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Immunotoxicity

• Environmental exposures and multiple myeloma risk: A contemporary review of epidemiologic associations and mechanistic plausibility
  Despite major advances in the molecular characterization and treatment of multiple myeloma (MM), the factors driving disease onset remain poorly defined. Environmental influences represent a critical but underexplored component. Epidemiologic studies have associated a range of environmental and occupational exposures with increased MM risk, including pesticides, dioxins, and combustion byproducts, with experimental data supporting biologic plausibility through mechanisms such as oxidative stress, DNA damage, and aryl hydrocarbon receptor signaling. However, the available evidence is heterogeneous and largely associative, limiting causal inference. In this review, we synthesize current epidemiologic and mechanistic evidence linking environmental exposures to MM risk. We also highlight key methodological gaps and future directions, including the need for more precise exposure assessment, biospecimen-linked cohorts, and integrative studies that connect environmental data with disease biology.
  [del Rosal, M. et al. (2026) Environmental exposures and multiple myeloma risk: A contemporary review of epidemiologic associations and mechanistic plausibility, Blood Reviews. Available at: https://www.sciencedirect.com/science/article/pii/S0268960X26000317.]
• Immunotoxic effects in children resulting from prenatal and early childhood exposure to pesticides: A systematic review and meta-analysis
  Pesticide exposure during critical developmental windows may have lasting effects on the immune system. This systematic review examines the evidence for immunotoxic effects in children resulting from prenatal and early childhood exposure to pesticides. The review followed the PRISMA 2020 guidelines. A comprehensive search of scientific literature was conducted to identify studies examining associations between pesticide exposure and immune system parameters in children. Seventeen studies met the inclusion criteria. The reviewed studies consistently demonstrated alterations in immune parameters following pesticide exposure, with particular effects on white blood cell populations, cytokine production, and clinical outcomes. Meta-analyses revealed significant reductions in neutrophil counts (effect size: −0.09, 95 % confidence interval (CI): −0.17, −0.01; p = 0.02) and eosinophil counts (effect size: -0.06, 95 % CI: −0.09, −0.03; p < 0.001). Pro-inflammatory cytokine production was significantly increased (effect size: 0.18, 95 % CI: 0.08, 0.28; p < 0.001), while mixed pesticide exposure showed elevated immunoglobulin responses (odds ratio (OR): 1.42, 95 % CI: 1.12, 1.80; p < 0.001). Prenatal exposure to organochlorine pesticides was associated with decreased lymphocyte counts, altered T-cell subpopulations, dysregulated cytokine production, and increased susceptibility to infections. Pesticide exposure was linked to both immunosuppression and pro-inflammatory/allergic responses, suggesting complex and potentially exposure-specific effects. This review provides evidence that prenatal and early childhood pesticide exposure is associated with measurable changes in immune system parameters. These alterations may have clinical implications for childhood infections, allergic diseases, and potentially autoimmune conditions. Further research with standardized exposure and outcome assessments is needed to better characterize exposure-response relationships and identify specific vulnerable periods of immune system development.
  [Sherif, Moustafa & Darwish, Aya & Samy, Aya & Sami, Shimaa & Ádám, Balázs. (2025). Immunotoxic effects in children resulting from prenatal and early childhood exposure to pesticides: A systematic review and meta-analysis. The Science of the total environment. 1002. 180484. 10.1016/j.scitotenv.2025.180484. ]
• A Th2-type immune response and low-grade systemic inflammatory reaction as potential immunotoxic effects in intensive agriculture farmers exposed to pesticides
  
  [Lozano-Paniagua, D. et al. (2024) ‘A th2-type immune response and low-grade systemic inflammatory reaction as potential immunotoxic effects in intensive agriculture farmers exposed to pesticides’, Science of The Total Environment, 938, p. 173545. doi:10.1016/j.scitotenv.2024.173545. ]
• Association between exposure to organophosphate pesticides and cytokine levels in a population of flower workers in Mexico
  The ability of organophosphate pesticides to disturb immune function has been demonstrated by in vivo and in vitro studies, but evidence of such effects on humans remains scarce. To assess the association between organophosphate pesticides exposure and cytokine levels in Mexican flower workers, a cross-sectional study was carried out. A questionnaire was provided to 121 male flower workers, and urine and blood samples were collected. Using gas chromatography, urinary concentrations of dialkylphosphate metabolites were determined. The serum cytokine levels, IL-4, IL-5, IL-6, IL-8, and IL-10, were measured using multiplex analysis, and levels of INF-γ and TNF-α by ELISA. We found that a higher dialkylphosphate concentration decreased the pro-inflammatory cytokines INF-γ (β = −0.63; 95 % CI: −1.22, −0.05), TNF-α (β= −1.18; 95 % CI: −2.38, 0.02), and IL-6 (β= −0.59; 95 % CI: −1.29, 0.12), and increased IL-10 (β=0.56; 95 % CI: 0.02, 1.09), the main anti-inflammatory cytokine, suggesting an imbalance of the immune response in flower workers.
