Toxicology of Impurities in Malathion: Potentiation of Malathion Toxicity and Lung Toxicity Caused by Trialkyl Phosphorothioates

  • W. N. Aldridge
  • D. Dinsdale
  • B. Nemery
  • R. D. Verschoyle


Organophosphorus compounds were first synthesised in the 1930s and because of their high toxicity were initially considered for use as chemical warfare agents. Since that time they have been developed for peaceful purposes and their effects on biological systems have been intensively studied. They are well known for their inhibition of acetylcholinesterase and there is considerable knowledge on their structure-activity relationships. The variety of directly toxic compounds is very large. Many compounds, although inactive in vitro, are metabolised in vivo to active inhibitors of esterases; this has greatly extended the range of toxic organophosphorus structures. It is not surprising therefore that amongst these structures, compounds are found with biological activities other than, and in addition to, those depending on inactivation of acetylcholinesterase. The range of structures and biological reactions are illustrated in figures 11.1 and 11.2.


Liver Slice Organophosphorus Compound Carbon Disulphide Lung Slice Neuropathy Target Esterase 
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  1. Aldridge, W. N. (1981). Organophosphorus compounds: molecular basis for their biological properties. Sci. Progr. Oxf., 67, 131–47Google Scholar
  2. Aldridge, W. N. and Nemery, B. (1984). Toxicology of trialkyl phosphorothioates with particular reference to lung toxicity. Fund. appl. Toxicol., 4, S215–S223Google Scholar
  3. Aldridge, W. N., Miles, J. W., Mount, D. L. and Verschoyle, R. D (1979). The toxicological properties of impurities in malathion. Arch. Toxicol., 42, 95–106PubMedCrossRefGoogle Scholar
  4. Aldridge, W. N., Verschoyle, R. D. and Peal, J. A. (1984). OSS-Trimethyl phos-phorodithioate and OOS-triethyl phosphorothioate: pharmacokinetics in rats and effect of pretreatment with compounds affecting drug processing systems. Pest. Biochem. Physiol., 21, 265–74CrossRefGoogle Scholar
  5. Aldridge, W. N., Grasdalen, H., Aarstad, K., Street, B. W. and Norkov, T. (1985a). Trialkyl phosphorothioates and glutathione S-transferases. Chem. Biol. Interactions, 54, 243–56CrossRefGoogle Scholar
  6. Aldridge, W. N., Dinsdale, D., Nemery, B. and Verschoyle, R. D. (1985b). Some aspects of the toxicology of trimethyl and triethyl phosphorothioates. Fund. appl. Toxicol., 5, S47–S60Google Scholar
  7. Ali, F. A. F. and Fukuto, T. R. (1982). Toxicity of OOS-trialkyl phosphorothioates in the rat. J. Agric. Food Chem., 30, 126–30PubMedCrossRefGoogle Scholar
  8. Bailey, E., Farmer, P. B. and Lamb, J. H. (1980). The enantiomer as internal standard for the quantitation of the alkylated amino acid S-methyl-L-cysteine in haemoglobin by gas chromatography-chemical ionisation mass spectrometry with single ion detection. J. Chromatogr., 200, 145–52PubMedCrossRefGoogle Scholar
  9. Bailey, E., Peal, J. A. and Verschoyle, R. D. (1981a). The determination of OSS-trim ethyl phosphorodithioate in the plasma and various tissues of rats using high-resolution gas chromatography with nitrogen-phosphorus detection. J. Chromatogr., 219, 285–90PubMedCrossRefGoogle Scholar
  10. Bailey, E., Connors, T. A., Farmer, P. B., Gorf, S. M. and Rickard, J. (1981b). Methylation of cysteine in haemoglobin following exposure to methylating agents. Cancer Res., 41, 2514–17PubMedGoogle Scholar
  11. Baker, E. L., Zack, M., Miles, J. W., Alderman, L., Warren, McW., Dobbin, R. D., Miller, S. and Teeters, W. R. (1978). Epidemic malathion poisoning in Pakistan malaria workers. Lancet, I, 31–3Google Scholar
  12. Buckpitt, A. R. and Warren, D. L. (1983). Evidence for hepatic formation, export and covalent binding of reactive naphthalene metabolites in extra hepatic tissues in vivo. J. Pharmacol exp. Ther., 225, 8–15Google Scholar
