Neurotoxicity symptoms

Hyjjerbilirubinaemia is an abnormality observed mainly in neonates in whom the liver is insufficiently developed to be able to detoxify the bile pigment bilirubin. This situation is known as neonatal jaundice and can sometimes become a serious disease causing neurotoxic symptoms. Bilirubin is produced by the degradation of heme [the Fe(II) complex of protoporphyrin IX] by heme oxygenase to give biliverdin, which is reduced by biliverdin reductase to... 

A few OP compounds cause delayed neuropathy in vertebrates because they inhibit another esterase located in the nervous system, which has been termed neuropathy target esterase (NTE). This enzyme is described in Chapter 10, Section 10.2.4. OPs that cause delayed neuropathy include diisopropyl phosphofluoridate (DFP), mipafox, leptophos, methamidophos, and triorthocresol phosphate. The delay in the appearance of neurotoxic symptoms following exposure is associated with the aging process. In most cases, nerve degeneration is not seen with initial inhibition of the esterase but appears some 2-3 weeks after commencement of exposure, as the inhibited enzyme undergoes aging (see Section 16.4.1). The condition is described as OP-induced delayed neuropathy (OPIDN). 

Aerosols of Cellulube 220 produced deaths associated with severe dyspnea and mild diarrhea in one of two rabbits exposed to 2,000 mg/m3 for <4 hours/day, 5 days/week for 11 or 22 days (Carpenter et al. 1959). Continuous exposure for 30-160 days to aerosols of a triaryl phosphate U.S. military hydraulic fluid (see Table 3-2), at concentrations <110 mg/m3, produced no deaths in dogs or rats, but deaths associated with severe neurotoxic symptoms occurred in chickens exposed to concentrations >23 mg/m3 and in rabbits exposed to 102 mg/m3 (Siegel et al. 1965). Aerosols of Durad MP280 or Fyrquel 220 (continuous exposure for 90 days) produced no deaths in rats or hamsters exposed to 100 mg/m3. Deaths associated with lethargy, cachexia, and head droop occurred in rabbits exposed to 101 mg/m3 Durad MP280, but not in rabbits exposed to 100 mg/m3 Fyrquel 220 (MacEwen and Vemot 1983). Some of the Durad MP280-exposed rabbits were also infected with Pasteurella, which may have contributed to neurological symptoms. No deaths occurred in rats exposed to cyclotriphosphazene at 990 mg/m3, 6 hours/day,... 

Several human fatalities have resulted from inhalation, dermal contact, or ingestion of ethylene chlorohydrin. Typically, neurotoxic symptoms were described, and death was attributed to cardiac and respiratory collapse. One fatality was caused by exposure to an estimated 300ppm for 2.25 hours. In another fatal case, autopsy showed pulmonary edema and damage to the liver, kidneys, and brain. ... 

A strong relationship has been noted between the concentration of 2,5-hexanedione in the urine and the onset of neuropathic symptoms (Eben et al. 1979). Similarly, 2,5-hexanedione was described as eliciting severe neurotoxic symptoms following oral, dermal, or intraperitoneal administration to hens (Abou-Donia et al. 1982, 1985b) and following oral administration to rats (Krasavage et al. 1980). 

Some authors claim to have had patients with Al neurotoxicity symptoms when the highest s-Al concentration was 17 to 22 pg/L [156, 157]. It seems very unlikely that these patients indeed suffered from Al encephalopathy because... 

Seizures and other neurological effects have been described in a few cases when lithium was added to clozapine (626), but in other instances the combination was beneficial in overcoming treatment resistance or attenuating clozapine-induced leukopenia. Five treatment-resistant patients were treated successfully with a combination of clozapine and lithium with no clinically significant adverse events (627). However, a 59-year-old woman developed neurotoxic symptoms 3 days after lithium was added to clozapine the symptoms resolved when both drugs were stopped and recurred with rechallenge (628). 

There have been occasional reports of neurotoxic symptoms when methyldopa was combined with lithium, both with and without an increase in serum lithium concentration (657). 

