Acute toluene exposure and rat visual function in proportion to momentary brain concentration.

Acute exposure to toluene was assessed in two experiments to determine the relationship between brain toluene concentration and changes in neurophysiological function. The concentration of toluene in brain tissue at the time of assessment was estimated using a physiologically based pharmacokinetic model. Brain neurophysiological function was measured using pattern-elicited visual evoked potentials (VEP) recorded from electrodes located over visual cortex of adult male Long-Evans rats. In the first experiment, VEPs were recorded before and during exposure to control air or toluene at 1000 ppm for 4 h, 2000 ppm for 2 h, 3000 ppm for 1.3 h, or 4000 ppm for 1 h. In the second experiment, VEPs were recorded during and after exposure to clean air or 3000 or 4000 ppm toluene. In both experiments, the response amplitude of the major spectral component of the VEP (F2 at twice the stimulus rate in steady-state responses) was reduced by toluene. A logistic function was fit to baseline-adjusted F2 amplitudes from the first experiment that described a significant relationship between brain toluene concentration and VEP amplitude deficits. In the second experiment, 3000 ppm caused equivalent VEP deficits during or after exposure as a function of estimated brain concentration, but 4000 ppm showed a rapid partial adaptation to the acute effects of toluene after exposure. In general, however, the neurophysiological deficits caused by acute toluene exposure could be described by estimates of the momentary concentration of toluene in the brain at the time of VEP evaluation.

Toluene inhalation exposure for 13 weeks causes persistent changes in electroretinograms of Long-Evans rats.

Studies of humans chronically exposed to volatile organic solvents have reported impaired visual functions, including low contrast sensitivity and reduced color discrimination. These reports, however, lacked confirmation from controlled laboratory experiments. To address this question experimentally, we examined visual function by recording visual evoked potentials (VEP) and/or electroretinograms (ERG) from four sets of rats exposed repeatedly to toluene. In addition, eyes of the rats were examined with an ophthalmoscope and some of the retinal tissues were evaluated for rod and M-cone photoreceptor immunohistochemistry. The first study examined rats following exposure to 0, 10, 100 or 1000ppm toluene by inhalation (6hr/d, 5d/wk) for 13 weeks. One week after the termination of exposure, the rats were implanted with chronically indwelling electrodes and the following week pattern-elicited VEPs were recorded. VEP amplitudes were not significantly changed by toluene exposure. Four to five weeks after completion of exposure, rats were dark-adapted overnight, anesthetized, and several sets of electroretinograms (ERG) were recorded. In dark-adapted ERGs recorded over a 5-log (cd-s/m(2)) range of flash luminance, b-wave amplitudes were significantly reduced at high stimulus luminance values in rats previously exposed to 1000ppm toluene. A second set of rats, exposed concurrently with the first set, was tested approximately one year after the termination of 13 weeks of exposure to toluene. Again, dark-adapted ERG b-wave amplitudes were reduced at high stimulus luminance values in rats previously exposed to 1000ppm toluene. A third set of rats was exposed to the same concentrations of toluene for only 4 weeks, and a fourth set of rats exposed to 0 or 1000ppm toluene for 4 weeks were tested approximately 1year after the completion of exposure. No statistically significant reductions of ERG b-wave amplitude were observed in either set of rats exposed for 4 weeks. No significant changes were observed in ERG a-wave amplitude or latency, b-wave latency, UV- or green-flicker ERGs, or in photopic flash ERGs. There were no changes in the density of rod or M-cone photoreceptors. The ERG b-wave reflects the firing patterns of on-bipolar cells. The reductions of b-wave amplitude after 13 weeks of exposure and persisting for 1year suggest that alterations may have occurred in the inner nuclear layer of the retina, where the bipolar cells reside, or the outer or inner plexiform layers where the bipolar cells make synaptic connections. These data provide experimental evidence that repeated exposure to toluene may lead to subtle persistent changes in visual function. The fact that toluene affected ERGs, but not VEPs, suggests that elements in the rat retina may be more sensitive to organic solvent exposure than the rat visual cortex.

Momentary brain concentration of trichloroethylene predicts the effects on rat visual function.

The relationship between the concentration of trichloroethylene (TCE) in the brain and changes in brain function, indicated by the amplitude of steady-state pattern-elicited visual evoked potentials (VEP), was evaluated in Long-Evans rats. VEPs were recorded from visual cortex following stimulation of the eyes and, thus, reflect the function of the afferent visual pathway and, in broad terms, may be indicative of overall brain function. The concentration of TCE in the brain at the time of VEP testing (i.e., momentary brain concentration) was hypothesized to predict the amplitude of the VEP across a range of inhalation concentrations, both during and after exposure. Awake restrained rats were exposed to clean air or TCE in the following combinations of concentration and duration: 500 ppm (4 h), 1000 ppm (4 h), 2000 (2 h), 3000 ppm (1.3 h), 4000 ppm (1 h), and 5000 ppm (0.8 h). VEPs were recorded several times during the exposure session, and afterward for experimental sessions of less than 4 h total duration (i.e., concentrations from 2000 to 5000 ppm). The sample collection time for each VEP was about 1 min. Brain concentrations of TCE were predicted using a physiologically based pharmacokinetic (PBPK) model. VEP waveforms were submitted to spectral analysis, and the amplitude of the largest response component, occurring at twice the temporal stimulation rate (F2), was measured. Exposure to all air concentrations of TCE in the study reduced F2 amplitude. The reduction of F2 amplitude was proportional to momentary brain TCE concentration during and after exposure. A logistical function fit to the combined data from all exposure conditions described a statistically significant relationship with 95% confidence limits between brain TCE concentration and F2 amplitude. The results support the hypothesis that momentary brain concentration of TCE is an appropriate dose metric to describe the effects of acute TCE inhalation exposure on rat VEPs. The combination of the PBPK model predicting brain TCE concentration from the exposure conditions with the logistical function predicting F2 amplitude from the brain TCE concentration constitute a quantitative exposure-dose-response model describing an acute change in neurological function following exposure to an important hazardous air pollutant.

