Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).
In three different frog species (Xenopus laevis (Pipidae) Bufo(tes) viridis(Bufonidae) and Hyla arborea (Hylidae)) exposed to three environmentally and/or physiologically relevant concentrations of Trenbolone (0.027 µg/L (10−10 M), 0.27 µg/L (10−9 M), 2.7 µg/L (10−8 M)) sex reversals nor masculinization of gonads was observed. Exposure only caused negative species-specific impacts on gonad morphology and differentiation after the completion of metamorphosis, independently of genetic sex. (Rozenblut-Kościsty et al., 2019).