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

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 to 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.