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Neurotoxicity

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To evaluate the neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, studies were conducted, which involved inhalation exposure of rats and humans to white spirit (WS). The specific objectives of these studies were to evaluate the behavioral effects of exposure to WS in rats and humans and to determine relationships between internal levels of exposure and behavioral effects. In both animals and volunteers, methods for assessment of similar functional effects were used to enable interspecies comparisons. A battery of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute central nervous system (CNS) depression. Groups of rats were exposed to WS at target concentrations of 0, 600, 2400 or 4800 mg/m3, 8 h/day for 3 consecutive days. Blood and brain concentrations of two WS constituents; 1,2,4-trimethylbenzene (TMB) and n-decane (NDEC), were used as biomarkers of internal exposure. The NOAEL for acute CNS effects in rats was determined to be 600 mg/m3. In a volunteer study, 12 healthy male subjects were exposed for 4 hours to either 57 or 570 mg/m(3) WS in two test sessions spaced 7 days apart, and neurobehavioral effects were measured using a computerized neurobehavioral test battery. Blood samples were taken at the end of the exposure period to measure internal concentrations of TMB and NDEC. Results of the behavioral tests in rats indicated WS-induced changes particularly in performance and learned behavior. In humans, some subtle performance deficits were observed, particularly in attention. The results indicated that the NOAEL for acute CNS effects in humans was at or near 570 mg/m3. The behavioral effects were related to concentrations of the WS components in the central nervous system. These studies demonstrated a qualitative similarity in response between rats and humans, adding support to the view that the rodent tests can be used to predict levels of response in humans and to assist in setting occupational exposure levels for hydrocarbon solvents.

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