A pragmatic framework for the application of new approach methodologies in one health toxicological risk assessment

Globally, industries and regulatory authorities are faced with an urgent need to assess the potential adverse effects of chemicals more efficiently by embracing new approach methodologies (NAMs). NAMs include cell and tissue methods (in vitro), structure-based/toxicokinetic models (in silico), methods that assess toxicant interactions with biological macromolecules (in chemico), and alternative models. Increasing knowledge on chemical toxicokinetics (what the body does with chemicals) and toxicodynamics (what the chemicals do with the body) obtained from in silico and in vitro systems continues to provide opportunities for modernizing chemical risk assessments. However, directly leveraging in vitro and in silico data for derivation of human health-based reference values has not received regulatory acceptance due to uncertainties in extrapolating NAM results to human populations, including metabolism, complex biological pathways, multiple exposures, interindividual susceptibility and vulnerable populations. The objective of this article is to provide a standardized pragmatic framework that applies integrated approaches with a focus on quantitative in vitro to in vivo extrapolation (QIVIVE) to extrapolate in vitro cellular exposures to human equivalent doses from which human reference values can be derived. The proposed framework intends to systematically account for the complexities in extrapolation and data interpretation to support sound human health safety decisions in diverse industrial sectors (food systems, cosmetics, industrial chemicals, pharmaceuticals etc.). Case studies of chemical entities, using new and existing data, are presented to demonstrate the utility of the proposed framework while highlighting potential sources of human population bias and uncertainty, and the importance of Good Method and Reporting Practices.