Skip to main content

Advertisement

SpringerLink
Log in

Carbofuran self-poisoning: forensic and analytic investigations in twins and literature review

  • Case Report
  • Published:
International Journal of Legal Medicine Aims and scope Submit manuscript

Abstract

Carbofuran is a pesticide widely used in agricultural context to kill insects, mites, and flies by ingestion or contact. Along with literature review, we aimed to (i) present the clinical, autopsy, and toxicological findings of carbofuran self-poisonings in two 69-year-old twins, resulting in the death of one of them and (ii) assess carbofuran metabolite distribution using molecular networking. Quantitative analysis of carbofuran and its main metabolites (3-hydroxycarbofuran and 3-ketocarbofuran) was carried out using an original liquid chromatography-tandem mass spectrometry method on biological samples (cardiac or peripheral blood, urine, bile, and gastric contents). Toxicological analysis of post-mortem samples (twin 1) highlighted high concentrations of carbofuran and its metabolites in cardiac blood, bile, and gastric contents. These compounds were also quantified in blood and/or urine samples of the living brother (twin 2), confirming poisoning. Using molecular networking approach to facilitate visualization of mass spectrometry datasets and sample-to-sample comparisons, we detected two more metabolites (7-phenol-carbofuran and 3-hydroxycarbofuran glucuronide) in bile (twin 1) and urine (twin 2). These results highlight the value of (i) these compounds as carbofuran consumption markers and (ii) bile samples in post-mortem analysis to confirm poisoning. From an analytical point of view, molecular networking allowed the detection and interpretation of carbofuran metabolite ammonium adducts which helped to confirm their identification annotations, as well as their structural data. From a clinical point of view, the different outcomes between the two brothers are discussed. Overall, these cases provide novel information regarding the distribution of carbofuran and its metabolites in poisoning context.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. The WHO Recommended Classification of Pesticides by Hazard and guidelines to classification, 2019 edn. https://www.who.int/publications/i/item/9789240005662. Accessed 18 Apr 2022

  2. Roberts JR, Reigart JR (2013) Recognition and management of pesticide poisonings, sixth edn. 2013: Chapter 6 Carbamates. EPA, pp 56–62. https://www.epa.gov/sites/default/files/2015-01/documents/rmpp_6thed_final_lowresopt.pdf. Accessed 18 Apr 2022

  3. Fukuto TR (1990) Mechanism of action of organophosphorus and carbamate insecticides. Environ Health Perspect 87:245–254. https://doi.org/10.1289/ehp.9087245

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. (2007) Avis aux fabricants, distributeurs et utilisateurs de produits phytopharmaceutiques contenant les substances carbosulfan, carbofuran, diuron, cadusafos, haloxyfop-R. https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000000464899. Accessed 18 Apr 2022

  5. Ameno K, Lee SK, In SW et al (2001) Blood carbofuran concentrations in suicidal ingestion cases. Forensic Sci Int 116:59–61. https://doi.org/10.1016/s0379-0738(00)00336-4

    Article  PubMed  CAS  Google Scholar 

  6. SakunthalaTennakoon DAS, Karunarathna WDV, Udugampala USS (2013) Carbofuran concentrations in blood, bile and tissues in fatal cases of homicide and suicide. Forensic Sci Int 227:106–110. https://doi.org/10.1016/j.forsciint.2012.10.039

    Article  CAS  Google Scholar 

  7. Otieno PO, Lalah JO, Virani M et al (2010) Carbofuran and its toxic metabolites provide forensic evidence for furadan exposure in vultures (Gyps africanus) in Kenya. Bull Environ Contam Toxicol 84:536–544. https://doi.org/10.1007/s00128-010-9956-5

    Article  PubMed  CAS  Google Scholar 

  8. Hassall KA, Hassall KA (1990) The biochemistry and uses of pesticides: structure, metabolism, mode of action, and uses in crop protection, 2nd edn. VCH, Weinheim, New York

