A novel method for combining outcomes with different severities or gene-level classifications.

Abstract

Chemical risk assessment is currently based on consideration of health effects individually. The present work discusses a method for combining data by characterizing the dose-related sequence of the development of lower- to higher-order toxicological effects or the range of bioactivity observed at genomic level caused by a chemical/mixture. A reference point profile (RPP) is defined as the relation between benchmark doses for considered effects (or bioactivity measures) and a standardized severity or rank score determined for these effects. For a given dose of a chemical/mixture, the probability for exceeding the RPP can be assessed. An overall toxicological response can also be derived at the same dose by integrating contributions across all effects, with a rational for severity weighing. Conversely, dose equivalents corresponding to specified responses can be estimated. The variation in RPPs across chemicals suggests that joint consideration of effects under the proposed concept differentiates the consequence of chemical exposure, both at genomic and apical levels, to a higher extent compared to using a specific effect as a basis. This may help to refine the development of points of departure or sets of such values describing a range of health concerns. Analysis and comparison of apical and genomic RPPs, as well as consideration of functional relations between gene sets within such analyses, may aid in the transition towards a new approach method-based risk assessment paradigm that to a higher degree may require methods for combination of effect data compared to relying on specific outcomes.