Sensory-evoked potentials (EPs) were studied in male Long-Evans and Fischer-344 rats in order to characterize the electrophysiological consequences of chronic inhalation exposure to trichloroethylene (TCE). Groups of ten Long-Evans rats were exposed to air or 1600 ppm or 3200 ppm TCE for twelve weeks and evaluated periodically with a multisensory test battery. Brainstem auditory-evoked response (BAER) amplitudes were depressed by TCE, whereas somatosensory and visual potentials remained normal. The effects on BAERs, which varied with tone intensity and frequency, suggested that TCE causes a predominantly high-frequency hearing loss. Comparable effects were obtained in both strains of rats and were like those previously observed following exposure to toluene.

Animals↗

PubMedDate not supplied

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

The purpose of these experiments was to determine the extent to which subchronic exposure of rats to toluene might cause symptoms similar to those seen in some heavy abusers of toluene-containing products. In the first exploratory experiment, weanling male Fischer-344 rats were exposed to air, toluene, n-hexane, or a mixture of toluene, n-hexane, and methyl ethyl ketone (8 h per day, 7 days per week) for 11 weeks. A mild peripheral neuropathy was revealed by measures of grip strength in the rats exposed to n-hexane alone or in the mixture, but not in the rats exposed to toluene. Instead, the rats exposed to toluene alone developed a persisting motor syndrome characterized by a shortened and widened gait and a widened landing foot splay. The rats exposed to toluene alone or in the mixture were also hearing impaired, but not the rats exposed to n-hexane alone. In the second experiment, done to confirm and extend these results, weanling male Fischer-344 rats were exposed to toluene under three different daily schedules--2,200 ppm continuously for 8 h per day; 4,400 ppm, 30 min each h, 8 h per day; or 6,200 ppm, 15 min each h, 8 h per day. The exposures were 7 days per week for 23 weeks. The motor syndrome and hearing impairment were replicated in all essential respects in all toluene-exposed groups with no appreciable differences attributable to the daily exposure schedules. The effects were still evident 15 weeks after the last exposure. Toluene inhibited weight gain in both experiments, and in the second experiment, it was found that skeletal growth (torso length, rump width) was also inhibited. Toluene did not significantly impair rotorod performance in either experiment or acquisition of a spatial-navigation task in the second experiment. No neuropathologic correlates of the persisting motor syndrome were found in either experiment when the rats were sacrificed 9 and 16 weeks after the last exposure, respectively. These results demonstrate that toluene can cause a persisting motor syndrome in rats that resembles, to some extent at least (i.e., wide-based ataxic gait), the syndrome seen in some heavy abusers of toluene-containing products.

Animals↗

PubMedDate not supplied

Toluene-induced ototoxicity by subcutaneous administration.

Inhalation exposure of rats to toluene causes irreversible hearing loss (e.g., Pryor et al.). To determine whether noise emanating from the inhalation system was a major contributing factor and whether exposure by a noninhalation route would cause a similar effect, weanling, male Fischer-344 rats were injected SC twice daily in a quiet environment with PEG-300 (control) or with 1.5 or 1.7 g/kg of toluene for 7 days. After being trained to perform a multisensory conditioned avoidance response (CAR) task, tone intensity-response functions were generated at 4, 8, 12, and 20 kHz, and behavioral auditory response thresholds were estimated. Toluene caused a dose-related hearing loss at frequencies of 8 kHz and above, with no effect on performance of the CAR in response to light, nonaversive footshock, or the 4-kHz tone. The similarity of this effect to that observed following inhalation exposure indicates that noise is not a major factor in the toluene-induced hearing loss, although possible interactions between noise and toluene remain to be investigated. These results also demonstrate that direct penetration of the toluene vapors through the external ear structure, as might occur during inhalation exposure, is not a necessary condition for inducing the hearing loss.

Air Pollutants↗

PubMedDate not supplied

Effects of intraperitoneal carbon disulfide on sensory-evoked potentials of Fischer-344 rats.

Sensory-evoked potentials (EPs) were studied in male Fischer-344 rats to characterize the electrophysiologic concomitants of carbon disulfide (CS2) neurotoxicity. Behavioral measures also studied were forelimb and hindlimb grip strengths and performance of a conditioned avoidance response task. CS2 (172, 286, and 400 mg/kg) administered intraperitoneally five days per week for eleven weeks caused a decrease in grip strength, interfered with escape from shock, and disturbed visual and auditory EPs. Latency of the fifth but not the first component of the brainstem auditory-evoked response was prolonged, indicating an effect on central auditory tract conduction. Conduction velocity in the ventral caudal nerve and latencies of somatosensory EP components were unaffected.

Animals↗

PubMedDate not supplied

Assessment of chemicals using a battery of neurobehavioral tests: a comparative study.

