APPLICATION OF
SYSTEMATIC REVIEW METHODS
IN AN OVERALL STRATEGY
FOR EVALUATING LOW-DOSE TOXICITY
FROM ENDOCRINE ACTIVE CHEMICALS

Committee on Endocrine-Related Low-Dose Toxicity

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

A Consensus Study Report of

THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001

This project was supported by Contract EP-C-14-005, Task Order #5, between the National Academy of Sciences and the US Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the view of any organization or agency that provided support for the project.

International Standard Book Number-13: 978-0-309-45862-7
International Standard Book Number-10: 0-309-45862-5
Digital Object Identifier: https://doi.org/10.17226/24758

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Printed in the United States of America

Suggested citation: 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: https://doi.org/10.17226/24758.

COMMITTEE ON ENDOCRINE-RELATED LOW-DOSE TOXICITY

Members

DAVID C. DORMAN (Chair), North Carolina State University, Raleigh, NC

WEIHSUEH CHIU, Texas A&M University, College Station, TX

BARBARA F. HALES, McGill University, Montreal, Quebec, Canada

RUSS B. HAUSER, Harvard T.H. Chan School of Public Health, Boston, MA

KAMIN J. JOHNSON, The Dow Chemical Company, Midland, MI

KAREN A. ROBINSON, Johns Hopkins University, Baltimore, MD

ANDREW A. ROONEY, National Toxicology Program, Research Triangle Park, NC

RUTHANN RUDEL, Silent Spring Institute, Newton, MA

SHEELA SATHYANARAYANA, University of Washington, Seattle, WA

SUSAN L. SCHANTZ, University of Illinois at Urbana-Champaign, IL

KATRINA WATERS, Pacific Northwest National Laboratory, Richland, WA

Staff

SUSAN N. J. MARTEL, Project Director

ELLEN K. MANTUS, Scholar and Director of Risk Assessment

LINDA O’DOUGHDA, Editor

MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center

RADIAH ROSE-CRAWFORD, Manager, Editorial Projects

TAMARA DAWSON, Program Coordinator

Sponsor

US ENVIRONMENTAL PROTECTION AGENCY

BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY

Members

WILLIAM H. FARLAND (Chair), Colorado State University, Fort Collins, CO

RICHARD A. BECKER, American Chemistry Council, Washington, DC

E. WILLIAM COLGLAZIER, American Association for the Advancement of Science, Washington, DC

DOMINIC M. DITORO, University of Delaware, Newark, DE

DAVID C. DORMAN, North Carolina State University, Raleigh, NC

CHARLES T. DRISCOLL, JR., Syracuse University, Syracuse, NY

ANNE FAIRBROTHER, Exponent Inc., Philomath, OR

GEORGE GRAY, The George Washington University, Washington, DC

STEVEN P. HAMBURG, Environmental Defense Fund, New York, NY

ROBERT A. HIATT, University of California, San Francisco, CA

SAMEUL KACEW, University of Ottawa, Ontario

H. SCOTT MATTHEWS, Carnegie Mellon University, Pittsburgh, PA

ROBERT PERCIASEPE, Center for Climate and Energy Solutions, Arlington, VA

R. CRAIG POSTLEWAITE, Burke, VA

MARK A. RATNER, Northwestern University, Evanston, IL

JOAN B. ROSE, Michigan State University, East Lansing, MI

GINA M. SOLOMON, California Environmental Protection Agency, Sacramento, CA

ROBERT M. SUSSMAN, Sussman and Associates, Washington, DC

DEBORAH L. SWACKHAMMER, University of Minnesota, St. Paul, MN

PETER S. THORNE, University of Iowa, Iowa City, IA

Senior Staff

TERESA A. FRYBERGER, Director

ELLEN K. MANTUS, Scholar and Director of Risk Assessment

RAYMOND A. WASSEL, Scholar and Director of Environmental Studies

SUSAN N. J. MARTEL, Senior Program Officer for Toxicology

Acknowledgments

This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.

