg/L and 350 mg/L, respectively, indicating a lethal dose. Despite decontamination with a gastric lavage and activated charcoal, he developed acute non-oliguric kidney injury within 48 hours and was transferred to a tertiary care center. His physical examination showed mild jaundice and swelling and redness of the throat while his laryngoscopy revealed redness and necroses of the hypopharynx, epiglottis, and vocal cords. Laboratory results revealed elevated liver enzymes, mildly elevated inflammatory markers and acute kidney injury. He underwent hemodialysis and received IV methylprednisolone and cyclophosphamide to delay the development of pulmonary fibrosis. In addition, he received tamoxifen (3 x 20 mg orally) due to its antiproliferative and anti-inflammatory effects in retroperitoneal fibrosis. About 72 hours postingestion, his condition deteriorated and he developed respiratory failure, necessitating oxygen supplementation. On day 9, invasive ventilation was required due to the progression of pulmonary fibrosis. He was placed on a high urgency lung transplantation list; however, his condition continued to deteriorate with the onset of systemic inflammatory response syndrome. On day 12, an extracorporeal membrane oxygenation (ECMO) was implemented, but despite further supportive care, he developed hemodynamic instability and septic multiorgan dysfunction with kidney, liver, and hemodynamic failure. The patient died 32 days postingestion from cardiac failure with pulseless electrical activity (Bertram et al, 2013).
h) RISK FACTOR FOR DEATH AND ORGAN FAILURE: Cardiac arrest is the main cause of death during the first 2 to 3 days of exposure to paraquat. Other critical complications causing death include respiratory failure and renal failure. In one study, 41 patients with acute paraquat poisoning were evaluated to determine risk factors for death and organ failure. Overall, respiratory failure, hepatic dysfunction, and acute kidney injury developed in 26, 19, and 35 patients, respectively. Twenty-one patients developed respiratory failure and died despite supportive care. The main significant independent risk factors predicting mortality included the amount of paraquat ingested, paraquat plasma concentrations, and the time to a negative urine dithionite test. The main significant independent risk factors predicting organ dysfunction included the amount of paraquat ingested and the time to a negative urine dithionite test. It was concluded that the time to a negative urine dithionite test was a reliable marker for predicting mortality and/or essential organ failure in patients with acute paraquat poisoning, who survive 72 hours (Seok et al, 2012).

B) HEMOLYTIC UREMIC SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 66-year-old man intentionally ingested 10 mL of paraquat (20% concentration) and was admitted to the ED within 1 hour of exposure. He appeared ill with a green tinged oral mucosa and the presence of a foul odor. His initial paraquat level was 0.24 mcg/mL (range, 0 to 0.1 mcg/mL). Immediate treatment included 50 g of activated charcoal orally and high dose N-acetylcysteine (150 mg/kg) infused over 4 hours and hemoperfusion (4 hours daily for 3 days). By the second day, creatinine had increased to 4.71 mg/dL and urine output was 200 mL/day. On day 4, hemodialysis was started due to volume overload and uremic symptoms. The patient was also treated for anemia with packed red blood cells. Due to ongoing anemia and thrombocytopenia 7 days after the withdrawal of hemoperfusion, hemolytic uremic syndrome (HUS) was suspected. No other sources for HUS were identified. Laboratory studies showed elevated levels of LDH (948 Units/L), a high reticulocyte count (5%) and a creatinine of 11.7 mg/dL even with ongoing hemodialysis. Plasma exchange (3600 mL) was done for 3 days with improvement in LDH and hemoglobin and resolution of thrombocytopenia. By day 18, urine output increased to 2240 mL/day and hemodialysis was discontinued. He was discharged on day 30 but it took 5 months for renal impairment to completely resolve. He has remained well up to 1.5 years later (Jang et al, 2014).

C) ACUTE TUBULAR NECROSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 44-year-old woman presented to hospital approximately 7 hours after ingesting approximately 5 mL of paraquat. She was lavaged and started on antioxidant medication intravenously (glutathione, 50 mg/kg every 4 h for 7 days; N-acetylcysteine, 70 mg/kg every 4 h for 7 days; deferoxamine, 3000 mg/day for 7 days; thioctic acid and vitamin E). On the fifth hospital day, hypophosphatemia, markedly decreased serum bicarbonate with a normal serum anion gap, and positive urine anion gap were observed. Because of severe phosphaturia, intravenous phosphate supplementation was started on day 7 and continued through day 17. A renal biopsy performed on day 23 revealed acute tubular necrosis. On day 24 she was discharged. One week later she had no glycosuria, acidosis, hypophosphatemia or aminoaciduria. The authors noted that this was a case of Fanconi syndrome and acute tubular necrosis presenting as severe hypophosphatemia from acute paraquat poisoning (Gil et al, 2005).

D) GLOMERULONEPHRITIS

1) WITH POISONING/EXPOSURE

a) Acute glomerulonephritis was seen some 3 months after acute exposure to paraquat. IgG and C3 were deposited along the glomeruli. No anti-GBM antibodies were detected, possibly because of the long time between exposure and onset of clinical effects (Stratta et al, 1988).

E) POISONING

1) WITH POISONING/EXPOSURE

a) VAGINAL ABSORPTION

1) CASE REPORT: A 28-year-old Chinese prostitute died 2 weeks after inadvertently inserting a tampon soaked in paraquat. It remained in contact with the vaginal surface for about 10 minutes, at which time it was removed because of the severe burning sensation. A small introital ulcer and extensive ulceration and sloughing of the vaginal epithelium were noted on vaginal examination 4 days after insertion. Serum paraquat concentration was not available. Postmortem examination was consistent with paraquat poisoning (Ong & Glew, 1989).

Acid-Base

3.11.2)

A) METABOLIC ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 21-year-old woman, 27 weeks pregnant, developed metabolic acidosis (PaO2 101.7 mmHg; elevated alveolar-arterial oxygen tension difference (A-aDO2) 19.4 on room air) after drinking one-third of a bowl (about 40 mL) of paraquat solution (24% solution of 1,1'-dimethyl-4,4'-bipyridylium dichloride; about 168 mg/kg paraquat ion) in a suicide attempt. Following supportive therapy, she recovered and delivered a healthy girl baby 14 weeks after the exposure. Upon follow-up to age 5, the child appeared healthy and reached normal developmental milestones (Jenq et al, 2005).

Hematologic

3.13.2)

A) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Methemoglobinemia was reported (18.7% of total hemoglobin) in a 32-year-old man who ingested 3 mouthfuls of 10% paraquat (Ng et al, 1982).
b) CASE REPORT: A 59-year-old farmer developed methemoglobinemia following fatal ingestion of a product containing paraquat and monolinuron, a chemical which produces methemoglobinemia in experimental animals (Casey et al, 1994).

B) NEUTROPENIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Neutropenia (leukocytes 3000/mm(3), neutrophils 1%) occurred in a 15-year-old girl 18 days after ingesting approximately 150 mL of paraquat 20% aqueous solution. Two hours postingestion, the patient was admitted to the hospital and received gastric lavage, charcoal hemoperfusion, and methylprednisolone. Paraquat plasma levels were not detectable 6 days after admission. Because the patient was not administered any medications that were believed to be associated with the development of neutropenia, the authors speculated that the neutropenia may have been the result of paraquat poisoning (Papanikolaou et al, 2001).

C) HEMOLYTIC ANEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 27-year-old man intentionally ingested approximately 50 mL of 24% paraquat mixed with approximately 50 mL of wine, and subsequently developed hemolytic anemia. It was discovered that the patient was glucose-6-phosphate dehydrogenase (G6PD) deficient. The combination of paraquat's generation of oxygen free radicals and the patient's G6PD deficiency may have contributed to the development of hemolytic anemia following paraquat poisoning (Liao & Hung, 2002).

Dermatologic

3.14.2)

A) DERMATITIS

1) WITH POISONING/EXPOSURE

a) Occupational injuries include a dry, cracking dermatitis and nail atrophy (Samman & Johnston, 1969; Garnier, 1995; Bismuth, 1995).

B) POISONING

1) WITH POISONING/EXPOSURE

a) Paraquat is well absorbed through injured or abraded skin, and dermal exposure may result in severe systemic toxicity and death (Soloukides et al, 2007; Gear et al, 2001; Garnier, 1995).
b) CASE REPORT: A 50-year-old crop-duster carrying a paraquat herbicide lost control of his plane and crashed. He was found semiconscious with second-degree burns on 37% of his total body surface area. Following stabilization the patient was transferred to a higher level of care, and the skin was decontaminated secondary to possible paraquat exposure (estimated absorption time was 9.5 hours). A paraquat level drawn 20 hours after injury was 0.169 mg (standard lethal dose at 16 hours is 0.16 mg/mL). The patient developed acute renal failure and respiratory failure, as evidence by increasing hypoxia and hypercarbia, and died on hospital day 4 (Gear et al, 2001).
c) CASE REPORT: A 44-year-old man who accidentally applied a concentrated PARAQUAT solution to his perineum developed a skin lesion, renal failure, respiratory failure, and hepatic damage (Tungsanga et al, 1983).
d) Since 1974 when the first fatal case of dermal absorption of paraquat was reported, there have been at least 11 fatal cases and 2 nonfatal cases of systemic poisoning by the dermal route (Ongom et al, 1974; Wohlfahrt, 1982; Binns, 1976; Tungsanga et al, 1983; Waight, 1979; Okonek et al, 1983; Jaros, 1978; Levin et al, 1979; Newhouse et al, 1978; Athanaselis et al, 1983).

C) DISORDER OF SKIN

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 27-year-old worker fell into a tank containing paraquat solution for approximately a minute and had no obvious dermal injury until 4 days later when superficial partial thickness burns to the lower back and gluteal region were observed (approximately 7% of the total body surface area). The lesions healed with conservative care with no evidence of systemic toxicity (Rahman et al, 2007).

D) BURN OF SKIN

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: Two young adults developed scrotal burns with one developing systemic toxicity (ie, mild derangements of hepatic and renal function) after coming in contact with the vomitus of a family member that had deliberately ingested paraquat. Both were unaware of the potential harm related to exposure, and did not remove their contaminated clothing for over 8 hours. The patient with systemic poisoning improved with conservative management. Four weeks after exposure, no permanent scarring was observed in either patient (Premaratna et al, 2008).

