Toxicological Reviews

, Volume 23, Issue 2, pp 65–73 | Cite as

Poisoning Due to Chlorophenoxy Herbicides

  • Sally M. Bradberry
  • Alex T. Proudfoot
  • J. Allister Vale
Review Article

Abstract

Chlorophenoxy herbicides are used widely for the control of broad-leaved weeds. They exhibit a variety of mechanisms of toxicity including dose-dependent cell membrane damage, uncoupling of oxidative phosphorylation and disruption of acetylcoenzyme A metabolism. Following ingestion, vomiting, abdominal pain, diarrhoea and, occasionally, gastrointestinal haemorrhage are early effects. Hypotension, which is common, is due predominantly to intravascular volume loss, although vasodilation and direct myocardial toxicity may also contribute. Coma, hypertonia, hyperreflexia, ataxia, nystagmus, miosis, hallucinations, convulsions, fasciculation and paralysis may then ensue. Hypoventilation is commonly secondary to CNS depression, but respiratory muscle weakness is a factor in the development of respiratory failure in some patients. Myopathic symptoms including limb muscle weakness, loss of tendon reflexes, myotonia and increased creatine kinase activity have been observed. Metabolic acidosis, rhabdomyolysis, renal failure, increased aminotransferase activities, pyrexia and hyperventilation have been reported. Substantial dermal exposure to 2,4-dichlorophenoxy acetic acid (2,4-D) has led occasionally to systemic features including mild gastrointestinal irritation and progressive mixed sensorimotor peripheral neuropathy. Mild, transient gastrointestinal and peripheral neuromuscular symptoms have occurred after occupational inhalation exposure.

In addition to supportive care, urine alkalinization with high-flow urine output will enhance herbicide elimination and should be considered in all seriously poisoned patients. Haemodialysis produces similar herbicide clearances to urine alkalinization without the need for urine pH manipulation and the administration of substantial amounts of intravenous fluid in an already compromised patient.

