Identifying human toxicodynamic variability: A systematic evidence map of the current knowledge

Regulatory Toxicology and Pharmacology, vol. 161, pp. 105842

Abstract

Current chemical risk assessment uses a default uncertainty factor (UF) of 3.16 for toxicodynamic (TD) variability in humans. The objective was to create a systematic evidence map (SEM) of the human variability in TD by identifying and organizing the available empirical data to assess if a further refinement of the default UF of 3.16 for TD can be achieved. PubMed and Web of Science™ were searched from 2004-2023. Studies were screened according to the eligibility criteria. Inclusion criteria included studies, where TD could be separated from toxicokinetics (TK) to exclude an impact of TK on TD variability. The literature search retrieved 2408 studies. Manual screening identified 23 in vitro studies assessing human TD variability quantitively, of which only seven in vitro studies provided quantitative estimates of a TD variability factor. No in vivo study met the inclusion criteria. Several studies found TD UF of 3.16 not covering human variability; others did. However, the data were heterogeneous, and variability in Points of Departure (PODs) and methods used to estimate TD variability complicated comparisons across studies. A standardized approach for TDVFs determination is identified . This SEM underscores the scarcity of data assessing human variability in TD, while omitting the influence of TK. • Limited data reporting quantitively on human TD variability without impact from TK • Only seven out of 23 eligible publications derived human TDVF (or similar value) • Some studies found default TD UF of 3.16 covered human variability; others didn't • Comparing derived TDVFs with default TD UF is difficult due to data heterogeneity • A need for a common method for determining TDVFs was identified

Authors 10

1. Annika Boye Petersen corresponding

   Technical University of Denmark

   Affiliation as printed

   National Food Institute, Technical University of Denmark (DTU), 2800, Lyngby, Denmark. Electronic address: abope@food.dtu.dk

2. Lea Bredsdorff

   Technical University of Denmark

   Affiliation as printed

   National Food Institute, Technical University of Denmark (DTU), 2800, Lyngby, Denmark

3. Marije Niemeijer Aachen Division of Cell Systems and Drug Safety

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, LACDR, Leiden University, 2333 CC, Leiden, the Netherlands

4. George E.N. Kass

   European Food Safety Authority

   Affiliation as printed

   European Food Safety Authority, 43126, Parma, Italy

5. Aiste Vitkauskaite

   Ollscoil na Gaillimhe – University of Galway

   Affiliation as printed

   School of Natural Sciences, University of Galway, Galway, H91 TK33, Ireland

6. Matthijs Moerland Aachen Centre for Human Drug Research (CHDR)

   Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research, 2333 CL, Leiden, the Netherlands

7. Frédéric Y. Bois
   Affiliation as printed

   Certara France S.A.R.L., 92200, Neuilly-sur-Seine, France

8. Nadia Quignot
   Affiliation as printed

   Certara France S.A.R.L., 92200, Neuilly-sur-Seine, France

9. Bob van de Water Aachen Division of Cell Systems and Drug Safety

   Leiden University

   Affiliation as printed

   Division of Cell Systems and Drug Safety, LACDR, Leiden University, 2333 CC, Leiden, the Netherlands

10. Susanne Hougaard Bennekou

    Technical University of Denmark

    Affiliation as printed

    National Food Institute, Technical University of Denmark (DTU), 2800, Lyngby, Denmark