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

Arguably the most famous principle of toxicology is "The dose makes the poison" formulated by Paracelsus in the 16th century. Application of the Paracelsus's principle to mechanistic toxicology may be challenging as one compound may affect many molecular pathways at different doses with different and often nonlinear dose-response relationships. As a result, many mechanistic studies of environmental and occupational compounds use high doses of xenobiotics motivated by the need to see a clear signal indicating disruption of a particular molecular pathway. This approach ignores the possibility that the same xenobiotic may affect different molecular mechanism(s) at much lower doses relevant to human exposures. To amend mechanistic toxicology with a simple and concise guiding principle, I suggest recontextualization of Paracelsus's following its letter and spirit: "The dose disrupts the pathway". Justification of this statement includes observations that many environmental and occupational xenobiotics affect a broad range of molecular cascades, that most molecular pathways are sensitive to chemical exposures, and that different molecular pathways are sensitive to different doses of a chemical compound. I suggest that this statement may become a useful guidance and educational tool in a range of toxicological applications, including experimental design, comparative analysis of mechanistic hypotheses, evaluation of the quality of toxicological studies, and risk assessment.