We thank the following individuals for their review of this report:

Sir Colin Berry, University of London

Kim Boekelheide, Brown University

Steven P. Bradbury, Iowa State University

Jonathan Chevrier, McGill University

Deborah Cory-Slechta, University of Rochester

George P. Daston, Proctor & Gamble Company

Brenda Eskenazi, University of California, Berkeley

Dale Hattis, Arlington, MA

Malcolm Macleod, University of Edinburgh

Bruce McEwen, The Rockefeller University

David Savitz, Brown University

Laura Vandenberg, University of Massachusetts, Amherst

Tracey Woodruff, University of California, San Francisco

Yiliang Zhu, University of South Florida

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by Gary Ginsberg, Connecticut Department of Public Health, and Martin Philbert, University of Michigan. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

The four protocols for conducting the systematic reviews contained in this report were also peer reviewed before the systematic reviews were undertaken. We thank the following individuals for their review of the protocols:

Sir Colin Berry, University of London

Kim Boekelheide, Brown University

Deborah Cory-Slechta, University of Rochester

Brenda Eskenazi, University of California, Berkeley

Malcolm Macleod, University of Edinburgh

John Meeker, University of Michigan

Tracey Woodruff, University of California, San Francisco

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the protocols, nor did they see the final protocols. The review of the protocols was overseen by David Eaton, University of Washington, and Martin Philbert, University of Michigan.

The committee is grateful to Juleen Lam and Tracey Woodruff at the University of California, San Francisco, for sharing a draft of their systematic review on PBDE (polybrominated diphenyl ether) exposure and neurodevelopmental effects in childhood. Their generosity and cooperation allowed the committee to demonstrate the methods by which a systematic review can be reviewed and updated. It is a fortunate development that our report has been published almost simultaneously with theirs.

The committee gratefully acknowledges the following individuals for their presentations to the committee during open sessions or their participation in a workshop: Stanley Barone, US Environmental Protection Agency; Kim Boekelheide, Brown University; Joseph Braun, Brown University; Germaine Buck-Louis, National Institute of Child Health and Human Development; Thomas Burke, US Environmental Protection Agency; Vincent Cogliano, US Environmental Protection Agency; Glinda Cooper, US Environmental Protection Agency; David Dix, US Environmental Protection Agency; Daniel Doerge, US Food and Drug Administration; Brenda Eskenazi, University of California, Berkeley; Jodi Flaws, University of Illinois at Urbana-Champaign; Catherine Gibbons, US Environmental Protection Agency; Earl Gray, US Environmental Protection Agency; and John Meeker, University of Michigan. The committee also thanks Robyn Blain and Pamela Hartman at ICF International for their assistance with data extraction, Jaime Blanck at the William H. Welch Medical Library at Johns Hopkins University for her assistance with planning and performing the literature searches to support the systematic reviews, and Anne Johnson for her editorial assistance and advice.

