The PrecisionTox Chemical Library: Creation of a Chemical Collection to Discover Evolutionary Conserved Biomolecular Signatures of Toxicity

The large number and diversity of chemicals currently in use present significant challenges in assessing their human and environmental health risks due to a paucity of toxicological data. To address this shortage, high-throughput screening technologies are used to rapidly evaluate the toxicity of these chemicals. Suitable chemical libraries are crucial to evaluate the performance of these technologies and generate the cognate toxicity data. Unlike traditional chemical libraries designed for specific disease targets or receptor interactions, the PrecisionTox collection prioritizes diversity in targets and mechanisms of toxicity to ensure broad applicability in toxicity predictions to test the concept of phylotoxicology. Phylotoxicology proposes that mechanisms of toxicity are evolutionary conserved among distantly related species. Furthermore, the application of phylotoxicology can contribute to the reduction of mammalian species in toxicity testing. Here an approach for generating a chemical library based on chemical properties; physicochemical, biomolecular and toxicological; as well as practical considerations; including compound availability, cost, purity and shipping regulations is reported. From an initial pool of over 1,500 nominees, a set of 200 chemicals was selected based on multiple criteria, including organ toxicity, environmental exposure, structure, MoA and toxicological relevance. Additionally, information on baseline toxicity, Absorption, Distribution, Metabolism and Excretion (ADME) properties and utility for in vitro testing was collected. This work underscores the necessity of thoughtful chemical selection to refine toxicological models, improve hazard identification and support regulatory efforts to protect human and environmental health.