title: A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals.
abstract: The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs.
  
  
  
  We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity.
  
  
  
  Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs.
  
  
  
  When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.
authors.affiliation: Department of Environmental Health Sciences, University of Massachusetts Amherst School of Public Health & Health Sciences, Amherst, MA, USA.
authors.forename: Laura N
authors.initials: LN
authors.lastname: Vandenberg
authors.affiliation: Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, Sweden.
authors.forename: Marlene
authors.initials: M
authors.lastname: Ågerstrand
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Beronius
authors.affiliation: ANSES (French Agency for Food, Environmental and Occupational Health Safety), Maisons Alfort, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Beausoleil
authors.affiliation: Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, Sweden.|Swedish Toxicology Sciences Research Center, Södertälje, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Bergman
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney, Australia.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Bero
authors.affiliation: Department of health sciences, Karlstad University, Karlstad, Sweden.|Icahn School of Medicine at Mount Sinai, New York City, USA.
authors.forename: Carl-Gustaf
authors.initials: CG
authors.lastname: Bornehag
authors.affiliation: Swedish Toxicology Sciences Research Center, Södertälje, Sweden.
authors.forename: C Scott
authors.initials: CS
authors.lastname: Boyer
authors.affiliation: US Environmental Protection Agency, Washington, DC, USA.
authors.forename: Glinda S
authors.initials: GS
authors.lastname: Cooper
authors.affiliation: Swedish Toxicology Sciences Research Center (Swetox), Karolinska Institutet, Södertälje, Sweden.
authors.forename: Ian
authors.initials: I
authors.lastname: Cotgreave
authors.affiliation: Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Gee
authors.affiliation: Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Philippe
authors.initials: P
authors.lastname: Grandjean
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Kathryn Z
authors.initials: KZ
authors.lastname: Guyton
authors.affiliation: National Food Institute, Technical University of Denmark, Søborg, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Hass
authors.affiliation: National Institute of Environmental Health Sciences, Division of Extramural Research and Training, Research Triangle Park, NC, USA.
authors.forename: Jerrold J
authors.initials: JJ
authors.lastname: Heindel
authors.affiliation: Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Jobling
authors.affiliation: Biology Department and Canadian Rivers Institute, University of New Brunswick, Saint John, New Brunswick, Canada.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Kidd
authors.affiliation: Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kortenkamp
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Scotland, UK.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Macleod
authors.affiliation: Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.
authors.forename: Olwenn V
authors.initials: OV
authors.lastname: Martin
authors.affiliation: Swedish Toxicology Sciences Research Center, Södertälje, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Norinder
authors.affiliation: Institute for Chemical and Bioengineering, ETH Zürich, Zürich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Scheringer
authors.affiliation: Department of Health and Human Services, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Thayer
authors.affiliation: University of Turku, Turku University Hospital, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Lancaster Environment Centre, Lancaster University, Lancaster, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Whaley
authors.affiliation: School of Medicine, Program on Reproductive Health and the Environment, University of California, San Francisco, Oakland, CA, USA.
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Woodruff
authors.affiliation: Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, Sweden. christina.ruden@aces.su.se.
authors.forename: Christina
authors.initials: C
authors.lastname: Rudén
mesh_terms: D000818:Animals; D052244:Endocrine Disruptors / Q000633:toxicity*; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D008962:Models, Theoretical; D018570:Risk Assessment / Q000379:methods*; D018675:Toxicity Tests
chemical_list: D052244:Endocrine Disruptors; D004785:Environmental Pollutants
keywords: Adverse effect; Endocrine disrupting activity; Endocrine disrupting chemicals; Epidemiology; Evidence integration; In vivo; Strength of evidence; Study evaluation; Systematic review; Weight of evidence