References

  1. 1.
    Litovitz TL, Klein-Schwartz W, Caravati EM, et al. 1998 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance system. Am J Emerg Med 1999; 17: 435–87PubMedCrossRefGoogle Scholar
  2. 2.
    Litovitz TL, Klein-Schwartz W, White S, et al. 1999 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance system. Am J Emerg Med 2000; 18: 517–74PubMedCrossRefGoogle Scholar
  3. 3.
    Litovitz TL, Klein-Schwartz W, White S, et al. 2000 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001; 19: 337–95PubMedCrossRefGoogle Scholar
  4. 4.
    Litovitz TL, Klein-Schwartz W, Rodgers Jr GC, et al. 2001 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2002; 20: 391–452PubMedCrossRefGoogle Scholar
  5. 5.
    Watson WA, Litovitz TL, Rodgers Jr GC, et al. 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2003; 21: 353–421PubMedCrossRefGoogle Scholar
  6. 6.
    Casey P, Vale JA. Deaths from pesticide poisoning in England and Wales: 1945–1989. Hum Exp Toxicol 1994; 13: 95–101PubMedCrossRefGoogle Scholar
  7. 7.
    Bradberry SM, Watt BE, Proudfoot AT, et al. Mechanisms of toxicity, clinical features, and management of acute chlorophenoxy herbicide poisoning: a review. J Toxicol Clin Toxicol 2000; 38: 111–22PubMedCrossRefGoogle Scholar
  8. 8.
    Sastry BVR, Clark CP, Janson VE. Formation of 2:4-dichlorophenoxy-acetylcholine (2:4-D-ACh) in human placenta and fetal growth retardation [abstract]. Neurotoxicology 1995; 16: 763Google Scholar
  9. 9.
    Sastry BVR, Janson VE, Clark CP, et al. Cellular toxicity of 2,4,5-trichlorophenoxyacetic acid: formation of 2,4,5-trichlorophenoxyacetylcholine. Cell Mol Biol 1997; 43: 549–57PubMedGoogle Scholar
  10. 10.
    Sauerhoff MW, Braun WH, Blau GE, et al. The fate of 2,4-dichlorophenoxyacetic acid (2,4-D) following oral administration to man. Toxicology 1977; 8: 3–11PubMedCrossRefGoogle Scholar
  11. 11.
    Arnold EK, Beasley VR. The pharmacokinetics of chlorinated phenoxy acid herbicides: a literature review. Vet Hum Toxicol 1989; 31: 121–5PubMedGoogle Scholar
  12. 12.
    Feldmann RJ, Maibach HI. Percutaneous penetration of some pesticides and herbicides in man. Toxicol Appl Pharmacol 1974; 28: 126–32PubMedCrossRefGoogle Scholar
  13. 13.
    Harris SA, Solomon KR. Percutaneous penetration of 2,4-dichlorophenoxyacetic acid and 2,4-D dimethylamine salt in human volunteers. J Toxicol Environ Health 1992; 36: 233–40PubMedCrossRefGoogle Scholar
  14. 14.
    Grover R, Cessna AJ, Muir NI, et al. Factors affecting the exposure of ground-rig applicators to 2,4-D dimethylamine salt. Arch Environ Contam Toxicol 1986; 15: 677–86PubMedCrossRefGoogle Scholar
  15. 15.
    Kohli JD, Khanna RN, Gupta BN, et al. Absorption and excretion of 2,4-dichlorophenoxyacetic acid in man. Xenobiotica 1974; 4: 97–100PubMedCrossRefGoogle Scholar
  16. 16.
    Rosso SB, Gonzalez M, Bagatolli LA, et al. Evidence of a strong interaction of 2,4-dichlorophenoxyacetic acid herbicide with human serum albumin. Life Sci 1998; 63: 2343–51PubMedCrossRefGoogle Scholar
  17. 17.
    Koschier FJ, Hong SK, Berndt WO. Serum protein and renal tissue binding of 2,4,5-trichlorophenoxyacetic acid. Toxicol Appl Pharmacol 1979; 49: 237–44PubMedCrossRefGoogle Scholar
  18. 18.
    Mason RW. The binding of some chlorophenoxy acids to bovine serum albumin in vitro. Proc Univ Otago Med Sch 1972; 50: 61–3Google Scholar
  19. 19.
    Piper WN, Rose JQ, Leng ML, et al. The fate of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) following oral administration in rats and dogs. Toxicol Appl Pharmacol 1973; 26: 339–51PubMedCrossRefGoogle Scholar
