Neurotoxicity known compounds

Organophosphate Ester Hydraulic Fluids. A number of studies have been conducted on organophosphate ester hydraulic fluids because of the well known neurotoxic effects caused by organophosphorus insecticides, organophosphorus nerve gases, and tri-ort/w-cresyl phosphate (TOCP). The following manifestations of acute exposure to organophosphorus compounds have been described ... 

One of the main human health concerns about organophosphate esters is the potential for neurotoxicity reactions, in particular a condition known as organophosphate-induced delayed neurotoxicity (OPIDN). Tri-ort/20-cresyl phosphate (TOCP) has been identified as one of the more potent OPIDN neurotoxins in humans, and was formerly a constituent in some organophosphate ester hydraulic fluid products (Marino 1992 Marino and Placek 1994). Production processes now routinely remove virtually all the TOCP. For instance, tricresyl phosphate (TCP) products now typically are manufactured to contain over 98% meta and para isomers and virtually no TOCP (Marino and Placek 1994). Products containing these compounds associated with OPIDN have now entirely disappeared from commercial use, and the vast majority of the industrial organophosphate esters are based on triaryl phosphates with no halogenated components (Marino 1992). At waste disposal sites, however, site contaminants from older product formulations containing the ortho form may be encountered. 

Some dinoflagellates of the genus Alexandrium produce neurotoxic compounds known as paralytic shellfish poisoning (PSP) toxins. Because these toxins can contaminate filter-feeding shellfish they may threaten public health and create economic problems for fisheries. PSP-toxins include at least a dozen saxitoxins, neosaxitoxins, and gonyautoxins (Scheme 1). 

Neurotoxic Shellfish Poisoning (NSP) is caused by a red-tide producer that was first identified in 1880 from Florida, with earlier historical references. It causes sickness in humans lasting several days. NSP is not fatal to humans however, it is known to kill fish, invertebrates, seabirds, and marine mammals (e.g., manatees). It is caused by the brevetoxin family (brevetoxin + 10 related compounds produced by the dinoflagellate Karenia brevis a.k.a. Gymnodinium breve. The main contamination problems include oysters, clams, and other filter feeders of the Gulf of Mexico and southeast Atlantic, including North Carolina. 

The tetrahydropyridine l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) 288 is a well-known neurotoxin that induces symptoms like those for Parkinson s disease. The toxic effects of this compound have been attributed to its oxidation by monoamine oxidase (MAO) to form the pyridine MPP+ 289. MPP+ migrates into the mitochondria of neural cells inhibiting the production of ATP and results in cell death <2000MI1, 2001MI1>. Numerous compounds, such as 4-phenoxy- 290<1997BMC1519> and 4-pyrrole-tetrahydropyridines 291 <2002BMC3031>, have been modelled on MPTP in an attempt to inhibit MAO without exhibiting neurotoxic effects. 

Application of in vitro test methods have become advantageous in specific cases, such as structurally defined compounds and delayed neuropathy, since target cell data and biochemical processes associated in delayed neuropathy are known. Microscopic studies reveal that cases of OPIDN have degeneration of axons followed by demyelination of the nervous system.25,26 Epidemiologic studies have indicated mild impairment of the brainstem, spinal cord, and peripheral nerve functions in Gulf War veterans.27 Such studies are consistent with the spectrum of OPIDN syndrome. The main nerve agents have been shown to inhibit NTE in vitro as well as in vivo. Sarin has been shown to produce delayed neurotoxicity when administered at higher doses in protected hens.25-27... 

Lactone An organic compound that contains an ester group incorporated into a carbon ring structure. Lactones include the coumarins, e.g. umbelliferone or 7-hydroxycoumarin. Lactones and furocoumarins, e.g. bergaptene, exist in small quantities in essential oils and should be used with care. Lactones can be neurotoxic (poisonous to the nervous system) and cause skin allergies. Bergaptene is well known for its phototoxicity on the skin. 

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