Musculoskeletal

3.15.2)

A) TOXIC MYOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Painful weakness of extremities, confirmed by biopsy, was reported in a 44-year-old woman who survived an ingestion, but continued to use paraquat occupationally for one and half more years (Yang et al, 1987c).
b) CASE REPORT: Severe degeneration of skeletal muscle (type 1 fibers) was reported on autopsy in a 65-year-old man who died after paraquat ingestion. Elevated CK levels had been observed 5 days after ingestion and the patient died of multiorgan failure 14 days after ingestion (Tabata et al, 1999).

B) INJECTION SITE REACTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 37-year-old adult expired due to multiple organ failure 87 hours after IM injection of a product containing 17.8% paraquat. High concentrations of paraquat were detected in thigh muscle biopsy, serum, and urine. Postmortem analysis detected paraquat in kidney, lung, heart, and liver tissues (Zoppellari R, Targa L & Droghetti L et al, 1994).
b) CASE REPORT: Chandrasiri (1999) reports another case of a woman who died after intramuscular injection (homicidal) of paraquat.

Endocrine

3.16.2)

A) DISORDER OF ENDOCRINE SYSTEM

1) WITH POISONING/EXPOSURE

a) Adrenal cortical necrosis can occur in severe acute paraquat poisoning (Pond, 1990).
b) POSTMORTEM: In a study of 23 fatal cases of paraquat poisoning, 12 cases of abnormal adrenal histology with seven cases of complete necrosis of the cortex were found at autopsy. In most cases, the degree of necrosis was consistent with the severity of the exposure. All patients were treated with corticosteroids. Of the survivors, there was no clinical evidence of adrenal insufficiency. The authors suggest that there may be a role for corticosteroid therapy in maintaining adrenal function, and the frequency of adrenal injury observed may indicate a need to assess adrenal function in survivors of paraquat poisoning (FitzGerald et al, 1977).

B) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: In a retrospective study of 103 patients with acute paraquat poisoning, hyperglycemia (greater than 150) was found to be an independent risk factor associated with a higher mortality rate (Chang et al, 2008). Of the non-survivors, 30 (42.9%) had developed hyperglycemia, as compared to 4 (12.1%) in the survivor group.

Immunologic

3.19.2)

A) GLOMERULONEPHRITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: IgG and C3 were detected in the glomeruli of a woman 3 months after acute exposure to paraquat. Anti-GBM antibodies were not detected, possibly because of the delay between exposure and development of symptoms. This condition may be similar to Goodpasture's syndrome (Stratta et al, 1988).

Reproductive

3.20.1)

A) Paraquat has been shown to cross the placental barrier and adverse reproductive effects, including fetotoxicity, have been observed in humans and animals after ingestion of paraquat.

3.20.2)

A) LACK OF EFFECT

1) CASE REPORT - A 21-year-old woman, 27 weeks pregnant, developed nausea, vomiting, mild oral mucosa pain, and hematemesis 2 hours after drinking one-third of a bowl (about 40 mL) of paraquat solution (24% solution of 1,1'-dimethyl-4,4'-bipyridylium dichloride; about 168 mg/kg paraquat ion) in a suicide attempt. Physical examination showed clear sensorium, anicteric sclera, and several ulcers on oral mucosa and tongue. The urine dithionate test revealed dark blue color. Laboratory results showed decreased hemoglobin (8.6 g/dL), elevated creatinine 6.8 mg/dL (on day 5; normal range 0.4-1.4), elevated ALT (62 Units/L (on day 1; normal range 0-37)), and metabolic acidosis (PaO2 101.7 mmHg; alveolar-arterial oxygen tension difference (A-aDO2) 19.4 on room air). Following two treatments with charcoal hemoperfusion, megadoses of cyclophosphamide, and methylprednisolone pulse therapy, she recovered and delivered a healthy girl baby 14 weeks after exposure. The child appeared healthy with no developmental delays on 5-year follow-up (Jenq et al, 2005).

B) ANIMAL STUDIES

1) SKELETAL MALFORMATION

a) RATS AND MICE - Specific developmental abnormalities of the musculoskeletal system were observed in rats and mice with exposure to paraquat via the intraperitoneal route; post-implantation mortality was also noted in rats and mice (RTECS , 1999).

2) LACK OF EFFECT

a) MICE - Administration of paraquat to mice daily on days 8 to 16 of gestation produced no significant teratogenic effects; however, a slight increase in non-ossification of sternebrae was noted as a result of significant maternal toxicity (Bus, 1975).

3.20.3)

A) FETOTOXICITY

1) CASE REPORT - Lung toxicity requiring 22 days of hospitalization was reported in an infant delivered 7 hours after his 17-year-old pregnant mother intentionally ingested 2 mouthfuls (30 mL) of a paraquat dichloride 27.6% w/v solution in a suicide attempt. The patient presented to the emergency room at more than 36 weeks gestational age and 5 hours after ingesting the paraquat. Management included gastric aspiration and lavage, a 50-gram oral dose of activated charcoal and a 150-gram dose of Fuller's Earth solution. Because paraquat was present in the gastric lavage fluid, the mother was initiated on a 14-day course of dexamethasone and cyclophosphamide and discharged. The infant had mild tachypnea that resolved over 24 hours. However, on day 6 of life, the infant experienced worsening tachypnea with subcostal retractions. A subsequent chest x-ray revealed a right lower lobe infiltrate. Penicillin and gentamicin were initiated. However, his respiratory status deteriorated over the next 4 days with a respiratory rate of 100 to 125 times/min. As a result, the infant was started on 2 L of supplemental oxygen. His antibiotics were changed to a 14-day course of cefotaxime and amikacin which he completed. There was minimal interstitial infiltrate and the infant was discharged with home oxygen therapy after 22 days of hospitalization. He continued to have symptoms of chronic lung disease, including recurrent wheezing, tachypnea, and hypoxia. At 10 months of age, he was weaned off of the oxygen therapy. Although he experienced several occurrences of wheezing related to respiratory ailments, his symptoms had improved significantly by 16 months of age (Chomchai & Tiawilai, 2007).
2) CASE SERIES - None of the fetuses survived following intentional maternal ingestion of paraquat during pregnancy in a case series of 9 pregnant women. Management of these patients was whole gut lavage and continuous hemoperfusion. Fetal condition deteriorated at delivery or in utero when gestational age was more than 30 weeks and emergency cesarean delivery did not effect outcome. In one case, simultaneous paraquat levels in the mother (5.6 ppm) were five times lower than in the cord blood (25.85 ppm) and the infant (20.6 ppm). In another case, paraquat levels in the aminiotic fluid were almost twice that of the maternal blood (Talbot et al, 1988).

B) PLACENTAL BARRIER

1) CASE REPORT - A therapeutic abortion was performed at 9 weeks of gestation due to maternal ingestion of 80 to 100 mL of paraquat solution by a 16-year-old female attempting suicide who was found to be carrying a 6-week live embryo. The paraquat concentration in the conceptus was 0.25 micrograms/gram, 5 times greater than the concentration in the amniotic fluid and greater than the maternal blood level (Tsatsakis et al, 1996).

C) LACK OF EFFECT

1) HUMAN

a) No increases in the incidence of anomalies or fetal loss were observed in a study of 459 pesticide applicators who sprayed paraquat, as well as 2,4,5-T (Smith et al, 1981). The AMA Council on Scientific Affairs concluded that workers who take appropriate precautions and do not exceed the permissible exposure limits (PEL) are at no significant risk of adverse reproductive effects (AMA, 1985).
b) CASE REPORT - A 21-year-old woman, 27 weeks pregnant, developed nausea, vomiting, mild oral mucosa pain, and hematemesis 2 hours after drinking one-third of a bowl (about 40 mL) of paraquat solution (24% solution of 1,1'-dimethyl-4,4'-bipyridylium dichloride; about 168 mg/kg paraquat ion) in a suicide attempt. Physical examination showed clear sensorium, anicteric sclera, and several ulcers on oral mucosa and tongue. The urine dithionate test revealed dark blue color. Laboratory results showed decreased hemoglobin (8.6 g/dL), elevated creatinine 6.8 mg/dL (on day 5; normal range 0.4-1.4), elevated ALT 62 Units/L (on day 1; normal range 0-37), and metabolic acidosis (PaO2 101.7 mmHg; elevated alveolar-arterial oxygen tension difference (A-aDO2) 19.4 on room air). Following two treatments with charcoal hemoperfusion, megadoses of cyclophosphamide, and methylprednisolone pulse therapy, she recovered and delivered a healthy girl baby 14 weeks after exposure. The child appeared healthy with no developmental delays on 5-year follow-up (Jenq et al, 2005).

D) ANIMAL STUDIES

1) In prenatal studies, paraquat was retained in the lung tissue of fetal rats following maternal administration on day 1 of gestation but not following similar dosing on day 16 of gestation (Bus, 1975).
2) Postnatal mortality of mice administered paraquat throughout perinatal development was high, in spite of low teratogenicity (Bus, 1974).

3.20.4)

A) BREAST MILK

1) CASE REPORT - No detectable levels of paraquat were found in the serum or urine of a 2-month-old infant breast fed by her 25-year-old mother who ingested a fatal dose of paraquat. Based on this case report, authors suggest that significant paraquat exposure does NOT occur through breast milk, even in the setting where the mother ingested a fatal overdose prior to breast-feeding her infant. (Yang et al, 1987a).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS4685-14-7 (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) Not Listed

B) IARC Carcinogenicity Ratings for CAS1910-42-5 (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) Not Listed

C) IARC Carcinogenicity Ratings for CAS2074-50-2 (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) Not Listed

3.21.2)

A) There is no direct evidence that paraquat is a human carcinogen.

3.21.3)

A) CARCINOMA

1) There is no direct evidence for the potential carcinogenicity of paraquat in humans (Dabney, 1995).
2) Premalignant skin lesions have been described in paraquat formulation workers, but these were felt to be due to exposure to precursors, NOT to paraquat (Dabney, 1995).
3) The US EPA has classified paraquat in its category C (possible human carcinogen) based on a rat study showing increased squamous cell carcinomas of the skin (IRIS , 1999).
4) Lung mesothelioma following paraquat ingestion has been described in a single case report (Fournier, 1974).

