Emerging concepts and opportunities for endocrine disruptor screening of the non-EATS modalities

Endocrine Disrupting Chemicals’ Effects in Children: What We Know and What We Need to Learn?

“…In recent years, EDCs that disrupt through non-EATS modalities have garnered significant interest from regulators and industry. Non-EATS pathways include retinoic acid, peroxisome proliferator-activated receptors (PPARs), GR signaling, insulin (INS) receptor signaling, gastrointestinal hormones, and cardiovascular-related hormones [ 56 ]. The development of new test methods to screen chemicals that can potentially alter these hormone signaling pathways is a challenge.…”

Using alternative test methods to predict endocrine disruption and reproductive adverse outcomes: do we have enough knowledge?

“…Another prevailing challenge with predicting in vivo effect outcomes caused by EDCs is the potential involvement of non-EATS modalities in the induction of ED effects. This potential gap in knowledge and test assays was highlighted by the OECD already a decade ago (OECD, 2012) and recently reiterated in the context of developing robust testing strategies with stronger reliance on alternative test methods (Martyniuk et al, 2021). But despite this, our understanding of how non-EATS modalities may contribute remains very limited, not least regarding chemical substances evaluated under current EDC guidance document, as for instance those regulated under the European Union's REACH regulation.…”

“…The retinoid signaling pathway has received increased attention within chemical risk assessment and regulation in recent years, with emerging evidence suggesting the pathway to be vulnerable to endocrine disruptors and a likely contributor to human endocrine disorders (Grignard et al, 2020;Knudsen et al, 2020;Martyniuk et al, 2021;OECD, 2012). Retinoid signaling is essential for normal development and is involved in numerous processes from axial patterning to organogenesis and reproductive development.…”

“…Currently, the most common modes-of-action that are considered when assessing whether a chemical has endocrine disrupting (ED) properties are estrogen, androgen, thyroid, and steroidogenesis, so-called EATS modalities (EFSA/ECHA et al, 2018;Kucheryavenko et al, 2020). It is recognized that disruption to other, non-EATS, modalities can cause adverse effects by an endocrine mode-of-action (EFSA/ECHA et al, 2018;Grignard et al, 2020;Martyniuk et al, 2021); however, the EATS modalities are the pathways for which we have the best mechanistic and causal knowledge with respect to adverse outcomes caused by endocrine disruption. They are also the modalities, or pathways, for which we have some standardized test guidelines for in vitro and in vivo testing (EFSA/ECHA et al, 2018).…”

Azole Fungicides and Their Endocrine Disrupting Properties: Perspectives on Sex Hormone-Dependent Reproductive Development

“…When assessing the endocrine disrupting potential of chemicals it is common to primarily consider the classic estrogenic, androgenic, thyroid, and steroidogenic modalities. This does not exclude that other modalities could be relevant for endocrine disruption, however, and many other signaling pathways have been highlighted as important to consider in this context ( Martyniuk et al, 2022 ). Our knowledge remains limited when considering the extent to which other mechanisms relevant for endocrine disruption can cause adverse health effects, but with respect to azole fungicides several alternative signaling pathways may be relevant.…”