Contents

ABBREVIATIONS AND ACRONYMS

SUMMARY

1 INTRODUCTION

Advances in Toxicity Testing

Endocrine Active Chemicals

Defining Low Dose

Low-Dose Effects

Nonmonotonic Dose-Response Curves

Systematic Review

Statement of Task

Committee’s Approach

Organization of the Consensus Study Report

References

2 STRATEGY FOR EVALUATING LOW-DOSE EFFECTS

Overview of the Committee’s Strategy

Surveillance

Investigation and Analysis

Actions

Findings and Recommendations

References

3 PHTHALATES AND MALE REPRODUCTIVE-TRACT DEVELOPMENT

Systematic Review Methods

Results

Evidence Integration for AGD

Evidence Integration for Fetal Testosterone

Evidence Integration for Hypospadias

Consideration of Low-Dose Effects

Other Phthalates

Relevance to Animal Toxicity Testing

Findings and Recommendations

References

4 EFFECT OF POLYBROMINATED DIPHENYL ETHERS ON NEURODEVELOPMENT

Systematic Review Methods

Results

Mechanistic Evidence

Evidence Integration

Analysis of Low-Dose Effects

Relevance to Animal Toxicity Testing

Findings and Recommendations

References

5 LESSONS LEARNED AND REFLECTIONS ON THE STATEMENT OF TASK

Committee Strategy

Characterizing Adversity

Reflections and Lessons Learned from the Systematic Reviews

Lessons Learned from Evidence Integration

Other Issues

References

APPENDIXES

A BIOSKETCHES OF THE COMMITTEE ON ENDOCRINE-RELATED LOW-DOSE TOXICITY

B WORKSHOP ON POTENTIAL CASE STUDIES FOR UNRAVELING ENDOCRINE-RELATED LOW-DOSE TOXICITY

C SUPPORTING MATERIALS FOR THE PHTHALATE (ANIMAL) SYSTEMATIC REVIEW

D SUPPORTING MATERIALS FOR THE PHTHALATE (HUMAN) SYSTEMATIC REVIEW

E SUPPORTING MATERIALS FOR THE PBDE (ANIMAL) SYSTEMATIC REVIEW

F SUPPORTING MATERIALS FOR THE PBDE (HUMAN) SYSTEMATIC REVIEW

BOXES, FIGURES, AND TABLES

BOXES

S-1 Statement of Task

S-2 Example 1

S-3 Example 2

1-1 Verbatim Statement of Task

1-2 Definitions of Terms Used in the Consensus Study Report

2-1 Potential Limitations of Traditional Toxicity Testing for Evaluating Low-Dose Effects of Endocrine Active Chemicals

2-2 Endometriosis: An Example in Which Traditional Toxicity Testing Might Be Inadequate to Evaluate Endocrine Active Chemicals

2-3 NHANES: A Platform for Surveillance

2-4 Overview of FDA’s Efforts in Postmarket Drug Safety Surveillance

2-5 Anogenital Distance and Its Addition to Regulatory Toxicity Tests

2-6 Bisphenol A: Generating Data to Address Uncertainty

3-1 PECO Statement for the Phthalate (Animal) Systematic Review

3-2 PECO Statement for the Phthalate (Human) Systematic Review

3-3 Uses of Meta-Analyses and Meta-Regression of Experimental Animal Studies

3-4 Summary of Meta-Analyses, Meta-Regression, and Benchmark Dose Estimation Methods for Experimental Animal Studies

3-5 Studies Included in the Phthalate (Animal) Systematic Review

3-6 Studies Included in the Phthalate (Human) Systematic Review

4-1 PECO Statement for the PBDE (Animal) Systematic Review

4-2 PECO Statement for the PBDE (Human) Systematic Review

4-3 Studies Included in the PBDE (Animal) Systematic Review

5-1 Examples of Targeted Analyses of Existing Data Performed by the Committee

FIGURES

S-1 Strategy for evaluating evidence of adverse human effects from low-dose exposure to chemicals

S-2 OHAT hazard identification scheme

2-1 Strategy for evaluating evidence of adverse human effects from low-dose exposure to chemicals

3-1 Overview of phthalate metabolism in mammals

3-2 Method for assessing confidence in the body of evidence

3-3 Method for translating confidence ratings into evidence for health effects

3-4 OHAT hazard identification scheme

3-5 Summary of the search and screening of the literature on the effects of in utero exposure to phthalates on male reproductive-tract development in animals

3-6 Summary of the search and screening of the literature on the effects of in utero exposure to phthalates on male reproductive-tract development in humans

3-7 Risk of bias heatmap of studies of DEHP and AGD in rodents

3-8 Risk of bias heatmap of studies of DEHP and fetal testosterone in rodents

3-9 Risk of bias heatmap of studies of DEHP and hypospadias in rodents

3-10 Results of the meta-regressions of studies on DEHP and AGD in rats

3-11 Results of the meta-analysis of studies on DEHP and AGD in mice

3-12 Results of the meta-regressions of studies on DEHP and fetal testosterone in different strains of rat