Dose-based duration adjustments for the effects of inhaled trichloroethylene on rat visual function.

Risk assessments often must consider exposures that vary over time or for which the exposure duration of concern differs from the available data, and a variety of extrapolation procedures have been devised accordingly. The present experiments explore the relationship(s) between exposure concentration (C) and time (t) to investigate procedures for assessing the risks of short-term solvent exposures. The first hypothesis tested was that the product of C x t would produce a constant health effect (Haber's rule). The second hypothesis tested was that exposure conditions produce effects in proportion to the tissue concentrations created. Awake, adult, male Long-Evans (LE) rats were exposed to trichloroethylene (TCE) vapor in a head-only exposure chamber while pattern onset/offset visual evoked potentials (VEPs) were recorded. Exposure conditions were designed to provide C x t products of 0 ppm/h (0 ppm for 4 h) or 4000 ppm/h created through four exposure scenarios: 1000 ppm for 4 h; 2000 ppm for 2 h; 3000 ppm for 1.3 h; or 4000 ppm for 1h (n = 9-10/concentration). The amplitude of the VEP frequency double component (F2) was decreased significantly by exposure; this decrease was related to C but not to t or to the C x t product, indicating that Haber's rule did not hold. The mean amplitude (+/- SEM in muV) of the F2 component in the control and treatment groups measured 4.4 +/- 0.5 (0 ppm/4 h), 3.1 +/- 0.5 (1000 ppm/4 h), 3.1 +/- 0.4 (2000 ppm/2 h), 2.3 +/- 0.3 (3000 ppm/1.3 h), and 1.9 +/- 0.4 (4000 ppm/1 h). A physiologically based pharmacokinetic (PBPK) model was used to estimate the concentrations of TCE in the brain achieved during each exposure condition. The F2 amplitude of the VEP decreased monotonically as a function of the estimated peak brain concentration but was not related to the area under the curve (AUC) of the brain TCE concentration. In comparison to estimates from the PBPK model, extrapolations based on Haber's rule yielded approximately a 6-fold error in estimated exposure duration when extrapolating across only a 4-fold change in exposure concentration. These results indicate that the use of a linear form of Haber's rule will not predict accurately the risks of acute exposure to TCE, nor will an estimate of AUC of brain TCE. However, an estimate of the brain TCE concentration at the time of VEP testing predicted the effects of TCE across exposure concentrations and durations.

Acute inhalation of 2,2,4-trimethylpentane alters visual evoked potentials and signal detection behavior in rats.

The volatile organic compound 2,2,4-trimethylpentane (TMP, "isooctane") is a constituent of gasoline for which the current health effects data are insufficient to permit the US Environmental Protection Agency to conduct a risk assessment. The potential neurological impairment from acute inhalation exposure to TMP was evaluated in adult male Long-Evans rats using both electrophysiological and behavioral assessments. Visual evoked potentials (VEPs) were recorded from rats viewing modulated visual patterns (0.16 cycles per degree visual angle (cpd), 60% contrast, 4.55Hz appear/disappear). Rats (n=7-10/dose) were exposed to TMP vapors in concentrations of 0, 500, or 1000 ppm for 60-min. A VEP was recorded before exposure and at 10 min intervals during exposure and also for 60 min after exposure terminated. The spectral amplitude of the frequency-double component (F2) was significantly reduced after exposure to TMP. In behavioral assessments, rats (n=14) performed an appetitively motivated visual signal detection task while breathing 0, 500, 1500, 1000, 2000, or 2500 ppm TMP for 62 min. Slight reductions in accuracy of performance were observed at the 2500 ppm concentration. Concentrations of TMP in the brain were estimated using a physiologically based pharmacokinetic (PBPK) model to be less than 0.2mM after 62 min at 2500 ppm. Together these data demonstrate that TMP, like other volatile organic substances, impairs neurological function during acute inhalation exposure and that the small magnitude of the observed effects is consistent with the low concentrations of this hydrocarbon that were estimated to reach the CNS.

Acute perchloroethylene exposure alters rat visual-evoked potentials in relation to brain concentrations.

These experiments sought to establish a dose-effect relationship between the concentration of perchloroethylene (PCE) in brain tissue and concurrent changes in visual function. A physiologically based pharmacokinetic (PBPK) model was implemented to predict concentrations of PCE in the brains of adult Long-Evans rats following inhalation exposure. The model was evaluated for performance against tissue concentrations from exposed rats (n = 40) and data from the published scientific literature. Visual function was assessed using steady-state pattern-elicited visual-evoked potentials (VEPs) recorded from rats during exposure to air or PCE in two experiments (total n = 84) with concentrations of PCE ranging from 250 to 4000 ppm. VEP waveforms were submitted to a spectral analysis in which the major response component, F2, occurring at twice the visual stimulation rate, was reduced in amplitude by PCE exposure. The F2 amplitudes were transformed to an effect-magnitude scale ranging from 0 (no effect) to 1 (maximum possible effect), and a logistical function was fit to the transformed values as a function of estimated concurrent brain PCE concentrations. The resultant function described a dose-response relationship between brain PCE concentration and changes in visual function with an ED(10) value of approximately 0.684 mg/l and an ED(50) value of approximately 46.5 mg/l. The results confirmed that visual function was disrupted by acute exposure to PCE, and the PBPK model and logistic model together could be used to make quantitative estimates of the magnitude of deficit to be expected for any given inhalation exposure scenario.