The Toxicologist - Society of Toxicology

of radiolabeled Mn (carrier-free 54 MnCl 2
). Model parameters governing dietary absorption
and biliary elimination were calibrated to whole body retention and tracer
fecal excretion data due to different dietary conditions. Simulation results accurately
recapitulated the fast and slow phases of elimination for all exposure routes in
monkeys. Model predictions for whole body retention in humans given an iv dose
of 54 Mn (2.5 μCi) compared well with retention characteristics of people on normal
(3 mg/day Mn) and reduced calorie (1 mg/day Mn) diets. The ability of the PBPK
models to provide consistent multispecies descriptions of Mn tracer kinetics across
multiple exposure routes indicates that the models can accurately predict conditions
where exposures will increase free Mn in various tissues throughout the body.
885 TARGET-TISSUE DOSIMETRY MODELING TO
SUPPORT THE RISK ASSESSMENT OF MANGANESE.
M. D. Taylor 1 , M. Yoon 2 , J. D. Schroeter 2 , D. C. Dorman 3 , M. E. Andersen 2
and H. J. Clewell 2 . 1 Afton Chemical Corp, Richmond, VA, 2 The Hamner Institutes,
Research Triangle Park, NC and 3 North Carolina State University, Raleigh, NC.
Manganese (Mn) is a ubiquitous, essential element that can be neurotoxic upon
overexposure. Although Mn neurotoxicity has most commonly been associated
with inhalation of excessive amounts of Mn-containing fumes and dusts, it may
occur upon over-exposure by other routes. Dose to target tissue, not exposure
route, is the critical determinant in the development of Mn neurotoxicity. Recently,
tissue Mn data from a series of pharmacokinetic studies have been used to develop
physiologically based pharmacokinetic (PBPK) models for ingested and inhaled
Mn in rats and non-human primates. The models demonstrated that dose-dependent
transitions exist for tissue accumulation of inhaled Mn, due in part to homeostatic
regulation. The purpose of this study was to use these PBPK models to improve
on traditional human health risk assessment approaches for environmental
exposures to Mn. The PBPK models were used to estimate chemical-specific adjustment
factors (CSAFs) in lieu of relying on default uncertainty factors (UFs).
CSAFs were calculated for pharmacokinetic differences among potentially susceptible
subpopulations and life stages. These comparisons included gender, and age, as
well as fetal and neonatal life stages. The resulting CSAFs were then used to replace
some of the default UFs that have been used in risk assessments for inhaled Mn
based on neurological effects observed in occupational studies in the derivation of
an acceptable environmental exposure concentration. Monte Carlo analysis
demonstrated that the variation in target tissue dose at the resulting environmental
exposure concentration was less than that associated with normal dietary variation.
This work shows how PBPK models can be used to produce more robust and biologically
based risk assessments of essential elements such as Mn by accounting for
innate homeostatic control processes, dose-dependent transitions for tissue accumulation,
and population variability.
886 APPLICATION OF A PHYSIOLOGICALLY-BASED
PHARMACOKINETIC MODEL OF
TRICHLOROETHYLENE IN RATS FOR ESTIMATION
OF INTERNAL DOSE.
C. R. Eklund, M. V. Evans and J. Simmons. Integrated Systems Toxicology
Division, U.S. EPA, Research Triangle Park, NC.
Potential human health risk from chemical exposure must often be assessed for conditions
for which suitable human or animal data are not available, requiring extrapolation
across duration and concentration. The default method for exposure-duration
adjustment is based on Haber’s rule which states that a constant toxic effect (K)
is a function of exposure concentration (C or C n ) and exposure duration (t), K = C
(or C n )×t. This approach has been criticized for poor predictability, with errors increasing
as the extrapolation interval increases. The purpose of the present work is
estimation of the internal doses that result from various exposure concentrations
and duration using a PBPK model developed in our laboratory for trichloroethylene
(TCE) (Simmons et al., 2005). The model compartments are liver, brain, fat,
richly-perfused and slowly-perfused tissues. TCE is a volatile organic compound
and a common environmental pollutant of air, water and food. Mortality data from
experimental animals are used in setting acute exposure guideline level-3 (AEGL-3)
values as these represent air concentrations above which exposure could result in
life-threatening adverse health effects or death (NRC, 2001). We compared results
from simulations of two inhalation exposure scenarios reported to cause 50% mortality
(LC 50
) in rats, 26,000 ppm for one hour and 12,000 ppm for four hours.