3-13 Risk of bias heatmap of studies of DEHP and AGD in humans

3-14 Results of the meta-analysis of studies on DEHP and AGD in humans are shown as the percent change per log₁₀ change in DEHP concentration

3-15 Results of the sensitivity analysis of the meta-regression of studies on DEHP and AGD in humans as shown as the percent change in AGD per log₁₀ change in DEHP concentration

3-16 Theoretical steps involved in male reproductive toxicity following phthalate exposure during the in utero male programming window

3-17 Meta-analysis of rodent-human xenograft studies of DBP and serum testosterone, shown as the log ratio of the mean between treated and control mice

3-18 Risk of bias heatmap of studies of BzBP and AGD in rats

3-19 Risk of bias heatmap of studies of DBP and AGD in rats

3-20 Risk of bias heatmap of studies of DINP and AGD in rats

3-21 Risk of bias heatmap of studies of BzBP and fetal testosterone in rats

3-22 Risk of bias heatmap of studies of DBP and fetal testosterone in rats

3-23 Risk of bias heatmap of studies of DIBP and fetal testosterone in rats

3-24 Risk of bias heatmap of studies of DINP and fetal testosterone in rats

3-25 Risk of bias heatmap of studies of DPP and fetal testosterone in rats

3-26 Risk of bias heatmap of studies of BzBP and hypospadias in rats

3-27 Risk of bias heatmap of studies on DBP and hypospadias in rats

3-28 Risk of bias heatmap of studies of other phthalates and AGD in humans

4-1 Generic structure of a polybrominated diphenyl ether (PBDE)

4-2 Steps in the Navigation Guide protocol

4-3 Method for assessing confidence in the body of evidence

4-4 Method for translating confidence ratings into evidence for health effects

4-5 OHAT hazard identification scheme

4-6 Summary of the search and screening of the literature on the effects of developmental exposure to PBDEs on learning, memory, attention, or response inhibition in animals

4-7 Summary of the search and screening of the literature on the effects of developmental exposure to PBDEs on intelligence or ADHD and attention-related behavioral conditions in humans

4-8 Risk of bias heatmap of studies of BDE-47 and learning in rodents

4-9 Risk of bias heatmap of studies of BDE-47 and memory in rodents

4-10 Forest plot of all studies of BDEs and latency in the last trial of the Morris water maze in rats and mice

4-11 Results of the meta-analysis of PBDEs and latency in the last trial of the Morris water maze in rats and mice sorted by congener and then by dose

4-12 Theoretical steps involved in PBDE developmental neurotoxicity

C4-1 Risk of bias heatmap of studies of DEHP and AGD in mice

C4-2 Risk of bias heatmap of studies of DEHP and AGD in rats

C4-3 Data pivot of animal studies of DEHP and AGD sorted by dose

C4-4 Data pivot of animal studies of DEHP and AGD sorted by study

C4-5 Risk of bias heatmap of studies of DEHP and fetal testosterone in rats

C4-6 Data pivot of animal of DEHP and fetal testosterone sorted by dose

C4-7 Data pivot of animal of DEHP and fetal testosterone sorted by study

C4-8 Risk of bias heatmap of studies of DEHP and hypospadias in rats

C4-9 Data pivot of animal studies of DEHP and hypospadias (% animals affected) sorted by dose

C4-10 Data pivot of animal studies of DEHP and hypospadias (% animals affected) sorted by study

C4-11 Risk of bias heatmap of studies of BzBP and AGD in rats

C4-12 Data pivot of animal studies of BzBP and AGD in rats sorted by dose

C4-13 Data pivot of animal studies of BzBP and AGD in rats sorted by study

C4-14 Risk of bias heatmap of studies of BzBP and fetal testosterone in rats

C4-15 Data pivot of animal studies of BzBP and fetal testosterone in rats sorted by dose

C4-16 Data pivot of animal studies of BzBP and fetal testosterone in rats sorted by study

C4-17 Risk of bias heatmap of studies of BzBP and hypospadias in rats

C4-18 Data pivot of animal studies of BzBP and hypospadias (% animals affected) in rats sorted by dose