Single-dose LD10S and LD50S were determined in male, Fischer-344 rats for acrylamide monomer, arsenic trioxide, chlordecone, lead acetate, methylmercury hydroxide, monosodium salicylate, tetraethyl tin, and triethyl lead chloride. Proportions of the single-dose LD10S were used in a subacute study to estimate the 28-day LD20S for each chemical. Proportions of the 28-day LD20S were used in a subchronic (105 days of dosing) study to determine the effectiveness of a battery of neurobehavioral tests for detecting and characterizing the neurotoxic effects of each chemical. The battery consisted of undifferentiated motor activity, forelimb and hindlimb grip strengths, rotation orientation, thermal sensitivity, startle responsiveness to acoustic and air-puff stimuli, and performance of a multisensory conditioned pole-climb avoidance response task; body weight and rectal temperature were also monitored. The battery of tests was administered on eight occasions, that is, before, at three-week intervals during dosing (PO or IP, five days each week for 15 weeks), and at three and six weeks after dosing. Normative data (controls from each experiment) indicated fair overall stability of the measures over the eight test sessions, but experiment-to-experiment variability in this regard was clearly evident. The inherent statistical sensitivity of the tests varied greatly as estimated by their coefficients of variation, which ranged from 1% (rectal temperature) to over 100% (rotation orientation). Intercorrelations among the various measures were low to moderate indicating relatively little redundancy. The various measures were differentially affected by the eight chemicals: body weight by all eight; rectal temperature by one; undifferentiated motor activity by three; forelimb grip strength by two; hindlimb grip strength by four; rotation orientation by one; thermal sensitivity by one; startle responsiveness by three; and CAR performance by five. A profile analysis using the slopes of the dose-response functions after 15 weeks of dosing indicated clearly different patterns of effect among the eight chemicals. A composite score derived from a multidimensional analysis of the data suggested that the eight chemicals could be ranked from most to least neurotoxic as defined by these tests as acrylamide greater than methylmercury greater than chlordecone greater than tetraethyl tin greater than triethyl lead greater than lead acetate greater than arsenic greater than monosodium salicylate. This ranking and the results in general are in good agreement with what is known about these chemicals from other experiments with animals and from human experience. This battery of tests, or subsets thereof, may therefore have utility in the assessment of the potential neurobehavioral toxicity of various chemicals.

Acrylamides↗

PubMedDate not supplied

A comparison of the rates of development of functional hexane neuropathy in weanling and young adult rats.

Chronic inhalation exposure of adult rats to hexane causes neural toxicities to develop over a period of several weeks. Because the developing organism is in many cases more vulnerable to toxic insult than the adult, and children make up a substantial proportion of the population of solvent abusers, we compared the effects of exposing weanling and young adult rats to 1000 ppm of hexane for 24 hrs/day, 6 days/week, for 11 weeks. Within two weeks of exposure, significance decreases in body weight and grip strength were observed in rats of both ages. However, the subsequent effects of the treatment on these indices of toxicity were greater in the young adults than in the rats first exposed as weanlings. The older rats also exhibited earlier and more severe signs of hindlimb flaccid paralysis. In contrast, the effects of hexane on tail nerve conduction time and on the brainstem auditory-evoked response were about the same in rats of both ages, with latencies increasing compared to controls over the exposure period. The relative resistance of the weanling rats to hexane neuropathy may be due to shorter, smaller-diameter axons, or to a greater rate of growth and repair in their peripheral nerves compared to those of adults.

Action Potentials↗

PubMedDate not supplied

Hearing loss in rats first exposed to toluene as weanlings or as young adults.

Male Fischer-344 rats were exposed by inhalation to 1200 ppm toluene (14 hr/day, 7 days/week for 5 weeks) beginning just after weaning or as young adults. During the fifth week of exposure, they were trained to perform a multisensory conditioned pole-climb avoidance response (CAR) task using a 4-kHz tone, a change in the intensity of the test chamber light, or a nonaversive current on the grill floor as the stimuli. When tested the week after the exposures ended, both groups of toluene-exposed rats were deficient in their performance of the CAR to a 20-kHz tone. This effect was significantly greater for the rats exposed beginning just after weaning than it was for the young adult rats. Subsequent behavioral and electrophysiologic audiometry confirmed the presence of a toluene-induced high-frequency hearing loss in both groups of rats with the more severe deficits occurring in the younger rats. Preliminary morphologic examinations revealed loss of, and/or damage to, hair cells in the basal turn of the cochlea of the younger toluene-exposed rats. These results confirm our earlier discovery that inhalation exposure to toluene causes hearing deficits in rats, and they indicate that young, prepubertal rats are more severely affected than older rats.

Age Factors↗

PubMedDate not supplied

Factors affecting toluene-induced ototoxicity in rats.

