A physiologically based toxicokinetic model of inhalation exposure to xylenes in Caucasian men

Widespread exposure to the volatile aromatic hydrocarbons, ortho-, meta-, and para-xylene occurs in many industries including the manufacture of plastics, pharmaceuticals, and synthetic fibers. This paper describes the development of a physiologically based toxicokinetic model using biomonitoring data to quantify the kinetics of ortho-, meta-, and para-xylenes. Serial blood concentrations of deuterium-labeled xylene isomers were obtained over 4 days after 37 controlled, 2 h inhalation exposures to different concentrations of the isomers. Peak toxicant concentrations in blood occurred in all subjects at the termination of exposure. Systemic clearance averaged 116 L/h ± 34 L/h, 117 L/h ± 23 L/h, and 129 L/h ± 33 L/h for ortho-, para-, and meta-xylene, respectively. The half-life of each toxicant in the terminal phase (>90 h post-exposure) was fit by the model, yielding values of 30.3 ± 10.2 h for para-xylene, 33.0 ± 11.7 h for meta-xylene and 38.5 ± 18.2 h for ortho-xylene. Significant isomeric differences were found (p < 0.05) for toxicant half-life, clearance and extrahepatic metabolism. Inter-individual variability seen in this study suggests that airborne concentration guidelines may not protect all workers. A Biological Exposure Index is preferred for this purpose since it is integrative and reflective of inter-individual kinetic variability.