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98-510: The first list of SVHCs was published on 28 October 2008 with the list being updated biannually since then. The most recent update occurred in June 2024, bringing the size to 241 SVHCs. The criteria are given in article 57 of the REACH Regulation. A substance may be proposed as an SVHC if it meets one or more of the following criteria: The "equivalent concern" criterion is significant because it

196-423: A exposure are loss of coordination, twitching , convulsions and rapid death by respiratory paralysis . The nerve tissues which communicate with muscles contain a receptor called the nicotinic acetylcholine receptor . Stimulation of these receptors causes a muscular contraction . The anatoxin- a molecule is shaped so it fits this receptor, and in this way it mimics the natural neurotransmitter normally used by

294-444: A metabolite of arsenic, arsenite is formed after ingestion of arsenic and has shown significant toxicity to neurons within about 24 hours of exposure. The mechanism of this cytotoxicity functions through arsenite-induced increases in intracellular calcium ion levels within neurons, which may subsequently reduce mitochondrial transmembrane potential which activates caspases , triggering cell death. Another known function of arsenite

392-433: A category of poisons produced by the marine cone snail, and are capable of inhibiting the activity of a number of ion channels such as calcium, sodium, or potassium channels. In many cases, the toxins released by the different types of cone snails include a range of different types of conotoxins, which may be specific for different ion channels, thus creating a venom capable of widespread nerve function interruption. One of

490-461: A consequence of increased concentrations, ammonia activity in-vivo has been shown to induce swelling of astrocytes in the brain through increased production of cGMP (Cyclic Guanosine Monophosphate) within the cells which leads to Protein Kinase G-mediated (PKG) cytoskeletal modifications. The resultant effect of this toxicity can be reduced brain energy metabolism and function. Importantly,

588-414: A more accurate distinction between true neurotoxins and cytotoxins in an in-vitro testing environment. Due to the significant inaccuracies associated with this process, however, it has been slow in gaining widespread support. Additionally, biochemical mechanisms have become more widely used in neurotoxin testing, such that compounds can be screened for sufficiency to induce cell mechanism interference, like

686-463: A number of potential chemical insults. This barrier creates a tight hydrophobic layer around the capillaries in the brain, inhibiting the transport of large or hydrophilic compounds. In addition to the BBB, the choroid plexus provides a layer of protection against toxin absorption in the brain. The choroid plexuses are vascularized layers of tissue found in the third, fourth, and lateral ventricles of

784-400: A postsynaptic neuron. The effect of this increased signaling threshold is a reduced excitability of postsynaptic neurons , and subsequent loss of motor and sensory function which can result in paralysis and death. Though assisted ventilation may increase the chance of survival after TTX exposure, there is currently no antitoxin. The use of the acetylcholinesterase inhibitor Neostigmine or

882-603: A predator or prey very rapidly, toxins have evolved to become highly specific to their target channels such that the toxin does not readily bind other targets (see Ion Channel toxins ). As such, neurotoxins provide an effective means by which certain elements of the nervous system may be accurately and efficiently targeted. An early example of neurotoxin based targeting used radiolabeled tetrodotoxin to assay sodium channels and obtain precise measurements about their concentration along nerve membranes . Likewise through isolation of certain channel activities, neurotoxins have provided

980-453: A result of early lead exposure. In addition to inducing apoptosis, lead inhibits interneuron signaling through the disruption of calcium-mediated neurotransmitter release. As a neurotoxin, ethanol has been shown to induce nervous system damage and affect the body in a variety of ways. Among the known effects of ethanol exposure are both transient and lasting consequences. Some of the lasting effects include long-term reduced neurogenesis in

1078-438: A result of increased generation of reactive oxidative species (ROS). This is a plausible mechanism, as there is a reduced presence in the fetal brain of antioxidant enzymes such as catalase and peroxidase . In support of this mechanism, administration of high levels of dietary vitamin E results in reduced or eliminated ethanol-induced neurotoxic effects in fetuses. n- Hexane is a neurotoxin which has been responsible for

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1176-496: A result of long term drug use are amyloid beta (Aβ), glutamate , dopamine , and oxygen radicals . When present in high concentrations, they can lead to neurotoxicity and death ( apoptosis ). Some of the symptoms that result from cell death include loss of motor control, cognitive deterioration and autonomic nervous system dysfunction. Additionally, neurotoxicity has been found to be a major cause of neurodegenerative diseases such as Alzheimer's disease (AD). Amyloid beta (Aβ)

1274-447: A substance on the list of SVHCs. Suppliers of pure SVHCs must provide their customers with a safety data sheet (SDS). Suppliers of mixtures of substances which contain more than 0.1% by weight of any SVHC must provide their customers with a safety data sheet on request . Manufacturers or importers of articles containing more than 0.1% by weight of any SVHC must provide their customers, and consumers on request, with adequate information on