    Book  Google Scholar 

  9. Abass K, Reponen P, Mattila S et al (2014) Human variation and CYP enzyme contribution in benfuracarb metabolism in human in vitro hepatic models. Toxicol Lett 224:300–309. https://doi.org/10.1016/j.toxlet.2013.08.023

    Article  PubMed  CAS  Google Scholar 

  10. Song X (2014) Carbofuran. In: Encyclopedia of toxicology, 3rd edn. Elsevier, pp 673–674

  11. Usmani KA, Hodgson E, Rose RL (2004) In vitro metabolism of carbofuran by human, mouse, and rat cytochrome P450 and interactions with chlorpyrifos, testosterone, and estradiol. Chem Biol Interact 150:221–232. https://doi.org/10.1016/j.cbi.2004.09.015

    Article  PubMed  CAS  Google Scholar 

  12. Vanhaebost J, Faouzi M, Mangin P, Michaud K (2014) New reference tables and user-friendly Internet application for predicted heart weights. Int J Legal Med 128:615–620. https://doi.org/10.1007/s00414-013-0958-9

    Article  PubMed  Google Scholar 

  13. Le Daré B, Ferron P-J, Allard P-M et al (2020) New insights into quetiapine metabolism using molecular networking. Sci Rep 10:19921. https://doi.org/10.1038/s41598-020-77106-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Le Daré B, Allard S, Bouvet R et al (2020) A case of fatal acebutolol poisoning: an illustration of the potential of molecular networking. Int J Legal Med 134:251–256. https://doi.org/10.1007/s00414-019-02062-9

    Article  PubMed  Google Scholar 

  15. Gicquel T, Pelletier R, Richeval C et al (2021) Metabolite elucidation of 2-fluoro-deschloroketamine (2F-DCK) using molecular networking across three complementary in vitro and in vivo models. Drug Test Anal. https://doi.org/10.1002/dta.3162

    Article  PubMed  Google Scholar 

  16. Ferron P-J, Le Daré B, Bronsard J et al (2021) Molecular networking for drug toxicities studies: the case of hydroxychloroquine in COVID-19 patients. Int J Mol Sci 23:82. https://doi.org/10.3390/ijms23010082

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Boumrah Y, Gicquel T, Hugbart C et al (2016) Suicide by self-injection of chlormequat trademark C5SUN ®. Forensic Sci Int 263:e9–e13. https://doi.org/10.1016/j.forsciint.2016.03.007

    Article  PubMed  CAS  Google Scholar 

  18. Gicquel T, Hugbart C, Le Devehat F et al (2016) Death related to consumption of Rauvolfia sp. powder mislabeled as Tabernanthe iboga. Forensic Sci Int 266:e38–e42. https://doi.org/10.1016/j.forsciint.2016.06.014

    Article  PubMed  Google Scholar 

  19. Le Daré B, Ferron P-J, Couette A et al (2021) In vivo and in vitro α-amanitin metabolism studies using molecular networking. Toxicol Lett 346:1–6. https://doi.org/10.1016/j.toxlet.2021.04.006

    Article  PubMed  CAS  Google Scholar 

  20. Allard S, Allard P-M, Morel I, Gicquel T (2019) Application of a molecular networking approach for clinical and forensic toxicology exemplified in three cases involving 3-MeO-PCP, doxylamine, and chlormequat. Drug Test Anal 11:669–677. https://doi.org/10.1002/dta.2550

    Article  PubMed  CAS  Google Scholar 

  21. Pluskal T, Castillo S, Villar-Briones A, Oresic M (2010) MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinformatics 11:395. https://doi.org/10.1186/1471-2105-11-395

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Wang M, Carver JJ, Phelan VV et al (2016) Sharing and community curation of mass spectrometry data with global natural products social molecular networking. Nat Biotechnol 34:828–837. https://doi.org/10.1038/nbt.3597

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Shannon P, Markiel A, Ozier O et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. https://doi.org/10.1101/gr.1239303

