Studies on the effects of pesticide mixtures on the nervous system have not been reviewed. The aim of this article was to systematically review the literature on neurotoxicity induced by a mixture of pesticides. The review was limited to mammalian, neurobehavioural, neuropathological and neuropharmacological studies; in vitro and in vivo and other biochemical studies were considered. Inclusion criteria were developed a priori to ensure consistent assessment of the studies. Only studies published from January 2000 to December 2022 were included in the study. Limitations included the use of a single dose and/or test time, small sample sizes, limited data presentation and/or obviously toxic doses. Of the 2145 studies selected, only 7 were included, including 6 in vivo studies and 1 in vitro study. The studies differed in terms of species tested, pesticides, dosing scenarios and experimental designs. Two studies had assessed the evidence of an additive or synergistic effect of pesticides in co-exposure, but further long-term analyses should confirm this hypothesis. Other studies had less convincing results due to their exposure protocols. Taken together, despite the differences in quality between the studies, the pesticides studied and the exposure method, these studies require additional tests. Taken together, despite the differences in quality between the studies, the pesticides studied and the exposure method, these studies require additional tests.
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Badjabaissi, E. , Dossou-Yovo, K. M. , Assih, M. , Assiki, T. , Sanvee, S. C. J. , Bakoma, B. and Diallo, A. (2025). Neurotoxic Effects of Pesticide Mixtures: A Systematic Review of the Experimental Literature . Open Access Library Journal, 12, e14002. doi: http://dx.doi.org/10.4236/oalib.1114002.
Damalas, C.A. and Eleftherohorinos, I.G. (2011) Pesticide Exposure, Safety Is-sues, and Risk Assessment Indicators. International Journal of Environmental Research and Public Health, 8, 1402-1419. https://doi.org/10.3390/ijerph8051402
Alexandratos, N. and Bruinsma, J. (2023) World Agriculture towards 2030/2050: The 2012 Revision. ESA Working Paper No. 12-03. 2012; FAO.https://www.fao.org/3/ap106e/ap106e.pdf
Anderson, S.E. and Meade, B.J. (2014) Potential Health Effects Associated with Dermal Exposure to Occupational Chemicals. Environmental Health Insights, 8, EHI.S15258. https://doi.org/10.4137/ehi.s15258
Zhao, Y., Yang, J., Ren, J., Hou, Y., Han, Z., Xiao, J., et al. (2020) Exposure Level of Neonicotinoid Insecticides in the Food Chain and the Evaluation of Their Human Health Impact and Environ-mental Risk: An Overview. Sustainability, 12, Article 7523. https://doi.org/10.3390/su12187523
Keikotlhaile, B.M., Spanoghe, P. and Steurbaut, W. (2010) Effects of Food Processing on Pesticide Residues in Fruits and Vegetables: A Meta-Analysis Approach. Food and Chemical Toxicology, 48, 1-6. https://doi.org/10.1016/j.fct.2009.10.031
Reiler, E., Jørs, E., Bælum, J., Huici, O., Alvarez Caero, M.M. and Cedergreen, N. (2015) The Influence of Tomato Processing on Residues of Organochlorine and Organ-ophosphate Insecticides and Their Associated Dietary Risk. Science of the Total Environment, 527, 262-269. https://doi.org/10.1016/j.scitotenv.2015.04.081
Hernández, A.F., Parrón, T., Tsatsakis, A.M., Requena, M., Alarcón, R. and López-Guarnido, O. (2013) Toxic Effects of Pesticide Mixtures at a Molecular Level: Their Relevance to Hu-man Health. Toxicology, 307, 136-145. https://doi.org/10.1016/j.tox.2012.06.009
Michel, C. (2021) The Impact of Endocrine Disruptors in the Prenatal Environment on Postnatal Cognitive De-velopment: More Specifically, the Impact of Prenatal Exposure to Polychlorin-ated Biphenyls (PCBs), Organochlorine Pesticides (OPs) and Perfluorinated Compounds (PFCs) on Postnatal Memory Development. Master: Social & Be-havioral Sciences: Psychology: Neurosciences & Behavior.
