title: Gaining acceptance for the use of in vitro toxicity assays and QIVIVE in regulatory risk assessment.
abstract: Testing strategies are anticipated to increasingly rely on in vitro data as a basis to characterize early steps or key events in toxicity at relevant dose levels in human tissues. Such strategies require quantitative in vitro to in vivo extrapolation to characterize dose-response as a basis for comparison with exposure to estimate risk. Current experience in the incorporation of mechanistic and in vitro data in risk assessment is considered here in the context of identified principles to increase the potential for timely acceptance of more progressive and tailored testing strategies by the regulatory community. These principles are outlined as transitioning in a familiar context, tiering to acquire experience and increase confidence, contextual knowledge transfer to facilitate interpretation and communication, coordination and development of expertise and continuing challenge. A proposed pragmatic tiered data driven framework which includes increasing reliance on in vitro data and quantitative in vitro to in vivo extrapolation is considered in the context of these principles. Based on this analysis, possible additional steps that might facilitate timely evolution and potentially, uptake are identified.
authors.affiliation: Chemical Risk Assessment, McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, University of Ottawa, Ottawa, ON K1H 8M5, Canada. Electronic address: bmeek@uottawa.ca.
authors.forename: M E Bette
authors.initials: ME
authors.lastname: Meek
authors.affiliation: United States Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH 45268, USA. Electronic address: lipscomb.john@epa.gov.
authors.forename: John C
authors.initials: JC
authors.lastname: Lipscomb
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D010599:Pharmacokinetics; D018570:Risk Assessment; D012307:Risk Factors; D049490:Systems Biology; D018675:Toxicity Tests / Q000379:methods*; D014116:Toxicology / Q000379:methods*
keywords: Dose–response; Extrapolation; In vitro; Mode of action; Risk assessment; Strategy; Tiered approach