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Archives of Toxicology

, Volume 91, Issue 10, pp 3211–3223 | Cite as

Toxicological interactions of pesticide mixtures: an update

  • Antonio F. HernándezEmail author
  • Fernando Gil
  • Marina Lacasaña
Review Article

Abstract

Pesticides can interact with each other in various ways according to the compound itself and its chemical family, the dose and the targeted organs, leading to various effects. The term interaction means situations where some or all individual components of a mixture influence each other’s toxicity and the joint effects may deviate from the additive predictions. The various mixture effects can be greatly determined by toxicokinetic and toxicodynamic factors involving metabolic pathways and cellular or molecular targets of individual pesticides, respectively. However, the complexity of toxicological interactions can lead to unpredictable effects of pesticide mixtures. Interactions on metabolic processes affecting the biotransformation of pesticides seem to be by far the most common mechanism of synergism. Moreover, the identification of pesticides responsible for synergistic interactions is an important issue for cumulative risk assessment. Cholinesterase inhibiting insecticides (organophosphates and N-methylcarbamates), triazole fungicides, triazine herbicides, and pyrethroid insecticides are overrepresented in the synergistic mixtures identified so far. Since the limited available empirical evidence suggests that synergisms at dietary exposure levels are rather rare, and experimentally occurred at unrealistic high concentrations, synergism cannot be predicted quantitatively on the basis of the toxicity of mixture components. The prediction of biological responses elicited by interaction of pesticides with each other (or with other chemicals) will benefit from using a systems toxicology approach. The identification of core features of pesticide mixtures at molecular level, such as gene expression profiles, could be helpful to assess or predict the occurrence of interactive effects giving rise to unpredicted responses.

Keywords

Pesticides Mixtures Cumulative risk assessment Additivity Synergism Antagonism 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Abass K, Lämsä V, Reponen P, Küblbeck J, Honkakoski P, Mattila S, Pelkonen O, Hakkola J (2012) Characterization of human cytochrome P450 induction by pesticides. Toxicology 294:17–26CrossRefPubMedGoogle Scholar
  2. Bain LJ, LeBlanc GA (1996) Interaction of structurally diverse pesticides with the human MDR1 gene product P-glycoprotein. Toxicol Appl Pharmacol 141:288–298CrossRefPubMedGoogle Scholar
  3. Belden JB, Gilliom RJ, Lydy MJ (2007) How well can we predict the toxicity of pesticide mixtures to aquatic life? Integr Environ Assess Manag 3:364–372CrossRefPubMedGoogle Scholar
  4. Berenbaum MC (1989) What is synergy? Pharmacol Rev 41:93–141PubMedGoogle Scholar
  5. Bircsak KM, Richardson JR, Aleksunes LM (2013) Inhibition of human MDR1 and BCRP transporter ATPase activity by organochlorine and pyrethroid insecticides. J Biochem Mol Toxicol 27:157–164CrossRefPubMedGoogle Scholar
  6. Bjergager MA, Dalhoff K, Kretschmann A, Nørgaard KB, Mayer P, Cedergreen N (2017) Determining lower threshold concentrations for synergistic effects. Aquat Toxicol 182:79–90CrossRefPubMedGoogle Scholar
  7. Boobis A, Budinsky R, Collie S, Crofton K, Embry M, Felter S, Hertzberg R, Kopp D, Mihlan G, Mumtaz M, Price P, Solomon K, Teuschler L, Yang R, Zaleski R (2011) Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment. Crit Rev Toxicol 41:369–383CrossRefPubMedGoogle Scholar