3.21.4)

A) CARCINOMA

1) In mice, paraquat fed orally at 25, 50, and 75 ppm in the diet for 80 weeks produced NO increase in cancers, as compared with controls (Clayton & Clayton, 1982). Paraquat has been found to enhance the carcinogenicity of urethane in mice. This is believed to be associated with its effect of increasing the number of proliferating target cells in the lung (Bojan, 1978). This study was judged not to be relevant for the assessment of the carcinogenic potential of paraquat (IPCS, 1984).

Genotoxicity

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) A full laboratory analysis, including liver function tests, basic metabolic panel, complete blood count, chest x-ray and urinalysis, should be performed on anyone ingesting paraquat. Arterial blood gas analysis should be performed on those with a late presentation or those with hypoxia. Those with chronic dermal exposures and systemic symptoms or those with hypoxia. Those with chronic dermal exposures and systemic symptoms should have the same testing as those acute ingestions. No testing is indicated in patients with acute dermal exposures without systemic symptoms.
B) Bedside testing can be performed using a 1% aqueous sodium dithionite in 0.1 normal sodium hydroxide to form a stable blue radical in the urine. If paraquat is present, the urine will appear blue compared with the control urine.
C) Serum paraquat concentrations (information available 24 hours a day 7 days a week through Zeneca Emergency Information Network, 1-800-327-8633, ctltestkitsupply@syngenta.com) can be useful for prognosis.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor renal and liver function tests.
2) Seto & Shinohara (1988) reported that paraquat strongly and selectively inhibited the acetylcholinesterase activities of human erythrocytes and electric eel, but not the butyrylcholinesterase of human plasma. However, the relationship to the clinical effects of paraquat poisoning in humans has not been established (Seto & Shinohara, 1988).

4.1.3)

A) URINALYSIS

1) Obtain baseline urinalysis and monitor urine output.

B) COLORIMETRIC STUDY

1) The urine dithionite test can confirm the presence of paraquat by turning the urine blue. Bedside testing can be performed using a 1% aqueous sodium dithionite in 0.1 normal sodium hydroxide to form a stable blue radical in the urine. If paraquat is present, the urine will appear blue compared with the control urine (Foo & Guo, 2007).
2) RISK FACTOR FOR DEATH AND ORGAN FAILURE: Cardiac arrest is the main cause of death during the first 2 to 3 days of exposure to paraquat. Other critical complications causing death include respiratory failure and renal failure. In one study, 41 patients with acute paraquat poisoning were evaluated to determine risk factors for death and organ failure. Overall, respiratory failure, hepatic dysfunction, and acute kidney injury developed in 26, 19, and 35 patients, respectively. Twenty-one patients developed respiratory failure and died despite supportive care. The main significant independent risk factors predicting mortality included the amount of paraquat ingested, paraquat plasma concentrations, and the time to a negative urine dithionite test. The main significant independent risk factors predicting organ dysfunction included the amount of paraquat ingested and the time to a negative urine dithionite test. It was concluded that the time to a negative urine dithionite test was a reliable marker for predicting mortality and/or essential organ failure in patients with acute paraquat poisoning, who survive 72 hours (Seok et al, 2012).

4.1.4)

A) OTHER

1) MONITORING

a) Obtain baseline pulmonary function tests and ABGs and monitor serially for several days.

2) OTHER

a) PROGNOSTIC TESTS

1) Almost all patients with urine paraquat levels less than 1 mcg/mL within 24 hours of ingestion survive, while those with greater than 10 mcg/mL die (Sato, 1995).
2) Admission renal function and acid-base balance data may also have some prognostic value (Sato, 1995).
3) The Respiratory Index (RI) (A-a dO2 / pO2) may be prognostic with an RI of 1.5 or greater, most patients die; while those with an RI of 1.5 or less survive (Sato, 1995).
4) The rate of increase in serum creatinine per unit of time over the first 5 hours of treatment may also be a useful prognostic indicator (Ragoucy-Sengler & Pileire, 1996).

Radiographic Studies

1) Follow serial chest X-rays in patients with pulmonary symptoms or significant paraquat exposure.

Methods

1) Urine can be tested for gross amounts of paraquat by alkalizing 3 to 5 mL with a few mg of sodium bicarbonate, then adding a few mg of sodium dithionite. An intense blue-green color is a positive test (Braithwaite, 1987). However, the validity of this method in estimating the level of paraquat exposure is questionable. The urine paraquat concentration may be influenced by an individual's renal function. A patient with excellent renal function will initially excrete more paraquat than a patient with poor renal function, who will excrete higher concentrations of paraquat at a later timepoint. Paraquat can also cause renal failure which would result in a decrease in urine production. These variations in urine production or excretion may result in a urine paraquat level above or below the threshold for detection (Eddleston et al, 2003).
2) Paraquat can be measured in urine using a modified derivative spectroscopic method (Fuke et al, 1992) or high performance liquid chromatography (Nakagiri et al, 1989).
3) Acidic resinous adsorbent Varion KS and photometric measurement are used to monitor blood and urine concentrations of paraquat (Niessen & Frehse, 1969).
4) Plasma paraquat levels can be determined using a spectrophotometric method with a detection limit of 0.1 mcg/mL (Sanchez-Sellero et al, 1993).
5) Paraquat may be determined in serum using a modified second derivative spectroscopic method (Fuke et al, 1992) or a high-performance liquid chromatographic method (HPLC) with a limit of detection of 0.1 mcg/mL (Paixao et al, 2002; Nakagiri et al, 1989).
6) Tissue paraquat concentrations can be measured by HPLC (Ito et al, 1993).
7) Thin-Layer Chromatography (TLC) may be used to determine tissue concentrations in postmortem human samples (Van den Heede et al, 1982).
8) Analysis for paraquat in serum or urine is difficult and requires special expertise that may not be available in most laboratory facilities (Baselt, 1988; Baselt & Cravey, 1989).

a) Physicians in the US can telephone 1-800-327-8633 (24-hour number) and arrange for serum, urine, or tissue analysis. There is NO CHARGE for this service.
b) Specimens should be transferred to plastic containers because paraquat binds to glass. Since paraquat is a stable molecule, no special shipping conditions are required except that the container lids should fit tightly to prevent leakage and specimen contamination.

SPECIMEN	QUANTITY REQUIRED
Serum	5 mL
Urine	50 to 100 mL
Tissue	25 grams

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Any patient with an intentional ingestion should be admitted to the hospital for monitoring. Patients with corrosive injury or other systemic toxicity should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients with dermal exposures involving a small body surface area to intact skin that do not have local symptoms or mucous membrane involvement can be managed at home with simple soap and water decontamination.

6.3.1.3) CONSULT CRITERIA/ORAL

A) A toxicologist should be consulted for all ingestions and all dermal exposures involving more than minimal body surface area. Appropriate medical subspecialties should be consulted to aid in the support of specific organ dysfunction due to toxicity.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with dermal, "lick", "sip" or "taste" exposures can be observed for 6 hours and evaluated for evidence of caustic injuries.

Monitoring

Oral Exposure

6.5.1)

A) EMESIS/NOT RECOMMENDED

1) Inducing emesis is NOT recommended.

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

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).

C) DERMAL EXPOSURE

1) Remove contaminated clothing and wash the exposure area thoroughly with soap and water.

6.5.2)

A) GASTRIC EMPTYING

1) Inducing emesis is NOT recommended. Gastric lavage may be useful when performed within one hour of ingestion, although some authors advocate its use up to 24 hours after ingestion (Huang et al, 2005). Because paraquat is a liquid a small nasogastric tube may be used. Risk of bleeding or perforation must be weighed against potential benefit of paraquat removal. Administer activated charcoal or clays (Fuller's Earth; Bentonite).

B) ACTIVATED CHARCOAL

1) Paraquat irreversibly binds to clays and activated charcoal. Activated charcoal should be administered if the ingestion is within the last 24 hours and the patient is alert or the airway is protected.
2) 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.

3) CHARCOAL DOSE

b) ADVERSE EFFECTS/CONTRAINDICATIONS

4) One animal study (Gaudreault et al, 1985) demonstrated increased efficacy of activated charcoal combined with magnesium citrate.

C) CLAYS

1) BENTONITE CLAY: DOSE: ADULT: 100 to 150 g; CHILD less than 12 years of age: 2 g/kg (7% suspension) (Bronstein, 2004)
2) FULLER'S EARTH: DOSE: ADULT: 100 to 150 g; CHILD less than 12 years of age: 2 g/kg (30% suspension) (Bronstein, 2004).
3) EXPERIMENTAL THERAPY: SODIUM POLYSTYRENE SULFONATE

a) CONCLUSION: Additional studies are needed before the use of SPS can be recommended.
b) The dose of SPS used in these studies was excessive compared to the dose used to treat hyperkalemia.
c) The survival data in the only trial in humans is not impressive. No details were provided on the actual cause of death in the 16 patients who died despite aggressive treatment with SPS and cathartics.
d) Sodium polystyrene sulfonate (SPS) (Kayexalate(R)) has been reported to have an adsorption capacity for paraquat 15 times greater than activated charcoal and 6 times greater than adsorption in vitro. The LD50 in rats increased from 144 mg/kg to 296 mg/kg when sodium polystyrene sulfonate (1,000 milligrams/kilogram) was instilled into the stomach a few minutes after the paraquat (Takagi et al, 1983). There were only 8 rats in each study group.
e) The effect of time between paraquat and sodium polystyrene sulfonate administration was examined in another study in rats. These animals were given 2 grams/kilogram of SPS at 0, 0.5, 1, 2, 3, and 4 hours after 200 mg/kg of paraquat. When survival was used as a measure of efficacy, 7 of 8 rats survived for 7 days when SPS was administered immediately after the paraquat, however, only 3 of 8 rats survived for 7 days when SPS administration was delayed until 4 hours after paraquat administration (Yamashita et al, 1987).
f) Yamashita et al (1987) used SPS in 22 patients with paraquat poisoning and reported survival in only 6 of 22 patients. There were no details on the severity of poisoning in any patients and the time elapsed between ingestion and treatment. The following protocol was used:

1) Gastric lavage was performed using 5 to 10 liters of normal saline containing 100 grams/Liter of SPS.
2) Intestinal lavage was performed by placing a duodenal tube under x-ray examination and administering 600 to 800 milliliter/hour of normal saline solution containing 100 grams/Liter of SPS.
3) Magnesium sulfate, magnesium citrate, or sorbitol was administered every 4 hours to induce catharsis.

