Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

TitleEvolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance
Publication TypeJournal Article
Year of Publication2017
AuthorsBhat V.S, Meek M.EB, Valcke M., English C., Boobis A., Brown R.
JournalCrit Rev Toxicol
Volume47
Pagination729-749
Date PublishedOct
ISBN Number1040-8444
Accession Number28681680
KeywordsChemical Safety/*legislation & jurisprudence/*trends, Chemical-specific adjustment factor, human variability, Humans, International Cooperation, interspecies extrapolation, physiologically based pharmacokinetic modeling, Research/standards/trends, Risk Assessment/*trends, toxicodynamics, toxicokinetics, uncertainty, uncertainty factor, United States, United States Environmental Protection Agency, World Health Organization
Abstract

The application of chemical-specific toxicokinetic or toxicodynamic data to address interspecies differences and human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared with the use of traditional default or categorically-based uncertainty factors. The present review summarizes the state-of-the-science since the introduction of the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) guidance on chemical-specific adjustment factors (CSAF) in 2005 and the availability of recent applicable guidance including the WHO/IPCS guidance on physiologically-based pharmacokinetic (PBPK) modeling in 2010 as well as the U.S. EPA guidance on data-derived extrapolation factors in 2014. A summary of lessons learned from an analysis of more than 100 case studies from global regulators or published literature illustrates the utility and evolution of CSAF in regulatory decisions. Challenges in CSAF development related to the adequacy of, or confidence in, the supporting data, including verification or validation of PBPK models. The analysis also identified issues related to adequacy of CSAF documentation, such as inconsistent terminology and often limited and/or inconsistent reporting, of both supporting data and/or risk assessment context. Based on this analysis, recommendations for standardized terminology, documentation and relevant interdisciplinary research and engagement are included to facilitate the continuing evolution of CSAF development and guidance.

Short TitleCrit. Rev. Toxicol.Crit. Rev. Toxicol.
Alternate JournalCritical reviews in toxicology