title: Integration of dosimetry, exposure, and high-throughput screening data in chemical toxicity assessment.
abstract: High-throughput in vitro toxicity screening can provide an efficient way to identify potential biological targets for chemicals. However, relying on nominal assay concentrations may misrepresent potential in vivo effects of these chemicals due to differences in bioavailability, clearance, and exposure. Hepatic metabolic clearance and plasma protein binding were experimentally measured for 239 ToxCast Phase I chemicals. The experimental data were used in a population-based in vitro-to-in vivo extrapolation model to estimate the daily human oral dose, called the oral equivalent dose, necessary to produce steady-state in vivo blood concentrations equivalent to in vitro AC(50) (concentration at 50% of maximum activity) or lowest effective concentration values across more than 500 in vitro assays. The estimated steady-state oral equivalent doses associated with the in vitro assays were compared with chronic aggregate human oral exposure estimates to assess whether in vitro bioactivity would be expected at the dose-equivalent level of human exposure. A total of 18 (9.9%) chemicals for which human oral exposure estimates were available had oral equivalent doses at levels equal to or less than the highest estimated U.S. population exposures. Ranking the chemicals by nominal assay concentrations would have resulted in different chemicals being prioritized. The in vitro assay endpoints with oral equivalent doses lower than the human exposure estimates included cell growth kinetics, cytokine and cytochrome P450 expression, and cytochrome P450 inhibition. The incorporation of dosimetry and exposure provide necessary context for interpretation of in vitro toxicity screening data and are important considerations in determining chemical testing priorities.
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709-2137, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Wetmore
authors.forename: John F
authors.initials: JF
authors.lastname: Wambaugh
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Ferguson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sochaski
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rotroff
authors.forename: Kimberly
authors.initials: K
authors.lastname: Freeman
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.forename: Brittany
authors.initials: B
authors.lastname: Allen
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
authors.forename: Reetu
authors.initials: R
authors.lastname: Singh
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kavlock
authors.forename: Ann M
authors.initials: AM
authors.lastname: Richard
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010539:Permeability; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods* / Q000706:statistics & numerical data
chemical_list: D001798:Blood Proteins; D054852:Small Molecule Libraries