Kara, M. and öztaş, E. (2020) Reproductive Toxicity of Insecticides. In: Animal Reproduction in Veterinary Medicine, IntechOpen, 237-240. https://doi.org/10.5772/intechopen.92890
Sabarwal, A., Kumar, K. and Singh, R.P. (2018) Hazardous Effects of Chemical Pesticides on Human Health–Cancer and Other Associated Disorders. Environmental Toxicology and Pharmacology, 63, 103-114. https://doi.org/10.1016/j.etap.2018.08.018
Vigar, V., Myers, S., Oliver, C., Arellano, J., Robinson, S. and Leifert, C. (2019) A Systematic Review of Or-ganic versus Conventional Food Consumption: Is There a Measurable Benefit on Human Health? Nutrients, 12, Article 7. https://doi.org/10.3390/nu12010007
Colosio, C., Tiramani, M. and Maroni, M. (2003) Neurobehavioral Effects of Pesticides: State of the Art. Neuro Toxicology, 24, 577-591. https://doi.org/10.1016/s0161-813x(03)00055-x
Bourguet, D., Delmotte, F., Franck, P., Guillemaud, T., Reboud, X., Vacher, C., et al. (2013) Heterogeneity of Selection and the Evolution of Resistance. Trends in Ecology & Evolution, 28, 110-118.
Liu, N. (2015) Insecticide Resistance in Mosqui-toes: Impact, Mechanisms, and Research Directions. Annual Review of Entomology, 60, 537-559. https://doi.org/10.1146/annurev-ento-010814-020828
Bass, C. and Jones, C.M. (2018) Editorial Overview: Pests and Resistance: Resistance to Pes-ticides in Arthropod Crop Pests and Disease Vectors: Mechanisms, Models and Tools. Current Opinion in Insect Science, 27, 4-7. https://doi.org/10.1016/j.cois.2018.04.009
Goumenou, M. and Tsatsakis, A. (2019) Proposing New Approaches for the Risk Characterisation of Single Chemicals and Chemical Mixtures: The Source Related Hazard Quotient (HQS) and Hazard Index (HIS) and the Adversity Specific Hazard Index (HIA). Toxicology Reports, 6, 632-636. https://doi.org/10.1016/j.toxrep.2019.06.010
Kostoff, R.N., Goumenou, M. and Tsatsakis, A. (2018) The Role of Toxic Stimuli Combinations in Deter-mining Safe Exposure Limits. Toxicology Reports, 5, 1169-1172. https://doi.org/10.1016/j.toxrep.2018.10.010
Drakvik, E., Altenburger, R., Aoki, Y., Backhaus, T., Bahadori, T., Barouki, R., et al. (2020) Statement on Advancing the Assessment of Chemical Mixtures and Their Risks for Human Health and the Environment. Environment International, 134, Article 105267. https://doi.org/10.1016/j.envint.2019.105267
Docea, A.O., Goumenou, M., Calina, D., Arsene, A.L., Dragoi, C.M., Gofita, E., et al. (2019) Adverse and Hormetic Effects in Rats Exposed for 12 Months to Low Dose Mixture of 13 Chemicals: RLRS Part III. Toxicology Letters, 310, 70-91. https://doi.org/10.1016/j.toxlet.2019.04.005
Tsatsakis, A., Tyshko, N.V., Docea, A.O., Shestakova, S.I., Sidorova, Y.S., Petrov, N.A., et al. (2019) The Ef-fect of Chronic Vitamin Deficiency and Long Term Very Low Dose Exposure to 6 Pesticides Mixture on Neurological Outcomes—A Real-Life Risk Simulation Ap-proach. Toxicology Letters, 315, 96-106. https://doi.org/10.1016/j.toxlet.2019.07.026
Fountoucidou, P., Veskoukis, A.S., Kerasioti, E., Docea, A.O., Taitzoglou, I.A., Liesivuori, J., et al. (2019) A Mixture of Routinely Encountered Xenobiotics Induces Both Redox Adaptations and Perturbations in Blood and Tissues of Rats after a Long-Term Low-Dose Exposure Regimen: The Time and Dose Issue. Toxicology Letters, 317, 24-44. https://doi.org/10.1016/j.toxlet.2019.09.015
Bopp, S., Berggren, E., Kienzler, A., van der Linden, S. and Worth, A. (2015) Scientific Methodologies for the Assessment of Combined Effects of Chemicals—A Survey and Literature Review. Publications Office of the European Union.
