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Pesticide-Induced Diseases: Immune System Disorders

Arthritis/Osteoporosis Celiac Disease ● Hepatitis HypersensitivityImmunotoxictyLiver DamageLupusMultiple Sclerosis

Immune System Disorders cause the immune system to respond with unusually low activity (immunosuppression) or overactivity (autoimmunity). As many as 50 million Americans live with an autoimmune disorder caused by the immune response, autoimmunity – an organism's immune response attacking its healthy cells and tissue. The genetic predisposition for autoimmunity is 30%. However, environmental factors (i.e., exposure to toxins, diet, infection, etc.) trigger an autoimmune response 70% of the time. Six million Americans are living with a primary immunodeficiency disorder caused by immunosuppression – the body’s inability to fight off infection – but between 70-90% go undiagnosed.

 

Common household products –detergents, disinfectants, plastics, and pesticides– contain chemical ingredients that can trigger autoimmunity or immunosuppression. Pesticide-induced immune system disorders are a major public health concern as scientific evidence asserts an association between pesticide exposure and weakened immune function and response. Significant experimental, epidemiological, and additional scientific evidence uphold that many commonly used pesticides are immunosuppressive. While some research associates immune system disorders with the use of general pesticides, organochlorine pesticide use is commonly linked to the worsening effects of autoimmune diseases like lupus and rheumatoid arthritis. An Environmental Health Center-Dallas case report, Effects of Pesticides on the Immune System, concludes that: “pesticides of all categories may influence the immune system resulting in human dysfunction. […] Further studies are required, but clinicians should already be mindful of these phenomena when evaluating and treating patients with disorders of the immune system.”

 

Immune System Disorders are the mechanism of, and for several health effect endpoints. See the related sections (Cancer, Diabetes, and Endocrine Disruption) for more information.

