title: Uncertainties in biological responses that influence hazard and risk approaches to the regulation of endocrine active substances.
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).
authors.affiliation: Environment and Climate Change Canada, Burlington, Ontario, Canada.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Parrott
authors.affiliation: Department of Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: Poul
authors.initials: P
authors.lastname: Bjerregaard
authors.affiliation: DuPont Crop Protection, Stine-Haskell Research Center, Newark, New Jersey, USA.
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Brugger
authors.affiliation: USEPA, Reproductive Toxicology Branch, Office of Research and Development, Research Triangle Park, North Carolina.
authors.forename: L Earl
authors.initials: LE
authors.lastname: Gray
authors.affiliation: Department of Bioenvironmental Research, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Japan.
authors.forename: Taisen
authors.initials: T
authors.lastname: Iguchi
authors.affiliation: University of Minnesota, Integrated Biosciences Graduate Program, Duluth, Minnesota, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Kadlec
authors.affiliation: BASF SE, Crop Protection-Ecotoxicology, Limburgerhof, Germany.
authors.forename: Lennart
authors.initials: L
authors.lastname: Weltje
authors.affiliation: Dow AgroSciences, Abingdon, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Wheeler
mesh_terms: D054750:Ecotoxicology; D052244:Endocrine Disruptors; D004784:Environmental Monitoring / Q000379:methods*; D004785:Environmental Pollutants; D018570:Risk Assessment / Q000379:methods
chemical_list: D052244:Endocrine Disruptors; D004785:Environmental Pollutants
keywords: Delayed effects; Endocrine; Multigenerational effects; Nonmonotonic dose-response