Human risk assessment of 4-n-nonylphenol (4-n-NP) using physiologically based pharmacokinetic (PBPK) modeling: analysis of gender exposure differences and application to exposure analysis related to large exposure variability in population.

As a toxic substance, 4-n-nonylphenol (4-n-NP) or 4-nonylphenol (4-NP) is widely present in the environment. 4-n-NP is a single substance with a linear-alkyl side chain, but 4-NP usually refers to a random mixture containing various branched types. Unfortunately, human risk assessment and/or exposure level analysis for 4-n-NP (or 4-NP) were almost nonexistent, and related research was urgently needed. This study aimed to analyze the various exposures of 4-n-NP (or 4-NP) through development of a physiologically based-pharmacokinetic (PBPK) model considering gender difference in pharmacokinetics of 4-n-NP and its application to human risk assessment studies. A PBPK model was newly developed considering gender differences in 4-n-NP pharmacokinetics and applied to a human risk assessment for each gender. Exposure analysis was performed using a PBPK model that considered gender differences in 4-n-NP (or 4-NP) exposure and high variabilities in several countries. Furthermore, an extended application was attempted as a human risk assessment for random mixture 4-NP, which is difficult to accurately evaluate in reality. External-exposure and margin-of-safety estimated with the same internal exposure amount differed between genders, meaning the need for a differentiated risk assessment considering gender. Exposure analysis based on biomonitoring data confirmed large variability in exposure to 4-n-NP (or 4-NP) by country, group, and period. External-exposures estimated using PBPK model varied widely, ranging from 0.039 to 63.875 mg/kg/day (for 4-n-NP or 4-NP). By country, 4-n-NP (or 4-NP) exposure was higher in females than in males and the margin-of-safety tended to be low. Overall, exposure to 4-n-NP (or 4-NP) in populations was largely not safe, suggesting need for ongoing management and monitoring. Considering low in vivo accumulation confirmed by PBPK model, risk reduction of 4-n-NP is possible by reducing its use.

Human risk assessment of di-isobutyl phthalate through the application of a developed physiologically based pharmacokinetic model of di-isobutyl phthalate and its major metabolite mono-isobutyl phthalate.

Di-isobutyl phthalate (DiBP) is a substance used in the production of objects frequently used in human life. Mono-isobutyl phthalate (MiBP), a major in vivo metabolite of DiBP, is a biomarker for DiBP exposure assessment. Therefore, risk assessment studies on DiBP and MiBP, which have not yet been reported in detail, are needed. The aim of this study was to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for DiBP and MiBP in rats and extend this to human risk assessment based on human exposure. Pharmacokinetic studies were performed in male rats following the administration of 5-100 mg/kg DiBP, and these results were used for the development and validation of the PBPK model. In addition, the previous pharmacokinetic results in female rats following DiBP administration and the pharmacokinetic results in both males and females according to multiple exposures to DiBP were used to develop and validate the PBPK model. The metabolism of DiBP to MiBP in the body was very significant and rapid, and the biodistribution of MiBP was broad and major. Furthermore, the amount of MiBP in the body showed a correlation with DiBP exposure, and from this, a PBPK model was developed to evaluate the external exposure of DiBP from the internal exposure of MiBP. The predicted rat plasma, urine, fecal, and tissue concentrations using the developed PBPK model fitted well with the observed values. The established PBPK model for rats was extrapolated to a human PBPK model of DiBP and MiBP based on human physiological parameters and allometric scaling. The reference dose of 0.512 mg/kg/day of DiBP and external doses of 6.14-280.90 µg/kg/day DiBP for human risk assessment were estimated using Korean biomonitoring values. Valuable insight and approaches to assessing human health risks associated with DiBP exposure were provided by this study.

Risk assessment for humans using physiologically based pharmacokinetic model of diethyl phthalate and its major metabolite, monoethyl phthalate.