Arthritis/Osteoporosis 

  • Exploratory analysis of the association between pyrethroid exposure and rheumatoid arthritis among US adults: 2007-2014 data analysis from the National Health and Nutrition Examination Survey (NHANES)
    Previous studies indicate that pesticide use may play an important role in the occurrence and development of rheumatoid arthritis (RA); however, little is known about the effect of specific pesticides on RA. The objective of this study was to evaluate whether pyrethroid exposure was linked to RA in adults. Data were originated from the 2007-2014 National Health and Nutrition Examination Survey (NHANES). The levels of pyrethroid exposure were assessed by 3-phenoxybenzoic acid (3-PBA) concentrations in urine samples. We built multivariate logistic regression models to assess associations between pyrethroid exposure and RA among US adults. A restricted cubic spline plot (three knots) was applied to test whether there was a nonlinear relationship between exposure to pyrethroid pesticides and the prevalence of RA. Finally, 4384 subjects were included in our analysis with 278 RA patients. In crude model, higher level of 3-PBA (creatinine-adjusted) was positively associated with RA (OR: 1.51, 95% CI: 1.07, 2.15). After adjustment for sex, race/ethnicity, education, body mass index, family poverty income, level of education, marital status, smoking status, alcohol usage, physical activity, hypertension, and urinary creatinine, the highest (vs lowest) quartile of 3-PBA was associated with an increased prevalence of RA (OR: 1.23, 95% CI: 0.86, 1.79). Significantly positive associations between 3-PBA concentration and RA were observed in the population aged between 40 and 59 years and with lower level of education. The restricted cubic spline plot presented an increase in trend and indicated that pyrethroid exposure was linearly associated with occurrence of RA (p for nonlinearity = 0.728). In conclusion, our study indicated that pyrethroid pesticide exposure was associated with an increased risk of RA. Higher levels of pyrethroid exposure were linearly associated with increased prevalence of RA in adults. Certainly, our findings are in great need of further corroboration by prospective studies with strict design.
    [Guo, X., Li, N., Wang, H., Su, W., Song, Q., Liang, Q., Sun, C., Liang, M., Ding, X., Lowe, S. and Sun, Y., 2022. Environmental Science and Pollution Research, pp.1-11.]
  • Pesticide Exposure and Risk of Rheumatoid Arthritis among Licensed Male Pesticide Applicators in the Agricultural Health Study.
    The occupation of farming has been associated with rheumatoid arthritis (RA); pesticides may account for this association, but there are few studies. Study investigated associations between RA and use of pesticides in the Agricultural Health Study.The study sample was drawn from male pesticide applicators enrolled in 1993-1997 who provided questionnaire data at baseline and at least once during follow-up (over a median 18 y; interquartile range 16-19). Incident RA cases confirmed by physicians or by self-reported use of disease-modifying antirheumatic drugs, were compared with noncases who did not report RA. Study evaluated the association of RA with the use of 46 pesticides and across 4 levels (never use and tertiles) of lifetime days of use for 16 pesticides with for ever use. Incident RA was associated with ever use of fonofos (OR = 1.70; 95% CI: 1.22, 2.37), carbaryl (OR = 1.51; 95% CI: 1.03, 2.23), and chlorimuron ethyl (OR = 1.45; 95% CI: 1.01, 2.07) compared with never use. Statistically significant exposure-response trends in association with RA were observed for lifetime days of use of atrazine [ 1.62 (95% CI: 1.09, 2.40)] and toxaphene [ 2.42 (95% CI: 1.03, 5.68)]. Exposure-response was nonlinear for fonofos [ 2.27 (95% CI: 1.44, 3.57); 0.98 (95% CI: 0.54, 1.80); 2.10 (95% CI: 1.32, 3.36)] and suggestive for carbaryl. Results provide novel evidence of associations between exposure to some pesticides and RA in male farmers. 
    [Meyer A, Sandler DP, Beane Freeman LE, et al. 2017. Environ Health Perspect. 125(7):077010]
  • Rheumatoid Arthritis in Agricultural Health Study Spouses: Associations with Pesticides and Other Farm Exposures
    Farming has been associated with rheumatoid arthritis (RA), but the role of pesticides is not known. We examined associations between RA and pesticides or other agricultural exposures among female spouses of licensed pesticide applicators in the Agricultural Health Study. Women were enrolled between 1993 and 1997 and followed through 2010. Cases (n = 275 total, 132 incident), confirmed by a physician or by self-reported use of disease modifying antirheumatic drugs, were compared with noncases (n = 24,018). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models adjusted for age, state, and smoking pack-years. Overall, women with RA were somewhat more likely to have reported lifetime use of any specific pesticide versus no pesticides (OR = 1.4; 95% CI: 1.0, 1.6). Of the 15 pesticides examined, maneb/mancozeb (OR = 3.3; 95% CI: 1.5, 7.1) and glyphosate (OR = 1.4; 95% CI: 1.0, 2.1) were associated with incident RA compared with no pesticide use. An elevated, but non-statistically significant association with incident RA was seen for DDT (OR = 1.9; 95% CI: 0.97, 3.6). Incident RA was also associated with the application of chemical fertilizers (OR = 1.7; 95% CI: 1.1, 2.7) and cleaning with solvents (OR = 1.6; 95% CI: 1.1, 2.4), but inversely associated with lifetime livestock exposure as a child and adult (OR = 0.48; 95% CI: 0.24, 0.97) compared with no livestock exposure. Our results suggest that specific agricultural pesticides, solvents, and chemical fertilizers may increase the risk of RA in women, while exposures involving animal contact may be protective. 
    [Parks CG, Hoppin JA, De Roos AJ, Costenbader KH, Alavanja MC, Sandler DP. 2016. Environ Health Perspect. 124(11):1728-1734]
  • Rheumatoid Arthritis in Agricultural Health Study Spouses: Associations with Pesticides and Other Farm Exposures
    Farming has been associated with rheumatoid arthritis (RA), but the role of pesticides is not known.
    We examined associations between RA and pesticides or other agricultural exposures among female spouses of licensed pesticide applicators in the Agricultural Health Study. Women were enrolled between 1993 and 1997 and followed through 2010. Cases (n = 275 total, 132 incident), confirmed by a physician or by self-reported use of disease modifying antirheumatic drugs, were compared with noncases (n = 24,018). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models adjusted for age, state, and smoking pack-years.
    Overall, women with RA were somewhat more likely to have reported lifetime use of any specific pesticide versus no pesticides (OR = 1.4; 95% CI: 1.0, 1.6). Of the 15 pesticides examined, maneb/mancozeb (OR = 3.3; 95% CI: 1.5, 7.1) and glyphosate (OR = 1.4; 95% CI: 1.0, 2.1) were associated with incident RA compared with no pesticide use. An elevated, but non-statistically significant association with incident RA was seen for DDT (OR = 1.9; 95% CI: 0.97, 3.6). Incident RA was also associated with the application of chemical fertilizers (OR = 1.7; 95% CI: 1.1, 2.7) and cleaning with solvents (OR = 1.6; 95% CI: 1.1, 2.4), but inversely associated with lifetime livestock exposure as a child and adult (OR = 0.48; 95% CI: 0.24, 0.97) compared with no livestock exposure. Our results suggest that specific agricultural pesticides, solvents, and chemical fertilizers may increase the risk of RA in women, while exposures involving animal contact may be protective.
    [Parks, C.G., Hoppin, J.A., De Roos, A.J., Costenbader, K.H., Alavanja, M.C. and Sandler, D.P., 2016. Environmental health perspectives, 124(11), pp.1728-1734.]
  • Pesticides and human chronic diseases: Evidences, mechanisms, and perspectives
    Along with the wide use of pesticides in the world, the concerns over their health impacts are rapidly growing. There is a huge body of evidence on the relation between exposure to pesticides and elevated rate of chronic diseases such as different types of cancers, diabetes, neurodegenerative disorders like Parkinson, Alzheimer, and amyotrophic lateral sclerosis (ALS), birth defects, and reproductive disorders. There is also circumstantial evidence on the association of exposure to pesticides with some other chronic diseases like respiratory problems, particularly asthma and chronic obstructive pulmonary disease (COPD), cardiovascular disease such as atherosclerosis and coronary artery disease, chronic nephropathies, autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis, chronic fatigue syndrome, and aging. The common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides' primary action like perturbation of ion channels, enzymes, receptors, etc., or can as well be mediated via pathways other than the main mechanism. In this review, we present the highlighted evidence on the association of pesticide's exposure with the incidence of chronic diseases and introduce genetic damages, epigenetic modifications, endocrine disruption, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress and unfolded protein response (UPR), impairment of ubiquitin proteasome system, and defective autophagy as the effective mechanisms of action.
    [Mostafalou, S. and Abdollahi, M., 2013. Toxicology and applied pharmacology, 268(2), pp.157-177.]
  • Insecticide Use and Risk Of Rheumatoid Arthritis And Systemic Lupus Erythematosus In The Women’s Health Initiative Observational Study
    Farming and agricultural pesticide use have been associated with two autoimmune rheumatic diseases, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, risk associated with other residential or workplace insecticide use is unknown. We analyzed data from the Women’s Health Initiative Observational Study (n=76,861, post-menopausal, age 50-79 years). Incident cases (n=213; 178 RA, 27 SLE, and 8 both) were identified based on self-report and use of disease modifying anti-rheumatic drugs at year 3 of follow-up. We examined self-reported residential or workplace insecticide use (personally mixing/applying by self and application by others) in relation to RA/SLE risk, overall and in relation to farm history. Hazard ratios (adj.HR) and 95% confidence intervals (CI) adjusted for age, race, region, education, occupation, smoking, reproductive factors, asthma, other autoimmune diseases and co-morbidities. Compared to never use, personal use of insecticides was associated with increased RA/SLE risk, with significant trends for greater frequency (adj.HR 2.04; 95%CI 1.17, 3.56 for ≥ 6 times/year) and duration (HR 1.97; 95% CI 1.20, 3.23 for ≥ 20 years). Risk was also associated with long-term insecticide application by others (adj.HR=1.85; 95% CI 1.07, 3.20 for ≥20 years), and frequent application by others among women with a farm history (adj.HR 2.73; 95% CI 1.10, 6.78 for ≥ 6 times/year). These results suggest residential and workplace insecticide exposure is associated with risk of ARD in post-menopausal women. Although these findings require replication in other populations, they support a role for environmental pesticide exposure in development of autoimmune rheumatic diseases.
    [Parks, C.G., Walitt, B.T., Pettinger, M., Chen, J.C., De Roos, A.J., Hunt, J., Sarto, G. and Howard, B.V., 2011. Arthritis care & research, 63(2), pp.184-194.]
  • Positive Associations of Serum Concentration of Polychlorinated Biphenyls or Organochlorine Pesticides with Self-Reported Arthritis, Especially Rheumatoid Type, in Women
    Persistent organic pollutants (POPs) can influence the immune system, possibly increasing the risk of rheumatoid arthritis (RA). In addition, as metabolic change due to obesity has been proposed as one mechanism of osteoarthritis (OA), POPs stored in adipose tissue may be also associated with OA. Our goal in this study was to examine associations of background exposure to POPs with arthritis among the general population. We investigated cross-sectional associations of serum POPs concentrations with the prevalence of self-reported arthritis in 1,721 adults ≥ 20 years of age in the National Health and Nutrition Examination Survey 1999–2002. Among several POPs, dioxin-like polychlorinated biphenyls (PCBs) or nondioxin-like PCBs were positively associated with arthritis in women. After adjusting for possible confounders, odds ratios (ORs) were 1.0, 2.1, 3.5, and 2.9 across quartiles of dioxin-like PCBs (p for trend = 0.02). Corresponding figures for nondioxin-like PCBs were 1.0, 1.6, 2.6, and 2.5 (p for trend = 0.02). Organochlorine (OC) pesticides were also weakly associated with arthritis in women. For subtypes of arthritis, respectively, RA was more strongly associated with PCBs than was OA. The adjusted ORs for RA were 1.0, 7.6, 6.1, and 8.5 for dioxin-like PCBs (p for trend = 0.05), 1.0, 2.2, 4.4, and 5.4 for nondioxin-like PCBs (p for trend < 0.01), and 1.0, 2.8, 2.7, and 3.5 for OC pesticides (p for trend = 0.15). POPs in men did not show any clear relation with arthritis.The possibility that background exposure to PCBs may be involved in pathogenesis of arthritis, especially RA, in women should be investigated in prospective studies.
    [Lee, D.H., Steffes, M. and Jacobs Jr, D.R., 2007. Environmental health perspectives, 115(6), pp.883-888.]