C4-19 Risk of bias heatmap of studies of DBP and AGD in rats

C4-20 Data pivot of animal studies of DBP and AGD in rats sorted by dose

C4-21 Data pivot of animal studies of DBP and AGD in rats sorted by study

C4-22 Risk of bias heatmap of studies of DBP and fetal testosterone in rats

C4-23 Data pivot of animal studies of DBP and fetal testosterone in rats sorted by dose

C4-24 Data pivot of animal studies of DBP and fetal testosterone in rats sorted by study

C4-25 Risk of bias heatmap of studies of DBP and hypospadias in rats

C4-26 Data pivot of animal studies of DBP and hypospadias in rats sorted by dose

C4-27 Data pivot of animal studies of DBP and hypospadias in rats sorted by study

C4-28 Risk of bias heatmap of studies of DIBP and fetal testosterone in rats

C4-29 Data pivot of animal studies of DIBP and fetal testosterone in rats sorted by dose

C4-30 Data pivot of animal studies of DIBP and fetal testosterone in rats sorted by study

C4-31 Risk of bias heatmap of studies of DINP and AGD in rats

C4-32 Data pivot of animal studies of DINP and AGD in rats sorted by dose

C4-33 Data pivot of animal studies of DINP and AGD in rats sorted by study

C4-34 Risk of bias heatmap of studies of DINP and fetal testosterone in rats

C4-35 Data pivot of animal studies of DINP and fetal testosterone in rats sorted by dose

C4-36 Data pivot of animal studies of DINP and fetal testosterone in rats sorted by study

C4-37 Risk of bias heatmap of studies of DPP and fetal testosterone in rats

C4-38 Data pivot of animal studies of DPP and fetal testosterone in rats sorted by dose

C4-39 Data pivot of animal studies of DPP and fetal testosterone in rats sorted by study

C5-1 Results of meta-analyses of studies on DEHP and AGD in different strains of rat using the random effects model

C5-2 Benchmark dose estimates from rat studies of DEHP and AGD

C5-3 Results of meta-analyses of studies on DEHP and AGD in mice using the random effects model

C5-4 Benchmark dose estimates from mouse studies of DEHP and AGD

C5-5 Results of meta-analyses of studies on DEHP and fetal testosterone in different strains of rat using the random effects model

C5-6 Benchmark dose estimates from rat studies of DEHP and fetal testosterone (effect size of 5%)

C5-7 Benchmark dose estimates from rat studies of DEHP and fetal testosterone (effect size of 40%)

C6-1 Meta-analyses of studies of BzBP and AGD in rats

C6-2 Benchmark dose estimates from rat studies of BzBP and AGD

C6-3 Meta-analyses of studies of BzBP and fetal testosterone in rats

C6-4 Benchmark dose estimates from rat studies of BzBP and fetal testosterone

C6-5 Meta-analyses of studies of DBP and AGD in rats

C6-6 Benchmark dose estimates from rat studies of DBP and AGD

C6-7 Meta-analyses of studies of DBP and fetal testosterone in rats

C6-8 Benchmark dose estimates from rat studies of DBP and fetal testosterone

C6-9 Meta-analyses of studies of DPP and fetal testosterone in rats

C6-10 Benchmark dose estimates from rat studies of DPP and fetal testosterone

C6-11 Meta-analyses of studies of DIBP and fetal testosterone in rats

C6-12 Benchmark dose estimates from rat studies of DIBP and fetal testosterone

C6-13 Meta-analyses of studies of DINP and AGD in rats

C6-14 Benchmark dose estimates from rat studies of DINP and AGD

C6-15 Meta-analyses of studies of DINP and fetal testosterone in rats

C6-16 Benchmark dose estimates from rat studies of DINP and fetal testosterone

D3-1 Data pivot of studies that measured sumDEHP metabolites and AGD (as) or AGD (ap)

D3-2 Data pivot of studies that measured DEHP metabolites and AGD (as) or AGD (ap)

