Estimation of the dermal absorption of m-xylene vapor in humans using breath sampling and physiologically based pharmacokinetic analysis

A physiologically-based pharmacokinetic model, containing a skin compartmen t, was derived and used to simulate experimentally determined exposure to m -xylene, using human volunteers exposed under controlled conditions. Biolog ical monitoring was conducted bq sampling, in exhaled alveolar air and bloo d, m-xylene and urinary methyl hippuric acid concentrations. The dermal abs orption of m-xylene vapor was successfully and conveniently studied using a breath sampling technique, and the contribution to m-xylene body burden fr om the dermal route of exposure was estimated to be 1.8%. The model was use d to investigate the protection afforded by an air-fed, half-face mask. By iteratively changing the dermal exposure concentration, it was possible to predict the ambient concentration that was required to deliver the observed urinary excretion of methylhippuric acid, during and following inhalation exposure to 50 ppm m-xylene vapor. This latter extrapolation demonstrates h ow physiologically-based pharmacokinetic modeling can be applied in a pract ical and occupationally relevant way, and permitted a further step not poss ible with biological monitoring alone. The ability of the model to extrapol ate an ambient exposure concentration was dependent upon human metabolism d ata, thereby demonstrating the mechanistic toxicological basis of model out put. The methyl hydroxylation of m-xylene is catalyzed by the hepatic mixed function oxidase enzyme, cytochrome P450 2E1 and is active in the occupati onally relevant, (<100 ppm) exposure range of m-xylene. The use of a scaled -up in vitro maximum rate of metabolism (V-maxc) in the model also demonstr ates the increasingly valuable potential utility of biokinetic data determi ned using alternative, non-animal methods in human chemical-risk assessment .