Nervous system toxicity demyelination

Effect of Dose and Duration of Exposure on Toxicity. The severity of neurological effects in humans and animals after acute oral exposure to cyanide is dose-related (Chen and Rose 1952 Lasch and El Shawa 1981). Central nervous system effects have been observed following acute-duration exposures (Levine and Stypulkowski 1959a) and chronic-duration exposures (Hertting et al. 1960), via the inhalation and oral routes. Necrosis is the most prevalent central nervous system effect following acute-duration exposure to high concentrations of cyanide, whereas demyelination is observed in animals that survive repeated exposure protocols (Bass 1968 Ibrahim et al. 1963). 

Demyelination. The role of myelin in the nervous system is to aid in signal transduction. Myelin acts like an electrical insulator by preventing loss of ion current, and intact myelin is critical for the fast saltatory nerve conduction discussed above. Neurotoxicants that target the synthesis or integrity of PNS myelin may cause muscle weakness, poor coordination, and paralysis. In the brain, white matter tracts that connect neurons within and between hemispheres may be destroyed, in a syndrome known as toxic leukoencephalopathy. A multifocal distribution of brain lesions is reflected in mental deterioration, vision loss, speech disturbances, ataxia (inability to coordinate movements), and paralysis. 

In general, thiram is not very toxic unless high levels of exposure occur. The oral LD50 in rats is 560 mg kg and the lowest lethal dermal dose in rabbits is 1 gkg . In contact with the skin and eyes of exposed rabbits, thiram caused irritation. In rabbits and guinea pigs, this substance has been shown to cause skin sensitization. Rats, cats, and rabbits survived a 4 h exposure to thiram dust at concentrations that ranged from 500 to 6225 mg m . Animals killed by single oral doses of thiram showed patchy demyelination in the central nervous system, initially in the cerebellum and medulla. Thiram (300 mg kg elicited convulsions and calcification... 

Secondary demyelination is the loss of myelin secondary to loss of axons. Axonal trophic factors sustain myelin. When the axon is severed or not sustained by its neuron of origin, the axon and then its myelin degenerates. This can happen secondary to infarcts, trauma, toxic, metabolic, or degenerative nervous system diseases. In contrast to primary demyelination, straight and long NF-positive axons are not seen in secondary demyelination. Acutely, the axons crumble into short pieces, and in a few days they are eaten by macrophages and disappear. NF stains thus distinguish secondary from primary demyelination. 

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