Last summer, an epizootic of paraquat poisoning caused the deaths of at least seven dogs in Portland, Ore.1 This epizootic is evidence that this type of poisoning remains a current problem in companion-animal practice in North America. Paraquat, a poisonous dipyridilium compound, is one of the few nonselective herbicides still available in the United States. Because paraquat is fast-acting, can be effectively used in wet environments, and has limited potential for environmental contamination and low rates of weed resistance, it is still widely used in various crop production systems. However, paraquat is highly toxic to domestic animals if ingested.2,3
Within the United States, paraquat is a restricted-use herbicide with the exception of pressurized spray formulations that contain no more than 0.44% paraquat bis (methyl sulfate) and liquid fertilizer formulations that contain no more than 0.04% paraquat dichloride. Current active U.S. registered brand names include Gramoxone Super (Syngenta), Gramoxone Max (Syngenta), Cyclone Max (Syngenta Crop Protection), Marman Herbiquat Herbicide (Marman USA), and Surefire Herbicide (UAP-Loveland Products). Because paraquat has been available for agricultural use since 1962, outdated stocks are relatively easy to obtain.2 Older, outdated domestic garden herbicides often contained a 50:50 (Wt:Wt) mixture of diquat and paraquat, and supplies of this mixture can still be found in the United States. Despite paraquat's restricted-use status, intentional paraquat poisoning of animals remains a problem.3,4
Exposure and toxicokinetics
Most cases of paraquat poisoning in people and animals involve ingestion of concentrated formulations.2-8 In dogs, only about 25% to 28% of orally administered paraquat is absorbed; the remainder is excreted unchanged in the feces.2 In experiments in rodents, paraquat was detected in the feces up to seven days after exposure.2 The oral LD50 of paraquat in cats is 35 to 50 mg/kg. The oral LD50 in dogs is unknown but is higher than that in cats, and the intravenous LD50 in dogs is 7.48 mg/kg.
Many of the current commercial paraquat preparations (e.g. Gramoxone) deliberately incorporate emetics and bitters in their concentrate formulations to reduce the dose absorbed after suicide-related oral poisoning in people.2,9 This protective measure causes fasting and nonfasting dogs to vomit 61% to 86% of an orally administered dose and reduces blood paraquat concentrations by about 170 times.9 Unfortunately, older concentrates are less likely to incorporate this key safety feature.
Irrespective of the administration route, absorbed and circulating paraquat is rapidly, selectively, and actively sequestered in type I and type II alveolar cells and Clara cells by an energy-dependent diamine/polyamine transport mechanism that follows saturation kinetics.10 The lungs have the greatest paraquat retention and, thus, the highest concentration of paraquat of any of the tissues four hours after ingestion.2 At four hours, the paraquat concentration in the lungs is about 10 times higher than at other selective accretion sites (e.g. kidneys, brain, adrenal glands).2 By four to 10 days after exposure, the paraquat concentration in the lungs is about 30 to 80 times higher than in plasma. The half-life of paraquat in the lungs is about 24 hours. Because of paraquat's rapid excretion, the paraquat concentration in the lungs and other tissues may fall below detectable limits in animals that die of this agent's delayed effects.2,3,11
Systemically circulating paraquat is actively excreted by renal proximal tubules by using a divalent/polyvalent organic cation/hydrogen ion exchanger mechanism.2,12,13 In rodents, urine paraquat concentrations rapidly decrease over the first 24 hours after ingestion. But paraquat can be detected in rodent urine up to 15 days after ingestion, despite the absence of detectable paraquat concentrations in the serum.2
Mechanism of action
Although paraquat is excreted largely unchanged, it undergoes extensive cyclic oxidation-reduction reactions in mammalian tissues in vivo. This redox cycling produces oxygen and hydroxyl, and the ensuing free-radical-mediated damage to cellular macromolecules, particularly membrane lipids, is primarily responsible for paraquat's toxic effects.2 Tissue damage is typically confined to selective paraquat accumulation sites (e.g. type I and type II alveolar cells, Clara cells, renal proximal tubular epithelia). Contact of mucosal surfaces and skin with concentrated paraquat solutions may also result in marked tissue damage.
