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Integrative Life-Stage Physiologically Based Pharmacokinetic (PBPK) and Thyroid Hormones Kinetics Model for In Vitro to In Vivo (IVIVE) Extrapolation of Thyroid High Throughput (HTP) Assays
Citation:
Bay, C., Mary E. Gilbert, AND H. El-Masri. Integrative Life-Stage Physiologically Based Pharmacokinetic (PBPK) and Thyroid Hormones Kinetics Model for In Vitro to In Vivo (IVIVE) Extrapolation of Thyroid High Throughput (HTP) Assays. Society of Toxicology 2021 Virtual Annual meeting, Virtual, Florida, March 12 - 26, 2021. https://doi.org/10.23645/epacomptox.16834516
Impact/Purpose:
Presentation to the Society of Toxicology 2021 Virtual Annual meeting March 2021. Adequate levels of thyroid hormone (TH) are needed for proper fetal and early life stage brain development. Exposure to thyroid disrupting chemicals (TDCs) can lead to deficiencies of serum THs during pregnancy, depriving the fetal brain of hormone and compromising neurodevelopment. We report here an integrative computational model including life-stage physiologically based pharmacokinetic (PBPK) and TH kinetic models. This model implements a mechanistic quantitative approach to translate TH disruption in vitro HTP assays to in vivo measures of circulating THs serum level in a pregnant mother, the fetus and the neonate. When combined with quantitative methods and literature data for PBPK chemical specific parameters, this integrative quantitative approach can be generalized across many chemicals and exposure scenarios to augment regulatory decision making
Description:
Adequate levels of thyroid hormone (TH) are needed for proper fetal and early life stage brain development. Exposure to thyroid disrupting chemicals (TDCs) can lead to deficiencies of serum THs during pregnancy, depriving the fetal brain of hormone and compromising neurodevelopment. Regulatory assessment of TDCs is largely informed by chemical disruption of serum hormone concentrations in rodent models. High throughput (HTP) in vitro assays of several biochemical pathways of thyroid hormone synthesis and metabolism are used to screen chemicals for their potential to disrupt the thyroid axis. Computational toxicology strives to translate in vitro based screening information to predict organismal outcomes of potential TDCs. To this end, estimates of target tissue concentrations are required (i.e. chemical and hormone concentrations in the serum, thyroid gland, and liver) during pregnancy and early-life stages. Chemical tissue concentrations are controlled by pharmacokinetic determinates such as absorption, distribution, metabolism and excretion (ADME). Thyroid hormone concentrations in serum are also influenced by TH kinetics of synthesis, distribution, catabolism, metabolism, and transport via placenta. We report here an integrative computational model including life-stage physiologically based pharmacokinetic (PBPK) and TH kinetic models. This model implements a mechanistic quantitative approach to translate TH disruption in vitro HTP assays to in vivo measures of circulating THs serum level in a pregnant mother, the fetus and the neonate. It was developed and calibrated using literature data on basal and disrupted levels of the hormones during pregnancy in the mother, fetus, newborn and neonate. When combined with quantitative methods and literature data for PBPK chemical specific parameters, this integrative quantitative approach can be generalized across many chemicals and exposure scenarios to augment regulatory decision making. This abstract does not necessarily reflect U.S. EPA policy.
URLs/Downloads:
DOI: Integrative Life-Stage Physiologically Based Pharmacokinetic (PBPK) and Thyroid Hormones Kinetics Model for In Vitro to In Vivo (IVIVE) Extrapolation of Thyroid High Throughput (HTP) Assays
BAY_SOT_PRESENTATION_THYROID.PDF (PDF, NA pp, 2741.985 KB, about PDF)