  20. 20.
    Brahmi N, Ben Mokhtar H, Thabet H, et al. 2,4-D (chlorophenoxy) herbicide poisoning. Vet Hum Toxicol 2003; 45: 321–2PubMedGoogle Scholar
  21. 21.
    Herbich J, Machata G. Vergiftung mit 2,4-dichlorphenoxyessigsäure (2,4-D). Beitr Gerichtl Med 1963; 22: 133–9Google Scholar
  22. 22.
    Nielsen K, Kæmpe B, Jensen-Holm J. Fatal poisoning in man by 2,4-dichlorophenoxyacetic acid (2,4-D): determination of the agent in forensic materials. Acta Pharmacol Toxicol 1965; 22: 224–34CrossRefGoogle Scholar
  23. 23.
    Jones DIR, Knight AG, Smith AJ. Attempted suicide with herbicide containing MCPA. Arch Environ Health 1967; 14: 363–6PubMedGoogle Scholar
  24. 24.
    Dudley Jr AW, Thapar NT. Fatal human ingestion of 2,4-D, a common herbicide. Arch Pathol 1972; 94: 270–5PubMedGoogle Scholar
  25. 25.
    Davies MK, Jung RT. Lung involvement with ‘Verdone’. Lancet 1976; II: 370CrossRefGoogle Scholar
  26. 26.
    Prescott LF, Park J, Darrien I. Treatment of severe 2,4-D and mecoprop intoxication with alkaline diuresis. Br J Clin Pharmacol 1979; 7: 111–6PubMedCrossRefGoogle Scholar
  27. 27.
    Fraser AD, Isner AF, Perry RA. Toxicologic studies in a fatal overdose of 2,4-D, mecoprop, and dicamba. J Forensic Sci 1984; 29: 1237–41PubMedGoogle Scholar
  28. 28.
    Meulenbelt J, Zwaveling JH, van Zoonen P, et al. Acute MCPP intoxication: report of two cases. Hum Toxicol 1988; 7: 289–92PubMedCrossRefGoogle Scholar
  29. 29.
    Kancir CB, Andersen C, Olesen AS. Marked hypocalcemia in a fatal poisoning with chlorinated phenoxy acid derivatives. J Toxicol Clin Toxicol 1988; 26: 257–64PubMedCrossRefGoogle Scholar
  30. 30.
    Flanagan RJ, Meredith TJ, Ruprah M, et al. Alkaline diuresis for acute poisoning with chlorophenoxy herbicides and ioxynil. Lancet 1990; 335: 454–8PubMedCrossRefGoogle Scholar
  31. 31.
    Friesen EG, Jones GR, Vaughan D. Clinical presentation and management of acute 2,4-D oral ingestion. Drug Saf 1990; 5: 155–9PubMedCrossRefGoogle Scholar
  32. 32.
    Keller T, Skopp G, Wu M, et al. Fatal overdose of 2,4-dichlorophenoxyacetic acid (2,4-D). Forensic Sci Int 1994; 65: 13–8PubMedCrossRefGoogle Scholar
  33. 33.
    Jorens PG, Heytens L, De Paep RJ, et al. A 2,4-dichlorophenoxyacetic acid induced fatality. Eur J Emerg Med 1995; 2: 52–5PubMedCrossRefGoogle Scholar
  34. 34.
    Schmoldt A, Iwersen S, Schlüter W. Massive ingestion of the herbicide 2-methyl-4-chlorophenoxyacetic acid (MCPA). J Toxicol Clin Toxicol 1997; 35: 405–8PubMedCrossRefGoogle Scholar
  35. 35.
    Lankosz-Lauterbach J, Kaczor Z, Kacinski M, et al. Severe polyneuropathy in a 3-year-old child after dichlorophenoxyacetic herbicide — Chwastox — intoxication, treated successfully with plasmapheresis (PF). Przegl Lek 1997; 54: 750–2PubMedGoogle Scholar
  36. 36.
    Berthelot-Moritz F, Daudenthun I, Goullé J-P, et al. Severe intoxication following ingestion of 2,4-D and MCPP. Intensive Care Med 1997; 23: 356–7PubMedGoogle Scholar
  37. 37.
    Durakovic Z, Durakovic A, Durakovic S, et al. Poisoning with 2,4-dichlorophenoxyacetic acid treated by hemodialysis. Arch Toxicol 1992; 66: 518–21PubMedCrossRefGoogle Scholar
  38. 38.
    Popham RD, Davies DM. A case of MCPA poisoning. BMJ 1964; I: 677–8CrossRefGoogle Scholar
  39. 39.
    Johnson HRM, Koumides O. A further case of MCPA poisoning. BMJ 1965; 2: 629–30PubMedCrossRefGoogle Scholar
  40. 40.
    de Larrard J, Barbaste M. Intoxication suicidaire mortelle agro-chimique à l’hormone desherbante 2,4-D. Arch Mal Prof Med Trav Secur Soc 1969; 30: 434Google Scholar
