Central nervous system high-dose exposure

Pathological changes that may occur in the central nervous system during acute exposure to high doses may complicate recovery. Severe Parkinsonism was one of the effects noted in four case reports resulting from severe acute oral exposure to cyanide (Carella et al. 1988 Grandas et al. 1989 Rosenberg et al. 

Attempts to diminish the overall metabolism of trichloroethylene might be useful (e.g., hypothermia, mixed-function oxidase inhibitors, competitive inhibitors of trichloroethylene metabolism [i.e., P-450 substrates]), if instituted soon enough after trichloroethylene exposure. Catecholamines (especially beta agonists) act in concert with trichloroethylene, increasing the risk of cardiac arrhythmias. Hence, catecholamines should be administered to patients only in the lowest efficacious doses and for certain limited presentations of trichloroethylene poisoning. Ethanol should also be avoided because concurrent exposure to trichloroethylene and ethanol can cause vasodilation and malaise and may potentiate central nervous system depression at high dosage levels of either compound. 

Exposure to Hg may cause serious harm to human health, at high doses it can even be fatal. Mercury toxicity usually involves the kidneys and/or nervous system disorders (central nervous system and neurobehavioral changes). Mercury contamination has been found in more than 70 federal sites with Hg-contaminated wastes. 

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). 

The nervous system is the most sensitive target for cyanide toxicity, partly because of its high metabolic demands. High doses of cyanide can result in death via central nervous system effects, which can cause respiratory arrest. In humans, chronic low-level cyanide exposure through cassava consumption (and possibly through tobacco smoke inhalation) has been associated with tropical neuropathy, tobacco amblyopia, and Leber s hereditary optic atrophy. It has been suggested that defects in the metabolic conversion of cyanide to thiocyanate, as well as nutritional deficiencies of protein and vitamin B12 and other vitamins and minerals may play a role in the development of these disorders (Wilson 1965). 

The primary target for cyanide toxicity is the central nervous system following both acute and chronic exposure. Exposure to high doses of cyanide can rapidly lead to death (see Section 2.2). Cyanide is not stored in the organism and one available study indicates that >50% of the received dose can be eliminated within 24 hours (Okoh 1983). However, because of the rapid toxic action of cyanide, development of methods that would enhance metabolism and elimination of cyanide is warranted. 

Toxicology. o-Dichlorobenzene is a skin and eye irritant. At high doses, it causes central nervous system depression and liver and kidney damage in animals. Heavy exposure is expected to produce the same effects in humans. 

Toxicology. Trichloroethylene (TCE) is primarily a central nervous system (CNS) depressant. Although it is carcinogenic at high doses in experimental animals, it is not considered to be a human carcinogen at low exposure levels. 

The principal effects of carbon tetrachloride in humans are on the liver, the kidneys and the central nervous system. These effects are apparent following either oral or inhalation exposure, and limited data indicate they can occur after dermal exposure as well. All of the effects seen in humans except renal injury are demonstrable at roughly comparable exposure levels in animals, although there are some variations in susceptibility between species that are likely to be related to differences in metabolism. No studies were located regarding reproductive and developmental effects in humans after exposure to carbon tetrachloride. In rats, carbon tetrachloride was not shown to adversely affect reproduction or development. Studies with both mice and rats suggest that sufficiently high doses of carbon tetrachloride may increase the risk of liver tumors in exposed humans. 

Other Systemic Effects. Studies in animals revealed that a number of other tissues besides liver, kidney, and the central nervous system can be affected by carbon tetrachloride, including the adrenals, pancreas, testes, pituitary, spleen and thyroid (Chatterjee 1966 De Castro et al. 1978 de Toranzo et al. 1978b Itoh et al. 1985 Kalla and Bansal 1975 Reuber and Glover 1970). However, effects on these tissues have been reported only after exposure to relatively high doses of carbon tetrachloride, indicating that these tissues are not as sensitive to carbon tetrachloride as liver, kidney, and brain. 

Reversibility of Noncarcinogenic Systemic Effects. Most case reports of humans intoxicated with carbon tetrachloride indicate that, if death can be averted, clinical signs of renal and hepatic dysfunction diminish within 1-2 weeks, and recovery often appears to be complete. This is primarily because both liver and kidney have excellent regenerative capacity and can repair injured cells or replace dead cells (Dragiani et al. 1986 Norwood et al. 1950). However, high doses or repeated exposure can lead to fibrosis or cirrhosis that may not be reversible. The depressant effects of carbon tetrachloride on the central nervous system do appear to be reversible, although any neural cell death that occurs (Cohen 1957) is presumably permanent. 

Methylmercury intoxication affects mainly the central nervous system and results in paresthesias, ataxia, hearing impairment, dysarthria, and progressive constriction of the visual fields. Signs and symptoms of methylmercury intoxication may first appear several weeks or months after exposure begins. Methylmercury is a reproductive toxin. High-dose prenatal exposure to methylmercury may produce mental retardation and a cerebral palsy-like syndrome in the offspring. Low-level prenatal exposures to methylmercury have been associated with a risk of subclinical neurodevelopmental deficits. 

Hydrazine is toxic and readily absorbed by oral, dermal, or inhalation routes of exposure. Contact with hydrazine irritates the skin. eyes, and respiratory tract. Liquid splashed into die eyes may cause permanent damage to the cornea. Al high doses it can cause convulsions, but even low doses may result in central nervous system depression. Death from acute exposure results from convulsions, respiratory arrest, and cardiovascular collapse. Repeated exposure may affect the lungs, liver, and kidneys. Evidence is limited as to the effect of hydrazine on reproduction and/or development however, animal studies demonstrate that only doses that produce toxicity in pregnant rats result in embryo-toxicity. 

Death. No case studies of human fatalities have been reported following exposure to chlorobenzene by inhalation, ingestion, or dermal contact. Death has been reported in animals at high doses for brief periods of exposure. Rabbits died within 2 weeks after removal from exposure at approximately 537 ppm (Rozenbaum et al. 1947). The cause of death has been attributed to central nervous system depression resulting in respiratory failure. Animal data suggest that lethality may not be a concern for humans unless the exposure level is very high. 

Animal testing has also demonstrated that animals exposed once to a high dose of chemicals or to a low dose of chemicals over a long period of time became hypersensitive such that additional exposures to chemicals began to affect the electrical activity in the limbic system. If the hypothalamus is thereby activated, this could explain many of the fundamental symptoms of MCS, because this gland influences the immune system, the central nervous system and the endocrine system (glands, hormones, and so forth). The limbic system is known for reacting to internal and external chemical stimulants. 

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