  • Association between pyrethroid exposure and osteoarthritis: a national population-based cross-sectional study in the US.
    With the restriction of organophosphorus and other insecticides, pyrethroids are currently the second most-used group of insecticides worldwide due to their advantages such as effectiveness and low toxicity for mammalian. Animal studies and clinical case reports have documented associations between adverse health outcomesand exposure to pyrethroids. At present, the association between chronic pyrethroid exposure and osteoarthritis (OA) remains elusive. Cross-sectional data from the National Health and Nutrition Examination Survey 1999–2002 and 2007–2014 were used to explore the associations of pyrethroid exposure and OA. Urinary level of 3-phenoxybenzoic acid (3-PBA) in urine samples was used to evaluate the exposure of pyrethroid, and OA was determined on the basis of self-reported physician diagnoses. Multivariable logistic regression models were used to investigate the association between pyrethroid exposure and OA. Among the 6528 participants, 650 had OA. The weighted geometric mean of urinary volume-based 3-PBA concentration were 0.45 µg/L. With adjustments for major confounders, compared to participants in the lowest quartile of urinary volume-based 3-PBA, those in the highest quartilehad higher odds of OA (odds ratio, 1.39; 95% confidence interval: 1.01, 1.92). There was no nonlinear relationship between urinary volume-based 3-PBA and OA (P for non-linearity = 0.89). High urinary 3-PBA concentration was associated with increased OA odds in the US adults. Pyrethroid exposure in the population should be monitored regularly.
    [Liang, Z., Sun, X., Lan, J., Guo, R., Tian, Y., Liu, Y. and Liu, S., 2023. BMC Public Health, 23(1), p.1521.]
  • Association between urinary triclosan with bone mass density and osteoporosis in the US adult women, 2005-2010.
    Laboratory studies have demonstrated that Triclosan (TCS) could result in significant interstitial collagen accumulation and an increase in trabecular bone. However, little is known about the relationship between TCS exposure and human bone health. We used 2005-2010 National Health and Nutrition Examination Survey data to examine the association between urinary TCS concentrations with BMD and osteoporosis in the US adult women (age ≥20 years). After inclusion and exclusion, 1,848 women were finally analyzed. After adjustment for other covariates, we observed significant associations between tertile 3 of TCS concentration and lower BMD in regions of total femur (β=-0.016, 95% CI=-0.032, -0.000), intertrochanter (β=-0.022, 95% CI=-0.042, -0.002), and lumbar spine (β=-0.014, 95% CI=-0.029, 0.001), respectively, relative to tertile 1. Compared with women at tertile 1, those at tertile 3 were more likely to have increased osteoporosis prevalence in intertrochanter [odd ratio (OR)=2.464, 95% CI = 1.190, 5.105]. This is the first epidemiological study to investigate the association between urinary TCS concentration with BMD and osteoporosis in the US adult women. We found urinary TCS concentration was negatively associated with BMD and was positively associated with the prevalence of osteoporosis. The evidence was stronger in postmenopausal women than in premenopausal women. Future prospective studies are needed to validate the findings.
    [Cai, S., Zhu, J., Sun, L., Fan, C., Zhong, Y., Shen, Q. and Li, Y., 2019. The Journal of Clinical Endocrinology & Metabolism.]

