Substances and Neurotoxicity

A large number of industrial chemicals are hindering children s development, lowering IQ scores, and triggering attention and behavior disorders. The National Institute of Occupational Safety and Health (NIOSH) studies have revealed a large number of chemical substances that cause damage to the human nervous system. The Lancet identified 201 chemicals with the ability to cause neurological effects in humans. Many chemical substances with neurotoxic potential have not been 

Besides causing other adverse health effects, prolonged periods of exposure to high concentrations of different chemical substances are known to induce neurotoxicity among workers. The symptoms of neurotoxicity become visible with the 

6 Morphological changes include cell death and axonopathy as well as subcellular morphological changes 

5 Neurological changes include abnormal findings in neurological examinations on single individuals 

3 Biochemical changes include evaluations and analysis of biochemical parameters (e.g., 

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Paralytic shellfish poison, like botulinum toxin, is a neurotoxic substance and can also affect certain muscles, including the heart, which are under nervous system control. Some poisoned humans who have recovered from the effects of PSP have described the early stages of intoxication as not at all unpleasant a tingling sensation in the lips and face and a feeling of calm. Those who die from PSP ingestion do so because of respiratory failure. 

The delayed neurotoxicity smdies of organophosphorus substances provide information on the delayed neurotoxicity arising from repeated exposure over a relatively limited period of the animal s life span. The smdy is used in the assessment and evaluation of the neurotoxic effects of organophosphorus substances and will provide information on dose-response relationship and can provide an estimate of a NOAEL for delayed neurotoxicity. See also Section 4.7.7. 

Neurotoxicity can be defined as any adverse effect on the structure or function of the nervous system related to exposure to a chemical substance (US-EPA 1998, OECD 2004c). According to the TGD (EC 2003), neurotoxicity can be defined as the induction by a chemical of adverse effects in the central or peripheral nervous system, or in sense organs and a substance is neurotoxic if it induces a reproducible lesion in the nervous system or a reproducible pattern of neural dysfunction. ... 

The adopted test guideline methods for repeated dose toxicity testing include a number of parameters relevant for the evaluation of a substance s neurotoxic potential. Eurthermore, specific test guidelines for neurotoxicity testing have also been adopted. These test methods are addressed in Section 4.7.3.1 and Tables 4.11 and 4.12. 

In other words, introduction of ortho substitutions into PBDEs or PCDEs does not create a spatial impediment for the two phenyl rings to assume a semi-flat position respect to each other as it does for PCBs or PBBs. This has implications not only for dioxin-type toxicities, but also for nondioxin-type toxicities. For example, studies have shown that mono- and diortho-substituted PCBs exhibit neurotoxic properties and structure-activity relationships for various neurological end points have been established (see Agency for Toxic Substances and Disease Registry 2000 for details). Although structure-activity relationships have not yet been fully examined for PBBs or PBDEs, it is reasonable to speculate that mono-and diortho-substituted PBDEs may not necessarily follow the neurotoxic potency rankings constructed with mono- and diortho-substituted PCBs. 

Prolonged periods of exposure to natural, synthetic, or man-made chemical substances cause neurotoxicity. The effects of neurotoxicity result in a variety of health disturbances. In simple terms, neurotoxic chemical substances change the normal activity of the nervous system, eventually leading to disruption of the network of neurons. Thus, the key cells of neural transmission and signal processing in the brain and other parts of the nervous system get damaged. 

Other less potent naturally occurring substances exhibit neurotoxic effects when encountered in large concentration for sufficient periods of time. Examples include metals (arsenic, lead, mercury) and certain compounds containing these elements (methylmercu-ry) (Table 2). Some elements (manganese, selenium) and compounds (vitamin Bg) in this group, while neurotoxic in sustained heavy doses, are required in smaller amounts to support normal physiological function, including that of the nervous system. 

Table 2 Heavy metals and synthetic substances with neurotoxic potential...

British Journal of Industrial Medicine 48 234-238, 1991 Neuberger M, Rape C, Bergek S, et al Persistent health effects of dioxin contamination in herbicide production. Environ Res 81 206-214, 1999 O Donoghue JL Cyclic halogenated hydrocarbons and related substances, in Neurotoxicity of Industrial and Commercial Chemicals, Vol II. Edited by O Donoghue JL. Boca Raton, FL, CRC Press, 1985, pp 155-168 Oliver RM Toxic effects of 2,3,7,8 tetrachlorodibenzo 1,4 dioxin in laboratory workers. British Journal of Industrial Medicine 32 49-53, 1975 Ott MG, Holder BB, Olson RD A mortality analysis of employees engaged in the manufacture of 2,4,5-trichlorophenoxyacetic acid. Journal of Occupational Medicine 22 47-50, 1980... 

The neurotoxic activity of HK seems to be well ascertained [93-95]. In fact, the substance showed neurotoxic properties when added to neuronal cell cultures [91] and provoked seizures when injected intracerebroven-tricularly [93]. As a significant and substantial increase of HK concentrations in brain samples taken post mortem from Huntington s disease patients was observed, a metabolic disorder of tryptophan degradation was associated with the disease. This disorder seems to be relatively specific to Huntington s disease, and normal levels of HK were found under the same conditions in Alzheimer s disease patients. 

The second type of test is the determination of neuro-toxic esterase activity (NTE), In its simplest form, this involves treatment of the adult hen with a single maximum tolerated dose of the test substance and sub-scquent assay of the brain enzyme after the time of peak inhibition but before substantial resynthesis of new enzyme has occurred (John.son, 1982). The time of peak inhibition, which can be from 3 to 48 hr postdosing (and is determined by the pharmacokinetics of the compound), can often be assessed by observation of the time of onset of cholinergic signs. The threshold level of NTE inhibition at this early stage, which correlates with delayed neurotoxicity, is approximately 80%. No clinical signs are associated with an inhibition of 60% or less. When multiple determinations of NTE are made during chronic exposures, plateau levels are observed after 2 or 3 weeks. If inhibition of NTE in the brain and spinal cord is Ies,s than 50%, delayed neuropathy doe.s not occur. 

The undesirable ecological effects have also restricted the applications of polychlorinated biphenyls (PCBs), the substances which are used in the cooling of high voltage electrical transformers. The main disadvantage of the use of PCB s is their slow rate of degradation after use. Dichlorodiphenyltrichloroethane (DDT) is a very efficient insecticide, but its use is restricted due to its carcinogenic and neurotoxic effects. 

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