D) WHOLE BOWEL IRRIGATION (WBI)

1) Whole bowel irrigation has NOT been shown to be of any benefit in paraquat poisoning (Meredith & Vale, 1995).

6.5.3)

A) AIRWAY MANAGEMENT

1) Airway management should be considered for patients with severe CNS depression or those at risk of aspiration.
2) OXYGEN THERAPY: Do NOT administer supplemental oxygen(Rhodes et al, 1976). Some clinicians advocate hypoxic (10% to 12%) atmospheres. Allow additional oxygen only in victims considered beyond rescue to relieve air hunger and terminal disease.

B) MONITORING OF PATIENT

1) A full laboratory analysis, including liver function tests, basic metabolic panel, complete blood count, chest x-ray and urinalysis, should be performed on anyone ingesting paraquat. Arterial blood gas analysis should be performed on those with a late presentation or those with hypoxia. Those with chronic dermal exposures and systemic symptoms or those with hypoxia. Those with chronic dermal exposures and systemic symptoms should have the same testing as those acute ingestions. No testing is indicated in patients with acute dermal exposures without systemic symptoms.
2) Bedside testing can be performed using a 1% aqueous sodium dithionite in 0.1 normal sodium hydroxide to form a stable blue radical in the urine. If paraquat is present, the urine will appear blue compared with the control (another urine sample).
3) Serum paraquat concentrations (information available 24 hours a day 7 days a week through Zeneca Emergency Information Network, 1-800-327-8633, ctltestkitsupply@syngenta.com) can be useful for prognosis.

C) FLUID/ELECTROLYTE BALANCE REGULATION

1) Replace fluid and electrolytes lost from vomiting or catharsis.

D) ACUTE TUBULAR NECROSIS

1) Acute tubular necrosis is almost always reversible. Adequate fluid resuscitation is primary therapy to limit secondary renal injury. Hemodialysis for oliguric renal failure is occasionally needed as a temporizing measure until renal function improves.

E) IMMUNOSUPPRESSIVE THERAPY

1) SUMMARY

a) The combination of corticosteroids and cyclophosphamide have been shown in 2, small, randomized controlled studies to reduce mortality in severe paraquat poisoning (Lin et al, 2006; Afzali & Gholyaf, 2008).
b) COCHRANE REVIEW: In a systematic review, patients with paraquat-induced lung fibrosis given standard therapy (eg, decontamination, hemoperfusion) and steroids and cyclophosphamide had a reduced risk of death of 28% (range: 11% to 41% reduction in deaths; RR 0.72; 95% Confidence Interval (CI) 0.59 to 0.89) compared to patients treated with standard therapy alone. The review was based on 3 small randomized control trials (RCTs) and included 164 patients with moderate to severe paraquat poisoning. The findings should be interpreted with caution because the studies were small and one was of poor methodological quality. Further randomized controlled trials were suggested by the authors (Li et al, 2012).
c) The use of immunosuppressive therapy is limited and large, adequately controlled randomized trials have not been conducted. In one uncontrolled study, no survival benefit was observed with the use of cyclophosphamide and dexamethasone (Gunawardena et al, 2007).

2) PULSE THERAPY

a) PULSE THERAPY PROTOCOL: The protocol used in one study was as follows (Lin et al, 2006):
b) Gastric lavage followed by administration of 1 gram/kilogram of activated charcoal in 250 milliliters of magnesium citrate in patients presenting within 24 hours of ingestion.
c) Two 8 hours courses of activated charcoal hemoperfusion within 24 hours of paraquat ingestion.
d) After hemoperfusion, administer intravenous cyclophosphamide 15 milligrams/kilogram/day in 200 ml D5NS infused over 2 hours for two consecutive days. Also administer 1 gram methylprednisolone in 200 milliliters D5NS infused over 2 hours daily for 3 consecutive days.
e) After the initial pulse therapy, administer dexamethasone 5 milligrams intravenously every 6 hours until PaO2 is 80 mmHg (11.5 kPa) or greater.
f) If PaO2 < 60 mmHg (8.64 kPa), repeat intravenous methylprednisolone 1 gram in 200 milliliters D5NS infused over 2 hours daily for 3 consecutive days. If WBC > 3000/m(3) and it has been 2 weeks since the initial pulse of cyclophosphamide, repeat intravenous infusion of cyclophosphamide 15 milligrams/kilogram in 200 milliliters D5NS infused over 2 hours as a single dose.
g) Then continue intravenous dexamethasone 5 milligrams every 6 hours until PaO2 is 80 mmHg (kPa 11.5) or greater. Then reduce dexamethasone dose gradually.

3) ALTERNATIVE THERAPIES

a) Other treatment methods have included the following:

1) High-dose therapy includes the same initial treatment (activated charcoal and hemoperfusion) as pulse therapy along with high-dose cyclophosphamide (5 mg/kg/d) and dexamethasone 24 mg/d for 14 days. However, this treatment remains controversial due to a lack of proven efficacy (Lin et al, 1999). Another study used a slightly different high dose therapy using cyclophosphamide 100 mg/day orally and 15 mg/day of IV dexamethasone for 14 days (Hsu et al, 2003).
2) Another method includes early decontamination and 15 mg/kg of cyclophosphamide in D5NS in 200 mL infused over 2 hrs for 2 days and methylprednisolone 1 g in 200 mL D5NS IV infused over 4 hrs and repeated for 3 consecutive days. Mesna (15 mg/kg) was also administered over 4 days to avoid side effects to cyclophosphamide (Li et al, 2012).

4) EVIDENCE

a) POSITIVE STUDY: A prospective randomized controlled trial evaluated 23 paraquat-poisoned patients with greater than 50% and less than 90% predictive mortality. The control group (n=7) received conventional therapy and the study group (n=16) received the novel repeated pulse treatment with long-term steroid therapy [methylprednisolone 1 g/day for 3 days, cyclophosphamide 15 mg/kg/day for 2 days, and then dexamethasone 20 mg/day until PaO2 was greater than 11.5 kPa (80 mm Hg) and repeated pulse therapy with methylprednisolone 1 g/day for 3 days and cyclophosphamide 15 mg/kg/day for 1 day, repeated if PaO2 was less than 8.64 kPa (60 mm Hg)]. The mortality rate of the study group was lower than that of the control group (5 of 16, 31.3% of study group vs 6 of 7, 85.7% of control group; p=0.0272) (Lin et al, 2006).
b) POSITIVE STUDY: A dramatic fall (68%: 41/61 cases compared to 28%: 20/72 cases) in mortality of paraquat poisoning was indicated by the combination therapy or treatment for 2 weeks with high doses of two immunosuppressants, dexamethasone and cyclophosphamide, and standard therapy to inactivate and eliminate the poison from gut and blood. Not all cases were confirmed by serum paraquat levels (Addo & Poon-King, 1986).
c) POSITIVE STUDY: In a retrospective study of 29 cases of paraquat poisoning, therapy with cyclophosphamide, dexamethasone, furosemide and vitamins B and C was associated with survival of 1 out of 11 patients ingesting <45 milliliters of 20% paraquat while conventional therapy (gastric decontamination and supportive care) was associated with survival in 0 of 6 patients (Botella de Magila & Tarin, 2000).
d) POSITIVE STUDY: In a prospective study of paraquat poisoning, use of cyclophosphamide and corticosteroids was associated with survival in 18 of 22 patients with moderate poisoning compared with 12 of 28 controls with moderate poisoning (Lin et al, 1999). No patients presenting with fulminant poisoning survived in either treatment group. When these data are reanalyzed on an intention to treat basis, this effect loses statistical significance (18 survivors of 56 patients in the treatment group vs 12 survivors of 65 control patients) (Buckley, 2001).
e) NEGATIVE STUDY: A prospective, nonrandomized study of paraquat poisoning treated with standard therapy (lavage, bentonite, magnesium sulfate, metoclopramide; 14 cases) or standard therapy plus dexamethasone/cyclophosphamide (33 cases) found no difference in survival between groups. Complications of immunosuppressant therapy included septicemia (2 cases), alopecia (9 cases), and acne (8 cases) (Perriens et al, 1992).
f) META-ANALYSIS: A meta-analysis of 10 clinical studies (1 randomized clinical trial and 9 nonrandomized studies) was conducted to determine the effectiveness of immunosuppressive therapy for treatment of paraquat-induced lung fibrosis. The results of the meta-analysis were inconclusive due to various confounding factors of each study (Eddleston et al, 2003).

F) ACETYLCYSTEINE

1) Cotgreave et al (1987) demonstrated that the combination of Ebselen (PZ51:2-phenyl-1,2-benzoisoselenazol-3(H)-one) and N-acetylcysteine may provide an effective antidote in cases of overexposure to paraquat through an in vitro study using isolated hepatocytes, but this has NOT been established clinically.
2) Drault et al (1999) reported a patient who survived the ingestion of 60 g of paraquat after treatment with IV N-acetylcysteine and early hemodialysis (within 4 hours of ingestion).

G) TRANSPLANT

1) LUNG TRANSPLANTATION: Lung transplants, both single and bilateral, have been performed in several patients who ingested toxic amounts of paraquat. Many patients died despite transplant (Toronto Lung Transplant Group, 1985; Kamholz et al, 1984; Cooke et al, 1973). Occasional survival has since been reported (Licker et al, 1998; Walder et al, 1997).