  [Blanco-Muñoz, J. et al. (2024) ‘Association between exposure to organophosphate pesticides and cytokine levels in a population of flower workers in Mexico’, Environmental Toxicology and Pharmacology, 110, p. 104521. doi:10.1016/j.etap.2024.104521. ]
• Occupational exposure to pesticides affects systemic cytokine profile and correlates with poor clinical prognosis in young women with breast cancer
  Aging is one of the main risk factors for breast cancer. However, the impact of environmental risk factors, such as pesticide exposure, on the clinical outcomes of patients with breast cancer, depending on disease onset, remains unclear.

  This study analyzed clinicopathological data from 188 women with breast cancer, who were either occupationally or domestically exposed to pesticides, or not exposed, according to their age at disease onset (early onset ≤50 years and late onset >50 years). Additionally, interleukin 4 (IL-4), interleukin 17A (IL-17A), and interleukin 12 (IL-12) levels were measured in plasma samples, and clinicopathological data were assessed.

  In the late-onset group, a greater frequency of low-grade tumors was detected in the exposed patients compared to the unexposed group (23.14 vs. 45.45%, p = 0.0181). A higher frequency of high-risk stratification for recurrence and death was found in early-onset patients when comparing exposed and unexposed groups (10.0 vs. 30.0%, p = 0.0488). Regarding the molecular subtypes of breast cancer, patients in the late-onset group showed a higher frequency of triple-negative tumors than unexposed women with the same disease onset (20.0 vs. 40.63%, p < 0.0001). IL-12 levels were significantly lower in exposed patients in the early-onset group compared to unexposed patients in the same group. Early-onset patients showed a principal component that positively correlated with pesticide exposure, IL-1β, IL-17A, and IL-4, while late-onset patients showed negative correlations between pesticide exposure and IL-12, IL-4, and IL-17A.

  These findings suggest that pesticide exposure induces an inflammaging-like state in younger women, contributing to an increased risk of developing more severe disease.
  [Cardoso Maciel Costa Silva, R. et al. (2024) ‘Occupational exposure to pesticides affects systemic cytokine profile and correlates with poor clinical prognosis in young women with breast cancer’, Immunopharmacology and Immunotoxicology, 47(1), pp. 34–41. doi:10.1080/08923973.2024.2430665. ]

• Public Health Risks of PFAS-Related Immunotoxicity Are Real
  Purpose of review: The discovery of per- and polyfluoroalkyl substances (PFAS) in the environment and humans worldwide has ignited scientific research, government inquiry, and public concern over numerous adverse health effects associated with PFAS exposure. In this review, we discuss the use of PFAS immunotoxicity data in regulatory and clinical decision-making contexts and question whether recent efforts adequately account for PFAS immunotoxicity in public health decision-making.

  Recent findings: Government and academic reviews confirm the strongest human evidence for PFAS immunotoxicity is reduced antibody production in response to vaccinations, particularly for tetanus and diphtheria. However, recent events, such as the economic analysis supporting the proposed national primary drinking water regulations and clinical monitoring recommendations, indicate a failure to adequately incorporate these data into regulatory and clinical decisions. To be more protective of public health, we recommend using all relevant immunotoxicity data to inform current and future PFAS-related chemical risk assessment and regulation. Biological measures of immune system effects, such as reduced antibody levels in response to vaccination, should be used as valid and informative markers of health outcomes and risks associated with PFAS exposure. Routine toxicity testing should be expanded to include immunotoxicity evaluations in adult and developing organisms. In addition, clinical recommendations for PFAS-exposed individuals and communities should be revisited and strengthened to provide guidance on incorporating immune system monitoring and other actions that can be taken to protect against adverse health outcomes.