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Schymanski EL, Jeon J, Gulde R et al (2014) Identifying small molecules via high resolution mass spectrometry: communicating confidence. Environ Sci Technol 48:2097–2098. https://doi.org/10.1021/es5002105

    Article  PubMed  CAS  Google Scholar 

  25. Pélissier-Alicot A-L, Gaulier J-M, Champsaur P, Marquet P (2003) Mechanisms underlying postmortem redistribution of drugs: a review. J Anal Toxicol 27:533–544. https://doi.org/10.1093/jat/27.8.533

    Article  PubMed  Google Scholar 

  26. Liu G, Liu J, Gao L (2017) An analysis of a suicide case by ingestion of carbofuran. Aust J Forensic Sci 49:699–703. https://doi.org/10.1080/00450618.2016.1177592

    Article  Google Scholar 

  27. Sancewicz-Pach K, Groszek B, Pach D, Kłys M (1997) Acute pesticides poisonings in pregnant women. Przegl Lek 54:741–744

    PubMed  CAS  Google Scholar 

  28. Lacassie E, Marquet P, Gaulier JM et al (2001) Sensitive and specific multiresidue methods for the determination of pesticides of various classes in clinical and forensic toxicology. Forensic Sci Int 121:116–125. https://doi.org/10.1016/s0379-0738(01)00461-3

    Article  PubMed  CAS  Google Scholar 

  29. Ferrari Júnior E, Caldas ED (2018) Simultaneous determination of drugs and pesticides in postmortem blood using dispersive solid-phase extraction and large volume injection-programmed temperature vaporization-gas chromatography-mass spectrometry. Forensic Sci Int 290:318–326. https://doi.org/10.1016/j.forsciint.2018.07.031

    Article  PubMed  CAS  Google Scholar 

  30. Barr DB, Ananth CV, Yan X et al (2010) Pesticide concentrations in maternal and umbilical cord sera and their relation to birth outcomes in a population of pregnant women and newborns in New Jersey. Sci Total Environ 408:790–795. https://doi.org/10.1016/j.scitotenv.2009.10.007

    Article  PubMed  CAS  Google Scholar 

  31. Papoutsis I, Mendonis M, Nikolaou P et al (2012) Development and validation of a simple GC-MS method for the simultaneous determination of 11 anticholinesterase pesticides in blood–clinical and forensic toxicology applications. J Forensic Sci 57:806–812. https://doi.org/10.1111/j.1556-4029.2011.02031.x

    Article  PubMed  CAS  Google Scholar 

  32. Lee SK, Ameno K, Yang JY et al (1999) Forensic toxicological implication of acute fatal poisoning cases due to benfuracarb ingestion. Int J Legal Med 112:268–270. https://doi.org/10.1007/s004140050247

    Article  PubMed  CAS  Google Scholar 

  33. Ferrari Júnior E, Dos Santos JBA, Caldas ED (2021) Drugs, pesticides and metabolites in forensic post-mortem blood samples. Med Sci Law 61:97–104. https://doi.org/10.1177/0025802420965006

    Article  PubMed  Google Scholar 

  34. Mostafa A, Medley G, Roberts DM et al (2011) Simultaneous quantification of carbamate insecticides in human plasma by liquid chromatography/tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 879:2234–2238. https://doi.org/10.1016/j.jchromb.2011.06.006

    Article  PubMed  CAS  Google Scholar 

  35. Petropoulou S-SE, Tsarbopoulos A, Siskos PA (2006) Determination of carbofuran, carbaryl and their main metabolites in plasma samples of agricultural populations using gas chromatography-tandem mass spectrometry. Anal Bioanal Chem 385:1444–1456. https://doi.org/10.1007/s00216-006-0569-0

    Article  PubMed  CAS  Google Scholar 

  36. Petropoulou S-SE, Gikas E, Tsarbopoulos A, Siskos PA (2006) Gas chromatographic–tandem mass spectrometric method for the quantitation of carbofuran, carbaryl and their main metabolites in applicators’ urine. J Chromatogr A 1108:99–110. https://doi.org/10.1016/j.chroma.2005.12.058

