Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Model Applications to Screen Environmental Hazards.
Citation:
El-Masri, H. Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Model Applications to Screen Environmental Hazards. SOT, New Orleans, LA, March 13 - 17, 2016.
Impact/Purpose:
This is an abstract for a presentation at the annual Society of Toxicology Meeting March 2016
Description:
This presentation discusses methods used to extrapolate from in vitro high-throughput screening (HTS) toxicity data for an endocrine pathway to in vivo for early life stages in humans, and the use of a life stage PBPK model to address rapidly changing physiological parameters. Adverse outcome pathways (AOPs), in this case endocrine disruption during development, provide a biologically-based framework for linking molecular initiating events triggered by chemical exposures to key events leading to adverse outcomes. The application of AOPs to human health risk assessment requires extrapolation of in vitro HTS toxicity data to in vivo exposures (IVIVE) in humans, which can be achieved through the use of a PBPK/PD model. Exposure scenarios for chemicals in the PBPK/PD model will consider both placental and lactational transfer of chemicals, with a focus on age dependent dosimetry during fetal development and after birth for a nursing infant. This talk proposes a universal life-stage computational model that incorporates changing physiological parameters to link environmental exposures to in vitro levels of HTS assays related to a developmental toxicological AOP for vascular disruption. In vitro toxicity endpoints discussed are based on two mechanisms: 1) Fetal vascular disruption, and 2) Neurodevelopmental toxicity induced by altering thyroid hormone levels in neonates via inhibition of thyroperoxidase in the thyroid gland. Application of our Life-stage computational framework to conduct IVIVE illustrated several critical data gaps such as maternal and fetal systemic and intrinsic clearance rates, placental transport kinetics, and partitioning of chemicals in milk during nursing.