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 lowerto higher-order toxicological effects, or the range of bioactivity observed at genomic level, caused by a chemical/mixture. A "reference point profile" 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 reference point profile 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 reference point profiles 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 development of points of departures or sets of such values describing a range of health concerns. Analysis and comparison of apical and genomic reference point profiles, as well as consideration of functional relations between gene-sets within such analyses, may aid in the transition towards a NAM-based risk assessment paradigm that to a higher degree may require methods for combination of effect data compared to relying on specific outcomes.

Guidance on the use of the benchmark dose approach in risk assessment

“…Whether or not various effects occur at similar doses might modulate the overall adversity associated with a BMD for a particular effect (Sand, 2021), and may thus potentially be relevant to consider in the process of selecting the BMR (for the critical effect). Ideally, the BMR is set numerically so that it reflects the onset of a human-relevant adverse effect, meaning that a response above the BMR is considered adverse.…”

“…For continuous data, the BMR should reflect the dose where an effect becomes adverse and, therefore, depends on the nature of the endpoint selected (including apical and non‐apical endpoints) and the relation to the BMD (also called relative deviations) is expressed as follow:Whether or not various effects occur at similar doses might modulate the overall adversity associated with a BMD for a particular effect (Sand, 2021), and may thus potentially be relevant to consider in the process of selecting the BMR (for the critical effect). Ideally, the BMR is set numerically so that it reflects the onset of a human‐relevant adverse effect, meaning that a response above the BMR is considered adverse.…”

Development of an Evidence-Based Risk Assessment Framework

“…The proposed method also appears to be robust with respect to minor and moderate changes in severity classification of BMDs. Further analyses indicate that the interpretation of effective doses or points of departures, based on individual health effects, may change when considering health effects jointly along the lines proposed (Sand, 2022). This influences the consideration of equipotent doses for different chemicals, and the concept of acceptable response levels for individual effects.…”

“…This influences the consideration of equipotent doses for different chemicals, and the concept of acceptable response levels for individual effects. Preliminary results to date suggest that estimation of exposure guidelines, or similar, by the proposed method may be sufficiently accurate and precise even if data for the most severe health effects, associated with the highest severity categories, are omitted (Sand, 2022). The method may therefore enable derivation of a surrogate for the probability of severe health effects, and/or the probability for exceeding corresponding BMDs, also in the case of using data on comparatively "mild" effects only.…”

“…The method may therefore enable derivation of a surrogate for the probability of severe health effects, and/or the probability for exceeding corresponding BMDs, also in the case of using data on comparatively "mild" effects only. Sand (2022) further extend the proposed concept to incorporate genomic dose-response information. A "genomic reference point profile", describing variability within and across affected gene-sets, is characterized by using an iterative method for combining all unique BMDs from a transcriptomic study.…”