Diethyl phthalate (DEP) belongs to phthalates with short alkyl chains. It is a substance frequently used to make various products. Thus, humans are widely exposed to DEP from the surrounding environment such as food, soil, air, and water. As previously reported in many studies, DEP is an endocrine disruptor with reproductive toxicity. Monoethyl phthalate (MEP), a major metabolite of DEP in vivo, is a biomarker for DEP exposure assessment. It is also an endocrine disruptor with reproductive toxicity, similar to DEP. However, toxicokinetic studies on both MEP and DEP have not been reported in detail yet. Therefore, the objective of this study was to evaluate and develop physiologically based pharmacokinetic (PBPK) model for both DEP and MEP in rats and extend this to human risk assessment based on human exposure. This study was conducted in vivo after intravenous or oral administration of DEP into female (2 mg/kg dose) and male (0.1-10 mg/kg dose) rats. Biological samples consisted of urine, plasma, and 11 different tissues. These samples were analyzed using UPLC-ESI-MS/MS method. For DEP, the tissue to plasma partition coefficient was the highest in the kidney, followed by that in the liver. For MEP, the tissue to plasma partition coefficient was the highest in the liver. It was less than unity in all other tissues. Plasma, urine, and fecal samples were also obtained after IV administration of MEP (10 mg/kg dose) to male rats. All results were reflected in a model developed in this study, including in vivo conversion from DEP to MEP. Predicted concentrations of DEP and MEP in rat urine, plasma, and tissue samples using the developed PBPK model fitted well with observed values. We then extrapolated the PBPK model in rats to a human PBPK model of DEP and MEP based on human physiological parameters. Reference dose of 0.63 mg/kg/day (or 0.18 mg/kg/day) for DEP and external doses of 0.246 µg/kg/day (pregnant), 0.193 µg/kg/day (fetus), 1.005-1.253 µg/kg/day (adults), 0.356-0.376 µg/kg/day (adolescents), and 0.595-0.603 µg/kg/day (children) for DEP for human risk assessment were estimated using Korean biomonitoring values. Our study provides valuable insight into human health risk assessment regarding DEP exposure.

Exploring sex differences in human health risk assessment for PFNA and PFDA using a PBPK model.

Perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), which are classified as perfluoroalkyl and polyfluoroalkyl substances (PFASs), have been widely used in industrial applications as a surface protectant. PFASs have been detected in wildlife and in humans around the globe. The purposes of this study are to develop and validate a physiologically based pharmacokinetic (PBPK) model for detecting PFNA and PFDA in male and female rats, and to apply the model to a human health risk assessment regarding the sex difference. A PBPK model of PFNA and PFDA was established based on an in vivo study in male and female rats. Analytes in biological samples (plasma, nine tissues, urine, and feces) were determined by ultra-liquid chromatography coupled tandem mass spectrometry (UPLC-MS/MS) method. PFNA and PFDA showed a gender differences in the elimination half-life and volume of distribution. The tissue-plasma partition coefficients were the highest in the liver in both male and female rats. The predicted rat plasma and urine concentrations simulated and fitted were in good agreement with the observed values. The PBPK models of PFNA and PFDA in male and female rats were then extrapolated to a human PBPK model based on human physiological parameters. The external doses were calculated at 3.35 ng/kg/day (male) and 17.0 ng/kg/day (female) for PFNA and 0.530 ng/kg/day (male) and 0.661 ng/kg/day (female) for PFDA. Human risk assessment was estimated using Korean biomonitoring values considering the gender differences. This study provides valuable insight into human health risk assessment regarding PFNA and PFDA exposure.

Sex-specific risk assessment of PFHxS using a physiologically based pharmacokinetic model.

Perfluorohexanesulfonate (PFHxS), which belongs to the group of perfluoroalkyl and polyfluoroalkyl substances (PFASs), has been extensively used in industry and subsequently detected in the environment. Its use may be problematic, as PFHxS is known to induce neuronal cell death, and has been associated with early onset menopause in women and with attention deficit/hyperactivity disorder. Due to these impending issues, the aim of this study is to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for PFHxS in male and female rats, and apply this to a human health risk assessment. We conducted this study in vivo after the oral or intravenous administration of PFHxS in male (dose of 10 mg/kg) and female rats (dose of 0.5-10 mg/kg). The biological samples consisted of plasma, nine tissues, urine, and feces. We analyzed the sample using ultra-liquid chromatography coupled tandem mass spectrometry (UPLC-MS/MS). Our findings showed the tissue-plasma partition coefficients for PFHxS were highest in the liver. The predicted rat plasma and tissue concentrations using a simulation fitted well with the observed values. We extrapolated the PBPK model in male and female rats to a human PBPK model of PFHxS based on human physiological parameters. The reference doses of 0.711 µg/kg/day (male) and 0.159 µg/kg/day (female) and external doses of 0.007 µg/kg/day (male) and 0.006 µg/kg/day (female) for human risk assessment were estimated using Korean biomonitoring values. This study provides valuable insight into human health risk assessment regarding PFHxS exposure.