  41. 41.
    Geldmacher-von Mallinckrodt M, Lautenbach L. Zwei tödliche Vergiftungen (Suicid) mit chlorierten Phenoxyessigsäuren (2,4-D und MCPA). Arch Toxicol 1966; 21: 261–78CrossRefGoogle Scholar
  42. 42.
    Smith RA, Lewis D. Suicide by ingestion of 2,4-D: a case history demonstrating the prudence of using GC/MS as an investigative rather than a confirmatory tool. Vet Hum Toxicol 1987; 29: 259–61PubMedGoogle Scholar
  43. 43.
    Wells WDE, Wright N, Yeoman WB. Clinical features and management of poisoning with 2,4-D and mecoprop. J Toxicol Clin Toxicol 1981; 18: 273–6CrossRefGoogle Scholar
  44. 44.
    Curry AS. Twenty-one uncommon cases of poisoning. BMJ 1962; 1: 687–9PubMedCrossRefGoogle Scholar
  45. 45.
    Nilsson L-G, Heijman L. Akut grav intoxikation med ogråsmedel. Opuse Med 1972; 17: 131–4Google Scholar
  46. 46.
    O’Reilly JF. Prolonged coma and delayed peripheral neuropathy after ingestion of phenoxyacetic acid weedkillers. Postgrad Med J 1984; 60: 76–7PubMedCrossRefGoogle Scholar
  47. 47.
    Durakovic Z, Gasparovic V. Otrovanje 2,4-diklorfenoksioctenom kiselinom praceno stanjem kome u bolesnika starije dobi. Arh Hig Rada Toksikol 1988; 39: 255–8PubMedGoogle Scholar
  48. 48.
    Brandt MR. Herbatox poisoning. Brief review and report of a new case [in Danish]. Ugeskr Laeger 1971; 133: 500–3PubMedGoogle Scholar
  49. 49.
    Prescott LF, Illingworth RN, Critchley JAJH, et al. Intravenous N-acetylcysteine: the treatment of choice in paracetamol poisoning. BMJ 1979; 2: 1097–100PubMedCrossRefGoogle Scholar
  50. 50.
    Mattsson JL, Eisenbrandt DL. The improbable association between the herbicide 2,4-D and polyneuropathy. Biomed Environ Sci 1990; 3: 43–51PubMedGoogle Scholar
  51. 51.
    Berkley MC, Magee KR. Neuropathy following exposure to a dimethylamine salt of 2,4-D. Arch Intern Med 1963; 111: 351–2PubMedCrossRefGoogle Scholar
  52. 52.
    Goldstein NP, Jones PH, Brown JR. Peripheral neuropathy after exposure to an ester of dichlorophenoxyacetic acid. JAMA 1959; 171: 1306–9CrossRefGoogle Scholar
  53. 53.
    Todd RL. A case of 2,4-D intoxication. J Iowa Med Soc 1962; 52: 663–4PubMedGoogle Scholar
  54. 54.
    Tsapko VG. On the probable harmful action of the herbicide 2,4-D on agricultural workers [in Russian]. Gig Sanit 1966; 31: 79–80PubMedGoogle Scholar
  55. 55.
    Kolny H, Kita K. Zatrucie Aminopielikiem D. Med Pr 1978; 29: 61–3PubMedGoogle Scholar
  56. 56.
    Paggiaro PL, Martino E, Mariotti S. Su un caso di intossicazione da acido 2,4-diclorofenossiacetico. Med Lav 1974; 65: 128–35PubMedGoogle Scholar
  57. 57.
    Bezuglyi VP, Fokina KV, Komarova LI, et al. Clinical manifestations of long-term sequels of acute poisoning with 2,4-dichlorophenoxyacetic acid [in Russian]. Gig Tr Prof Zabol 1979; (3): 47–8Google Scholar
  58. 58.
    McMillin RB, Samples JR. Iritis after herbicide exposure. Am J Ophthalmol 1985; 99: 726–7PubMedGoogle Scholar
  59. 59.
    Marrs TC, Ballantyne B, editors. Pesticide toxicology and international regulation. Chichester: John Wiley & Sons, 2004Google Scholar
  60. 60.
    Garabrant DH, Philbert MA. Review of 2,4-dichlorophenoxyacetic acid (2,4-D) epidemiology and toxicology. Crit Rev Toxicol 2002; 32: 233–57PubMedCrossRefGoogle Scholar
  61. 61.
    Hoar SK, Blair A, Holmes FF, et al. Agricultural herbicide use and risk of lymphoma and soft-tissue sarcoma. JAMA 1986; 256: 1141–7PubMedCrossRefGoogle Scholar
  62. 62.
    Hardell L, Eriksson M. A case-control study of non-Hodgkin lymphoma and exposure to pesticides. Cancer 1999; 85: 1353–60PubMedCrossRefGoogle Scholar
