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
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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
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Digital Object Identifier: https://doi.org/10.17226/24758
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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.
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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
Nonmonotonic Dose-Response Curves
Organization of the Consensus Study Report
2 STRATEGY FOR EVALUATING LOW-DOSE EFFECTS
Overview of the Committee’s Strategy
3 PHTHALATES AND MALE REPRODUCTIVE-TRACT DEVELOPMENT
Evidence Integration for Fetal Testosterone
Evidence Integration for Hypospadias
Consideration of Low-Dose Effects
Relevance to Animal Toxicity Testing
4 EFFECT OF POLYBROMINATED DIPHENYL ETHERS ON NEURODEVELOPMENT
5 LESSONS LEARNED AND REFLECTIONS ON THE STATEMENT OF TASK
Reflections and Lessons Learned from the Systematic Reviews
Lessons Learned from Evidence Integration
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
1-1 Verbatim Statement of Task
1-2 Definitions of Terms Used in the Consensus Study Report
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
3-5 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
3-7 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
3-13 Risk of bias heatmap of studies of DEHP and AGD in humans
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
4-8 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
4-12 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
C4-19 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
C5-2 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
C5-6 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)
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
E4-7 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
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
3-6 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
3-22 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
3-27 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
C1-2 Answers to the Risk of Bias Questions
C5-1 Subgrouping Analyses of Rat Studies on DEHP and AGD
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
C5-8 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
D1-2 Answers to the Risk of Bias Questions
D3-1 Sources of Funding for the Human Studies on Phthalates
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
E1-2 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
Abbreviations and Acronyms
ADHD | attention deficit/hyperactivity disorder |
ADR | adverse drug reaction |
AGD | anogenital distance |
AGD ap | anogenital distance (anopenile) |
AGD as | anogenital (anoscrotal) |
AGI | anogenital index |
AHRQ | Agency for Healthcare Research and Quality |
AICc | Akaieke information criterion corrected |
AOP | adverse outcome pathway |
APD | anopenile distance |
ASD | anoscrotoal distance |
BASC-2 | Behavioral Assessment System for Children-2 |
BDE | brominated diphenyl ether |
BMD | benchmark dose |
BMDL | benchmark dose modeling |
BMR | benchmark response |
BPA | bisphenol A |
BzBP | benzylbutyl phthalate |
CADS-P | Conners’ ADHD Index (derived from Conners’ Parent Rating Scale) |
CASTNET | Clean Air Status and Trends Network |
CBCL | Child Behavior Checklist |
CDC | US Centers for Disease Control and Prevention |
CI | confidence interval |
COI | conflict of interest |
cpAOP | computationally predicted adverse outcome pathway |
CPRS | Conners’ Parent Rating Scale‐Revised |
CPT II | Conners’ Continuous Performance Test II |
CRS‐T | Conners’ Rating Scale‐Teachers |
DBD | Disruptive Behavior Disorders Rating Scale |
DBP | dibutyl phthalate |
DEHP | di(2-ethylhexyl) phthalate |
DEP | diethyl phthalate |
DES | diethylstilbestrol |
DIBP | diisobutyl phthalate |
DIDP | diisodecyl phthalate |
DINP | diisononyl phthalate |
DIOP | diisooctyl phthalate |
DMP | dimethyl phthalate |
DNOP | di-n-octylphthalate |
DPP | dipentyl phthalate |
EAC | endocrine active chemical |
EDSP | Endocrine Disruptor Screening Program |
EFSA | European Food Safety Authority |
EPA | US Environmental Protection Agency |
ExpoCast | EPA’s computer model to predict chemical exposure |
FAERS | FDA Adverse Event Reporting System |
FDA | US Food and Drug Administration |
FQPA | Food Quality Protection Act (of 1996) |
GRADE | Grading of Recommendations, Assessment, Development and Evaluation |
HAWC | Health Assessment Workspace Collaborative |
INSL-3 | insulin-like 3 |
IRIS | Integrated Risk Information System |
K‐CPT | Conners’ Kiddie Continuous Performance Test |
LOAEL | lowest-observed-adverse-effect level |
LOEL | lowest-observed-effect level |
MBP | monobutylphthalate |
MBzP | mono-benzyl phthalate |
MCNP | mono-(carboxynonyl) phthalate |
MCOP | mono-carboxy-isooctyl phthalate |
MCPP | mono-(3-carboxypropyl) phthalate |
MECPP | mono-(2-ethyl-5-carboxypentyl) phthalate |
MEHP | mono-2-ethylhexyl phthalate |
MEP | mono-ethyl phthalate |
MeO-BDE | methoxylated BDE |
MeSH | medical subject heading |
MIBP | mono-isobutyl phthalate |
MMP | mono-methyl phthalate |
MSCA | McCarthy Scales of Children’s Abilities |
NHANES | National Health and Nutrition Examination Survey |
NMDR | nonmonotonic dose-response |
NOAEL | no-observed-adverse-effect level |
NOEL | no-observed-effect level |
NRC | National Research Council |
NTP | National Toxicology Program |
OECD | Organisation for Economic Co-operation and Development |
OH-BDE | hydroxylated BDE |
OHAT | National Toxicology Program’s Office of Health Assessment and Translation |
PBDE | polybrominated diphenyl ether |
PBPK | physiologically based pharmacokinetic |
PCB | polychlorinated biphenyl |
PECO | Population, Exposure, Comparator, and Outcome |
PM | particulate matter |
PND | postnatal day |
QSAR | quantitative structure-activity relationship |
RE | random effects |
RfD | reference dose |
ROM | ratio of means |
RR | relative risk |
SD | standard deviation |
TCDD | 2,3,7,8-tetrachlorodibenzo-p-dioxin |
ToxCast | Toxicity Forecaster |
VAERS | Vaccine Adverse Event Reporting System |
WHO | World Health Organization |
WISC | Wechsler Intelligence Scale for Children |
WPPSI | Wechsler Preschool and Primary Scale of Intelligence |