Seven experiments with young male Fischer rats were done to examine concentration and exposure parameters necessary and sufficient to cause toluene-induced ototoxicity. Hearing loss, measured by behavioral and electrophysiologic methods, was repeatedly observed after as few as 2 weeks of exposure to 1000 ppm toluene for 14 hours per day, but lower concentrations (400 and 700 ppm) were without effect even after 16 weeks of exposure. Three-day exposures to 1500 ppm for 14 hours per day or 2000 ppm for 8 hours per day were ototoxic, whereas single exposures to 4000 ppm for 4 hours or 2000 ppm for 8 hours were without effect. Intermittent exposure to 3000 ppm for 30 minutes every hour for 8 hours per day caused hearing loss within 2 weeks, but a similar exposure schedule for 4 hours per day was ineffective even after 9 weeks. The results of these experiments repeatedly confirmed our earlier finding that toluene causes hearing loss in rats and defined many of the exposure parameters important to this effect. The results are discussed in terms of their relevance to industrial exposure, industrial accidents, and, especially, voluntary, high-level exposure by solvent abusers.

Animals↗

PubMedDate not supplied

Transient cognitive deficits and high-frequency hearing loss in weanling rats exposed to toluene.

In a previous experiment we found that weanling rats subchronically exposed to toluene by inhalation were deficient in learning a multisensory conditioned avoidance response (CAR) task and a tone-intensity discrimination task when trained several hours after each daily 14-hour exposure ended. The present experiment was done to determine whether this deficit represented a residual pharmacologic effect or more persisting nervous system damage. Independent groups of rats were trained on the CAR task either during the last week of a 5-week exposure to 1400 or to 1200 pm toluene (14 hr/day, 7 days/week) or during the first or third weeks after the exposures ended. None of the three groups of toluene-exposed rats were able to acquire the auditory CAR, whereas it had been 4 kHz in the previous experiment. Subsequent tests, in which the frequency and intensity of the tone were varied, revealed that hearing in these rats was unimpaired at 4 kHz, slightly impaired at 8 kHz, and markedly impaired at 12 kHz and above. Thus, although toluene has been shown to be relatively innocuous as a toxicant, this new finding suggests that this solvent should be examined further in terms of its potential hazard, especially with regard to its frequent abuse.

Animals↗

PubMedDate not supplied

Neurobehavioral effects of subchronic exposure of weanling rats to toluene or hexane.

Using several behavioral and neurophysiologic tests, we examined the effects of subchronic inhalation exposure of rats to toluene and compared them with the effects of the known neurotoxicant hexane. The rats were exposed to toluene (900 and 1400 ppm) or hexane (2000 ppm) 14 hr/day, 7 days/week for 14 weeks. Both solvents inhibited weight gain. Hexane caused a neurotoxic syndrome characterized by reductions of grip strength (especially hindlimb), motor activity, and startle responses, and increased latencies of several evoked potential components. Initial acquisition of a conditioned avoidance response (CAR) was also impaired, but subsequent performance was intact. Toluene did not cause the peripheral motor symptoms associated with exposure to hexane. However, a component of the brainstem auditory-evoked response was depressed and CAR acquisition was impaired along with the acquisition of a tone-intensity discrimination task when tested within hours after the daily exposure ended.

Action Potentials↗

PubMedDate not supplied

Toluene-induced hearing loss in rats evidenced by the brainstem auditory-evoked response.

Behavioral results showing that toluene causes hearing loss in rats precipitated an electrophysiologic study of the auditory thresholds of these rats using the brainstem auditory-evoked response (BAER). Twenty-three-day-old male Fischer-344 rats had been exposed to 1400 or 1200 ppm toluene 14 hrs/day, for 4 or 5 weeks while a control group was exposed only to air. The rats were tested 2.5 mo after termination of the exposures. BAERs, recorded with 25-gauge needle electrodes placed over the nose and posterior skull, were evoked by 100-microseconds-duration clicks and 1-msec-duration tone pips at eight intensities. Thresholds for the appearance of BAERs in the toluene-exposed rats were elevated by 13 to 27 dB, and latency-intensity functions were consistent with the occurrence of sensorineural hearing loss. The amplitudes of the third and fifth components of the BAER were attenuated at high stimulus intensities in the toluene-exposed rats. These behavioral and electrophysiologic results are apparently the first to indicate the ototoxicity of toluene in experimental animals.

Animals↗

PubMedDate not supplied

Importance of schedule of exposure to hexane in causing neurotoxicity.

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.

Animals↗

PubMedDate not supplied

Effects of hexane on the brainstem auditory response and caudal nerve action potential.

In a study on the neurotoxicity of abused inhalants, male Fischer rats were exposed by inhalation to several concentrations of hexane, administered continuously or intermittently. The fifth component of the brainstem auditory-evoked response (BAER) increased in latency and decreased in amplitude in rats exposed to 1,000 ppm of hexane 24 hours per day, 5 days per week, for 11 weeks. The first component of the BAER was only slightly affected, indicating that the increased latency of the fifth component reflected a brainstem dysfunction. Latency returned to normal within 5 weeks after termination of exposures, but amplitude did not. Latency of the compound action potential of the ventral caudal nerve of the tail of these rats was also increased, and this effect was still present 22 weeks after termination of the exposure. Other rats were not as severely affected by repeated, brief (10 minutes) exposures to 24,000 or 48,000 ppm hexane 6 or 12 times per day; only the amplitude of the fifth BAER component was affected by the 48,000-ppm exposure.

Animals↗

PubMedDate not supplied

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

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.

Animals↗