Over 1.3 million civilian and military personnel are occupationally exposed to hydrocarbon fuels, emphasizing gasoline, jet fuel, diesel fuel, or kerosene. These exposures may occur acutely or chronically to raw fuel, vapor, aerosol, or fuel combustion exhaust by dermal, respiratory inhalation, or oral ingestion routes, and commonly occur concurrently with exposure to other chemicals and stressors. Hydrocarbon fuels are complex mixtures of 150-260+ aliphatic and aromatic hydrocarbon compounds containing varying concentrations of potential neurotoxicants including benzene, n-hexane, toluene, xylenes, naphthalene, and certain n-C9-C12 fractions (n-propylbenzene, trimethylbenzene isomers). Due to their natural petroleum base, the chemical composition of different hydrocarbon fuels is not defined, and the fuels are classified according to broad performance criteria such as flash and boiling points, complicating toxicological comparisons. While hydrocarbon fuel exposures occur typically at concentrations below...

A review of the neurotoxicity risk of selected hydrocarbon fuels.

Alterations in nervous system function after exposure to a developmental neurotoxicant may be identified and characterized using neurobehavioral methods. A number of methods can evaluate alterations in sensory, motor, and cognitive functions in laboratory animals exposed to toxicants during nervous system development. Fundamental issues underlying proper use and interpretation of these methods include a) consideration of the scientific goal in experimental design, b) selection of an appropriate animal model, c) expertise of the investigator, d) adequate statistical analysis, and e) proper data interpretation. Strengths and weaknesses of the assessment methods include sensitivity, selectivity, practicality, and variability. Research could improve current behavioral methods by providing a better understanding of the relationship between alterations in motor function and changes in the underlying structure of these systems. Research is also needed to develop simple and sensitive assays for use in screening assessments of sensory and cognitive function. Assessment methods are being developed to examine other nervous system functions, including social behavior, autonomic processes, and biologic rhythms. Social behaviors are modified by many classes of developmental neurotoxicants and hormonally active compounds that may act either through neuroendocrine mechanisms or by directly influencing brain morphology or neurochemistry. Autonomic and thermoregulatory functions have been the province of physiologists and neurobiologists rather than toxicologists, but this may change as developmental neurotoxicology progresses and toxicologists apply techniques developed by other disciplines to examine changes in function after toxicant exposure.

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. I: behavioral effects.

Rats were exposed to xylene, to n-hexane, or to xylene together with n-hexane, each solvent 1000 p.p.m. (1000 + 1000 p.p.m. in mixed exposure), 18 hr/day, 7 days/week during 61 days. Neurophysiological recordings were made 2 days, 4 months, and 10 months after the end of exposure. Exposure to n-hexane alone, or xylene alone, caused a slight loss of auditory sensitivity as recorded by auditory brainstem response 2 days after the exposure. Exposure to n-hexane together with xylene caused persistent loss of auditory sensitivity (7-17 dB; P < 0.05) which was non-additively enhanced (P < 0.01). The latencies of the flash evoked potentials in the group exposed to n-hexane alone were prolonged (re C group) 2 days after exposure, while smaller prolongations were found in the group exposed to xylene together with n-hexane. Exposure to n-hexane alone caused a marked decrease in nerve conduction velocity, while simultaneous exposure to xylene inhibited n-hexane-induced velocity reduction in peripheral nerve (P < 0.01).

Function of the Auditory and Visual Systems, and of Peripheral Nerve, in Rats after Long-Term Combined Exposure to n-Hexane and Methylated Benzene Derivatives. II. Xylene

The effects of chronic trichloroethylene exposure on neurobehavioral functioning in the rat

A toluene-induced motor syndrome in rats resembling that seen in some human solvent abusers

Male Fischer rats exposed continuously (24 hr per day) to 1,000 ppm hexane five days per week for 11 weeks developed clear and long-lasting neurotoxic signs, as reflected by a marked decrease in hind-limb grip strength and severe impairment of performance of a multisensory conditioned avoidance response (CAR); transient decreases in undifferentiated motor activity and fore-limb grip strength were also seen. Other rats were only slightly affected by repeated, brief (10 min) exposures to high concentrations (24,000 or 48,000 ppm) of hexane 6 or 12 times per day, five days per week for 18 weeks; when the frequency of exposure to 48,000 ppm hexane was increased to 24 times per day (10 min on and 5 min off), five days per week, for 4 additional weeks, more severe signs of neurobehavioral toxicity appeared.

Importance of schedule of exposure to hexane in causing neurotoxicity.

Male Fischer rats were exposed repeatedly to high concentrations of hexane for 10 minutes in a pattern resembling human solvent abuse or to low concentrations of hexane continuously for 8 or 24 hours daily. Concentrations of hexane in blood and brain were linearly related to the concentrations of hexane in the chamber after a 10-minute exposure, and declined thereafter, with half lives of about 2 1/2 and 4 minutes in blood and brain, respectively. Despite the rapid elimination of hexane, neurotoxic levels of 2,5-hexanedione (2,5-HD) were formed from repeated 10-minutes exposures to a high concentration of hexane when the interexposure interval was 20 minutes. Neurotoxic levels of 2,5-HD also resulted from continuous exposure to much lower concentrations of hexane. Both exposure schedules caused an increase in 2,5-HD concentrations in blood after repeated daily treatments, suggesting induction of liver microsomal enzymes synthesizing 2,5-HD from hexane. The minimal sustained plasma 2,5-HD concentration that will result in neurotoxicity appears to be less than 50 micrograms/ml in the rat.

L R Bingham

Papers

Importance of schedule of exposure to hexane in causing neurotoxicity.

Relation between schedules of exposure to hexane and plasma levels of 2,5-hexanedione.