title: Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening.
abstract: Many chemicals in commerce today have undergone limited or no safety testing. To reduce the number of untested chemicals and prioritize limited testing resources, several governmental programs are using high-throughput in vitro screens for assessing chemical effects across multiple cellular pathways. In this study, metabolic clearance and plasma protein binding were experimentally measured for 35 ToxCast phase I chemicals. The experimental data were used to parameterize a population-based in vitro-to-in vivo extrapolation model for estimating the human oral equivalent dose necessary to produce a steady-state in vivo concentration equivalent to in vitro AC(50) (concentration at 50% of maximum activity) and LEC (lowest effective concentration) values from the ToxCast data. For 23 of the 35 chemicals, the range of oral equivalent doses for up to 398 ToxCast assays was compared with chronic aggregate human oral exposure estimates in order to assess whether significant in vitro bioactivity occurred within the range of maximum expected human oral exposure. Only 2 of the 35 chemicals, triclosan and pyrithiobac-sodium, had overlapping oral equivalent doses and estimated human oral exposures. Ranking by the potencies of the AC(50) and LEC values, these two chemicals would not have been at the top of a prioritization list. Integrating both dosimetry and human exposure information with the high-throughput toxicity screening efforts provides a better basis for making informed decisions on chemical testing priorities and regulatory attention. Importantly, these tools are necessary to move beyond hazard rankings to estimates of possible in vivo responses based on in vitro screens.
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rotroff
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Wetmore
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Ferguson
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.forename: Edward L
authors.initials: EL
authors.lastname: Lecluyse
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Smith
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sochaski
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kavlock
authors.forename: Frank
authors.initials: F
authors.lastname: Boellmann
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Martin
authors.forename: David M
authors.initials: DM
authors.lastname: Reif
authors.forename: John F
authors.initials: JF
authors.lastname: Wambaugh
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D011485:Protein Binding / Q000187:drug effects; D018570:Risk Assessment; D018675:Toxicity Tests; D015262:Xenobiotics / Q000145:classification / Q000378:metabolism / Q000633:toxicity*
chemical_list: D015262:Xenobiotics