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 compartment, was derived and used to simulate experimentally determined exposure to m-xylene, using human volunteers exposed under controlled conditions. Biological monitoring was conducted by sampling, in exhaled alveolar air and blood, m-xylene and urinary methyl hippuric acid concentrations. The dermal absorption of m-xylene vapor was successfully and conveniently studied using a breath sampling technique, and the contribution to m-xylene body burden from the dermal route of exposure was estimated to be 1.8%. The model was used 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 how physiologically-based pharmacokinetic modeling can be applied in a practical and occupationally relevant way, and permitted a further step not possible with biological monitoring alone. The ability of the model to extrapolate an ambient exposure concentration was dependent upon human metabolism data, thereby demonstrating the mechanistic toxicological basis of model output. The methyl hydroxylation of m-xylene is catalyzed by the hepatic mixed function oxidase enzyme, cytochrome P450 2E1 and is active in the occupationally relevant, (<100 ppm) exposure range of m-xylene. The use of a scaled-up in vitro maximum rate of metabolism (Vmaxc) in the model also demonstrates the increasingly valuable potential utility of biokinetic data determined using alternative, non-animal methods in human chemical-risk assessment.