These resulted in simulated arterial blood concentrations at the end of the exposure
period of 888 and 733 mg/L, respectively. While there was a 4-fold difference in exposure
duration and a 2.17 fold difference (percent difference, 74%) in external exposure
concentration, there was only a 1.2-fold difference (percent difference,
19%) in estimated arterial blood concentrations. This highlights the utility of
PBPK modeling for estimation of internal dose when considering the health implications
of exposures of varying duration and concentration and for extrapolation
from one concentration-duration to another. (This abstract may not reflect EPA
policy.)
887 MODELING THE IMPACT OF WORKLOAD ON THE
BIOLOGICAL EXPOSURE INDICATORS OF STYRENE:
COMPARISON BETWEEN SINGLE EXPOSURE AND
BINARY EXPOSURE WITH ACETONE.
A. Bérubé 1 , G. Truchon 2 , G. Charest-Tardif 1 and R. Tardif 1 . 1 Santé
environnementale et santé au travail, Université de Montréal, Montréal, QC, Canada
and 2 Institut de recherche Robert-Sauvé en santé et sécurité du travail, Montréal, QC,
Canada.
Workload has been recognized as a major determinant of the absorbed dose for
many solvents. This study was undertaken to assess the impact of physical exertion
(workload) on the biological levels of unchanged styrene (STYR) or STYR-metabolites
used as biological exposure indices (BEIs). Physiologically based toxicokinetic
models were adapted and validated in order to simulate a typical weekly occupational
exposure (8 h/day, 5 days) to STYR alone and combined with acetone (ACE)
at their current threshold limit values (ACGIH) of 20 ppm and 500 ppm, respectively.
Simulations were then conducted under workload levels corresponding to
rest (12.5W), 25W and 50W, and the impact on the levels of STYR in venous
blood (STY-B) and on urinary mandelic (MA) and phenylglyoxylic (PGA) acids at
the end of the last work shift of a week was examined for a typical worker. The predicted
values were compared to results of both experimental and field studies which
supported the adoption of the current BEIs for STYR. For an exposure to 20 ppm,
the end-of-shift values of STY-B for a workload of 50W showed a 3-fold increase
compared to the value at rest (0.17 mg/L), whereas the sum of MA and PGA in
urine was 2.7 times higher than at rest (144 mg/g creatinine). The model predicted
slight effect of co-exposure to ACE on biological levels of STYR at these exposure
levels. Based on the relation between physical activity and the values of BEIs predicted
by the model, the average workload level in field studies was approximately
50W. Overall, the model described well the impact of workload on biological levels
of STYR and showed that workload needs to be taken into account to avoid underestimation
of the internal exposure of workers and health risk. (Supported by
Afsset, France and IRSST, Canada)
888 MODELING THE TOXICOKINETICS OF 24-HOUR
TOLUENE EXPOSURE IN RATS: IMPACT OF ACTIVITY
PATTERNS AND ENZYME INDUCTION.
E. Kenyon, W. Oshiro, C. Eklund, C. Gordon, T. Krantz and P. Bushnell.
ORD/NHEERL/ISTD/PB, U.S. EPA, Research Triangle Park, NC.
Toluene, a solvent used in numerous consumer and industrial applications, exerts
its critical effects on the brain and nervous system following inhalation exposure.
Our previously published PBPK model successfully predicted toluene concentrations
in blood and brain over a range of conditions, but in recent experimental
studies it over-predicted (by ~2-fold) concentrations in blood and brain after 24 hrs
of continuous exposure to 775 or 1125 ppm toluene. The goal of this current modeling
effort was to determine if changes in physical activity patterns (as measured by
telemetry) and/or enzyme induction could explain toluene pharmacokinetics following
24 hrs of continuous exposure to toluene. Compartments in the model are
lung, slowly and rapidly-perfused tissue groups, fat, liver, GI tract and brain; tissue
transport is blood-flow limited and metabolism occurs in the liver. Chemical-specific
parameters and initial organ volumes and blood flow rates were obtained from
the literature. Observed changes in motor activity and heart rate during the period
of exposure were implemented in the model by increasing cardiac output and alveolar
ventilation up to 10%, but this was insufficient to account for the observed
pharamacokinetic behavior. Alternatively, incorporation of cytochrome P450-mediated
enzyme induction (increasing VmaxC up to 5-fold) allowed successful prediction
of the experimental data. The degree of enzyme induction tested was biologically
plausible based on literature data for shorter term toluene exposure which
report up to 8.3-fold induction. Our results suggest the need to consider the potential
impact of enzyme induction when simulating chronic toxicity studies for purposes
of risk analysis, i.e. when using a PBPK model to obtain estimates of internal
dose for application to dose-response analysis. (This abstract does not necessarily
reflect EPA policy.)
SOT 2010 ANNUAL MEETING 189