D3-3 Risk of bias of bias heatmap of studies of DEHP and AGD in humans

D3-4 Data pivot of the Jensen et al. (2016) study of sumDEHP metabolites and AGD (as) or AGD (ap)

D3-5 Data pivot of studies that measured MBzP and AGD (as) or AGD (ap)

D3-6 Data pivot of studies that measured MBP and AGD (as) or AGD (ap)

D3-7 Data pivot of studies that measured MEP and AGD (as) or AGD (ap)

D3-8 Data pivot of studies that measured MIBP and AGD (as) or AGD (ap)

D3-9 Data pivot of the study that measured MCNP and AGD (as) or AGD (ap)

D3-10 Data pivot of studies that measured MCOP and AGD (as) or AGD (ap)

D3-11 Data pivot of the study that measured MMP and AGD (as) or AGD (ap)

D3-12 Data pivot of studies that measured MCPP and AGD (as) or AGD (ap)

D5-1 Meta-analysis of human studies of BzBP and AGD; reported effect estimates [95% confidence interval] from individual studies and overall pooled estimate from random effects (RE) model per 10-fold increase in BzBP exposure

D5-2 Sensitivity analyses of human studies of BzBP and AGD performed by leaving one study out at a time

D5-3 Sensitivity analyses of human studies of BzBP and AGD performed by restricting analysis to the same outcome measure (AGD [ap])

D5-4 Meta-analysis of human studies of DBP and AGD; reported effect estimates [95% confidence interval] from individual studies and overall pooled estimate from random effects (RE) model per 10-fold increase in DBP exposure

D5-5 Sensitivity analysis of human studies of DBP and AGD performed by leaving one study out at a time

D5-6 Sensitivity analysis of human studies of DBP and AGD performed by restricting analysis to the same outcome measure (AGD [ap])

D5-7 Meta-analysis of human studies of DEP and AGD; reported effect estimates [95% confidence interval] from individual studies and overall pooled estimate from random effects (RE) model per 10-fold increase in DEP exposure

D5-8 Sensitivity analysis of human studies of DEP and AGD performed by leaving one study out at a time

D5-9 Sensitivity analysis of human studies of DEP and AGD performed by restricting analysis to the same outcome measure (AGD [ap])

D5-10 Meta-analysis of human studies of DIBP and AGD; reported effect estimates [95% confidence interval] from individual studies and overall pooled estimate from random effects (RE) model per 10-fold increase in DIBP exposure

D5-11 Sensitivity analysis of human studies of DIBP and AGD performed by leaving one study out at a time

D5-12 Sensitivity analysis of human studies of DIBP and AGD performed by restricting analysis to the same outcome measure (AGD [ap])

D5-13 Meta-analysis of human studies of DINP and AGD; reported effect estimates [95% confidence interval] from individual studies and overall pooled estimate from random effects (RE) model per 10-fold increase in DINP exposure

D5-14 Sensitivity analysis of human studies of DINP and AGD performed by leaving one study out at a time

D5-15 Sensitivity analysis of human studies of DINP and AGD performed by restricting analysis to the same outcome measure (AGD [ap])

E4-1 Risk of bias heatmap of studies of BDE-47 and learning in rodents

E4-2 Risk of bias heatmap of studies of BDE-47 and memory in rodents

E4-3 Risk of bias heatmap of studies of BDE-99 and learning in rodents

E4-4 Risk of bias heatmap of studies of BDE-99 and memory in rodents

E4-5 Risk of bias heatmap of studies of BDE-153 and learning or memory in rodents

E4-6 Risk of bias heatmap of study of BDE-203 and learning and memory and BDE-206 and learning in mice

E4-7 Risk of bias heatmap of studies of BDE-209 and learning in rodents

E4-8 Risk of bias heatmap of studies of BDE-209 and memory in rodents

E4-9 Risk of bias heatmap of studies of DE-71 and learning in rats

E4-10 Risk of bias heatmap of studies of DE-71 and memory in rats

E4-11 Risk of bias heatmap of studies of DE-71 and attention in rats

E5-1 Risk of bias heatmap of studies of PBDEs and latency in last trial of the Morris water maze with standard deviations reported or digitized from figures in the publication