  [Bline AP, DeWitt JC, Kwiatkowski CF, Pelch KE, Reade A, Varshavsky JR. Public Health Risks of PFAS-Related Immunotoxicity Are Real. Curr Environ Health Rep. 2024 Jun;11(2):118-127. doi: 10.1007/s40572-024-00441-y.]

• What immunology has to say about pesticide safety
  The use of pesticides has enabled the development of contemporary industrial agriculture and significantly increased crop yields. However, they are also considered a source of environmental pollution and a potential hazard to human health. Despite national agencies and the scientific community analyzing pesticide safety, immunotoxicity assays are often not required, poorly designed, or underestimated. Epidemiological evidence indicates that pesticide exposure increases the risk of developing cancer. Therefore, pesticides may not only act as carcinogens per se but also as immunosuppressive agents that create a permissive context for tumor development. Given recent evidence demonstrating the critical role of the immune response in cancer progression, we will highlight the necessity of assessing the potential impacts of pesticides on the immune response, particularly on tumor immunosurveillance. In this Perspective article, we will focus on the need to critically review fundamental aspects of toxicological studies conducted on pesticides to provide a clearer understanding of the risks associated with exposure to these compounds to human health.
  [Friedrich, A.D. and Zwirner, N.W. (2024) ‘What immunology has to say about pesticide safety’, Frontiers in Immunology, 15. doi:10.3389/fimmu.2024.1487805. ]
• Pesticides and Their Impairing Effects on Epithelial Barrier Integrity, Dysbiosis, Disruption of the AhR Signaling Pathway and Development of Immune-Mediated Inflammatory Diseases
  The environmental and occupational risk we confront from agricultural chemicals increases as their presence in natural habitats rises to hazardous levels, building a major part of the exposome. This is of particular concern in low- and middle-income countries, such as Brazil, known as a leading producer of agricultural commodities and consumer of pesticides. As long as public policies continue to encourage the indiscriminate use of pesticides and governments continue to support this strategy instead of endorsing sustainable agricultural alternatives, the environmental burden that damages epithelial barriers will continue to grow. Chronic exposure to environmental contaminants in early life can affect crucial barrier tissue, such as skin epithelium, airways, and intestine, causing increased permeability, leaking, dysbiosis, and inflammation, with serious implications for metabolism and homeostasis. This vicious cycle of exposure to environmental factors and the consequent damage to the epithelial barrier has been associated with an increase in immune-mediated chronic inflammatory diseases. Understanding how the harmful effects of pesticides on the epithelial barrier impact cellular interactions mediated by endogenous sensors that coordinate a successful immune system represents a crucial challenge. In line with the epithelial barrier hypothesis, this narrative review reports the available evidence on the effects of pesticides on epithelial barrier integrity, dysbiosis, AhR signaling, and the consequent development of immune-mediated inflammatory diseases.
  [Lima, C., Falcão, M.A.P., Rosa, J.G.S., Disner, G.R. and Lopes-Ferreira, M., 2022. International Journal of Molecular Sciences, 23(20), p.12402.]
• Potential neurotoxicity, immunotoxicity, and carcinogenicity induced by metribuzin and tebuconazole exposure in earthworms (Eisenia fetida) revealed by transcriptome analysis
  Metribuzin and tebuconazole have been widely used in agriculture for several decades. Apart from endocrine disruption, little is known about their toxicological effects on organisms without thyroid organs, at the transcriptional level. To explore this toxicity, model earthworm species Eisenia fetida, hatched from the same cocoon and cultured under identical environmental conditions, were independently exposed to the two chemicals at non-lethal concentrations in OECD artificial soil for 48 h after exposure. RNA-seq technology was used to analyze and compare the gene expression profiles of earthworms exposed to metribuzin and tebuconazole. The functions of differentially expressed genes and their standard response patterns of upregulated and downregulated expression for both pesticides were verified. The findings demonstrated that metribuzin and tebuconazole are both potentially toxic to earthworms. Toxicological effects mainly involved the nervous system, immune system, and tumors, at the transcriptional level, as well as the induction of cytochrome P450-dependent detoxification and oxidative stress. In addition, the mitogen-activated protein kinase kinase kinase gene was identified as a biomarker, and the mitogen-activated protein kinase signaling pathway was verified to be a part of the adverse outcome pathway of metribuzin and tebuconazole and their structural analogs.