1372-1161: A substance – specifically, a neurotoxin or neurotoxicant – alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue . This can eventually disrupt or even kill neurons , which are cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from organ transplants , radiation treatment , certain drug therapies , recreational drug use , exposure to heavy metals , bites from certain species of venomous snakes , pesticides , certain industrial cleaning solvents , fuels and certain naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction. Chronic mold exposure in homes can lead to neurotoxicity which may not appear for months to years of exposure. All symptoms listed above are consistent with mold mycotoxin accumulation. The term neurotoxicity implies

1470-454: Is a chemical found in the brain that poses a toxic threat to neurons when found in high concentrations. This concentration equilibrium is extremely delicate and is usually found in millimolar amounts extracellularly. When disturbed, an accumulation of glutamate occurs as a result of a mutation in the glutamate transporters , which act like pumps to clear glutamate from the synapse. This causes glutamate concentration to be several times higher in

1568-610: Is a neurotoxin commonly found concentrated in areas exposed to agricultural runoff , mining , and smelting sites (Martinez-Finley 2011). One of the effects of arsenic ingestion during the development of the nervous system is the inhibition of neurite growth which can occur both in PNS and the CNS. This neurite growth inhibition can often lead to defects in neural migration , and significant morphological changes of neurons during development , ) often leading to neural tube defects in neonates . As

1666-428: Is a new nonpeptide amino acid toxin that stimulate the glutamate receptors in neurons. Caramboxin is an agonist of both NMDA and AMPA glutamatergic ionotropic receptors with potent excitatory, convulsant, and neurodegenerative properties. The term " curare " is ambiguous because it has been used to describe a number of poisons which at the time of naming were understood differently from present day understandings. In

1764-411: Is a particularly useful molecule for investigating acetylcholine receptors in the nervous system. The deadliness of the toxin means that it has a high military potential as a toxin weapon. Bungarotoxin is a compound with known interaction with nicotinic acetylcholine receptors (nAChRs), which constitute a family of ion channels whose activity is triggered by neurotransmitter binding. Bungarotoxin

1862-471: Is a poison produced by organisms belonging to the Tetraodontiformes order , which includes the puffer fish , ocean sunfish , and porcupine fish . Within the puffer fish, TTX is found in the liver , gonads , intestines , and skin . TTX can be fatal if consumed, and has become a common form of poisoning in many countries. Common symptoms of TTX consumption include paraesthesia (often restricted to

1960-431: Is a potent neurotoxin whose toxicity has been recognized for at least thousands of years. Though neurotoxic effects for lead are found in both adults and young children , the developing brain is particularly susceptible to lead-induced harm, effects which can include apoptosis and excitotoxicity. An underlying mechanism by which lead is able to cause harm is its ability to be transported by calcium ATPase pumps across

2058-453: Is based on its importance in glutamate excitotoxicity, as NO is generated in a calcium-dependent manner in response to glutamate mediated NMDA activation, which occurs at an elevated rate in glutamate excitotoxicity. Though NO facilitates increased blood flow to potentially ischemic regions of the brain, it is also capable of increasing oxidative stress , inducing DNA damage and apoptosis. Thus an increased presence of NO in an ischemic area of

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2156-471: Is common. Support has been shown for a number of treatments aimed at attenuating neurotoxin-mediated injury, such as antioxidant and antitoxin administration. Exposure to neurotoxins in society is not new, as civilizations have been exposed to neurologically destructive compounds for thousands of years. One notable example is the possible significant lead exposure during the Roman Empire resulting from

2254-472: Is important in the study of nervous systems. Common examples of neurotoxins include lead , ethanol (drinking alcohol), glutamate , nitric oxide , botulinum toxin (e.g. Botox), tetanus toxin , and tetrodotoxin . Some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations. Neurotoxins inhibit neuron control over ion concentrations across

2352-483: Is its destructive nature towards the cytoskeleton through inhibition of neurofilament transport. This is particularly destructive as neurofilaments are used in basic cell structure and support. Lithium administration has shown promise, however, in restoring some of the lost neurofilament motility. Additionally, similar to other neurotoxin treatments, the administration of certain antioxidants has shown some promise in reducing neurotoxicity of ingested arsenic. Lead

2450-400: Is often seen through two routes of administration, either through consumption or through endogenous ailments such as liver failure . One notable case in which ammonia toxicity is common is in response to cirrhosis of the liver which results in hepatic encephalopathy , and can result in cerebral edema (Haussinger 2006). This cerebral edema can be the result of nervous cell remodeling. As

