Human plasma and liver concentrations of styrene estimated by combining a simple physiologically based pharmacokinetic model with rodent data

Abstract

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.

Investigations on the genotoxic potential of styrene in Fischer 344 rats using multiple endpoints

“…In the DRF study, the animals (5 rats/dose) were administered styrene at dose levels of 0, 100, 500, and 1000 mg/kg/day for 28 days and the surviving animals were euthanized 24 h after the final dose for the collection of tissues (bone marrow, glandular stomach, kidney, liver, and lung) for histopathological examination. Plasma concentrations of styrene were determined from satellite animals (3/dose/time point) using a GC–MS/MS method; considering the reported rapid metabolism of orally administered styrene in the rat (Miura et al, 2019), blood samples were targeted for collection approximately at 7‐ and 15‐min post exposure.…”

Forward and reverse dosimetry for aniline and 2,6-dimethylaniline in humans extrapolated from humanized-liver mouse data using simplified physiologically based pharmacokinetic models

“…The expression 1 + fu,p 2 corresponds to the ratio of f u,p to the tissue fraction unbound. The in vivo hepatic intrinsic clearance (CL h,int ) in humans was estimated based on that of humanized liver-mice, with no application of interspecies factors in vitro, as previously described (Miura et al, 2021b(Miura et al, , 2019a(Miura et al, , 2019b. CL r was generated using rodent body weights of 0.025 kg (mouse) and 0.25 kg (rat) and a human body weight of 70 kg as follows (Kamiya et al, 2020):…”

Pharmacokinetics of primary oxidative metabolites of thalidomide in rats and in chimeric mice humanized with different human hepatocytes

“…Three male Sprague-Dawley rats (7 weeks old, Charles River Laboratory, Tokyo, Japan) and 20 male humanized-liver immunodeficient TK-NOG mice (20-30 g body weight) (Hasegawa et al, 2011) were used in this study. Four differ-ent sources of human hepatocytes were used: lot BPI-HEP187273, genotyped as CYP3A5*3/*3, was obtained from Biopredic, St Gregoire, France, whereas lots TRL-HUM4122B, genotyped as CYP3A5*1/*3; TRL-HUM4119F, genotyped as CYP3A5*1/*7; and TRL-HUM4129, genotyped as CYP3A5*3/*3 were obtained from Lonza TRL, Morrisville, NC, USA (Miura et al, 2019b(Miura et al, , 2020(Miura et al, , 2021. After liver-specific damage was induced in the TK-NOG mice, these human hepatocytes were transplanted to reconstitute the liver.…”