EVALUATION OF THE DERMAL ABSORPTION OF AQUEOUS TOLUENE IN F344 RATS USING REAL-TIME BREATH ANALYSIS AND PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING

Abstract

Toluene is a ubiquitous chemical that is commonly used for its solvent properties in industry and manufacturing, and is a component of many paint products. Because of its widespread use, there is potential for both occupational and nonoccupational dermal exposure to toluene. To understand the significance of these exposures, the dermal bioavailability of toluene was assessed in F344 male rats using a combination of real-time exhaled breath analysis and physiologically based pharmacokinetic (PBPK) modeling. Animals were exposed to toluene at 0.5 or 0.2 mg/ml aqueous concentration (0.05% or 0.02%) using a 2.5-cm-diameter occluded glass patch system attached to a clipper-shaved area on the back of the rat. Immediately following exposure, individual animals were placed in a glass off-gassing chamber and exhaled breath was monitored as chamber concentration in real time using an ion-trap mass spectrometer (MS/MS). The real-time exhaled breath profile clearly demonstrated the rapid absorption of toluene, with peak chamber concentrations observed within 1 h from the start of exposure. The PBPK model describing the exposure and off-gassing chamber was used to estimate a dermal permeability coefficient ( K p ) to describe each set of exhaled breath data. Regardless of exposure level, a single K p value of 0.074 - 0.005 cm/h provided a good fit to all data sets. These rat studies using aqueous toluene will form the basis for comparing the dermal bioavailability of toluene in various paint products and may ultimately aid in understanding human health risk under a variety of exposure scenarios.