You are here:
Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards
El-Masri, H., N. Kleinstreuer, R. Hines, Lindad Adams, T. Tal, K. Isaacs, B. Wetmore, AND C. Tan. Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 152(1):230-243, (2016).
Developing fetuses and infants are especially sensitive to toxicity caused by exposure to xenobiotics. The time and dose to which a developing target tissue is exposed during pregnancy or via lactation after birth are critical factors in developmental toxicology. Exposure to fetal tissues is furthermore complicated by the changing physiological functions of a pregnant mother. Application of PBPK models to describe temporal physiological changes during pregnancy and fetal development is a more scientifically-credible method to investigate the complex relationships between environmental exposure, time, and target fetal tissue levels of developmentally toxic chemicals. Specifically, the utilization of life-stage PBPK models in combination with, HTS in vitro data interpretable of an AOP, and observed or predicted environmental concentrations can together provide a biologically-based method to estimate and compare safe margins of exposure (MOE) across chemicals of concern. Here we present the development of a universal computational model considering life-stage ADME linking environmental exposures to in vitro levels of sensitive high-throughput screening (HTS) assays related to an AOP for embryonic vascular disruption. The computational modeling effort in this paper considers biologically relevant determinants of toxicokinetics (IVIVE), toxicodynamics (developmental AOP), and real-life exposure levels of chemicals of interest in framework that is applicable to any number of chemicals of interest to EPA’s Children Health research program.
A Life-stage Physiologically-Based Pharmacokinetic (PBPK) model was developed to include descriptions of several life-stage events such as pregnancy, fetal development, the neonate and child growth. The overall modeling strategy was used for in vitro to in vivo (IVIVE) extrapolation to help contextualize activity in ToxCast assays that were mapped to an adverse outcome pathway (AOP) for embryonic vascular disruption. Using life-stage PBPK models, we estimated maternal exposures that would yield fetal blood levels equivalent to in vitro activity from ToxCast assays with critical vascular signaling targets. The resulting in vivo dose estimates were then compared to life-time exposures using literature data or exposure models (SHEDS-LITE) to derive AOP-based Margins of Exposure (ME). This computational framework was applied to a list of five chemicals with varying activity against the putative Vascular Disruption AOP. The idea of linking biological information related to toxicity (using AOPs), high throughput in vitro data (ToxCast), and age-varying physiological and biochemical information to estimate AOP-based MEs is novel and can be used to help regulators in realistically assessing chemicals based on toxicity, dosimetry, and real-life exposures.