Human urinary concentrations of monoisononyl phthalate estimated using physiologically based pharmacokinetic modeling and experimental pharmacokinetics in humanized-liver mice orally administered with diisononyl phthalate

Abstract

1. Diisononyl phthalate (DINP) used as a plasticizer is a mixture of compounds consisting of isononyl esters of phthalic acid. There are concerns about the bioaccumulation of such esters in humans. A [phenyl-U-¹⁴C]DINP mixture was synthesized and orally administered (50 mg/kg body weight) to control and humanized-liver mice and their pharmacokinetics were determined.

2. Monoisononyl phthalate (MINP, a primary metabolite of DINP), oxidized MINP (isomers with hydroxy, carbonyl, and carboxy functional groups), and their glucuronides were detected in plasma from control and humanized-liver mice. Biphasic plasma concentration–time curves of MINP and its glucuronide were seen in control mice. In contrast, no such biphasic relationship was seen in humanized-liver mice, in which MINP and oxidized MINP were extensively excreted in the urine within 48 h.

3. Animal biomonitoring equivalents of MINP and oxidized MINP from humanized-liver mice studies were scaled to human equivalents using known species allometric scaling factors with a simple physiologically based pharmacokinetic (PBPK) model.

4. Estimated urinary oxidized MINP concentrations in humans were roughly consistent with reported concentrations of MINP (with a different side chain). The simplified PBPK model could estimate human urinary concentrations of MINP after ingestion of DINP and was capable of both forward and reverse dosimetry.

Keywords:

• Allometric scaling
• kinetic modeling
• phthalate
• species difference
• urine

Acknowledgements

The authors thank Megumi Nishiwaki, Nao Yoneda, Shotaro Uehara, and Norie Murayama for their technical help and we thank David Smallbones for his advice on English language usage.

Disclosure statement

The authors declare that there are no conflicts of interest except for part of the funding came from the Japan Plasticizer Industry Association.

Additional information

Funding

This work was supported in part by the METI Artificial Intelligence-Substances Hazardous Integrated Prediction System Project, Japan.