E5-2 Risk of bias heatmap of studies of PBDEs and latency in last trial of the Morris water maze without standard deviations

E5-3 Benchmark dose estimates from studies of PBDEs and latency in last trial of the Morris water maze in rats and mice

E5-4 Results of meta-analysis of studies of BDE-47 and latency in last trial of the Morris water maze

E5-5 Benchmark dose estimates from studies of BDE-47 and latency in last trial of the Morris water maze

E5-6 Results of meta-analysis of studies of BDE-153 and latency in last trial of the Morris water maze

E5-7 Benchmark dose estimates from studies of BDE-153 and latency in last trial of the Morris water maze in rats and mice

E5-8 Results of meta-analysis of studies of BDE-209 and latency in last trial of the Morris water maze

E5-9 Benchmark dose estimates from studies of BDE-209 and latency in last trial of the Morris water maze

TABLES

1-1 Methods Used in the Systematic Reviews and Evidence Integration Presented in Chapters 3 and 4

3-1 Parent Phthalate and Oxidative Metabolites Found in Urine Following Exposure

3-2 Summary of Animal Studies of DEHP and AGD

3-3 Profile of the Confidence in the Body of Evidence on DEHP and AGD in Animals

3-4 Summary of Animal Studies of DEHP and Testosterone

3-5 Profile of the Confidence in the Body of Evidence on DEHP and Fetal Testosterone Concentrations in Animals

3-6 Summary of Animal Studies of DEHP and Hypospadias

3-7 Profile of the Confidence in the Body of Evidence on DEHP and Hypospadias in Animals

3-8 Summary of Human Studies of DEHP and AGD

3-9 Profile of the Confidence in the Body of Evidence on DEHP and AGD in Humans

3-10 Summary of Human Data Used in Meta-Analysis of DEHP and AGD

3-11 Comparison of Human and Rat Intake and Internal Concentrations of DEHP

3-12 Studies of BzBP and AGD in Rats

3-13 Studies of DBP and AGD in Rats

3-14 Studies of DINP and AGD in Rats

3-15 Profile of the Confidence in the Body of Evidence on BzBP, DBP, and DINP and AGD in Animals

3-16 Studies of BzBP and Fetal Testosterone in Rats

3-17 Studies of DBP and Fetal Testosterone in Rats

3-18 Studies of DIBP and Fetal Testosterone in Rats

3-19 Studies of DINP and Fetal Testosterone in Rats

3-20 Studies of DPP and Fetal Testosterone in Rats

3-21 Profile of the Confidence in the Body of Evidence on BzBP, DBP, DIBP, DINP, and DPP and Fetal Testosterone Concentrations in Animals

3-22 Studies of BzBP and Hypospadias in Rats

3-23 Studies of DBP and Hypospadias in Rats

3-24 Profile of the Confidence in the Body of Evidence on BzBP and DBP and Hypospadias in Animals

3-25 Summary of Meta-Analyses for BzBP and DBP Effects on Rat AGD

3-26 Summary of the Meta-Analyses for BzBP, DBP, DIBP, DINP, and DPP Effects on Rat Fetal Testosterone

3-27 Profile of the Confidence in the Body of Evidence on Phthalates and AGD in Humans

3-28 Summary of Meta-Analyses of Human Studies of BzBP, DBP, DEP, DIBP, DINP and AGD

3-29 Initial Hazard Evaluations for Other Phthalates and AGD in Humans

3-30 Initial Hazard Evaluations for Other Phthalates and Fetal Testosterone in Humans