There have been several reports of raised serum lithium concentrations and neurotoxic symptoms when COX-2 inhibitors (celecoxib and rofecoxib) were added to an otherwise stable lithium regimen (130)(672,673). In 10 patients taking lithium who took rofecoxib 50 mg/day for 5 days serum lithium concentrations increased in 9 and reached 1.26, 1.47, and 1.63 mmol/1 in three (details not provided) (674). 

A possible, noneholinesterase-based explanation for the neurotoxic symptoms observed in humans from the examples cited above is that workers were also exposed to a combination of chemicals including heavy metals, solvents, herbicides, and fumigants. The symptoms may actually have been caused by these chemicals and not by the OP (Kamel and Hoppin, 2004). However, the animal data cannot be explained this way because the animals were treated only with OP. In conclusion, OP targets that are not acetylcholinesterase or butyrylcholinesterase are involved in chronic neurotoxicity. These unknown targets bind OP at doses too low to inhibit acetylcholinesterase. 

Acute and chronic ingestions should be discontinued and any toxic effects treated symptomatically. A study on healthy volunteers reported neurotoxic symptoms to progress for 2-3 weeks upon discontinuation of pyridoxine. 

Systemic absorption of Elapidae venom is dependent on lymphatic transport following subcutaneous envenomation. The onset of neurotoxic symptoms usually occurs within 4h but can be delayed up to 10 h following a bite. The metabolism of venom components is not well understood. It is likely that venom components are inactivated by enzymes within tissues where the venom is ultimately distributed. The distribution of venom is variable and complex and possibly reaches different tissue sites unevenly. The biological half-life of Elapidae venom has not been determined. It is likely that metabolized venom fractions are eliminated primarily by the kidneys. 

The clinical symptoms of the disease are variable and depend upon the intensity of the infection. The presence of adult and larval parasites may give rise to abdominal pain, nausea, vomiting, diarrhea and blood in stool. The migration of larvae leads to high fever, edema of face, eyelids, muscular pain in chest wall, cough, dyspnoea and stiffness of limbs. In severe cases, neurotoxic symptoms, myocardiasis, meningiHs and encephalitis may also be observed in some patients. 

Chang and Verity 1995 ATSDR 1999). Mitochondrial changes, induction of lipid peroxi tion, microtuble disruption, and disrupted protein synthesis have all been proposed as possible mechanisms. In developmental toxicity, disruption of cell-surface recognition has also been proposed as a possible mech sm (Baron et al. 1998 Dey et al. 1999). To date, no definitive data are available that point to any one mechanism as the proximate cause for the neurotoxic symptoms associated with MeHg exposure in adults. 

Neurological Effects. Neurotoxic symptoms reported in humans after inhalation exposure to nitrobenzene have included headache, confusion, vertigo and nausea (Ikeda and Kita 1964) effects in orally exposed persons have also included those symptoms as well as apnea and coma (Carter 1936 Leader 1932 Myslak et al. 1971). Studies in animals exposed via inhalation have shown morphological damage to the hindbrain (cerebellar peduncle) (Medinsky and Irons 1985). Damage to the brainstem, cerebellum and fourth ventricle was observed in orally exposed animals. Thus, it is possible that similar neurological changes may occur in humans as a result of nitrobenzene exposure. 

In 1937, a study found that aluminum salts caused uniformly fatal, neurotoxic symptoms when injected intracerebrally in animals (Scherp and Church 1937). Experimental work in the 1960s later showed that intracerebral or intrathecal injections of aluminum in rabbits caused neurotoxic reactions and neurofibrillary tangles (NFTs) similar to those observed in Alzheimer s disease (AD) (Klatzo et al. 1965 Terry and Pena 1965). Between 1973 and 1976, three landmark articles reported aluminum in the NFTs of AD patients (Crapper 1974 Crapper et al. 1973, 1976). 

The toxicities of thiotepa are essentially the same as those of the other alkylating agents, namely myelosuppres-sion and to a lesser extent mucositis. Myelosuppression tends to develop somewhat later than with cyclophosphamide, with leukopenic nadirs at 2 weeks and platelet nadirs at 3 weeks. In high-dose regimens thiotepa produces neurotoxic symptoms, including coma and seizures. 

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