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

Area of Science:

• Toxicology
• Environmental Health
• Pharmacology

Background:

• Chemical risk assessment commonly uses a default uncertainty factor (UF) of 3.16 to account for human toxicodynamic (TD) variability.
• Refining this UF requires robust empirical data on human TD variability, separated from toxicokinetic (TK) influences.

Purpose of the Study:

• To systematically map the evidence on human TD variability.
• To assess the feasibility of refining the default UF of 3.16 for TD variability.

Main Methods:

• A systematic evidence map (SEM) was created by searching PubMed and Web of Science from 2004 to 2023.
• Inclusion criteria focused on studies where TD variability could be quantitatively isolated from TK.
• 2408 studies were retrieved, with 23 in vitro studies meeting criteria for assessing human TD variability, and only seven providing quantitative TD variability factors (TDVFs).

Main Results:

• No in vivo studies met the inclusion criteria.
• The 23 in vitro studies revealed heterogeneous data and varied methodologies, complicating comparisons.
• Seven studies provided quantitative TDVFs, with some suggesting the default UF of 3.16 may not adequately cover human variability, while others indicated it might.

Conclusions:

• There is a significant scarcity of empirical data for assessing human TD variability, especially data that excludes TK influences.
• The heterogeneity and methodological differences in existing studies hinder the refinement of the default UF.
• A standardized approach for determining TDVFs is identified as crucial for future assessments.