  13. Cain, K. and Clothier, B. (1986). The identification, characterisation and partial purification of two separate carboxylesterases in guinea pig serum. Human Toxicology, Abstract to British Toxicology Society, September 1985Google Scholar
  14. Cain, K., Reiner, E. and Williams, D. G. (1983). The identification and characterisation of two separate carboxylesterases in guinea pig serum. Biochem. J., 215, 91–9PubMedPubMedCentralCrossRefGoogle Scholar
  15. Casida, J. E. (1970). Mixed function oxidases involvement in the biochemistry of insecticide synergists. J. Agric. Food Chem., 18, 753–72PubMedCrossRefGoogle Scholar
  16. Casida, J. E. (1984). Oxidative bioactivation of acetylcholinesterase inhibitors with emphasis on S-alkyl phosphorothiolate pesticides. In: Cholinesterases, Walter de Gruyter & Co., Berlin, pp. 427–40Google Scholar
  17. Casida, J. E., Baron, R. L., Eto, M. and Engel, J. L. (1963). Potentiation and neuro-toxicity induced by certain organophosphates. Biochem. Pharmacol., 12, 73–83PubMedCrossRefGoogle Scholar
  18. Clothier, B. and Cain, K. (1986). Kinetic properties of two separate carboxylesterases isolated from guinea pig serum. Human Toxicology. Abstract to British Toxicology Society, September 1985Google Scholar
  19. Clothier, B., Johnson, M. K. and Reiner, E. (1981). Interaction of some trialkyl phosphorothiolates with acetylcholinesterase. Characterisation of inhibition, aging and reactivation. Biochim. Biophys. Acta, 660, 306–16PubMedCrossRefGoogle Scholar
  20. Dauterman, W. C. and Main, A. R. (1966). Relationship between acute toxicity and in vitro inhibition and hydrolysis of a series of carbalkoxy homologs of Malathion. Toxicol. appl. Pharmacol., 9, 408–17PubMedCrossRefGoogle Scholar
  21. De Jong, L. P. A., Wolring, G. Z. and Benschop, H. P. (1982). Reactivation of acetylcholinesterase inhibited by methamidophos and analogous (Di)methyl-phosphoramidates. Arch. Toxicol., 49, 175–83PubMedCrossRefGoogle Scholar
  22. Dinsdale, D., Verschoyle, R. D. and Cabrai, J. R. P. (1982). Cellular responses to trialkyl phosphorothioate induced injury in rat lung. Arch. Toxicol., 51, 79–89CrossRefGoogle Scholar
  23. Dinsdale, D., Verschoyle, R. D. and Ingham, J. E. (1984). Ultrastructural change in rat Clara cells induced by a single dose of OSS-trimethyl phosphorodithioate. Arch. Toxicol., 56, 59–65PubMedCrossRefGoogle Scholar
  24. Eto, M., Okabe, S., Ozoe, Y. and Mackawa, K. (1977). Oxidative activation of OS-dimethyl phosphoramidothiolate. Pestic. Biochem. Physiol., 7, 367–77CrossRefGoogle Scholar
  25. Frawley, J. P., Fuyat, H. N., Hajan, E. C., Blake, J. R. and Fitzhugh, O. G. (1957). Marked potentiation in mammalian toxicity from simultaneous administration of two anticholinesterase compounds. J. Pharmacol., 121, 96–106Google Scholar
  26. Gandy, J., Ali, F. A. F., Hasegawa, L. and Imamura, T. (1984). Morphological alterations of rat lung bronchiolar epithelium produced by various trialkyl phosphorothioates. Toxicology, 32, 37–46PubMedCrossRefGoogle Scholar
  27. Hammond, P. S., Badawy, S. M. A., March, R. B. and Fukuto, T. R. (1982). Delayed acute toxicity of OSS-trimethyl phosphorodithioate and OOS-trimethyl phos-phorothioate to the rat. Pestic. Biochem. Physiol., 8, 90–100CrossRefGoogle Scholar
  28. Imamura, T., Gandy, J., Fukuto, T. R. and Talbot, P. (1983). An impurity of malathion alters the morphology of rat lung bronchiolar epithelium. Toxicology, 26, 73–9PubMedCrossRefGoogle Scholar
  29. Jakoby, W. B., Ketterer, B. and Mannervik, B. (1984). Glutathione transferases: Nomenclature. Biochem. Pharmacol., 33, 2539–40PubMedCrossRefGoogle Scholar
  30. James, R. C. and Harbison, R. D. (1982). Hepatic glutathione and hepatotoxicity. Effects of cytochrome P-450 complexing compounds SKF 525-A, 1-αacetyl methadol (LAAM), nor LAAM and piperonyl butoxide. Biochem. Pharmacol., 31, 1829–35PubMedCrossRefGoogle Scholar
