Toxicological Sciences 64, 151-161 (2001)
Copyright © 2001 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETIC |
Physiological Modeling of the Relative Contributions of Styrene-7,8-oxide Derived from Direct Inhalation and from Styrene Metabolism to the Systemic Dose in Humans
Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599–7400
Workers in the reinforced plastics industry are exposed to large quantities of styrene and to small amounts of the carcinogen, styrene-7,8-oxide (SO), in air. Since SO is also the primary metabolite of styrene, we modified a published physiologically based pharmacokinetic (PBPK) model to investigate the relative contributions of inhaled SO and metabolically derived SO to the systemic levels of SO in humans. The model was tested against air and blood measurements of styrene and SO from 252 reinforced plastics workers. Results suggest that the highly efficient first-pass hydrolysis of SO via epoxide hydrolase in the liver greatly reduces the systemic availability of SO formed in situ from styrene. In contrast, airborne SO, absorbed via inhalation, is distributed to the systemic circulation, thereby avoiding such privileged-access metabolism. The best fit to the model was obtained when the relative systemic availability (the ratio of metabolic SO to absorbed SO per unit exposure) equaled 2.75 x 10-4, indicating that absorbed SO contributed 3640 times more SO to the blood than an equivalent amount of inhaled styrene. Since the ratio of airborne styrene to SO rarely exceeds 1500 in the reinforced plastics industry, this indicates that inhalation of SO presents a greater hazard of cytogenetic damage than inhalation of styrene. We conclude that future studies should assess exposures to airborne SO as well as styrene.
Key Words: bioavailability; inhalation; physiologically based modeling; reinforced plastics; styrene; styrene-7,8-oxide.
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