Health Effects of Chronic Low-Dose Exposure to Pesticide Mixtures: A Systematic Review

Abstract

Chronic human exposure to pesticide mixtures, even at low doses, is widespread but remains poorly characterized in conventional risk assessment, which largely focuses on single compounds. This systematic review synthesizes current evidence on the health effects of long-term exposure to pesticide mixtures. Bibliographic searches were conducted in PubMed Central, ScienceDirect, and Google Scholar using predefined PICO criteria and structured search equations. After screening 608 records and applying eligibility criteria, 63 experimental and epidemiological studies addressing chronic, low-dose exposure to pesticide mixtures were included. Across diverse designs and biological models, the reviewed studies consistently reported multi-system toxicity. Documented outcomes included metabolic disturbances (glucose and lipid dysregulation, hepatic steatosis, diabetes risk), enzymatic alterations (CYP induction, AChE/BChE inhibition), neurological and neurobehavioral effects, oxidative stress, genotoxicity, epigenetic alterations, endocrine disruption, reproductive toxicity, respiratory impairment, and histopathological damage in hepatic, renal, hematopoietic, and reproductive tissues. Several studies also suggested emerging multidrug resistance phenomena following chronic pesticide-mixture exposure. Mechanistically, oxidative stress, mitochondrial dysfunction, endocrine and immune dysregulation, DNA damage, and persistent epigenetic reprogramming emerged as recurrent pathways, often amplified by additive, synergistic, or non-linear interactions within mixtures. Methodological heterogeneity, incomplete exposure characterization, and limited multigenerational data remain important constraints, particularly for vulnerable populations such as agricultural workers, children, and pregnant women. Nevertheless, the overall convergence of findings underscores that chronic exposure to pesticide mixtures cannot be considered innocuous, even at doses individually deemed acceptable. These results highlight the urgent need to integrate mixture toxicity and cumulative risk assessment into regulatory frameworks, strengthen environmental and occupational monitoring, and promote safer pest-management strategies to better protect public and environmental health. Despite the overall convergence of findings, the interpretation of results remains constrained by methodological heterogeneity, variable exposure assessment, and limited multigenerational and longitudinal data.