  8. Bopp S, Berggren E, Kienzler A, van der Linden S, Worth A (2015) Scientific methodologies for the combined effects of chemicals—a survey and literature review. EUR 27471 EN. doi: 10.2788/093511. http://publications.jrc.ec.europa.eu/repository/bitstream/JRC97522/jrc_tech_rep_sci%20meth%20for%20mix_final.pdf. Accessed 21 Aug 2017
  9. Bopp SK, Kienzler A, van der Linden S, Lamon L, Paini A, Parissis N, Richarz AN, Triebe J, Worth A (2016) Review of case studies on the human and environmental risk assessment of chemical mixtures. EUR 27968 EN. doi: 10.2788/272583. http://publications.jrc.ec.europa.eu/repository/bitstream/JRC102111/jrc102111_jrc_tech-rep_mix%20case%20studies_2016_vf.pdf. Accessed 21 Aug 2017
  10. Bucher S, Le Vee M, Jouan E, Fardel O (2014) Regulation of hepatic drug transporter activity and expression by organochlorine pesticides. J Biochem Mol Toxicol 28:119–128CrossRefPubMedGoogle Scholar
  11. Caballero MV, Ares I, Martínez M, Martínez-Larrañaga MR, Anadón A, Martínez MA (2015) Fipronil induces CYP isoforms in rats. Food Chem Toxicol 83:215–221CrossRefPubMedGoogle Scholar
  12. Cedergreen N (2014) Quantifying synergy: a systematic review of mixture toxicity studies within environmental toxicology. PLoS One 9(5):e96580CrossRefPubMedPubMedCentralGoogle Scholar
  13. Cedergreen N, Sørensen H, Svendsen C (2012) Can the joint effect of ternary mixtures be predicted from binary mixture toxicity results? Sci Total Environ 427–428:229–237CrossRefPubMedGoogle Scholar
  14. Chedik L, Bruyere A, Le Vee M, Stieger B, Denizot C, Parmentier Y, Potin S, Fardel O (2017) Inhibition of human drug transporter activities by the pyrethroid pesticides allethrin and tetramethrin. PLoS One 12(1):e0169480CrossRefPubMedPubMedCentralGoogle Scholar
  15. Christen V, Crettaz P, Fent K (2014) Additive and synergistic antiandrogenic activities of mixtures of azol fungicides and vinclozolin. Toxicol Appl Pharmacol 279:455–466CrossRefPubMedGoogle Scholar
  16. Dalhoff K, Gottardi M, Kretschmann A, Cedergreen N (2016) What causes the difference in synergistic potentials of propiconazole and prochloraz toward pyrethroids in Daphnia magna? Aquat Toxicol 172:95–102CrossRefPubMedGoogle Scholar
  17. de Sousa G, Nawaz A, Cravedi JP, Rahmani R (2014) A concentration addition model to assess activation of the pregnane X receptor (PXR) by pesticide mixtures found in the French diet. Toxicol Sci 141:234–243CrossRefPubMedPubMedCentralGoogle Scholar
  18. Dunn ST, Hedges L, Sampson KE, Lai Y, Mahabir S, Balogh L, Locuson CW (2011) Pharmacokinetic interaction of the antiparasitic agents ivermectin and spinosad in dogs. Drug Metab Dispos 39:789–795CrossRefPubMedGoogle Scholar
  19. EFSA (European Food Safety Authority) (2013a) International framework dealing with human risk assessment of combined exposure to multiple chemicals. EFSA J 11(7):3313CrossRefGoogle Scholar
  20. EFSA (European Food Safety Authority) (2013b) Scientific Opinion on relevance of dissimilar mode of action and its appropriate application for cumulative risk assessment of pesticides residues in food. EFSA J 11(12):3472CrossRefGoogle Scholar
  21. EFSA (European Food Safety Authority) (2017) The 2015 European Union report on pesticide residues in food. EFSA J 15(4). doi: 10.2903/j.efsa.2017.4791
  22. González-Alzaga B, Lacasaña M, Aguilar-Garduño C, Rodríguez-Barranco M, Ballester F, Rebagliato M, Hernández AF (2014) A systematic review of neurodevelopmental effects of prenatal and postnatal organophosphate pesticide exposure. Toxicol Lett 230:104–121CrossRefPubMedGoogle Scholar
