October 20, 2017 by Olivia Tran
Olivia Tran attended the 3rd International Conference on Endocrine Disruptors (ED) held on the 16th and 17th October in Berlin. There were about 50 participants from regulatory agencies, industry and consultancies from the EU and USA. Fifteen talks were held over the 2 days and a general overview of the discussion points is presented below.
ED criteria for the Plant Protection Products Regulation (PPPR) and Biocidal Products Regulation (BPR): The ED criteria for pesticides were recently rejected (4th October) by the European Parliament (EP) based on legal issues, rather than technical issues. Particularly, the proposed exemption for substances designed to affect the endocrine system exceeded the scope of the mandate. There is some indication that the criteria (which do not include the exemption) will be accepted for biocides, which will be voted on later this month. The criteria will come into force 6 months after adoption by the EP (as soon as mid-2018 for biocides) and it will affect any new and ongoing applications in the approval process. Although regulators have tried to align the criteria for pesticides and biocides, the pesticides criteria need to be reworked and the process and criteria may fall out of step. There are no timelines for the revised pesticides criteria, and regulators will wait for the vote on the biocides criteria before deciding what to do with the pesticides criteria. Guidance will need to be in place before the criteria are regulated against. EFSA, ECHA and JRC have been working on a guidance document on ED identification which has gone through 2 rounds of closed consultations, but will need a public consultation before it is finalised. As soon as the criteria are adopted, the draft guidance will be open for public consultation. The guidance will be focussed on the Estrogen, Androgen, Thyroid and Steroidogenesis (EATS) pathways, however both regulators and industry recognise that other endocrine pathways (e.g. involving the hypothalamus and pituitary glands or insect retinoid receptors) are important and will need to be considered as well.
Potency: The definition for an ED substance has 3 elements (endocrine mode of action (MoA), causality / correlation and adverse effects), in which the MoA is linked to the adverse effects based on “biological plausibility” (not “conclusive causality”). The mandate for the criteria is hazard identification, not hazard characterisation (i.e. how hazardous is it), therefore potency, which seen as a parameter for risk assessment, has been left out of the criteria. However, potency was revisited during the conference with regards to interaction, (i.e. how well will the ED substance interact with the endocrine system), which would support the assessment of “biological plausibility”. Most participants agreed that “mechanistic potency” is worth considering, however more research is required to evaluate substance activity in different species.
REACH: There are no criteria for ED identification in REACH and the legislation does not require it. ED substances applying for authorisation have two options: setting exposure limits or undertaking a socio-economic analysis (SEA). As ED effects may not necessarily manifest as a dose-response relationship, it is difficult to derive a PNEC/DNEL for the first option, therefore authorisation will likely require a SEA with an assessment of alternatives. For ED substances where a PNEC/DNEL can be derived, risk assessment is possible (and appropriate, as supported by the SETAC Pellston workshop). Some consultants and industry have said that ED evaluation in REACH works fine without criteria.
Testing methods: The OECD and EU (separately) are working on in vitro mechanistic methods, thyroid testing for mechanism and effects, and are considering monitoring endocrine biomarkers and integrating epigenetics into the OECD Conceptual Framework (CF) for ED testing. Industry were very critical of the OECD chronic ecotox test guidelines being poorly validated, expensive, a lack of experience in contract research organisations (CROs) in conducting these methods, and inconsistency and uncertainty around how the data will be received by regulators. However, regulators defended the science behind the OECD methods and called for more feedback and support from the industry to help validate the tests. A major issue in developing the ED test methods is funding. The US continue to develop computational tools for high throughput endocrine screening.
wca contributed to a number of ED work programmes presented in the conference, particularly the expert workshop on test methods for evaluating endocrine disrupters and the ECETOC Seven Steps for the Identification of Endocrine Disrupting Properties (ECETOC 7SI-ED) guidance document. Recently, our colleague Melanie Gross worked with the European Crop Protection Association (ECPA) to publish “Weight of evidence approaches for the identification of endocrine disrupting properties of chemicals: Review and recommendations for EU regulatory application” (Regulatory Toxicology and Pharmacology, 91 (2017) 20-28).
From our blog
October 25, 2017 by Dean Leverett
October 20, 2017 by Olivia Tran