Toxicological Sciences, Vol 48, 170-179, Copyright © 1999 by Society of Toxicology
GD Loizou, K Jones, P Akrill, D Dyne and J Cocker
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.
ARTICLES
Estimation of the dermal absorption of m-xylene vapor in humans using breath sampling and physiologically based pharmacokinetic analysis
Health and Safety Laboratory, Biomedical Sciences Group, Organic Toxicology, Sheffield, United Kingdom. george.loizou@hsl.gov.uk
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