The project

The translation of subtle functional deficits within individuals into population-level effects is identified as a main challenge for the hazard and risk assessment of endocrine disruptor (ED) compounds in fish. Data collected at the different biological levels of organization could be integrated into a pathway-based toxicological framework (AOP) using a modelling approach. This implies establishing and modelling functional and quantitative links between a molecular initiating event and population-level effects, with the final goal of supporting regulatory decision-making regarding EDs. One of the mechanisms of action of endocrine disruption often studied is the disruption of the gonadal cytochrome P450 aromatase because of its involvement in the reproductive process. The experimental data and mechanistic models already available at INERIS for the zebrafish could support the development and/or improvement of quantitative AOP for EDs leading to a decrease in the fecundity, mediated by an inhibition of aromatase A or by other molecular initiating events.

The objective of the project will therefore be the development and improvement of multi-scale models of toxicity pathways enabling to more accurate predictions of ED impacts on the populations. To accomplish this, three objectives will be targeted:

• Enhance the previously published aromatase A qAOP using the mathematical models available at Ineris for ZF (Pery et al., 2014; Beaudouin et al., 2015), the toxicological data produced in the AIDEZ project, and by generating new data on steroid hormone dynamics.

• Integrate into this qAOP another toxicity pathway for EDCs leading to decreased fecundity in zebrafish.

• Use this qAOP, as well as all the data produced, in a regulatory context in order to demonstrate the interest in the implementation of the ECHA/EFSA guide for the identification of PE properties.