Making the Case for Quantum Mechanics in Predictive Toxicology─Nearly 100 Years Too Late?

The use of quantum mechanics (QM) has long been the norm to study covalent-binding phenomena in chemistry and biochemistry. The pharmaceutical industry leverages QM models explicitly in covalent drug discovery and implicitly to characterize short-range interactions in noncovalent binding. Predictive toxicology has resisted widespread adoption of QM, including in the pharmaceutical industry, despite its obvious relevance to the metabolic processes in the upstream of adverse outcome pathways and advances in both QM methods and computational resources, which support fit-for-purpose applications in reasonable timeframes. Here, we make the case for embracing QM as an indispensable part of a toxicologist’s toolkit. We argue that QM provides the necessary orthogonality to alert-based expert systems and traditional QSARs, consistent with calls for animal-free integrated testing strategies for safety assessments of commercial chemicals. We outline existing roadblocks to this transition, including the need to train model developers in QM and the shift toward service-based toxicity models that utilize high-performance computing clusters. Lastly, we describe recent examples of successful implementations of QM in hazard assessments and propose how in silico toxicology can be further advanced by integrating QM with artificial intelligence.