National Academies Press: OpenBook

Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals (2017)

Chapter: Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review

« Previous: Appendix D: Supporting Materials for the Phthalate (Human) Systematic Review
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

Appendix E

Supporting Materials for the PBDE (Animal) Systematic Review

SECTION E-1

PBDE (ANIMAL) SYSTEMATIC REVIEW PROTOCOL

August 3, 2016
(Modified on September 15, 2016—See Section E-1f)

BACKGROUND AND INTRODUCTION

Polybrominated diphenyl ethers (PBDEs) are synthetic brominated flame retardants that are ubiquitous environmental contaminants that have been measured in animals and in humans. Because the developing organism has been shown to be particularly vulnerable to endocrine-disrupting chemicals, such as PBDEs, the committee decided to focus on studies of developmental exposure. PBDEs have been linked to effects on neurodevelopment after developmental exposure in animal studies.

OBJECTIVE AND SPECIFIC AIMS

Review Question

The overall objective of this systematic review is to answer the question is developmental exposure to PBDEs in nonhuman mammals associated with alterations in learning, memory, attention, or response inhibition?

The specific aims of the review are to:

  • Identify literature reporting the effects of developmental PBDE exposure on learning, memory, attention, or response inhibition in nonhuman mammals.
  • Extract data on learning, memory, attention, or response inhibition from relevant studies.
  • Assess the internal validity (risk of bias) of individual studies.
  • Summarize the extent of evidence available.
  • Synthesize the evidence using a narrative approach or meta-analysis (if appropriate) considering limitations on data integration, such as study-design heterogeneity.
  • Rate the confidence in the body of evidence for studies in nonhuman mammals according to one of five statements: (1) high; (2) moderate; (3) low; (4) very low/no evidence available; or (5) evidence of lack of neurotoxicity.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

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: Nonhuman mammals

Exposure:

  • PBDE refers to any single PBDE congener or combination of grouped congeners.
  • Any developmental exposure to PBDEs, with no restrictions based on route of exposure or administered dose or concentration. To be considered “developmental,” the exposure occurred during any of the following periods: prior to conception in one or both parents, prenatal in the pregnant female (exposure to offspring in utero), or postnatal until sexual maturation.

Comparator: Nonhuman mammals exposed during development to different doses of PBDEs or vehicle-only treatment.

Outcomes: Measures of learning, memory, attention, or response inhibition. Examples of tests include Morris water maze, radial arm maze, and operant tests of cognition.

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 on effects appears to be associated with different exposure levels of that chemical and due to perturbation of the estrogen or androgen hormone system. PBDEs appeared to fit this case criterion.

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.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

Review Team

The review team for this case study will be a subgroup of the committee (BH, SSc), two National Academies staff members (EM, SM), and an information specialist (JB). If a member of the review team was 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 E-1a.

Search Methods

Search for Existing Systematic Reviews

The review team will consider using existing systematic reviews to address or help to address its research question. English-language systematic reviews conducted within the last 3 years will be sought. The review team will incorporate prior reviews, update prior reviews, and/or use the reviews as part of its searching, depending on determination of their relevancy and quality (Whitlock et al. 2008). Current guidance on using existing systematic reviews will be used (Robinson et al. 2014, 2015, 2016).

Search

Recent, relevant high-quality systematic reviews addressing the research question about PBDEs and neurodevelopment will be searched. PubMed will be searched 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 E-1b). Language and date restrictions will be applied (English language; published 2013 to present). The systematic review protocol registries PROSPERO (CRD) and CAMARADES 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,
    • 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.

___________________

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).

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
  • 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 and CAMARADES 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

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.

Use of Existing Reviews

Eligible systematic reviews of high quality will be reviewed, considering date of search, match with the PECO statement, as well as availability of data from the primary studies, how risk of bias was conducted, and other factors. Current 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. If no relevant systematic reviews are found, an independent systematic review will be performed.

Literature Search for Independent Systematic Review

The review team will collaborate with an information specialist (JB) who has training, expertise, and familiarity with developing and performing systematic review literature searches. A variety of methods will be used to identify relevant data (see below). Literature searches will not be limited by publication date.

Online Databases

Electronic searches of the following three online databases will be performed using the search terms outlined in Section E-1b: PubMed, Embase, and Toxline. The search strategy and search terms will be developed by the information specialist (JB), who will implement the search for relevant studies.

Other Resources

Hand searching the reference lists of all the included studies after full-text review will be conducted using the same study selection process as was used for screening records retrieved from the electronic search. Relevant studies identified through these steps will be marked as “provided from other sources” in the study selection flow diagram.

Study Selection

All search results will be imported or manually entered into EndNote (Version x7) reference management software. EndNote will be used to eliminate any duplicate citations before evaluating the eligibility of the citations.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

Screening Process

References retrieved from the literature search will be screened for relevance and eligibility against the evidence selection criteria using DistillerSR (Evidence Partners; https://www.evidencepartners.com). Screeners from the review team will be trained with an initial pilot phase on 25 studies undertaken to improve clarity of the evidence selection criteria and to improve accuracy and consistency among screeners. Screening forms are presented in Section E-1c.

Title and Abstract Screening

Each citation will be independently screened by two reviewers (SM, EM) to determine whether it meets the selection criteria for inclusion that reflect the PECO statement with some additional considerations as listed below. Citations included at the title/abstract screening level will be subject to a full-text review by the same two reviewers. Disagreements regarding citation eligibility will be resolved via consensus and, where necessary, by consulting a committee member.

The title/abstract screening form will be used to screen and EXCLUDE references if at least one of the following criteria is met:

  1. No original data (e.g., review article, commentary, editorial)
  2. Study does not include nonhuman mammals
  3. Study does not report PBDE exposure
  4. No relevant outcomes
  5. Incomplete information (e.g., conference abstract, meeting poster)
  6. Not in English and unable to determine eligibility
  7. Other (explanation required)

The following types of records will be INCLUDED at the title/abstract level: any English-language study of nonhuman mammals exposed to PBDEs.

Only English-language publications will be included, because of time and resource constraints. There appears to be no indication that foreign-language publications would make a contribution that is distinct from what is found in the English-language literature.

Updated details to instructions and interpretations for title and abstract screening will be added to Section E-1f to document the process of the review team during the screening process.

Full-Text Screening

Citations included at the title/abstract screening level will be subject to a full-text review by the same two reviewers involved in title and abstract screening (SM, EM). Each reference will be screened in duplicate and independently. Disagreements regarding citation eligibility will be resolved via consensus and, where necessary, by consulting a committee member.

Citations will be EXCLUDED at the full-text level if at least one of the following criteria is met:

  1. No original data (e.g., review article, commentary, editorial)
  2. Study does not include nonhuman mammals
  3. Study does not report experimental PBDE exposure
  4. Study does not quantify exposure to PBDE
  5. Study does not include developmental exposure (prior to conception in one or both parents, prenatal in the pregnant female [exposure to offspring in utero], or postnatal until sexual maturation)
  6. Study does not assess or report quantitative measures of learning, memory, attention, or response inhibition
  7. No comparator group (animals exposed to different doses of PBDEs or vehicle-only treatment)
  8. Not in English
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
  1. Other reason (explanation required)

The reason for exclusion at the full-text-review stage will be annotated and reported in a study selection flow diagram in the final report (following PRISMA [Moher et al. 2009]). The reasons for exclusion will be documented from the list (1-9) above.

Citations will be INCLUDED if they meet the PECO statement criteria:

  • Study includes nonhuman mammals
  • Study includes developmental exposure
  • Study includes comparison with animals exposed to different doses of PBDEs or vehicle-only treatment
  • Study measures (1) learning, (2) memory, (3) attention, or (4) response inhibition.

Updated details to instructions and interpretations for full-text screening will be added to Section E-1f to document the process of the review team during the screening process.

Data Extraction

Data will be collected and recorded (i.e., extracted) from included studies by one member of the review team and checked by a second member for completeness and accuracy. Any discrepancies in data extraction will be resolved through discussion. The extracted data will be used to summarize study designs and findings and/or to conduct statistical analyses. Section E-1d presents the data extraction elements that will be used.

The review team will attempt to contact authors of included studies to obtain missing data considered important for evaluating key study findings (e.g., level of data required to conduct a meta-analysis). The study extraction files will note whether an attempt was made to contact study authors by email for missing data considered important for evaluating key study findings (and whether or not a response was received).

Multiple publications with overlapping data for the same study (e.g., publications reporting subgroups, additional outcomes or exposures outside the scope of an evaluation, or longer follow-up) are identified by examining author affiliations, study designs, cohort name, enrollment criteria, and enrollment dates. If necessary, study authors will be contacted to clarify any uncertainty about the independence of two or more articles. The review will include all publications on the study, select one publication to use as the primary publication, and consider the others as secondary publications with the annotation as being related to the primary record during data extraction. The primary study will generally be the publication with the longest follow-up or, for studies with equivalent follow-up periods, the study with the largest number of cases or the most recent publication date. The review will include relevant data from all publications of the study, although if the same outcome is reported in more than one report, the review team will include a single instance of the data (and avoid more than one; that is, duplicate instances of the data).

Data extraction will be completed using the Health Assessment Workspace Collaborative (HAWC) software, an open source and freely available Web-based interface application, for visualization and warehousing.2

Risk of Bias (Quality) Assessment of Individual Studies

Risk of bias is related to the internal validity of a study and reflects study-design characteristics that can introduce a systematic error (or deviation from the true effect) that might affect the magnitude and

___________________

2 HAWC (Health Assessment Workspace Collaborative): A Modular Web-based Interface to Facilitate Development of Human Health Assessments of Chemicals (https://hawcproject.org/portal/).

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

even the direction of the apparent effect. Internal validity or risk of bias will be assessed for individual studies using a tool developed by the National Toxicology Program’s Office of Health Assessment and Translation (OHAT) that outlines an approach to evaluating risk of bias for experimental animal studies. The risk of bias domains and questions for experimental animal studies are based on established guidance for experimental human studies (randomized clinical trials) (Viswanathan et al. 2012, 2013; Sterne et al. 2014; Higgins and Green 2011) and recent tools for animal studies (Hooijmans et al. 2014; Koustas et al. 2014). The risk of bias tool includes a common set of questions (Section E-1e) that are answered based on the specific details of individual studies to develop risk of bias ratings (using the four options: definitely low risk of bias; probably low risk of bias; probably high risk of bias; or definitely high risk of bias). Information or study procedures that were not reported are assumed not to have been conducted, resulting in an assessment of “probably high” risk of bias. Study design determines the subset of questions that should be used to assess risk of bias for an individual study (see Table E1-1).

Studies are independently assessed by two assessors (BH, SSc) who answer all applicable risk of bias questions with one of four options (see Table E1-2) following prespecified criteria detailed in Section E-1e. The criteria describe aspects of study design, conduct, and reporting required to reach risk of bias ratings for each question and specify factors that can distinguish among ratings (e.g., what separates “definitely low” from “probably low” risk of bias). The instructions and detailed criteria are tailored to the specific type of human study designs. Risk of bias will be assessed at the outcome level because study-design or method specifics may increase the risk of bias for some outcomes and not others within the same study. Information or study procedures that were not reported are assumed not to have been conducted, resulting in an assessment of “probably high” risk of bias. Authors will be queried by email to obtain missing information, and responses received will be used to update risk of bias ratings.

Assessors will be trained using the criteria in an initial pilot phase undertaken to improve clarity of criteria that distinguish between adjacent ratings and to improve consistency among assessors. All team members involved in the risk of bias assessment will be trained on the same set of studies and asked to identify potential ambiguities in the criteria used to assign ratings for each question. Any ambiguities and rating conflicts will be discussed relative to opportunities to refine the criteria to more clearly distinguish between adjacent ratings. If major changes to the risk of bias criteria are made based on the pilot phase (i.e., those that would likely result in revision of response), they will be documented in a protocol amendment along with the date modifications were made and the logic for the changes. It is also expected that information about confounding, exposure characterization, outcome assessment, and other important issues may be identified during or after data extraction, which can lead to further refinement of the risk of bias criteria.

After assessors have independently made risk of bias determinations for a study across all risk of bias questions, the two assessors will compare their results to identify discrepancies and attempt to resolve them. Any remaining discrepancies will be considered and resolved with the review team. The final risk of bias rating for each question will be recorded along with a statement of the basis for that rating.

Data Analysis and 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 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:

  • Experimental design (e.g., acute, chronic, multigenerational)
  • Animal model used (e.g., species, strain, sex, genetic background)
  • Age of animals (e.g., at start of treatment, mating, and/or pregnancy status)
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

TABLE E1-1 OHAT Risk of Bias Tool

Risk-of-Bias Questions Experimental Animal* Human Controlled Trials** Cohort Case-Control Cross-Sectional*** Case Series
  1. Was administered dose or exposure level adequately randomized?
X X
  1. Was allocation to study groups adequately concealed?
X X
  1. Did selection of study participants result in the appropriate comparison groups?
X X X
  1. Did study design or analysis account for important confounding and modifying variables?
X X X X
  1. Were experimental conditions identical across study groups?
X
  1. Were research personnel blinded to the study group during the study?
X X
  1. Were outcome data complete without attrition or exclusion from analysis?
X X X X X
  1. Can we be confident in the exposure characterization?
X X X X X X
  1. Can we be confident in the outcome assessment (including blinding of outcome assessors)?
X X X X X X
  1. Were all measured outcomes reported?
X X X X X X
  1. Were there no other potential threats to internal validity?
X X X X X X

* Experimental animal studies are controlled exposure studies. Nonhuman animal observational studies can be evaluated using the design features of observational human studies such as cross-sectional study design.

** Human Controlled Trials are studies in humans with controlled exposure (e.g., randomized controlled trials, nonrandomized experimental studies).

*** Cross-sectional studies include population surveys with individual data (e.g., NHANES) and surveys with aggregate data (i.e., ecological studies).

SOURCE: NTP (2015, p. 37).

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

TABLE E1-2 Answers to the Risk of Bias Questions

images Definitely Low risk of bias: There is direct evidence of low risk-of-bias practices.
images Probably Low risk of bias: There is indirect evidence of low risk-of-bias practices OR it is deemed that deviations from low risk-of-bias practices for these criteria during the study would not appreciably bias results, including consideration of direction and magnitude of bias.
images Probably High risk of bias: There is indirect evidence of high risk-of-bias practices (indicated with “-”) OR there is insufficient information provided about relevant risk-of-bias practices (indicated with “NR” for not reported). Both symbols indicate probably high risk of bias.
images Definitely High risk of bias: There is direct evidence of high risk-of-bias practices.

SOURCE: NTP (2015, p. 36).

  • Developmental stage of animals at treatment and outcome assessment
  • Dose levels, frequency of treatment, timing, duration, and exposure route
  • Health outcome(s) reported
  • 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. If a meta-analysis is considered appropriate, the review team will stratify by species and further consider separate meta-analyses by species. 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, benchmark dose (BMD) estimates (and their associated confidence intervals) with a benchmark response (BMR) set to a common percent of control (for continuous outcomes) or extra risk (for dichotomous outcomes) are preferred. A secondary alternative, when there are more than two groups, is the conduct of BMD modeling and the use of the derived BMD estimates. Meta-analyses are not possible with lowest-observed-adverse-effect levels or no-observed-adverse-effect levels, since no confidence interval can be derived for these measures.

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 exclusion of individual studies in succession.

If sufficient studies are available, subgroup analyses will be performed based on the following characteristics described above: experimental design, animal model used (e.g., species and/or strain), age of animals, and developmental stage of animals at treatment and outcome assessment.

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.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

Confidence Rating: Assessment of the Body of Evidence

The quality of evidence for each outcome will be evaluated using the GRADE system for rating the confidence in the body of evidence (Guyatt et al. 2011; Rooney et al. 2014). More detailed guidance on reaching confidence ratings in the body of evidence as “high,” “moderate,” “low,” or “very low” is provided in NTP (2016, see Step 5). In brief, available studies on a particular outcome are initially grouped by key study-design features, and each grouping of studies is given an initial confidence rating by those features.

