The current study aims to assess the long-term effects of very low dose exposures to a complex chemical mixture on motor performance and behavioural changes in rats. For twelve months (equivalent to ...thirty years in human terms), four groups of Sprague Dawley rats (five males and five females per group) were exposed to a thirteen chemical mixture (in drinking water) in doses of 0, 0.25, 1 and 5xADI/TDI (acceptable daily intake/tolerable daily intake) (mg/kg body weight/day). After twelve month exposure, the rats' motor performances were assessed by rotarod test, and their behavioural changes were assessed by open field exploratory test and elevated plus maze test. Exposure to the chemical mixture resulted in a statistically significant increase in the locomotor activity quantified by the number of crossings over external squares and in the spatial orientation activity quantified as the number of rearings in the lower dose group (0.25xADI/TDI) compared with the control group (p < 0.05). No significant changes were observed in the two higher dose groups (1xADI/TDI, 5xADI/TDI) compared with the control group. The administration of a very low doses of a cocktail of 13 chemicals led to a dose-dependent stimulation of the nervous system, rather than its inhibition.
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•Very low doses combined exposure to 13 chemicals revealed hormetic effects on nervous system.•Locomotor activity testing showed two phase dose-dependent effects in rats.•Spatial orientation activity showed non-monotonic response in rats.•Neurobehavioral tests disclose hormesis after exposure to chemical mixture in doses below NOAEL.
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•Exposure to very low dose of chemicals mixture can lead in various adverse effects.•Monotonic increase of appetite in both sexes and of body weight gain in females.•Non-monotonic ...effects on anabolism, AST, ALT and PChE in males.•Monocytes significantly increased in both sexes only in low dose group.•TNF-α and IFN-γ increased in male rats from medium dose groups.
The aim of the current study was to evaluate the effects of a mixture of thirteen common chemicals on rats, after a one-year exposure to doses around the acceptable daily intake (ADIs), using blood and urinary tests. The influence of low doses of the mixture on weight gain, water consumption, feed consumption and feed efficiency, biochemistry parameters, haematological parameters, blood lymphocytes subsets, serum inflammation profile and urine parameters was evaluated. Our mixture caused a moderate monotonic increase of the males’ appetite and a non-monotonic increase of anabolism and a monotonic increase of appetite for the females. Regarding biochemical parameters, the exposure to the test mixture caused non-monotonic increases of AST and ALT, a decrease of PChE in males and plausibly a monotonic biliary obstruction in both sexes. Monocytes significantly increased in low dose groups of both sexes. A significant decrease of all the lymphocytes subclasses and an increased expression of TNF-α protein associated with an increased expression of IFN-γ protein observed in various groups. It became apparent that after twelve months of exposure very low doses of the tested mixture had both non-monotonic and monotonic harmful effects on different levels on rats.
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•The effects of long-term low-dose exposure to a chemical mixture on redox biomarkers in rats were evaluated.•The mixture induces physiological redox adaptations in all three doses ...(below NOAEL) in blood after 12 months of exposure.•The dose of the mixture at 0.05 × NOAEL causes remarkable redox perturbations in blood and tissues after 18 months of exposure.•This study points out the effects of low-dose long-term combined stimuli in redox status.
Exposure of humans to xenobiotic mixtures is a continuous state during their everyday routine. However, the majority of toxicological studies assess the in vivo effects of individual substances rather than mixtures. Therefore, our main objective was to evaluate the impact of the 12- and 18-month exposure of rats to a mixture containing 13 pesticides, food, and life-style additives in three dosage levels (i.e. 0.0025 × NOAEL, 0.01 × NOAEL, and 0.05 × NOAEL), on redox biomarkers in blood and tissues. Our results indicate that the exposure to the mixture induces physiological adaptations by enhancing the blood antioxidant mechanism (i.e., increased glutathione, catalase and total antioxidant capacity and decreased protein carbonyls and TBARS) at 12 months of exposure. On the contrary, exposure to the 0.05 × NOAEL dose for 18 months induces significant perturbations in blood and tissue redox profile (i.e., increased carbonyls and TBARS). This study simulates a scenario of real-life risk exposure to mixtures of xenobiotics through a long-term low-dose administration regimen in rats. The results obtained could support, at least in part, the necessity of introducing testing of combined stimuli at reference doses and long term for the evaluation of the risk from exposure to chemicals.
Research over the past years has indicated that chronic human exposure to very low doses of various chemical species in mixtures and administered via different routes (percutaneous, orally, etc.) ...should be the main focus of new biochemical and toxicological studies. Humans have daily contact with various chemicals, such as food additives, pesticides from fruits/vegetables, antibiotics (and other veterinary drugs) from meat, different types of preservatives from cosmetics, to name a few. Simultaneous exposure to this wide array of chemicals does not produce immediate effects, but summative effect/s over time that may be clinically manifested several years thereafter. Classical animal studies designed to test the toxic outcome of a single chemical are not suitable to assess, and then extrapolate to humans, the effects of a whole mixture of chemicals. Testing the aftermath of a combination of chemicals, at low doses, around or below the no observed adverse effect is stressed by many toxicologists. Thus, there is a need to reformulate the design of biochemical and toxicological studies in order to perform real-life risk simulation. This review discuss the potential use of computational methods as a complementary tool for
in vitro
and
in vivo
toxicity tests with a high predictive potential that could contribute to reduce animal testing, cost and time, when assessing the effects of chemical combinations. This review focused on the use of these methods to predict the potential endocrine disrupting activity of a mixture of chemicals.