Euro-pean Commission (2012) Communication from the Commission to the Coun-cil—The Combination Effects of Chemicals. Chemical Mixtures. COM(2012) 252 Final 10.
Kienzler, A., Berggren, E., Bessems, J., Bopp, S., Van Der, L.S. and Worth, A. (2014) Assessment of Mixtures—Review of Regulatory Re-quirements and Guidance.
Baltazar, M.T., Dinis-Oliveira, R.J., de Lourdes Bastos, M., Tsatsakis, A.M., Duarte, J.A. and Carvalho, F. (2014) Pesticides Ex-posure as Etiological Factors of Parkinson’s Disease and Other Neurodegenera-tive Diseases—A Mechanistic Approach. Toxicology Letters, 230, 85-103. https://doi.org/10.1016/j.toxlet.2014.01.039
Petrakis, D., Vassilopoulou, L., Mamoulakis, C., Psycharakis, C., Anifantaki, A., Sifakis, S., et al. (2017) Endocrine Disruptors Leading to Obesity and Related Diseases. Interna-tional Journal of Environmental Research and Public Health, 14, Article 1282. https://doi.org/10.3390/ijerph14101282
Ruszkiewicz, J.A., Pinkas, A., Ferrer, B., Peres, T.V., Tsatsakis, A. and Aschner, M. (2017) Neurotoxic Effect of Active Ingredients in Sunscreen Products, a Contemporary Review. Toxicology Reports, 4, 245-259. https://doi.org/10.1016/j.toxrep.2017.05.006
Iavicoli, I., Fontana, L. and Bergamaschi, A. (2009) The Effects of Metals as Endocrine Disruptors. Journal of Toxicology and Environmental Health, Part B, 12, 206-223. https://doi.org/10.1080/10937400902902062
Rattan, S.I.S. (2004) The Future of Aging Interventions: Aging Intervention, Prevention, and Thera-py through Hormesis. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 59, B705-B709. https://doi.org/10.1093/gerona/59.7.b705
Moher, D., Shamseer, L., Clarke, M., Ghersi, D., Liberati, A., Petticrew, M., et al. (2016) Preferred Re-porting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 Statement. Revista Española de Nutrición Humana y Dietética, 20, 148-160.
Hooijmans, C.R., Rovers, M.M., de Vries, R.B., Leenaars, M., Ritskes-Hoitinga, M. and Langendam, M.W. (2014) SYRCLE’s Risk of Bias Tool for Animal Studies. BMC Medical Research Methodology, 14, Article No. 43. https://doi.org/10.1186/1471-2288-14-43
Higgins, J.P.T., Altman, D.G., Gotzsche, P.C., Juni, P., Moher, D., Oxman, A.D., et al. (2011) The Cochrane Collaboration’s Tool for Assessing Risk of Bias in Randomised Trials. British Medical Journal, 343, d5928. https://doi.org/10.1136/bmj.d5928
Kumar, V., Basniwal, P.K. and Vi-jayaraghavan, R. (2018) Effect of Combined Exposure of Dichlorvos and Mono-crotophos on Neurotransmitters and Acetylcholinesterase in Rat. International Journal of Pharmaceutical Sciences and Research, 9, 4956-4962.