Clinical signs and diagnostic tests
Single-dose paraquat poisoning has been classified into three dose-related syndromes2:
1. High-dose, fulminant, systemic poisoning with death occurring one to four days after ingestion due to a combination of acute pulmonary edema, renal failure, hepatocellular damage, necrosis of both intrahepatic and extrahepatic bile ducts and the gallbladder, adrenal failure, and biochemical disturbances;
2. Subacute poisoning with a slower onset of organ failure and eventual death from pulmonary edema and respiratory failure;
3. A low-dose, late, irreversible pulmonary fibrosis syndrome with death ensuing several days to several weeks after exposure.
Typically, early clinical signs of paraquat toxicosis involve acute gastrointestinal upset, particularly vomiting, since paraquat is a gastrointestinal irritant.3-6,8 Other common clinical signs include anorexia, inappetence, and lethargy. These clinical signs, frequently combined with a history of consumption of unknown food items, often lead to an initial misdiagnosis of acute gastroenteritis. The inclusion of emetics in concentrated paraquat formulations may increase the risk of misdiagnosis.
Clinical experience gained during the recent outbreak in Portland demonstrates that elevated serum lipase activities are common at presentation. This elevation may lead to an initial presumptive diagnosis of acute pancreatitis. Stasis of the pancreatic duct, pancreatic failure, and elevated serum amylase activities have been detected in cases of paraquat poisoning in people.14-16 In people, the severity of pancreatic injury at the time of initial treatment helps to predict survival from acute paraquat poisoning.15 However, serum lipase activities are also commonly increased in dogs with compromised renal function.17 Thus, hyperlipasemia may be a secondary consequence of paraquat-induced acute renal failure rather than the result of direct damage to the exocrine pancreas.
Concentrated paraquat solutions cause severe irritation to the skin and mucous membranes; oropharyngeal pain and swelling followed by ulceration and mucosal sloughing a few days later are common.2 In extreme cases, complete sloughing and perforation of the esophagus can occur.
Evidence of compromised renal function (i.e. increased blood urea nitrogen and creatinine concentrations) and mild systemic hypertension are also often present at admission. Death after paraquat ingestion is typically caused by an insidious and irreversible form of respiratory failure. The time of onset of the respiratory syndrome after paraquat poisoning is dose-related and may occur a few days to more than a week after exposure.2
It is uncommon to detect abnormalities by thoracic radiographic examination at the early stages of the paraquat-induced respiratory syndrome; however, thoracic radiographs may provide useful information during the later stages. In people, thoracic abnormalities that are detectable by radiography the first week after paraquat ingestion include a bilateral ground-glass pulmonary shadow, diffuse consolidation, pneumomediastinum with or without pneumothorax, and cardiomegaly with widening of the superior mediastinum.18-20
Histologic evidence of widespread pulmonary alveolar damage, hemorrhage, and edema are typical of the early stages of paraquat poisoning in dogs.2,3 The classic progression of lung changes in people starts with detachment or necrosis of alveolar type I and type II cells, edema, and hemorrhage. These changes are followed by the proliferation of fibroblasts and polymorphic cells, the loss of surfactant secretion, attempts at re-epithelialization of the alveolar surface, and eventual thickening of the alveolar septa from interstitial fibrosis. In people that survive the acute phases of paraquat toxicosis, marked pulmonary fibrosis usually develops two or three weeks after ingestion.2
Selective accumulation in the kidneys is associated with dose-related damage to the renal proximal tubules.2,3,11,21 Evidence of tubular regeneration is often present if a patient survives the initial stages of paraquat toxicosis.2,3,11,21
Paraquat toxicosis is usually diagnosed through a combination of clinical history, the results of a histologic examination of affected tissues, and detection of paraquat in tissue or bait samples. Spectrophotometry, gas and liquid chromatography, and radioimmunoassay have all been used to measure paraquat concentrations in biologic fluids; however, because prompt recognition of paraquat poisoning is a key factor in its treatment, using fast qualitative tests based on the dithionite reaction (i.e. dithionite spot test) may offer an important advantage.3 In the acute stages of paraquat poisoning, vomitus, gastric contents, bait or concentrate samples, feces, and lung and renal tissue are ideal samples. Blood or plasma may be tested, but circulating paraquat concentrations are much lower in blood and plasma than concentrations in the lungs.