2548-532: Is particularly specific for α7-nAChR . This α7-nAChR functions to allow calcium ion influx into cells, and thus when blocked by ingested bungarotoxin will produce damaging effects, as ACh signaling will be inhibited. Likewise, the use of α-bungarotoxin can be very useful in neuroscience if it is desirable to block calcium flux in order to isolate effects of other channels. Additionally, different forms of bungarotoxin may be useful for studying inhibited nAChRs and their resultant calcium ion flow in different systems of

2646-431: Is produced by monoamine oxidase B as a metabolite of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) , and its toxicity is particularly significant to dopaminergic neurons because of an active transporter on those cells that bring it into the cytoplasm. The neurotoxicity of MPP+ was first investigated after MPTP was produced as a contaminant in the pethidine synthesized by a chemistry graduate student, who injected

2744-494: Is produced in a number of different forms, though one of the commonly used forms is the long chain alpha form, α-bungarotoxin , which is isolated from the banded krait snake . Though extremely toxic if ingested, α-bungarotoxin has shown extensive usefulness in neuroscience as it is particularly adept at isolating nAChRs due to its high affinity to the receptors. As there are multiple forms of bungarotoxin, there are different forms of nAChRs to which they will bind, and α-bungarotoxin

2842-598: Is referred to as the "candidate" list because all substances placed on it are candidates for inclusion in Annex XIV of REACH. If a substance is added to Annex XIV, it is given a "latest application date" and a "sunset date". The sunset date is the date after which the substance cannot be used or imported into the EU without authorisation from the ECHA, and the latest application date is the date by which any applications for use must be submitted to

2940-822: Is the ability for ethanol to inhibit NMDA receptors in the hippocampus, resulting in reduced long-term potentiation (LTP) and memory acquisition. NMDA has been shown to play an important role in LTP and consequently memory formation. With chronic ethanol intake, however, the susceptibility of these NMDA receptors to induce LTP increases in the mesolimbic dopamine neurons in an inositol 1,4,5-triphosphate (IP3) dependent manner. This reorganization may lead to neuronal cytotoxicity both through hyperactivation of postsynaptic neurons and through induced addiction to continuous ethanol consumption. It has, additionally, been shown that ethanol directly reduces intracellular calcium ion accumulation through inhibited NMDA receptor activity, and thus reduces

3038-405: Is this capability to inhibit potassium flux in neurons that has made TEA one of the most important tools in neuroscience. It has been hypothesized that the ability for TEA to inhibit potassium channels is derived from its similar space-filling structure to potassium ions. What makes TEA very useful for neuroscientists is its specific ability to eliminate potassium channel activity, thereby allowing

Substance of very high concern - Misplaced Pages Continue

3136-403: Is this classification which allows substances which are, for example, neurotoxic , endocrine-disrupting or otherwise present an unanticipated environmental health risk to be regulated under REACH. Simply because a substance meets one or more of the criteria does not necessarily mean that it will be proposed as an SVHC. Many such substances are already subject to restrictions on their use within

3234-536: Is usually associated is muscle paralysis and resultant death. Curare notably functions to inhibit nicotinic acetylcholine receptors at the neuromuscular junction . Normally, these receptor channels allow sodium ions into muscle cells to initiate an action potential that leads to muscle contraction. By blocking the receptors, the neurotoxin is capable of significantly reducing neuromuscular junction signaling, an effect which has resulted in its use by anesthesiologists to produce muscular relaxation. Ammonia toxicity

3332-523: The European Chemicals Agency (ECHA) and are open for public comment for 60–90 days. If the substance is deemed to meet one or more of the criteria, it is then listed as an SVHC. Once a substance has been listed as an SVHC, the Agency commissions a technical report from one or more national or private laboratories, which analyses the available information on manufacture, imports, uses and releases of

3430-571: The TRPV1 receptor expressed on cholinergic neurons and inhibit the toxic effects of BTX. Tetanus neurotoxin (TeNT) is a compound that functionally reduces inhibitory transmissions in the nervous system resulting in muscular tetany. TeNT is similar to BTX, and is in fact highly similar in structure and origin; both belonging to the same category of clostridial neurotoxins . Like BTX, TeNT inhibits inter-neuron communication by means of vesicular neurotransmitter (NT) release. One notable difference between

3528-521: The cell membrane, or communication between neurons across a synapse . Local pathology of neurotoxin exposure often includes neuron excitotoxicity or apoptosis but can also include glial cell damage. Macroscopic manifestations of neurotoxin exposure can include widespread central nervous system damage such as intellectual disability , persistent memory impairments, epilepsy , and dementia . Additionally, neurotoxin-mediated peripheral nervous system damage such as neuropathy or myopathy