H) EXTRACORPOREAL MEMBRANE OXYGENATION

1) CASE REPORT: A 23-year-old man presented to a local ED after inadvertently ingesting a mouthful of paraquat 20% (about 6 to 10 g). He immediately induced vomiting after ingestion. On admission, his paraquat concentrations in serum and urine were 2.12 mg/L and 350 mg/L, respectively, indicating a lethal dose. Despite decontamination with a gastric lavage and activated charcoal, he developed acute non-oliguric kidney injury within 48 hours and was transferred to a tertiary care center. His physical examination showed mild jaundice and swelling and redness of the throat while his laryngoscopy revealed redness and necroses of the hypopharynx, epiglottis, and vocal cords. Laboratory results revealed elevated liver enzymes, mildly elevated inflammatory markers and acute kidney injury. He underwent hemodialysis and received IV methylprednisolone and cyclophosphamide to delay the development of pulmonary fibrosis. In addition, he received tamoxifen (3 x 20 mg orally) due to its antiproliferative and anti-inflammatory effects in retroperitoneal fibrosis. About 72 hours postingestion, his condition deteriorated and he developed respiratory failure, necessitating oxygen supplementation. On day 9, invasive ventilation was required due to the progression of pulmonary fibrosis. He was placed on a high urgency lung transplantation list; however, his condition continued to deteriorate with the onset of systemic inflammatory response syndrome. On day 12, an extracorporeal membrane oxygenation (ECMO) was implemented, but despite further supportive care, he developed hemodynamic instability and septic multiorgan dysfunction with kidney, liver, and hemodynamic failure. The patient died 32 days postingestion from cardiac failure with pulseless electrical activity (Bertram et al, 2013).
2) CASE REPORT: A 24-year-old woman with a history of chronic hepatitis B and depression presented to a local ED about 2 hour after ingesting about 50 mL of 20% of paraquat (about 188 mg/kg). Despite supportive care, including gastric lavage, activated charcoal, cyclophosphamide, methylprednisolone, and hemoperfusion (3 sessions), her symptoms did not improve significantly. On day 2, she developed elevated liver enzymes, renal insufficiency, pulmonary fibrosis, and severe respiratory failure. Her condition gradually deteriorated and on day 44, she underwent veno-venous extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation. She received a bilateral sequential lung transplantation on day 56. Following further supportive care, including respiratory and physical rehabilitation, her condition gradually improved and she was discharged on day 80 (Tang et al, 2015).

I) PROLONGED QT INTERVAL

1) In a retrospective study, the prognostic value of QTc prolongation in severely paraquat-poisoned patients was evaluated. Overall, 53 non-survivors and 7 survivors were included in the study. QTc intervals ranged from 0.35 to 0.48 seconds and 0.32 to 0.63 seconds in the survivor and non-survivor groups, respectively. One (14.3%) survivor and 32 (60.4%) non-survivors had a QTc of 0.45 seconds or higher, with a median survival time of 26 hours; 50% of these patients died within 1 day. QTc of less than 0.45 seconds was observed in 6 (85.7%) survivors and 21 (39.6%) non-survivors, with a median survival time of 95 hours. It was concluded that QTc prolongation can be a useful prognostic factor for predicting the severity of poisoning and mortality risk in acute paraquat-poisoned patients. In addition, QTc prolongation of greater than 45 msec predicted mortality regardless of potassium concentration (Lin et al, 2014).

J) EXPERIMENTAL THERAPY

1) Nonsteroidal antiinflammatory agents, colchicine, collagen synthesis inhibitors, deferoxamine, or total exclusion from external respiration may prevent lung fibrosis. However, the efficacy of these treatments has yet to be established in the treatment of human paraquat poisonings (Bismuth et al, 1990; Shahar et al, 1989; Akahori & Oehme, 1983; Vincken et al, 1981; Pasi, 1978; Fogt & Zilker, 1989; Jaeger et al, 1995; Pond, 1990).
2) GLUCOCORTICOID WITH CYCLOPHOSPHAMIDE: In 3 small randomized controlled trials of patients (n=164) with moderate or severe paraquat poisoning, the use of glucocorticoid and cyclophosphamide with standard care was beneficial in treating patients with paraquat-induced lung fibrosis. Overall, the risk of death in patients receiving this combination was reduced by 28% (statistically estimated likely range of reduced deaths from 41% to 11%) as compared with patients receiving just standard care (Li et al, 2012).
3) L'Heureux et al (1995) reported the survival of a man who ingested 50 to 60 mL of a paraquat-containing solution and benzodiazepine tablets. Treatment included early decontamination, hemodialysis, 100 mg deferoxamine/kg in 24 hours, and 300 mg acetylcysteine/kg/day for a 3 week period. Reversible, acute renal failure and mild hepatic enzyme elevation occurred. Pulmonary effects were limited. Fibrosis did not occur (L'Heureux et al, 1995).
4) Paraquat-specific IgG and Fab fragments have reduced cellular uptake of paraquat by isolate rat alveolar type II cells (Chen et al, 1994).
5) High molecular-weight polyvinyl sulfate (PVP) or polyvinyl sulfonate (PVS), as well as low molecular weight alkylsulfonates, resulted in 100% survival of mice given paraquat dichloride at 200 mg/kg (Tsuchiya et al, 1995).

a) The mechanism of their protection appears to be prevention of paraquat absorption from the intestine. The low molecular weight alkyldisulfonates also inhibited the formation of pulmonary lipid peroxides.

6) NITRIC OXIDE INHALATION: Nitric Oxide (NO) is a vasodilating gas that has been used successfully to increase the pO2 in patients with adult respiratory distress syndrome (ARDS) (Bismuth, 1995).

a) NO inhalation did improve the pO2 and stabilized the pulmonary status for three days in one patient with acute paraquat poisoning (Koppel et al, 1994).
b) While still experimental, in serious paraquat poisoning cases, NO inhalation to maintain tissue oxygenation in anticipation of lung transplantation once all absorbed paraquat has been eliminated deserves further study.

7) SIROLIMUS: A man ingested approximately 120 mL of Gramoxone Inteon(R) and developed diffuse pulmonary fibrosis and pneumomediastinum about 12 days after exposure and was started on sirolimus to limit further pulmonary fibrosis. Therapy was continued for 15 days. Sirolimus, a triene macrolide immunosuppressant, has antiproliferative effects on fibroblasts and on lymphoid and nonlymphoid tumor cells. Other agents included cyclophosphamide, methylprednisolone and dexamethasone. The patient gradually improved and his oxygen saturation increased to 90% on 2 liters of oxygen by hospital day 39 (Barrueto et al, 2008). The authors suggested that sirolimus along with the other concomitant therapies were responsible for halting the progression of paraquat-induced pulmonary fibrosis.
8) SURFACTANT THERAPY: Exogenous surfactant did improve lung function for several hours in paraquat poisoned rats (So et al, 1998). No human data was located at the time of this revision.
9) HIGH-DOSE VITAMIN C: In one study, the administration of high-dose vitamin C, in combination with anti-inflammatory and immunosuppressant agents, was effective in preventing acute renal injury in patients with paraquat poisoning (an average ingestion of 134.1 +/- 126.3 mL of 24.5% liquid paraquat; serum paraquat concentration of 30.8 +/- 45.5 mcg/mL). Fifty-seven patients received pulse therapy (cyclophosphamide and methylprednisolone, then dexamethasone) for 2 weeks and 77 patients received the same pulse therapy with high-dose vitamin C for 2 weeks. A significant decrease in the incidence of paraquat-induced acute renal injury was observed in the high-dose vitamin C group. In addition, the use of vitamin C with pulse therapy was significantly associated with an increased survival of the patients (Moon & Chun, 2010).

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.

6.7.2)

A) SUPPORT

1) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary. There have been no substantiated cases of paraquat poisoning due to inhalation of "fumes". Inhalation of spray mist has occurred, but the droplets are usually large and deposit in the upper respiratory tract where they cause local irritant effects, not severe pulmonary toxicity.

B) OXYGEN

1) Although inhalation of paraquat spray has never been reported to cause significant pulmonary toxicity, supplemental oxygen should be avoided (Rhodes et al, 1976).

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

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).

6.8.2)

A) IRRITATION SYMPTOM

1) Paraquat may cause severe eye irritation, reaching its maximum in 12 to 24 hours postexposure. Healing may be slow, but recovery is usually complete. Ophthalmologic consultation may be advisable.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) DERMAL ABSORPTION

1) Paraquat is poorly absorbed through intact skin (Hoffer & Taitelman, 1989), but fatalities following skin exposure have been reported when absorption occurred through damaged or abraded skin (Wohlfahrt, 1982; Garnier, 1995). Paraquat left on the skin will cause enough damage to facilitate its own absorption (Smith, 1988; Garnier, 1995). Medical personnel must take precautions so as not to become contaminated.

a) IN VITRO STUDY: Using human skin, found that skin does not bind paraquat itself and intact skin is relatively impermeable. Lightly abraded skin, however, was over 100 times more permeable to paraquat, and concentrated solutions also increased permeability (Tabak et al, 1990). This study did NOT address the permeability of conjunctival or other mucous membranes.

B) 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) Hemoperfusion may increase survival if initiated early (ideally within 4 hours), based on data from retrospective studies. Both hemoperfusion and hemodialysis have been shown to increase paraquat clearance (Hong et al, 2003).

1) SUMMARY

a) There are no randomized controlled trials evaluating the effects of hemoperfusion in paraquat poisoning. Small retrospective studies suggest that early hemoperfusion may improve survival in severe paraquat poisoning. If it is used, hemoperfusion needs to be done early (ie, within 2 to 4 hours of exposure) to minimize the rapid onset of renal injury and the rapid distribution of paraquat into the lungs, liver and muscle following paraquat exposure (Kang et al, 2009; Gawarammana & Buckley, 2011).
b) In an in vitro study, hemoperfusion with a blood flow of 250 mL/min provided paraquat clearance rates of 199 to 215 mL/min over the first 90 minutes, by 6 hours clearance had decreased to 22 mL/min (Hong et al, 2003)

2) TECHNIQUE

a) PLASMA PARAQUAT CONCENTRATIONS: Hemoperfusion is effective if the initial plasma paraquat concentration is high (ie, 200 ng/mL or more); plasma clearance is less effective at paraquat concentrations of less than 200 ng/mL (Shi et al, 2012).
b) TIMING OF THERAPY: Hemoperfusion should ideally be performed early (less than 4 hours) after exposure to improve survival of severely poisoned patients (Hsu et al, 2012).
c) BLOOD FLOW: The suggested flow across the cartridge is 200 mL/min in adults using AK-200 hemoperfusion machine (Gambro, Germany) and a resin containing column coated with polycarbonate (HA-230) (Shi et al, 2012). The charcoal-based sorbent frequently used with paraquat poisoning is Adsorba (Gambro, Inc) (Hsu et al, 2012; Kang et al, 2009; Gil et al, 2010) which helps to prevent direct contact between blood and sorbent, improve biocompatibility and aid in the prevention of charcoal embolization (Gil et al, 2010).
d) Each hemoperfusion session may cause a rapid fall in paraquat blood concentrations, followed by a significant rebound in blood levels as paraquat redistributes from the tissues (Tsatsakis et al, 1996).
e) HEPARIN: Loading and maintenance dosing heparin are administered before and during hemoperfusion to prevent coagulation in tubing and cartridge.

