ToxBase: A Multidimensional ToxCast Reference Database for High-Throughput Human Exposome Analysis

Area of Science:

• Environmental chemistry
• Analytical chemistry
• Toxicology

Background:

• High-resolution mass spectrometry (HRMS) is vital for human exposome research, but lacks standardized reference data for chemical identification.
• Scarcity of collision cross-section (CCS) and MS/MS fragmentation data impedes accurate structural annotation of chemical exposures.

Purpose of the Study:

• To develop ToxBase, a comprehensive multidimensional reference database for chemical exposure agents.
• To facilitate high-confidence structural annotation and standardization in human exposome research.

Main Methods:

• Generated a multidimensional database (m/z, retention time, CCS, MS/MS) for over 2,000 chemicals using high-throughput liquid chromatography-ion mobility-tandem mass spectrometry (LC-IM-MS/MS).
• Assembled a high-quality MS/MS reference library using targeted data-dependent acquisition and a novel data extraction algorithm (DDARawProcessor).
• Validated ToxBase using human plasma, urine, and fecal samples.

Main Results:

• ToxBase contains 3,598 precursor ions for 2,075 compounds with high precision and cross-platform agreement.
• Application to human samples enabled rapid identification of 42 high-confidence (Level 1) chemical exposures.
• The database demonstrated excellent interday CCS precision (98.5% < 1% RSD).

Conclusions:

• ToxBase provides a valuable, freely available resource for standardized, large-scale exposome analysis.
• The database supports vendor-agnostic suspect screening workflows via compatibility with the open-source Skyline platform.
• ToxBase significantly advances confident structural annotation of chemical exposures in complex biological matrices.