Cross-species comparisons of plasma binding and considerations for data evaluation

Area of Science:

• Environmental Science
• Toxicology
• Biochemistry

Background:

• The US Environmental Protection Agency (EPA) is adopting new approach methods (NAMs) for chemical safety assessments.
• In vitro methods like plasma binding assays are crucial for generating chemical-specific data.

Purpose of the Study:

• To present data from in vitro plasma binding experiments across human, rat, and rainbow trout.
• To evaluate the impact of physicochemical properties on chemical assay performance and facilitate cross-species comparisons.

Main Methods:

• Utilized rapid equilibrium dialysis (RED) with plasma from three species and 54 chemicals at two concentrations.
• Assessed data quality using mass balance controls for chemical stability and recovery.
• Analyzed correlations between fraction unbound in plasma (fup) and log K_ow.

Main Results:

• Generated 238 chemical-species specific datasets, with 92 (approx. 40%) yielding quantitative measurements.
• Observed higher unbound fractions (fup) in rat plasma compared to human plasma.
• Found lower fup values in trout plasma than in rat or human plasma.
• Identified the strongest correlation between fup and log K_ow for values between 1.5 and 4.

Conclusions:

• Chemicals with log K_ow > 4.5 are highly bound, difficult to measure, and show low reproducibility.
• Robust data quality assessment is essential due to variable assay performance.
• Methodologies may need to be adapted based on chemical physicochemical properties, particularly for highly bound substances.