Toxicological Sciences, Vol 51, 184-194, Copyright © 1999 by Society of Toxicology
A Nihlen and G Johanson
A physiologically based toxicokinetic (PBTK) model was developed for
evaluation of inhalation exposure in humans to the gasoline additive, ethyl
tertiary-butyl ether (ETBE). PBTK models are useful tools to relate
external exposure to internal doses and biological markers of exposure in
humans. To describe the kinetics of ETBE, the following compartments were
used: lungs (including arterial blood), liver, fat, rapidly perfused
tissues, resting muscles, and working muscles. The same set of compartments
and, in addition, a urinary excretion compartment were used for the
metabolite tertiary-butyl alcohol (TBA). First order metabolism was assumed
in the model, since linear kinetics has been shown experimentally in humans
after inhalation exposure up to 50 ppm ETBE. Organ volumes and blood flows
were calculated from individual body composition based on published
equations, and tissue/blood partition coefficients were calculated from
liquid/air partition coefficients and tissue composition. Estimates of
individual metabolite parameters of 8 subjects were obtained by fitting the
PBTK model to experimental data from humans (5, 25, 50 ppm ETBE, 2-h
exposure; Nihlen et al., Toxicol. Sci., 1998; 46, 1-10). The PBTK model was
then used to predict levels of the biomarkers ETBE and TBA in blood, urine,
and exhaled air after various scenarios, such as prolonged exposure,
fluctuating exposure, and exposure during physical activity. In addition,
the interindividual variability in biomarker levels was predicted, in the
eight experimentally exposed subjects after a working week. According to
the model, raising the work load from rest to heavy exercise increases all
biomarker levels by approximately 2-fold at the end of the work shift, and
by 3-fold the next morning. A small accumulation of all biomarkers was seen
during one week of simulated exposure. Further predictions suggested that
the interindividual variability in biomarker levels would be higher the
next morning than at the end of the work shift, and higher for TBA than for
ETBE. Monte Carlo simulations were used to describe fluctuating exposure
scenarios. These simulations suggest that ETBE levels in blood and exhaled
air at the end of the working day are highly sensitive to exposure
fluctuations, whereas ETBE levels the next morning and TBA in urine and
blood are less sensitive. Considering these simulations, data from the
previous toxicokinetic study and practical issues, we suggest that TBA in
urine is a suitable biomarker for exposure to ETBE and gasoline vapor.
ARTICLES
Physiologically based toxicokinetic modeling of inhaled ethyl tertiary- butyl ether in humans
Department of Toxicology and Risk Assessment, National Institute for Working Life, Solna, Sweden. Annsofi.Nihlen@niwl.se
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