Raquel Alarcón

Toxic effects of pesticide mixtures at a molecular level: their relevance to human health.

Pesticides almost always occur in mixtures with other ones. The toxicological effects of low-dose pesticide mixtures on the human health are largely unknown, although there are growing concerns about their safety. The combined toxicological effects of two or more components of a pesticide mixture can take one of three forms: independent, dose addition or interaction. Not all mixtures of pesticides with similar chemical structures produce additive effects; thus, if they act on multiple sites their mixtures may produce different toxic effects. The additive approach also fails when evaluating mixtures that involve a secondary chemical that changes the toxicokinetics of the pesticide as a result of its increased activation or decreased detoxification, which is followed by an enhanced or reduced toxicity, respectively. This review addresses a number of toxicological interactions of pesticide mixtures at a molecular level. Examples of such interactions include the postulated mechanisms for the potentiation of pyrethroid, carbaryl and triazine herbicides toxicity by organophosphates; how the toxicity of some organophosphates can be potentiated by other organophosphates or by previous exposure to organochlorines; the synergism between pyrethroid and carbamate compounds and the antagonism between triazine herbicides and prochloraz. Particular interactions are also addressed, such as those of pesticides acting as endocrine disruptors, the cumulative toxicity of organophosphates and organochlorines resulting in estrogenic effects and the promotion of organophosphate-induced delayed polyneuropathy.

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 Alzheimers disease, Parkinsons 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 Alzheimers disease, Parkinsons 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 Alzheimers 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.

Pesticides and asthma.

Purpose of reviewSeveral clinical and epidemiological studies have reported an association between exposure to pesticides, bronchial hyper-reactivity and asthma symptoms. This article reviews the mechanistic evidence lending support to the concept that either acute or chronic low-level inhalation of pesticides may trigger asthma attacks, exacerbate asthma or increase the risk of developing asthma. Recent findingsPesticide aerosols or gases, like other respiratory irritants, can lead to asthma through interaction with functional irritant receptors in the airway and promoting neurogenic inflammation. Cross-talk between airway nerves and inflammatory cells helps to maintain chronic inflammation that eventually damages the bronchial epithelium. Certain organophosphorus insecticides cause airway hyper-reactivity via a common mechanism of disrupting negative feedback control of cholinergic regulation in the lungs. These pesticides may interact synergistically with allergen sensitization rendering individuals more susceptible for developing asthma. SummaryMany pesticides are sensitizers or irritants capable of directly damaging the bronchial mucosa, thus making the airway very sensitive to allergens or other stimuli. However, most pesticides are weakly immunogenic so that their potential to sensitize airways in exposed populations is limited. Pesticides may increase the risk of developing asthma, exacerbate a previous asthmatic condition or even trigger asthma attacks by increasing bronchial hyper-responsiveness.

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 Hodgkins 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.

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.

Pesticide exposure and genetic variation in xenobiotic-metabolizing enzymes interact to induce biochemical liver damage

Metabolic activation of pesticides in the liver may result in highly reactive intermediates capable of impairing various cellular functions. Nevertheless, the knowledge about the effect of pesticide exposure on liver function is still limited. This study assessed whether exposure to pesticides elicits early biochemical changes in biomarkers of liver function and looked for potential gene-environmental interactions between pesticide exposure and polymorphisms of pesticide-metabolizing genes. A longitudinal study was conducted in farm-workers from Andalusia (South Spain), during two periods of the same crop season with different degree of pesticide exposure. Blood samples were taken for the measurement of serum and erythrocyte cholinesterase activities as well as for determining clinical chemistry parameters as biomarkers of liver function. Serum lipid levels were also measured as they may help to monitor the progress of toxic liver damage. A reduction in serum cholinesterase was associated with decreased levels of all clinical chemistry parameters studied except HDL-cholesterol. Conversely, a decreased erythrocyte cholinesterase (indicating long-term pesticide exposure) was associated with increased levels of aspartate aminotransferase and alkaline phosphatase and increased levels of triglycerides, total cholesterol and LDL-cholesterol, but reduced levels of HDL-cholesterol. Changes in liver biomarkers were particularly associated with the PON155M/192R haplotype. The obtained results therefore support the hypothesis that pesticide exposure results in subtle biochemical liver toxicity and highlight the role of genetic polymorphisms in pesticide-metabolizing enzymes as biomarkers of susceptibility for developing adverse health effects.

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.

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.

Association between environmental exposure to pesticides and epilepsy

HighlightsThe relationship between environmental exposure to pesticides and epilepsy is unknown.4007 subjects diagnosed with epilepsy over the years 1998 and 2010 were examined.Areas of high vs. low pesticide used were defined based on agronomic data.A high prevalence rate of epilepsy was found in areas of greater pesticide use.Environmental exposure to pesticides might increase the risk of having epilepsy. ABSTRACT 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.

Predictive risk model for the diagnosis of diabetes mellitus type 2 in a follow-up study 15 years on: PRODI2 Study

Background The prevalence and mortality related to diabetes mellitus type 2 (DM2) have increased consistently for decades. Identifying adults at high risk of diabetes incidence is important for the execution of intervention. Methods The participants in the PRODI2 study (n=273), who come from the southeast of Spain and did not have diabetes at the start of the study, were followed for 15 years (1999-2014), and their risk parameters were measured, from which a predictive model was obtained which indicates the level of influence of each factor in the development of DM2. The expected risk of diabetes was calculated by binary logistic regression. Results Those participants whose father has suffered an acute myocardial infarction are 3.9 times more likely to develop DM2 (confidence interval 95%: 1.498, 10.339); those with at least one parent who has a history of diabetes are 2.7 times more at risk (confidence interval 95%: 1.224, 6.101); the risk of being diabetic was 1.13 times higher for every extra unit on the waist-hip ratio (confidence interval 95%: 1.073, 1.195), and for the hip perimeter an OR of 0.93 was obtained (confidence interval 95%: 0.876, 0.982). Statistically significant differences were observed in all cases (P<0.05). Conclusion This study shows that the risk of being diabetic rises in patients whose father has suffered an acute myocardial infarction, in those whose mother or father is diabetic and in patients with a high waist perimeter.