  63. 63.
    Hooiveld M, Heederik DJJ, Kogevinas M, et al. Second follow-up of a Dutch cohort occupationally exposed to phenoxy herbicides, chlorophenols, and contaminants. Am J Epidemiol 1998; 147: 891–901PubMedCrossRefGoogle Scholar
  64. 64.
    Vineis P, Faggiano F, Tedeschi M, et al. Incidence rates of lymphomas and soft-tissue sarcomas and environmental measurements of phenoxy herbicides. J Natl Cancer Inst 1991; 83: 362–3PubMedCrossRefGoogle Scholar
  65. 65.
    International Agency for Research on Cancer Working Group, Johnson ES, Winkelmann R, et al. Phenoxy acid herbicides and contaminants: description of the IARC International Register of Workers. Am J Ind Med 1990; 18: 39–45CrossRefGoogle Scholar
  66. 66.
    Saracci R, Kogevinas M, Bertazzi P-A, et al. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 1991; 338: 1027–32PubMedCrossRefGoogle Scholar
  67. 67.
    Lynge E. A follow up study of cancer incidence among workers in manufacture of phenoxy herbicides in Denmark. Br J Cancer 1985; 52: 259–70PubMedCrossRefGoogle Scholar
  68. 68.
    Coggon D, Pannett B, Winter P. Mortality and incidence of cancer at four factories making phenoxy herbicides. Br J Ind Med 1991; 48: 173–8PubMedGoogle Scholar
  69. 69.
    Green LM. A cohort mortality study of forestry workers exposed to phenoxy acid herbicides. Br J Ind Med 1991; 48: 234–8PubMedGoogle Scholar
  70. 70.
    Burns CJ. Amyotrophic lateral sclerosis and occupational exposure to 2,4-dichlorophenoxyacetic acid: Burns replies [letter]. Occup Environ Med 2001; 58: 609–10CrossRefGoogle Scholar
  71. 71.
    Lynge E. Cancer incidence in Danish phenoxy herbicide workers, 1947–1993. Environ Health Perspect 1998; 106: 683–8PubMedGoogle Scholar
  72. 72.
    Wiklund K, Lindefors BM, Holm LE. Risk of malignant lymphoma in Swedish agricultural and forestry workers. Br J Ind Med 1988; 45: 19–24PubMedGoogle Scholar
  73. 73.
    Kogevinas M, Becher H, Benn T, et al. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins: an expanded and updated international cohort study. Am J Epidemiol 1997; 145: 1061–75PubMedCrossRefGoogle Scholar
  74. 74.
    Fleming LE, Bean JA, Rudolph M, et al. Cancer incidence in a cohort of licensed pesticide applicators in Florida. J Occup Environ Med 1999; 41: 279–88PubMedCrossRefGoogle Scholar
  75. 75.
    Asp S, Riihimäki V, Hernberg S, et al. Mortality and cancer morbidity of Finnish chlorophenoxy herbicide applicators: an 18-year prospective follow-up. Am J Ind Med 1994; 26: 243–53PubMedCrossRefGoogle Scholar
  76. 76.
    Riihimäki V, Asp S, Hernberg S. Mortality of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid herbicide applicators in Finland: first report of an ongoing prospective cohort study. Scand J Work Environ Health 1982; 8: 37–42PubMedCrossRefGoogle Scholar
  77. 77.
    Grover R, Smith AE. Adsorption studies with the acid and dimethylamine forms of 2,4-D and dicamba. Can J Soil Sci 1974; 54: 179–86CrossRefGoogle Scholar
  78. 78.
    Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. J Toxicol Clin Toxicol 2004; 42: 1–26PubMedCrossRefGoogle Scholar
  79. 79.
    Park J, Darrien I, Prescott LF. Pharmacokinetic studies in severe intoxication with 2,4-D and mecoprop. Proc Eur Soc Toxicol 1977; 18: 154–5Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Sally M. Bradberry
    • 1
  • Alex T. Proudfoot
    • 1
  • J. Allister Vale
    • 1
  1. 1.National Poisons Information Service (Birmingham Centre) and West Midlands Poisons UnitCity HospitalBirminghamUK

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