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The relative sensitivity of rats and humans to volatile organic compounds (VOCs) such as toluene (TOL) and perchloroethylene (PERC) is unknown and adds to uncertainty in assessing risks for human exposures to VOCs. Recent studies have suggested that ion channels, including nicotinic acetylcholine receptors (nAChRs), are targets of TOL effects. However, studies comparing TOL effects on human and rat ligand-gated ion channels have not been conducted. To examine potential toxicodynamic differences between these species, the sensitivity of human and rat nAChRs to TOL was assessed. Since PERC has similar effects, in vivo, to TOL, effects of PERC on nAChR function were also examined. Two-electrode voltage-clamp techniques were utilized to measure acetylcholine-induced currents in neuronal nAChRs (α4β2, α3β2, and α7) expressed in Xenopus oocytes. PERC (0.065 mM) inhibited α7 nAChR currents by 60.1 ± 4.0% (human, n = 7) and 40 ± 3.5% (rat, n = 5), and inhibited α4β2 nAChR currents by 42.0 ± 5.2% (human, n = 6) and 52.2 ± 5.5% (rat, n = 8). Likewise, α3β2 nAChRs were significantly inhibited by 62.2 ± 3.8% (human, n = 7) and 62.4 ± 4.3% (rat, n = 8) in the presence of 0.065 mM PERC. TOL also inhibited both rat and human α7, α4β2, and α3β2 nAChRs. Statistical analysis indicated that although there was not a species (human vs. rat) difference with PERC (0.0015–0.065 mM) or TOL (0.03–0.9 mM) inhibition of α7, α4β2, or α3β2 nAChRs, all receptor types were more sensitive to PERC than TOL. These results demonstrate that human and rat nACh receptors represent a sensitive target for VOCs. This toxicodynamic information will help decrease the uncertainty associated with animal to human extrapolations in the risk assessment of VOCs.