The industrialization of the agricultural sector has increased the chemical burden on natural ecosystems. Pesticides are agrochemicals used in agricultural lands, public health programs and urban green areas in order to protect plants and humans from various diseases. However, due to their known ability to cause a large number of negative health and environmental effects, their side effects can be an important environmental health risk factor. The urgent need for a more sustainable and ecological approach has produced many innovative ideas, among them agriculture reforms and food production implementing sustainable practice evolving to food sovereignty. It is more obvious than ever that the society needs the implementation of a new agricultural concept regarding food production which is safer for man and the environment, and to this end, steps such as the declaration of Nyeleni have been taken.

/pdf/chemical-pesticides-and-human-health-the-urgent-need-for-a-4k913yglgk.pdf

Chemical Pesticides and Human Health: The Urgent Need for a New Concept in Agriculture.

Synthetic pyrethroid insecticides were introduced into widespread use for the control of insect pests and disease vectors more than three decades ago. In addition to their value in controlling agricultural pests, pyrethroids are at the forefront of efforts to combat malaria and other mosquito-borne diseases and are also common ingredients of household insecticide and companion animal ectoparasite control products. The abundance and variety of pyrethroid uses contribute to the risk of exposure and adverse effects in the general population. The insecticidal actions of pyrethroids depend on their ability to bind to and disrupt voltage-gated sodium channels of insect nerves. Sodium channels are also important targets for the neurotoxic effects of pyrethroids in mammals but other targets, particularly voltage-gated calcium and chloride channels, have been implicated as alternative or secondary sites of action for a subset of pyrethroids. This review summarizes information published during the past decade on the action of pyrethroids on voltage-gated sodium channels as well as on voltage-gated calcium and chloride channels and provides a critical re-evaluation of the role of these three targets in pyrethroid neurotoxicity based on this information.

Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances

At the end of the class, students will be able to answer the following questions: • What is organic agriculture? • Where do I go to get certification in organic agriculture? • How can I get more information about organic agriculture? What is organic? • The term " organic " is not synonymous to the terms " natural " or " eco-friendly. " • The label " natural " on foodstuff does not guarantee complete adherence to organic practices as defined by a law. • Produce food of high quality in sufficient quantity • Maintain biological diversity within the farming system • Maintain long-term soil fertility • Rely on renewable resources in locally organized agricultural systems • Minimize pollution and protect the environment What is allowed in organic crop production? • New varieties of crops and agricultural technologies • Crop rotations, cover crops and natural-based products that maintain soil fertility • Biological, cultural and physical methods to limit pest expansion and increase population of beneficial insects

英国有机农业（Organic farming）的新举措

Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development.

/pdf/potential-developmental-neurotoxicity-of-pesticides-used-in-594wodwhoj.pdf

Potential developmental neurotoxicity of pesticides used in Europe

Microelectrode arrays (MEAs) have been in use over the past decade and a half to study multiple aspects of electrically excitable cells. In particular, MEAs have been applied to explore the pharmacological and toxicological effects of numerous compounds on spontaneous activity of neuronal and cardiac cell networks. The MEA system enables simultaneous extracellular recordings from multiple sites in the network in real time, increasing spatial resolution and thereby providing a robust measure of network activity. The simultaneous gathering of action potential and field potential data over long periods of time allows the monitoring of network functions that arise from the interaction of all cellular mechanisms responsible for spatio-temporal pattern generation. In these functional, dynamic systems, physical, chemical, and pharmacological perturbations are holistically reflected by the tissue responses. Such features make MEA technology well suited for the screening of compounds of interest, and also allow scaling to high throughput systems that can record from multiple, separate cell networks simultaneously in multi-well chips or plates. This article is designed to be useful to newcomers to this technology as well as those who are currently using MEAs in their research. It explains how MEA systems operate, summarizes what systems are available, and provides a discussion of emerging mathematical schemes that can be used for a rapid classification of drug or chemical effects. Current efforts that will expand this technology to an influential, high throughput, electrophysiological approach for reliable determinations of compound toxicity are also described and a comprehensive review of toxicological publications using MEAs is provided as an appendix to this publication. Overall, this article highlights the benefits and promise of MEA technology as a high throughput, rapid screening method for toxicity testing.

Microelectrode arrays: a physiologically based neurotoxicity testing platform for the 21st century.