Celiac Disease

  • Persistent organic pollutant exposure and celiac disease: A pilot study
    Celiac disease affects approximately 1% of the population worldwide. Little is known about environmental factors that may modulate risk in genetically susceptible populations. Persistent organic pollutants (POPs) are known endocrine disruptors and, given the interplay between the endocrine and immune systems, are plausible contributors to celiac disease. The current study aims to elucidate the association between POPs and celiac disease. We conducted a single-site pilot study of 88 patients recruited from NYU Langone's Hassenfeld Children's Hospital outpatient clinic, 30 of which were subsequently diagnosed with celiac disease using standard serology and duodenal biopsy examination. Polybrominated diphenyl ether (PBDEs), perfluoroalkyl substances (PFASs), and p,p’-dichlorodiphenyldichloroethylene (DDE) and HLA-DQ genotype category were measured in blood serum and whole blood, respectively. Multivariable logistic regressions were used to obtain odds ratios for celiac disease associated with serum POP concentrations. Controlling for sex, race, age, BMI, and genetic susceptibility score, patients with higher serum DDE concentrations had 2-fold higher odds of celiac disease (95% CI: 1.08, 3.84). After stratifying by sex, we found higher odds of celiac disease in females with serum concentrations of DDE (OR = 13.0, 95% CI = 1.54, 110), PFOS (OR = 12.8, 95% CI = 1.17, 141), perfluorooctanoic acid (OR = 20.6, 95% CI = 1.13, 375) and in males with serum BDE153, a PBDE congener (OR = 2.28, 95% CI = 1.01, 5.18). This is the first study to report on celiac disease with POP exposure in children. These findings raise further questions of how environmental chemicals may affect autoimmunity in genetically susceptible individuals.
    [Gaylord, A., Trasande, L., Kannan, K., Thomas, K.M., Lee, S., Liu, M. and Levine, J., 2020. Environmental Research, p.109439.]
  • Glyphosate, pathways to modern diseases II: Celiac sprue and gluten intolerance
    Celiac disease, and, more generally, gluten intolerance, is a growing problem worldwide, but especially in North America and Europe, where an estimated 5% of the population now suffers from it. Symptoms include nausea, diarrhea, skin rashes, macrocytic anemia and depression. It is a multifactorial disease associated with numerous nutritional deficiencies as well as reproductive issues and increased risk to thyroid disease, kidney failure and cancer. Here, we propose that glyphosate, the active ingredient in the herbicide, Roundup®, is the most important causal factor in this epidemic. Fish exposed to glyphosate develop digestive problems that are reminiscent of celiac disease. Celiac disease is associated with imbalances in gut bacteria that can be fully explained by the known effects of glyphosate on gut bacteria. Characteristics of celiac disease point to impairment in many cytochrome P450 enzymes, which are involved with detoxifying environmental toxins, activating vitamin D3, catabolizing vitamin A, and maintaining bile acid production and sulfate supplies to the gut. Glyphosate is known to inhibit cytochrome P450 enzymes. Deficiencies in iron, cobalt, molybdenum, copper and other rare metals associated with celiac disease can be attributed to glyphosate's strong ability to chelate these elements. Deficiencies in tryptophan, tyrosine, methionine and selenomethionine associated with celiac disease match glyphosate's known depletion of these amino acids. Celiac disease patients have an increased risk to non-Hodgkin's lymphoma, which has also been implicated in glyphosate exposure. Reproductive issues associated with celiac disease, such as infertility, miscarriages, and birth defects, can also be explained by glyphosate. Glyphosate residues in wheat and other crops are likely increasing recently due to the growing practice of crop desiccation just prior to the harvest. We argue that the practice of “ripening” sugar cane with glyphosate may explain the recent surge in kidney failure among agricultural workers in Central America. We conclude with a plea to governments to reconsider policies regarding the safety of glyphosate residues in foods.
    [Samsel, A. and Seneff, S., 2013. Interdisciplinary toxicology, 6(4), pp.159-184.]