The initial rating is downgraded for factors that decrease confidence in the results, including

  • risk of bias
  • unexplained inconsistency
  • indirectness or lack of applicability
  • imprecision
  • publication bias

The initial rating is upgraded for factors that increase confidence in the results, including

  • large magnitude of effect
  • dose response
  • consistency across study designs/populations/animal models or species
  • consideration of residual confounding
  • other factors that increase confidence in the association or effect (e.g., particularly rare outcomes)

The reasons for downgrading (or upgrading) confidence may not be due to a single domain of the body of evidence. If a decision to downgrade is borderline for two domains, the body of evidence is downgraded once in a single domain to account for both partial concerns based on considering the key drivers of the strengths or weaknesses. Similarly, the body of evidence is not downgraded twice for what is essentially the same limitation (or upgraded twice for the same asset) that could be considered applicable to more than one domain of the body of evidence. Consideration of consistency across study designs, human populations, or animal species is not included in the GRADE guidance (Guyatt et al. 2011); however, it is considered in the modified version of GRADE used by OHAT (Rooney et al. 2014).

Confidence ratings are independently assessed by members of the review team, and discrepancies will be resolved by consensus and consultation with technical advisors as needed. Confidence ratings will be summarized in evidence profile tables.

REFERENCES

Guyatt, G.H., A.D. Oxman, R. Kunz, J. Brozek, P. Alonso-Coello, D. Rind, P.J. Devereaux, V.M. Montori, B. Freyschuss, G. Vist, R. Jaeschke, J.W. Williams, Jr., M.H. Murad, D. Sinclair, Y. Falck-Ytter, J. Meerpohl, C. Whittington, K. Thorlund, J. Andrews, and H.J. Schunemann. 2011. GRADE guidelines 6. Rating the quality of evidence—imprecision. J. Clin. Epidemiol. 64(12):1283-1293.

Higgins, J., and S. Green, eds. 2011. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 (updated March 2011). The Cochrane Collaboration [online]. Available: http://handbook.cocharne.org [accessed May 6, 2016].

Hooijmans, C.R., M.M. Rovers, R.B. de Vries, M. Leenars, M. Ritskes-Hoitinga, and M.W. Langendam. 2014. SYRCLE’s risk of bias tool for animal studies. BMC Med. Res. Method. 14:43.

IOM (Institute of Medicine). 2011. Finding What Works in Health Care: Standards for Systematic Reviews. Washington, DC: The National Academies Press.

Koustas, E., J. Lam, P. Sutton, P.I. Johnson, D.S. Atchley, S. Sen, K.A. Robinson, D.A. Axelrad, and T.J. Woodruff. 2104. The Navigation Guide—evidence-based medicine meets environmental health: Systematic review of nonhuman evidence for PFOA effects on fetal growth. Environ. Health Perspect. 122(10):1015-1027.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

Moher, D., A. Liberati, J. Tetzlaff, and D.G. Altman. 2009. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. J. Clin. Epidemiol. 62(10):1006-1012.

NTP (National Toxicology Program). 2015. Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration. Office of Health Assessment and Translation, Division, National Toxicology Program, National Institute of Environmental Health Sciences. January 9, 2015 [online]. Available: http://ntp.niehs.nih.gov/ntp/ohat/pubs/handbookjan2015_508.pdf [accessed September 21, 2015].

Robinson, K.A., E.P. Whitlock, M.E. O’Neil, J.K. Anderson, L. Hartling, D.M. Dryden, M. Butler, S.J. Newberry, M. McPheeters, N.D. Berkman, J.S. Lin, and S. Chang S. 2014. Integration of Existing Systematic Reviews. Research white paper. AHRQ Publication No. 14-EHC016-EF. Rockville, MD: Agency for Healthcare Research and Quality [online]. Available: https://www.ncbi.nlm.nih.gov/books/NBK216379/ [accessed May 9, 2016].

Robinson, K.A., R. Chou, N.D. Berkman, S.J. Newberry, R. Fu, L. Hartling, D. Dryden, M. Butler, M. Foisy, J. Anderson, M. Motu’apuaka, R. Relevo, J.M. Guise, and S. Chang. 2015. Integrating Bodies of Evidence: Existing Systematic Reviews and Primary Studies. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 15-EHC007-EF. Rockville, MD: Agency for Healthcare Research and Quality [online]. Available: https://www.ncbi.nlm.nih.gov/books/NBK279904/ [accessed May 9, 2016].

Robinson, K.A., R. Chou, N.D. Berkman, S.J. Newberry, R. Fu, L. Hartling, D. Dryden, M. Butler, M. Foisy, J. Anderson, M. Motu’apuaka, R. Relevo, J.M. Guise, and S. Chang. 2016. Twelve recommendations for integrating existing systematic reviews into new reviews: EPC guidance. J. Clin. Epidemiol. 70:38-44.

Rooney, A.A., A.L. Boyles, M.S. Wolfe, J.R. Bucher, and K.A. Thayer. 2014. Systematic review and evidence integration for literature-based environmental health assessments. Environ. Health Perspect. 122(7):711-718.

Sterne, J.A.C., J.P.T. Higgins, and B.C. Reeves. 2014. ACROBAT-NRSI: A Cochrane risk of Bias Assessment Tool for Non-randomized Studies of Interventions. Version 1.0.0. September 24, 2014 [online]. Available: www.riskofbias.info [accessed May 6, 2016].

Viswanathan, M., M. Ansari, N.D. Berkman, S. Chang, L. Hartling, L.M. McPheeters, P.L. Santaguida, T. Shamliyan, K. Singh, A. Tsertsvadze, and J.R. Treadwell. 2012. Assessing the Risk of Bias of Individual Studies when Comparing Medical Interventions. AHRQ Publication No. 12-EHC047-EF. Rockville, MD: Agency for Healthcare Research and Quantitative Methods Guide for Comparative Effectiveness Reviews [online]. Available www.effectivehealthcare.ahrq.gov/ [accessed May 6, 2016].

Viswanathan, M., N.D. Berkman, D.M. Dryden, and L. Hartling. 2013. Assessing Risk of Bias and Confounding in Observational Studies of Interventions or Exposures: Further Development of the RTI Item Bank. Methods Research Report. AHRQ Publication No. 13-EHC106-EF. Rockville, MD: Agency for Healthcare Research and Quantitative Methods Guide for Comparative Effectiveness Reviews [online]. Available www.effectivehealthcare.ahrq.gov/reports/final.cfm [accessed May 6, 2016].

Whiting, P., J. Savovic, J.B. Higgins, D.M. Caldwell, B.C. Reeves, B. Shea, P. Davies, J. Kleijnen, and R. Churchill. 2016. ROBIS: A new tool to assess risk of bias in systematic reviews was developed. J. Clin. Epidemiol. 69:225-234.

Whitlock, E.P., J.S. Lin, R. Chou, P. Shekelle, and K.A. Robinson. 2008. Using existing systematic reviews in complex systematic reviews. Ann. Intern. Med. 148(10):776-782.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-1a

REVIEW TEAM BIOGRAPHICAL INFORMATION

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.

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.

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.

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.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-1b

LITERATURE SEARCH STRATEGY

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. The PubMed search strategy will be considered the primary search strategy and will provide the basis of the other electronic search strategies. 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 and timing of exposure in a parallel human population. 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.”
  • Exposure—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 exposure 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. All MeSH terms and keyword synonyms will be searched together as one concept using the Boolean operator “OR.”
  • Animal studies—The review team will adapt the search filter published in Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M. Enhancing search efficiency by means of a search filter for finding all studies on animal experimentation in PubMed. Laboratory Animals. 2010;44(3):170-175 to eliminate nonmammalian animals. doi:10.1258/la.2010.009117.
  • 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

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

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.

Embase

The controlled vocabulary database Emtree is used by Embase. For each MeSH term identified through process above, Emtree will be searched for the appropriate corresponding term. Additional keywords will identified using the list of synonyms from each Emtree record and added to the keywords from the MeSH records. The review team will substitute the animal study search filter used in the PubMed search with the comparable Embase filter published in De Vries RBM, Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M. A search filter for increasing the retrieval of animal studies in Embase. Laboratory Animals. 2011; 45(4):268-270. doi:10.1258/la.2011.011056. This version of the animal filter will also be adapted to remove all nonmammalian animals.

Toxline

The review team will develop the Toxline search strategy by removing any database specific formatting from the PubMed search strategy to create a keyword-only search (Toxline does not employ a controlled vocabulary).

Search Strategies

PubMed

(“Flame Retardants”[Mesh] OR”Flame Retardants” [Pharmacological Action] OR “Halogenated Diphenyl Ethers”[Mesh] OR (“Phenyl Ethers”[Mesh:NoExp] AND (“1974/01/01”[PDAT]: “2008/12/31”[PDAT])) OR “pentabromodiphenyl ether” [Supplementary Concept] 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’‐nonabromo-diphenyl 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]

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

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” OR “6876‐00‐2” OR “101‐55‐3” OR “51452-870” OR “446254‐14‐4” OR “147217‐72‐9” OR “171977‐449” OR “147217‐71‐8” OR “33513‐66‐3” OR “51930‐04‐2” OR “6903‐63‐5” OR “189084‐59‐1” OR “83694‐71‐7” OR “46438‐88‐4” OR “2050‐47‐7” OR “147217‐74‐1” OR “147217‐75‐2” OR “407606‐55‐7” OR “147217‐73‐0” OR “147217‐76‐3” OR “337513‐67‐4” OR “446254‐15‐5” OR “446254‐16‐6” OR “147217‐77‐4” OR “337513‐75‐4” OR “337513‐53‐8” OR “41318‐75‐6” OR “337513‐56‐1” OR “155999‐95‐4” OR “65075‐08‐3” OR “189084-60‐4” OR “147217‐78‐5” OR “446254‐17‐7” OR “147217‐80‐9” OR “147217‐79‐6” OR “147217‐81‐0” OR “337513‐54‐9” OR “337513‐68‐5” OR “446254‐18‐8” OR “446254‐19‐9” OR “446254‐20‐2” OR “446254‐22‐4” OR “5436‐43‐1” OR “337513‐55‐0” OR “243982‐82‐3” OR “446254‐23‐5” OR “189084-57‐9” OR “446254‐24‐6” OR “446254‐25‐7” OR “446254‐31‐5” OR “446254‐32‐6” OR “446254‐33‐7” OR “446254‐34‐8” OR “189084‐61‐5” OR “446254‐37‐1” OR “446254‐38‐2” OR “327185‐09‐1” OR “446254‐39‐3” OR “189084‐62‐6” OR “446254‐40‐6” OR “446254‐41‐7” OR “446254‐42‐8” OR “189084‐63‐7” OR “446254‐43‐9” OR “93703‐48‐1” OR “446254‐45‐1” OR “446254‐48‐4” OR “103173-66‐6” OR “446254‐50‐8” OR “446254‐51‐9” OR “182346‐21‐0” OR “446254‐53‐1” OR “446254‐54‐2” OR “446254‐55‐3” OR “446254‐55‐3” OR “446254‐57‐5” OR “446254‐59‐7” OR “446254‐61‐1” OR “446254‐64‐4” OR “38463‐82‐0” OR “60348‐60‐9” OR “189084‐64‐8” OR “446254‐65‐5” OR “446254-66‐6” OR “446254‐67‐7” OR “446254‐68‐8” OR “373594‐78‐6” OR “446254‐69‐9” OR “446254‐71‐3” OR “446254‐72‐4” OR “446254‐74‐6” OR “446254‐77‐9” OR “446254‐78‐0” OR “189084‐65‐9” OR “446254‐80‐4” OR “189084‐66‐0” OR “182677‐30‐1” OR “243982‐83‐4” OR “68631‐49‐2” OR “207122-15‐4” OR “35854‐94‐5” OR “189084‐58‐0” OR “189084‐67‐1” OR “207122‐16‐5” OR “189084‐68‐2” OR “1163‐19‐5” OR “109945‐70‐2” OR “113152‐37‐7” OR “113172‐79‐5” OR “139598‐16‐6” OR “139749-52‐3” OR “145538‐74‐5” OR “32534‐81‐9” OR “32536‐52‐0” OR “40088‐47‐9” OR “446254‐27‐9” OR “446255‐20‐5” OR “446255‐22‐7” OR “49690‐94‐0” OR “63936‐56‐1” OR “64589‐00‐0” OR “68928‐80-3” OR “85446‐17‐9” OR “36483‐60‐0” OR “437701‐79‐6” OR “446255‐26‐1” OR “117948‐63‐7” OR “446255‐30‐7” OR “61262‐53‐1” OR “405237‐85‐6” OR “39275‐89‐3” OR “13654‐09‐6” OR “61288‐13-9” OR “446255‐39‐6” OR “337513‐72‐1” OR “366791‐32‐4” OR “2050‐47‐7”) AND (“Occupational Exposure”[Mesh:NoExp] OR “Maternal Exposure”[Mesh] OR “Environmental Exposure”[Mesh] OR “Prenatal Exposure Delayed Effects”[Mesh] OR “Exposure”[tw] OR “Exposed”[tw] OR “exposures”[tw] OR “exposing”[tw]) AND (“animal experimentation”[MeSH Terms] OR “models, animal”[MeSH Terms] OR “invertebrates”[MeSH Terms] OR “Animals”[Mesh:noexp] OR “animal population groups”[MeSH Terms] OR “mammals”[MeSH Terms:noexp] OR “primates”[MeSH Terms:noexp] OR “artiodactyla”[MeSH Terms] OR “carnivora”[MeSH Terms] OR “cetacea”[MeSH Terms] OR “chiroptera”[MeSH Terms] OR “elephants”[MeSH Terms] OR “hyraxes”[MeSH Terms] OR “insectivora”[MeSH Terms] OR “lagomorpha”[MeSH Terms] OR “marsupialia”[MeSH Terms] OR “monotremata”[MeSH Terms] OR “perissodactyla”[MeSH Terms] OR “rodentia”[MeSH Terms] OR “scandentia”[MeSH Terms] OR “sirenia”[MeSH Terms] OR “xenarthra”[MeSH Terms] OR “haplorhini”[MeSH Terms:noexp] OR “strepsirhini”[MeSH Terms] OR “platyrrhini”[MeSH Terms] OR “tarsii”[MeSH Terms] OR “catarrhini”[MeSH Terms:noexp] OR “cercopithecidae”[MeSH Terms] OR “hylobatidae”[MeSH Terms] OR “hominidae”[MeSH Terms:noexp] OR “gorilla gorilla”[MeSH Terms] OR “pan paniscus”[MeSH Terms] OR “pan troglodytes”[MeSH Terms] OR “pongo pygmaeus”[MeSH Terms] animals[tiab] OR animal[tiab] OR mice[Tiab] OR mus[Tiab] OR mouse[Tiab] OR murine[Tiab] OR woodmouse[tiab] OR rats[Tiab] OR rat[Tiab] OR murinae[Tiab] OR muridae[Tiab] OR cottonrat[tiab] OR cottonrats[tiab] OR hamster[tiab] OR hamsters[tiab] OR cricetinae[tiab] OR rodentia[Tiab] OR rodent[Tiab] OR rodents[Tiab] OR pigs[Tiab] OR pig[Tiab] OR swine[tiab] OR swines[tiab] OR piglets[tiab] OR piglet[tiab] OR boar[tiab] OR boars[tiab]