•Pesticide exposure has been associated with cognitive decline and dementia.•The estimation of the exposure to pesticides is frequently performed without measuring the toxicants’ synergic ...effects.•Low exposures to environmental toxicants has been overlooked.•Real-Life Risk Simulation approach would represent a robust alternative for future studies.•There is an association between exposure to pesticides and cognitive dysfunction, dementia and Alzheimer’s disease.
Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person’s quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer’s disease.
Pesticides can potentially contribute to the development of numerous neurodegenerative diseases. This study evaluates the effects of a six-pesticide mixture at doses around the ...no-observed-adverse-effectlevels (0 × NOAEL, control) and 0.25, 1 and 5 × NOAEL on behavior of Wistar rats. After 3, 6 and 12 months, rats were observed for neurobehavioral changes using the techniques of elevated plus maze and universal problemchamber, and the experiment was conducted thrice. The 3-month exposure revealed a decrease in the cognitive ability at the dose of 5 × NOAEL, and a dose-dependent research activity and anxiety. The 6-month exposurerevealed non-monotonic effects on the cognitive ability, with a decrease by 0.25 and 5 × NOAEL, as well as non-monotonic effects on anxiety, withan increase by 0.25 and 1 × NOAEL. A decrease was also observed in research activity at 5 × NOAEL. However, the 12-month exposure resulted to an increase in cognitive ability by 0.25 × NOAEL and in anxiety by 1 × NOAEL, as well as to a dose-dependent research activity. Repeating the trial showed that the cognitive ability increased from one trial to another, while the researching activity decreased and the anxiety increased by 0× NOAEL. In the groups exposed to pesticides mixture, the trends were different, showing that the exposure to pesticides combined with repeated trials, also influence the response of the animals. The resultsdemonstrate the occurrence of several dose-dependent behavioral responses, with negative effects occurring at doses that are considered safe. This study provides novel insights about time-dependent mixtures biology, and an important perspective to consider when conducting risk assessments.
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•We tested the 12 months effect of a 6-pesticide mixture on the neurobehavior of rats.•The effects on research activity and anxiety were dose- and time-dependent.•At 3 months, cognitive ability behavior was suppressed only by high doses.•At 6 months, the effects on cognitive abilities and anxiety were non-monotonic.•The nature of the mixture dose responses is time- and endpoint-specific.
•Chronic exposure to vitamin deficiency and a very low dose of pesticides mixture determine stimulation of SNC.•Chronic vitamin deficiency decreased locomotor and spatial orientation activity in ...rats.•Exposure to very low doses of a mixture of 6 pesticides caused an inhibition of the central nervous system.•Chronic vitamin deficiency and exposure to a very low dose of pesticides mixture affect long term memory.
We investigate the long-term effect of very-low dose exposure to a mixture of six pesticides associated with hydrophilic vitamin deficiency on the neurobehavioral outcomes of rats. Two hundred Wistar rats were divided into four groups, two control groups, a vitamin sufficient control group and a vitamin deficiency control group and 2 test groups, a vitamin sufficient test group, and a vitamin deficiency group. The test groups were exposed for 9 months to a mixture of diquat, imazamox, imazethapyr, tepraloxydin, bentazone and acifluorfen in doses of 0.01xNOAEL (mg/kg bw/day). After 9 months of exposure, the behavior changes were evaluated by open field test and elevated plus maze test and the memory was assessed by passive avoidance test. Chronic vitamin deficiency decreased locomotor and special orientation activity and increased anxiety-like behavior in rats. Exposure to very low doses of a mixture of 6 pesticides caused central nervous effects, manifested as decreased locomotor activity, and increased anxiety levels. Vitamin deficiency and low dose chronic pesticides mixture exposure thus affected the central nervous system, especially long-term memory.
•Calculated total Hazard Index (HI) values for pesticides indicated no major risk.•Incremental Life Time Cancer Risks (ILCRs) for carcinogenic metals (As and Pb) did not exhibit significant ...risk.•Non-carcinogenic metals did not show significant risk (HI values were <1.0).•ILCR and Margins of Exposure (MoE) for PAHs indicated no risk.