Hepatitis

  • Carbaryl, A Pesticide Causes "Toxic Hepatitis" in Albino Rats
    Pesticides are one of the most alarming toxic substances that are deliberately added to our environment. Food and agricultural organization (FAO) has defined the term pesticide as: Any substance or mixture of substances intended for preventing, destroying or controlling any pest including vectors of human or animal disease, unwanted species of plants or animals causing harm during or otherwise interfering with the production, processing, storage, transport or marketing of food, agricultural commodities, wood and wood products or animal feedstuffs or substances which may be administered to animals for control of insects, arachnids or other pests in or on their bodies [1]. But it is a matter of concern that along with the pests, they prove harmful to many other living beings on this planet as well as human beings including newborns [2]. CARBARYL, a synthetic 1-napthyl-N-methyl carbamate is being used extensively or its broad-spectrum activity in commercial agriculture, poultry, livestock, home and garden pest control. It was the most frequently detected carbamate in juice samples studied [3]. Thorough scanning reveals that there is dearth of literature regarding the histopathological changes in liver associated with administration of carbaryl which has prompted us to initiate this study as liver plays an important role in the first pass metabolism of carbaryl. The present study was conducted on 40 albino rats. The adult albino rats (150-200 gm) were injected with 200 mg/ kg body weight of carbaryl intrapeitoneally, five days a week for 30 days. Controls were maintained. There was a significant increase in weight of the experimental rats recorded before the onset of the experiment & prior to their sacrifice (p<0.001) as compared to the controls. The rats were sacrificed within 24 hours of the last injection. The blocks of the liver were prepared for section cutting with a microtome by paraffin wax embedding method. Sections of 5-7 µm thickness were cut and stained with Haematoxylin and Eosin stain. In the study, the histomorphological changes, in the liver of Carbaryl treated rats was significantly different from that of the normal and the control rats. The disheveled pattern of the one cell thick orderly arrangement of hepatocytic cords, evidence of increased cellular metabolism co-existent with ballooning degeneration, councilman bodies, inflammatory infiltrate around the portal triads along with the dilatation of the blood vessels and the bile canaliculi were seen as signs of degeneration. B enucleated hepatocytes were suggestive of regenerative attempts by the degenerative cells. These findings are highly conclusive of toxic hepatitis induced by an insecticide, Carbaryl.
    [Hamid, S., Mahajan, R. and Singh, H., 2012. J Cytol Histol, 3(4), pp.149-154.]

Hypersensitivity

  • Toxicant-induced loss of tolerance for chemicals, foods, and drugs: assessing patterns of exposure behind a global phenomenon
    Despite 15–36% of the U.S. population reporting Chemical Intolerances (CI) or sensitivity, the condition has been overlooked in medicine and public health. CI is characterized by multisystem symptoms and new-onset intolerances that develop in a subset of individuals following a major chemical exposure event or repeated low-level exposures. While Toxicant-Induced Loss of Tolerance (TILT) is a two-stage disease mechanism proposed to explain CI, less is known about the exposures that initiate the disease, than about the intolerances that have been documented. We reviewed eight major exposure events that preceded onset of chemical intolerance in groups of individuals sharing the same exposure. Our goal was to identify the chemicals and/or groups of chemicals that were most pervasive during each exposure event as well as identify the concentrations of key chemicals involved in each exposure event and the proportions of exposed individuals who ultimately developed TILT following exposure. Case studies we selected for review included (1) workers at U.S. Environmental Protection Agency (EPA) headquarters during renovations; (2) Gulf War veterans; (3) pesticide exposure among casino workers; (4) exposure to aircraft oil fumes; (5) the World Trade Center tragedy; (6) surgical implants; (7) moldy environments; and (8) tunnel workers exposed to solvents. Mixed volatile and semi-volatile organic compounds (VOCs and SVOCs), followed by pesticides and combustion products were most prevalent across TILT initiation events. As a broader category, synthetic organic chemicals and their combustion products were the primary exposures associated with chemical intolerance. Such chemicals included pesticides, peroxides, nerve agents, anti-nerve agent drugs, lubricants and additives, xylene, benzene, and acetone. A select group of exposures were predominant in several major initiating events, suggesting their potential role in TILT initiation. Such insights are useful to public health scientists, physicians, and policymakers seeking to minimize harmful exposures and prevent future disease.
    [Masri, S., Miller, C.S., Palmer, R.F. and Ashford, N. Environmental Sciences Europe, 33(1), pp.1-19.]
  • Clinical Immunotoxicity of Pesticides
    Because of the wide use of pesticides for domestic and industrial purposes, the evaluation of their immunotoxic effects is of major concern for public health. Despite the large amount of experimental data describing pesticide-induced immunosuppression, evidence that pesticides may severely impair immune functions in humans is lacking or scarce. Contact hypersensitivity is a well-identified immunotoxic effect of pesticides but remains a rare complaint in pesticide-exposed workers. By contrast, immunologically mediated systemic reactions have been described only as debatable case reports. The association between autoimmune diseases and pesticide exposure has more recently been suggested. Despite the lack of convincing human data, a potential risk for the immune system should not be excluded, especially during chronic exposure to pesticides or in otherwise (immuno) compromised patients (malnutrition, children, old patients). Epidemiological studies including markers of exposure and the assessment of immune competence in exposed individuals, or registries of sentinel diseases related to immunosuppression (e.g., non-Hodgkin's lymphoma, opportunistic infections) or autoimmunity (e.g., lupus erythematosus, rheumatoid arthritis), are warranted.
    [Vial, T., Nicolas, B. and Descotes, J., 1996. Journal of toxicology and environmental health, 48(3), pp.215-229.]
  • Pesticide-Induced Modulation of the Immune System
    The immune system is a recognized target organ for the toxicologic effects of pesticides. Studies in animals have documented immune dysfunction following relatively short-term exposure to pesticides leading to an increased susceptibility to infection and, arguably, cancer. However, other than hypersensitivity reactions, the evidence in humans linking exposure to pesticides and adverse health effects associated with immune dysfunction is inconclusive at this time.
    [Thomas, P.T. and House, R.V., 1989. ACS Symposium Series. Vol. 414.]

