Neurotoxic effect

The experimental species recommended by OECD guidelines is the adult domestic hen. During the tests the animals are to be observed for behavioral abnormalities, locomotor ataxia, and paralysis. Twice a week the animals are subjected to a period of forced motor activity (ladder climbing). Animals that show signs of neurotoxic effects are sacrificed and examined by gross necropsy and histopathologically. 

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One noteworthy neurotoxic response was demonstrated in laboratory pyrolysis studies using various types of phosphoms flame retardants in rigid urethane foam, but the response was traced to a highly specific interaction of trimethylolpropane polyols, producing a toxic bicycHc trimethylolpropane phosphate [1005-93-2] (152). Formulations with the same phosphoms flame retardants but other polyols avoided this neurotoxic effect completely. 

Particular attention should be paid to anrinopyridines, especially unsubstituted ones, which tend to exert severe neurotoxic effects on exposure. 

It is estimated that concentrations of 3000 ppm cause unconsciousness in less than 10 minutes (39). Anesthetic effects have been reported at concentrations of 400 ppm after 20-min exposure. Decrease in psychomotor performance at a trichloroethylene concentration of 110 ppm has been reported in one study (33), whereas other studies find no neurotoxic effects at concentrations of 200 ppm (40—43). 

In a cross-sectional study, exposure and effect are studied simultaneously. This approach contains an inherent problem because exposure must precede the effect. However, it can he used to investigate acute effects and also mild chronic effects (which do not force people to leave their jobs) if exposure has remained rather stable for a long time. When the prevalence of the effects studied are compared with the prevalence in other worker groups (controls or references) which correspond otherwise with the study group but are not exposed to the agent investigated, indicative evidence of possible causality may be obtained. For example, cross-sectional studies have been applied successfully to reveal the associations between mild neurotoxic effects and exposure to organic solvents. ... 

Adult dopamin-containing neurons in the substantia nigra rely on Cavl. 3 channels as pacemaker channels. It appears that the resulting enhanced Ca2+ load renders these channels more susceptible to neurotoxic effects and neurodegeneration as observed in Parkinson s disease. Preclinical evidence suggests that block of these with dihydropyridines causes a switch to a Cavl.3-independent pacemaker and protects these neurons from neurotoxicity. 

The database for monomethyltin is not conclusive for neurotoxic effects, and, therefore, a NOAEL could not be determined. However, on the basis of 90-day studies on monomethyltin/dimethyltin mixtures detailing histopathology, dose comparisons between studies on different mixtures suggest that dimethyltin is the predominant active ingredient, and, taking into account structure-activity relationships, it would be expected that the neurotoxicity of monomethyltin is lower than that of dimethyltin. 

Ross WD, Emmett EA, Steiner J, Tureen R (1981) Neurotoxic effects of occupational exposure to organotins. American Journal of Psychiatry, 138 1092-1095. 

In summary, neurotoxic effects of endosulfan are usually apparent only after acute ingestion of relatively high doses. Cumulative neurotoxicity does not appear to be significant. If the animal survives the acute toxic effects, then no long-term neurotoxic effects are evident from behavioral, gross, and microscopic observations. However, some impairment may occur that can be detected only by specialized neurobehavioral testing. 

The distribution of endosulfan and endosulfan sulfate was evaluated in the brains of cats given a single intravenous injection of 3 mg/kg endosulfan (Khanna et al. 1979). Peak concentrations of endosulfan in the brain were found at the earliest time point examined (15 minutes after administration) and then decreased. When tissue levels were expressed per gram of tissue, little differential was observed in distribution among the brain areas studied. However, if endosulfan levels were expressed per gram of tissue lipid, higher initial levels were observed in the cerebral cortex and cerebellum than in the spinal cord and brainstem. Loss of endosulfan was most rapid from those areas low in Upid. Endosulfan sulfate levels peaked in the brain at 1 hour postadministration. In contrast, endosulfan sulfate levels in liver peaked within 15 minutes postadministration. The time course of neurotoxic effects observed in the animals in this study corresponded most closely with endosulfan levels in the central nervous system tissues examined. 

In summary, the frank neurotoxic effects of endosulfan are apparent only after acute ingestion of relatively high doses in animals. However, long-term decreased psychomotor function, possibly resulting from acute endosulfan exposure, have been reported by two authors (Aleksandrowicz 1979 Shemesh et al. 1988). Such effects cannot be easily measured in animals. Hence, the fact that long-term neurotoxic effects have not been observed in animals does not mean that such effects caimot occur in humans. However, no information was located that indicated that persons exposed to low levels of endosulfan might experience any neurotoxicity. 

Experimental animals exposed to sublethal doses of cyclodienes show a similar picture, with changes in EEG patterns, disorientation, loss of muscular coordination and vomiting, as well as convulsions, the latter becoming more severe with increasing doses (Hayes and Laws 1991). It is clear from these wide-ranging studies that a number of neurotoxic effects can be caused by cyclodienes at levels well below those that are lethal. In the human studies described here, subclinical symptoms were frequently reported when dieldrin blood levels were in the range 50-100 pg/L, an order of magnitude below those associated with lethal intoxication. 

It is very clear, therefore, that there have been many examples of neurotoxic effects, both lethal and sublethal, caused by pesticides in the field over a long period of time. Far less clear, despite certain well-documented cases, is to what extent these effects, especially sublethal ones, have had consequent effects at the population level and above. Interest in this question remains because neurotoxic pesticides such as pyre-throids, neonicotinoids, OPs, and carbamates continue to be used, and questions continue to be asked about their side effects, for example, on fish (Sandahl et al. 2005), and on bees and other beneficial insects (see, for example, Barnett et al. 2007). 

The spontaneous electrical activity of the brain can be measured by electroencephalography (EEG), a technique that has been widely employed to study neurotoxic effects of chemicals both in humans and in experimental animals. EEG waves represent summated synaptic potentials generated by the pyramidal cells of the cerebral cortex (Misra 1992). These potentials are the responses of cortical cells to rhythmical changes arising from thalamic nuclei. The signals recorded can be separated into frequency bands—faster waves exceeding 13 Hz, and slower ones below 4 Hz. 

Colborn, T., Smolen, M.J., and Rolland, R. (1998). Environmental neurotoxic effects the search for new protocols in functional teratology. Toxicology and Industrial Health 14, 9-23. 

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