  23. Halwachs S, Schäfer I, Kneuer C, Seibel P, Honscha W (2016) Assessment of ABCG2-mediated transport of pesticides across the rabbit placenta barrier using a novel MDCKII in vitro model. Toxicol Appl Pharmacol 305:66–74CrossRefPubMedGoogle Scholar
  24. Hernández AF, Tsatsakis AM (2017) Human exposure to chemical mixtures: challenges for the integration of toxicology with epidemiology data in risk assessment. Food Chem Toxicol 103:188–193CrossRefPubMedGoogle Scholar
  25. Hernández AF, Parrón T, Tsatsakis AM, Requena M, Alarcón R, López-Guarnido O (2013) Toxic effects of pesticide mixtures at a molecular level: their relevance to human health. Toxicology 307:136–145CrossRefPubMedGoogle Scholar
  26. Hodgson E, Rose RL (2007) Human metabolic interactions of environmental chemicals. J Biochem Mol Toxicol 21:182–186CrossRefPubMedGoogle Scholar
  27. Jackson CJ, Oakeshott JG, Sanchez-Hernandez JC, Wheelock CE (2010) Carboxylesterases in the metabolism and toxicity of pesticides. In: Satoh T, Gupta RC (eds) Anticholinesterase pesticides: metabolism, neurotoxicity, and epidemiology. Wiley, Hoboken, New Jersey, pp 57–75Google Scholar
  28. Junghans M, Backhaus T, Faust M, Scholze T, Grimme LH (2006) Application and validation of approaches for the predictive hazard assessment of realistic pesticide mixtures. Aquat Toxicol 76:93–110CrossRefPubMedGoogle Scholar
  29. Kadar A, de Sousa G, Peyre L, Wortham H, Doumenq P, Rahmani R (2017) Evidence of in vitro metabolic interaction effects of a chlorfenvinphos, ethion and linuron mixture on human hepatic detoxification rates. Chemosphere 181:666–674CrossRefPubMedGoogle Scholar
  30. Kienzler A, Berggren E, Bessems J, Bopp S, Van Der Linden S, Worth A (2014) Assessment of mixtures-review of regulatory requirements and guidance JRC Science and Policy Report European Commission. Joint Res Center, IspraGoogle Scholar
  31. Kienzler A, Bopp SK, van der Linden S, Berggren E, Worth A (2016) Regulatory assessment of chemical mixtures: requirements, current approaches and future perspectives. Regul Toxicol Pharmacol 80:321–334CrossRefPubMedGoogle Scholar
  32. Kojima H, Sata F, Takeuchi S, Sueyoshi T, Nagai T (2011) Comparative study of human and mouse pregnane X receptor agonistic activity in 200 pesticides using in vitro reporter gene assays. Toxicology 280:77–87CrossRefPubMedGoogle Scholar
  33. Kortenkamp A, Backhaus T, Faust M (2009) State of the art report on mixture toxicity. Directorate General for the Environment: Report to the EU Commission. http://www.ec.europa.eu/environment/chemicals/effects/pdf/report_mixture_toxicity.pdf. Accessed 21 Aug 2007
  34. Letelier ME, Faúndez M, Jara-Sandoval J, Molina-Berríos A, Cortés-Troncoso J, Aracena-Parks P, Marín-Catalán R (2009) Mechanisms underlying the inhibition of the cytochrome P450 system by copper ions. J Appl Toxicol 29:695–702CrossRefPubMedGoogle Scholar
  35. Meek ME, Boobis AR, Crofton KM, Heinemeyer G, Raaij MV, Vickers C (2011) Risk assessment of combined exposure to multiple chemicals: a WHO/IPCS framework. Regul Toxicol Pharmacol 2011(60):S1–S14Google Scholar
  36. Meijer M, Hamers T, Westerink RH (2014a) Acute disturbance of calcium homeostasis in PC12 cells as a novel mechanism of action for (sub)micromolar concentrations of organophosphate insecticides. Neurotoxicology 43:110–116CrossRefPubMedGoogle Scholar
  37. Meijer M, Dingemans MM, van den Berg M, Westerink RH (2014b) Inhibition of voltage-gated calcium channels as common mode of action for (mixtures of) distinct classes of insecticides. Toxicol Sci 141:103–111CrossRefPubMedPubMedCentralGoogle Scholar
  38. Mokarizadeh A, Faryabi MR, Rezvanfar MA, Abdollahi M (2015) A comprehensive review of pesticides and the immune dysregulation: mechanisms, evidence and consequences. Toxicol Mech Methods 25:258–278CrossRefPubMedGoogle Scholar