  31. Kamienski, F. X. and Casida, J. E. (1970). Importance of demethylenation in the metabolism in vivo and in vitro of methylene dioxyphenyl synergists and related compounds in mammals. Biochem. Pharmacol., 19, 91–112PubMedCrossRefGoogle Scholar
  32. Lee, S. G. K. and Fukuto, T. R. (1982). Inhibition of rat liver and plasma carboxyl-esterases by impurities present in technical phenthoate. J. Toxicol. Environ. Hlth, 10, 717–28CrossRefGoogle Scholar
  33. Main, A. R. and Braid, P. E. (1962). Hydrolysis of malathion by aliesterases in vitro and in vivo. Biochem. J., 84, 255–63Google Scholar
  34. Main, A. R. and Hastings, F. L. (1966). A comparison of acylation, phosphorylation and binding in related substrates and inhibitors of serum cholinesterase. Biochem. J., 101, 584–90PubMedPubMedCentralCrossRefGoogle Scholar
  35. Malik, J. K. and Summer, K. H. (1982). Toxicity and metabolism of malathion and its impurities in isolated rat hepatocytes: role of glutathione. Toxicol. appl. Pharmacol., 66, 69–76PubMedCrossRefGoogle Scholar
  36. Mallipudi, N. M., Umetsu, N., Toia, R. F., Talcott, R. E. and Fukuto, T. R. (1979). Toxicity of OOS-Trimethyl and Triethyl Phosphorothioate to the rat. J. Agric. Food Chem., 27, 463–6PubMedCrossRefGoogle Scholar
  37. Mallipudi, N. M., Talcott, R. E., Ketterman, A. and Fukuto, T. R. (1980). Properties and inhibition of rat malathion carboxylesterases. J. Toxicol. Environ. Hlth, 6, 585–96CrossRefGoogle Scholar
  38. Marshall, R. S. and Wilkinson, C. F. (1973). The interaction of insecticide synergists with non-enzymic model systems. Pestic. Biochem. Physiol., 2, 425–36CrossRefGoogle Scholar
  39. Miles, J. W., Mount, D. L., Staiger, M. A. and Teeters, W. R. (1979). The S-methyl isomer content of stored malathion and fenitrothion water-dispersible powders and its relationship to toxicity. J. Agric. Food Chem., 27, 421–5PubMedCrossRefGoogle Scholar
  40. Miles, J. W., Mount, D. L. and Churchill, F. C. (1980). The effect of storage on the formation of minor components in malathion powders. CIPAC Proceedings Symposium (ed. F. Sanchez-Rasero), Series 2, pp. 176–92Google Scholar
  41. Murphy, S. D. and DuBois, K. P. (1957). Quantitative measurement of inhibition of the enzymic detoxification of malathion by EPN (ethyl p-nitrophenyl thiono-benzenephosphonate). Proc. Soc. exp. Biol. Med., 96, 813–18PubMedCrossRefGoogle Scholar
  42. Neal, R. A. (1985). Thiono-sulphur compounds. In: Bioactivation of Foreign Compounds (ed. M. W. Anders), Academic Press, Orlando, pp. 519–37Google Scholar
  43. Nemery, B. (1986). Ph.D. thesis. Council for National Academic Awards, London.Google Scholar
  44. Nemery, B., Smith, L. L. and Aldridge, W. N. (1986). Assessment of cell selectivity in toxic lung damage by simultaneous measurement of putrescine and 5-hydroxy-tryptamine uptake in rat lung slices: OSS-trimethyl phosphorodithioate and other pneumotoxins. Submitted for publicationGoogle Scholar
  45. Patel, J. M., Harper, C. and Drew, R. T. (1978). The biotransformation of p-xylene to a toxic aldehyde. Drug Metab. Dis., 6, 368–74Google Scholar
  46. Patel, J. M., Wolf, C. R. and Philpot, R. M. (1979). Interaction of 4-methylbenz-aldehyde with rabbit pulmonary cytochrome P-450 in the intact animal, micro-somes and purified systems. Biochem. Pharmacol., 28, 2031–6PubMedCrossRefGoogle Scholar
  47. Philpot, R. M. and Hodgson, E. (1972). Effect of piperonyl butoxide concentration on the formation of cytochrome P-450 difference spectra in hepatic microsomes from mice. Molec. Pharmacol., 8, 204–14Google Scholar
  48. Ryan, D. L. and Fukuto, T. R. (1984). The effect of isomalathion and OSS-tri-methyl phosphorodithioate on the in vivo metabolism of malathion in rats. Pestic. Biochem. Physiol., 21, 349–57CrossRefGoogle Scholar
  49. Seawright, A. A., Hrdlika, J. and De Matteis, F. (1976). The hepatotoxicity of O, O-diethyl O-phenyl phosphorothionate (SVl) for the rat. Brit. J. exp. Pathol., 57, 16–22Google Scholar
