Establishing the relevance of endocrine-disrupting effects for nontarget vertebrate populations

European Commission (EC) criteria to identify the endocrine-disrupting properties of plant protection products (PPPs) have been developed in a regulation for application across the European Union (EU) beginning 10 November 2018 (EC 2018), with implementation of this regulation supported by an accompanying guidance document (ECHA/EFSA 2018). The endocrine assessment required for PPPs under this regulation is hazard based rather than risk based, but there are inherent challenges in such hazard-based regulations (Nordlander et al. 2010). For example, 1) safe products may be restricted (because humans or animals may never be exposed to doses that cause adverse effects), 2) beneficial products may be restricted with consequent loss of consumer benefits, 3) restrictions on the use of one product may lead to increased use of another product with equal or greater risks, and 4) product stigmatization and loss of incentives to innovate may occur. These statements contradict the PPP regulation clauses that a substance should be considered to have endocrine-disrupting properties “unless there is evidence demonstrating that the adverse effects identified are not relevant at the (sub)population level for non-target organisms,” and that “adequate, reliable and representative field or monitoring data and/or results from population models shall as well be considered where available” [EC 2018]. This inconsistency between regulation and guidance threatens to make it difficult to disprove the relevance of endocrine effects on nontarget wildlife vertebrate populations because of an apparent reliance on a hazard assessment approach in which any indication of an endocrine-mediated individual adverse effect in any laboratory test is considered to indicate that a PPP is an endocrine disruptor with wildlife population relevance. This excludes any consideration of population relevance based on modeling or field data, which is clearly not the intention of the regulation. Participants at a recent SETAC Pellston Workshop® on Endocrine-Active Substances (Matthiessen et al. 2017) suggested that regulation of endocrine-disrupting chemicals based on hazard alone may be partly driven by a perception that there is no toxic threshold for these substances. The workshop concluded that 1) it is impossible to prove that toxic thresholds do not exist, 2) a viable physiological basis for no thresholds has not been clearly identified, and 3) there is no evidence that no-threshold effects apply to populations. Workshop participants determined that thresholds of toxicity existed for all 6 data-rich case study substances examined, and that theoretical considerations suggested that endocrine systems could not actually function if such thresholds were absent. Agreement on scientifically defensible methods to assess adverse population effects of PPPs in the context of endocrine-disrupting activity is urgently required. In an associated paper (Crane et al. this issue), we propose a practical and scientifically robust way to bridge the gap between the guidance and the legal requirements of the regulation. The approach maintains the hazard-based intent of the PPPs regulation and introduces the necessary steps between demonstration of individual adverse endocrine effects in laboratory organisms and demonstration of adverse effects on wildlife populations. We hope that this proposal initiates a debate among relevant stakeholders to establish scientifically sound regulatory solutions to resolve the inconsistency between the legally mandated regulation (EC 2018), the supporting guidance document (ECHA/EFSA 2018), and the intent of science-based regulation in the EU.