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

OR “sus scrofa”[tiab] OR ferrets[tiab] OR ferret[tiab] OR polecat[tiab] OR polecats[tiab] OR “mustela putorius”[tiab] OR “guinea pigs”[Tiab] OR “guinea pig”[Tiab] OR cavia[Tiab] OR callithrix[Tiab] OR marmoset[Tiab] OR marmosets[Tiab] OR cebuella[Tiab] OR hapale[Tiab] OR octodon[Tiab] OR chinchilla[Tiab] OR chinchillas[Tiab] OR gerbillinae[Tiab] OR gerbil[Tiab] OR gerbils[Tiab] OR jird[Tiab] OR jirds[Tiab] OR merione[Tiab] OR meriones[Tiab] OR rabbits[Tiab] OR rabbit[Tiab] OR hares[Tiab] OR hare[Tiab] OR cats[Tiab] OR cat[Tiab] OR felis[Tiab] OR dogs[Tiab] OR dog[Tiab] OR canine[Tiab] OR canines[Tiab] OR canis[Tiab] OR sheep[Tiab] OR sheeps[Tiab] OR mouflon[Tiab] OR mouflons[Tiab] OR ovis[Tiab] OR goats[Tiab] OR goat[Tiab] OR capra[Tiab] OR capras[Tiab] OR rupicapra[Tiab] OR chamois[Tiab] OR haplorhini[Tiab] OR monkey[Tiab] OR monkeys[Tiab] OR anthropoidea[Tiab] OR anthropoids[Tiab] OR saguinus[Tiab] OR tamarin[Tiab] OR tamarins[Tiab] OR leontopithecus[Tiab] OR hominidae[Tiab] OR ape[Tiab] OR apes[Tiab] OR pan[Tiab] OR paniscus[Tiab] OR “pan paniscus”[Tiab] OR bonobo[Tiab] OR bonobos[Tiab] OR “pan troglodytes”[Tiab] OR gibbon[Tiab] OR gibbons[Tiab] OR siamang[Tiab] OR siamangs[Tiab] OR nomascus[Tiab] OR symphalangus[Tiab] OR chimpanzee[Tiab] OR chimpanzees[Tiab] OR prosimians[Tiab] OR “bush baby”[Tiab] OR prosimian[Tiab] OR bush babies[Tiab] OR galagos[Tiab] OR galago[Tiab] OR pongidae[Tiab] OR gorilla[Tiab] OR gorillas[Tiab] OR pongo[Tiab] OR “pongo pygmaeus”[Tiab] OR orangutans[Tiab] OR lemur[Tiab] OR lemurs[Tiab] OR lemuridae[Tiab] OR horse[Tiab] OR horses[Tiab] OR pongo[Tiab] OR equus[Tiab] OR cow[Tiab] OR calf[Tiab] OR bull[Tiab] OR chicken[Tiab] OR chickens[Tiab] OR squirrel[Tiab] OR squirrels[Tiab] OR chipmunk[Tiab] OR chipmunks[Tiab] OR suslik[Tiab] OR susliks[Tiab] OR vole[Tiab] OR voles[Tiab] OR lemming[Tiab] OR lemmings[Tiab] OR muskrat[Tiab] OR muskrats[Tiab] OR lemmus[Tiab] OR otter[Tiab] OR otters[Tiab] OR marten[Tiab] OR martens[Tiab] OR martes[Tiab] OR weasel[Tiab] OR badger[Tiab] OR badgers[Tiab] OR ermine[Tiab] OR mink[Tiab] OR minks[Tiab] OR sable[Tiab] OR sables[Tiab] OR gulo[Tiab] OR gulos[Tiab] OR wolverine[Tiab] OR wolverines[Tiab] OR minks[Tiab] OR mustela[Tiab] OR llama[Tiab] OR llamas[Tiab] OR alpaca[Tiab] OR alpacas[Tiab] OR camelid[Tiab] OR camelids[Tiab] OR guanaco[Tiab] OR guanacos[Tiab] OR chiroptera[Tiab] OR chiropteras[Tiab] OR bat[Tiab] OR bats[Tiab] OR fox[Tiab] OR foxes[Tiab] OR donkey[Tiab] OR donkeys[Tiab] OR mule[Tiab] OR mules[Tiab] OR zebra[Tiab] OR zebras[Tiab] OR shrew[Tiab] OR shrews[Tiab] OR bison[Tiab] OR bisons[Tiab] OR buffalo[Tiab] OR buffaloes[Tiab] OR deer[Tiab] OR deers[Tiab] OR bear[Tiab] OR bears[Tiab] OR panda[Tiab] OR pandas[Tiab] OR “wild hog”[Tiab] OR “wild boar”[Tiab] OR fitchew[Tiab] OR fitch[Tiab] OR beaver[Tiab] OR beavers[Tiab] OR jerboa[Tiab] OR jerboas[Tiab] OR capybara[Tiab] OR capybaras[Tiab]) AND (“Attention”[Mesh] OR “attention”[tiab] OR “concentration”[tiab] OR “attentiveness”[tiab] OR “Behavior”[Mesh] OR “behavior”[tiab] OR “behaviour”[tiab] OR “behavioral”[tiab] OR “behavioural”[tiab] OR “behaviors”[tiab] OR “behaviours”[tiab] OR “Cognition”[Mesh] OR “Cognition Disorders”[Mesh] OR “cognition”[tiab] OR “cognitive”[tiab] OR “Developmental Disabilities”[Mesh] OR “developmental”[tiab] OR “Neurodevelopmental Disorders”[Mesh] OR “neurodevelopmental”[tiab] OR “neurodevelopment”[tiab] OR “neuropsychological”[tiab] OR “Executive Function”[Mesh] OR “executive function”[tiab] OR “executive functioning”[tiab] OR “Motor Activity”[Mesh] OR “locomotor”[tiab] OR “motor”[tiab] OR “Memory”[Mesh] OR “memory”[tiab] OR “Metacognition”[Mesh] OR “metacognition”[tiab] OR “metacognitive”[tiab] OR “Neurobehavioral Manifestations”[Mesh] OR “neurobehavioural”[tiab] OR “neurobehavioral”[tiab] OR “Neurotoxicity Syndromes”[Mesh] OR “neurotoxic”[tiab] OR “neurotoxicity” OR “neurotoxicant”[tiab] OR “neurotoxicants”[tiab] OR “neurotoxia”[tiab] OR “neurotoxicosis”[tiab] OR “processing speed”[tiab] OR “Spatial Learning”[Mesh] OR “spatial learning”[tiab] OR “Maze Learning”[Mesh] OR “maze”[tiab])

Embase

(‘flame retardant’/de OR ‘2,2’,4,4’,5,5’ hexabromodiphenyl ether’/exp OR ‘polybrominated diphenyl ether’/exp OR ‘diphenyl ether derivative’/exp OR ((flame NEXT/1 retard*) OR (fire NEXT/1 retard*) OR (fireproofing NEXT/1 agent*) OR “FireMaster” OR “Bromkal” OR (‘diphenyl ether’ NEXT/1 deriv*) OR (Halogenated NEXT/1 Diphenyl*) OR (Brominated NEXT/1 Diphenyl*) OR PBDE* OR (Polybrominated NEXT/1 Diphenyl*) OR polybromodiphenyl* OR PBDP* OR BDE* OR pentabromo-

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

diphenyl* OR PentaBDE* OR “PeBDE” OR “DE 71” OR “DE71” OR “pentabrominated diphenyl” OR “pentabrominated diphenyls” OR “PBDPO” OR “Planelon PB 501” OR (pentabromo NEXT/1 deriv*) OR Pentabromophenyl* OR octabromodiphenyl* OR OctaBDE* OR “OcBDE” OR “Octabrom” OR “OBDE” OR “OBDPO” OR (octabromo NEXT/1 deriv*) OR “octabrominated diphenyl” OR “octabrominated diphenyls” OR decabromodiphenyl* OR DecaBDE* OR “DeBDE” OR “DBDPO” OR “decabrominated diphenyl” OR “decabrominated diphenyls” OR (decabromo NEXT/1 deriv*) OR “Decabrom” OR “Berkflam B 10E” OR “FR 300BA” OR “FR 300 BA” OR tribromodiphenyl* OR “tribrominated diphenyl” OR “tribrominated diphenyls” OR “TrBDE” OR (tribromo NEXT/1 deriv*) OR tetrabromodiphenyl* OR TetraBDE* OR “TeBDE” OR “TBDE” OR “BPDE” OR (tetrabromo NEXT/1 deriv*) OR “TBDP” OR “tetrabrominated diphenyl” OR “tetrabrominated diphenyls” OR hexabromodiphenyl* OR HexaBDE* OR “HxBDE” OR “hexabrominated diphenyl” OR “hexabrominated diphenyls” OR (hexabromo NEXT/1 deriv*) OR heptabromodiphenyl* OR HeptaBDE* OR “HeBDE” OR “heptabrominated diphenyl” OR “heptabrominated diphenyls” OR (heptabromo NEXT/1 deriv*) OR nonabromodiphenyl* OR NonaBDE* OR “NoBDE” OR “nonabrominated diphenyl” OR “nonabrominated diphenyls” OR (nonabromo NEXT/1 deriv*)):ti,ab,tn,rn OR (“7025‐06‐1” OR “6876‐00‐2” OR “101‐55‐3” OR “51452‐87‐0” OR “44625414‐4” OR “147217‐72‐9” OR “171977‐44‐9” OR “147217‐71‐8” OR “33513‐663” OR “51930‐04‐2” OR “6903‐63‐5” OR “189084‐59‐1” OR “83694‐71‐7” OR “46438‐88‐4” OR “2050‐47‐7” OR “147217‐74‐1” OR “147217‐75‐2” OR “407606‐55‐7” OR “147217‐73‐0” OR “147217‐76‐3” OR “337513‐67‐4” OR “446254‐15‐5” OR “446254‐16‐6” OR “147217‐77‐4” OR “337513‐75‐4” OR “337513‐53‐8” OR “41318‐75‐6” OR “337513‐56‐1” OR “155999‐95‐4” OR “65075-08‐3” OR “189084‐60‐4” OR “147217‐78‐5” OR “446254‐17‐7” OR “147217‐80‐9” OR “147217‐79‐6” OR “147217‐81‐0” OR “337513‐54‐9” OR “337513‐68‐5” OR “446254‐18‐8” OR “446254‐19‐9” OR “446254‐20‐2” OR “446254‐22‐4” OR “5436‐43‐1” OR “337513‐55‐0” OR “243982‐82‐3” OR “446254-23‐5” OR “189084‐57‐9” OR “446254‐24‐6” OR “446254‐25‐7” OR “446254‐31‐5” OR “446254‐32‐6” OR “446254‐33‐7” OR “446254‐34‐8” OR “189084‐61‐5” OR “446254‐37‐1” OR “446254‐38‐2” OR “327185‐09‐1” OR “446254‐39‐3” OR “189084‐62‐6” OR “446254‐40‐6” OR “446254‐417” OR “446254‐42‐8” OR “189084‐63‐7” OR “446254‐43‐9” OR “93703‐481” OR “446254‐45‐1” OR “446254‐48‐4” OR “103173‐66‐6” OR “446254‐508” OR “446254‐51‐9” OR “182346‐21‐0” OR “446254‐53‐1” OR “446254‐542” OR “446254‐55‐3” OR “446254‐55‐3” OR “446254‐57‐5” OR “44625459‐7” OR “446254‐61‐1” OR “446254‐64‐4” OR “38463‐82‐0” OR “6034860‐9” OR “189084-64‐8” OR “446254‐65‐5” OR “446254‐66‐6” OR “446254‐67‐7” OR “446254‐68‐8” OR “373594‐78‐6” OR “446254‐69‐9” OR “446254‐71‐3” OR “446254‐72‐4” OR “446254‐74‐6” OR “446254‐779” OR “446254‐78‐0” OR “189084‐65‐9” OR “446254‐80‐4” OR “18908466‐0” OR “182677‐30‐1” OR “243982‐83‐4” OR “68631‐49‐2” OR “20712215‐4” OR “35854‐94‐5” OR “189084‐58‐0” OR “189084-67‐1” OR “20712216‐5” OR “189084‐68‐2” OR “1163‐19‐5” OR “109945‐70‐2” OR “113152‐37‐7” OR “113172‐79‐5” OR “139598‐16‐6” OR “139749‐52‐3” OR “145538‐74‐5” OR “32534‐81‐9” OR “32536-52‐0” OR “40088‐47‐9” OR “446254‐27‐9” OR “446255‐20‐5” OR “446255‐22‐7” OR “49690‐94‐0” OR “63936‐56‐1” OR “64589‐00‐0” OR “68928‐80‐3” OR “85446‐17‐9” OR “36483‐60‐0” OR “437701‐79‐6” OR “446255‐26‐1” OR “117948‐63‐7” OR “446255‐30‐7” OR “61262‐53‐1” OR “405237‐85‐6” OR “39275‐89‐3” OR “13654‐09‐6” OR “61288‐13‐9” OR “446255‐39‐6” OR “337513-72‐1” OR “366791‐32‐4” OR “2050‐47‐7”):ti,ab,rn) AND (‘ape’/de OR ‘bat’/exp OR ‘carnivora’/exp OR ‘catarrhini’/de OR ‘cercopithecidae’/exp OR ‘cetacea’/exp OR ‘chimpanzee’/exp OR ‘chordata’/de OR ‘elephant’/exp OR ‘gorilla’/exp OR ‘haplorhini’/de OR ‘hominid’/de OR ‘hylobatidae’/exp OR ‘hyrax’/exp OR ‘lagomorph’/exp OR ‘mammal’/de OR ‘marsupial’/exp OR ‘monotremate’/exp OR ‘orangutan’/exp OR ‘placental mammals’/de OR ‘platyrrhini’/exp OR ‘primate’/de OR ‘prosimian’/exp OR ‘rodent’/exp OR ‘scandentia’/exp OR ‘simian’/de OR ‘sirenia’/exp OR ‘tarsiiform’/exp OR ‘ungulate’/exp OR ‘vertebrate’/de OR ‘xenarthra’/exp OR animals:ti,ab OR animal:ti,ab OR mice:ti,ab OR mus:ti,ab OR mouse:ti,ab OR murine:ti,ab OR woodmouse:ti,ab OR rats:ti,ab OR rat:ti,ab OR murinae:ti,ab OR muridae:ti,ab OR cottonrat:ti,ab OR cottonrats:ti,ab OR hamster:ti,ab OR hamsters:ti,ab OR cricetinae:ti,ab OR rodentia:ti,ab OR rodent:ti,ab OR rodents:ti,ab OR pigs:ti,ab OR pig:ti,ab OR swine:ti,ab OR

