“The Dose Makes the Poison”: Relevance of Paracelsus’s Principle for Modern Chemical Hazard Assessment with New Approach Methodologies

New approach methodologies (NAMs) including in vitro assays and in silico prediction methods that are based on mechanistic understanding of the pathways of toxicity have changed how we nowadays assess the hazard and risk of chemicals in commerce. Quantitative dose-response relationships obtained from NAMs are often dichotomized into categorical outcomes (toxic/nontoxic), introducing uncertainty and potential misclassification in hazard characterization because the applicability domain of NAMs is currently constrained to the medium-hydrophobicity segment of the chemical universe. Until physicochemical limitations to the testability of (super)hydrophobic chemicals are overcome and hydrophilic and charged chemicals are tested at higher doses than is present practice, "no response" should not be equated with an absence of toxicity. Toxicity is not categorical─it is the dose that makes the poison. Data gaps for difficult-to-test chemicals can be filled with baseline toxicity predictions. Baseline toxicity is the minimum toxicity, but it is often a robust predictor. Persistence constitutes a hazard criterion in its own right. Combining persistence with toxicity into a "persistent toxicity" metric may provide a more integrative indicator of the hazard potential. Persistent toxicity indicators measured with NAMs could play a pivotal role in comparative hazard assessment for substitution chemicals and the development of safe and sustainable by design (SSbD) chemicals.