3626-455: The central nervous system to cause cell death. An example is through the nicotinic acetylcholine receptor (nAchRs), which is a receptor commonly found along the surfaces of the cells that respond to nicotine stimulation, turning them on or off. Aβ was found manipulating the level of nicotine in the brain along with the MAP kinase , another signaling receptor, to cause cell death. Another chemical in

3724-539: The hippocampus , widespread brain atrophy, and induced inflammation in the brain. Of note, chronic ethanol ingestion has additionally been shown to induce reorganization of cellular membrane constituents, leading to a lipid bilayer marked by increased membrane concentrations of cholesterol and saturated fat . This is important as neurotransmitter transport can be impaired through vesicular transport inhibition, resulting in diminished neural network function. One significant example of reduced inter-neuron communication

3822-436: The mouth and limbs ), muscle weakness, nausea , and vomiting and often manifest within 30 minutes of ingestion . The primary mechanism by which TTX is toxic is through the inhibition of sodium channel function, which reduces the functional capacity of neuron communication. This inhibition largely affects a susceptible subset of sodium channels known as TTX-sensitive (TTX-s), which also happens to be largely responsible for

3920-439: The BBB, allowing for direct contact with the fragile cells within the central nervous system. Neurotoxicity results from lead's ability to act in a similar manner to calcium ions, as concentrated lead will lead to cellular uptake of calcium which disrupts cellular homeostasis and induces apoptosis. It is this intracellular calcium increase that activates protein kinase C (PKC), which manifests as learning deficits in children as

4018-637: The BBB. To even further complicate the process of determining neurotoxins when testing in-vitro, neurotoxicity and cytotoxicity may be difficult to distinguish as exposing neurons directly to compounds may not be possible in-vivo, as it is in-vitro. Additionally, the response of cells to chemicals may not accurately convey a distinction between neurotoxins and cytotoxins, as symptoms like oxidative stress or skeletal modifications may occur in response to either. In an effort to address this complication, neurite outgrowths (either axonal or dendritic) in response to applied compounds have recently been proposed as

Substance of very high concern - Misplaced Pages Continue

4116-448: The CNS can produce significantly toxic effects. Glutamate , like nitric oxide, is an endogenously produced compound used by neurons to perform normally, being present in small concentrations throughout the gray matter of the CNS. One of the most notable uses of endogenous glutamate is its functionality as an excitatory neurotransmitter. When concentrated, however, glutamate becomes toxic to surrounding neurons. This toxicity can be both

4214-460: The Ca and NOS results in the formation of the cofactor tetrahydrobiopterin (BH4), which then moves from the plasma membrane into the cytoplasm. As a final step, NOS is dephosphorylated yielding nitric oxide (NO), which accumulates in the brain, increasing its oxidative stress . There are several ROS, including superoxide , hydrogen peroxide and hydroxyl , all of which lead to neurotoxicity. Naturally,

4312-499: The ECHA. This table includes the Candidate list updates as of January 2024; find the complete list in references. (2,4,6-TTBP) Persistent, bioaccumulative and toxic (Octrizole) (DBP) Neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system . It occurs when exposure to

4410-646: The European Union, such as those in Annex XVII of the REACH Regulation. SVHCs are substances for which the current restrictions on use (where these exist) might be insufficient. There are three priority groups for assessment: Proposals for inclusion of a substance on the list of SVHCs can come either from the European Commission or one of the Member States of the European Union. The proposals are made public by

4508-477: The ability to improve the original Hodgkin-Huxley model of the neuron in which it was theorized that single generic sodium and potassium channels could account for most nervous tissue function. From this basic understanding, the use of common compounds such as tetrodotoxin, tetraethylammonium , and bungarotoxins have led to a much deeper understanding of the distinct ways in which individual neurons may behave. As neurotoxins are compounds which adversely affect

4606-412: The activation of nitric oxide synthase , ultimately leading to cell death. Aβ was also found aiding this route to neurotoxicity by enhancing neuron vulnerability to glutamate. The formation of oxygen radicals in the brain is achieved through the nitric oxide synthase (NOS) pathway. This reaction occurs as a response to an increase in the Ca concentration inside a brain cell. This interaction between

4704-427: The blood than in the brain; in turn, the body must act to maintain equilibrium between the two concentrations by pumping the glutamate out of the bloodstream and into the neurons of the brain. In the event of a mutation, the glutamate transporters are unable to pump the glutamate back into the cells; thus a higher concentration accumulates at the glutamate receptors . This opens the ion channels, allowing calcium to enter