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

swines:ti,ab OR piglets:ti,ab OR piglet:ti,ab OR boar:ti,ab OR boars:ti,ab OR “sus scrofa”:ti,ab OR ferrets:ti,ab OR ferret:ti,ab OR polecat:ti,ab OR polecats:ti,ab OR “mustela putorius”:ti,ab OR “guinea pigs”:ti,ab OR “guinea pig”:ti,ab OR cavia:ti,ab OR callithrix:ti,ab OR marmoset:ti,ab OR marmosets:ti,ab OR cebuella:ti,ab OR hapale:ti,ab OR octodon:ti,ab OR chinchilla:ti,ab OR chinchillas:ti,ab OR gerbillinae:ti,ab OR gerbil:ti,ab OR gerbils:ti,ab OR jird:ti,ab OR jirds:ti,ab OR merione:ti,ab OR meriones:ti,ab OR rabbits:ti,ab OR rabbit:ti,ab OR hares:ti,ab OR hare:ti,ab OR cats:ti,ab OR cat:ti,ab OR felis:ti,ab OR dogs:ti,ab OR dog:ti,ab OR canine:ti,ab OR canines:ti,ab OR canis:ti,ab OR sheep:ti,ab OR sheeps:ti,ab OR mouflon:ti,ab OR mouflons:ti,ab OR ovis:ti,ab OR goats:ti,ab OR goat:ti,ab OR capra:ti,ab OR capras:ti,ab OR rupicapra:ti,ab OR chamois:ti,ab OR haplorhini:ti,ab OR monkey:ti,ab OR monkeys:ti,ab OR anthropoidea:ti,ab OR anthropoids:ti,ab OR saguinus:ti,ab OR tamarin:ti,ab OR tamarins:ti,ab OR leontopithecus:ti,ab OR hominidae:ti,ab OR ape:ti,ab OR apes:ti,ab OR pan:ti,ab OR paniscus:ti,ab OR “pan paniscus”:ti,ab OR bonobo:ti,ab OR bonobos:ti,ab OR “pan troglodytes”:ti,ab OR gibbon:ti,ab OR gibbons:ti,ab OR siamang:ti,ab OR siamangs:ti,ab OR nomascus:ti,ab OR symphalangus:ti,ab OR chimpanzee:ti,ab OR chimpanzees:ti,ab OR prosimians:ti,ab OR “bush baby”:ti,ab OR prosimian:ti,ab OR bush babies:ti,ab OR galagos:ti,ab OR galago:ti,ab OR pongidae:ti,ab OR gorilla:ti,ab OR gorillas:ti,ab OR pongo:ti,ab OR “pongo pygmaeus”:ti,ab OR orangutans:ti,ab OR lemur:ti,ab OR lemurs:ti,ab OR lemuridae:ti,ab OR horse:ti,ab OR horses:ti,ab OR pongo:ti,ab OR equus:ti,ab OR cow:ti,ab OR calf:ti,ab OR bull:ti,ab OR chicken:ti,ab OR chickens:ti,ab OR squirrel:ti,ab OR squirrels:ti,ab OR chipmunk:ti,ab OR chipmunks:ti,ab OR suslik:ti,ab OR susliks:ti,ab OR vole:ti,ab OR voles:ti,ab OR lemming:ti,ab OR lemmings:ti,ab OR muskrat:ti,ab OR muskrats:ti,ab OR lemmus:ti,ab OR otter:ti,ab OR otters:ti,ab OR marten:ti,ab OR martens:ti,ab OR martes:ti,ab OR weasel:ti,ab OR badger:ti,ab OR badgers:ti,ab OR ermine:ti,ab OR mink:ti,ab OR minks:ti,ab OR sable:ti,ab OR sables:ti,ab OR gulo:ti,ab OR gulos:ti,ab OR wolverine:ti,ab OR wolverines:ti,ab OR minks:ti,ab OR mustela:ti,ab OR llama:ti,ab OR llamas:ti,ab OR alpaca:ti,ab OR alpacas:ti,ab OR camelid:ti,ab OR camelids:ti,ab OR guanaco:ti,ab OR guanacos:ti,ab OR chiroptera:ti,ab OR chiropteras:ti,ab OR bat:ti,ab OR bats:ti,ab OR fox:ti,ab OR foxes:ti,ab OR donkey:ti,ab OR donkeys:ti,ab OR mule:ti,ab OR mules:ti,ab OR zebra:ti,ab OR zebras:ti,ab OR shrew:ti,ab OR shrews:ti,ab OR bison:ti,ab OR bisons:ti,ab OR buffalo:ti,ab OR buffaloes:ti,ab OR deer:ti,ab OR deers:ti,ab OR bear:ti,ab OR bears:ti,ab OR panda:ti,ab OR pandas:ti,ab OR “wild hog”:ti,ab OR “wild boar”:ti,ab OR fitchew:ti,ab OR fitch:ti,ab OR beaver:ti,ab OR beavers:ti,ab OR jerboa:ti,ab OR jerboas:ti,ab OR capybara:ti,ab OR capybaras:ti,ab) AND (“attention”/exp OR “attention”:ti,ab OR “concentration”:ti,ab OR “attentiveness”:ti,ab OR “behavior”/exp OR “behavior”:ti,ab OR “behaviour”:ti,ab OR “behavioral”:ti,ab OR “behavioural”:ti,ab OR “behaviors”:ti,ab OR “behaviours”:ti,ab OR “cognition”/exp OR “cognition”:ti,ab OR “cognitive”:ti,ab OR “cognition assessment”/exp OR “developmental disorder”/exp OR “developmental”:ti,ab OR “executive function”/exp OR “executive function”:ti,ab OR “executive functioning”:ti,ab OR “motor activity”/exp OR “locomotor”:ti,ab OR “motor”:ti,ab OR “memory”/exp OR “memory”:ti,ab OR “metacognition”/exp OR “metacognition”:ti,ab OR “metacognitive”:ti,ab OR “neurobehavioural”:ti,ab OR “neurobehavrioral”:ti,ab OR “neurotoxicity”/exp OR “neurotoxic”:ti,ab OR “neurotoxicity” OR “neurotoxicant”:ti,ab OR “neurotoxicants”:ti,ab OR “neurotoxia”:ti,ab OR “neurotoxicosis”:ti,ab OR “processing speed”:ti,ab OR “spatial learning”/exp OR “spatial learning”:ti,ab OR “maze test”/exp OR “maze”:ti,ab)

Toxline

(“flame retard*” OR “fire retard*” OR “fireproofing agent*” OR “FireMaster” OR “Bromkal” OR “diphenyl ether deriv*” OR “Halogenated Diphenyl*” OR “Brominated Diphenyl*” OR PBDE* OR “Polybrominated Diphenyl*” OR polybromodiphenyl* OR PBDP* OR BDE* OR pentabromodiphenyl* OR “c‐pentaBDE*” OR PentaBDE* OR “PeBDE” OR “DE 71” OR “DE71” OR “pentabrominated diphenyl*” OR “PBDPO” OR “Planelon PB 501” OR “pentabromo deriv*” OR Pentabromophenyl* OR octabromodiphenyl* OR “c‐octaBDE*” OR OctaBDE* OR “OcBDE” OR “Octabrom” OR “octabromo deriv*” OR “OBDE” OR “OBDPO” OR “octabrominated diphenyl*” OR decabromodiphenyl* OR “cdecaBDE*” OR DecaBDE* OR “DeBDE” OR “DBDPO” OR “decabrominated diphenyl*” OR

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

“decabromo deriv*” OR “Decabrom” OR “Berkflam B 10E” OR “FR 300BA” OR “FR 300 BA” OR tribromodiphenyl* OR “tribrominated diphenyl*” OR “TrBDE” OR “tribromo deriv*” OR tetrabromodiphenyl* OR TetraBDE* OR “TeBDE” OR “TBDE” OR “BPDE” OR “tetrabromo deriv*” OR “TBDP” OR “tetrabrominated diphenyl*” OR hexabromodiphenyl* OR HexaBDE* OR “HxBDE” OR “hexabrominated diphenyl*” OR “hexabromo deriv*” OR heptabromodiphenyl* OR HeptaBDE* OR “HeBDE” OR “heptabrominated diphenyl*” OR “heptabromo deriv*” OR nonabromodiphenyl* OR NonaBDE* OR “NoBDE” OR “nonabrominated diphenyl*” OR “nonabromo deriv*” OR “7025‐06‐1” OR “6876‐00‐2” OR “101‐55‐3” OR “51452‐87‐0” OR “446254‐14‐4” OR “147217‐72‐9” OR “171977‐44‐9” OR “147217‐71‐8” OR “33513‐66‐3” OR “51930‐04‐2” OR “6903‐63‐5” OR “189084‐59‐1” OR “83694‐71-7” OR “46438‐88‐4” OR “2050‐47‐7” OR “147217‐74‐1” OR “147217‐75‐2” OR “407606‐55‐7” OR “147217‐73‐0” OR “147217‐763” OR “337513‐67‐4” OR “446254‐15‐5” OR “446254‐16‐6” OR “14721777‐4” OR “337513‐75‐4” OR “337513‐53‐8” OR “41318‐75‐6” OR “337513‐56‐1” OR “155999‐95‐4” OR “65075‐08‐3” OR “189084‐60‐4” OR “147217‐78‐5” OR “446254‐17‐7” OR “147217‐80‐9” OR “147217‐796” OR “147217‐81‐0” OR “337513‐54‐9” OR “337513‐68‐5” OR “44625418‐8” OR “446254‐19‐9” OR “446254‐20‐2” OR “446254‐22‐4” OR “5436‐43‐1” OR “337513-55‐0” OR “243982‐82‐3” OR “446254‐23‐5” OR “189084‐57‐9” OR “446254‐24‐6” OR “446254‐25‐7” OR “446254‐31‐5” OR “446254‐32‐6” OR “446254‐33‐7” OR “446254‐348” OR “189084‐61‐5” OR “446254‐37‐1” OR “446254‐38‐2” OR “327185‐09‐1” OR “446254‐39‐3” OR “189084‐62‐6” OR “446254‐406” OR “446254‐41‐7” OR “446254‐42‐8” OR “189084‐63‐7” OR “446254‐43‐9” OR “93703‐48‐1” OR “446254‐45‐1” OR “446254‐48‐4” OR “103173‐66‐6” OR “446254‐50‐8” OR “446254‐51‐9” OR “18234621‐0” OR “446254‐53‐1” OR “446254‐54‐2” OR “446254‐55‐3” OR “446254‐55‐3” OR “446254‐57‐5” OR “446254‐59‐7” OR “446254‐611” OR “446254‐64‐4” OR “38463‐82‐0” OR “60348‐60‐9” OR “189084‐64‐8” OR “446254‐65‐5” OR “446254‐66‐6” OR “446254-677” OR “446254‐68‐8” OR “373594‐78‐6” OR “446254‐69‐9” OR “446254‐71‐3” OR “446254‐72‐4” OR “446254‐74‐6” OR “446254‐779” OR “446254‐78‐0” OR “189084‐65‐9” OR “446254‐80‐4” OR “189084‐66‐0” OR “182677‐30‐1” OR “243982‐83‐4” OR “68631‐49‐2” OR “207122‐15‐4” OR “35854-94‐5” OR “189084‐58‐0” OR “18908467‐1” OR “207122‐16‐5” OR “189084‐68‐2” OR “1163‐19‐5” OR “109945‐70‐2” OR “113152‐37‐7” OR “113172‐79‐5” OR “139598‐16‐6” OR “139749‐52‐3” OR “145538‐74‐5” OR “32534‐81‐9” OR “32536‐520” OR “40088‐47‐9” OR “446254‐27‐9” OR “446255-20‐5” OR “446255‐22‐7” OR “49690‐94‐0” OR “63936‐56‐1” OR “64589‐00‐0” OR “68928‐80‐3” OR “85446‐17‐9” OR “36483‐60‐0” OR “437701‐796” OR “446255‐26‐1” OR “117948‐63‐7” OR “446255-30‐7” OR “6126253‐1” OR “405237‐85‐6” OR “39275‐89‐3” OR “13654‐09‐6” OR “61288‐13‐9” OR “446255‐39‐6” OR “337513‐72‐1” OR “366791‐32‐4” OR “2050‐47‐7”) AND (animals OR animal OR mice OR mus OR mouse OR murine OR woodmouse OR rats OR rat OR murinae OR muridae OR cottonrat OR cottonrats OR hamster OR hamsters OR cricetinae OR rodentia OR rodent OR rodents OR pigs OR pig OR swine OR swines OR piglets OR piglet OR boar OR boars OR “sus scrofa” OR ferrets OR ferret OR polecat OR polecats OR “mustela putorius” OR “guinea pigs” OR “guinea pig” OR cavia OR callithrix OR marmoset OR marmosets OR cebuella OR hapale OR octodon OR chinchilla OR chinchillas OR gerbillinae OR gerbil OR gerbils OR jird OR jirds OR merione OR meriones OR rabbits OR rabbit OR hares OR hare OR cats OR cat OR felis OR dogs OR dog OR canine OR canines OR canis OR sheep OR sheeps OR mouflon OR mouflons OR ovis OR goats OR goat OR capra OR capras OR rupicapra OR chamois OR haplorhini OR monkey OR monkeys OR anthropoidea OR anthropoids OR saguinus OR tamarin OR tamarins OR leontopithecus OR hominidae OR ape OR apes OR pan OR paniscus OR “pan paniscus” OR bonobo OR bonobos OR “pan troglodytes” OR gibbon OR gibbons OR siamang OR siamangs OR nomascus OR symphalangus OR chimpanzee OR chimpanzees OR prosimians OR “bush baby” OR prosimian OR bush babies OR galagos OR galago OR pongidae OR gorilla OR gorillas OR pongo OR “pongo pygmaeus” OR orangutans OR lemur OR lemurs OR lemuridae OR horse OR horses OR pongo OR equus OR cow OR calf OR bull OR chicken OR chickens OR squirrel OR squirrels OR chipmunk OR chipmunks OR suslik OR susliks OR vole OR voles OR lemming OR lemmings OR muskrat OR muskrats OR lemmus OR otter OR otters OR marten OR martens OR martes OR weasel OR

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

badger OR badgers OR ermine OR mink OR minks OR sable OR sables OR gulo OR gulos OR wolverine OR wolverines OR minks OR mustela OR llama OR llamas OR alpaca OR alpacas OR camelid OR camelids OR guanaco OR guanacos OR chiroptera OR chiropteras OR bat OR bats OR fox OR foxes OR donkey OR donkeys OR mule OR mules OR zebra OR zebras OR shrew OR shrews OR bison OR bisons OR buffalo OR buffaloes OR deer OR deers OR bear OR bears OR panda OR pandas OR “wild hog” OR “wild boar” OR fitchew OR fitch OR beaver OR beavers OR jerboa OR jerboas OR capybara OR capybaras) AND (“Exposure” OR “Exposed” OR “exposures” OR “exposing”) AND (“attention” OR “concentration” OR “attentiveness” OR “behavior” OR “behaviour” OR “behavioral” OR “behavioural” OR “behaviors” OR “behaviours” OR “Cognition Disorders”[Mesh] OR “cognition” OR “cognitive” OR “developmental” OR “executive function” OR “executive functioning” OR “locomotor” OR “motor” OR “memory” OR “metacognition” OR “metacognitive” OR “neurobehavioural” OR “neurobehavrioral” OR “neurotoxic” OR “neurotoxicity” OR “neurotoxicant” OR “neurotoxicants” OR “neurotoxia” OR “neurotoxicosis” OR “processing speed” OR “spatial learning” OR “maze”)

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-1c

SCREENING FORMS

Title and Abstract Screening Form

Instructions: When a citation is excluded, reason should be specified.

Exclusion Reasons
No original data (e.g., review article, commentary, editorial)
Study does not include nonhuman mammals
Study does not report PBDE exposure
No relevant outcomes
Incomplete information (e.g., conference abstract, meeting poster)
Not in English and unable to determine eligibility
Other (explanation required)

Full-Text Screening Form

Instructions: When a citation is excluded, reason should be specified.

Exclusion Reasons
No original data (e.g., review article, commentary, editorial)
Study does not include nonhuman mammals
Study does not report PBDE exposure
Study does not quantify exposure to PBDE
Study does not include developmental exposure
Study does not assess or report quantitative measures of learning, memory, attention, or response inhibition
No comparator group (different doses or vehicle-only treatment)
Not in English and unable to determine eligibility
Other (explanation required)
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-1d

DATA EXTRACTION ELEMENTS FOR ANIMAL STUDIES

Funding Funding source(s)
Reporting of COI by authors (*reporting bias)
Animal Model Sex
Species
Strain
Source of animals
Age or life stage at start of dosing and at health outcome assessment
Diet and husbandry information (e.g., diet name/source)
Treatment Chemical name and CAS number
Source of chemical
Purity of chemical (*information bias)
Dose levels or concentration (as presented and converted to mg/kg bw/d when possible)
Other dose-related details, such as whether administered dose level was verified by measurement, information on internal dosimetry (*information bias)
Vehicle used for exposed animals
Route of administration (e.g., oral, inhalation, dermal, injection)
Duration and frequency of dosing (e.g., hours, days, weeks when administration was ended, days per week)
Methods Study design (e.g., single treatment, acute, subchronic (e.g., 90 days in a rodent), chronic, multigenerational, developmental, other)
Guideline compliance (i.e., use of EPA, OECD, NTP or another guideline for study design, conducted under GLP guideline conditions, non-GLP but consistent with guideline study, non-guideline peer-reviewed publication)
Number of animals per group (and dams per group in developmental studies) (*missing data bias)
Randomization procedure, allocation concealment, blinding during outcome assessment (*selection bias)
Method to control for litter effects in developmental studies (*information bias)
Use of negative controls and whether controls were untreated, vehicle-treated, or both
Report on data from positive controls—was expected response observed? (*information bias)
End point health category (e.g., reproductive)
End point (e.g., infertility)
Diagnostic or method to measure end point (*information bias)
Statistical methods (*information bias)
Results Measures of effect at each dose or concentration level (e.g., mean, median, frequency, and measures of precision or variance) or description of qualitative results. When possible, measures of effect will be converted to a common metric with associated 95% confidence intervals (CI). Most often, measures of effect for continuous data will be expressed as mean difference, standardized mean difference, and percent control response. Categorical data will be expressed as relative risk (RR, also called risk ratio).
No-observed-effect level (NOEL), lowest-observed-effect level (LOEL), benchmark dose (BMD) analysis, statistical significance of other dose levels, or other estimates of effect presented in paper. Note: The NOEL and LOEL are highly influenced by study design do not give any quantitative information about the relationship between dose and response; and can be subject to author’s interpretation (e.g., a statistically significant effect may not be considered biologically important). Also, a NOEL does not necessarily mean zero response. Ideally, the response rate at specific dose levels is used as the primary measure to characterize the response.
Observations on dose response (e.g., trend analysis, description of whether dose-response shape appears to be monotonic, nonmonotonic)
Data on internal concentration, toxicokinetics, or toxicodynamics (when reported)
Other Documentation of author queries, use of digital rulers to estimate data values from figures, exposure unit, and statistical result conversions, etc.

Items marked with an asterisk (*) are examples of items that can be used to assess internal validity/risk of bias.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-1e

RISK OF BIAS QUESTIONS FOR ANIMAL STUDIES

1. Was administered dose or exposure level adequately randomized?

Definitely Low Risk of Bias (++)
  • Direct evidence that animals were allocated to any study group including controls using a method with a random component,
  • AND there is direct evidence that the study used a concurrent control group as an indication that randomization covered all study groups.
  • Note: Acceptable methods of randomization include: referring to a random number table, using a computer random number generator, coin tossing, or shuffling cards (Higgins and Green, 2011).
  • Note: Restricted randomization (e.g., blocked randomization) to ensure that particular allocation ratios will be considered low bias. Similarly, stratified randomization approaches that attempt to minimize imbalance between groups on important prognostic factors (e.g., body weight) will be considered acceptable.
Probably Low Risk of Bias (+)
  • Indirect evidence that animals were allocated to any study group including controls using a method with a random component (i.e., authors state random allocation, without description of method),
  • AND evidence that the study used a concurrent control group as an indication that randomization covered all study groups,
  • OR it is deemed that allocation without a clearly random component would not appreciably bias results.
Probably High Risk of Bias (-) or (NR)
  • Indirect evidence that animals were allocated to study groups using a method with a nonrandom component,
  • OR indirect evidence that there was a lack of a concurrent control group,
  • OR there is insufficient information provided about how animals were allocated to study groups (record “NR” as basis for answer).
Definitely High Risk of Bias (--)
  • Direct evidence that animals were allocated to study groups using a nonrandom method, including judgment of the investigator, the results of a laboratory test, or a series of tests,
  • OR direct evidence that there was a lack of a concurrent control group.

2. Was allocation to study groups adequately concealed?

Definitely Low Risk of Bias (++)
  • Direct evidence that at the time of assigning study groups the research personnel did not know what group animals were allocated to, and it is unlikely that they could have broken the blinding of allocation until after assignment was complete and irrevocable.
  • Note: Acceptable methods used to ensure allocation concealment include sequentially numbered treatment containers of identical appearance or equivalent methods.
Probably Low Risk of Bias (+)
  • Indirect evidence that at the time of assigning study groups the research personnel did not know what group animals were allocated to and it is unlikely that they could have broken the blinding of allocation until after assignment was complete and irrevocable,
  • OR it is deemed that lack of adequate allocation concealment would not appreciably bias results.
Probably High Risk of Bias (-) or (NR)
  • Indirect evidence that at the time of assigning study groups it was possible for the research personnel to know what group animals were allocated to, or it is likely that they could have broken the blinding of allocation before assignment was complete and irrevocable,
  • OR there is insufficient information provided about allocation to study groups (record “NR” as basis for answer).
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Definitely High Risk of Bias (--)
  • Direct evidence that at the time of assigning study groups it was possible for the research personnel to know what group animals were allocated to, or it is likely that they could have broken the blinding of allocation before assignment was complete and irrevocable.

3. Did selection of study participants result in the appropriate comparison groups? [NA]

4. Did study design or analysis account for important confounding and modifying variables? [NA]

5. Were experimental conditions identical across study groups?

Definitely Low Risk of Bias (++)
  • Direct evidence that the same vehicle was used in control and experimental animals,
  • AND direct evidence that non-treatment-related experimental conditions were identical across study groups (i.e., the study report explicitly provides this level of detail).
Probably Low Risk of Bias (+)
  • Indirect evidence that the same vehicle was used in control and experimental animals,
  • OR it is deemed that the vehicle used would not appreciably bias results,
  • AND identical non-treatment-related experimental conditions are assumed if authors did not report differences in housing or husbandry.
Probably High Risk of Bias (-) or (NR)
  • Indirect evidence that the vehicle differed between control and experimental animals,
  • OR authors did not report the vehicle used (record “NR” as basis for answer),
  • OR there is indirect evidence that non-treatment-related experimental conditions were not comparable between study groups.
Definitely High Risk of Bias (--)
  • Direct evidence from the study report that control animals were untreated, or treated with a different vehicle than were experimental animals,
  • OR there is direct evidence that non-treatment-related experimental conditions were not comparable between study groups.

6. Were the research personnel blinded to the study group during the study?

Definitely Low Risk of Bias (++)
  • Direct evidence that the research personnel were adequately blinded to study group, and it is unlikely that they could have broken the blinding during the study. Methods used to ensure blinding include central allocation; sequentially numbered treatment containers of identical appearance; sequentially numbered animal cages; or equivalent methods.
Probably Low Risk of Bias (+)
  • Indirect evidence that the research personnel were adequately blinded to study group, and it is unlikely that they could have broken the blinding during the study,
  • OR it is deemed that lack of adequate blinding during the study would not appreciably bias results. This would include cases where blinding was not possible but research personnel took steps to minimize potential bias, such as restricting the knowledge of the study group to veterinary or supervisory personnel monitoring for overt toxicity, or randomized husbandry or handling practices (e.g., placement in the animal room, necropsy order).
Probably High Risk of Bias (-) or (NR)
  • Indirect evidence that the research personnel were not adequately blinded to study group,
  • OR there is insufficient information provided about blinding to study group during the study (record “NR” as basis for answer).
Definitely High Risk of Bias (--)
  • Direct evidence that the research personnel were not adequately blinded to study group.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

7. Were outcome data complete without attrition or exclusion from analysis?

Definitely Low Risk of Bias (++)
  • Direct evidence that loss of animals was adequately addressed and reasons were documented when animals were removed from a study,
  • Note: Acceptable handling of attrition includes very little missing outcome data; reasons for missing animals unlikely to be related to outcome (or for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across study groups, with similar reasons for missing data across groups; missing outcomes is not enough to impact the effect estimate.
  • OR missing data have been imputed using appropriate methods (ensuring that characteristics of animals are not significantly different from animals retained in the analysis).
Probably Low Risk of Bias (+)
  • Indirect evidence that loss of animals was adequately addressed and reasons were documented when animals were removed from a study,
  • OR it is deemed that the proportion lost would not appreciably bias results. This would include reports of no statistical differences in characteristics of animals removed from the study from those remaining in the study.
Probably High Risk of Bias (-) or (NR)
  • Indirect evidence that loss of animals was unacceptably large and not adequately addressed,
  • OR there is insufficient information provided about loss of animals (record “NR” as basis for answer).
Definitely High Risk of Bias (--)
  • Direct evidence that loss of animals was unacceptably large and not adequately addressed.
  • Note: Unacceptable handling of attrition or exclusion includes: reason for loss is likely to be related to true outcome, with either imbalance in numbers or reasons for loss across study groups.

8. Can we be confident in the exposure characterization?

Definitely Low Risk of Bias (++)
  • Direct evidence that the exposure to the PBDE was independently characterized (including purity, stability, and compliance with the treatment, if applicable) and confirmed generally as ≥98% purity,
  • OR direct evidence that all individual congeners were independently assessed for purity if a “mixture” is developed by the researchers,
  • OR the mixture should be independently assessed and non-target congeners or other impurities confirmed to contribute less than 2% (purity is ≥98%),
  • AND that exposure was consistently administered (i.e., with the same method and time frame) across treatment groups,
  • AND for gavage, dietary, or drinking water studies, that information is provided on consumption or internal dose metrics to confirm expected exposure levels sufficiently to allow discrimination between exposure groups,
  • AND if internal dose metrics are available, there is evidence that most of the exposure data measurements are above the limit of quantitation for the assay such that different exposure groups can be distinguished.
Probably Low Risk of Bias (+)
  • Indirect evidence that the exposure to the PBDE was independently characterized (including purity, stability, and compliance with the treatment, if applicable) and confirmed generally as ≥98% (i.e., the supplier of the chemical provides documentation of the purity of the chemical),
  • OR indirect evidence that all individual congeners were independently assessed for purity if a “mixture” is developed by the researchers (the supplier of the chemical provides documentation of the purity of each chemical) and non-target congeners/impurities confirmed as less than 98%,
  • OR the mixture is provided by a supplier and the supplier provides documentation of the purity of the mixture with non-target congeners/impurities confirmed to contribute less than 2% (i.e. purity is ≥98%),
  • OR direct evidence that the purity of the congener(s) was independently confirmed as ≥95% and it is deemed that impurities of up to 5% would not appreciably bias results,
  • AND that exposure was consistently administered (i.e., with the same method and time frame) across treatment groups,
  • AND for dietary or drinking water studies, no information is provided on consumption or internal dose metrics,
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
  • AND if internal dose metrics are available, there is indirect evidence that most of the exposure data measurements are above the limit of quantitation for the assay such that different exposure groups can be distinguished.
Probably High Risk of Bias (-) or (NR)
  • Indirect evidence that the exposure (including purity of the test substance and compliance with the treatment, if applicable) was assessed using poorly validated methods,
  • OR there is insufficient information provided about the validity of the exposure assessment method, but no evidence for concern (record “NR” as basis for answer),
  • AND if internal dose metrics are available, there is indirect evidence that most of the exposure data measurements are below the limit of quantitation for the assay such that different exposure groups cannot be distinguished.
Definitely High Risk of Bias (--)
  • Direct evidence that the exposure (including purity of the test substance and compliance with the treatment, if applicable) was assessed using poorly validated methods.

9. Can we be confident in the outcome assessment?

Definitely Low Risk of Bias (++)
  • Direct evidence that the outcome was assessed using well-established methods (e.g., Morris water maze, radial arm maze, operant tests of cognition)
  • AND assessed at the same length of time (i.e., same day of life) after initial exposure in all study groups,
  • AND there is direct evidence that the outcome assessors were adequately blinded to the study group, and it is unlikely that they could have broken the blinding prior to reporting outcomes.
Probably Low Risk of Bias (+)
  • Indirect evidence that the outcome was assessed using acceptable methods (i.e., deemed valid and reliable),
  • AND assessed at the same length of time (i.e., same day of life) after initial exposure in all study groups,
  • OR it is deemed that the outcome assessment methods used would not appreciably bias results,
  • AND there is indirect evidence that the outcome assessors were adequately blinded to the study group, and it is unlikely that they could have broken the blinding prior to reporting outcomes,
  • OR it is deemed that lack of adequate blinding of outcome assessors would not appreciably bias results, which is more likely to apply to objective outcome measures.
Probably High Risk of Bias (-) or (NR)
  • Indirect evidence that the outcome assessment method is an insensitive instrument,
  • OR the length of time after initial exposure differed by study group,
  • OR there is indirect evidence that it was possible for outcome assessors to infer the study group prior to reporting outcomes without sufficient quality control measures,
  • OR there is insufficient information provided about blinding of outcome assessors (record “NR” as basis for answer).
Definitely High Risk of Bias (--)
  • Direct evidence that the outcome assessment method is an insensitive instrument,
  • OR the length of time after initial exposure differed by study group,
  • OR there is direct evidence for lack of adequate blinding of outcome assessors, including no blinding or incomplete blinding without quality control measures.

10. Were all measured outcomes reported?

Definitely Low Risk of Bias (++)
  • Direct evidence that all of the study’s measured outcomes outlined in the protocol, methods, abstract, and/or introduction (that are relevant for the evaluation) have been reported.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Probably Low Risk of Bias (+)
  • Indirect evidence that all of the study’s measured outcomes outlined in the protocol, methods, abstract, and/or introduction (that are relevant for the evaluation) have been reported,
  • OR analyses that had not been planned in advance (i.e., retrospective unplanned subgroup analyses) are clearly indicated as such and deemed that unplanned analyses were appropriate and selective reporting would not appreciably bias results (e.g., appropriate analyses of an unexpected effect). This would include outcomes reported with insufficient detail such as only reporting that results were statistically significant (or not).
Probably High Risk of Bias (-) or (NR)
  • Indirect evidence that all of the study’s measured outcomes outlined in the protocol, methods, abstract, and/or introduction (that are relevant for the evaluation) have not been reported,
  • OR and there is indirect evidence that unplanned analyses were included that may appreciably bias results,
  • OR there is insufficient information provided about selective outcome reporting (record “NR” as answer basis).
Definitely High Risk of Bias (--)
  • Direct evidence that all of the study’s measured outcomes outlined in the protocol, methods, abstract, and/or introduction (that are relevant for the evaluation) have not been reported. In addition to not reporting outcomes, this would include reporting outcomes based on a composite score without individual outcome components or outcomes reported using measurements, analysis methods, or subsets of the data (e.g., subscales) that were not prespecified or reporting outcomes not prespecified, or that unplanned analyses were included that would appreciably bias results.

11. Was litter or litter effects considered appropriately in the statistical analyses and were there no other potential threats to internal validity?
Because this evaluation is focused on developmental exposure, this question was added to address litter effects in data analysis. This question will be used to examine individual studies for appropriate statistical methods (e.g., confirmation of homogeneity of variance for ANOVA and other statistical tests that require normally distributed data). It will also be used for risk of bias considerations that do not fit under the other questions.

Definitely Low Risk of Bias (++)
  • Direct evidence that litter effects were appropriately considered in the study design or analysis, using one of the following approaches:
  • The dam used as the statistical unit of analysis,
  • OR the fetus/pup used as the statistical unit of analysis AND litter effects were appropriately considered in the analysis AND the statistical method was stated.
Probably Low Risk of Bias (+)
  • Indirect evidence that litter effects were appropriately considered in the study design or analysis, using one of the following approaches:
  • The dam used as the statistical unit of analysis,
  • OR the fetus/pup used as the statistical unit of analysis AND litter-effects were appropriately considered in the analysis BUT the statistic method used to address litter effects was not stated.
Probably High Risk of Bias (-) or (NR)
  • Indirect evidence that litter effects were not appropriately considered in the study design or analysis,
  • OR the fetus/pup used as the statistical unit of analysis AND litter-effects were not considered in the statistical analysis.
Definitely High Risk of Bias (--)
  • Direct evidence that litter effects were not appropriately considered in the study design or analysis,
  • OR the fetus/pup used as the statistical unit of analysis AND litter effects were not considered in the statistical analysis.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-1f

AMENDMENTS TO THE PROTOCOL

Changes to the Review Team
(September 15, 2016)

Original review team members Barbara Hales and Susan Schantz were replaced by the following committee members who have more experience conducting risk of bias evaluations and data extraction:

  • 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 he is a diplomate of the American Board of Veterinary Toxicology and the American Board of Toxicology.
  • 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.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-2

Results of Literature Searches for Animal Studies on the Effects of Developmental Exposure to PBDEs on Learning, Memory, Attention, or Response Inhibition

Literature searches were performed on August 15, 2016, using the search strategy presented in the PBDE (Animal) Systematic Review Protocol (Section E-1). A summary of the results is presented below.

Embase:

1,326

PubMed: 1,173
Toxline: 489

Total citations found:

2,988

Duplicates removed: 1,137
Total unique citations: 1,851
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-3

Funding Sources of the Animal Studies on PBDEs and Learning, Memory, or Attention

Sources of funding were used to evaluate publication bias in terms of whether a particular sector funded more studies than another.

Reference Governmental NIH/Federal Industry Other Unknown
Biesemeier et al. 2011 X
Blanco et al. 2013 X (Spain)
Bowers et al. 2015 X (Canada)
Buratovic et al. 2014 X (Sweden)
Chen et al. 2014 X (China)
Cheng et al. 2009 X (China)
de-Miranda et al. 2016 X (Brazil)
Driscoll et al. 2009 X (Colorado)
Driscoll et al. 2012 X
Dufault et al. 2005 X (Colorado)
Eriksson et al. 2001 X (Sweden)
Fischer et al. 2008 X (Sweden)
He et al. 2009 X (China)
He et al. 2011 X (China)
Koenig et al. 2012 X (NIEHS) JB Johnson Foundation
Llansola et al. 2009 X (EU)
Reverte et al. 2013 X (FEDR; EU)
Reverte et al. 2014 X (FEDR; EU)
Rice et al. 2009 X (Maine)
Ta et al. 2011 X (NIEHS; EPA)
Verma et al. 2013 X (India)
Verma et al. 2014 X (India)
Viberg et al. 2003 X (Sweden; EU)
Viberg et al. 2006 X (EU)
Woods et al. 2012 X (NIH; NIEHS; EPA)
Zhang et al. 2013 X (China)
Zhao et al. 2014 X (China)
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-4

Confidence Ratings for the Body of Evidence from Animal Studies of PBDEs

The body of evidence from animal studies of the PBDEs and learning, memory, and attention, were rated in accordance with the guidance presented in Section E-1. No studies of response inhibition were found.

BDE-47

Studies of BDE-47 and effects on learning (see Table E4-1) and memory (see Table E4-2) were available.

Learning: There is moderate confidence in the body of evidence on developmental exposure to BDE-47 and effects on learning in rodents. Six studies in mice and rats were available. The two studies in rats found several indications of decreased learning in the Morris water maze (e.g., prolonged latency periods) after treatment with BDE-47 at doses of 1, 5, or 10 mg/kg-day on PND 10. Both studies were from the same laboratory (He et al. 2009, 2011). Three of the four mouse studies reported decreased learning in at least one test, strain, or sex and were conducted by different research groups (Eriksson et al. 2001; Ta et al. 2011; Koenigs et al. 2012; Woods et al. 2012). Nevertheless, the mouse results were variable across all the tests administered and a clear pattern was not identified to explain the heterogeneity in response relative to a susceptible strain, sex, or dose.

  • Risk of bias: Downgraded because all studies had at least one rating of probably high or definitely high risk of bias in one of the key issues (e.g., lack of randomization of treatment), and most of the studies had multiple risk of bias issues, including not controlling for litter effects in the study design or analysis (see Figure E4-1).
  • Unexplained inconsistencies: A qualitative evaluation of the evidence suggested a possible downgrade because of the heterogeneity in the evidence. However, a meta-analysis of studies of several PBDEs (see Chapter 4 and Appendix E, Section E-5), including BDE-47, and latency in the last trial of the Morris water maze showed consistent evidence of an effect on this measure of learning, so confidence was not downgraded.
  • Indirectness: No downgrade because tests used are considered direct measures of learning.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: No upgrade. Only two studies in rats were available, and the studies were from the same laboratory. The evidence base was judged to be inadequate for making judgments about cross-species consistency.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.

TABLE E4-1 Studies of BDE-47 and Learning in Rodents

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Eriksson et al. 2001 NMRI mice PND 10 5 months Morris water maze 10.5 None
He et al. 2009 Sprague-Dawley rats PND 10 2 months Morris water maze None 1
He et al. 2011 Sprague-Dawley rats PND 10 2 months Morris water maze None 1
Koenig et al. 2012 C57BL/6J mice GD 0 - PND 21 2 months Barnes maze None 0.03
Ta et al. 2011 C57BL/6J mice GD 0 - PND 21 2 months Morris water maze 0.1 1
Woods et al. 2012 Female Mecp2 308+/- mice GD 0 - PND 21 PND 50-54 Morris water maze None 0.03
Male Mecp2 308+/- mice GD 0 - PND 21 PND 50-54 Morris water maze 0.03 None
Female C57Bl6 mice GD 0 - PND 21 PND 50-54 Morris water maze 0.03 None
Male C57Bl6 mice GD 0 - PND 21 PND 50-54 Morris water maze 0.03 None

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E4-1 Risk of bias heatmap of studies of BDE-47 and learning in rodents. In HAWC: https://hawcproject.org/summary/visual/353/.

Memory: There is low confidence in the body of evidence on developmental exposure to BDE-47 and effects on memory in rodents. Five studies in rats and mice were available. The one study in rats (He et al. 2011) reported decreased memory in the Morris water maze (e.g., prolonged latency periods) after exposure at 1, 5, and 10 mg/kg-day on PND 10. Three of the mouse studies (Eriksson et al. 2001; Ta et al. 2011; Koenig et al. 2012) reported no effects on memory at doses up to 12 mg/kg-day; however, Woods et al. (2012) reported decrements in memory in female Mecp2 308+/− mice with no effects on males or in C57BL6 mice of either sex. The body of evidence contained only a single study in rats and inconsistent results in mice. The dataset is similar and contains some of the same studies discussed above with respect to effects of BDE-47 on learning; fewer studies reported an effect, however, and one less study overall.

  • Risk of bias: Downgraded because all the studies had a probably high risk of bias rating for at least one major issue (e.g., researchers were not blinded to the study groups during outcome assessment), and most of the studies had multiple risk of bias issues, including not controlling for litter effects in the study design or analysis (Eriksson et al. 2001; Woods et al. 2012) (see Figure E4-2).
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

TABLE E4-2 Studies of BDE-47 and Memory in Rodents

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Eriksson et al. 2001 NMRI mice PND 10 5 months Morris water maze 10.5 None
He et al. 2009 Sprague-Dawley rats PND 10 2 months Morris water maze None 1
Koenig et al. 2012 C57BL/6J mice GD 0 - PND 21 2 months Barnes maze 1 None
Ta et al. 2011 C57BL/6J mice GD 0 - PND 21 2 months Morris water maze 1 None
Woods et al. 2012 Female Mecp2 308+/- mice GD 0 - PND 21 PND 50-54 Morris water maze None 0.03
Male Mecp2 308+/- mice GD 0 - PND 21 PND 50-54 Morris water maze 0.03 None
Female C57Bl6 mice GD 0 - PND 21 PND 50-54 Morris water maze 0.03 None
Male C57Bl6 mice GD 0 - PND 21 PND 50-54 Morris water maze 0.03 None

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

  • Unexplained inconsistencies: Downgraded because of the heterogeneity of the evidence.
  • Indirectness: No downgrade because tests used are considered direct measures of memory.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: No upgrade. Only one study in rats was available, so the evidence base was judged to be inadequate to make judgments about cross-species consistency.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.
images
FIGURE E4-2 Risk of bias heatmap of studies of BDE-47 and memory in rodents. In HAWC: https://hawcproject.org/summary/visual/354/.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

BDE-99

Studies of BDE-99 and effects on learning (see Table E4-3) and memory (see Table E4-4) were available.

TABLE E4-3 Studies of BDE-99 and Learning in Rodents

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Blanco et al. 2013 Sprague-Dawley rats GD 6 to PND 21 PND 26-35 Morris water maze 1 2
Cheng et al. 2009 Sprague-Dawley rats GD 6 - PND 21 PND 34-36 Morris water maze None 2
Fischer et al. 2008 NMRI mice PND 10 4 months Morris water maze None 0.8
NMRI mice PND 10 4 months Radial maze None 0.8
Llansola et al. 2009 Wistar rats GD 2-9 PND 68-70 Y maze 30 None
Wistar rats GD 11-19 PND 68-70 Y maze 30 None
Zhao et al. 2014 Sprague-Dawley rats GD 1 - PND 21 PND 34-36 Morris water maze 0.2 None

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Learning: There is moderate confidence in the body of evidence on developmental exposure to BDE-99 and learning in mice and rats based on five studies. Two of the three studies in rats reported longer latency during the acquisition period of tests using the Morris water maze at a dose of 2 mg/kg-day (Cheng et al. 2009; Blanco et al. 2013). Zhao et al. (2014) reported no effects at a lower dose (0.2 mg/kg-day) under similar exposure and testing conditions. In contrast, developmental exposure of Wistar rats at doses up to 30 mg/kg-day had no effect on learning tested with a Y maze (Llansola et al. 2009). A single study (Fischer et al. 2008) in NMRI mice also reported decrements in learning during the acquisition period in tests using either a radial maze or a Morris water maze at a dose of 0.8 mg/kg-day.

  • Risk of bias: Downgraded because of serious concerns about several risk of bias issues. All of the studies were rated as having probably high risk of bias for at least one key risk of bias issue (e.g., researchers were not blinded to the study groups during outcome assessment), two of the studies had a definitely high risk of bias rating for not controlling for litter effects in the study design or analysis, and most of the studies had multiple risk of bias issues (see Figure E4-3).
  • Unexplained inconsistencies: A qualitative evaluation of the evidence suggested a possible downgrade because of the heterogeneity in the evidence. Nevertheless, a meta-analysis of studies of several PBDEs (see Chapter 4 and Appendix E, Section E-5), including BDE-99, and latency in the last trial of the Morris water maze showed consistent evidence of an effect on this measure of learning, so confidence was not downgraded.
  • Indirectness: No downgrade because tests used were considered direct measures of learning.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: No upgrade.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E4-3 Risk of bias heatmap of studies of BDE-99 and learning in rodents. In HAWC: https://hawcproject.org/summary/visual/355/.

TABLE E4-4 Studies of BDE-99 and Memory in Rodents

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Blanco et al. 2013 Sprague-Dawley rats GD 6 - PND 21 PND 26-35 Morris water maze 2 None
Fischer et al. 2008 NMRI mice PND 10 6 months Radial maze 0.8 None
Zhao et al. 2014 Sprague-Dawley rats GD 1 - PND 21 PND 34-36 Morris water maze 0.2 None

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Memory: There is moderate confidence in the data to evaluate whether developmental exposure to BDE-99 affects memory in rodents. The three available studies found no effects in several memory tests at doses of 0.2-2 mg/kg-day.

  • Risk of bias: Downgraded because of serious concerns about several risk of bias issues. All the studies had a rating of probably high risk of bias for at least one key risk of bias issue (e.g., researchers were not blinded to the study groups during outcome assessment) and one study had a definitely high risk of bias rating for not controlling for litter effects in the study design or analysis (see Figure E4-4).
  • Unexplained inconsistencies: No downgrade for inconsistency.
  • Indirectness: No downgrade because tests used are considered direct measures of memory.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: No upgrade because one study in mice and two in rats is insufficient to upgrade for evidence of consistency across species for a no-effect finding.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E4-4 Risk of bias heatmap of studies of BDE-99 and memory in rodents. In HAWC: https://hawcproject.org/summary/visual/356/.

BDE-153

Studies of BDE-153 and effects on learning (see Table E4-5) and memory (see Table E4-6) were available.

TABLE E4-5 Studies of BDE-153 and Learning in Rodents

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Viberg et al. 2003 NMRI mouse PND 10 PND 180 Morris water maze 0.45 0.9
Zhang et al. 2013 Sprague-Dawley rats PND 10 PND 40 Morris water maze 10 None
Sprague-Dawley rats PND 10 PND 70 Morris water maze 10 None
Sprague-Dawley rats PND 10 PND 40 Passive avoidance 10 None
Sprague-Dawley rats PND 10 PND 70 Passive avoidance 10 None

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Learning: There is low confidence in the body of evidence to evaluate whether developmental exposure to BDE-153 affects learning in mice or rats. Two studies were available, one in mice and one in rats. Viberg et al. (2003) reported longer latencies in the acquisition period in the Morris water maze when mice were exposed to BDE-153 at 0.9 or 9 mg/kg-day on PND 10. The rat study (Zhang et al. 2013) reported no effect of BDE-153 at 10 mg/kg-day in performance in either the Morris water maze or the passive avoidance test when evaluated at PND 40 or PND 70.

  • Risk of bias: Downgraded twice because of serious concerns about multiple risk of bias issues, including lack of randomization of treatment; reduced confidence in outcome assessment due to lack of blinding of outcome assessors; and definitely high risk of bias ratings for not controlling for litter effects in the study design or analysis (see Figure E4-5).
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
  • Unexplained inconsistencies: A qualitative evaluation of the evidence suggested a possible downgrade because of the heterogeneity in the evidence. Nevertheless, a meta-analysis of studies of several PBDEs (see Chapter 4 and Appendix E, Section E-5), including BDE-153, and of latency in the last trial of the Morris water maze showed consistent evidence of an effect on this measure of learning, so confidence was not downgraded.
  • Indirectness: No downgrade because the tests used are considered direct measures of learning.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: No upgrade because no evidence of consistency across species.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.
images
FIGURE E4-5 Risk of bias heatmap of studies of BDE-153 and learning or memory in rodents. In HAWC: https://hawcproject.org/summary/visual/357/.

TABLE E4-6 Studies of BDE-153 and Memory in Rodents

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Viberg et al. 2003 NMRI mouse PND 10 PND 180 Morris water maze 0.45 0.9
Zhang et al. 2013 Sprague-Dawley rats PND 10 PND 40 Morris water maze 1 5
Sprague-Dawley rats PND 10 PND 70 Morris water maze 1 5
Sprague-Dawley rats PND 10 PND 40 Passive avoidance 10 None
Sprague-Dawley rats PND 10 PND 70 Passive avoidance 5 10

NOTE: LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

Memory: There is low confidence in the body of evidence on developmental exposure to BDE-153 and effect on memory in rodents. One study in mice and one in rats reported effects. (The two studies are the same ones that tested the effects of BDE-153 on learning.) The mouse study (Viberg et al. 2003) reported longer latencies in the relearning period of mice tested at 6 months of age in the Morris water maze after exposure to BDE-153 at 0.9 or 9 mg/kg-day. The rat study (Zhang et al. 2013) reported increased swimming time in the Morris water maze 1 month after treatment with BDE-153 at 5 and 10 mg/kg-day evaluated at PND 40 or PND 70 and memory impairment in the passive avoidance test at 10 mg/kg-day at PND 70. The two studies report results that were consistent in direction (both decreased performance on a memory test) across species.

  • Risk of bias: Downgraded twice because of serious concerns about multiple risk of bias issues, including lack of randomization of treatment; reduced confidence in outcome assessment due to lack of blinding of outcome assessors; and definitely high risk of bias ratings for not controlling for litter effects in the study design or analysis. (See heatmap in Figure E4-5.)
  • Unexplained inconsistencies: Confidence is usually downgraded if only one study in each tested species is available because the database is insufficient to establish or evaluate consistency for a particular species. Consistency across species (see below), however, would be a reason to upgrade confidence. Considering both factors, there was no downgrade for unexplained inconsistency.
  • Indirectness: No upgrade because tests were considered direct measures of memory.
  • Imprecision: No upgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No change, no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: Confidence is usually upgraded if consistent results are observed across species. As noted above, however, it was not possible to evaluate consistency for each species because of the small data set. Considering both factors, there was no upgrade for consistency.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.

BDE-203

One study of BDE-203 and effects on learning (see Table E4-7) or memory (see Table E4-8) was found.

TABLE E4-7 Studies of BDE-203 and Learning in Mice

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Viberg et al. 2006 NMRI mouse PND 3 PND 90 Morris water maze 16.8 None
NMRI mouse PND 10 PND 90 Morris water maze None 16.8

NOTE: LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Learning: There is very low confidence in the data to evaluate whether developmental exposure to BDE-203 affects learning in mice from the single study available. The results suggest that timing of exposure might have an influence on effects because exposure to BDE-203 at 16.8 mg/kg-day on PND 10 affected learning during the acquisition period, whereas exposure on PND 3 had no effect on learning (Viberg et al. 2006).

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
  • Risk of bias: Downgraded twice because of serious concerns about multiple risk of bias issues, including lack of randomization of treatment; reduced confidence in outcome assessment due to lack of blinding of outcome assessors and a definitely high risk of bias rating for not controlling for litter effects in the study design or analysis (see Figure E4-6).
  • Unexplained inconsistencies: Downgraded because unable to establish or evaluate consistency because the study did not have elements that would strengthen conclusions from a single study, such as multiple species, strains, or particularly large sample sizes (n = 50-100).
  • Indirectness: No downgrade because test used is considered a direct measure of learning.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because only one dose was tested.
  • Cross-species consistency: No upgrade because only mice were tested.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.

Memory: There is very low confidence in the data to evaluate whether developmental exposure to BDE-203 affects memory in mice because the single study found no effect at a single dose (16.8 mg/kg-day). The study is the same one that also assessed learning.

images
FIGURE E4-6 Risk of bias heatmap of study of BDE-203 and learning and memory and BDE-206 and learning in mice. In HAWC: https://hawcproject.org/summary/visual/358/.

TABLE E4-8 Studies of BDE-203 and Memory in Mice

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Viberg et al. 2006 NMRI mouse PND 3 PND 90 Morris water maze 16.8 None
NMRI mouse PND 10 PND 90 Morris water maze 16.8 None

NOTE: LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
  • Risk of bias: Downgraded twice because of serious concerns about multiple risk of bias issues, including lack of randomization of treatment; reduced confidence in outcome assessment due to lack of blinding of outcome assessors; and a definitely high risk of bias rating for not controlling for litter effects in the study design or analysis. (See heatmap in Figure E4-6.)
  • Unexplained inconsistencies: Downgraded because unable to establish or evaluate consistency because the study did not have elements that would strengthen conclusions from a single study, such as multiple species, strains, or particularly large sample sizes (n = 50-100).
  • Indirectness: No downgrade because test used is considered a direct measure of memory.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because only one dose was tested.
  • Cross-species consistency: No upgrade because only mice were tested.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.

BDE-206

One study of BDE-206 and effects on learning was found (see Table E4-9).

Learning: There is very low confidence in the data to evaluate whether developmental exposure to BDE-206 affects learning in mice as the single study found no effect at a single exposure level (16.8 mg/kg-day). The study is the same one that also tested BDE-203 (see above).

  • Risk of bias: Downgraded twice because of serious concerns about multiple risk of bias issues, including lack of randomization of treatment; reduced confidence in outcome assessment due to lack of blinding of outcome assessors; and a definitely high risk of bias rating for not controlling for litter effects in the study design or analysis. (see heatmap in Figure E4-6.)
  • Unexplained inconsistencies: Downgraded because unable to establish or evaluate consistency because the study did not have elements that would strengthen conclusions from a single study, such as multiple species, strains, or particularly large sample sizes (n = 50-100).
  • Indirectness: No downgrade because test used is considered a direct measure of learning.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because only one dose was tested.
  • Cross-species consistency: No upgrade because only mice were tested.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.

TABLE E4-9 Studies of BDE-206 and Learning in Mice

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Viberg et al. 2006 NMRI mouse PND 10 PND 90 Morris water maze 16.8 None

NOTE: LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

BDE-209

Studies of BDE-209 and effects on learning (see Table E4-10) and memory (see Table E4-11) were available.

Learning: There is moderate confidence in the body of evidence to evaluate whether developmental exposure to BDE-209 affects learning in rodents. Multiple studies show effects on learning at doses of 20 mg/kg-day or greater when learning was assessed using a Morris water maze; other studies, however, show no effects in the same dose range using other test methods.

  • Risk of bias: Downgraded because of serious concerns about multiple risk of bias issues, including reduced confidence in outcome assessment due to lack of blinding of outcome assessors in all studies and a definitely high risk of bias rating in three studies because of failure to control for litter effects in the study design or analysis (see Figure E4-7).

TABLE E4-10 Studies of BDE-209 and Learning in Rodents

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Biesemeier et al. 2011 Sprague-Dawley rats GD 6 - PND 21 PND 22, 62 Water T maze 1000 None
Buratovic et al. 2014 NMRI mice PND 3 5 months Morris water maze 7.9 None
NMRI mice PND 3 7 months Morris water maze 7.9 None
Chen et al. 2014 Sprague-Dawley rats GD 1 - 14 PND 25 Morris water maze 10 30
Eriksson et al. 2001 NMRI mice PND 10 5 months Morris water maze 10.5 None
Reverte et al. 2013 apoE2 female mouse PND 10 PND 120 Morris water maze 30 None
apoE2 male mouse PND 10 PND 120 Morris water maze 30 None
apoE4 female mouse PND 10 PND 120 Morris water maze 30 None
apoE4 male mouse PND 10 PND 120 Morris water maze 10 30
apoE4 female mouse PND 10 PND 120 Morris water maze 30 None
apoE4 male mouse PND 10 PND 120 Morris water maze 10 30
apoE2 female mouse PND 10 PND 360 Morris water maze 30 None
apoE4 female mouse PND 10 PND 360 Morris water maze 30 None
apoE4 female mouse PND 10 PND 360 Morris water maze 30 None
apoE2 mouse PND 10 PND 150-180 Cued fear 10 30
apoE4 mouse PND 10 PND 150-180 Cued fear None 10
apoE4 mouse PND 10 PND 150-180 Cued fear 30 None
Rice et al. 2009 C57BL6/J mouse PND 2-15 PND 87 FR performance 20 None
C57BL6/J mouse PND 2-15 PND 87 FI performance 20 None
C57BL6/J mouse PND 2-15 PND 87 Visual discrimination 6 20
C57BL6/J mouse PND 2-15 PND 497 FR performance None 6
C57BL6/J mouse PND 2-15 PND 497 FI performance 20 None
C57BL6/J mouse PND 2-15 PND 497 Visual discrimination None 6
Verma et al. 2013 Swiss albino mouse PND 3-10 PND 60-66 Morris water maze None 20
Verma et al. 2014 Swiss albino mouse PND 3-10 NR Morris water maze 20 None

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; NR, not reported; PND, postnatal day.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E4-7 Risk of bias heatmap of studies of BDE-209 and learning in rodents. In HAWC: https://hawcproject.org/summary/visual/349/.
  • Unexplained inconsistencies: A qualitative evaluation of the evidence suggested a possible downgrade because of the heterogeneity in the evidence. Nevertheless, a meta-analysis of studies of several PBDEs (see Chapter 4 and Appendix E, Section E-5), including BDE-209, and of latency in the last trial of the Morris water maze showed consistent evidence of an effect on this measure of learning, so confidence was not downgraded.
  • Indirectness: No downgrade because tests used were considered direct measures of learning.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: No upgrade because of inconsistencies in the results between rat and mouse studies.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.

Memory: There is low confidence in the body of evidence to evaluate whether developmental exposure to BDE-209 affects learning in rodents. Multiple mouse studies show effects on memory at doses of 3.4 mg/kg-day or greater when memory was assessed using a Morris water maze; other studies, however, show no effects on memory at the same dose range using other methods.

  • Risk of bias: Downgraded because of serious concerns about multiple risk of bias issues, including reduced confidence in outcome assessment due to lack of blinding of outcome assessors in all studies and a definitely high risk of bias rating in three studies because of failure to control for litter effects in the study design or analysis (see Figure E4-8).
  • Unexplained inconsistencies: Downgraded for inconsistency.
  • Indirectness: No downgrade because tests used were considered direct measures of memory.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

TABLE E4-11 Studies of BDE-209 and Memory in Rodents

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Biesemeier et al. 2011 Sprague-Dawley rats GD6-PND 21 PND 22, 62 Water T maze 1000 None
Buratovic et al. 2014 NMRI mice PND 3 5 months Morris water maze None 3.4
NMRI mice PND 3 7 months Morris water maze None 3.4
Eriksson et al. 2001 NMRI mice PND 10 5 months Morris water maze None 10.5
Reverte et al. 2013 apoE2 female mouse PND 10 PND 120 Morris water maze 30 None
apoE2 male mouse PND 10 PND 120 Morris water maze 30 None
apoE4 female mouse PND 10 PND 120 Morris water maze 30 None
apoE4 male mouse PND 10 PND 120 Morris water maze None 10
apoE4 female mouse PND 10 PND 120 Morris water maze 30 None
apoE4 male mouse PND 10 PND 120 Morris water maze None 10
apoE2 female mouse PND 10 PND 360 Morris water maze 30 None
apoE4 female mouse PND 10 PND 360 Morris water maze 30 None
apoE4 female mouse PND 10 PND 360 Morris water maze 30 None
Verma et al. 2013 Swiss albino mouse PND 3-10 PND 60-66 Morris water maze None 20
Swiss albino mouse PND 3-10 PND 60-66 Radial maze None 20
Swiss albino mouse PND 3-10 PND 60-66 Radial maze None 20
Verma et al. 2014 Swiss albino mouse PND 3-10 NR Morris water maze 20 None
Swiss albino mouse PND 3-10 NR Radial maze 20 None
Swiss albino mouse PND 3-10 NR Radial maze 20 None

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; NR, not reported; PND, postnatal day.

images
FIGURE E4-8 Risk of bias heatmap of studies of BDE-209 and memory in rodents. In HAWC: https://hawcproject.org/summary/visual/350/.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: No upgrade because of inconsistencies in the results between rat and mouse studies.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.

DE-71

Studies of DE-71 and effects on learning (see Table E4-12), memory (see Table E4-13), and attention (see Table E4-14) were available.

Learning: There is very low confidence in the body of evidence on developmental exposure to DE-71 and effects on learning in rats. The results of the three available studies were inconsistent and used different tests (Morris water maze, radial maze, and visual discrimination) and animals of different ages. One study (Dufault et al. 2005) reported increased errors in the visual discrimination task at the single dose tested (30 mg/kg-day). The other two studies reported no effects of DE-71 on learning at the same dose using longer exposure windows; however, the animals in these studies were evaluated at older ages than were the rats tested in the Dufault et al. (2005) study.

  • Risk of bias: Downgraded twice because of serious concerns about multiple risk of bias issues, including reduced confidence in outcome assessment due to lack of blinding of outcome assessors and a definitely high risk of bias rating for exposure characterization in two of the studies (see Figure E4-9).

TABLE E4-12 Studies of DE-71 and Learning in Rats

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Bowers et al. 2015 Sprague-Dawley rats GD 1 - PND 21 PND 235 Morris water maze 30 None
de-Miranda et al. 2016 Wistar rats PND 5-22 PND 100 Radial maze 30 None
Dufault et al. 2005 Long-Evans rats PND 6-12 PND 30 Visual discrimination None 30

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E4-9 Risk of bias heatmap of studies of DE-71 and learning in rats. In HAWC: https://hawcproject.org/summary/visual/344/.

TABLE E4-13 Studies of DE-71 and Memory in Rats

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Bowers et al. 2015 Sprague-Dawley rats GD 1 - PND 21 PND 235 Morris water maze 30 None
de-Miranda et al. 2016 Wistar rats (female) PND 5-22 PND 100 Radial maze None 30
Wistar rats (male) PND 5-22 PND 100 Radial maze 30 None

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Memory: There is very low confidence in the body of evidence on developmental exposure to DE-71 and effects on memory in rats. The results of the two available studies were inconsistent and were evaluated in animals of different ages and with different tests (Morris water maze and radial maze). One study (de-Miranda et al. 2016) reported a reference memory deficit in female Wistar rats (not males) in the radial maze at the single dose tested (30 mg/kg-day).

  • Risk of bias: Downgraded twice because of serious concerns about multiple risk of bias issues, including reduced confidence in outcome assessment due to lack of blinding of outcome assessors and a definitely high risk of bias rating for exposure characterization in one of the studies (see Figure E4-10).
  • Unexplained inconsistencies: Downgrade for inconsistency.
  • Indirectness: No downgrade because tests used are considered direct measures of memory.
  • Imprecision: No downgrade because no or minimal indications of large standard deviations (i.e., SD > mean).
  • Dose-response: No upgrade because no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: No upgrade because only rats were tested.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E4-10 Risk of bias heatmap of studies of DE-71 and memory in rats. In HAWC: https://hawcproject.org/summary/visual/345/.

TABLE E4-14 Studies of DE-71 and Attention in Rats

Study Species Life Stage Exposed Observation Time Test NOAEL (mg/kg-day) LOAEL (mg/kg-day)
Driscoll et al. 2009 Long-Evans rats Lifetime* PND 40-95 Visual task 4.5 None
Long-Evans rats Lifetime* PND 40-95 Attention task I 3 4.5
Long-Evans rats Lifetime* PND 40-95 Attention task II 4.5 None
Driscoll et al. 2012 Long-Evans rats PND 6-12 PND 40-95 Attention task 15 None
Long-Evans rats PND 6-12 PND 40-95 Visual task 15 None
Dufault et al. 2005 Long-Evans rats PND 6-12 PND 30 Attention task 30 None

* Animals were exposed throughout gestation via treated dams and via chow after weaning.

NOTE: GD, gestation day; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; PND, postnatal day.

Attention: There is very low confidence in the body of evidence on developmental exposure to DE-71 and effects on attention in rats. All of the data are from a single laboratory (Dufault et al. 2005; Driscoll et al. 2009, 2012) and the majority of the tests reported no effects at doses up to 30 mg/kg-day across multiple tests (various attention tasks and a visual task). In one experiment (Driscoll et al. 2009), rats exposed to DE-71 at 4.5 mg/kg-day demonstrated lower accuracy in Attention Task 1.

  • Risk of bias: Downgraded twice because of serious concerns about multiple risk of bias issues, including reduced confidence in outcome assessment due to lack of blinding of outcome assessors and a definitely high risk of bias rating for exposure characterization in one of the studies (see Figure E4-11).
  • Unexplained inconsistencies: Downgrade for inconsistency.
  • Indirectness: No downgrade because tests used are considered direct measures of attention.
  • Imprecision: No downgraded because no or minimal indications of large standard deviations (i.e., SD > mean).
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
  • Dose-response: No upgrade because no clear evidence of dose-response gradient within or across studies.
  • Cross-species consistency: No upgrade because only rats were tested.
  • Other potential downgrades or upgrades: No evidence of publication bias (see Section E-3), large magnitude of effect, or residual confounding or other related factors that would affect confidence in the estimated effect.
images
FIGURE E4-11 Risk of bias heatmap of studies of DE-71 and attention in rats. In HAWC: https://hawcproject.org/summary/visual/347/.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

SECTION E-5

Supporting Information for the Meta-Analyses of Studies of PBDEs

Meta-Analyses on Combined Data on PBDEs

TABLE E5-1 Overall Analyses and Sensitivity Analyses of Studies of PBDEs and Latency in Last Trial of the Morris Water Maze

Analysis Estimate Beta CI, Lower Bound CI, Upper Bound P value tau I2 P value for Heterogeneity AICc
Primary Analyses
Overall intrcpt 25.76 20.32 31.19 0.000000 4.65 24.46 0.2685 101.48
Trend in log10(dose) log10(dose) 5.74 -2.16 13.63 0.154334 3.41 14.58 0.3825 96.49*
Linear in dose10 dose10 9.61 3.79 15.42 0.001209 17.12 81.59 0.0000 116.50
Linear-Quadratic in dose10 dose10 28.07 11.22 44.91 0.001093 13.92 72.33 0.0001 108.36
I(dose10^2) -4.45 -8.30 -0.60 0.023373
Sensitivity Analyses
Overall minus Viberg et al. 2003 intrcpt 25.77 20.07 31.46 0.000000 4.95 32.02 0.1180 77.61
Overall minus Chen et al. 2014 intrcpt 25.60 18.33 32.86 0.000000 5.17 22.40 0.3185 81.54
Overall minus Verma et al. 2013 intrcpt 25.52 20.08 30.97 0.000000 4.65 26.04 0.3070 90.62
Overall minus He et al. 2011 intrcpt 27.13 20.03 34.22 0.000000 4.14 13.54 0.4338 81.26
Overall minus Woods et al. 2012 intrcpt 25.87 20.38 31.36 0.000000 4.64 27.53 0.2743 82.77
Overall minus Cheng et al. 2009 intrcpt 25.12 19.24 30.99 0.000000 5.03 27.26 0.2377 94.83
Highest Doses-Overall intrcpt 32.95 26.67 39.23 0.000000 0.00 0.00 0.6596 56.49
Highest Doses-Overall minus Viberg et al. 2003 intrcpt 32.91 26.55 39.26 0.000000 0.00 0.00 0.5325 50.67
Highest Doses-Overall minus Chen et al. 2014 intrcpt 32.39 24.92 39.86 0.000000 0.00 0.00 0.5419 52.83
Highest Doses-Overall minus Verma et al. 2013 intrcpt 32.67 26.38 38.97 0.000000 0.00 0.00 0.7322 47.94
Highest Doses-Overall minus He et al. 2011 intrcpt 33.34 24.55 42.14 0.000000 0.00 0.00 0.5336 53.08
Highest Doses-Overall minus Woods et al. 2012 intrcpt 33.32 26.95 39.70 0.000000 0.00 0.00 0.8448 45.18
Highest Doses-Overall minus Cheng et al. 2009 intrcpt 33.13 26.28 39.98 0.000000 0.00 0.00 0.5337 52.46
Highest Doses-Trend in log10(dose) log10(dose) 3.40 -6.47 13.28 0.499553 0.00 0.00 0.5978 70.61
Highest Doses-Linear in dose10 dose10 10.01 0.06 19.95 0.048547 26.04 88.45 0.0000 67.93
Highest Doses-Linear-Quadratic in dose10 dose10 48.56 17.03 80.08 0.002536 15.99 55.56 0.0236 76.79
I(dose10^2) -8.34 -14.87 -1.81 0.012356

* Indicates the lowest AICc.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E5-3 Benchmark dose estimates from studies of PBDEs and latency in last trial of the Morris water maze in rats and mice. Points without error bars are studies for which a standard deviation was not reported or could not be digitized from figures in the publication. They were not included in the model fitting but are shown for comparison. There is no obvious bias between studies that reported standard deviations and those that did not.

Meta-Analyses on Individual PBDEs

BDE-47

  • Statistically significant overall effect. Heterogeneity (I2 = 44%), but it was not statistically significant. Overall effect was robust to using only highest dose from each study.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
  • Positive trends in log10(dose) and in dose, but only the latter was statistically significant. Reduced heterogeneity for log10(dose) and linear model. Benchmark dose for a 5% change was estimated to be 1.4 mg/kg-day (95% CI: 1.0, 2.4) from the linear model and 0.83 mg/kg-day (95% CI: 0.34, 5.9) from the linear-quadratic model.
images
FIGURE E5-4 Results of meta-analysis of studies of BDE-47 and latency in last trial of the Morris water maze.

TABLE E5-2 Overall Analyses and Sensitivity Analyses of Studies BDE-47 and Latency in Last Trial of the Morris Water Maze

Analysis Estimate Beta CI, Lower Bound CI, Upper Bound P value tau I2 P value for Heterogeneity AICc
Primary Analyses
Overall intrcpt 23.56 14.04 33.07 0.0000 6.72 44.43 0.1092 49.01*
Trend in log10(dose) log10(dose) 7.19 -6.23 20.61 0.2939 4.72 27.79 0.1610 54.64
Linear in dose10 dose10 34.55 20.13 48.97 0.0000 6.76 41.56 0.0957 50.90
Linear-Quadratic in dose10 dose10 60.96 -27.12 149.04 0.1750 10.24 48.02 0.0829 58.02
Linear-Quadratic in dose10 I(dose10^2) -29.19 -124.65 66.27 0.5490 10.24 48.02 0.0829 58.02
Sensitivity Analyses
Highest Doses-Overall intrcpt 31.87 23.15 40.59 0.0000 0.00 0.00 0.2638 34.52

* Indicates the lowest AICc.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E5-5 Benchmark dose estimates from studies of BDE-47 and latency in last trial of the Morris water maze.

BDE-153

  • Statistically significant overall effect; no heterogeneity. Too few data for a sensitivity analysis.
  • Positive trend, but not a statistically significant trend. Only central estimate and lower bound could be estimated for a benchmark dose for a 5% change: 1.2 mg/kg-day (95% CI: 0.6, >10).

TABLE E5-3 Overall Analyses and Sensitivity Analyses of Studies BDE-153 and Latency in Last Trial of the Morris Water Maze

Analysis Estimate Beta CI, Lower Bound CI, Upper Bound P value tau I2 P value for Heterogeneity AICc
Primary Analyses
Overall intrcpt 25.40 -0.18 50.99 0.052 0 0 0.82 32.56*
Trend in log10(dose) log10(dose) 14.03 -30.94 58.99 0.541 0 0 0.88 38.16
Linear in dose10 dose10 41.17 -4.69 87.04 0.078 0 0 0.58 33.38
Linear-Quadratic in dose10 dose10 304.47 -193.63 802.57 0.231 0 0 0.93 38.17
Linear-Quadratic in dose10 I(dose10^2) -295.30 -851.58 260.97 0.298 0 0 0.93 38.17

* Indicates the lowest AICc.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E5-6 Results of meta-analysis of studies of BDE-153 and latency in last trial of the Morris water maze.

BDE-209

  • Statistically significant overall effect. Heterogeneity (I2 = 42%), but it was not statistically significant. Overall effect was robust to using only highest dose from each study (only two studies).
  • Statistically significant trends in log10(dose) and linear trend in dose, with reduced heterogeneity. BMD estimates for a 5% change were 6.3 mg/kg-day (95% CI: 4.8, 9.2) from the linear model and 3.5 mg/kg-day (95% CI: 2.2, 7.9) from the linear-quadratic model.
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E5-7 Benchmark dose estimates from studies of BDE-153 and latency in last trial of the Morris water maze in rats and mice.

TABLE E5-4 Overall Analyses and Sensitivity Analyses of Studies BDE-209 and Latency in Last Trial of the Morris Water Maze

Analysis Estimate Beta CI, Lower Bound CI, Upper Bound P value tau I2 P value for Heterogeneity AICc
Primary Analyses
Overall intrcpt 26.69 16.79 36.60 0.00000 6.36 42.27 0.12 41.15*
Trend in log10(dose) log10(dose) 23.92 0.01 47.83 0.04990 0.00 0.00 0.37 46.48
Linear in dose10 dose10 7.70 5.32 10.08 0.00000 4.01 22.14 0.16 41.33
Linear-Quadratic in dose10 dose10 14.68 5.98 23.39 0.00094 0.00 0.00 0.27 46.94
Linear-Quadratic in dose10 I(dose10^2) -1.60 -3.53 0.33 0.10377 0.00 0.00 0.27 46.94
Sensitivity Analyses
Highest Doses-Overall intrcpt 39.61 9.96 69.26 0.00883 14.90 18.95 0.27 25.90

* Indicates the lowest AICc.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
images
FIGURE E5-9 Benchmark dose estimates from studies of BDE-209 and latency in last trial of the Morris water maze.

REFERENCES

Biesemeier, J.A., M.J. Beck, H. Silberberg, N.R. Myers, J.M. Ariano, A. Radovsky, L. Freshwater, D.W. Sved, S. Jacobi, D.G. Stump, M.L. Hardy, and T. Stedeford. 2011. An oral developmental neurotoxicity study of decabromodiphenyl ether (DecaBDE) in rats. Birth Defects Res. B Dev. Reprod. Toxicol. 92(1):17-35.

Blanco, J., M. Mulero, L. Heredia, A. Pujol, J.L. Domingo, and D.J. Sánchez. 2013. Perinatal exposure to BDE-99 causes learning disorders and decreases serum thyroid hormone levels and BDNF gene expression in hippocampus in rat offspring. Toxicology 308:122-128.

Bowers, W.J., P.M. Wall, J.S. Nakai, A. Yagminas, M. Wade, and N. Li. 2015. Behavioral and thyroid effects of in utero and lactational exposure of Sprague-Dawley rats to the polybrominated diphenyl ether mixture DE71. Neurotoxicol. Teratol. 52(Pt. B):127-142.

Buratovic, S., H. Viberg, A. Fredriksson, and P. Eriksson. 2014. Developmental exposure to the polybrominated diphenyl ether PBDE 209: Neurobehavioural and neuroprotein analysis in adult male and female mice. Environ. Toxicol. Pharmacol. 38(2):570-585.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

Chen, A., K. Yolton, S.A. Rauch, G.M. Webster, R. Hornung, A. Sjödin, K.N. Dietrich, and B.P. Lanphear. 2014. Prenatal polybrominated diphenyl ether exposures and neurodevelopment in U.S. children through 5 years of age: The HOME study. Environ. Health Perspect. 122(8):856-862.

Cheng, J., J. Gu, J. Ma, X. Chen, M. Zhang, and W. Wang. 2009. Neurobehavioural effects, redox responses and tissue distribution in rat offspring developmental exposure to BDE-99. Chemosphere 75(7):963-968.

de-Miranda, A.S., S.N. Kuriyama, C.S. da-Silva, M.S. do-Nascimento, T.E. Parente, and F.J. Paumgartten. 2016. Thyroid hormone disruption and cognitive impairment in rats exposed to PBDE during postnatal development. Reprod. Toxicol. 63:114-124.

Driscoll, L.L., A.M. Gibson, and A. Hieb. 2009. Chronic postnatal DE-71 exposure: Effects on learning, attention and thyroxine levels. Neurotoxicol. Teratol. 31(2):76-84.

Driscoll, L.L., J. Kaplan, E. Bucuvalas, H. Allen, J. Kraut, and J. Fitzpatrick. 2012. Acute postnatal exposure to the pentaBDE commercial mixture DE-71 at 5 or 15mg/kg/day does not produce learning or attention deficits in rats. Neurotoxicol. Teratol. 34(1):20-26.

Dufault, C., G. Poles, and L.L. Driscoll. 2005. Brief postnatal PBDE exposure alters learning and the cholinergic modulation of attention in rats. Toxicol. Sci. 88(1):172-180.

Eriksson, P., E. Jakobsson, and A. Fredriksson. 2001. Brominated flame retardants: A novel class of developmental neurotoxicants in our environment? Environ. Health Perspect. 109(9):903-908.

Fischer, C., A. Fredriksson, and P. Eriksson. 2008. Coexposure of neonatal mice to a flame retardant PBDE 99 (2, 2',4, 4',5-pentabromodiphenyl ether) and methyl mercury enhances developmental neurotoxic defects. Toxicol. Sci. 101(2):275-285.

He, P., A.G. Wang, T. Xia, P. Gao, Q. Niu, L.J. Guo, and X.M. Chen. 2009. Mechanisms underlying the developmental neurotoxic effect of PBDE-47 and the enhanced toxicity associated with its combination with PCB153 in rats. NeuroToxicology 30(6):1088-1095.

He, P., A. Wang, Q. Niu, L. Guo, T. Xia, and X. Chen. 2011. Toxic effect of PBDE-47 on thyroid development, learning, and memory, and the interaction between PBDE-47 and PCB153 that enhances toxicity in rats. Toxicol. Ind. Health 27(3):279-288.

Koenig, C.M., J. Lango, I.N. Pessah, and R.F. Berman. 2012. Maternal transfer of BDE-47 to offspring and neurobehavioral development in C57BL/6J mice. Neurotoxicol. Teratol. 34(6):571-580.

Llansola, M., M. Hernandez-Viadel, S. Erceg, C. Montoliu, and V. Felipo. 2009. Increasing the function of the glutamate-nitric oxide-cyclic guanosine monophosphate pathway increases the ability to learn a Y-maze task. J. Neurosci. Res. 87(10):2351-2355.

Reverte, I., A.B. Klein, J.L. Domingo, and M.T. Colomina. 2013. Long term effects of murine postnatal exposure to decabromodiphenyl ether (BDE-209) on learning and memory are dependent upon APOE polymorphism and age. Neurotoxicol. Teratol. 40:17-27.

Rice, D. C., W.D. Thompson, E.A. Reeve, K.D. Onos, M. Assadollahzadeh, and V.P. Markowski. 2009. Behavioral changes in aging but not young mice after neonatal exposure to the polybrominated flame retardant decaBDE. Environ. Health Perspect. 117(12):1903-1911.

Ta, T.A., C.M. Koenig, M.S. Golub, I.N. Pessah, L. Qi, P.A. Aronov, and R.F. Berman. 2011. Bioaccumulation and behavioral effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in perinatally exposed mice. Neurotoxicol. Teratol. 33(3):393-404.

Verma, P., P. Singh, and B.S. Gandhi. 2013. Prophylactic efficacy of Bacopa monnieri on decabromodiphenyl ether (PBDE-209)-induced alterations in oxidative status and spatial memory in mice. Asian J. Pharm. Clin. Res. 6(3):242-247.

Verma, P., P. Singh, and B.S. Gandhi. 2014. Neuromodulatory role of Bacopa monnieri on oxidative stress induced by postnatal exposure to decabromodiphenyl ether (PBDE -209) in neonate and young female mice. Iran. J. Basic Med. Sci. 17(4):307-311.

Viberg, H., A. Fredriksson, and P. Eriksson. 2003. Neonatal exposure to polybrominated diphenyl ether (PBDE 153) disrupts spontaneous behaviour, impairs learning and memory, and decreases hippocampal cholinergic receptors in adult mice. Toxicol. Appl. Pharmacol. 192(2):95-106.

Viberg, H., N. Johansson, A. Fredriksson, J. Eriksson, G. Marsh, and P. Eriksson. 2006. Neonatal exposure to higher brominated diphenyl ethers, hepta-, octa-, or nonabromodiphenyl ether, impairs spontaneous behavior and learning and memory functions of adult mice. Toxicol. Sci. 92(1):211-218.

Woods, R., R.O. Vallero, M.S. Golub, J.K. Suarez, T.A. Ta, D.H. Yasui, L.H. Chi, P.J. Kostyniak, I.N. Pessah, R.F. Berman, and J.M. LaSalle. 2012. Long-lived epigenetic interactions between perinatal PBDE exposure and Mecp2308 mutation. Hum. Mol. Genet. 21(11):2399-2411.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×

Zhang, H., X. Li, J. Nie, and Q. Niu. 2013. Lactation exposure to BDE-153 damages learning and memory, disrupts spontaneous behavior and induces hippocampus neuron death in adult rats. Brain Res. 1517:44-56.

Zhao, W., J. Cheng, J. Gu, Y. Liu, M. Fujimura, and W. Wang. 2014. Assessment of neurotoxic effects and brain region distribution in rat offspring prenatally co-exposed to low doses of BDE-99 and methylmercury. Chemosphere 112:170-176.

Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 329
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 330
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 331
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 332
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 333
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 334
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 335
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 336
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 337
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 338
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 339
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 340
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 341
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 342
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 343
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 344
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 345
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 346
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 347
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 348
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 349
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 350
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 351
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 352
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 353
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 354
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 355
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 356
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 357
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 358
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 359
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 360
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 361
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 362
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 363
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 364
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 365
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 366
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 367
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 368
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 369
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 370
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 371
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 372
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 373
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 374
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 375
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 376
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 377
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 378
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 379
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 380
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 381
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 382
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 383
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 384
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 385
Suggested Citation:"Appendix E: Supporting Materials for the PBDE (Animal) Systematic Review." National Academies of Sciences, Engineering, and Medicine. 2017. Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/24758.
×
Page 386
Next: Appendix F: Supporting Materials for the PBDE (Human) Systematic Review »
Application of Systematic Review Methods in an Overall Strategy for Evaluating Low-Dose Toxicity from Endocrine Active Chemicals Get This Book
×
Buy Paperback | $70.00 Buy Ebook | $59.99
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

To safeguard public health, the US Environmental Protection Agency (EPA) must keep abreast of new scientific information and emerging technologies so that it can apply them to regulatory decision-making. For decades the agency has dealt with questions about what animal-testing data to use to make predictions about human health hazards, how to perform dose-response extrapolations, how to identify and protect susceptible subpopulations, and how to address uncertainties. As alternatives to traditional toxicity testing have emerged, the agency has been faced with additional questions about how to incorporate data from such tests into its chemical assessments and whether such tests can replace some traditional testing methods.

Endocrine active chemicals (EACs) have raised concerns that traditional toxicity-testing protocols might be inadequate to identify all potential hazards to human health because they have the ability to modulate normal hormone function, and small alterations in hormone concentrations, particularly during sensitive life stages, can have lasting and significant effects. To address concerns about potential human health effects from EACs at low doses, this report develops a strategy to evaluate the evidence for such low-dose effects.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!