  [Li, G., Li, D., Rao, H., & Liu, X. (2022). Potential neurotoxicity, immunotoxicity, and carcinogenicity induced by metribuzin and tebuconazole exposure in earthworms (Eisenia fetida) revealed by transcriptome analysis. The Science of the total environment, 807(Pt 1), 150760. https://doi.org/10.1016/j.scitotenv.2021.150760]
• The potential immunotoxicity of emamectin benzoate on the human THP-1 macrophages
  Emamectin benzoate (EMB) as one of the typical biological pesticides has a wide range of applications in agriculture. However, the immune toxic effects of EMB in human received limited attention. In our study, THP-1 macrophage as an in vitro model was used to evaluate immune functions exposed to EMB. We observed that EMB inhibited phagocytic activity and respiratory burst capacity of macrophages without inducing cellular toxicity, implying the potential immunosuppression. Besides, EMB disturbed the cytokines balance embodied in the increase of TNF-α, IL-1β, IL-6, CCL27, CXCL8 mRNA expression and the decrease of IL-4, IL-13, IL-10 mRNA expression. EMB could exhibit pro-inflammatory responses in macrophages and promote the conversion of macrophages to M1 phenotype. Moreover, NF-κB pathway involved in regulating immune function from KEGG pathway analysis. EMB exposure could activate the NF-κB pathway in THP-1 macrophages by exploring the critical proteins. This research provided insights on immunotoxicity evaluation and clarified EMB-induced immunotoxicity was related to NF-κB pathway activation.
  [Wei, Z., Wang, W., Fu, W., Zhang, P., Feng, H., Xu, W., Tao, L., Li, Z., Zhang, Y. and Shao, X., 2022. Environmental Toxicology.]
• Immune response of Brazilian farmers exposed to multiple pesticides
  Occupational exposure to pesticides has been identified as a factor that predisposes to disorders of the immune system. Immunosuppression, autoimmunity, cancer of various organs and other diseases in people who apply these products have been reported by the studies. This study aimed to investigate the relationship between occupational exposure to pesticides and the immunological profile in 43 farmers exposed to mixtures of pesticides for at least 15 years. A control group composed of 30 individuals without a history of occupational exposure to pesticides was also evaluated. Peripheral blood samples were processed by flow cytometry and cells were labelled with an 8-color monoclonal antibody panel. Plasma cytokines were also measured. Significant increase in classical monocytes (p < 0.001) and dendritic cells (p < 0.001) in the exposed group was observed as well in total T cells (p = 0.04), central memory CD8 T cells (p = 0.02) and effector memory CD8 T cells (p = 0.01). On the other hand, the activation markers of T cells as the expression of CD57, HLA-DR, CD25 and CD28 were evaluated and no difference was found between groups. When the B cells were analyzed, a significant decrease in total B cells (p = 0.01), regulatory B cells (p < 0.001) and plasmablasts (p < 0.001) in the exposed group, compared to healthy controls, was observed. Pro-inflammatory IL-6 was significantly elevated (p = 0.04) in the plasma of farmers compared to that of controls. The constant antigenic stimulus that occurs during exposure to pesticides can favor the recruitment of dendritic cells and macrophages (APCs) presents in the skin and respiratory tract. In the secondary lymphoid organs, the CD4 T and B cells that process such antigens are possibly undergoing proliferative exhaustion, with the consequent depletion of all mature B subpopulations. The resulting drop in humoral immunity may be offset by an increase in the number of circulating CD8 T lymphocytes due to their cytotoxic action.
