Prior ECETOC work related to endocrine disruptors

In recognition of the Commission’s activities for the establishment of a legislative-based strategy for endocrine disruption, the ECETOC has been proactively engaged in developing guidance to implement regulatory actions for endocrine disrupting substances. The first European industry task force (named Environmental Oestrogens) to address endocrine disruption was formed by ECETOC in 1995. In 2009, ECETOC published a Technical Report (TR) Guidance on identifying endocrine disrupting effects (ECETOC, 2009a) that addressed comments provided at a Workshop Guidance on interpreting endocrine disrupting effects that took place on 29-30 June 2009, in Barcelona, Spain (ECETOC, 2009b). Specific scientific criteria for the determination of endocrine disrupting properties that integrate information from both regulatory toxicity and ecotoxicity studies and mechanistic/screening studies were proposed. These scientific criteria rely on the nature of the adverse effects detected in the studies that give concern for endocrine toxicity and the description/understanding of the MoA of toxicity which scientifically support and explain the adverse effects. Importantly, the TR (ECETOC, 2009a) and the follow up publications Bars et al. (2011, 2012) provided guidance, in the form of flow charts that could be used as decision trees for the identification of endocrine disrupting effects in human health and environmental hazard assessments.

As further explored in ECETOC (2009b), ecotoxicity test methods typically focus on measuring impacts on development, growth and reproduction, which often give limited insight into the toxicological MoA that leads to the adverse effect. Environmental hazard assessment also differs from human health hazard assessment in that the protection goal is at the population rather than the individual (human) level. Beyond this, environmental hazard assessment has to consider many species over different taxonomic groups. Oftentimes, the data that are available from mammalian toxicity studies drive the cause for concern for endocrine disruption and trigger further investigation in environmental species.

Since all substances having endocrine disrupting properties may not represent the same hazard, ECETOC (2009a) and Bars et al. (2011, 2012) propose specific criteria for potency to assess the level of hazard resulting from endocrine toxicity and to discriminate substances of high concern from those of lower concern. These criteria should be considered collectively, using a WoE approach, to determine the potency of the substance as an endocrine disruptor:

• The dose level at which adverse effects on endocrine endpoints occur.
• The duration of exposure that is required for an adverse effect to be induced.
• The nature, incidence and severity of the adverse effects.
• The number of animal species from regulatory toxicity studies showing adverse endocrine effects.

Another option to quantify the potency of a substance is to compare its effect thresholds with those of a reference substance. The reference substance would be assigned a potency of 1 and the test substance is normalized by dividing the (no) effect concentration of the reference substance by the (no) effect concentration of the test substance (Weltje et al., 2013).

In 2011, the discussion on best practices for the risk assessment of endocrine disrupting substances was further advanced at an ECETOC workshop Risk assessment of endocrine disrupting chemicals (ECETOC, 2011). There was agreement that the hazard and risk assessment of endocrine disruptors would require a consistent WoE approach, which would be applicable under various regulatory regimes. For human health hazard assessment, the systematic and structured approach of the WHO/IPCS framework for evaluating the MoA for cancer and non-cancer endpoints (Sonich-Mullin et al., 2001; Boobis et al., 2006, 2008, 2009; Fenner-Crisp and Dellarco, 2016) was suggested as practicable means to evaluate available mechanistic and apical information (ECETOC, 2011). For ecotoxicological assessment, it was acknowledged that no direct equivalent to this WHO/IPCS framework existed. However, several specific WoE frameworks for the evaluation of endocrine disrupting effects had been published. These should be evaluated and combined for the requirements under current legislation. Specific guidance was considered necessary to aid in the identification of endpoints in ecotoxicological studies that were of population relevance. Some endpoints are clearly directly population related, whereas others are more diagnostic in nature and do not necessarily lead to an adverse population-relevant effect(s). As a follow-up to these ECETOC workshops, the flow charts originally published in ECETOC (2009a) were further refined as described and presented in Bars et al. (2011, 2012); Lewis (2013) and Weltje et al. (2013).

Finally, in 2016, ECETOC published a TR Guidance on assessment and application of AOPs relevant to the endocrine system (ECETOC, 2016). AOPs can help identify if an observed adverse outcome can be plausibly linked to an endocrine mechanism, which is a key requirement for identification of a substance is an endocrine disruptor according to the WHO/IPCS (2002) definition. AOPs could also potentially be used to help predict the potential for an adverse outcome in vivo based on the results of in vitro mechanistic data. If AOPs are to be used to identify endocrine disrupting properties, it must be ensured that they are sufficiently robust and fit for purpose. To this end, the TR (ECETOC, 2016) provides guidance on identifying the basic requirements of a defined AOP and how to establish the minimum scientific standards that allow the use of AOPs in different contexts, such as hazard identification, read-across and risk assessment (ECETOC, 2016).