Pyrethroid insecticides have been used for more than 40 years and account for 25% of the worldwide insecticide market. Although their acute neurotoxicity to adults has been well characterized, information regarding the potential developmental neurotoxicity of this class of compounds is limited. There is a large age dependence to the acute toxicity of pyrethroids in which neonatal rats are at least an order of magnitude more sensitive than adults to two pyrethroids. There is no information on age-dependent toxicity for most pyrethroids. In the present review we examine the scientific data related to potential for age-dependent and developmental neurotoxicity of pyrethroids. As a basis for understanding this neurotoxicity, we discuss the heterogeneity and ontogeny of voltage-sensitive sodium channels, a primary neuronal target of pyrethroids. We also summarize 22 studies of the developmental neurotoxicity of pyrethroids and review the strengths and limitations of these studies. These studies examined numerous end points, with changes in motor activity and muscarinic acetylcholine receptor density the most common. Many of the developmental neurotoxicity studies suffer from inadequate study design, problematic statistical analyses, use of formulated products, and/or inadequate controls. These factors confound interpretation of results. To better understand the potential for developmental exposure to pyrethroids to cause neurotoxicity, additional, well-designed and well-executed developmental neurotoxicity studies are needed. These studies should employ state-of-the-science methods to promote a greater understanding of the mode of action of pyrethroids in the developing nervous system.

https://www.jstor.org/stable/pdfplus/3436455.pdf

Developmental Neurotoxicity of Pyrethroid Insecticides: Critical Review and Future Research Needs

Effects of pyrethroids on voltage-sensitive calcium channels: a critical evaluation of strengths, weaknesses, data needs, and relationship to assessment of cumulative neurotoxicity.

Pyrethroid insecticides have potent actions on voltage-gated sodium channels (VGSC), inhibiting inactivation and increasing channel open times. These are thought to underlie, at least in part, the clinical symptoms of pyrethroid intoxication. However, disruption of neuronal activity at higher levels of organization is less well understood. In order to characterize pyrethroid effects on neurotransmitter release and neuronal excitability in glutamatergic networks, we examined the effects of deltamethrin (DM) and permethrin (PM) on neuronal activity in hippocampal neuronal cultures using patch-clamp and microelectrode array (MEA) recordings. In the presence of inhibitors of GABA receptors, spontaneous excitatory post-synaptic currents (sEPSCs) and spontaneous spike rates were reduced in a concentration-dependent manner by both DM and PM. IC(50) values were 0.037 and 0.70microM for inhibition of sEPSCs and 0.60 and 21.8microM for inhibition of spontaneous spike rate by DM and PM, respectively. Both compounds altered burst activity by decreasing the number of spikes during spontaneous bursting, the number of sEPSCs within a bursting release event and the duration of sEPSC bursts while increasing both the interspike interval and the time between sEPSCs. Exposure of neurons to the VGSC-specific modulator veratridine had effects similar to both DM and PM, while inhibition of voltage-gated calcium channels had no effect on spontaneous spike rates. In the absence of GABA receptor antagonists, both DM and PM increased spontaneous spike rates. Altogether, these data demonstrate that DM and PM disrupt network activity in vitro, largely via a VGSC-dependent mechanism.

Pyrethroid modulation of spontaneous neuronal excitability and neurotransmission in hippocampal neurons in culture.

Pyrethroid insecticide modulation of the voltage-gated sodium channel (VGSC) is proposed to underlie their effects on neuronal excitability. However, some in vitro evidence indicates that target sites other than VGSCs could contribute to pyrethroid disruption of neuronal activity. VGSC-independent, pyrethroid-induced changes in neurotransmitter release were examined to investigate the possibility that target sites other than VGSCs contribute to pyrethroid effects. Using whole-cell patch clamp recordings, deltamethrin and permethrin effects on glutamate-mediated miniature excitatory postsynaptic currents (mEPSCs) from pyramidal neurons in mixed hippocampal cultures were examined. In the presence of the VGSC antagonist tetrodotoxin, the type I pyrethroid permethrin (10 microM) increased the average frequency of mEPSCs from a basal level of 1.0+/-0.4 to 3.5+/-0.6 Hz, with peak frequency of 9.9+/-1.5 Hz (n=6). Permethrin did not affect the distribution of current amplitudes, indicating that permethrin increased the probability of glutamate release at the presynaptic terminal without effects on postsynaptic responses. Removal of calcium from the extracellular solution following the induction of the permethrin-mediated effect decreased mEPSC frequency (6.8+/-1.8 Hz, n=3) to near control levels (1.9+/-0.8 Hz for control versus 2.5+/-0.6 Hz for permethrin minus Ca(2+), respectively). However, the N- and P/Q-type voltage-gated calcium channel antagonist omega-conotoxin MVIIC had no effect on the permethrin-dependent increase in mEPSC frequency. In contrast to permethrin, the type II pyrethroid deltamethrin (10 microM) failed to affect mEPSC frequency. These results indicate that permethrin causes a calcium-dependent increase in glutamate release from hippocampal neurons that is independent of effects on voltage-gated sodium or N- or P/Q-type voltage-gated calcium channels. The data indicate that permethrin increases mEPSC frequency via an alteration in intracellular calcium dynamics at the presynaptic terminal.

Douglas A Meyer

Papers

Developmental Neurotoxicity of Pyrethroid Insecticides: Critical Review and Future Research Needs

Effects of pyrethroids on voltage-sensitive calcium channels: a critical evaluation of strengths, weaknesses, data needs, and relationship to assessment of cumulative neurotoxicity.

Pyrethroid modulation of spontaneous neuronal excitability and neurotransmission in hippocampal neurons in culture.

Permethrin, but not deltamethrin, increases spontaneous glutamate release from hippocampal neurons in culture.