Singh, R. and Sharma, P. (2012) Dichlorvos and Lindane Induced Oxidative Stress in Rat Brain: Protective Effects of Ginger. Pharmacognosy Research, 4, 27-32. https://doi.org/10.4103/0974-8490.91031
Latuszynska, J., Luty, S., Raszewski, G., Przebirowska, D. and Tokarska-Rodak, M. (2003) Neurotoxic Effect of Dermally Applied Chlorpyrifos and Cypermethrin. Reversibility of Changes. Annals of Agricultural and Environmental Medicine, 10, 197-201.
Ma, J., Huang, C., Ma, K., Wu, Y., Li, B. and Sun, Y. (2017) Effect of Wnt1 and Wnt5a on the Development of Dopaminergic Neurons, and Toxicity Induced by Combined Exposure to Paraquat and Maneb during Gestation and Lactation. Molecular Medicine Reports, 16, 9721-9728. https://doi.org/10.3892/mmr.2017.7833
Forner-Piquer, I., Klement, W., Gangarossa, G., Zub, E., de Bock, F., Blaquiere, M., et al. (2021) Varying Modalities of Perinatal Exposure to a Pesticide Cocktail Elicit Neurological Ad-aptations in Mice and Zebrafish. Environmental Pollution, 278, Article 116755. https://doi.org/10.1016/j.envpol.2021.116755
Klement, W., Oliviero, F., Gangarossa, G., Zub, E., De Bock, F., Forner-Piquer, I., et al. (2020) Life-Long Dietary Pesticide Cocktail Induces Astrogliosis along with Behavioral Adapta-tions and Activates P450 Metabolic Pathways. Neuroscience, 446, 225-237. https://doi.org/10.1016/j.neuroscience.2020.07.039
Drakvik, E., Al-tenburger, R., Aoki, Y., Backhaus, T., Bahadori, T., Barouki, R., et al. (2020) Statement on Advancing the Assessment of Chemical Mixtures and Their Risks for Human Health and the Environment. Environment International, 134, Arti-cle 105267. https://doi.org/10.1016/j.envint.2019.105267
Martin, O., Scholze, M., Ermler, S., McPhie, J., Bopp, S.K., Kienzler, A., et al. (2021) Ten Years of Research on Synergisms and Antagonisms in Chemical Mixtures: A Systematic Review and Quantitative Reappraisal of Mixture Studies. Environment International, 146, Article 106206. https://doi.org/10.1016/j.envint.2020.106206
OECD (Organization for Economic Co-Operation and Development) (1997) Guideline No. 424: Neuro-toxicity Study in Rodents. Organization for Economic Co-Operation and Devel-opment (OECD).
OECD (Organization for Economic Co-Operation and De-velopment) (2004) OECD Series on Testing and Assessment Number 20: Guidelines for Neurotoxicity Testing. ENV/DM/MONO.
NAFTA (North American Free Trade Agreement) (2016) Pesticides Technical Working Group (TWG). Developmental Neurotoxicity (DNT) Guidance Document. https://www.epa.gov/pesticidescience-andassessing-pesticide-risks/developmentalneurotoxicitystudy-guidance
Mac Phail, R.C., Peele, D.B. and Crofton, K.M. (1989) Motor Activity and Screening for Neurotoxicity. Journal of the American College of Toxicology, 8, 117-125. https://doi.org/10.3109/10915818909009098
Docea, A.O., Gofita, E., Goumenou, M., Calina, D., Rogoveanu, O., Varut, M., et al. (2018) Six Months Exposure to a Real Life Mixture of 13 Chemicals’ Below Individual NOAELs In-duced Non Monotonic Sex-Dependent Biochemical and Redox Status Changes in Rats. Food and Chemical Toxicology, 115, 470-481. https://doi.org/10.1016/j.fct.2018.03.052