Adult Central-Nervous-System Toxicity

Peripheral neuropathy is observed in 10-20% of patients given dosages greater than 5 mg/kg/d, but it is infrequently seen with the standard 300-mg adult dose. Peripheral neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 10 mg/d. Central nervous system toxicity, which is less common, includes memory loss, psychosis, and seizures. These may also respond to pyridoxine. 

In the U.S., the central nervous system syndrome is usually more common among children, and the gastrointestinal syndrome is more prevalent in adults. Exposure to lead is also linked to decreased fertility in men. Lead is a probable human carcinogen, based on sufficient animal evidence. Populations at increased risk of toxicity from exposure to lead include developing fetuses and young children, individuals with decreased kidney function, and children with sickle-cell anemia. 

Paradoxically, pyridoxine itself can also cause pathology in the central nervous system consisting of necrosis of dorsal root ganglia neurons and a centrifugal axonal atrophy and breakdown of peripheral and central sensory axons (Xu et al., 1989). This may occur at doses as low as 200-500 mg/d. However, in clinical trials using 100-150 mg/d to treat carpal tunnel syndrome, no toxicity was reported, suggesting that this a safe dose in adults. On the other hand, there are insufficient data to recommend long-term use of pyridoxine in children. 

Phenol is highly corrosive and toxic, the main effects being on the central nervous system. The lethal human oral dose is estimated to be 1 g for an adult. 

Acute exposure to allyl alcohol causes liver and kidney damage. Allyl alcohol is classified as a periportal hepatotoxicant since it selectively damages the periportal region of the liver. Studies have shown that in adult rats, allyl alcohol produces a moderate to marked periportal necrosis with attendant inflammation, hemorrhage, and also decreases hepatic cytochrome P-450, benzphentamine N-demethyla-tion, and ethoxyresorufin 0-deethylation activities by 30%. In immature rats, it lowered both cytochrome P-450 activity (30%) and ethoxyresorufin O-deethylation (75%). Benzphetamine N-demethyl-ation was not significantly affected in immature rats. Intraperitoneal administration of 1.5 mmol kg of allyl alcohol to starved Swiss albino mice causes the development of hemolysis in 50% of the animals. Other toxic effects include renal necrosis, pulmonary edema, and central nervous system effects at higher dose levels. 

The deliberate or accidental ingestion of belladonna alkaloids is a major cause of toxicity in humans. The most dangerous and spectacular manifestation of poisoning arises from the intense excitation of the central nervous system (CNS). Infants and young children are especially susceptible to the toxic effects of atropinic drugs. In adults, delirium or toxic psychoses without undue peripheral manifestations have been reported after instillation of atropine eye drops. Transdermal preparation of scopolamine has been reported to cause toxic psychoses, especially in children and in the elderly. Serious intoxication may occur in children who ingest berries or seeds containing... 

As little as 0.1 mg of clonidine has produced toxicity in children determination of adult toxicity is based on observation as there is no milligram per kilogram toxic dose established. Clonidine levels are not clinically useful. Toxicity can result from ingestion of used clonidine transdermal patches as residual clonidine remains after full therapeutic use. Symptoms generally begin within 30-90 min and include hypotension, central nervous system depression, bradycardia, and... 

Sodium borate decomposes into borate and peroxide and is less toxic than potassium bromate. From 3 to 6g and from 15 to 30 g boric acid is potentially fatal to children and adults, respectively. Cutaneous manifestations include desquamating, erythematous rash commonly over palms, soles, buttocks, and scrotum. The lesion may progress to exfoliation. Central nervous system (CNS) effects range from irritability, restlessness, and headache to coma and convulsions in severe cases. Gastrointestinal symptoms include anorexia, nausea, vomiting, and diarrhea. Acute renal tubular necrosis may lead to renal failure in moderate to severe cases. 

Rat pups exposed in utero to 8000 ppm MTBE and, to a lesser extent, those exposed to 3000 ppm, had statistically significant decreases in body weight during lactation compared with control pups and pups exposed in utero to 400 ppm. Effects on the central nervous system consisting of hypoactivity, ataxia, and loss of startle reflex were seen in adult rats exposed in utero to 3000 or 8000 ppm MTBE. No malformations were reported in the fetuses examined in the three studies in rats described above. Increased frequencies of skeletal malformations were found in fetuses from mice exposed to 4000 or 8000 ppm MTBE. When administered to mice at lower concentrations (1000 ppm), MTBE was neither teratogenic nor toxic to the mother or fetuses. 

Today the predominant if not the sole source of methylmercury is derived from the methylation of inorganic mercury in aquatic sediments and soils. Methylmercury is well absorbed from the diet and distributes within a few days to all tissues in the body. It is present in the body as water-soluble complexes mainly, if not exclusively, attached to the sulfur atom of thiol ligands, and crosses the blood—brain barrier without hindrance, entering the endothelial cells of the blood—brain barrier as a complex with L-cysteine. The principal target tissue of MeHg is the brain, and its major toxic effects are on the central nervous system. Whereas adult poisoning affects the visual cortex and the cerebellum, in neonatal infants the outcome can be much more serious, ranging in its effects from cerebral palsy to developmental retardation. 

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