title: Incorporating new technologies into toxicity testing and risk assessment: moving from 21st century vision to a data-driven framework.
abstract: Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency.
authors: * The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709;
authors: Russell S
authors: RS
authors: Thomas
authors: Martin A
authors: MA
authors: Philbert
authors: Scott S
authors: SS
authors: Auerbach
authors: Barbara A
authors: BA
authors: Wetmore
authors: Michael J
authors: MJ
authors: Devito
authors: Ila
authors: I
authors: Cote
authors: J Craig
authors: JC
authors: Rowlands
authors: Maurice P
authors: MP
authors: Whelan
authors: Sean M
authors: SM
authors: Hays
authors: Melvin E
authors: ME
authors: Andersen
authors: M E Bette
authors: ME
authors: Meek
authors: Lawrence W
authors: LW
authors: Reiter
authors: Jason C
authors: JC
authors: Lambert
authors: Harvey J
authors: HJ
authors: Clewell
authors: Martin L
authors: ML
authors: Stephens
authors: Q Jay
authors: QJ
authors: Zhao
authors: Scott C
authors: SC
authors: Wesselkamper
authors: Lynn
authors: L
authors: Flowers
authors: Edward W
authors: EW
authors: Carney
authors: Timothy P
authors: TP
authors: Pastoor
authors: Dan D
authors: DD
authors: Petersen
authors: Carole L
authors: CL
authors: Yauk
authors: Andy
authors: A
authors: Nong
mesh_terms: D000826:Animal Testing Alternatives / Q000639:trends*; D000818:Animals; D057225:Data Mining / Q000639:trends*; D062126:Databases, Chemical / Q000639:trends*; D062313:Databases, Pharmaceutical / Q000639:trends*; D004305:Dose-Response Relationship, Drug; D005544:Forecasting; D057166:High-Throughput Screening Assays / Q000639:trends; D006801:Humans; D023421:Models, Animal; D008954:Models, Biological; D009152:Mutagenicity Tests / Q000639:trends; D010599:Pharmacokinetics; D018570:Risk Assessment; D012307:Risk Factors; D018675:Toxicity Tests / Q000639:trends*
keywords: biotransformation and toxicokinetics; exposure.; in vitro and altenatives; predictive toxicology; risk assessment; safety evaluation
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