  50. Smith, L. L. (1982). The identification of an accumulation system for diamines and polyamines into the lung and its relevance to paraquat toxicity. Arch. Toxicol. (Suppl. 5), 1–14Google Scholar
  51. Smith, L. L., Cohen, G. M. and Aldridge, W. N. (1986). Morphological and biochemical correlates of chemical induced injury in the lung. A discussion. Arch. Toxicol., 58, 214–18PubMedCrossRefGoogle Scholar
  52. Talcott, R. E., Mallipudi, N. M. and Fukuto, T. R. (1977). Malathion carboxyl-esterase titer and its relationship to malathion toxicity. Toxicol. appl. Pharmacol., 50, 501–4CrossRefGoogle Scholar
  53. Talcott, R. E., Mallipudi, N.M., Umetsu, N. and Fukuto, T. R. (1979a). Inactivation of esterases by impurities isolated from technical malathion. Toxicol. appl. Pharmacol., 49, 107–12PubMedCrossRefGoogle Scholar
  54. Talcott, R. E., Denk, H. and Mallipudi, N. M. (1979b). Malathion carboxylesterase activity in human liver and its inactivation by isomalathion. Toxicol. appl. Pharmacol., 49, 373–6PubMedCrossRefGoogle Scholar
  55. Toia, R. F., March, R. B., Umetsu, N., Mallipudi, N. M., Allahyari, R. and Fukuto, T. R. (1980). Identification and toxicological evaluation of impurities in technical malathion and fenthion. J. Agric. Food Chem., 28, 599–604PubMedCrossRefGoogle Scholar
  56. Umetsu, N., Grose, F. H., Allahyari, R., Abu-El-Haj, S. and Fukuto, T. R. (1977). Effect of impurities on the mammalian toxicity of technical malathion and acephate. J. Agric. Food Chem., 25, 946–53PubMedCrossRefGoogle Scholar
  57. Umetsu, N., Toia, R. F., Mallipudi, N. M., March, R. B. and Fukuto, T. R. (1979). Novel antagonistic effect to the toxicity in the rat of O, O, S-trimethylphosphoro-thioate by its phosphorothionate isomer. J. Agric. Food Chem., 27, 1423–5PubMedCrossRefGoogle Scholar
  58. Umetsu, N., Mallipudi, N. M., Toia, R. F., March, R. B. and Fukuto, T. R. (1981). Toxicological properties of phosphorothioate and related esters present as impurities in technical organophosphorus insecticides. J. Toxicol. Environ. Hlth, 7, 481–97CrossRefGoogle Scholar
  59. Verschoyle, R. D. and Cabrai, J. R. P. (1982). Investigation of the acute toxicity of some trimethyl and triethyl phosphorothioates with particular reference to those causing lung damage. Arch. Toxicol., 51, 221–31Google Scholar
  60. Verschoyle, R. D., Aldridge, W. N. and Cabrai, J. R. P. (1980). Toxicology of trimethyl and triethyl phosphorothioates. In: Mechanisms of Toxicity and Hazard Evaluation (ed. B. Holmstedt, R. Lauwerys, M. Mercier and M. Roberfroid), Elsevier/North Holland Biomedical Press, Amsterdam, pp. 631–4Google Scholar
  61. Verschoyle, R. D., Reiner, E., Bailey, E. and Aldridge, W. N. (1982). Dimethyl-phosphorothioates. Reaction with malathion and effect on malathion toxicity. Arch. Toxicol., 49, 293–301PubMedCrossRefGoogle Scholar
  62. Wilkinson, C. F. and Hicks, L. T. (1969). Microsomal metabolism of the 1,3-benzo-dioxole ring and its probable significance in synergistic action. J. Agric. Food Chem., 17, 829–36CrossRefGoogle Scholar
  63. Wing, K. D., Glickman, A. H. and Casida, J. E. (1983). Oxidative bioactivation of S-alkyl phosphorothiolate pesticides: stereospecificity of profenofos insecticide activation. Science, N. Y., 219, 63–5CrossRefGoogle Scholar
  64. Wing, K. D., Glickman, A. H. and Casida, J. E. (1984). Phosphorothiolate pesticides and related compounds: oxidative bioactivation and aging of the inhibited acetylcholinesterase. Pestic. Biochem. Physiol, 21, 22–30CrossRefGoogle Scholar
  65. World Health Organisation (1979). Specification for pesticides used in public health. Geneva, pp. 102–14Google Scholar

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© W. N. Aldridge, D. Dinsdale, B. Nemery and R. D. Verschoyle 1987

Authors and Affiliations

  • W. N. Aldridge
  • D. Dinsdale
  • B. Nemery
  • R. D. Verschoyle

There are no affiliations available

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