4802-449: The blood, such as those experiencing renal failure . Patients experiencing aluminium toxicity can exhibit symptoms such as impaired learning and reduced motor coordination . Additionally, systemic aluminium levels are known to increase with age, and have been shown to correlate with Alzheimer's disease , implicating it as a neurotoxic causative compound of the disease. Despite its known toxicity in its ionic form, studies are divided on

4900-432: The body in useful and healthy ways, such as nitric oxide which is used in cell communication. It is often only when these endogenous compounds become highly concentrated that they lead to dangerous effects. Though nitric oxide (NO) is commonly used by the nervous system in inter-neuron communication and signaling, it can be active in mechanisms leading to ischemia in the cerebrum (Iadecola 1998). The neurotoxicity of NO

4998-632: The body utilizes a defensive mechanism to diminish the fatal effects of the reactive species by employing certain enzymes to break down the ROS into small, benign molecules of simple oxygen and water. However, this breakdown of the ROS is not completely efficient; some reactive residues are left in the brain to accumulate, contributing to neurotoxicity and cell death. The brain is more vulnerable to oxidative stress than other organs, due to its low oxidative capacity. Because neurons are characterized as postmitotic cells, meaning that they live with accumulated damage over

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5096-444: The body. For example, α-bungarotoxin is specific for nAChRs found in the musculature and κ-bungarotoxin is specific for nAChRs found in neurons. Caramboxin (CBX) is a toxin found in star fruit ( Averrhoa carambola) . Individuals with some types of kidney disease are susceptible to adverse neurological effects including intoxication, seizures and even death after eating star fruit or drinking juice made of this fruit. Caramboxin

5194-485: The brain , which through the function of their ependymal cells, are responsible for the synthesis of cerebrospinal fluid (CSF). Importantly, through selective passage of ions and nutrients and trapping heavy metals such as lead, the choroid plexuses maintain a strictly regulated environment which contains the brain and spinal cord. By being hydrophobic and small, or inhibiting astrocyte function, some compounds including certain neurotoxins are able to penetrate into

5292-427: The brain and induce significant damage. In modern times, scientists and physicians have been presented with the challenge of identifying and treating neurotoxins, which has resulted in a growing interest in both neurotoxicology research and clinical studies. Though clinical neurotoxicology is largely a burgeoning field, extensive inroads have been made in the identification of many environmental neurotoxins leading to

5390-419: The brain and inhibit some of the crucial functions of the blood brain barrier (BBB). A loss of function in the BBB can produce significant damage to the neurons in the CNS, as the barrier protecting the brain from other toxins found in the blood will no longer be capable of such action. Though the metal is known to be neurotoxic, effects are usually restricted to patients incapable of removing excess ions from

5488-412: The brain requires nutrient entry and waste removal, it is perfused by blood flow. Blood can carry a number of ingested toxins, however, which would induce significant neuron death if they reach nervous tissue. Thus, protective cells termed astrocytes surround the capillaries in the brain and absorb nutrients from the blood and subsequently transport them to the neurons, effectively isolating the brain from

5586-549: The brain such as vitamin E . As the fetal brain is relatively fragile and susceptible to induced stresses, severe deleterious effects of alcohol exposure can be seen in important areas such as the hippocampus and cerebellum . The severity of these effects is directly dependent upon the amount and frequency of ethanol consumption by the mother, and the stage in development of the fetus. It is known that ethanol exposure results in reduced antioxidant levels, mitochondrial dysfunction (Chu 2007), and subsequent neuronal death, seemingly as

5684-444: The brain that Aβ regulates is JNK ; this chemical halts the extracellular signal-regulated kinases (ERK) pathway, which normally functions as memory control in the brain. As a result, this memory favoring pathway is stopped, and the brain loses essential memory function. The loss of memory is a symptom of neurodegenerative disease , including AD. Another way Aβ causes cell death is through the phosphorylation of AKT ; this occurs as

5782-693: The capacity for the occurrence of LTP. In addition to the neurotoxic effects of ethanol in mature organisms, chronic ingestion is capable of inducing severe developmental defects. Evidence was first shown in 1973 of a connection between chronic ethanol intake by mothers and defects in their offspring. This work was responsible for creating the classification of fetal alcohol syndrome , a disease characterized by common morphogenesis aberrations such as defects in craniofacial formation, limb development, and cardiovascular formation. The magnitude of ethanol neurotoxicity in fetuses leading to fetal alcohol syndrome has been shown to be dependent on antioxidant levels in

5880-507: The case of botulinum toxin , or even nervous tissue death. The time required for the onset of symptoms upon neurotoxin exposure can vary between different toxins, being on the order of hours for botulinum toxin and years for lead. Tetanus toxin Mercury Curare Caramboxin , 25I-NBOMe , JWH-018 , 5-MEO-DiPT Arsenic N-Hexane , Methanol Glutamate , Dopamine Tetrodotoxin (TTX)

