Abstract
The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-species uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.
Highlights
Concentration of a chemical that, if present in the organism, can lead to adverse effects allows the transition from hazard identification to risk assessment for a realistic exposure scenario
adverse outcome pathway (AOP) are relevant for risk management since they are intended to cover all levels of biological organization, so that, once an AOP is established, risk can be assessed on the basis of the most relevant part of the pathway for different target-species and the most relevant exposure route
Considering the critical role of PK/PD in predictive toxicology, in this study we investigated the role played by internal exposure dynamics and chemical-specific properties in the development of quantitative AOPs (qAOPs)
Summary
Concentration of a chemical that, if present in the organism, can lead to adverse effects allows the transition from hazard identification (in vitro) to risk assessment (in vivo) for a realistic exposure scenario (e.g. daily chemical intake). In human health risk assessment many efforts have been allocated to the in vitro to in vivo extrapolation (IVIVE) of effect concentrations established using in vitro assays[2,7,8] In these cases, IVIVE is highly relevant to drive risk assessment since, in line with the precautionary principle, the risk of effects at levels of organization higher than those considered in the in vitro assay has very narrow limits of tolerance. In other cases a certain level of risk is accepted and the attention is focused instead on risk management In this context, the modulation of a molecular target (or pathway) does not automatically imply that the potential consequent effects will be adverse or adverse enough to be not tolerable. We propose that the explicit consideration of PK and PD during the development phase will enhance the predictive power of qAOPs and their transferability across chemicals and across species
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