Immunotoxicity

 

  • 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.]
  • 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.]

Liver Damage

  • 2,4-D Herbicide-Induced Hepatotoxicity: Unveiling Disrupted Liver Functions and Associated Biomarkers

    Abstract

    2,4-dichlorophenoxyacetic acid (2,4-D) is a widely used herbicide worldwide and is frequently found in water samples. This knowledge has prompted studies on its effects on non-target organisms, revealing significant alterations to liver structure and function. In this review, we evaluated the literature on the hepatotoxicity of 2,4-D, focusing on morphological damages, toxicity biomarkers and affected liver functions. Searches were conducted on PubMed, Web of Science and Scopus and 83 articles were selected after curation. Among these studies, 72% used in vivo models and 30% used in vitro models. Additionally, 48% used the active ingredient, and 35% used commercial formulations in exposure experiments. The most affected biomarkers were related to a decrease in antioxidant capacity through alterations in the activities of catalase, superoxide dismutase and the levels of malondialdehyde. Changes in energy metabolism, lipids, liver function, and xenobiotic metabolism were also identified. Furthermore, studies about the effects of 2,4-D in mixtures with other pesticides were found, as well as hepatoprotection trials. The reviewed data indicate the essential role of reduction in antioxidant capacity and oxidative stress in 2,4-D-induced hepatotoxicity. However, the mechanism of action of the herbicide is still not fully understood and further research in this area is necessary.

    [Martins, R.X. et al. (2024) ‘2,4-D herbicide-induced hepatotoxicity: Unveiling disrupted liver functions and associated biomarkers’, Toxics, 12(1), p. 35. doi:10.3390/toxics12010035. ]
  • Human serum lipidomics analysis revealed glyphosate may lead to lipid metabolism disorders and health risks
    Glyphosate-based herbicides (GBH) are one of the most widely used pesticides worldwide. Industrial workers in glyphosate-based herbicides manufacture are the populations who experience long-term exposure to high glyphosate levels. The impacts of glyphosate on human health are the important public health problem of great concern. Up to date, the potential adverse effects of glyphosate on humans or other mammals have been reported in multiple studies. However, limited research is available on lipid alternations related to human exposure to glyphosate. In fact, the perturbations in some lipid metabolisms have been found in industrial workers in previous work. This study aims to explore the serum lipidomic characterization and to understand the underlying mechanisms of health risks associated with glyphosate exposure. A nontargeted lipidomics study was conducted to investigate the 391 serum samples from the general population and chemical factory workers. It was demonstrated that glyphosate caused significant perturbations of 115 differentially expressed lipids. The main manifestations were the elevation of circulating diacylglycerols (DG), cholesteryl esters (CE), ceramides (Cer), sphingomyelins (SM), lysophosphatidylethanolamines (LPE) and phosphatidylcholines (PC), and the decrease of ysophosphatidylcholines (LPC), triacylglycerols (TG), fatty acids (FA) and phosphatidylethanolamines (PE). A total of 88 lipids were further screened as potential lipid biomarkers associated closely with glyphosate using partial correlation analysis, and five of which (including PC 16:0/18:2; O, PC 18:0/18:2; O, PC 18:0/20:4; O, PC O-40:9 and CE 18:3) showed excellent superior performance (AUC = 1) to evaluate and monitor health risks due to glyphosate exposure. The present work discovered glyphosate-induced potential health risks, including chronic hepatic and renal dysfunction, atherosclerosis, cardiovascular disease and neurodegenerative diseases from a lipidomic perspective, and could inform the identification of early indicators and interpretation of biological mechanisms to detect health risks of the glyphosate-exposed populations as early as possible.
    [Zhang, F., Zhang, Q., Liu, X., Gao, M., Li, X., Wang, Y., Chang, Y., Zhang, X., Huo, Z., Zhang, L. and Shan, J., 2023. Environment International, 171, p.107682.]
  • Harmful health effects of pesticides used on museum textile artifacts - overview
    The paper discusses the types of fibers contained in the museum textile artifacts and the types of pests and pesticides. Also, the main health problems associated with pesticide exposure are presented. Textile fibers represent an excellent source of food for microbes and insects. The key to the long-term preservation of textiles is by implementing an integrated management program for pest and environmental conditions control. The main types of pesticides are insecticides, herbicides, fungicides, rodenticides, acaricides, and fumigants and a way for classification can be made according to the LD50 (lethal dose) value which evaluates the toxicity of a pesticide. Depending on the LD50 values, pesticides can be very toxic, moderately toxic, slightly toxic, and relatively non-toxic. Exposure to pesticides can occur through 4 four routes: oral, dermal, respiratory, and eye exposure. The main diseases that can be associated with exposure to pesticides are discussed in the paper. In the end, a basic set of precautionary recommendations when handling museum objects that may contain hazardous materials was presented.
    [Tănăsescu, E.C. and Lite, M.C., 2022. Ecotoxicology and Environmental Safety, 247, p.114240.]
  • Perinatal exposure to a glyphosate pesticide formulation induces offspring liver damage
    The present study investigated the effects of perinatal exposure to glyphosate-based herbicide (GBH) in offspring's liver. Pregnant Wistar rats were exposed to GBH (70 mg glyphosate/Kg body weight/day) in drinking water from gestation day 5 to postnatal day 15. The perinatal exposure to GBH increased 45Ca2+ influx in offspring's liver. Pharmacological tools indicated a role played by oxidative stress, phospholipase C (PLC) and Akt pathways, as well as voltage-dependent Ca2+ channel modulation on GBH-induced Ca2+ influx in offspring's liver. In addition, changes in the enzymatic antioxidant defense system, decreased GSH content, lipid peroxidation and protein carbonylation suggest a connection between GBH-induced hepatotoxic mechanism and redox imbalance. The perinatal exposure to GBH also increased the enzymatic activities of transaminases and gamma-glutamyl transferase in offspring's liver and blood, suggesting a pesticide-induced liver injury. Moreover, we detected increased iron levels in liver, blood and bone marrow of GBH-exposed rats, which were accompanied by increased transferrin saturation and decreased transferrin levels in blood. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were increased in the liver of rats perinatally exposed to GBH, which were associated with. Increased phospho-p65NFκB immunocontent. Therefore, we propose that excessive amounts of iron in offspring's liver, blood and bone marrow induced by perinatal exposure to GBH may account for iron-driven hepatotoxicity, which was associated with Ca2+ influx, oxidative damage and inflammation. Further studies will clarify whether these events can ultimately impact on liver function.
    [Rieg, C.E.H., Cattani, D., Naspolini, N.F., Cenci, V.H., Cavalli, V.L.D.L.O., Jacques, A.V., Nascimento, M.V.P.D.S., Dalmarco, E.M., De Moraes, A.C.R., Santos-Silva, M.C. and Silva, F.R.M.B., 2022. Toxicology and Applied Pharmacology, 454, p.116245.]