5978-472: The cell causing excitotoxicity. Glutamate results in cell death by turning on the N-methyl-D-aspartic acid receptors (NMDA); these receptors cause an increased release of calcium ions (Ca ) into the cells. As a result, the increased concentration of Ca directly increases the stress on mitochondria , resulting in excessive oxidative phosphorylation and production of reactive oxygen species (ROS) via

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6076-514: The classification of 750 to 1000 known potentially neurotoxic compounds. Due to the critical importance of finding neurotoxins in common environments, specific protocols have been developed by the United States Environmental Protection Agency (EPA) for testing and determining neurotoxic effects of compounds (USEPA 1998). Additionally, in vitro systems have increased in use as they provide significant improvements over

6174-438: The conductance of chloride channels . Ingestion of lethal volumes of Cltx results in paralysis through this ion channel disruption. Similar to botulinum toxin, Cltx has been shown to possess significant therapeutic value. Evidence has shown that Cltx can inhibit the ability for gliomas to infiltrate healthy nervous tissue in the brain, significantly reducing the potential invasive harm caused by tumors. Conotoxins represent

6272-1312: The contaminated drug and developed overt Parkinson's within weeks. Discovery of the mechanism of toxicity was an important advance in the study of Parkinson's disease, and the compound is now used to induce the disease in research animals. The prognosis depends upon the length and degree of exposure and the severity of neurological injury. In some instances, exposure to neurotoxins or neurotoxicants can be fatal. In others, patients may survive but not fully recover. In other situations, many individuals recover completely after treatment. The word neurotoxicity ( / ˌ n ʊər oʊ t ɒ k ˈ s ɪ s ɪ t i / ) uses combining forms of neuro- + tox- + -icity , yielding " nervous tissue poisoning". Neurotoxin Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity ). Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. Though neurotoxins are often neurologically destructive, their ability to specifically target neural components

6370-430: The death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is eliminated from the body. In some cases the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods. Some of the most common naturally occurring brain toxins that lead to neurotoxicity as

6468-522: The deaths of cows that drank from a lake containing an algal bloom in Saskatchewan, Canada. It is a cyanotoxin produced by at least four different genera of cyanobacteria , and has been reported in North America, Europe, Africa, Asia, and New Zealand. Toxic effects from anatoxin- a progress very rapidly because it acts directly on the nerve cells ( neurons ). The progressive symptoms of anatoxin-

6566-498: The development of extensive plumbing networks and the habit of boiling vinegared wine in lead pans to sweeten it, the process generating lead acetate, known as "sugar of lead". In part, neurotoxins have been part of human history because of the fragile and susceptible nature of the nervous system, making it highly prone to disruption. The nervous tissue found in the brain , spinal cord , and periphery comprises an extraordinarily complex biological system that largely defines many of

6664-401: The disruption or destruction of necessary components within the nervous system . Neurotoxins, however, by their very design can be very useful in the field of neuroscience . As the nervous system in most organisms is both highly complex and necessary for survival, it has naturally become a target for attack by both predators and prey. As venomous organisms often use their neurotoxins to subdue

6762-500: The final recommendations are sent to the commission. The first draft recommendations were published on 14 January 2009, and new draft recommendations must be issued at least once every two years. The list of SVHCs is primarily a public list of substances for which the European Chemicals Agency is considering imposing a requirement for authorisation for some or all uses. However, there are some direct consequences of including

6860-455: The function of motor nerves and thus the contraction of the musculature in a manner similar to that of curare. Additionally, through chronic TEA administration, muscular atrophy would be induced. It was later determined that TEA functions in-vivo primarily through its ability to inhibit both the potassium channels responsible for the delayed rectifier seen in an action potential and some population of calcium-dependent potassium channels. It

6958-449: The inhibition of acetylcholinesterase capacity of organophosphates (includes parathion and sarin gas). Though methods of determining neurotoxicity still require significant development, the identification of deleterious compounds and toxin exposure symptoms has undergone significant improvement. Though diverse in chemical properties and functions, neurotoxins share the common property that they act by some mechanism leading to either

7056-405: The involvement of a neurotoxin; however, the term neurotoxic may be used more loosely to describe states that are known to cause physical brain damage , but where no specific neurotoxin has been identified. The presence of neurocognitive deficits alone is not usually considered sufficient evidence of neurotoxicity, as many substances may impair neurocognitive performance without resulting in

7154-463: The membranes of neurons but not those of muscle cells. Botulinum toxin (BTX) is a group of neurotoxins consisting of eight distinct compounds, referred to as BTX-A,B,C,D,E,F,G,H, which are produced by the bacterium Clostridium botulinum and lead to muscular paralysis . A notably unique feature of BTX is its relatively common therapeutic use in treating dystonia and spasticity disorders, as well as in inducing muscular atrophy despite being