  39. Mumtaz MM, Durkin PR (1992) A weight-of-evidence approach for assessing interactions in chemical mixtures. Toxicol Ind Health 8:377–406PubMedGoogle Scholar
  40. Ntzani EE, Chondrogiorgi M, Ntritsos G, Evangelou E, Tzoulaki I (2013) Literature review on epidemiological studies linking exposure to pesticides and health effects. EFSA Supporting Publication, EN-497, New York, 159 p. doi: 10.2903/sp.efsa.2013.EN-497
  41. Orton F, Ermler S, Kugathas S, Rosivatz E, Scholze M, Kortenkamp A (2014) Mixture effects at very low doses with combinations of anti-androgenic pesticides, antioxidants, industrial pollutant and chemicals used in personal care products. Toxicol Appl Pharmacol 278:201–208CrossRefPubMedGoogle Scholar
  42. Parrón T, Requena M, Hernández AF, Alarcón R (2011) Association between environmental exposure to pesticides and neurodegenerative diseases. Toxicol Appl Pharmacol 256:379–385CrossRefPubMedGoogle Scholar
  43. Parrón T, Requena M, Hernández AF, Alarcón R (2014) Environmental exposure to pesticides and cancer risk in multiple human organ systems. Toxicol Lett 230:157–165CrossRefPubMedGoogle Scholar
  44. Quignot N, Béchaux C, Amzal B (2015) Data collection on toxicokinetic and toxicodynamic interactions of chemical mixtures for human risk assessment. EFSA Supporting Publication, EN-711, New York, 85 p. doi: 10.2903/sp.efsa.2015.EN-711
  45. Raies AB, Bajic VB (2016) In silico toxicology: computational methods for the prediction of chemical toxicity. Wiley Interdiscip Rev Comput Mol Sci 6:147–172CrossRefPubMedPubMedCentralGoogle Scholar
  46. Reffstrup TK, Larsen JC, Meyer O (2010) Risk assessment of mixtures of pesticides. Current approaches and future strategies. Regul Toxicol Pharmacol 56:174–192CrossRefPubMedGoogle Scholar
  47. Rider CV, Furr JR, Wilson VS, Gray LE Jr (2010) Cumulative effects of in utero administration of mixtures of reproductive toxicants that disrupt common target tissues via diverse mechanisms of toxicity. Int J Androl 33:443–462CrossRefPubMedPubMedCentralGoogle Scholar
  48. Rieke S, Koehn S, Hirsch-Ernst K, Pfeil R, Kneuer C, Marx-Stoelting P (2014) Combination effects of (tri)azole fungicides on hormone production and xenobiotic metabolism in a human placental cell line. Int J Environ Res Public Health 11:9660–9679CrossRefPubMedPubMedCentralGoogle Scholar
  49. Rizzati V, Briand O, Guillou H, Gamet-Payrastre L (2016) Effects of pesticide mixtures in human and animal models: an update of the recent literature. Chem Biol Interact 254:231–246CrossRefPubMedGoogle Scholar
  50. Rodea-Palomares I, González-Pleiter M, Martín-Betancor K, Rosal R, Fernández-Piñas F (2015) Additivity and interactions in ecotoxicity of pollutant mixtures: some patterns, conclusions, and open questions. Toxics 3:342–369CrossRefPubMedPubMedCentralGoogle Scholar
  51. Sams C (2006) A pilot study to assess the effects of co-exposure to organophosphates, carbamates and pyrethroids on the rate of metabolic detoxification via hydrolysis. Project code: T10017. Contractor: Health and Safety Laboratory. http://www.food.gov.uk/science/research/foodcomponentsresearch/mixturesresearch/t10prog/T10projlist/t10017project/. Accessed 21 Aug 2017
  52. Sams C, Jones K (2011) Human volunteer studies investigating the potential for toxicokinetic interactions between the pesticides deltamethrin; pirimicarb and chlorpyrifos-methyl following oral exposure at the acceptable daily intake. Toxicol Lett 200:41–45CrossRefPubMedGoogle Scholar
