“The dose makes the poison”: Key implications for mode of action (mechanistic) research in a 21st century toxicology paradigm

The concept of “the dose makes the poison” is a core organizing tenet of toxicology, and associated investigations of mode of action (MoA) are a key means by which toxicity test data are translated to robust evidence-based human health risk assessments. As such, toxicology is responsible for providing the science and leadership assuring that dose considerations are fully integrated into design and interpretation of toxicity testing and MoA datasets. Such considerations are likely to impact MoA research in that many such investigations are not justified, if at all, when toxicity is noted only under conditions of excessively high-dose testing that is not quantitatively relevant to human risk, e.g., test dose(s) above onset of nonlinear ADME behavior; in vitro test concentrations not biologically attainable in vivo. Toxicology must also challenge continued use of the Linear-No-Threshold (LNT) hypothesis as a biologically-valid dose-response model for cancer risk assessment in that decades of modern biology has increasingly exposed its flawed fundamental assumption that biology has no compensatory homeostatic mechanisms protecting against low exposures. Thus, expanded attention to “dose” is essential in order for toxicology to fulfill its promise as a credible 21st century science protecting public health in an increasingly chemical technology-dependent world.