Only
a small fraction of chemicals possesses adequate in
vivo toxicokinetic data for assessing potential hazards.
The aim of the present study was to model the plasma and hepatic pharmacokinetics
of more than 50 disparate types of chemicals and drugs after virtual
oral administrations in rats. The models were based on reported pharmacokinetics
determined after oral administration to rats. An inverse relationship
was observed between no-observed-effect levels after oral administration
and chemical absorbance rates evaluated for cell permeability (r = −0.98, p < 0.001, n = 17). For a varied selection of more than 30 chemicals,
the plasma concentration curves and the maximum concentrations obtained
using a simple one-compartment model (recently recommended as a high-throughput
toxicokinetic model) and a simple physiologically based pharmacokinetic
(PBPK) model (consisting of chemical receptor, metabolizing, and central
compartments) were highly consistent. The hepatic and plasma concentrations
and the hepatic and plasma areas under the concentration–time
curves of more than 50 chemicals were roughly correlated; however,
differences were evident between the PBPK-modeled values in livers and
empirically obtained values in plasma. Of the compounds selected
for analysis, only seven had the lowest observed effect level (LOEL)
values for hepatoxicity listed in the Hazard Evaluation Support System
Integrated Platform in Japan. For these seven compounds, the LOEL
values and the areas under the hepatic concentration–time curves
estimated using PBPK modeling were inversely correlated (r = −0.78, p < 0.05, n = 7). This study provides important information to help simulate
the high hepatic levels of potent hepatotoxic compounds. Using suitable
PBPK parameters, the present models could estimate the plasma/hepatic
concentrations of chemicals and drugs after oral doses using both
PBPK forward and reverse dosimetry, thereby indicating the potential
value of this modeling approach in predicting hepatic toxicity as
a part of risk assessments of chemicals absorbed in the human body.
Long-term exposure to certain volatile organic compounds is a significant public health concern. A variety of food containers and drinking cups prepared from polystyrene or polystyrene-related plastics could contain styrene monomer. In the current study, the concentrations of styrene in plasma and liver were surveyed and determined after oral doses of 25 mg/kg to rats and 200 mg/kg to control and humanized-liver mice. Plasma concentrations of styrene in rats were still detected 2 hr after 10-25 mg/kg oral doses. In contrast, after an order of magnitude higher oral dose of styrene (200 mg/kg) to mice, styrene in mouse plasma was rapidly cleared within 15 min to the limit-of-detection level. However, unmetabolized styrene was detected in mouse liver 24 hr after oral treatment. A simple physiologically based pharmacokinetic (PBPK) model capable of estimating blood and liver concentrations of styrene was established for rats. A human PBPK model was then set up for styrene by using the same intrinsic hepatic clearances in rats and humans and by applying allometric scaling to rat parameters obtained from the plasma concentrations of styrene in rats. By reverse dosimetry analysis (from concentrations to doses), we found that the 95th percentile values of styrene concentrations (0.132 ng/mL) reported in United States biomonitoring data of more than 1000 human blood samples may imply exposure to repeated oral doses of styrene of 2.89 µg/kg/day. These results suggest that styrene biomonitoring data in human blood samples imply exposures roughly similar to or lower than the established tolerable daily intake level of 7.7 μg/kg/day.
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