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

Abstract

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.

A Workflow for Global Sensitivity Analysis of PBPK Models

“…Liver, adipose, richly and slowly perfused tissues, and the bladder represents the body. The model parameter abbreviations and point values, which are similar to previous models, are listed in Table 1 along with the ranges used in the SA (Loizou et al, 1999; MacDonald et al, 2002). Exhalation, metabolism, and renal excretion were the routes of elimination.…”

Evaluation of dermal absorption and protective effectiveness of respirators for xylene in spray painters

“…Xylene vapor can also be absorbed through the skin. Four volunteers were exposed to m-xylene vapor either skin plus inhalation or via skin only and the contribution to xylene body burden from the dermal route of exposure was estimated to be 1-2% (Brooke et al 1998;Loizou et al 1999). The purpose of this study was to determine the contribution of dermal absorption on the total exposure dose and the performance of respirators in the Weld for xylene in spray painters.…”

Dermal Absorption of Solvents as a Major Source of Exposure Among Shipyard Spray Painters

“…Xylene vapor can also be absorbed through the skin, and it has been estimated that xylene contributes 1% to 2% of exposure through the skin. 5,6 Shih et al 7 conducted a study of percutaneous uptake of 2-methoxy ethanol vapor in humans. The arms of seven volunteers were exposed to 2-methoxy ethanol vapor, and uptakes during a 4-hour single-arm exposure at 25 ppm and 300 ppm were 7.0 mg and 65.3 Ϯ 25.0 mg, respectively, with corresponding uptake rates of 1.36 g/cm 2 /hr and 13.2 Ϯ 5.0 g/cm 2 /hr.…”