3) COMPLICATIONS

a) Complications of charcoal hemoperfusion may include thrombocytopenia, hypocalcemia, hypotension, hypoglycemia, 1 to 2 degrees of hypothermia, and reduced white blood cell count. Systemic bleeding may develop with hemoperfusion (Gil et al, 2010).
b) Although hemoperfusion is performed in many clinical centers and can improve survival time, it may not improve overall mortality. The overall case fatality rate in centers frequently performing either hemoperfusion or hemodialysis is over 50% which is similar to rates reported in centers that do not use enhanced elimination (Gawarammana & Buckley, 2011).

4) STUDIES

a) RETROSPECTIVE STUDY: In a retrospective study of 207 paraquat poisoned patients admitted to 2 hospitals between 2000 to 2009, patients were grouped based on early (less than 4 hrs after paraquat ingestion) or late hemoperfusion (greater than or equal to 4 hrs after ingestion). This study also looked at initial hemoperfusion at less than 6 hrs and less than 7 hrs after ingestion. Early hemoperfusion of less than 4 hours (hazard ratio (HR) = 0.38, 95% Confidence Interval (CI) 0.16 to 0.86; p = 0.020) or hemoperfusion of less than 5 hrs (HR = 0.60, 95% CI 0.39 to 0.92; p = 0.019) significantly reduced mortality risk in severely poisoned patients after adjusting for related variables. It was also found that patients treated with early hemoperfusion and pulse therapy (ie, cyclophosphamide, methylprednisolone and dexamethasone; see Immunosuppressive Therapy) compared to high-dose cyclophosphamide and dexamethasone therapies had a reduced relative risk of mortality of 81% and 51%, respectively (Hsu et al, 2012).
b) CASE SERIES: In a study of 10 adults with acute paraquat poisoning, early hemoperfusion was found to as effective or more effective than renal elimination as creatinine clearance declined following acute exposure. Hemoperfusion was performed for 3 hrs at a blood flow rate of 200 mL/min using an Adsorba 300 C Gambro (Germany) hemoperfusion membrane. Paraquat clearance was 111 +/- 11 mL/min (range: 13.2 to 162.2 mL/min) and the actual amount of paraquat eliminated was 251.4 +/- 506.3 mg (range: 4.6 to 1655.7 mg) compared to renal elimination of 79.8 +/- 56 mL/min (range: 9.7 to 177.0) and 75.4 +/- 73.6 mg (range: 4.9 to 245.8 mg). In addition, paraquat elimination was higher with hemoperfusion when the paraquat concentration was 1 mcg/mL or higher while renal paraquat elimination was higher with plasma paraquat concentrations of less than 1 mcg/mL (Kang et al, 2009).
c) CASE SERIES: Hemoperfusion therapy for 10 hours or longer, initiated within the first 2 to 4 hours of paraquat ingestion, may improve survival in some patients more than conventional, shorter duration hemoperfusion. In a study, 21 patients receiving 10 hours or more of hemoperfusion during the first day had longer survival times as compared to 19 patients treated with less than 10 hours on the first day. However, there was no difference in long-term survival between the groups (4 of 21 and 5 of 19 patients, respectively). Additional research is needed to determine if longer duration hemoperfusion is efficacious and to determine which patients may benefit from this treatment (Suzuki et al, 1993).
d) CASE SERIES: Hemoperfusion was successful in removing paraquat in a study of 105 patients. There were 50 survivors and 55 nonsurvivors; hemoperfusion was performed for 4 hours. The reduction rate was significantly higher in the survivors (80 +/- 20% vs 67 +/- 19%). There was no difference in time to hemoperfusion between survivors and nonsurvivors (approximately 11 hrs); however, nonsurvivors had ingested significantly more paraquat than survivors (28 +/- 23 mL vs 55 +/- 44 mL) (Hong et al, 2003).
e) CASE SERIES: When plasma paraquat concentrations and the specific times postingestion were plotted on a contour graph that predicts the probability of survival for 42 hemoperfused paraquat poisoned patients, probability of survival versus actual outcomes demonstrated that hemoperfusion (single or repeated) did NOT alter the predicted outcome. Survivors did receive initiation of hemoperfusion 3 hours earlier and for durations of 15 hours longer than non-survivors (Hampson & Pond, 1988).
f) CASE REPORT: A removal of 80% (110 mg) of the total amount of paraquat excreted (hemoperfusion + renal: 139 mg) by 3 hemoperfusion runs of 8 hours duration each has been reported. Hemoperfusion began 13 hours postingestion in a 19-year-old woman who ingested 10 to 20 mL of 24% w/w paraquat. Paraquat became undetectable in the urine 39 days postingestion. The patient developed severe restrictive ventilatory impairment, but survived (Yang et al, 1987b).
g) CASE REPORT: A 21-year-old woman, 27 weeks pregnant, was treated with charcoal hemoperfusion, cyclophosphamide (1 gram/day for 2 days), and methyl prednisolone pulse therapy after drinking one-third of a bowl (about 40 mL) of paraquat solution (24% solution of 1,1'-dimethyl-4,4'-bipyridylium dichloride; about 168 mg/kg paraquat ion) in a suicide attempt. She recovered and delivered a healthy girl baby 14 weeks after exposure (Jenq et al, 2005).
h) CASE REPORT: A patient was treated with hemoperfusion-hemodialysis (HP-HD) for severe paraquat poisoning. Approximately, 130 mg out of an estimated ingestion of 315 mg was removed after 5 hours of treatment. The authors concluded that in severe paraquat overdoses that are treated with short-time HP-HD, the amount of paraquat remaining in the tissues is considerable, as compared to quantities of chemical removed (Van de Vyver et al, 1985).
i) Hoffman et al (1983) successfully reduced the amount of paraquat by using forced diuresis, hemodialysis, and charcoal hemoperfusion for 8 hours (Hoffman et al, 1983). Tabak et al (1983) were also successful in removing paraquat by hemoperfusion by using a column of Fuller's earth and agarose beads (Tabak et al, 1983).
j) Mascie-Taylor et al (1983) and van der Vyver et al (1983) found that charcoal hemoperfusion for 3 to 27 hours did remove paraquat, but not enough to be clinically significant (Mascie-Taylor et al, 1983; van de Vyver et al, 1983).

5) ANIMAL STUDY/EXPERIMENTAL THERAPY

a) In a dog study, repeated charcoal hemoperfusion treatment, begun 12 hours after IV dosing, removed paraquat poorly (less than 2% of an LD100 dose) and did not reduce mortality (Hampson et al, 1990). A single, EARLY (within 2 to 4 hours) charcoal hemoperfusion treatment, after an IV infusion of paraquat in another dog study, did reduce mortality by 50 percent (Hampson et al, 1990).
b) In one study, 12 mongrel dogs were randomly assigned to receive standard hemoperfusion (n=6) or twin pulse life support (able to produce dual pulsatile flow by an electromechanical blood pump) following paraquat (30 mg/kg) intoxication. One hour following exposure, hemoperfusion was started for 4 hours at a rate of 125 mL/min with laboratory and hemodynamic levels monitored. After completing hemoperfusion in both groups the animals were euthanized, postmortem paraquat plasma and tissue concentrations were found to be similar in both groups (Suh et al, 2008). The authors suggested that this method may have applications in the emergency department when hemoperfusion is needed, and could be performed by healthcare personnel (physicians or nurses) with minimal training.

1) There are no clinical studies of hemodialysis for severe paraquat poisoning. In an in vitro study, hemodialysis with a blood flow of 250 mL/min provided paraquat clearance rates of 150 to 201 mL/min that was sustained over 6 hours (Hong et al, 2003).
2) CASE REPORT: Hemodialysis was used, together with rapid oral decontamination and antioxidant therapy, in an adult patient who survived a large ingestion of paraquat (L'Heureux et al, 1995).

1) L'Heureux et al (1995) reported the survival of a man who ingested 50 to 60 mL of a paraquat-containing solution and benzodiazepine tablets. Treatment included early decontamination, hemodialysis, 100 mg of deferoxamine/kg/day, and 300 mg acetylcysteine/kg/day for a 3 week period. Reversible, acute renal failure and mild hepatic enzyme elevation occurred. Pulmonary effects were limited. Fibrosis did not occur (L'Heureux et al, 1995).
2) Drault et al (1999) reported a patient who survived the ingestion of 60 g of paraquat after treatment with IV N-acetylcysteine and early hemodialysis (within 4 hours of ingestion) (Drault et al, 1999).

1) Paraquat is NOT significantly removed by forced diuresis, tubular reabsorption is minimal, and the volume of fluid required could aggravate pulmonary edema (Pond, 1990).

1) CONTINUOUS ARTERIOVENOUS HEMODIALYSIS/HEMOPERFUSION (CAVHD-HP): A study was conducted comparing 5 paraquat-poisoned patients treated with CAVHD-HP with 6 paraquat-poisoned patients treated with intermittent charcoal hemoperfusion (Chyr et al, 1995).

a) Compared to the intermittent charcoal hemoperfusion group, the patients who underwent CAVHD-HP had non-detectable paraquat serum concentrations following 2 to 3 days of treatment.
b) No clinical outcome measures were reported in this study; therefore, this method of treatment cannot be routinely recommended.

