A Dosimetric Analysis of the Acute Behavioral Effects of Inhaled Toluene in Rats

Abstract

Knowledge of the appropriate metric of dose for a toxic chemical facilitates quantitative extrapolation of toxicity observed in the laboratory to the risk of adverse effects in the human population. Here, we utilize a physiologically based toxicokinetic (PBTK) model for toluene, a common volatile organic compound (VOC), to illustrate that its acute behavioral effects in rats can be quantitatively predicted on the basis of its concentration in the brain. Rats previously trained to perform a visual signal detection task for food reward performed the task while inhaling toluene (0, 1200, 1600, 2000, and 2400 ppm in different test sessions). Accuracy and speed of responding were both decreased by toluene; the magnitude of these effects increased with increasing concentration of the vapor and with increasing duration of exposure. Converting the exposure conditions to brain toluene concentration using the PBTK model yielded a family of overlapping curves for each end point, illustrating that the effects of toluene can be described quantitatively by its internal dose at the time of behavioral assessment. No other dose metric, including inhaled toluene concentration, duration of exposure, the area under the curve of either exposure (ppm h), or modeled brain toluene concentration (mg-h/kg), provided unambiguous predictions of effect. Thus, the acute behavioral effects of toluene (and of other VOCs with a similar mode of action) can be predicted for complex exposure scenarios by simulations that estimate the concentration of the VOC in the brain from the exposure scenario.

Attention-modulating effects of cognitive enhancers

“…Chlordiazepoxide, a benzodiazepine agonist that potentiates the effects of GABA at GABA-ergic receptors, impairs performance of the SDT in young and old rats (McGaughy and Sarter, 1995b), but may do so by affecting visual thresholds rather than impairing attention (Bushnell et al, 1997a). Alcohol and many organic solvents, which among other things potentiate chloride flux through GABA-mediated ion channels and inhibit activity at glutamatergic ion channels, impair sustained attention in this task (Bushnell, 1997; Bushnell et al, 2007; Rezvani and Levin, 2003a). Antipsychotic drugs such as clozapine, risperidone and haloperidol, which block a variety of receptors including dopamine, serotonin, norepinephrine, histamine and cholinergic receptors, also impair sustained attention in rats (Rezvani and Levin, 2004b).…”

In vivo visualization of olfactory pathophysiology induced by intranasal cadmium instillation in mice

“…parosmia; see Doty, 2009). A behavioral signal detection task could provide a more sensitive metric for assessing sensory function (Bushnell et al, 2007). Sun et al (1996) found no evidence of a cadmium-induced change in absolute olfactory threshold using a task in which odorant presentation signals an impending footshock, thus spontaneously suppressing conditioned licking for a water reward.…”

Cognitive Function

“…The 2-lever method has been used to assess effects of inhaled organic solvents (Bushnell, 1997;Bushnell et al, 2007;Oshiro et al, 2001), pesticides Samsam et al, 2005); PCBs (Bushnell et al, 2002;Geller et al, 2001), and algal toxins (Rezvani et al, 2001). For this reason, a response failure does not occur because the animal was not attending to the signal, but instead reflects reduced motivation or motor capacity.…”