DRAFT NTP MONOGRAPH ON THE SYSTEMATIC REVIEW OF FLUORIDE EXPOSURE AND NEURODEVELOPMENTAL AND COGNITIVE HEALTH EFFECTS September 6, 2019 Office of Health Assessment and Translation Division of the National Toxicology Program National Institute of Environmental Health Sciences National Institutes of Health U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NOTICE: This DRAFT Monograph is distributed solely for the purpose of pre-dissemination peer review under the applicable information quality guidelines. It has not been formally disseminated by NTP. It does not represent and should not be construed to represent any NTP determination or policy. This DRAFT Monograph is distributed solely for the purpose of pre-dissemination peer review and does not represent and should not be construed to represent any NTP determination or policy. TABLE OF CONTENTS List of Tables and Figures .................................................................................................................. iv Abstract ............................................................................................................................................. 1 Introduction ...................................................................................................................................... 3 Objective and Specific Aims ................................................................................................................ 4 Objective ............................................................................................................................................. 4 Specific Aims ....................................................................................................................................... 4 Methods ............................................................................................................................................ 5 Problem Formulation and Protocol Development .............................................................................. 5 PECO Statements ................................................................................................................................ 5 Literature Search ................................................................................................................................. 7 Databases Searched ................................................................................................................................. 8 Searching Other Resources ...................................................................................................................... 8 Unpublished Data ..................................................................................................................................... 8 Study Selection .................................................................................................................................... 8 Evidence Selection Criteria ....................................................................................................................... 8 Screening Process ..................................................................................................................................... 9 Data Extraction .................................................................................................................................... 9 Quality Assessment of Individual Studies ......................................................................................... 10 Key Risk-of-bias Questions ..................................................................................................................... 10 Organizing and Rating Confidence in Bodies of Evidence ................................................................. 12 Health Outcome Categories for Neurodevelopmental and Cognitive Effects ....................................... 12 Considerations for Pursuing a Narrative or Quantitative Evidence Synthesis .................................. 12 Confidence Rating: Assessment of Body of Evidence ....................................................................... 13 Preparation of Level of Evidence Conclusions .................................................................................. 14 Integrate Evidence to Develop Hazard Identification Conclusions ................................................... 14 Consideration of Human and Animal Data ............................................................................................. 15 Consideration of Mechanistic Data ........................................................................................................ 15 Results and Evidence Synthesis ........................................................................................................ 17 Literature Search Results .................................................................................................................. 17 Neurodevelopmental and Cognitive Health Effects Results ............................................................. 18 Risk-of-bias Considerations .................................................................................................................... 19 Human Neurodevelopmental and Cognitive Data ................................................................................. 19 Animal Learning and Memory Data ....................................................................................................... 42 In Vitro/Mechanistic Data on Neurodevelopmental or Cognitive Effects .............................................. 49 Evidence Synthesis for Neurodevelopmental or Cognitive Effects ........................................................ 49 Discussion ........................................................................................................................................ 52 Generalizability to the U.S. Population ............................................................................................. 53 Limitations of the Evidence Base ...................................................................................................... 57 Limitations of the Systematic Review ............................................................................................... 59 Conclusion ....................................................................................................................................... 59 References ....................................................................................................................................... 60 Data Figures ..................................................................................................................................... 69 ii This DRAFT Monograph is distributed solely for the purpose of pre-dissemination peer review and does not represent and should not be construed to represent any NTP determination or policy. Neurodevelopmental or Cognitive Effects and Outcomes ............................................................... 69 About This Review ........................................................................................................................... 78 Sources of Support ............................................................................................................................ 78 Contributors ...................................................................................................................................... 78 Peer Reviewers .................................................................................................................................. 79 Protocol Reviewers ................................................................................................................................ 79 Technical Review of Draft Monograph ................................................................................................... 79 Protocol History and Revisions ......................................................................................................... 79 Appendices ...................................................................................................................................... 80 Appendix 1. Literature Search Strategy ............................................................................................ 80 Appendix 2. List of Included Studies ................................................................................................. 82 Studies in Humans .................................................................................................................................. 82 Studies in Non-human Animals .............................................................................................................. 92 In Vitro Experimental Studies ............................................................................................................... 113 Appendix 3. Risk-of-bias Figures ..................................................................................................... 117 Studies in Humans ................................................................................................................................ 117 Studies in Non-human Animals ............................................................................................................ 120 iii This DRAFT Monograph is distributed solely for the purpose of pre-dissemination peer review and does not represent and should not be construed to represent any NTP determination or policy. LIST OF TABLES AND FIGURES TABLES: Table