7252-399: The more common in vivo systems of the past. Examples of improvements include tractable, uniform environments, and the elimination of contaminating effects of systemic metabolism. In vitro systems, however, have presented problems as it has been difficult to properly replicate the complexities of the nervous system, such as the interactions between supporting astrocytes and neurons in creating

7350-632: The most poisonous substance known. BTX functions peripherally to inhibit acetylcholine (ACh) release at the neuromuscular junction through degradation of the SNARE proteins required for ACh vesicle-membrane fusion . As the toxin is highly biologically active, an estimated dose of 1μg/kg body weight is sufficient to induce an insufficient tidal volume and resultant death by asphyxiation . Due to its high toxicity, BTX antitoxins have been an active area of research. It has been shown that capsaicin (active compound responsible for heat in chili peppers ) can bind

7448-411: The most potent neurotoxins ever discovered. MeHg is usually acquired through consumption of seafood , as it tends to concentrate in organisms high on the food chain. It is known that the mercuric ion inhibits amino acid (AA) and glutamate (Glu) transport, potentially leading to excitotoxic effects. Investigations into anatoxin- a , also known as "Very Fast Death Factor", began in 1961 following

7546-408: The muscarinic acetylcholine antagonist atropine (which will inhibit parasympathetic activity), however, can increase sympathetic nerve activity enough to improve the chance of survival after TTX exposure. Tetraethylammonium (TEA) is a compound that, like a number of neurotoxins, was first identified through its damaging effects to the nervous system and shown to have the capacity of inhibiting

7644-425: The nervous system, a number of mechanisms through which they function are through the inhibition of neuron cellular processes. These inhibited processes can range from membrane depolarization mechanisms to inter-neuron communication . By inhibiting the ability for neurons to perform their expected intracellular functions, or pass a signal to a neighboring cell, neurotoxins can induce systemic nervous system arrest as in

7742-515: The past the characterization has meant poisons used by South American tribes on arrows or darts , though it has matured to specify a specific categorization of poisons which act on the neuromuscular junction to inhibit signaling and thus induce muscle relaxation. The neurotoxin category contains a number of distinct poisons, though all were originally purified from plants originating in South America. The effect with which injected curare poison

7840-427: The pathology of Parkinson's disease . Certain drugs, most famously the pesticide and metabolite MPP+ (1-methyl-4-phenylpyridin-1-ium) can induce Parkinson's disease by destroying dopaminergic neurons in the substantia nigra . MPP+ interacts with the electron transport chain in the mitochondria to generate reactive oxygen species which cause generalized oxidative damage and ultimately cell death. MPP+

7938-401: The persistence of neurons through an individual's lifetime, leading to compounding of damages. As a result, the nervous system has a number of mechanisms designed to protect it from internal and external assaults, including the blood brain barrier. The blood–brain barrier (BBB) is one critical example of protection which prevents toxins and other adverse compounds from reaching the brain. As

8036-555: The phosphate group is bound to several sites on the protein. This phosphorylation allows AKT to interact with BAD , a protein known to cause cell death. Thus an increase in Aβ results in an increase of the AKT/BAD complex, in turn stopping the action of the anti-apoptotic protein Bcl-2 , which normally functions to stop cell death, causing accelerated neuron breakdown and the progression of AD. Glutamate

8134-454: The poisoning of several workers in Chinese electronics factories in recent years. MPP , the toxic metabolite of MPTP is a selective neurotoxin which interferes with oxidative phosphorylation in mitochondria by inhibiting complex I , leading to the depletion of ATP and subsequent cell death. This occurs almost exclusively in dopaminergic neurons of the substantia nigra , resulting in

8232-399: The potential toxicity of using aluminium in packaging and cooking appliances. Mercury is capable of inducing CNS damage by migrating into the brain by crossing the BBB. Mercury exists in a number of different compounds, though methylmercury (MeHg ), dimethylmercury and diethylmercury are the only significantly neurotoxic forms. Diethylmercury and dimethylmercury are considered some of

8330-419: The presentation of permanent parkinsonism in exposed subjects 2–3 days after administration. Unlike most common sources of neurotoxins which are acquired by the body through ingestion, endogenous neurotoxins both originate from and exert their effects in-vivo . Additionally, though most venoms and exogenous neurotoxins will rarely possess useful in-vivo capabilities, endogenous neurotoxins are commonly used by

8428-399: The receptor, acetylcholine . Once it has triggered a contraction, anatoxin- a does not allow the neurons to return to their resting state, because it is not degraded by cholinesterase which normally performs this function. As a result, the muscle cells contract permanently, the communication between the brain and the muscles is disrupted and breathing stops. When it was first discovered,