  [Jacobsen-Pereira, C.H. et al. (2020) ‘Immune response of Brazilian farmers exposed to multiple pesticides’, Ecotoxicology and Environmental Safety, 202, p. 110912. doi:10.1016/j.ecoenv.2020.110912. ]
• Immunosuppression in Honeybee Queens by the Neonicotinoids Thiacloprid and Clothianidin
  Queen health is crucial to colony survival of honeybees, since reproduction and colony growth rely solely on the queen. Queen failure is considered a relevant cause of colony losses, yet few data exist concerning effects of environmental stressors on queens. Here we demonstrate for the first time that exposure to field-realistic concentrations of neonicotinoid pesticides can severely affect the immunocompetence of queens of western honeybees (Apis mellifera L.). In young queens exposed to thiacloprid (200 µg/l or 2000 µg/l) or clothianidin (10 µg/l or 50 µg/l), the total hemocyte number and the proportion of active, differentiated hemocytes was significantly reduced. Moreover, functional aspects of the immune defence namely the wound healing/melanisation response, as well as the antimicrobial activity of the hemolymph were impaired. Our results demonstrate that neonicotinoid insecticides can negatively affect the immunocompetence of queens, possibly leading to an impaired disease resistance capacity.
  [Brandt, A. et al. (2017) Immunosuppression in honeybee queens by the neonicotinoids Thiacloprid and Clothianidin, Scientific Reports. Available at: https://pubmed.ncbi.nlm.nih.gov/28680118/. ]
• Environmental immune disruptors, inflammation and cancer risk
  An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.
  [Thompson, P. A., Khatami, M., Baglole, C. J., Sun, J., Harris, S. A., Moon, E. Y., Al-Mulla, F., Al-Temaimi, R., Brown, D. G., Colacci, A., Mondello, C., Raju, J., Ryan, E. P., Woodrick, J., Scovassi, A. I., Singh, N., Vaccari, M., Roy, R., Forte, S., Memeo, L., … Bisson, W. H. (2015). Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis, 36 Suppl 1(Suppl 1), S232–S253. https://doi.org/10.1093/carcin/bgv038]
• A patient fatality following the ingestion of a small amount of chlorfenapyr
  Chlorfenapyr has been used worldwide for agricultural pest control since 1995. Despite its widespread use, acute human poisoning data are insufficient; only a small number of fatalities from chlorfenapyr poisoning have been reported. The signs and symptoms of chlorfenapyr toxicity include nausea, vomiting, fever, rhabdomyolysis, among others. In addition, central nervous system effects in association with delayed toxicity have also been observed. Here, we detail a fatality resulting from delayed chlorfenapyr toxicity following the ingestion of a small amount of pesticide.
  [Kang, C. et al. (2014) A patient fatality following the ingestion of a small amount of Chlorfenapyr, Journal of Emergencies, Trauma, and Shock. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126128/.]
• Pesticide induced immunotoxicity in humans: a comprehensive review of the existing evidence
  The immune system can be the target of many chemicals, with potentially severe adverse effects on the host's health. In Western countries pesticides, together with new and modified patterns of exposure to chemicals, have been implicated in the increasing prevalence of diseases associated with alterations of the immune response, such as hypersensitivity reactions, certain autoimmune diseases and cancers. Xenobiotics may initiate, facilitate or exacerbate pathological immune processes, resulting in immunotoxicity by induction of mutations in genes coding for immunoregulatory factors, modifying immune tolerance and activation pathways. The purpose of this article is to update the evidence of pesticide immunotoxicity. Even if experimental data as well as sporadic human studies indicate that some pesticides can affect the immune system, overall, existing epidemiological studies are inadequate to raise conclusions on the immunotoxic risk associated to pesticide exposure. The available studies on the effects of pesticides on human immune system have several limitations including poor indication on exposure levels, multiple chemical exposures, heterogeneity of the approach, and difficulty in giving a prognostic significance to the slight changes often observed. Further studies are necessary, and they should be preferably carried out through comparison of pre and post-exposure findings in the same group of subjects with a matched control group. Attempt should be made to define the prognostic significance of slight changes often observed. Animal and in vitro studies are also important and necessary to scientifically support epidemiological evidences on pesticide-induced immunotoxicity.
  [Corsini, E., Sokooti, M., Galli, C. L., Moretto, A., & Colosio, C. (2013). Pesticide induced immunotoxicity in humans: a comprehensive review of the existing evidence. Toxicology, 307, 123–135. https://doi.org/10.1016/j.tox.2012.10.009]