A Th2-type immune response and low-grade systemic inflammatory reaction as potential immunotoxic effects in intensive agriculture farmers exposed to pesticides.

Pesticides are chemicals widely used in agriculture to keep crops healthy and prevent them from being destroyed by pests, thus contributing to a sustainable food and feed production. However, long-term exposure to these compounds may be harmful to human health as they can affect the function of various organs systems, including the immune system. There is growing evidence that pesticides may increase the risk of developing immune-based diseases and inflammation. This study assessed whether greenhouse farmers occupationally exposed to pesticides presented alterations in immunoregulatory proteins, used as surrogate biomarkers of immune function. The study population consisted of 175 greenhouse workers occupationally exposed to pesticides and 91 non-exposed controls. Serum levels of 27 cytokines, chemokines and growth factors were measured using a magnetic bead-based immunoassay in a subpopulation of 111 greenhouse workers and 79 non-exposed controls. Since analytical determinations were performed in two periods of the same crop season with different use of pesticides (period of high and low pesticide exposure), linear mixed models for repeated measures were used to optimize statistical inference. The increase in IL-13, IL-4 and IL-6 observed in greenhouse workers compared to controls, and in the period of high exposure to pesticides relative to that of low exposure, suggest an altered Th1/Th2 balance towards the Th2 response. This finding points to a type-2 inflammation commonly presented as allergic inflammation, which has often been reported in farm-workers and in which pesticide exposure is considered a risk factor. Furthermore, the increase in IL-1ß and VEGF, mediators of inflammation and angiogenesis, may suggest a low-grade systemic inflammation that might underlie chronic pathological conditions linked to pesticide exposure.

Exposure to Environmental Pesticides and the Risk of Autism Spectrum Disorders: A Population-Based Case-Control Study.

Background and Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by challenges in communication, social interactions, and repetitive behaviors. Although the factors that influence the development of this condition are unknown, certain chemical compounds such as pesticides have been proposed as possible contributors. Due to the lack of an established causal link between pesticide exposure and ASD, this study aimed to evaluate this potential association. Materials and Methods: A case-control study was carried out to ascertain the prevalence and risk associated with ASD in relation to pesticide exposure over a 21-year study period (2000-2021). Results: We included 2821 individuals diagnosed with ASD residing in areas of both high and low pesticide exposure in southern Spain. There was a rise in the ASD prevalence rate in regions with elevated pesticide use when compared to regions with low use [odds ratio (OR): 1.34, 95% confidence interval (CI), (1.24-1.44)]. Notably, men had the highest likelihood, with an OR: 1.42, 95% CI, (1.30-1.55). Furthermore, after performing multiple binary logistic regression adjusted for age, sex, and geographical area, males exhibited a higher likelihood compared to females [OR: 2.41, 95% CI, (2.21-2.62)]. Conclusions: Overall, this research suggests a connection between heightened environmental pesticide exposure due to increased agricultural use and autism.

Renal tubular dysfunction in greenhouse farmers exposed to pesticides unveiled by a panel of molecular biomarkers of kidney injury.

Growing evidence suggests that chronic exposure to pesticides may cause adverse effects on the health of the exposed population leading to organ-specific toxicity, including kidney damage. Traditional markers used to assess renal function (glomerular filtration rate (GFR), and serum creatinine and cystatin C -Cys-C-) are inadequate to evaluate a potential subclinical renal impairment linked to occupational exposure to pesticides, since levels above the upper limit of normal only occur when renal damage is very extensive. The use of more sensitive biomarkers is therefore needed. This study investigated novel urinary biomarkers of kidney function (microalbuminuria, osteopontin (OPN), trefoil factor 3 (TFF3), ß-2-microglobulin, neutrophil gelatinase-associated lipocalin (NGAL), and Cys-C), together with the aforementioned traditional serum biomarkers, to assess potential kidney damage in farmers exposed to pesticides in an intensive agriculture setting. The study population consisted of 175 greenhouse workers and 91 healthy control subjects from Almeria (Southeastern Spain), a major hub of greenhouse agriculture. Data were collected at two different time-points of the same crop season: a period with greater pesticide use (high exposure period) and another with lower pesticide use (low exposure period). Significantly higher urinary levels of OPN and TFF3 were found in greenhouse workers than in controls, and in the high pesticide exposure period compared to that of low exposure. These changes suggest a subclinical tubular damage linked to pesticide exposure. In contrast, microalbuminuria, GFR, serum creatinine and Cys-C failed to be associated with pesticide exposure, suggesting that glomerular function was spared. Increased OPN and TFF3 levels over time may suggest a gradual progression from tubular dysfunction to chronic kidney disease in the exposed population.