Systemic Lupus Erythematosus (Lupus)

  • Pesticides, chemical and industrial exposures in relation to systemic lupus erythematosus
    Growing evidence suggests exposure to chemicals and industrial pollutants may increase risk of systemic lupus erythematosus (SLE). Here we review research on SLE associations with occupational and industrial exposures, primarily drawing on studies in human populations and summarizing epidemiologic research published in the past decade. The association of occupational silica exposure with SLE is well established, but key questions remain, including the required dose and susceptibility factors, and SLE risk due to other silicate exposures. Research on SLE and other exposures is less well developed, though several potential associations merit further consideration because of the consistency of preliminary human findings, experimental animal research, and biologic plausibility. These include pesticides and solvents, for which experimental findings also support investigation of specific agents, including organochlorines and trichloroethylene. Experimental findings and biologic plausibility suggest research on SLE and occupational exposure to hydrocarbons (i.e. mineral oils) is warranted, especially given the widespread exposures in the population. Experimental and limited human findings support further investigation of SLE related to mercury exposure, especially in dental occupations. Research on environmental risk factors in risk-enriched cohorts (family-based) is recommended, as is further investigation of exposures in relation to intermediate markers of effect (e.g. antinuclear antibodies), clinical features (e.g. nephritis), and outcomes.
    [Parks, C.G. and De Roos, A.J., 2014. Lupus, 23(6), pp.527-536.]
  • Pesticides and human chronic diseases: Evidences, mechanisms, and perspectives
    Along with the wide use of pesticides in the world, the concerns over their health impacts are rapidly growing. There is a huge body of evidence on the relation between exposure to pesticides and elevated rate of chronic diseases such as different types of cancers, diabetes, neurodegenerative disorders like Parkinson, Alzheimer, and amyotrophic lateral sclerosis (ALS), birth defects, and reproductive disorders. There is also circumstantial evidence on the association of exposure to pesticides with some other chronic diseases like respiratory problems, particularly asthma and chronic obstructive pulmonary disease (COPD), cardiovascular disease such as atherosclerosis and coronary artery disease, chronic nephropathies, autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis, chronic fatigue syndrome, and aging. The common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides' primary action like perturbation of ion channels, enzymes, receptors, etc., or can as well be mediated via pathways other than the main mechanism. In this review, we present the highlighted evidence on the association of pesticide's exposure with the incidence of chronic diseases and introduce genetic damages, epigenetic modifications, endocrine disruption, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress and unfolded protein response (UPR), impairment of ubiquitin proteasome system, and defective autophagy as the effective mechanisms of action.
    [Mostafalou, S. and Abdollahi, M., 2013. Toxicology and applied pharmacology, 268(2), pp.157-177.]
  • Alterations in T-lymphocyte sub-set profiles and cytokine secretion by PBMC of systemic lupus erythematosus patients upon in vitro exposure to organochlorine pesticides
    Chronic exposure to organochlorine pesticides (OCP) has been suspected of causing immunoregulatory abnormalities that eventually lead to development and progression of Systemic Lupus Erythematosus (SLE), but the role of these non-genetic stimuli has remained poorly understood. The objectives of the study were to quantify the levels of different OCP residues in the blood of SLE patients and to study the effects of in vitro treatment of peripheral blood mononuclear cells (PBMC) from these patients and healthy controls with OCP. Levels of different OCP residues in the blood were measured by gas-liquid chromatography. Isolated PBMC were treated in vitro with hexachlorocyclohexane (HCH), o,p’-dichlorodiphenyltrichloroethane (DDT), or phytohemagglutinin-M (PHA-M) for 72 h, then stained with different dye-labeled monoclonal antibodies to analyze alterations in T-lymphocytes using flow cytometry. Levels of different TH1 and TH2 cytokines were also estimated by ELISA. Significantly higher levels of p,p’-DDE and β-HCH were detected in the blood of SLE patients than in healthy controls. HCH exposure markedly increased the percentages of CD3+CD4+ T-lymphocytes and expression of CD45RO+ on CD4+ and CD8+ T-lymphocytes, but decreased CD4+CD25+ T-lymphocytes in SLE patients. DDT exposure increased the percentages of CD3+CD4+ T-lymphocytes and decreased those of CD4+CD25+ T-lymphocytes in SLE patients as compared to healthy controls. No significant responsiveness of patient PBMC to PHA-M stimulation was observed indicating suppression of T-lymphocytes by these OCP. Further, both HCH and DDT decreased the levels of IL-2 and IFNγ but had no effect on IL-4 levels in SLE patients. DDT also increased significantly the levels of IL-10 in patients. It is likely that higher levels and prolonged durations of exposure to HCH and DDT may significantly influence T-lymphocyte sub-sets and cytokine expression in vivo that could lead to the development or exacerbation of SLE.
    [Dar, S.A., Das, S., Ramachandran, V.G., Bhattacharya, S.N., Mustafa, M.D., Banerjee, B.D. and Verma, P., 2012. Journal of immunotoxicology, 9(1), pp.85-95.]
  • Lupus erythematosus. Are residential insecticides exposure the missing link?
    Although the etiology of systemic lupus erythematosus (SLE) remains to be fully elucidated, it is now apparent that multiple genetic and environmental factors are at play. Because lupus has a strong female preponderance, several studies have examined the role of female hormones in disease etiology. Yet this knowledge has not helped to explain lupus etiology or to prevent it. Estrogens exist not only as natural or drug compounds, but also as environmental chemical contaminant and women are highly exposed to all of them. Estrogenic activity has been found in a number of pesticides including pyrethroids that are largely used in the household. Although there is only a small amount of published data examining a possible causal relationship between lupus and pesticides it can be hypothesized that pesticides, in particular insecticides, through their estrogenic activity and capacity to induce oxidative stress provoke autoimmune reaction influencing lupus development.
    [Fortes, C., 2010. Medical hypotheses, 75(6), pp.590-593.]
  • Acceleration of Autoimmunity by Organochlorine Pesticides: A Comparison of Splenic B-Cell Effects of Chlordecone and Estradiol in (NZBxNZW)F1 Mice
    The weakly estrogenic organochlorine pesticide chlordecone can accelerate the development of systemic lupus erythematosus (SLE) in ovariectomized (NZB x NZW)F1 mice, with a shortened time to appearance of autoantibodies and disease similar to that produced by treatment with the sex hormone 17β-estradiol (E2). It is unclear whether chlordecone and E2 share the same pathways in mediating this effect. The effects of chlordecone and E2 treatment on splenic germinal center (GC) and marginal zone B cells were examined. Both chlordecone and E2 activated splenic B cells and enhanced GC reactions, as shown by upregulated protein expression of GL7, CXCR5, and CXCR4. Both treatments increased B-cell bcl-2 and shp-1 gene expression and enhanced ICAM-1 and VCAM-1 protein levels in GC B cells. Chlordecone reduced total B cell and GC B-cell apoptosis without affecting proliferation, another feature shared by E2 treatment. However, chlordecone treatment did not alter the composition of splenic B-cell subsets in marked contrast to the decrease in transitional B cells and increase in marginal zone B cells seen in E2-treated mice. The differences in effects between chlordecone and E2 indicate that chlordecone is not functioning simply as an estrogen mimic with respect to effects on the immune system. Similarities in the effects of chlordecone and E2 on specific immune functions, such as diminished apoptosis in GC B cells, may provide valuable clues regarding key events in the acceleration of autoimmunity by E2, chlordecone, and other agents.
    [Wang, F., Roberts, S.M., Butfiloski, E.J., Morel, L. and Sobel, E.S., 2007. Toxicological sciences, 99(1), pp.141-152.]

