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

  • Toxicokinetics and Metabolism
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Abstract

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.

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Abbreviations

DEP:

Diethyl phthalate

MEP:

Monoethyl phthalate

BBP:

Butyl benzyl phthalate

DBP:

Di-n-butyl phthalate

MBP:

Mono-n-butyl phthalate

DEHP:

Di-(2-ethylhexyl) phthalate

DiDP:

Diisodecyl phthalate

MEHP:

Mono-(2-ethylhexyl) phthalate

DiNP:

Diisononyl phthalate

DnOP:

Di-n-octyl phthalate

REACH:

Registration, evaluation, authorization and restriction of chemicals

CPSIA:

Consumer product safety improvement act

RoHS:

Restriction of hazardous substances directive

WHO:

World health organization

US EPA:

United states environmental protection agency

PBPK:

Physiologically based pharmacokinetic

UPLC–ESI–MS/MS:

Ultraperformance liquid chromatography–electrospray ionization-tandem mass spectrometer

MS:

Mass spectrometer

ESI:

Electrospray ionization

HPLC:

High performance liquid chromatography

IV:

Intravenous

MRM:

Multiple reaction monitoring

IS:

Internal standard

LLE:

Liquid–liquid extraction

QC:

Quality control

PP:

Protein precipitation

SD:

Standard deviation

CV:

Coefficient of variation

CL:

Clearance

Vd :

Volume of distribution

BTB:

Blood–testis barrier

NOAEL:

No observed adverse effect level

PK:

Pharmacokinetic

POD:

Points of departure

UF:

Uncertainty factor

RfD:

Reference dose

MOE:

Margin of exposure

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea

    Seung-Hyun Jeong, Ji-Hun Jang & Yong-Bok Lee

  2. College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-Do, 13488, Republic of Korea

    Hea-Young Cho

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  1. Seung-Hyun Jeong
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Correspondence to Hea-Young Cho or Yong-Bok Lee.

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The animal experiment was approved by the Chonnam National University Animal Experimental Ethics Committee, Republic of Korea (approval number: CNU IACUC-YB-2017-45). In addition, this study was conducted according to revised Guidelines for Ethical Conduct in the Care and Use of Animals and the rules of Good Laboratory Practice.

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Jeong, SH., Jang, JH., Cho, HY. et al. Risk assessment for humans using physiologically based pharmacokinetic model of diethyl phthalate and its major metabolite, monoethyl phthalate. Arch Toxicol 94, 2377–2400 (2020). https://doi.org/10.1007/s00204-020-02748-9

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