2) CONTINUOUS VENOVENOUS HEMOFILTRATION (CVVH): A study was conducted to evaluate the effectiveness of prophylactic CVVH in paraquat-poisoned patients. Each patient (n=80) ingested approximately 2 mouthfuls (40 mL) of 20% paraquat concentrate and subsequently underwent hemoperfusion (HP), as the sole enhanced elimination method, 24 hours post-ingestion. The 80 patients were then randomly assigned to be treated with HP only (n=44) or CVVH immediately after HP (n=36). All patients also received IV dexamethasone and vitamin C in order to reduce the extent of oxygen free radical-induced organ injury.

a) The study showed that treatment with HP-CVVH prolonged the time of death after ingestion. The study also showed that early circulatory collapse was the major cause of death in the HP only group, as compared to late respiratory failure as the major cause of death in the HP-CVVH group. Although the study showed that prophylactic CVVH after HP could prevent early death caused by multiorgan failure, there were no significant differences in mortality rates between the two groups, indicating that prophylactic treatment with CVVH after HP did not provide a survival benefit in paraquat poisoning (Koo et al, 2002).

Abstracts

Case Reports

1) A 59-year-old man survived an episode of massive ingestion of paraquat. Adverse effects consisted mild renal failure without oliguria, mild alterations in liver function enzymes, and impairment of CO transfer factor. Treatment involved early prevention of absorption and hemodialysis followed by deferoxamine (100 mg/kg in 24 hours) and continuous infusion of acetylcysteine (300 mg/kg/day for 3 weeks) (L'Heureux et al, 1995).
2) There are 2 case reports of patients developing acute oliguric renal failure following ingestion of paraquat who did not develop significant pulmonary toxicity (Sobha et al, 1989; Florkowski et al, 1992).
3) There are 4 case reports of patients who unexpectedly survived despite having apparently fatal plasma paraquat concentrations (Ragoucy-Sengler et al, 1991; Florkowski et al, 1992).

a) All 4 of these patients were heavy consumers of alcohol, suggesting alcohol abuse may protect against paraquat toxicity.
b) All patients ingested more than 20 mL of 20% v/v paraquat.
c) All patients had serum paraquat concentrations below 3 mg/L, but above the limit for survival based on assessment by methods published by Proudfoot et al (1979), Scherrmann et al (1987), and Sawada et al (1988).
d) Limited animal data in rats suggests that acute ethanol ingestion does decrease the pulmonary toxicity of paraquat (Puapairoj et al, 1994).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) ESTIMATED LETHAL DOSE: Although laboratory animal studies suggest relatively moderate toxicity of paraquat (LD50 about 150 mg/kg), some cases of fatal pulmonary fibrosis in man have apparently occurred following ingestion of very small amounts. The estimated human lethal dose is 10 to 15 mL of the concentrate (Fletcher, 1974).
2) Toxicity increases with the dose ingested. Clinical experience has suggested the following:

a) MILD TOXICITY: Ingestion of less than 20 mg paraquat ion per kg body weight (less than 7.5 mL of 20% [w/v] paraquat concentrate): No symptoms or mild GI effects; recovery likely (Reigart and Roberts, 1999).
b) MODERATE to SEVERE TOXICITY: 20 to 40 mg paraquat ion per kg body weight (7.5 to 15 mL of 20% [w/v] paraquat concentrate): Pulmonary fibroplasia develops. Death occurs in most cases, but may be delayed 2 to 3 weeks (Reigart and Roberts, 1999).
c) FATAL: Greater than 40 mg paraquat ion per kg body weight (more than 15 mL of 20% [w/v] paraquat concentrate): Multiple organ failure occurs; toxicity progresses rapidly. Mortality is essentially 100% in 1 to 7 days (Reigart and Roberts, 1999). Progressive gastrointestinal, renal, hepatic and pulmonary damage occurs very rapidly (Morgan, 1993)

3) Paraquat was responsible for 75% of all pesticide-related deaths in England and Wales in 1990 and 1991 (Thompson et al, 1995).

1) CUTANEOUS

a) An 81-year-old man was minimally sprayed on the leg with a paraquat pesticide and failed to remove the contaminated clothing until the following day. A small burn (approximately 4% of the total body surface area) on the leg was treated empirically with a topical steroid. Four days later the patient became short of breath, and was admitted with evidence of acute respiratory distress syndrome, leukocytosis, and acute renal failure. Despite care, respiratory function continued to deteriorate and the patient died two days later (Soloukides et al, 2007).
b) A 50-year-old crop-duster carrying a load of paraquat herbicide lost control of his plane and crashed. Extensive burns (37% of total body surface area) on the skin resulted in cutaneous paraquat absorption. Skin decontamination occurred approximately 9.5 hours after exposure. The patient had a paraquat blood level of 0.169 mg/mL (standard lethal dose at 16 hours is 0.16 mg/mL) 20 hours after injury. The patient died 4 days after exposure with acute renal failure and progressive respiratory failure (Gear et al, 2001).
c) Prolonged contact with dilute spray (5 g/L) after spillage or leakage from a knapsack sprayer was associated with a fatal outcome in one case (Athanaselis et al, 1983).
d) A fatality was reported following alleged insertion of a tampon, inadvertently soaked in paraquat, into the vagina for approximately 10 minutes; it was removed because of burning sensation (Ong & Glew, 1989). Concentration was not specified and serum paraquat concentration was not available. Postmortem examination findings were consistent with paraquat poisoning.

2) INTRAVENOUS

a) A 35-year-old woman intentionally injected 5 mL of a 24% (estimated dose of 1.2 g) paraquat solution into a superficial vein. Initial plasma paraquat concentration was 18 mcg/mL 5 hours after exposure with a urine paraquat level exceeding 50 mcg/mL. Following 2 consecutive sessions of hemoperfusion, her blood paraquat level was 6.4 mcg/mL (24 hours after exposure). However, progressive dyspnea developed, and the patient died on hospital day 4 of multiple organ failure (Hsu et al, 2003).

1) In a similar case, a 37-year-old man injected 5 mL of 24% paraquat into a femoral vein and was hospitalized within one hour. Initial plasma paraquat level was 19.6 mcg/mL and urine paraquat exceeded 50 mcg/mL. Despite hemoperfusion and intensive care, he died of multiorgan failure 5 days after exposure (Hsu et al, 2003). The authors suggested that higher bioavailability occurred following intravenous exposure leading to higher plasma levels. As compared with an oral ingestion, these patients displayed signs and symptoms of severe toxicity almost immediately. Both patients became dyspneic within 24 hours of exposure, despite aggressive care.

b) Intravenous injection of 4 mL of 20% paraquat (approximately 20 mg/kg) resulted in fatality from pulmonary dysfunction at 15 days after injection in a 21-year-old man (Fernandez et al, 1991).

3) ORAL

a) GENERAL: Prudence requires that all cases of paraquat ingestion be treated as potentially fatal poisonings. Systemic absorption of paraquat in the course of ordinary occupational use is apparently minimal.
b) An adult died several days after ingesting 5 to 10 mL of paraquat concentrate. He presented to hospital 41 hours postingestion and died 4 days later (Tsatsakis et al, 1996).
c) In accidental ingestions, the minimum lethal dosage of paraquat is estimated to be 30 mg/kg (Harsanyi et al, 1987).
d) A 9-year-old boy died 17 days after drinking water from an empty bottle that had once contained paraquat concentrate (Fernando et al, 1990).
e) In a series of 10 paraquat poisonings in Crete, all patients who ingested more than 100 mL of paraquat solution died, although some were still alive at hospital presentation 7 to 8 hours after ingestion (Tsatsakis et al, 1996).
f) A 23-year-old man presented to a local ED after inadvertently ingesting a mouthful of paraquat 20% (about 6 to 10 g). On admission, his paraquat concentrations in serum and urine were 2.12 mg/L and 350 mg/L, respectively, indicating a lethal dose. Despite supportive care, including extracorporeal membrane oxygenation therapy, he developed respiratory failure due to pulmonary fibrosis. He later developed hemodynamic instability and multiorgan failure and died 32 days postingestion from cardiac failure with pulseless electrical activity. No paraquat was detected in postmortem tissue specimen (Bertram et al, 2013).

Maximum Tolerated Exposure

1) MILD TOXICITY: Ingestion of less than 20 mg paraquat ion per kg body weight (less than 7.5 mL of 20% [w/v] paraquat concentrate): No symptoms or mild GI effects; recovery likely (Reigart and Roberts, 1999).
2) MODERATE to SEVERE TOXICITY: 20 to 40 mg paraquat ion per kg body weight (7.5 to 15 mL of 20% [w/v] paraquat concentrate): Pulmonary fibroplasia develops. Death occurs in most cases, but may be delayed 2 to 3 weeks (Reigart and Roberts, 1999).
3) Nearly all paraquat adsorbed on treated marijuana plants is pyrolyzed to dipyridyl as the leaves burn. Dipyridyl is one of the natural products of combustion of vegetable matter. Paraquat treatment of leaves is not likely to increase the adverse effects of natural marijuana smoke on the lungs (Morgan, 1993).
4) Systemic absorption of paraquat in the course of ordinary occupational use is apparently minimal, however paraquat absorption does occur through the skin, especially in the presence of mechanical or chemical lesions (Hayes & Laws, 1991).

1) A 59-year-old man who received early, aggressive medical treatment survived after ingesting an estimated 50 to 60 milliliters of a 20% paraquat solution (Gramoxone(R)) and an unknown number of benzodiazepine tablets (L'Heureux et al, 1995).

a) Nonoliguric acute renal failure and mildly elevated liver enzymes were reported, but resolved within 1 month. Pulmonary effects were minor and reversible, except for a low CO transfer factor which persisted for more than 1 year.
b) Two adults survived an ingestion of 30 to 40 mL and 80 to 100 mL of paraquat solution, respectively (Tsatsakis et al, 1996).