Occupational exposure to pesticides as a potential risk factor for epilepsy.

Epilepsy is a chronic neurological disorder in which brain activity becomes abnormal, causing seizures. In a previous study we found that environmental exposure to pesticides was associated with a greater risk of epilepsy. The present study examined possible occupational risk factors that may contribute to the occurrence of epilepsy in farmers and pesticide applicators (sprayers). A case-referent study was conducted on 19,704 individuals over a 17-year study period (2000-2016). Epilepsy cases (n = 5091) were collected from Hospital records and referents (non-epilepsy cases, n = 14.613) from the Centre for Prevention of Occupational Risks, both from Almería (South-Eastern Spain). A significant increased risk of having epilepsy was found in farmers working in intensive agriculture (high-yield greenhouse crops) compared to extensive agriculture (open-air crops). The risk was greater for farmers residing in rural areas with high pesticide use (intensive farming crops in plastic greenhouses) and for those not wearing protective gloves. As for sprayers, the greatest risk of epilepsy was observed in those not wearing face mask, and in those living in areas with high pesticide use (greenhouse intensive agriculture). Overall, this study supports previous findings on the association between epilepsy and pesticide exposure in the general population, and extends the risk to farmers occupationally exposed to pesticides, mainly those engaged in intensive agriculture.

Evaluation of conventional and non-conventional biomarkers of liver toxicity in greenhouse workers occupationally exposed to pesticides.

The liver plays a prominent role in maintenance of homeostasis and is the major organ for xenobiotic metabolism, including pesticides. Conventional liver function tests are widely used to assess hepatocellular and biliary system dysfunction by measuring serum levels of aminotransferases (ALT, AST) and cholestasis enzymes (alkaline phosphatase -ALP- and γ-glutamyl transferase -GGT-), respectively. Although these tests are not entirely specific for liver damage, their specificity increases when measured concurrently, but still have limited usefulness to predict early liver dysfunction. Hence, non-conventional biomarkers may have a better performance for the early detection of biochemical hepatotoxicity with a greater specificity and sensitivity. A cross-sectional study with a follow-up component was conducted on 175 greenhouse workers regularly exposed to pesticides under integrated production system, and 91 controls living in the same geographical area. All individuals were evaluated for conventional (ALT, AST, ALP, GGT) and non-conventional biomarkers of hepatotoxicity (ornithine transcarbamylase (-OTC-), Arginase-1 -ARG1- and glutathione S-transferase alpha -GSTα-) over two periods of the same crop season, one of high pesticide exposure and other of low exposure. A slight increase in AST was observed in greenhouse workers relative to controls, suggestive of subtle hepatocellular toxicity. Although ALP, ARG1 and GST-α levels were decreased in greenhouse workers, this might be related to a potential homeostatic mechanism that regulates their expression. Altogether, these findings do not represent unambiguous evidence of liver dysfunction (e.g., hepatocellular or biliary system impairment) but may be the result of the low-toxicity pesticides used by greenhouse workers.

Environmental exposure to pesticides and risk of thyroid diseases.