3-31 Initial Hazard Evaluations for Other Phthalates and Hypospadias in Humans

4-1 Studies Included in the PBDE (Animal) Systematic Review

4-2 Studies of BDE-47 and Learning in Rodents

4-3 Studies of BDE-47 and Memory in Rodents

4-4 Profile of the Body of Evidence on PBDEs and Learning, Memory, and Attention

4-5 Comparison of Human and Rat Intake and Internal Concentrations of BDE-47

C1-1 OHAT Risk of Bias Tool

C1-2 Answers to the Risk of Bias Questions

C5-1 Subgrouping Analyses of Rat Studies on DEHP and AGD

C5-2 Overall Analyses and Sensitivity Analyses of Rat Studies of DEHP and AGD Without Strain Subgrouping

C5-3 Benchmark Dose Estimates for DEHP and AGD in Rats

C5-4 Overall Analyses and Sensitivity Analyses of Mouse Studies of DEHP and AGD

C5-5 Benchmark Dose Estimates for DEHP and AGD in Mice

C5-6 Subgrouping Analyses of Rat Studies on DEHP and Fetal Testosterone

C5-7 Overall Analyses and Sensitivity Analyses of Rat Studies of DEHP and Fetal Testosterone Without Subgrouping

C5-8 Benchmark Dose Estimates for DEHP and Fetal Testosterone (Effect Size of 5%) in Rats

C5-9 Benchmark Dose Estimates for DEHP and Fetal Testosterone (Effect Size of 40%) in Rats

C6-1 Overall Analyses and Sensitivity Analyses of Rat Studies of BzBP and AGD

C6-2 Benchmark Dose Estimates for BzBP and AGD in Rats

C6-3 Overall Analyses of Rat Studies of BzBP and Fetal Testosterone

C6-4 Benchmark Dose Estimates for BzBP and Fetal Testosterone in Rats

C6-5 Overall Analyses and Sensitivity Analyses of Rat Studies of DBP and AGD

C6-6 Benchmark Dose Estimates for DBP and AGD in Rats

C6-7 Overall Analyses and Sensitivity Analyses of Rat Studies of DBP and Fetal Testosterone

C6-8 Benchmark Dose Estimates for DBP and Fetal Testosterone in Rats

C6-9 Overall Analyses and Sensitivity Analyses of Rat Studies of DPP and Fetal Testosterone

C6-10 Benchmark Dose Estimates for DPP and Fetal Testosterone in Rats

C6-11 Overall Analyses of Rat Studies of DIBP and Fetal Testosterone

C6-12 Benchmark Dose Estimates for DIBP and Fetal Testosterone in Rats

C6-13 Overall Analyses and Sensitivity Analyses of Rat Studies of DINP and AGD

C6-14 Benchmark Dose Estimates for DINP and AGD in Rats

C6-15 Overall Analyses of Rat Studies of DINP and Fetal Testosterone

C6-16 Benchmark Dose Estimates for DINP and Fetal Testosterone in Rats

D1-1 OHAT Risk of Bias Tool

D1-2 Answers to the Risk of Bias Questions

D3-1 Sources of Funding for the Human Studies on Phthalates

D4-1 Sensitivity Analyses Performed by Leaving One Study Out at a Time, Using Alternative Exposure and Outcome Measures for Each Study One at a Time, and Restricting Analyses to Use the Same Exposure Measure (sumDEHP or MEHP) and/or the Same Outcome Measure (AGD [as] or AGD [ap])

D5-1 Studies Included in the Meta-Analysis of BzBP and AGD

D5-2 Sensitivity Analyses of Human Studies of BzBP and AGD

D5-3 Studies Included in the Meta-Analysis of DBP and AGD

D5-4 Sensitivity Analyses of Human Studies of DBP and AGD

D5-5 Studies Included in the Meta-Analysis of DEP and AGD

D5-6 Sensitivity Analyses of Human Studies of DEP and AGD

D5-7 Studies Included in the Meta-Analysis of DIBP and AGD

D5-8 Sensitivity Analyses of Human Studies of DIBP and AGD

D5-9 Studies Included in the Meta-Analysis of DINP and AGD

D5-10 Sensitivity Analyses of Human Studies of DINP and AGD

E1-1 OHAT Risk of Bias Tool

E1-2 Answers to the Risk of Bias Questions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Abbreviations and Acronyms