2) CASE REPORT/MINOR TOXICITY: In Sri Lanka, a 25-year-old man intentionally ingested 35 mL of paraquat (the principal compound; Inteon(R) formulation) and developed acute renal failure (serum creatinine peaked at 5.6 mg/dL and oliguria), which resolved with conservative therapy. No other systemic effects were observed; radiology and arterial blood gases were normal. Follow-up at 3 months showed no evidence of permanent sequelae (Mettananda et al, 2008). The authors suggested that the relatively minor toxic effects observed with this patient, despite systemic absorption, were possibly related to a reformulation of paraquat (ie, Inteon(R) technology; an alginate is added that converts to a gel in the stomach and acts as a purgative).
3) Okonek et al (1983) reported a near fatal case of paraquat poisoning after skin contamination of a relatively large surface area with a concentrated solution.
4) Kaojarern & Ongphiphadhanakul (1991) derived the following discriminant function which classified patients into the survival group if the function was positive. The prognostic factors are values obtained at admission. This model was validated by the jackknife method.

1) 0.027 AGE + 0.022 INGESTED AMOUNT + 0.0002 WBC - 4.06

5) Yamaguchi et al (1990) found that the interval of time from ingestion to admission, serum potassium concentration, creatinine concentration, and arterial blood bicarbonate were best associated with the prognosis in acute paraquat poisoning in a retrospective review of 160 patients who had ingested paraquat in a suicide attempt.
6) SURVIVAL/DEATH

a) The survival rate of those who lived more than a week following ingestion of a paraquat-containing product was significantly (p less than 0.05) improved in the group ingesting the low concentration paraquat product (paraquat 4.5% w/v and diquat 4.5% w/v, 84.6% survived) when compared to the group ingesting the paraquat concentrate (20% v/v, 57.8% survived) (Yoshioka et al, 1992).
b) All of the deaths from the low concentration paraquat product (paraquat 4.5% and diquat 4.5%) were associated with suicidal intent (Yoshioka et al, 1992). No deaths occurred following accidental ingestion of the low concentration paraquat product.

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) Blood and urine concentrations of paraquat measured prior to initiation of treatment did not correlate with the degree of toxicity in one study (Harsanyi et al, 1987).
2) In a retrospective review of 42 case reports, no patient with a plasma level greater than 3 milligrams/liter survived, despite therapeutic interventions (Hampson & Pond, 1988).
3) A 23-year-old man presented to a local ED after inadvertently ingesting a mouthful of paraquat 20% (about 6 to 10 g). On admission, his paraquat concentrations in serum and urine were 2.12 mg/L and 350 mg/L, respectively, indicating a lethal dose. Despite supportive care, including extracorporeal membrane oxygenation therapy, he developed respiratory failure due to pulmonary fibrosis. He later developed hemodynamic instability and multiorgan failure and died 32 days postingestion from cardiac failure with pulseless electrical activity. No paraquat was detected in postmortem tissue specimen (Bertram et al, 2013).
4) Survival curves have been developed to predict the chance of survival: Proudfoot's curve (Proudfoot et al, 1979), Scherrmann's curve (Scherrmann et al, 1987), and Severity Index of Paraquat Poisoning (SIPP) (Sawada et al, 1988).

a) Fatality was likely with plasma paraquat levels of 2, 0.6, 0.3, 0.16, and 0.1 milligram/liter at 4, 6, 10, 16, and 24 hours after ingestion (Proudfoot et al, 1979). These curves accurately predict the outcome in approximately 90% of cases (Prod Info Predictive value of early plasma paraquat concentrations, in: Bismuth C & Hall AH (Eds), Paraquat Poisoning: Mechanisms-Prevention-Treatment, 1995; Tsatsakis et al, 1996).
b) Suzuki et al (1991) concluded that Proudfoot's curve was a better index for predicting the outcome of patients who were admitted within 24 hours based on their analysis of 233 cases of paraquat poisoning.

5) A plasma paraquat concentration of 0.62 microgram/milliliter was reported at 12 hours after intravenous injection of 4 milliliters of 20 percent paraquat in a 21-year-old male (Fernandez et al, 1991).
6) Survival curves based on plasma paraquat levels obtained 24 or more hours after ingestion have also been determined (Scherrmann, 1995) -

Hours PI	Plasma Paraquat (ng/mL)
24	100
48	86
72	74
96	63
120	54
144	48
168	42
192	37
216	32
240	27
264	23.5
288	20
312	18

Workplace Standards

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Paraquat

a) TLV:

1) TLV-TWA: 0.1 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: R
3) Definitions:

a) R: Respirable fraction; see Appendix C, paragraph C (of TLV booklet).

c) TLV Basis - Critical Effect(s): Lung dam
d) Molecular Weight: 257.18

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

b) Adopted Value

1) Paraquat

a) TLV:

1) TLV-TWA: 0.5 mg/m(3)
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Not Listed
3) Definitions: Not Listed

c) TLV Basis - Critical Effect(s): Lung dam
d) Molecular Weight: 257.18

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

c) Under Study

1) Paraquat

a) TLV:

1) TLV-TWA:
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: Not Listed
2) Codes: Not Listed
3) Definitions: Not Listed

c) TLV Basis - Critical Effect(s):
d) Molecular Weight:

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) ACGIH TLV Values for CAS1910-42-5 (American Conference of Governmental Industrial Hygienists, 2010):

1) Not Listed

C) ACGIH TLV Values for CAS2074-50-2 (American Conference of Governmental Industrial Hygienists, 2010):

1) Not Listed

D) NIOSH REL and IDLH Values for CAS4685-14-7 (National Institute for Occupational Safety and Health, 2007):

1) Not Listed

E) NIOSH REL and IDLH Values for CAS1910-42-5 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Paraquat (Paraquat dichloride)
2) REL:

a) TWA: 0.1 mg/m(3) (resp)
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: [skin]

1) Indicates the potential for dermal absorption; skin exposure should be prevented as necessary through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment.

f) Note(s):

3) IDLH:

a) IDLH: 1 mg/m3
b) Note(s): Not Listed

F) NIOSH REL and IDLH Values for CAS2074-50-2 (National Institute for Occupational Safety and Health, 2007):

1) Not Listed

G) Carcinogenicity Ratings for CAS4685-14-7 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Paraquat
2) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Paraquat
3) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Paraquat
4) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
5) 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): Not Listed
6) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
7) MAK (DFG, 2002): Not Listed
8) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

H) Carcinogenicity Ratings for CAS1910-42-5 :

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

a) C : Possible human carcinogen.

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

I) Carcinogenicity Ratings for CAS2074-50-2 :

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

J) OSHA PEL Values for CAS4685-14-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Paraquat, respirable dust
2) Table Z-1 for Paraquat, respirable dust:

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 0.5

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: Yes
5) Notation(s): Not Listed

K) OSHA PEL Values for CAS1910-42-5 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Paraquat, respirable dust
2) Table Z-1 for Paraquat, respirable dust:

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 0.5

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: Yes
5) Notation(s): Not Listed

L) OSHA PEL Values for CAS2074-50-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Paraquat, respirable dust
2) Table Z-1 for Paraquat, respirable dust:

a) 8-hour TWA:

1) ppm:

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 0.5

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value:
4) Skin Designation: Yes
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) Paraquat, bis(methylsulfate) salt (CAS 2074-50-2)

1) LD50- (INTRAPERITONEAL)RAT:

a) 35 mg/kg -- changes in recordings in specific areas of CNS and in motor activity, respiratory stimulation

2) LD50- (ORAL)RAT:

a) 100 mg/kg -- hypermotility, diarrhea, respiratory depression and other changes in respiratory system

B) Paraquat, dichloride salt (CAS 1910-42-5)

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 20 mg/kg

2) LD50- (ORAL)MOUSE:

a) 120 mg/kg

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 37 mg/kg

4) LD50- (INTRAPERITONEAL)RAT:

a) 26 mg/kg

5) LD50- (ORAL)RAT:

a) 57 mg/kg

6) LD50- (SKIN)RAT:

a) 80 mg/kg

7) LD50- (SUBCUTANEOUS)RAT:

a) 24 mg/kg

8) TCLo- (INHALATION)RAT:

a) 1100 mcg/m(3) for 4H/19W - I -- structural or functional changes in trachea or bronchi, tubular changes, altered phosphatase activity

C) Paraquat (CAS 4685-14-7)

1) LD50- (ORAL)MOUSE:

a) 120 mg/kg

2) LD50- (SKIN)MOUSE:

a) 62 mg/kg

3) LD50- (INTRAPERITONEAL)RAT:

a) 14,800 mcg/kg -- acute pulmonary edema, gastrointestinal and liver changes

4) LD50- (ORAL)RAT:

a) 50 mg/kg
b) 100-200 mg/kg
c) 100 mg/kg
d) Male, 100 mg/kg
e) Female, 150 mg/kg

5) LD50- (SKIN)RAT:

a) 80-350 mg/kg

Pharmacology Toxicology

Toxicologic Mechanism

1) Human toxicity has most often been associated with the 20 to 42% concentrates and not with the usually dilute formulations sold OTC.
2) The agent is strongly adsorbed on plant and soil particles.
3) In addition to a corrosive effect on skin and mucous membranes, paraquat is toxic to the lung, liver, kidney, and myocardium.
4) Death is due to asphyxia, caused by progressive and generalized proliferation of fibrous connective tissue in the pulmonary alveoli where paraquat is selectively concentrated. This reaction develops from 3 days to 2 weeks after ingestion and is accelerated by administration of oxygen (Harsanyi et al, 1987).
5) Type I and type II pneumocytes selectively accumulate paraquat. Biotransformation processes within these cells are believed to result in the generation of free radicals which may cause lipid peroxidation and cell injury. Cell wall injury causes mononuclear macrophage activation, and eventually, pulmonary fibrosis (Honore et al, 1994).

Physicochemical

Physical Characteristics

1) Paraquat, dichloride salt: colorless crystals (Budavari, 1996)
2) Paraquat, Bis(methylsulfate) salt: yellow solid (Budavari, 1996)

1) paraquat dichloride: mild ammonia smell (NIOSH , 1999)
2) odorless (HSDB , 1999)

Ph

1) No information found at the time of this review.

Molecular Weight

1) Paraquat Dichloride: 257.16
2) Paraquat, Bis(methylsulfate) salt: 408.50

Animal Toxicology

References

General Bibliography

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FeedBack

PARAQUAT

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography