Appendix F

Supporting Materials for the PBDE (Human) Systematic Review

SECTION F-1

PBDE (HUMAN) PROTOCOL
TO UPDATE SYSTEMATIC REVIEW OF THE ASSOCIATION BETWEEN
DEVELOPMENTAL EXPOSURES TO PBDES AND HUMAN NEURODEVELOPMENT

August 3, 2016
(Modified on November 11, 2016—See Section F-1c)

BACKGROUND AND INTRODUCTION

Polybrominated biphenyl ethers (PBDEs) are synthetic brominated flame retardants that are ubiquitous environmental contaminants that have been measured in animals and in humans. They have been linked to neurological impairments after developmental exposure in animal and in human studies. During the course of exploring this class of chemicals, the committee learned of other systematic reviews on this topic and decided that using one of them could provide a case study of how to evaluate an existing review for risk of bias and how to update an existing review.

OBJECTIVE AND SPECIFIC AIMS

Review Question

The overall objective of this systematic review is to answer the question is developmental exposure to PBDEs in humans associated with alterations in quantitative measures of intelligence or attention-deficit/hyperactivity disorder (ADHD) and attention-related behavioral conditions?

The specific aims of the review are to:

• Evaluate a systematic review using the risk of bias tool ROBIS (Whiting et al. 2016).
• Update an existing review by doing the following:
  • Identify new literature reporting the effects of developmental exposure to PBDEs on measures of intelligence or on ADHD and attention-related behavioral conditions.
  • Extract data on the effects of developmental exposure to PBDEs on alterations in quantitative measures of intelligence or on ADHD and attention-related behavioral conditions from relevant new studies.
  • Assess the internal validity (risk of bias) of relevant new studies.
  • Summarize the extent of available new evidence.
  • Synthesize the evidence using a narrative approach or meta-analysis (if appropriate) considering limitations on data integration, such as study-design heterogeneity.
  • Rate the quality and strength of evidence.

PECO Statement

A PECO (Population, Exposure, Comparator, and Outcome) statement was developed by the review team as an aid to identify search terms and inclusion/exclusion criteria as appropriate for addressing the review question for the systematic review.

Population: Humans without restriction based on age

Exposure:

• PBDE refers to any single PBDE congener or combination of grouped congeners.
• Developmental exposure to PBDEs. To be considered developmental, the exposure occurred during any of the following: prior to conception for one or both parents, during pregnancy (exposure to offspring in utero), perinatally, or in childhood.
• Exposure measurements must be from human biological samples (e.g., urine, blood, or other specimens).

Comparator: Humans exposed to lower levels of PBDEs.

Outcomes:

• Quantitative measures of intelligence. For example, measures from the Wechsler Preschool and Primary Scale of Intelligence (WPPSI), Wechsler Intelligence Scale for Children (WISC), Stanford‐Binet Intelligence Scale, or the McCarthy Scales of Children’s Abilities (MSCA).
• Outcome measures of ADHD and attention-related behavioral conditions. For example, measures from the Child Behavior Checklist (CBCL)/1.5‐5, Conners’ Kiddie Continuous Performance Test (K‐CPT), Conners’ Rating Scale‐Teachers (CRS‐T), Conners’ Parent Rating Scale‐Revised (CPRS), WISC‐III (selected subscales), the Disruptive Behavior Disorders Rating Scale (DBD), or Continuous ADHD Confidence Index score.

METHODS

Problem Formulation and Protocol Development

The review question and specific aims were developed and refined through a series of problem formulation steps. The committee considered review articles on endocrine disruptors in surveying the types of chemicals that might make good case examples and held a workshop to explore potential case examples. The committee sought an example of a chemical for which both the human and the animal evidence appears to be associated with different exposure levels of that chemical and due to perturbation of the estrogen or androgen hormone system. PBDEs appear to fit this case criterion. Because the committee learned that other systematic reviews on PBDEs and human neurodevelopment are available, it decided to demonstrate how an existing systematic review can be evaluated for risk of bias and updated.

The protocol will be peer reviewed by subject-matter and systematic-review experts in accordance with standard report-review practices of the National Academies of Sciences, Engineering, and Medicine. The protocols will be revised in response to peer review comments and will subsequently be published as appendices to the committee’s final report. The identity of the peer reviewers will remain anonymous to the committee until the publication of the final report, when their names and affiliations are disclosed in the Preface.

Committee and Staff

There are 11 committee members, supported by two staff members of the National Academies. The committee members were appointed in accordance with the standard policies and practices of the National Academies on the basis of their expertise in general toxicology, reproductive toxicology, developmental toxicology, endocrinology, neurotoxicology, epidemiology, risk assessment, biostatistics, and systematic-review methods. The membership of the committee and the staff was determined before the topic of the systematic review was selected. It was known, however, that each case study would be on an endocrine-disrupting chemical, so committee members who have relevant expertise were specifically recruited and appointed.

Review Team

The review team for this case study will be two committee members (KR, AR), two National Academies staff members (EM, SM), and an information specialist (JB). If a member of the review team is found to be a coauthor of a study under review, that member will recuse himself or herself from the evaluation of the quality of that study.

The review team will be responsible for performing all aspects of the review, including conducting the literature searches; applying inclusion/exclusion criteria to screen studies; extracting data; assessing risk of bias for included studies; and analyzing and synthesizing data. The roles and responsibilities of the team members will be documented throughout the protocol. Throughout the course of its work, the review team will also engage other members of the committee to provide consultation as needed. The involvement of those individuals will be documented and acknowledged.

Biographical information on the review team is presented in Section F-1a.

Search Methods

The review team will collaborate with an information specialist (JB) who has training, expertise, and familiarity with developing and performing systematic review literature searches. Recent (within the past 3 years), relevant high-quality systematic reviews addressing the research question about PBDEs and neurodevelopment will be searched. PubMed will be search by adding the qualifier “systematic review”[ti] OR “meta-analysis”[pt] OR “meta-analysis”[ti] OR (“systematic”[ti] AND “review”[ti]) OR (systematic review [tiab] AND review [pt]) OR “meta synthesis”[ti] OR “meta synthesis”[ti] OR “integrative review”[tw] OR “integrative research review”[tw] OR “cochrane database syst rev”[ta] OR “evidence synthesis”[tiab] to the preliminary search strategy (see Section F-1b). Language and date restrictions will be applied (English language; published 2013 to present). The systematic review protocol registry PROSPERO (CRD) will also be searched using key terms from the preliminary PubMed strategy.

Study Selection

Two team members (SM, EM) will independently screen search results, applying the following exclusion criteria:

• Not a systematic review.¹ The minimum criteria for a study to be considered a systematic review are
  • conduct of an explicit and adequate literature search,
  • application of predefined eligibility criteria,

___________________

¹ A systematic review “is a scientific investigation that focuses on a specific question and uses explicit, prespecified scientific methods to identify, select, assess, and summarize the findings of similar but separate studies” (IOM 2011, p. 1).

• • consideration of the quality of included studies or risk of bias assessment, and
  • synthesis (or attempt at synthesis) of the findings, either qualitatively or quantitatively.
• Not in English.
• Search date prior to 2013.
• Does not match the research question or PECO elements.

For PubMed results, screening will be conducted first using abstracts and then at the full-text level. Results from PROSPERO will be conducted at one level, using the information in the registry. Disagreements regarding eligibility will be resolved through discussion or, where necessary, by a third team member.

Assessment for Quality

Eligible systematic reviews of high quality will be reviewed, considering date of search and match with the PECO statement as well as availability of data from the primary studies, how risk of bias was conducted, and other factors. Two investigators (KR, AR) will independently assess the risk of bias of eligible systematic reviews using ROBIS (Whiting et al. 2016). Disagreements in rating will be resolved through discussion or, where necessary, through consultation with a third team member. Systematic reviews rated as low quality will be excluded from further consideration at this stage. Systematic reviews considered a good match will be used to address the research question. Reviews that are a good match but with search dates more than a year ago will be updated.

Updating a Systematic Review

The review team will use the same methods as the existing systematic review to update it.

Search Methods and Study Selection

The review team will update the literature search of the existing review using the strategies from that review and searching from 1 year before the last search date of the review (i.e., an overlap of 1 year). Two team members (SM, EM) will independently apply the same eligibility criteria used in the existing review, first at the title and abstract level and then at the full-text level. A third team member will resolve disagreements, as needed.

Data Extraction and Analysis

The review team will extract data from any newly identified studies into evidence tables with the same structure as in the existing review. Risk of bias will be assessed by two independent team members using the same tool(s) applied in the existing systematic review.

Evidence Synthesis

The review team will qualitatively synthesize the body of evidence for each outcome and, where appropriate, a meta-analysis will be performed. If a meta-analysis is performed, summaries of the main characteristics for each included study will be compiled and reviewed by two team members to determine comparability between studies, to identify data transformations necessary to ensure comparability, and to determine whether heterogeneity is a concern. The main characteristics considered across all eligible studies include the following:

• Study design (e.g., cross-sectional, cohort)
• Details on how participants were classified into exposure groups (e.g., quartiles of exposure)

• Biological measurement for each exposure group
• Health outcome(s) reported
• Conditioning variables in the analysis (e.g., variables considered confounders)
• Type of data (e.g., continuous or dichotomous), statistics presented in paper, access to raw data
• Variation in degree of risk of bias at individual study level

The review team expects to require input from subject-matter experts to help assess the heterogeneity of the studies. Subgroup analyses to examine the extent to which risk of bias contributes to heterogeneity will be performed. Situations where it may not be appropriate to include a study are when data on exposure or outcome are too different to be combined or other circumstances that may indicate that averaging study results would not produce meaningful results. When considering outcome measures for conducting meta-analyses, continuous outcome measures, such as beta-coefficients (and their associated confidence intervals) from regression analysis, are preferred. A secondary alternative, when there are more than two groups, is to conduct regression analysis of the odds or risk ratios across exposure groups and to use the derived beta coefficient. A tertiary alternative when there are only two groups (e.g., higher and lower exposure) is to use the odds or risk ratio itself.

If a meta-analysis is conducted, a random effects model will be used for the analysis. Heterogeneity will be assessed using the I-squared statistic. Interpretation of I-squared will be based on the Cochrane Handbook: 0% to 40% (might not be important); 30% to 60% (may represent moderate heterogeneity); 50% to 90% (may represent substantial heterogeneity); and 75% to 100% (considerable heterogeneity). Additionally, as described in the Cochrane Handbook, for the last three categories, the importance of the I-squared will be interpreted considering not only the magnitude of effects but also the strength of the evidence (90% two-tailed confidence interval).

The review team will also perform sensitivity analyses on the following aspects:

• Sensitivity to exclusion of individual studies in succession,
• Sensitivity to alternative exposure metrics (if available), and
• Sensitivity to alternative outcome metrics (if available).

It is unlikely that there will be enough studies or information to meaningfully assess publication bias or to perform subgroup analyses, so no such analyses are planned.

In the event that these proposed methods for data analysis are altered to tailor to the evidence base from included studies, the protocol will be amended accordingly and the reasons for change will be justified in the documentation.

Grading/Strength of Evidence

The same system and approach that was used to draw conclusions and grade the evidence in the existing systematic review will be used to characterize the evidence.

REFERENCES

SECTION F-1a

BIOGRAPHICAL INFORMATION ON THE REVIEW TEAM

Jaime F. Blanck is a clinical informationist at the Welch Medical Library at Johns Hopkins University. She creates and implements systematic review search strategies across multiple databases and provides comprehensive reference, research, and information services to multiple departments within the School of Medicine. She received an MLIS from the University of Pittsburgh and an MPA from the University of Baltimore.

Ellen Mantus is a scholar and director of risk assessment on the Board on Environmental Studies and Toxicology at the National Academies of Sciences, Engineering, and Medicine with more than 20 years of experience in the fields of toxicology and risk assessment. She has served as the study director on numerous projects, including ones that have assessed the health implications of various chemical exposures; developed strategies for applying modern scientific approaches in toxicology and risk assessment; provided guidance to federal agencies on risk-based decision making; and evaluated barriers to deployment of electric vehicles and associated charging infrastructure. Before joining the National Academies, Dr. Mantus was a project manager with ICF Consulting where she served as a primary reviewer for numerous toxicological studies and provided risk assessment and regulatory support on a wide array of projects. Dr. Mantus received a PhD in chemistry from Cornell University.

Susan Martel is a senior program officer in the Board on Environmental Studies and Toxicology at the National Academies of Sciences, Engineering, and Medicine. She has 20 years of experience in supporting toxicology and risk assessment projects for the US Environmental Protection Agency, the US Department of Defense, and the National Aeronautics and Space Administration. Recent projects include working with committees evaluating the toxicological effect of arsenic, developing exposure guidelines for use on spacecraft, and assessing pesticide risks-assessment practices. Before joining the National Academies, she was the administrator of the Registry for Toxicology Pathology for Animals at the American Registry of Pathology. She received a BA in biology from Skidmore College.

Karen A. Robinson is an associate professor at the Johns Hopkins University School of Medicine. She also serves as director of the Johns Hopkins University Evidence-based Practice Center and is a member of the core faculty in the Center for Clinical Trials and Evidence Synthesis at the university’s Bloomberg School of Public Health. Her research focuses on evidence-based health care and evidence-based research. She conducts systematic reviews that are used to develop clinical practice guidelines and to inform other health decisions. Dr. Robinson received an MSc in health sciences from the University of Waterloo, Ontario, and a PhD in epidemiology from the Johns Hopkins Bloomberg School of Public Health.

Andrew A. Rooney is deputy director of the Office of Health Assessment and Translation (OHAT) in the National Toxicology Program at the National Institute of Environmental Health Sciences. He has been developing risk assessment methods and guidance throughout his professional career and is a principal author of the 2012 WHO/IPCS Guidance for Immunotoxicity Risk Assessment for Chemicals. Most recently, he has been working on emerging issues in toxicology and environmental health, including methods to address study quality in terms of risk of bias for human, animal, and mechanistic studies and adaptation of systematic review methods for addressing environmental health questions. He led the team that developed the OHAT approach to systematic review. Dr. Rooney has an MS and a PhD in zoology from the University of Florida.

SECTION F-1b

The review team will employ a multi-method process to identify all potentially relevant studies as detailed below.

Electronic Searches

PubMed

A search string employing medical subject heading (MeSH) terms and keyword synonyms will be developed. To assist in compiling these terms, the review team will consult an existing systematic review protocol studying PBDEs in humans (J. Lam et al. Applying the navigation guide systematic review methodology. Case study #5: association between developmental exposures to PBDEs and human neurodevelopment. PROSPERO 2015:CRD42015019753 Available from http://www.crd.york.ac.uk/PROSPERO_REBRANDING/display_record.asp?ID=CRD42015019753). This protocol was selected because it examines the substances of interests, timing of exposure, and outcomes of interest. The search strategies will address each of the following concepts:

• Flame retardants (PBDEs)—The review team will use the MeSH database (http://www.ncbi.nlm.nih.gov/mesh) to find all MeSH heading and Supplementary Concept headings that relate to the Flame retardants (PBDEs) concept. The review team will mine the “Entry Terms” list for each of the controlled vocabulary terms identified and include all unique keyword synonyms listed for each. CAS registry numbers for each PBDE substance will also be included in the list of search terms. All MeSH terms, Supplementary Concept terms, keyword synonyms, and CAS registry numbers will be searched together as one concept using the Boolean operator “OR.”
• Human studies—The search filter developed by the Cochrane Library to identify human studies (see http://handbook.cochrane.org/ part 2, section 6.4.f) will be modified to comply with PubMed formatting.
• Outcomes—The review team will use the MeSH database (http://www.ncbi.nlm.nih.gov/mesh) to find all MeSH heading and Supplementary Concept headings that relate to measures of learning, memory, attention, and cognition. The review team will mine the “Entry Terms” list for each of the controlled vocabulary terms identified and include all unique keyword synonyms listed for each. All MeSH terms and keyword synonyms will be searched together as one concept using the Boolean operator “OR.”

Each of the above concepts will be searched together using the Boolean operator “AND.” There will not be limitations on date of publication, language, or publication type. All citation records will be exported to EndNote. Additional citations identified through the search processes identified below will also be exported to the project EndNote library. Duplicates will be removed from the citation library using the “Find Duplicates” tool in EndNote as well as a manual review of citations by the project librarian to identify any duplicates not found during the automated process. The number of citations found in each database will be recorded, as well as the number of duplicates and final tally of unique citations. The final library of citations will be uploaded to the Health Assessment Workspace Collaboration Web-based tool (www.hawcproject.org) for systematic reviews where they will be reviewed by the team.

Search Strategies

PubMed

(“Flame Retardants”[Mesh] OR “Flame Retardants” [Pharmacological Action] OR “Halogenated Diphenyl Ethers”[Mesh] OR “Phenyl Ethers”[Mesh:NoExp] OR “pentabromodiphenyl ether” [Supplementary Con-

cept] OR “2,2’,3,3’,4,4’,6,6’‐octabromodiphenyl ether”[Supplementary Concept] OR “decabromobiphenyl ether”[Supplementary Concept] OR “tribromodiphenyl ether 28”[Supplementary Concept] OR “2,2’,4,4’-tetrabromodiphenyl ether”[Supplementary Concept] OR “2,2’,4,5’‐tetrabromodiphenyl ether”[Supplementary Concept] OR “hexabromodiphenyl ether 154”[Supplementary Concept] OR “2,2’,4,4’,5,6’hexabromodiphenyl ether”[Supplementary Concept] OR “2,2’,3,4,4’,5’,6heptabromodiphenyl ether”[Supplementary Concept] OR “2,2’,3,3’,4,5,5’,6,6’‐nonabromodiphenyl ether”[Supplementary Concept] OR “2,2’,3,3’,4,4’,5,6,6’‐nonabromodiphenyl ether”[Supplementary Concept] OR “2,2’,3,3’,4,4’,5,5’,6‐nonabromodiphenyl ether”[Supplementary Concept] OR “2,2’,4,4’,5,5’-hexabrominated diphenyl ether”[Supplementary Concept] OR “hexabrominated diphenyl ether 153”[Supplementary Concept] OR “pentabrominated diphenyl ether 100”[Supplementary Concept] OR “5-OH‐BDE‐47”[Supplementary Concept] OR “6‐OH‐BDE‐47”[Supplementary Concept] OR flame retard*[tw] OR fire retard*[tw] OR fireproofing agent*[tw] OR “FireMaster”[tw] OR “Bromkal”[tw] OR diphenyl ether deriv*[tw] OR halogenated diphenyl*[tw] OR brominated diphenyl*[tw] OR PBDE*[tw] OR polybrominated diphenyl*[tw] OR polybromodiphenyl*[tw] OR PBDP*[tw] OR BDE*[tw] OR pentabromodiphenyl*[tw] OR cpentaBDE*[tw] OR PentaBDE*[tw] OR “PeBDE”[tw] OR “DE 71”[tw] OR “DE71”[tw] OR “pentabrominated diphenyl”[tw] OR “pentabrominated diphenyls”[tw] OR “PBDPO”[tw] OR “Planelon PB 501”[tw] OR pentabromo deriv*[tw] OR pentabromophenyl*[tw] OR octabromodiphenyl*[tw] OR c‐octaBDE*[tw] OR OctaBDE*[tw] OR “OcBDE”[tw] OR “Octabrom”[tw] OR octabromo deriv*[tw] OR “OBDE”[tw] OR “OBDPO”[tw] OR “octabrominated diphenyl”[tw] OR “octabrominated diphenyls”[tw] OR decabromodiphenyl*[tw] OR cdecaBDE*[tw] OR DecaBDE*[tw] OR “DeBDE”[tw] OR “DBDPO”[tw] OR “decabrominated diphenyl”[tw] OR “decabrominated diphenyls”[tw] OR decabromo deriv*[tw] OR “Decabrom”[tw] OR “Berkflam B 10E”[tw] OR “FR 300BA”[tw] OR “FR 300 BA”[tw] OR tribromodiphenyl*[tw] OR “tribrominated diphenyl”[tw] OR “tribrominated diphenyls”[tw] OR “TrBDE”[tw] OR tribromo deriv*[tw] OR tetrabromodiphenyl*[tw] OR TetraBDE*[tw] OR “TeBDE”[tw] OR “TBDE”[tw] OR “BPDE”[tw] OR tetrabromo deriv*[tw] OR “TBDP”[tw] OR “tetrabrominated diphenyl”[tw] OR “tetrabrominated diphenyls”[tw] OR hexabromodiphenyl*[tw] OR HexaBDE*[tw] OR “HxBDE”[tw] OR “hexabrominated diphenyl”[tw] OR “hexabrominated diphenyls”[tw] OR hexabromo deriv*[tw] OR heptabromodiphenyl*[tw] OR HeptaBDE*[tw] OR “HeBDE”[tw] OR “heptabrominated diphenyl”[tw] OR “heptabrominated diphenyls”[tw] OR heptabromo deriv*[tw] OR nonabromodiphenyl*[tw] OR NonaBDE*[tw] OR “NoBDE”[tw] OR “nonabrominated diphenyl”[tw] OR “nonabrominated diphenyls”[tw] OR nonabromo deriv*[tw] OR “7025‐06‐1”[tw] OR “6876‐00‐2”[tw] OR “101‐55‐3”[tw] OR “51452‐870”[tw] OR “446254‐14‐4”[tw] OR “147217‐72‐9”[tw] OR “171977‐449”[tw] OR “147217-71‐8”[tw] OR “33513‐66‐3”[tw] OR “51930‐04‐2”[tw] OR “6903‐63‐5”[tw] OR “189084‐59‐1”[tw] OR “83694‐71‐7”[tw] OR “46438‐88‐4”[tw] OR “2050‐47‐7”[tw] OR “147217‐74‐1”[tw] OR “147217‐75-2”[tw] OR “407606‐55‐7”[tw] OR “147217‐73‐0”[tw] OR “147217‐76‐3”[tw] OR “337513‐67‐4”[tw] OR “446254‐15‐5”[tw] OR “446254‐16‐6”[tw] OR “147217‐77‐4”[tw] OR “337513‐75‐4”[tw] OR “337513-53‐8”[tw] OR “41318‐75‐6”[tw] OR “337513‐56‐1”[tw] OR “155999‐95‐4”[tw] OR “65075‐08‐3”[tw] OR “189084‐60‐4”[tw] OR “147217‐78‐5”[tw] OR “446254‐17‐7”[tw] OR “147217‐80‐9”[tw] OR “147217-79‐6”[tw] OR “147217‐81‐0”[tw] OR “337513‐54‐9”[tw] OR “337513‐68‐5”[tw] OR “446254‐18‐8”[tw] OR “446254‐19‐9”[tw] OR “446254‐20‐2”[tw] OR “446254‐22‐4”[tw] OR “5436‐43‐1”[tw] OR “337513-55‐0”[tw] OR “243982‐82‐3”[tw] OR “446254‐23‐5”[tw] OR “189084‐57‐9”[tw] OR “446254‐24‐6”[tw] OR “446254‐25‐7”[tw] OR “446254‐31‐5”[tw] OR “446254‐32‐6”[tw] OR “446254‐33‐7”[tw] OR “446254‐34‐8”[tw] OR “189084‐61‐5”[tw] OR “446254‐37‐1”[tw] OR “446254‐38‐2”[tw] OR “327185-09‐1”[tw] OR “446254‐39‐3”[tw] OR “189084‐62‐6”[tw] OR “446254‐40‐6”[tw] OR “446254‐41‐7”[tw] OR “446254‐42‐8”[tw] OR “189084‐63‐7”[tw] OR “446254‐43‐9”[tw] OR “93703‐48‐1”[tw] OR “446254-45‐1”[tw] OR “446254‐48‐4”[tw] OR “103173‐66‐6”[tw] OR “446254‐50‐8”[tw] OR “446254‐51‐9”[tw] OR “182346‐21‐0”[tw] OR “446254‐53‐1”[tw] OR “446254‐54‐2”[tw] OR “446254‐55‐3”[tw] OR “446254‐55‐3”[tw] OR “446254‐57‐5”[tw] OR “446254‐59‐7”[tw] OR “446254‐61‐1”[tw] OR “446254-64‐4”[tw] OR “38463‐82‐0”[tw] OR “60348‐60‐9”[tw] OR “189084‐64‐8”[tw] OR “446254‐65‐5”[tw] OR “446254‐66‐6”[tw] OR “446254‐67‐7”[tw] OR “446254‐68‐8”[tw] OR “373594‐78‐6”[tw] OR “446254--

69‐9”[tw] OR “446254‐71‐3”[tw] OR “446254‐72‐4”[tw] OR “446254‐74‐6”[tw] OR “446254‐77‐9”[tw] OR “446254‐78‐0”[tw] OR “189084‐65‐9”[tw] OR “446254‐80‐4”[tw] OR “189084‐66‐0”[tw] OR “182677‐30‐1”[tw] OR “243982‐83‐4”[tw] OR “68631‐49‐2”[tw] OR “207122‐15‐4”[tw] OR “35854‐94-5”[tw] OR “189084‐58‐0”[tw] OR “189084‐67‐1”[tw] OR “207122‐16‐5”[tw] OR “189084‐68‐2”[tw] OR “1163‐19‐5”[tw] OR “109945‐70‐2”[tw] OR “113152‐37‐7”[tw] OR “113172‐79‐5”[tw] OR “139598‐16-6”[tw] OR “139749‐52‐3”[tw] OR “145538‐74‐5”[tw] OR “32534‐81‐9”[tw] OR “32536‐52‐0”[tw] OR “40088‐47‐9”[tw] OR “446254‐27‐9”[tw] OR “446255‐20‐5”[tw] OR “446255‐22‐7”[tw] OR “49690‐94-0”[tw] OR “63936‐56‐1”[tw] OR “64589‐00‐0”[tw] OR “68928‐80‐3”[tw] OR “85446‐17‐9”[tw] OR “36483‐60‐0”[tw] OR “437701‐79‐6”[tw] OR “446255‐26‐1”[tw] OR “117948‐63‐7”[tw] OR “446255‐30-7”[tw] OR “61262‐53‐1”[tw] OR “405237‐85‐6”[tw] OR “39275‐89‐3”[tw] OR “13654‐09‐6”[tw] OR “61288‐13‐9”[tw] OR “446255‐39‐6”[tw] OR “337513‐72‐1”[tw] OR “366791‐32‐4”[tw] OR “2050‐47-7”[tw]) AND (“Psychological Tests”[Mesh] OR “Mental Disorders Diagnosed in Childhood”[Mesh] OR “Mental Processes”[Mesh] OR “Attention”[Mesh] OR “Human Development”[Mesh] OR “Intelligence”[Mesh] OR “Neurobehavioral Manifestations”[Mesh] OR “Psychomotor Performance”[Mesh] OR “Behavior”[Mesh:NoExp] OR “Adolescent Behavior”[Mesh] OR “Behavioral Symptoms”[Mesh] OR “Child Behavior”[Mesh] OR “Communication”[Mesh] OR “Impulsive Behavior”[Mesh] OR “Motor Activity”[Mesh] OR “Social Behavior”[Mesh] OR “Hyperkinesis”[Mesh] OR “Brain/drug effects”[Mesh] OR “Spatial Behavior”[Mesh] OR neurodevelopment*[tw] OR neurotoxic*[tw] OR neurobehav*[tw] OR neuropsychologic*[tw] OR neurocogniti*[tw] OR psychologic*[tw] OR aptitude*[tw] OR mental*[tw] OR intelligence*[tw] OR “IQ”[tw] OR intellectual*[tw] OR language*[tw] OR comprehension*[tw] OR impulsiv*[tw] OR “ADHD”[tw] OR “ADDH”[tw] OR “ADHS”[tw] OR “AD/HD”[tw] OR “hkd”[tw] OR hyperactiv*[tw] OR hyper activ*[tw] OR hyperkin*[tw] OR hyper kin*[tw] OR attention defic*[tw] OR attention related*[tw] OR inattention*[tw] OR inattentiv*[tw] OR “sustained attention”[tw] OR “attention span”[tw] OR attention dysfunc*[tw] OR attention disorder*[tw] OR “distractibility”[tw] OR Behavioral*[tw] OR behavioural*[tw] OR behavior defic*[tw] OR behaviour defic*[tw] OR behavior dysfunc*[tw] OR behavior disorder*[tw] OR behavior disorder*[tw] OR behavior effect*[tw] OR behaviour effect*[tw] OR behavior checklist*[tw] OR behaviour checklist*[tw] OR disruptive behav*[tw] OR disruption behav*[tw] OR disruptive disorder*[tw] OR disruption disorder*[tw] OR defiance behav*[tw] OR defiant behav*[tw] OR defiance disorder*[tw] OR defiant disorder*[tw] OR spontaneous behav*[tw] OR externalizing behav*[tw] OR “cognitive”[tw] OR “cognition”[tw] OR “psychomotor”[tw] OR “learning”[tw] OR “memory”[tw] OR executive function*[tw] OR executive control*[tw] OR executive dysfunction*[tw] OR executive impairment*[tw] OR motor abilit*[tw] OR motor activit* [tw] OR “motor performance”[tw] OR motor function*[tw] OR motor skill*[tw] OR “fine motor”[tw] OR “vigilance”[tw] OR “reaction time”[tw] OR “processing speed”[tw] OR “response inhibition”[tw] OR “Stanford Binet”[tw] OR Binet Test*[tw] OR “Bender Gestalt Test”[tw] OR Aphasia Test*[tw] OR Bayley*[tw] OR “Wechsler”[tw] OR “WISC”[tw] OR McCarthy Scale*[tw] OR “Continuous Performance Test”[tw] OR “Continuous Performance Tests”[tw] OR “Continuous Performance Task”[tw] OR “Continuous Performance Tasks”[tw] OR Conners*[tw] OR “CRS‐T”[tw] OR “CRS‐P”[tw] OR “academic achievement”[tw] OR “scholastic achievement”[tw] OR brain disorder*[tw] OR brain damage*[tw] OR brain dysfunct*[tw]) AND ((“systematic review”[ti] OR “meta-analysis”[pt] OR “meta-analysis”[ti] OR (“systematic”[ti] AND “review”[ti]) OR (systematic review [tiab] AND review [pt]) OR “meta synthesis”[ti] OR “meta synthesis”[ti] OR “integrative review”[tw] OR “integrative research review”[tw] OR “cochrane database syst rev”[ta] OR “evidence synthesis”[tiab])) NOT (((“Animals”[Mesh] NOT (“Animals”[Mesh] AND (“Humans”[Mesh]))))

SECTION F-1c

AMENDMENTS TO THE PROTOCOL
(November 11, 2016)

Additions to the Review Team

The following committee members were added to the review team to supplement expertise:

• David C. Dorman (Chair) is a professor of toxicology in the Department of Molecular Biosciences of North Carolina State University. The primary objective of his research is to provide a refined understanding of chemically induced neurotoxicity in laboratory animals that will lead to improved assessment of potential toxicity in humans. Dr. Dorman’s research interests include neurotoxicology, nasal toxicology, pharmacokinetics, and cognition and olfaction in animals. He has chaired or served on several NRC committees, including the Committee on Design and Evaluation of Safer Chemical Substitutions: A Framework to Inform Government and Industry Decisions, the Committee to Review EPA’s Draft IRIS Assessment of Formaldehyde, and the Committee to Review the IRIS Process. He has served on other advisory boards for the US Navy, NASA, and USDA and is currently a member of NTP’s Board of Scientific Counselors. Dr. Dorman is an elected fellow of the Academy of Toxicological Sciences and a fellow of the American Association for the Advancement of Sciences. He received a DVM from Colorado State University. He completed a combined PhD and residency program in toxicology at the University of Illinois at Urbana-Champaign, and is a diplomate of the American Board of Veterinary Toxicology and the American Board of Toxicology.
• Barbara F. Hales is a James McGill Professor in the Department of Pharmacology and Therapeutics at McGill University. Her research interests are in the mechanisms of action of drugs as teratogens. She studies developmental toxicity using a combination of in vivo, in vitro, and molecular approaches with the goal of elucidating how the embryo responds to insult after direct or maternal exposure and the consequences to progeny of paternal drug exposure. Dr. Hales is a past president of the Teratology Society and is currently co-chair of the Chemicals Management Plan Science Committee of the Government of Canada. She received an MSc in pharmacognosy from the Philadelphia College of Pharmacy and Science and a PhD in pharmacology and therapeutics from McGill University.
• Susan L. Schantz is a professor of toxicology in the Department of Comparative Biosciences, College of Veterinary Medicine, at the University of Illinois at Urbana-Champaign. She is also director of a National Institute of Environmental Health Sciences (NIEHS) T32 training program in endocrine, developmental, and reproductive toxicology and director of a Children’s Environmental Health Research Center jointly funded by the NIEHS and the EPA. In addition, she is currently the interim director of the Neuroscience Program. Dr. Schantz’s research interests involve understanding the neurobehavioral effects of chemical exposures during development and aging. She conducts research in both laboratory-based animal studies and parallel epidemiologic studies. She has served as president of the Neurotoxicology Specialty Section of the Society of Toxicology and president of the Neurobehavioral Teratology Society. Dr. Schantz was also a member of the NRC’s Committee to Assess the Health Implications of Perchlorate Ingestion. She received a PhD in environmental toxicology from the University of Wisconsin–Madison.

SECTION F-2

Results of Literature Searches for Existing or Ongoing Systematic Reviews

Searches for systematic reviews or ongoing reviews were performed on August 3, 2016. Five publications were found in PubMed and 13 protocols in PROSPERO. Below is the list of the18 reports.

Sadeghirad, B., J. Erickson, L. Lytvyn, T. Webber-Adams, J. Slavin, and B. Johnston. 2015. Scientific Basis for Recommendations on Sugars From Authoritative Health Organizations: A Systematic Review of Public Health Guidelines. PROSPERO 2015:CRD42015029182 [online]. Available: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015029182 [accessed August 3, 2016].

Sugeng, E., M. de Cock, and M. van de Bor. 2016. Toddler Exposure to Flame Retardant Chemicals: Magnitude, Health Concern and Potential Sources of Exposure: Observational Studies Summarized in a Systematic Review. PROSPERO 2016:CRD42016043245 [online]. Available: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016043245 [accessed August 3, 2016].

Tarp, S., E.M. Bartels, H. Bliddal, B. Danneskiold,-Samsøe, M. Rasmussen, and R. Christensen. 2011. Effect of Non-steroidal Anti-inflammatory Drugs on C-reactive Protein Levels in Patients with Rheumatoid Arthritis: A Meta-analysis of Randomized, Double Blind, Placebo-controlled Trials. PROSPERO 2011:CRD 42011001157 [online]. Available: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42011001157 [accessed August 3, 2016].

Zhao, X.M. 2016. Hair as Noninvasive Biomarkers of Human Exposure to Polybrominated Diphenyl Ethers (PBDEs). PROSPERO 2016:CRD42016039582 [online]. Available: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016039582 [accessed August 3, 2016].

Zhao, X.M., J. Li, and H.L. Wang. 2014. The Correlations Between Polybrominated Diphenyl Ethers (PBDEs) and Thyroid Hormones in the General Population: A Meta-analysis. PROSPERO 2014:CRD42014013289 [online]. Available: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014013289 [accessed August 3, 2016].

SECTION F-3

Results of Literature Searches for Human Studies on the Effects of Developmental Exposure to PBDEs on Intelligence or ADHD and Attention-Related Behavioral Conditions

Literature searches were performed on September 28, 2016, using the search strategy presented in Lam et al. (2015). The search was restricted to reports published after March 5, 2014, so that the search would have a 1-year overlap with the ongoing Lam et al. review. A summary of the results is presented below.

SECTION F-4

Human Studies of PBDES and Intelligence and ADHD and Attention-Related Behavioral Conditions

Studies in the Lam et al. (2015 Systematic Review and Three New Reports (highlighted in table)

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