February 2, 2017 by Louise Youngs
I recently attended the RSA Conference on the regulatory implications of ED assessment, which explored the relevance and reliability of available tools. The conference collated leading industry experts to present their view on the polarised and contentious issue of endocrine disruption. Chaired by Dr Steve Fairhurst (UK HSE), the first session outlined the regulatory implications of endocrine disruption. Professor Alan Boobis (Imperial College London) highlighted the illogicality of hazard based approaches, which may not be justifiable for many endpoints. Assessing chemicals on their potential, rather than their probability, to cause adverse effects was comically compared to encountering a shark in an aquarium versus at sea. Whilst the hazard may be the same, the probability of harm greatly differs. Using the Hypothalamus-Pituitary-Adrenocorticoid (HPA) axis as an example, the importance of defining causality by plausible and probable pathways was stressed - bridging the gap between in vitro and in vivo data.
Providing an overview of the SETAC Pellston Workshop, Professor Peter Matthiessen (independent consultant) compared the conventional approach adopted by the US and Japan, to the precautionary measures to EDs in the EU. Aiming to resolve the scientific disagreement regarding the reliability of predicted-no-effect-concentrations (PNEC) for Endocrine Disrupting Chemicals, the perception was considered as important as the reality. The overall conclusion was that if environmental exposure, effects on relevant taxa/life-stages, delayed effects and dose/concentration-response relationships are adequately characterised, then conducting environmental risk assessment of EDs is scientifically sound.
Providing a different perspective on hazard versus risk approaches, Christian Strupp (Adama) highlighted the potential economic disruption to trade and innovation. Whilst toxicological science should be evidence-based, it was suggested that public opinion and political will is currently guiding assessments and scientific convictions. Christian highlighted the importance of elucidating the presumed relevance of rodent data for human health prior to embarking on vertebrate studies which use thousands of animals (>2500 per active ingredient).
In Session 2, Dr Richard Green (Dow Agrosciences) and Dr Malgorzata Nepelska (Unilever, UK) discussed the use of Adverse Outcome Pathways (AOP) to elucidate endocrine modes of action. Quantification of the plausibility and probability of the Key Event Relationships (KER), believed to mediate adverse outcomes from molecular initiating events (MIE), is required. To elucidate the probability of causation, the relevance of MIE predicted in vitro to in vivo pathology must be considered. Outlining the OECD Conceptual Framework, Dr Jenny Odum (RSA) provided an overview of Guidance Document 150, highlighting that no single test is sufficient to evaluate ED, which requires a Weight of Evidence (WoE) approach.
Session 3 focused on the assessment of endocrine disruptors in the environment. Richard Murray-Smith (RSA) highlighted the need to “demystify” ED and consider exposure. Dr Lennart Weltje (BASF) provided a “reality check” on the possible involvement of azoles in masculinisation of wild fish. Azoles have been shown to inhibit the aromatase (CYP19) enzymes involved in steroid metabolism, presenting a plausible endocrine mode of action. However, azole concentrations in the environment are too low to induce masculinisation effects in fish. Further discussing the importance of potency to quantitatively evaluate the relevance of MIE and KER in disease outcomes, Dr James Wheeler (Dow Agrosciences) highlighted the need for better mechanistic understanding of both endocrine and non-endocrine toxicities. In two engaging and amusing presentations, Dr Stewart Owen and Professor Mark Cronin outlined current approaches to the Replacement, Reduction and Refinement of animal testing for endocrine disruption in Session 4. The potential for quantitative AOP and science based approaches to guide testing strategies were discussed.
During discussions, the panel reflected upon the wider society, raising concerns regarding the reliability, repeatability and retraction of science. Powerful, contemporary and innovative communication is needed. Ultimately, it was stated that “this is not about science, this is a chemophobic strategy” that aims to appease public opinion. The epistemological limitations in endocrine disruptor science were highlighted and concerns were raised regarding the applicability of AOP. It was also questioned whether there will be any chemicals that do not perturb the endocrine system, when our understanding of endocrine mode of actions extends beyond the Estrogen, Androgen, Thyroid and Steroidogenic (EATS) pathways. Further clarification on what constitutes an ED mode of action is required.