Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2012 Apr 11;294(2-3):94-103.
doi: 10.1016/j.tox.2012.02.005. Epub 2012 Feb 16.

A Role for Solvents in the Toxicity of Agricultural Organophosphorus Pesticides

Affiliations
Free PMC article
Comparative Study

A Role for Solvents in the Toxicity of Agricultural Organophosphorus Pesticides

Michael Eddleston et al. Toxicology. .
Free PMC article

Abstract

Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarter of global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase (AChE); however, AChE-reactivating drugs do not benefit poisoned humans. We therefore studied the role of solvent coformulants in OP toxicity in a novel minipig model of agricultural OP poisoning. Gottingen minipigs were orally poisoned with clinically relevant doses of agricultural emulsifiable concentrate (EC) dimethoate, dimethoate active ingredient (AI) alone, or solvents. Cardiorespiratory physiology and neuromuscular (NMJ) function, blood AChE activity, and arterial lactate concentration were monitored for 12h to assess poisoning severity. Poisoning with agricultural dimethoate EC40, but not saline, caused respiratory arrest within 30 min, severe distributive shock and NMJ dysfunction, that was similar to human poisoning. Mean arterial lactate rose to 15.6 [SD 2.8] mM in poisoned pigs compared to 1.4 [0.4] in controls. Moderate toxicity resulted from poisoning with dimethoate AI alone, or the major solvent cyclohexanone. Combining dimethoate with cyclohexanone reproduced severe poisoning characteristic of agricultural dimethoate EC poisoning. A formulation without cyclohexanone showed less mammalian toxicity. These results indicate that solvents play a crucial role in dimethoate toxicity. Regulatory assessment of pesticide toxicity should include solvents as well as the AIs which currently dominate the assessment. Reformulation of OP insecticides to ensure that the agricultural product has lower mammalian toxicity could result in fewer deaths after suicidal ingestion and rapidly reduce global suicide rates.

Figures

Fig. 1
Fig. 1
Cardiovascular and biochemical consequences of oral poisoning with dimethoate EC40 pesticide in Gottingen minipigs. (A) Systemic vascular resistance, (B) mean arterial pressure, (C) noradrenaline requirements, (D) arterial lactate concentration, and (E) red cell AChE activity in dimethoate EC40 (red squares) and saline placebo (blue rings) poisoned minipigs. Pralidoxime was administered from 2 h post poison administration. (F) Plasma concentration of dimethoate (brown squares), and its active metabolite omethoate (green circles), and of (G) the main solvent cyclohexanone (brown squares), and its metabolite cyclohexanol (green diamond), in minipigs poisoned with dimethoate EC40. The graphs show data over the 12 h of the study; mean ± SEM, n = 5–7 pigs. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Fig. 2
Fig. 2
Neuromuscular function in poisoned minipigs. Neuromuscular function shown by mechanomyography in pigs poisoned with saline placebo, dimethoate EC40, and dimethoate AI at baseline. NMJ dysfunction is clearly visible at 6 h in pigs poisoned by dimethoate EC40; NMJ function was normal throughout the study in the other pigs. Four stimuli were produced at 2 Hz as per standard TOF methodology (Fuchs-Buder et al., 2009).
Fig. 3
Fig. 3
Cardiovascular and biochemical consequences of oral poisoning with dimethoate EC40 pesticide, dimethoate AI, and/or cyclohexanone in Gottingen minipigs. (A and B) systemic vascular resistance (SVR), (C and D) noradrenaline requirements, (E and F) arterial lactate concentration, and (G and H) red cell AChE activity in groups of pigs poisoned with saline placebo (blue circles), dimethoate EC40 (red squares), dimethoate AI (green triangles), cyclohexanone (purple diamonds) and dimethoate AI plus cyclohexanone (blue-green diamonds). The saline and dimethoate EC40 data from Fig. 1 are repeated here to contrast the effect of different poisons. The graphs show data over the 12 h of the study; mean ± SEM, n = 3–6 pigs. The dot plots show the AUC and median for each group. Comparison of all groups with a Kruskal–Wallis test indicated significant differences for all four variables. The results of pairwise comparisons using the Mann–Whitney test are given in the figures (*P < 0.05 and **P < 0.01 compared to saline placebo; #P < 0.05 and ##P < 0.01 compared to dimethoate EC40). Abbreviations: cyclo, cyclohexanone; dim, dimethoate. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Fig. 4
Fig. 4
Pharmacokinetics of dimethoate and cyclohexanone, and their metabolites, in poisoned minipigs. Plasma (A) dimethoate and (B) omethoate concentrations in pigs poisoned with dimethoate EC40 (red squares), dimethoate AI (green triangles) and dimethoate AI and cyclohexanone together (blue-green diamonds). Plasma (C) cyclohexanone and (D) cyclohexanol concentrations in pigs poisoned with dimethoate EC40 (red squares), cyclohexanone (purple circles) and dimethoate AI and cyclohexanone together (blue-green diamonds). Plasma (E) dimethoate and (F) omethoate in pigs poisoned by dimethoate EC35 (purple triangles) compared to dimethoate EC40 (red squares) and dimethoate AI (green circles). The graphs show data over the 12 h of the study; mean ± SEM, n = 3–6 pigs. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Fig. 5
Fig. 5
Cardiovascular and biochemical consequences of oral poisoning with dimethoate EC35 pesticide versus saline placebo and dimethoate EC40 in Gottingen minipigs. (A) Systemic vascular resistance, (B) noradrenaline requirements, (C) arterial lactate concentration, and (D) red cell AChE activity in groups of pigs poisoned with saline placebo (blue circles), dimethoate EC40 (red squares), or dimethoate EC35 (purple triangles). The saline and dimethoate EC40 data from Fig. 1 are repeated here to contrast with the effect of dimethoate EC35. The graphs show data over the 12 h of the study; mean ± SEM, n = 4–6 pigs. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Similar articles

See all similar articles

Cited by 21 articles

See all "Cited by" articles

References

    1. Aurbek N., Thiermann H., Szinicz L., Eyer P., Worek F. Analysis of inhibition, reactivation and aging kinetics of highly toxic organophosphorus compounds with human and pig acetylcholinesterase. Toxicology. 2006;224:91–99. - PubMed
    1. Benjamini Y., Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B: Methodol. 1995;57:289–300.
    1. Bradberry S.M., Proudfoot A.T., Vale J.A. Glyphosate poisoning. Toxicol. Rev. 2004;23:159–167. - PubMed
    1. Buckley N.A., Eddleston M., Li Y., Bevan M., Robertson J. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst. Rev. 2011;2:CD005085. - PubMed
    1. Buckley N.A., Roberts D.M., Eddleston M. Overcoming apathy in research on organophosphate poisoning. BMJ. 2004;329:1231–1233. - PMC - PubMed

Publication types

MeSH terms

Feedback