Uncertainties in biological responses that influence hazard and risk approaches to the regulation of endocrine active substances
Authors: Parrott Joanne L , Bjerregaard Poul , Brugger Kristin E , Gray L Earl , Iguchi Taisen , Kadlec Sarah M , Weltje Lennart , Wheeler James R 
Published: November 2016

Abstract

Endocrine-disrupting substances (EDS) may have certain biological effects including delayed effects, multigenerational effects, and may display nonmonotonic dose–response (NMDR) relationships that require careful consideration when determining environmental hazards. Endocrine disrupting substances can have specific and profound effects when exposure occurs during sensitive windows of the life cycle (development, reproduction). This creates the potential for delayed effects that manifest when exposure has ceased, possibly in a different life stage. This potential underscores the need for testing in appropriate (sensitive) life stages and full life cycle designs. Such tests are available in the Organisation for Economic Co-operation and Development (OECD) tool box and should be used to derive endpoints that can be considered protective of all life stages. Similarly, the potential for effects to be manifest in subsequent generations (multigenerational effects) has also been raised as a potential issue in the derivation of appropriate endpoints for EDS. However, multigenerational studies showing increasing sensitivity of successive generations are uncommon. Indeed this is reflected in the design of new higher tier tests to assess endocrine active substances (EAS) that move to extended one-generation designs and away from multi-generational studies. The occurrence of NMDRs is also considered a limiting factor for reliable risk assessment of EDS. Evidence to date indicates NMDRs are more prevalent in in vitro and mechanistic data, not often translating to adverse apical endpoints that would be used in risk assessment. A series of steps to evaluate NMDRs in the context of endocrine hazard and risk assessment procedures is presented. If careful consideration of delayed, multigenerational effects and NMDRs is made, it is feasible to assess environmental endocrine hazards and derive robust apical endpoints for risk assessment procedures ensuring a high level of environmental protection. Integr Environ Assess Manag 2017;13:293–301. © 2016 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

Key Points
Endocrine-disrupting substances may have certain biological effects that require careful consideration when determining environmental hazards. Delayed and multigenerational effects underscore the need for testing in appropriate, sensitive life stages and full life cycle test designs. Nonmonotonic dose–responses should be evaluated for repeatability and plausibility and any impact on the reliability of thresholds needs to be considered. If any delayed and multigenerational effects and non monotonic dose–response relationships are addressed, it is scientifically feasible to assess environmental endocrine hazards and derive robust apical endpoints for risk assessment procedures, ensuring a high level of environmental protection.