Occupational and environmental exposure to pesticides has been associated with thyroid dysfunction, particularly changes in circulating thyroid hormone levels (T3, T4) and thyroid stimulating hormone (TSH). This study assessed the association between environmental exposure to pesticides and the risk of developing thyroid diseases. A population-based case-control study was carried out among Spanish populations living in areas categorized as of high or low pesticide use according to agronomic criteria, which were used as surrogates for environmental exposure to pesticides. The study population consisted of 79.431 individuals diagnosed with goiter, thyrotoxicosis, hypothyroidism, and thyroiditis (according to the International Classification of Diseases, Ninth Revision) and 1.484.257 controls matched for age, sex and area of residence. Data were collected from computerized hospital records for the period 1998 to 2015. Prevalence rates and risk of having thyroid diseases were significantly higher in areas with higher pesticide use, with a 49% greater risk for hypothyroidism, 45% for thyrotoxicosis, 20% for thyroiditis and 5% for goiter. Overall, this study indicates an association between increased environmental exposure to pesticides as a result of a greater agricultural use and diseases of the thyroid gland, thus supporting and extending previous evidence. This study also provides support to the methodology proposed for real-life risk simulation, thus contributing to a better understanding of the real life threat posed by exposure to multiple pesticides from different sources.

Association between environmental exposure to pesticides and epilepsy.

There is increasing evidence of an association between long-term environmental exposure to pesticides and neurodegenerative disorders; however, the relationship with epilepsy has not been addressed thus far. This study was aimed at determining the prevalence and risk of developing epilepsy among people from South-East Spain living in areas of high vs. low exposure to pesticides based on agronomic data. The study population consisted of 4007 subjects with a diagnosis of epilepsy and 580,077 control subjects adjusted for age, sex and geographical area. Data were collected from hospital records of the Spanish health care system (basic minimum dataset) between the years 1998 and 2010. The prevalence of epilepsy was significantly higher in areas of greater pesticide use relative to areas of lesser use. Overall, an increased risk of epilepsy was observed in the population living in areas of high vs. low use of pesticides (OR: 1.65; p < 0.001). Although this study was exploratory in nature, the results suggest that environmental exposure to pesticides might increase the risk of having epilepsy.

Biomarkers of oxidative stress in blood of workers exposed to non-cholinesterase inhibiting pesticides.

In occupational settings workers are often exposed to pesticides at relatively high doses compared to environmental exposures. Long-term exposure to pesticides has been associated with numerous adverse health effects in epidemiological studies, and oxidative stress is often claimed as one of the underlying mechanisms. In fact, different pesticides have been reported to induce oxidative stress due to the generation of free radicals and/or alteration in antioxidant defense enzymes. The present study examined greenhouse workers regularly exposed to diverse pesticides under integrated production system, and a group of controls of the same geographic area without any chemical exposure. Two different periods of the same crop season were assessed, one of high exposure (with greater use of pesticides) and other of low exposure (in which a less use of these compounds was made). Non-specific biomarkers of oxidative stress, e.g. thiobarbituric acid reactive substances (TBARS), ferric reducing ability of serum (FRAS), total thiol groups (SHT), gamma-glutamyl transpeptidase (GGT) and paraoxonase-1 (PON1) were measured in serum samples from all study subjects, alongside erythrocyte acetylcholinesterase (AChE). Results are suggestive of a mild increase in oxidative stress associated with pesticide exposure, which was compensated by an adaptive response to raise the antioxidant defenses and thus counter the detrimental effects of sustained oxidative stress. This response led to significantly increased levels of FRAS, SHT and PON1 in greenhouse workers relative to controls. Furthermore, AChE was decreased likely as a result of oxidative stress as workers did not use organophosphate insecticides.

Association of reproductive disorders and male congenital anomalies with environmental exposure to endocrine active pesticides.

There is growing evidence that environmental exposure to pesticides may increase the risk of developing reproductive and developmental disorders. This study determined the prevalence and risk of developing gestational disorders and male congenital genitourinary malformations in areas with distinct exposure to pesticides, many of them with potential endocrine disrupting properties. A population-based case-control study was carried out on pregnant women and male children living in ten health districts of Andalusia classified as areas of high and low environmental exposure to pesticides according to agronomic criteria. The study population included 45,050 cases and 950,620 controls matched for age and health district. Data were collected from computerized hospital records between 1998 and 2005. Prevalence rates and risk of miscarriage, low birth weight, hypospadias, cryptorchidism and micropenis were significantly greater in areas with higher use of pesticides in relation to those with lower use, thus supporting and extending previous information.

