November 17, 2022 by Grace Panter

Last week I presented at the Fresenius Endocrine Disruptor (ED) conference in Cologne. It was a hybrid meeting, with as many people attending virtually, as in person. Some of the meeting highlights are detailed below (discussions on the thyroid have been summarised separately here):

1. Regulatory Landscape:

The regulatory landscape has and is about to go through some notable changes. New ED hazard categories have been proposed under REACH (Regulation on the Registration, Evaluation, Authorisation and Restriction of Chemicals) and CLP (Classification, Labelling and Packaging). Substances classed as “Category 1” will be known or presumed EDs, and those classed as “Category 2” will be suspected EDs. It is very likely that additional testing will be required under these proposed changes. Entry into force could be as early as May 2023.

European Food Safety Authority (EFSA) are currently developing an adverse outcome pathway (AOP) framework for EDs that portray existing knowledge concerning the linkage between direct molecular initiating events and an adverse outcome. Such a tool should help to strengthen the regulatory ED assessment. The Federal Institute for Risk Assessment, Germany (BfR) have so far evaluated over 100 active substances as biocidal products/plant protection products for endocrine disruption. Most findings have been inconclusive and require more data, underlining the importance of good data documentation, clear approaches in the ED assessment strategy and a need to increase our understanding of endocrine-mediated mechanisms of action (i.e, AOPs).

The UK will continue to follow the EFSA/ECHA (European Chemical Agency) guidance for ED assessments, but will make an independent assessment of the data which could result in different outcomes for the same substance. The US EPA gave a very detailed overview on using ToxCast and the CompTox chemicals dashboard as a resource for endocrine information. In the EU, the oestrogen receptor and not the androgen receptor bioactivity model score is accepted in ED assessments, despite performance matrices for both models being very similar. The bioactivity model score should also always be used over the individual assay findings for the equivalent modality. It is unlikely that such a model would be developed for the thyroid, as it would be too challenging.

Aside from the regulatory landscape there was an interesting presentation on low-dose non-monotonic effects and their lack of reproducibility in guideline studies. Despite this lack of reproducibility, such effects have the potential to influence and guide regulatory decisions.

2. wca at Fresenius:

wca have been involved in two projects which were presented at the meeting. The first was an overview of results from a recent UK’s National Centre for the 3Rs (NC3Rs) survey which gathered information on the measurement and analysis of vitellogenin (VTG) in fish studies. Reliable and robust measurements of VTG are required to support decision-makers in the regulation of chemicals for their environmental endocrine activity. Consequences of an equivocal VTG result include the need for additional fish testing in higher tier tests to refute or confirm a result, and in a regulatory context this could potentially lead to not identifying a substance with ED properties or conversely the removal or severe restriction of a substance from the market. The survey confirmed that there were areas around sample collection and storage, VTG quantification, and data handling which could potentially be harmonised to improve the robustness, reliability and reporting of VTG measurements. For more information please contact Becky Brown.

The second presentation was on the robustness of the fish short-term reproduction assay (FSTRA) to detect anti-androgens. A systematic review was conducted to assess the sensitivity of fish and fish test guidelines to detect anti-androgenic mechanisms of action. A comprehensive review of existing evidence, including conservation of the androgen receptor, data from fish in vitro and in vivo studies was undertaken. Findings found that the FSTRA did not underperform compared to other standard test guidelines, but assays employing co-exposure to an androgen appeared to be more suitable to detect anti-androgenic substances. For more information please contact Grace Panter.

wca provide a study monitoring service for endocrine studies and can prepare weight of evidence risk assessments (ecotoxicology and toxicology). If you would like more information on our services in this area, please contact Grace Panter, Becky Brown or Owen Green.