    Article  PubMed  CAS  Google Scholar 

  37. Schmid R, Petras D, Nothias L-F et al (2021) Ion identity molecular networking for mass spectrometry-based metabolomics in the GNPS environment. Nat Commun 12:3832. https://doi.org/10.1038/s41467-021-23953-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Gonzalez-Riano C, Gradillas A, Barbas C (2021) Exploiting the formation of adducts in mobile phases with ammonium fluoride for the enhancement of annotation in liquid chromatography-high resolution mass spectrometry based lipidomics. J Chromatogr Open 1:100018. https://doi.org/10.1016/j.jcoa.2021.100018

    Article  Google Scholar 

  39. Sugimura N, Furuya A, Yatsu T et al (2017) Observed adducts on positive mode direct analysis in real time mass spectrometry – proton/ammonium adduct selectivities of 600-sample in-house chemical library. Eur J Mass Spectrom 23:4–10. https://doi.org/10.1177/1469066717693851

    Article  CAS  Google Scholar 

  40. Eslam M, Sanyal AJ, George J et al (2020) MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 158:1999-2014.e1. https://doi.org/10.1053/j.gastro.2019.11.312

    Article  PubMed  CAS  Google Scholar 

  41. Buechler CS, Weiss T (2011) Does Hepatic steatosis affect drug metabolizing enzymes in the liver? Curr Drug Metab 12:24–34. https://doi.org/10.2174/138920011794520035

    Article  PubMed  CAS  Google Scholar 

  42. El-Nahhal Y, El-Nahhal I (2021) Cardiotoxicity of some pesticides and their amelioration. Environ Sci Pollut Res 28:44726–44754. https://doi.org/10.1007/s11356-021-14999-9

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. INSERM, INRAE, Institut NUMECAN (Nutrition, Metabolisms and Cancer) UMR_A 1341, UMR_S 1241, Univ Rennes, F-35000, Rennes, France

    Angéline Kernalléguen, Brendan Le Daré, Romain Pelletier, Pierre-Jean Ferron, Isabelle Morel & Thomas Gicquel

  2. Pharmacy, Rennes University Hospital, F-35033, Rennes, France

    Brendan Le Daré

  3. Clinical and Forensic Toxicology Laboratory, Rennes University Hospital, F-35033, Rennes, France

    Romain Pelletier, Isabelle Morel & Thomas Gicquel

  4. Rennes University Hospital Infectious Diseases and Medical Intensive Care Unit, F-35033, Rennes, France

    Adel Maamar

  5. Forensic Medicine Department, Rennes University Hospital, F-35033, Rennes, France

    Renaud Bouvet & Alain Baert

Authors
  1. Angéline Kernalléguen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brendan Le Daré
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Romain Pelletier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pierre-Jean Ferron
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adel Maamar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Renaud Bouvet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alain Baert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Isabelle Morel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Thomas Gicquel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: Angéline Kernalléguen, Brendan Le Daré, Romain Pelletier, Pierre-Jean Ferron, Thomas Gicquel; methodology: Angéline Kernalléguen, Brendan Le Daré, Romain Pelletier, Pierre-Jean Ferron, Thomas Gicquel; formal analysis and investigation: all the authors; writing — original draft preparation: Angéline Kernalléguen, Brendan Le Daré; writing — review and editing: all the authors; supervision: Thomas Gicquel.

Corresponding author

Correspondence to Thomas Gicquel.

Ethics declarations

Ethics approval and consent to participate

Ethical approval was waived in view of the retrospective nature of the study, and all the procedures being performed were part of the routine care.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kernalléguen, A., Le Daré, B., Pelletier, R. et al. Carbofuran self-poisoning: forensic and analytic investigations in twins and literature review. Int J Legal Med 136, 1585–1596 (2022). https://doi.org/10.1007/s00414-022-02885-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00414-022-02885-z

Keywords

Search

Navigation