The dose disrupts the pathway: application of Paracelsus principle to mechanistic toxicology.

The article focuses on proposing a revised toxicological principle, "The dose disrupts the pathway," as an adaptation of Paracelsus's classical dictum "The dose makes the poison" for mechanistic molecular toxicology. It highlights that environmental and occupational xenobiotics can affect multiple molecular pathways at different doses, often with nonlinear dose-response relationships, complicating the direct application of the original principle. The new principle emphasizes that different molecular pathways have varying sensitivities to chemical exposures, and relevant toxicological studies should consider doses reflective of human exposures to accurately identify mechanisms of toxicity. This concept aims to guide experimental design, mechanistic hypothesis development, study evaluation, toxicological education, and risk assessment, particularly in the context of modern pathway-based and high-throughput testing methods.