Currently, no specific antidote for paraquat poisoning is available. The most important determinant of survival after ingestion is early treatment.2 Treatment must be instituted within hours of exposure to be effective. The initial treatment priorities for paraquat poisoning are administering an adsorbent to neutralize ingested paraquat and removing the poison by emesis or gastric lavage. Traditionally, fuller's earth (i.e. attapulgite clay, calcium montmorillonite) or bentonite (i.e. sodium montmorillonite) adsorbents have been used. Keep in mind that the adsorbent capacity of fuller's earth varies among manufacturers and that only highly adsorbent, pharmaceutical-grade preparations should be used.22
Experimental studies have demonstrated that activated charcoal is an effective in vivo paraquat adsorbent. Activated charcoal's in vitro binding of paraquat is equivalent to that of fuller's earth.23 Thirty percent activated charcoal administered as an aqueous oral slurry is as effective as 30% fuller's earth administered as an aqueous oral slurry in reducing the systemic absorption of paraquat up to one hour after ingestion.24 In cases of experimental paraquat poisoning in rodents, concomitantly administering activated charcoal and magnesium citrate improved the survival rate.23 Since fuller's earth and bentonite are usually not on hand, it's better to go ahead and administer activated charcoal.25 In an emergency, pulverized clay-based cat litter has also been suggested as an alternative adsorbent.25 Cation exchange resins, such as sodium polystyrene sulfonate (Kayexalate—Sanofi-Synthelabo), have much higher paraquat-binding capacities than other adsorbents, increase the LD50 up to 2.1 times in rats, and improve survival rates in people.26 Unfortunately, these materials are not routinely available in veterinary practice. Because of the risk of esophageal perforation, use extreme care when administering adsorbents through a stomach tube.
Because systemically absorbed paraquat is eliminated primarily through renal excretion and the presence of oliguric renal failure markedly contributes to paraquat accumulation in the lungs, maintaining urine production is critical when treating an animal with paraquat toxicosis.2 Forced diuresis can remove large quantities of circulating paraquat if it is initiated within a day or so of ingestion.2,27-30 However, forced diuresis carries with it the risks of electrolyte disturbances and exacerbation of paraquat-induced pulmonary edema. Particular caution is required during the first 24 hours after ingestion, especially if oliguria is present.2
Antioxidant therapy has been extensively studied in experimental models and cases involving people with paraquat toxicosis with variable results.31 Recent studies using trimetazidine (an anti-ischemic), S-carboxymethylcysteine (a respiratory drug), propofol, and epigallocatechin gallate (from green tea) have shown promising results, but clinical experience with these agents is limited, and little controlled clinical trial data are available.31-34 Because of the risk of enhanced oxidative effects, oxygen administration in patients with paraquat toxicosis should be avoided except when necessary for comfort (e.g. patients in respiratory distress).2 Hypoxic ventilation has been used in paraquat poisoning cases in people, but its effectiveness has not been extensively studied.35,36 Collagen synthesis inhibitors may offer some control or prevention of pulmonary fibrosis, but their use has not been extensively studied in field conditions.37 Corticosteroids, immunosuppressants, vitamins, ?-blockers, alkylating agents, chlorpromazine hydrochloride, ?-tocopherol, superoxide dismutase, glutathione peroxidase, and nitric oxide inhalation have all been used to treat paraquat toxicosis with little clearly documented effectiveness.2,14,38,39 Currently available immuno-antidotes are ineffective.40