Activity and determinants of cholinesterases and paraoxonase-1 in blood of workers exposed to non-cholinesterase inhibiting pesticides.

Pesticide exposure has been associated with different adverse health effects which may be modulated to some extent by paraoxonase-1 (PON1) activity and genetic polymorphisms. This study assessed seasonal variations in PON1 activity (using paraoxon -POase-, phenylacetate -AREase-, diazoxon -DZOase- and dihydrocoumarin -DHCase- as substrates), erythrocyte acetylcholinesterase (AChE) and plasma cholinesterase (using butyrylthiocholine -BuChE- and benzoylcholine -BeChE- as substrates. The study population consisted of intensive agriculture workers regularly exposed to pesticides other than organophosphates and non-exposed controls from Almería (Southeastern Spain). The effect of common genetic polymorphisms of PON1 and BCHE on paraoxonase-1 and cholinesterase activities toward different substrates was also assessed. Linear mixed models were used to compare esterase activities in agricultural workers and control subjects over the two study periods (high and low exposure to pesticides). The significant decrease in AChE and increase in BuChE and BeChE activities observed in workers with respect to control subjects was attributed to pesticide exposure. Workers also had higher levels of AREase, DZOase and, to a lesser extent, of POase, but showed decreased DHCase activity. While PON1 Q192R and PON1 -108C/T gene polymorphisms were significantly associated with all PON1 activities, PON1 L55M showed a significant association with AREase, DZOase and DHCase. BCHE-K (Karlow variant) was significantly associated with lower BeChE activity (but not with BuChE) and BCHE-A (atypical variant) showed no significant association with any cholinesterase activity. These findings suggest that increased PON1, BuChE and BeChE activities in exposed workers might result from an adaptive response against pesticide exposure to compensate for adverse effects at the biochemical level. This response appears to be modulated by PON1 and BCHE gene polymorphisms.

No association between fish consumption and risk of stroke in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain): a 13·8-year follow-up study.

OBJECTIVE: To prospectively assess the associations between lean fish, fatty fish and total fish intakes and risk of stroke in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). DESIGN: Fish intake was estimated from a validated dietary questionnaire. Cox proportional hazards regression models were used to assess the association between the intakes of lean fish, fatty fish and total fish and stroke risk. Models were run separately for men and women. SETTING: Five Spanish regions (Asturias, San Sebastian, Navarra, Granada and Murcia). SUBJECTS: Individuals (n 41 020; 15 490 men and 25 530 women) aged 20-69 years, recruited from 1992 to 1996 and followed-up until December 2008 (December 2006 in the case of Asturias). Only participants with definite incident stroke were considered as cases. RESULTS: During a mean follow-up of 13·8 years, 674 strokes were identified and subsequently validated by record linkage with hospital discharge databases, primary-care records and regional mortality registries, comprising 531 ischaemic, seventy-nine haemorrhagic, forty-two subarachnoid and twenty-two unspecific strokes. After multiple adjustments, no significant associations were observed between lean fish, fatty fish and total fish consumption and the risk of stroke in men or women. In men, results revealed a non-significant trend towards an inverse association between lean fish (hazard ratio=0·84; 95 % CI 0·55, 1·29, P trend=0·06) and total fish consumption (hazard ratio=0·77; 95 % CI 0·51, 1·16, P trend=0·06) and risk of total stroke. CONCLUSIONS: In the EPIC-Spain cohort, no association was found between lean fish, fatty fish and total fish consumption and risk of stroke.

Occupational pesticide exposure and adverse health effects at the clinical, hematological and biochemical level.