The present study assessed the risk posed by simultaneous oral exposure to a mixture of 22 pesticides, 6 metals, and 16 Polycyclic Aromatic Hydrocarbons (PAHs) in fruits of date palms, to Iranian consumers. Various cultivars of dates were collected from six regions in Iran. Concentrations of organic compounds and metals in 900 samples of date fruits were quantified by chromatography-mass spectrometry (GC–MS) and inductively coupled plasma-optical emission spectrometry (ICP-OES), respectively. No significant associations between any of the contaminants and cultivation zones were observed. Calculated Hazard Quotients (HQ) was <1.0 for all pesticides and calculated total Hazard Index (HI) values indicated no major risk. For the carcinogenic metals, estimated Incremental Life Time Cancer Risk (ILCRs) at the 50th and 95th percentiles were respectively 2.25 × 10−7 and 7.10 × 10−7 for As, and respectively 1.24 × 10-9 and 5.38 × 10-9 for Pb which indicated no risk. Notably, non-carcinogenic metals did not exhibit a significant risk (HI values <1.0 for both cases). In addition, at the 50th and 95th percentiles, ILCR and Margins of Exposure (MoE) for PAHs indicated no risk. Based on sensitivity analysis, concentrations of analytes had the greatest effects on risk with regard to carcinogenic and non-carcinogenic assessment endpoints. However, consumers are aware of the composition of the fruits they eat, because harmful substances in fruits normally cannot be perceived by tasting or smelling. It can also be noted that general awareness of Iranian farmers need to be upgraded for a more cautious utilization of pesticides and fertilizers in agricultural practices. Moreover, our results about the PAHs indicated that the consumption of dates grown near the industrial sites is risky and should be completely avoided.
Redox biology and toxicology are interrelated fields that have produced valuable evidence regarding the role and clinical significance of reactive species. These issues are analyzed herein by ...presenting 6 arguments, as follows: Argument 1: There is no direct connection of redox-related pathologies with specific reactive species; Argument 2: The measurement of reactive species concentration is a major challenge due to their very short half lives; Argument 3: There is an interplay between reactive species generation and fundamental biological processes, such as energy metabolism; Argument 4: Reactive species exert beneficial biological action; Argument 5: Reactive species follow the hormesis phenomenon; Argument 6: Oxidative modifications of redox-related molecules are not necessarily interpreted as oxidative damage. We conclude that reactive species do not seem to exert clinical significance, which means that they lack a measurable cause-effect relation with chronic diseases. Unpredictable results could, nevertheless, arise through novel experimental setups applied in the field of toxicology. These are related to the real-life exposure scenario via the regimen of long-term low-dose (far below NOAEL) exposure to mixtures of xenobiotics and can potentially offer perspectives in order to investigate in depth whether or not reactive species can be introduced as clinically significant redox biomarkers.
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•Reactive species (RS) formation is the outcome of numerous chronic diseases.•Acute intoxications leading to severe illnesses are linked to effects of RS.•No cause-effect relation of RS with chronic diseases has been established yet.•The real-life exposure scenario offers insight in the clinical significance of RS.
Smallholder cocoa agroforestry systems provide most of the cocoa produced world-wide and can improve the livelihoods of rural families in the tropics. However, many smallholder cocoa producers ...experience low cocoa yields due to generally poor management practices, pests, disease, and low soil fertility. In Papua New Guinea, pest and disease management systems have been developed to provide improved yields and revenues, but there has been limited uptake.
We hypothesized that the low uptake of these systems may be due to the improved yields not being sufficient to justify the required increase in labour and capital inputs. Our objective was to assess if the integrated pest and disease management systems were financially viable.
Our methods involved developing discounted cash flow models that incorporated Monte Carlo risk analysis software. We populated the models with labour inputs, costs, and revenue data collected in country, and from scientific literature. In addition to net present value, we evaluated the production systems with additional criteria we deemed appropriate for assessing the required labour inputs and capital outlays; return on labour; mean labour hours/day; mean annual capital outlays, mean hourly income, and mean annual income.
Our results show that under the current cocoa prices being received, all the production systems had a negative net present value, and a mean hourly income that was below the Papua New Guinea minimum wage and less than 1 USD/h. Furthermore, the progressive addition of labour inputs and capital outlays of the pest and disease management systems resulted in mean hourly incomes that are less than currently being received. These decreased hourly earnings may explain the low adoption of these technologies.
Financial analyses of new smallholder agroforestry technologies should be used to evaluate the viability and likelihood of smallholder technology adoption. Previous research on cocoa pest and disease management systems failed to account for costs related to labour and capital inputs. Even if farm family labour does not incur a direct cash outflow, it does represent an opportunity cost to farmers. Including additional criteria that measure financial returns to farmers relative to labour and capital requirements should be a part these assessments. These additional criteria can aid in evaluating all the economic thresholds that may impact if and how smallholders will incorporate new agroforestry technologies, which can help improve the success for agriculture-based development projects throughout the global tropics.
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•In Papua New Guinea, many smallholder cocoa farmers experience low cocoa yields despite receiving training in pest and disease management systems.•We hypothesized that the low system uptake may be due to the improved yields not being sufficient to justify the increase in labour and capital.•We developed discounted cash flow models that incorporated Monte Carlo risk analysis software to evaluate the systems against selected criteria.•The pest and disease cocoa management systems provided lower mean hourly earnings than the low input cocoa system and this limited adoption.•Smallholder agroforestry technologies should be evaluated for viability and likelihood of smallholder technology adoption during development.
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