Prognosis and prevention
Despite treatment, the overall prognosis for paraquat toxicosis is poor. Disappointingly, survival from paraquat poisoning may be more strongly associated with the circumstances of the poisoning rather than any treatment administered.35 Situational factors associated with higher survival rates in people include inhalation or dermal exposure, ingestion of less than 35 mg/kg, a young age at the time of poisoning, the time between paraquat ingestion and the last meal (because paraquat is adsorbed and neutralized by foodstuffs), accidental ingestion rather than homicidal intention, ingestion of diluted materials rather than liquid concentrates or granular formulations, and aggressive treatment within two to five hours of ingestion.2,15,28,35 In people, a lack of caustic gastric lesions; lower urine and plasma paraquat concentrations; lesser degrees of leukocytosis, acidosis, and respiratory distress; and absence of renal, hepatic, and pancreatic failure at the time of admission are all considered to be good predictors of survival.15,28,35
Because of the severe consequences of paraquat toxicosis, early diagnosis and aggressive treatment are paramount if the survival prospects of a severely poisoned patient are to be improved. Given the limited effectiveness of current treatment modalities, the best solution to the problem of paraquat poisoning in companion animals is to prevent exposure.
1. Cope, R.B. et al.: Seven cases of fatal paraquat poisoning in Portland Oregon dogs. Vet. Human Toxicol. (in press).
2. Akintonwa, D.A. et al.: Paraquat and diquat. Environ. Health Criteria 38:1-131; 1984.
3. Bischoff, K. et al.: Malicious paraquat poisoning in Oklahoma dogs. Vet. Hum. Toxicol. 40:151-153; 1998.
4. Longstaffe, J.A. et al.: Paraquat poisoning in dogs and cats—Differences between accidental and malicious poisoning. J. Small Anim. Pract. 22:153-156; 1981.
5. Cruickshank, A.K.: Metaldehyde and paraquat poisoning. Vet. Rec. 111:149-150; 1982.
6. Johnson, R.P.; Huxtable, C.R.: Paraquat poisoning in a dog and cat. Vet. Rec. 98:189-191; 1976.
7. Kelly, D.F. et al.: Pathology of acute respiratory distress in the dog associated with paraquat poisoning. J. Comp. Pathol. 88:275-294; 1978.
8. Quick, M.P. et al.: Acute and sub-acute paraquat poisoning in a pack of foxhounds. J. Forensic Sci. Soc. 30:371-376; 1990.
9. Kawai, S. et al.: Studies on preventive treatment of paraquat dichloride intoxication. Part 2. Nippon Noson Igakkai Zasshi 29:546-547; 1980.
10. Chen, N. et al.: Prevention of paraquat toxicity in suspensions of alveolar type II cells by paraquat-specific antibodies. Hum. Exp. Toxicol. 13:551-557; 1994.
11. Nagata, T. et al.: Acute toxicological studies on paraquat: Pathological findings in beagle dogs following single subcutaneous injections. Vet. Hum. Toxicol. 34:105-112; 1992.
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13. Machaalani, Retal The characterisation and uptake of paraquat in cultured baboon kidney proximal tubule cells (bPTC). Hum. Exp. Toxicol. 20:90-99; 2001.
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17. Lassen, E.D.: Laboratory evaluation of the exocrine pancreas. Veterinary Hematology and Clinical Chemistry (M.A. Thrall, ed.). Lippincott Williams & Wilkins, Baltimore, Md., 2003; pp 377-385.
18. Hara, H. et al.: Observations of the fibrosing process in paraquat lung injury by chest X-ray and CT [in Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi 29:638-643; 1991.
19. Im, J.G. et al.: Paraquat poisoning: Findings on chest radiography and CT in 42 patients. Am. J. Roentgenol. 157:697-701; 1991.