AIMS: Although epidemiological studies have investigated associations between occupational pesticide exposures and different adverse health outcomes, they have rarely assessed individuals at two time-points of a same crop season with different pesticide use. MATERIAL AND METHODS: Clinical symptoms, physical examination signs, hematological and clinical chemistry parameters were measured in 189 intensive agriculture workers and 91 healthy control subjects from Almeria coastline (Southeastern Spain) to evaluate potential effects of pesticide exposure. KEY FINDINGS: Greenhouse workers showed an increased risk of ocular and skin signs relative to controls at the period of high pesticide exposure (OR: 4.80 and 2.87, respectively); however, no differences were observed for clinical symptoms. A greater risk for ECG changes (OR: 3.35) and altered spirometry (OR: 5.02) was found at the period of low exposure. Erythrocyte acetylcholinesterase was significantly decreased in greenhouse workers relative to controls in both periods. Assessment of hematological parameters revealed increased counts of erythrocytes, leukocytes, platelets and hemoglobin in greenhouse workers relative to controls, and also in the period of high versus low pesticide exposure. Changes in clinical chemistry parameters included decreased levels of glucose, creatinine, total cholesterol, triglyceride and alkaline phosphatase in greenhouse workers relative to controls; however, these parameters were raised in the period of high versus low pesticide exposure. SIGNIFICANCE: These findings suggest that chronic occupational exposure to pesticides of lower toxicity than former compounds under integrated production systems elicit mild toxic effects, particularly targeting the skin and eyes, as well as subtle subclinical (biochemical) changes of unknown long-term consequences.

Risk of second cancers cancer after a first primary breast cancer: a systematic review and meta-analysis.

OBJECTIVE: To examine the scientific evidence and the risk of second primary cancers in women diagnosed with a first primary breast cancer. METHODS: The literature was searched in Pubmed and Embase and included studies published up to June 2013, using population-based data and IARC/AICR codification rules for multiple primary cancers. A qualitative synthesis was carried out and the methodological quality of the studies evaluated. Standardised incidence ratios (SIRs) on second cancer risk, weighted by the standard error of each study, were pooled using fixed and random effects models. SIRs were also pooled by age at diagnosis (<50 and ≥ 50 years), and time since diagnosis of the first breast cancer (<10 and ≥ 10 years). RESULTS: 15 out of 710 articles fulfilled the inclusion criteria. All of them were retrospective cohort studies either population-based (13 studies) or hospital-based studies (2 studies). The studies varied with respect to number of cases, selection criteria, definition of multiple primary cancers, and the second cancer sites included. SIRs reported in these studies for all cancers combined varied from 1.0 to 1.4. The pooled SIR estimate for second cancer risk was 1.17 (95% CI: 1.10-1.25). By age groups, SIR estimates were 1.51 (95% CI: 1.35-1.70) for women younger than 50 years and 1.11 (95% CI: 1.02-1.21) for those who were older. Women with breast cancer are at risk of second cancers within the first 10 years after the first breast cancer diagnosis (SIR: 1.19; 95% CI: 1.06-1.33), and thereafter (SIR: 1.26; 95% CI: 1.05-1.52). CONCLUSION: This higher risk of second cancers in women diagnosed with a first primary breast cancer with respect to the general population emphasises the importance of prevention and control policies aimed at reducing incidence of second cancers.

Environmental exposure to pesticides and cancer risk in multiple human organ systems.

There is growing evidence on the association between long-term exposure to pesticides in occupational settings and an elevated rate of chronic diseases, including different types of cancer. However, data on non-occupational exposures are scarce to draw any conclusion. The objective of this study was to investigate the putative associations of environmental pesticide exposures in the general population with several cancer sites and to discuss potential carcinogenic mechanisms by which pesticides develop cancer. A population-based case-control study was conducted among people residing in 10 Health districts from Andalusia (South Spain) to estimate the risk of cancer at different sites. Health districts were categorized into areas of high and low environmental pesticide exposure based on two quantitative criteria: number of hectares devoted to intensive agriculture and pesticide sales per capita. The study population consisted of 34,205 cancer cases and 1,832,969 age and health district matched controls. Data were collected by computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of cancer at most organ sites were significantly higher in districts with greater pesticide use related to those with lower pesticide use. Conditional logistic regression analyses showed that the population living in areas with high pesticide use had an increased risk of cancer at all sites studied (odds ratios between 1.15 and 3.45) with the exception of Hodgkin's disease and non-Hodgkin lymphoma. The results of this study support and extend previous evidence from occupational studies indicating that environmental exposure to pesticides may be a risk factor for different types of cancer at the level of the general population.

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.