Neuro toxicity

Almost all systemic effects of methyl parathion are related to the action of this compound on the nervous system or are secondary to this primary action. It is therefore necessary to preface a description of the mechanisms of toxicity of methyl parathion with a brief discussion of the nervous system and neuro-humoral transmitters (excerpted from Lefkowitz et al. 1996). 

On the one hand, the biochemical study of the neuro-pathological lesions led to the identification of their main molecular components. On the other hand, the study of rare, familial forms of Alzheimer s disease, frontotemporal dementia and Parkinson s disease led to the identification of gene defects that cause inherited variants of the different diseases. Remarkably, in these cases, the defective genes have been found to encode or increase the expression of the main components of the neuropathological lesions. It has therefore been established that the basis of the familial forms of these diseases is a toxic property conferred by mutations in the proteins that make up the filamentous lesions. A corollary of this insight is that a similar toxic property may also underlie the much more common, sporadic forms of the diseases. 

Gray, A.J. 1985. Pyrethroid structure-toxicity relationships in mammals. Neuro toxicology 6 127-137. 

Shulga V., Delayed neuro-endocrine toxicity indused by organophosphorus compounds-natural consequence of poisonous substances application for terrorist purpose , In Medical Aspects of Chemical and Biological Terrorism -Chemical Terrorism and Tramautism, Alexander Monov and Christophor Dishovsky, eds, Publishing House of the Union of Scientists in Bulgaria, 2005 ( in press). 

In the neurotoxicity study (OECD TG 424/EU Annex B.43), the animals are tested to allow the detection or the characterization of behavioral and/or neurological abnormalities. A range of behaviors that could be affected by neuro toxic ants is assessed during each observation period. At the end of the test, a subset of animals of each sex from each group are perfused in situ and sections of the brain, spinal cord, and peripheral nerves are prepared and examined. 

Toxicological observations indicate that pulegone is an insect neuro-toxin, as well as an abortifacient in women and in animals. (15)-( — )-Pulegone is far less toxic in mice than (li )-(+) pulegone (both hepatotoxic and pneumotoxic). 

Makkawy HM, Graham DG, Abou-Donia MB. 1981. Differential neuro toxicity ofn-hexane methyl-n -butyl ketone, 2,5-hexanediol and 2,5-hexanedione following subchronic 90 days oral administration in hens. Fed Proc 40 678. 

Cholinesterase inhibitors are a very important class of compounds related to cholinomimetics. Besides their therapeutic importance, a few of them are used as pesticides in agriculture, and the most toxic are used as chemical poisoning agents. Use of these substances is based on changes that take place after inactivation of cholinesterase or pseudocholinesterase (a less specific enzyme), i.e. effects observed as a result of acetylcholine buildup in neuro-effector compounds. Cholinesterase inhibitors are classified both by their chemical structure as well as by the type of their chemical reaction with the enzyme, which determines their temporary action. 

There are of course many mathematically complex ways to perform a risk assessment, but first key questions about the biological data must be resolved. The most sensitive endpoint must be defined along with relevant toxicity and dose-response data. A standard risk assessment approach that is often used is the so-called divide by 10 rule . Dividing the dose by 10 applies a safety factor to ensure that even the most sensitive individuals are protected. Animal studies are typically used to establish a dose-response curve and the most sensitive endpoint. From the dose-response curve a NOAEL dose or no observed adverse effect level is derived. This is the dose at which there appears to be no adverse effects in the animal studies at a particular endpoint, which could be cancer, liver damage, or a neuro-behavioral effect. This dose is then divided by 10 if the animal data are in any way thought to be inadequate. For example, there may be a great deal of variability, or there were adverse effects at the lowest dose, or there were only tests of short-term exposure to the chemical. An additional factor of 10 is used when extrapolating from animals to humans. Last, a factor of 10 is used to account for variability in the human population or to account for sensitive individuals such as children or the elderly. The final number is the reference dose (RfD) or acceptable daily intake (ADI). This process is summarized below. 

Gates DJ, Harrington RM. 1996. Neuro-reproductive toxicity issues concerning chlorine dioxide and the chlorite ion in public drinking water supplies. In Proceedings 1995 water quality technology conference. Part I, University of California Berkeley, November 12-16, 1995. Denver, CO AWWA, 813-830. 

Moochhala. 1 Methyl 4 phenyh 1,2,3, 6 tetrahydropyridine induced neuro-toxicity partial protection against striato-nigral dopamine depletion in C57BL/6J mice by cigarette smoke ex-posure and by beta-naphthoflavone-pretreatment. Neurosci Lett 1991 127(2) 247-250. 

Non-toxic, non-sensitizing to skin, absence of eye irritation and neuro-toxicity. 

Hydroxy dopamine is a selectively neuro toxic compound, which damages the sympathetic nerve endings. It can be seen from Figure 7.43 that 6-hydroxydopamine is structurally very similar to dopamine and noradrenaline, and because of this similarity it is actively taken up into the synaptic system along with other catecholamines. Once localized in the synapse, the 6-hydroxydopamine destroys the nerve terminal. A single small dose of 6-hydroxydopamine destroys all the nerve terminals and possibly the nerve cells as well. 

Before implantation several in vitro tests were performed. For evaluation of a possible toxic reaction, we investigated the material and the whole devices in vitro with cell culture methods. Direct contact and extraction tests with a mouse fibroblasts cell line (L 929) and a neuroblastoma cell line (neuro-2-a) were performed according to the international standard ISO 10993 ( Biological Evaluation of Medical Devices ). The materials and devices showed no toxicity, i.e. no significant differences in membrane integrity of the cell membranes, mitochondrial activity and DNA synthesis rate. The neuro-2-a cell line is so sensitive that even small changes in process technology are detectable. The flexible polyimide structures proved to be non toxic. 

Toxicology, Pharmacology and Metabolism. The dose-limiting toxicity of AMD473 in mice (and rats) is myelosuppression (leukopenia and thrombocytopenia). No renal-, liver- or neuro-toxicity has been observed [54]. Platinum pharmacokinetics following i.v. administration to mice (20 mg/kg) showed a biexponential decay in plasma with a rapid distribution (f1/2a °f 24 min) followed by a slow elimination (ti/2p of 44 h). Following oral dosing, platinum absorption was rapid (rmax of 0.5h) with a bioavailability of 40% [54]. Platinum accumulated mainly in the liver, kidney and spleen [54]. 

Hornykiewicz, O. (1967). Extrapyramidal side effects of neuro-(psycho-)tropic drugs. Proceedings of the European Society for the Study of Drug Toxicity, 8, 122-135. 

The investigation of neuro-toxicity in short-term studies has been proposed. Especially cage site observations, physical conditions and behavioral observations are of value. 

The FDA has established criteria for neuro-toxicity screens as a component of short-term and sub-chronic studies (FDA/FDCA 1993) ... 

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