Multiple Sclerosis (MS)

  • Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation
    Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.
    [Wheeler, M.A., Jaronen, M., Covacu, R., Zandee, S.E., Scalisi, G., Rothhammer, V., Tjon, E.C., Chao, C.C., Kenison, J.E., Blain, M. and Rao, V.T., 2019. Cell, 176(3), pp.581-596.]
  • Pesticides and human chronic diseases: Evidences, mechanisms, and perspectives
    Along with the wide use of pesticides in the world, the concerns over their health impacts are rapidly growing. There is a huge body of evidence on the relation between exposure to pesticides and elevated rate of chronic diseases such as different types of cancers, diabetes, neurodegenerative disorders like Parkinson, Alzheimer, and amyotrophic lateral sclerosis (ALS), birth defects, and reproductive disorders. There is also circumstantial evidence on the association of exposure to pesticides with some other chronic diseases like respiratory problems, particularly asthma and chronic obstructive pulmonary disease (COPD), cardiovascular disease such as atherosclerosis and coronary artery disease, chronic nephropathies, autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis, chronic fatigue syndrome, and aging. The common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides' primary action like perturbation of ion channels, enzymes, receptors, etc., or can as well be mediated via pathways other than the main mechanism. In this review, we present the highlighted evidence on the association of pesticide's exposure with the incidence of chronic diseases and introduce genetic damages, epigenetic modifications, endocrine disruption, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress and unfolded protein response (UPR), impairment of ubiquitin proteasome system, and defective autophagy as the effective mechanisms of action.
    [Mostafalou, S. and Abdollahi, M., 2013. Toxicology and applied pharmacology, 268(2), pp.157-177.]
  • Association between environmental exposure to pesticides and neurodegenerative diseases
    Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population.
    [Parrón, T., Requena, M., Hernández, A.F. and Alarcón, R., 2011. Toxicology and applied pharmacology, 256(3), pp.379-385.]