  53. Sarigiannis DA, Hansen U (2012) Considering the cumulative risk of mixtures of chemicals-a challenge for policy makers. Environ Health 11(Suppl 1):S18CrossRefPubMedPubMedCentralGoogle Scholar
  54. Savary CC, Jossé R, Bruyère A, Guillet F, Robin MA, Guillouzo A (2014) Interactions of endosulfan and methoxychlor involving CYP3A4 and CYP2B6 in human HepaRG cells. Drug Metab Dispos 42:1235–1240CrossRefPubMedGoogle Scholar
  55. SCHER, SCCS, SCENIHR (2012) Opinion on the toxicity and assessment of chemical mixtures. http://ec.europa.eu/health/scientific_committees/environmental_risks/docs/scher_o_155.pdf. Accessed 21 Aug 2017
  56. Schmidt F, Marx-Stoelting P, Haider W, Heise T, Kneuer C, Ladwig M, Banneke S, Rieke S, Niemann L (2016) Combination effects of azole fungicides in male rats in a broad dose range. Toxicology 355–356:54–63CrossRefPubMedGoogle Scholar
  57. Sultana Shaik A, Shaik AP, Jamil K, Alsaeed AH (2016) Evaluation of cytotoxicity and genotoxicity of pesticide mixtures on lymphocytes. Toxicol Mech Methods 26:588–594CrossRefPubMedGoogle Scholar
  58. Suzuki H, Ito Y, Noro Y, Koketsu M, Kamijima M, Tomizawa M (2014) Organophosphate agents induce plasma hypertriglyceridemia in mouse via single or dual inhibition of the endocannabinoid hydrolyzing enzyme(s). Toxicol Lett 225:153–157CrossRefPubMedGoogle Scholar
  59. Takakura N, Sanders P, Fessard V, Le Hégarat L (2013) In vitro combined cytotoxic effects of pesticide cocktails simultaneously found in the French diet. Food Chem Toxicol 52:153–162CrossRefPubMedGoogle Scholar
  60. Tian D, Lin Z, Yu J, Yin D (2012) Influence factors of multicomponent mixtures containing reactive chemicals and their joint effects. Chemosphere 88:994–1000CrossRefPubMedGoogle Scholar
  61. US-EPA (U.S. Environmental Protection Agency) (2007) Considerations for developing a dosimetry-based cumulative risk assessment approach for mixtures of environmental contaminants. National Center for Environmental Assessment, Cincinnati, OH. EPA/600/R-07/064, 2007Google Scholar
  62. Wang P, Xu MY, Liang YJ, Wang HP, Sun YJ, Long DX, Wu YJ (2017) Subchronic toxicity of low dose propoxur, permethrin, and their combination on the redox status of rat liver. Chem Biol Interact 272:21–27CrossRefPubMedGoogle Scholar
  63. Warne MS, Hawker DW (1995) The number of components in a mixture determines whether synergistic and antagonistic or additive toxicity predominate: the funnel hypothesis. Ecotoxicol Environ Saf 31:23–28CrossRefPubMedGoogle Scholar
  64. Xu MY, Wang P, Sun YJ, Wu YJ (2017) Metabolomic analysis for combined hepatotoxicity of chlorpyrifos and cadmium in rats. Toxicology 384:50–58CrossRefPubMedGoogle Scholar
  65. Yagdiran Y, Oskarsson A, Knight CH, Tallkvist J (2016) ABC- and SLC-transporters in murine and bovine mammary epithelium-effects of prochloraz. PLoS One 11(3):e0151904CrossRefPubMedPubMedCentralGoogle Scholar
  66. You L (2004) Steroid hormone biotransformation and xenobiotic induction of hepatic steroid metabolizing enzymes. Chem Biol Interact 147:233–246CrossRefPubMedGoogle Scholar
  67. Zhang J, Liu L, Ren L, Feng W, Lv P, Wu W, Yan Y (2017) The single and joint toxicity effects of chlorpyrifos and beta-cypermethrin in zebrafish (Danio rerio) early life stages. J Hazard Mater 334:121–131CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Antonio F. Hernández
    • 1
    Email author
  • Fernando Gil
    • 1
  • Marina Lacasaña
    • 2
    • 3
    • 4
  1. 1.Department of Legal Medicine and Toxicology, School of MedicineUniversity of GranadaGranadaSpain
  2. 2.Andalulsian School of Public HealthGranadaSpain
  3. 3.CIBERESPMadridSpain
  4. 4.ibs.GRANADAGranadaSpain

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