8526-725: The safe use and disposal of the article, including the name of the SVHC(s) concerned. From 1 June 2011, manufacturers and importers of articles also have to notify the European Chemicals Agency of the quantities of SVHCs used in their articles. In addition to the obviously involved chemical industry, there are many more industries affected by this regulation: drapery and leather industry, plastic processing, cosmetic industry, food industry, petroleum processing, printing industry, sports equipment industry, toys industry, recycling industry, electrical engineering industry, fine mechanics industry, optics industry, engine and plant production industry. This list

8624-539: The sodium current that drives the depolarization phase of neuron action potentials . TTX-resistant (TTX-r) is another form of sodium channel which has limited sensitivity to TTX, and is largely found in small diameter axons such as those found in nociception neurons . When a significant level of TTX is ingested, it will bind sodium channels on neurons and reduce their membrane permeability to sodium. This results in an increased effective threshold of required excitatory signals in order to induce an action potential in

8722-401: The spinal cord after entering through endocytosis . This results in a loss of function in inhibitory neurons within the CNS resulting in systemic muscular contractions . Similar to the prognosis of a lethal dose of BTX, TeNT leads to paralysis and subsequent suffocation . Neurotoxic behavior of Aluminium is known to occur upon entry into the circulatory system , where it can migrate to

8820-432: The study of neuron response contributions of other ion channels such as voltage gated sodium channels. In addition to its many uses in neuroscience research, TEA has been shown to perform as an effective treatment of Parkinson's disease through its ability to limit the progression of the disease. Chlorotoxin (Cltx) is the active compound found in scorpion venom, and is primarily toxic because of its ability to inhibit

8918-469: The substance, as well as possible alternatives. On the basis of this technical report, the Agency decides whether to prioritise the substance, in effect, whether to make a recommendation to the European Commission to add the substance to Annex XIV of the REACH Regulation, making its use subject to authorisation. The draft recommendations must be made public and opened for comment for three months before

9016-499: The toxic effects of ammonia on astrocyte remodeling can be reduced through administration of L-carnitine . This astrocyte remodeling appears to be mediated through ammonia-induced mitochondrial permeability transition. This mitochondrial transition is a direct result of glutamine activity a compound which forms from ammonia in-vivo. Administration of antioxidants or glutaminase inhibitor can reduce this mitochondrial transition, and potentially also astrocyte remodeling. Arsenic

9114-539: The toxin was called the Very Fast Death Factor (VFDF) because when it was injected into the body cavity of mice it induced tremors, paralysis and death within a few minutes. In 1977, the structure of VFDF was determined as a secondary, bicyclic amine alkaloid , and it was renamed anatoxin- a . Structurally, it is similar to cocaine. There is continued interest in anatoxin- a because of the dangers it presents to recreational and drinking waters, and because it

9212-422: The two compounds is that while BTX inhibits muscular contractions , TeNT induces them. Though both toxins inhibit vesicle release at neuron synapses, the reason for this different manifestation is that BTX functions mainly in the peripheral nervous system (PNS) while TeNT is largely active in the central nervous system (CNS). This is a result of TeNT migration through motor neurons to the inhibitory neurons of

9310-407: The unique forms of conotoxins, ω-conotoxin ( ω-CgTx ) is highly specific for Ca channels and has shown usefulness in isolating them from a system. As calcium flux is necessary for proper excitability of a cell, any significant inhibition could prevent a large amount of functionality. Significantly, ω-CgTx is capable of long term binding to and inhibition of voltage-dependent calcium channels located in

9408-404: The unique traits of individuals. As with any highly complex system, however, even small perturbations to its environment can lead to significant functional disruptions. Properties leading to the susceptibility of nervous tissue include a high surface area of neurons, a high lipid content which retains lipophilic toxins, high blood flow to the brain inducing increased effective toxin exposure, and

9506-400: The years, accumulation of ROS is fatal. Thus, increased levels of ROS age neurons, which leads to accelerated neurodegenerative processes and ultimately the advancement of AD. The endogenously produced autotoxin metabolite of dopamine, 3,4-Dihydroxyphenylacetaldehyde (DOPAL), is a potent inducer of programmed cell death (apoptosis) in dopaminergic neurons. DOPAL may play an important role in

9604-410: Was found to cause neurotoxicity and cell death in the brain when present in high concentrations. Aβ results from a mutation that occurs when protein chains are cut at the wrong locations, resulting in chains of different lengths that are unusable. Thus they are left in the brain until they are broken down, but if enough accumulate, they form plaques which are toxic to neurons . Aβ uses several routes in

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