20. Lee, S.H. et al.: Paraquat poisoning of the lung: Thin-section CT findings. Radiology 195:271-274; 1995.
21. Nagata, T. et al.: Subacute toxicity of paraquat in beagle dogs: Clinicopathology and pathologic examinations. Vet. Hum. Toxicol. 34:15-20; 1992.
22. Okonek, S. et al.: Activated charcoal is as effective as fuller's earth or bentonite in paraquat poisoning. Klin. Wochenschr. 60:207-210; 1982.
23. Gaudreault, P. et al.: Efficacy of activated charcoal and magnesium citrate in the treatment of oral paraquat intoxication. Ann. Emerg. Med. 14:123-125; 1985.
24. Idid, S.Z.; Lee, C.Y.: Effects of fuller's earth and activated charcoal on oral absorption of paraquat in rabbits. Clin. Exp. Pharmacol. Physiol. 23:679-681; 1996.
25. Gfeller, R.W.; Messonnier, S.P.: Paraquat. Handbook of Small Animal Toxicology and Poisoning, 2nd Ed. (R.W. Gfeller et al., eds.). Mosby, St. Louis, Mo., 2004; pp 255-257.
26. Yamashita, M. et al.: The effectiveness of a cation resin (Kayexalate) as an adsorbent of paraquat: Experimental and clinical studies. Hum. Toxicol. 6:89-90; 1987.
27. Fennelly, J.J. et al.: Recovery from severe paraquat poisoning following forced diuresis and immunosuppressive therapy. J. Ir. Med. Assoc. 64:69-71; 1971.
28. Kaojarern, S.; Ongphiphadhanakul, B.: Predicting outcomes in paraquat poisonings. Vet. Hum. Toxicol. 33:115-118; 1991.
29. Kerr, F. et al.: Paraquat poisoning treated by forced diuresis. Br. Med. J. 3:290-291; 1968.
30. Fairshter, R.D. et al.: Paraquat poisoning: An analytical toxicologic study of three cases. Toxicology 12:259-266; 1979.
31. Suntres, Z.E.: Role of antioxidants in paraquat toxicity. Toxicology 180:65-77; 2002.
32. Higuchi, A. et al.: Inhibitory activity of epigallocatechin gallate (ECGg) in paraquat-induced microsomal lipid peroxidation—A mechanism of protective effects of ECGg against paraquat toxicity. Toxicology 183:143-149; 2003.
33. Lugo-Vallin Ndel, V. et al.: Prolonged survival after experimental paraquat intoxication: Role of alternative antioxidants. Vet. Hum. Toxicol. 44:40-41; 2002.
34. Hong, S.Y. et al.: Effect of vitamin C on plasma total antioxidant status in patients with paraquat intoxication. Toxicol. Lett. 126:51-59; 2002.
35. Bismuth, C. et al.: Prognosis and treatment of paraquat poisoning: A review of 28 cases. J. Toxicol. Clin. Toxicol. 19:461-474; 1982.
36. Demeere, J.L.: Paraquat toxicity. The use of hypoxic ventilation. Acta Anaesthesiol. Belg. 35:219-230; 1984.
37. Akahori, F. et al.: Effect of dehydroproline as a collagen synthetic inhibitor in paraquat-induced pulmonary fibrosis in beagle dogs. Vet. Hum. Toxicol. 35:216-222; 1993.
38. Yamada, Y. et al.: Chlorpromazine and paraquat poisoning. Vet. Hum. Toxicol. 35:112-115; 1993.
39. Eisenman, A. et al.: Nitric oxide inhalation for paraquat-induced lung injury. J. Toxicol. Clin. Toxicol. 36:575-584; 1998.
40. Nagao, M.: Production and toxicological application of anti-paraquat antibodies. Nippon Hoigaku Zasshi 43:134-147; 1989.
"Toxicology Brief" was contributed by R.B. Cope, BSc, BVSc, PhD, Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331. The department editor is Petra A. Volmer, DVM, MS, DABVT, DABT, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.