title: Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards.
abstract: A computational framework was developed to assist in screening and prioritizing chemicals based on their dosimetry, toxicity, and potential exposures. The overall strategy started with contextualizing chemical activity observed in high-throughput toxicity screening (HTS) by mapping these assays to biological events described in Adverse Outcome Pathways (AOPs). Next, in vitro to in vivo (IVIVE) extrapolation was used to convert an in vitro dose to an external exposure level, which was compared with potential exposure levels to derive an AOP-based margins of exposure (MOE). In this study, the framework was applied to estimate MOEs for chemicals that can potentially cause developmental toxicity following a putative AOP for fetal vasculogenesis/angiogenesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe chemical disposition during pregnancy, fetal, neonatal, and infant to adulthood stages. Using this life-stage PBPK model, maternal exposures were estimated that would yield fetal blood levels equivalent to the chemical concentration that altered in vitro activity of selected HTS assays related to the most sensitive vasculogenesis/angiogenesis putative AOP. The resulting maternal exposure estimates were then compared with potential exposure levels using literature data or exposure models to derive AOP-based MOEs.
authors.affiliation: *National Human and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, RTP, North Carolina el-masri.hisham@epa.gov.
authors.forename: Hisham
authors.initials: H
authors.lastname: El-Masri
authors.affiliation: National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, National Institute of Environmental Health Sciences, North Carolina.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kleinstreuer
authors.affiliation: *National Human and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, RTP, North Carolina.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Hines
authors.affiliation: *National Human and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, RTP, North Carolina.
authors.forename: Linda
authors.initials: L
authors.lastname: Adams
authors.affiliation: *National Human and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, RTP, North Carolina.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tal
authors.affiliation: National Exposure Research Laboratory, Office of Research and Development, US Environmental Protection Agency.
authors.forename: Kristin
authors.initials: K
authors.lastname: Isaacs
authors.affiliation: ScitoVation, Research Triangle Park, North Carolina, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Wetmore
authors.affiliation: National Exposure Research Laboratory, Office of Research and Development, US Environmental Protection Agency.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Tan
mesh_terms: D000328:Adult; D000367:Age Factors; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects*; D004785:Environmental Pollutants / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005260:Female; D005865:Gestational Age; D057166:High-Throughput Screening Assays; D006801:Humans; D007231:Infant, Newborn; D018811:Maternal Exposure / Q000009:adverse effects; D008954:Models, Biological; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D018570:Risk Assessment
chemical_list: D004785:Environmental Pollutants
keywords: AOPs; PBPK; developmental toxicology; environmental toxicology; life-stage