PHTHALATES AND CUMULATIVE RISK ASSESSMENT

The Tasks Ahead

Committee on the Health Risks of Phthalates

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
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Committee on the Health Risks of Phthalates Board on Environmental Studies and Toxicology Division on Earth and Life Studies

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Insti- tute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This project was supported by Contract 68-C-03-081 between the National Academy of Sciences and the U.S. Environmental Protection Agency. Any opinions, findings, conclu- sions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-12841-4 International Standard Book Number-10: 0-309-12841-2 Additional copies of this report are available from: The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2008 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON THE HEALTH RISKS OF PHTHALATES Members DEBORAH CORY-SLECHTA (Chair), University of Rochester School of Medicine and Dentistry, Rochester, NY EDMUND CROUCH, Cambridge Environmental Inc., Cambridge, MA PAUL FOSTER, National Institute of Environmental Health Sciences, Research Triangle Park, NC MARY FOX, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD KEVIN GAIDO, Hamner Institutes for Health Sciences, Research Triangle Park, NC MAIDA GALVEZ, Mount Sinai School of Medicine, New York, NY CHRIS GENNINGS, Virginia Commonwealth University, Richmond J. PAUL GILMAN, Covanta Energy Corporation, Fairfield, NJ RUSS HAUSER, Harvard School of Public Health, Boston, MA ANDREAS KORTENKAMP, University of London School of Pharmacy, London, UK JEFFREY PETERS, Pennsylvania State University, University Park, PA DONNA VORHEES, The Science Collaborative–North Shore, Ipswich, MA MARY SNOW WOLFF, Mount Sinai School of Medicine, New York, NY Staff ELLEN MANTUS, Project Director NORMAN GROSSBLATT, Senior Editor HEIDI MURRAY-SMITH, Research Associate MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center JOHN BROWN, Program Associate PANOLA GOLSON, Senior Program Assistant Sponsor U.S. ENVIRONMENTAL PROTECTION AGENCY v

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Members JONATHAN M. SAMET (Chair), University of Southern California, Los Angeles RAMON ALVAREZ, Environmental Defense Fund, Austin, TX JOHN M. BALBUS, Environmental Defense Fund, Washington, DC DALLAS BURTRAW, Resources for the Future, Washington, DC JAMES S. BUS, Dow Chemical Company, Midland, MI RUTH DEFRIES, Columbia University, New York, NY COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie, Farr & Gallagher LLP, Washington, DC MARY R. ENGLISH, University of Tennessee, Knoxville J. PAUL GILMAN, Covanta Energy Corporation, Fairfield, NJ JUDITH A. GRAHAM (Retired), Pittsboro, NC WILLIAM M. LEWIS, JR., University of Colorado, Boulder JUDITH L. MEYER, University of Georgia, Athens DENNIS D. MURPHY, University of Nevada, Reno DANNY D. REIBLE, University of Texas, Austin JOSEPH V. RODRICKS, ENVIRON International Corporation, Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta ROBERT F. SAWYER, University of California, Berkeley KIMBERLY M. THOMPSON, Harvard School of Public Health, Boston, MA MARK J. UTELL, University of Rochester Medical Center, Rochester, NY Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Studies EILEEN N. ABT, Senior Program Officer for Risk Analysis SUSAN N.J. MARTEL, Senior Program Officer for Toxicology KULBIR BAKSHI, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer RUTH E. CROSSGROVE, Senior Editor vi

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OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Science and Decisions: Advancing Risk Assessment (2008) Estimating Mortality Risk Reduction and Economic Benefits from Controlling Ozone Air Pollution (2008) Respiratory Diseases Research at NIOSH (2008) Evaluating Research Efficiency in the U.S. Environmental Protection Agency (2008) Hydrology, Ecology, and Fishes of the Klamath River Basin (2008) Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007) Models in Environmental Regulatory Decision Making (2007) Toxicity Testing in the Twenty-first Century: A Vision and a Strategy (2007) Sediment Dredging at Superfund Megasites: Assessing the Effectiveness (2007) Environmental Impacts of Wind-Energy Projects (2007) Scientific Review of the Proposed Risk Assessment Bulletin from the Office of Management and Budget (2007) Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006) New Source Review for Stationary Sources of Air Pollution (2006) Human Biomonitoring for Environmental Chemicals (2006) Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006) Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006) State and Federal Standards for Mobile-Source Emissions (2006) Superfund and Mining Megasites—Lessons from the Coeur d’Alene River Basin (2005) Health Implications of Perchlorate Ingestion (2005) Air Quality Management in the United States (2004) Endangered and Threatened Species of the Platte River (2004) Atlantic Salmon in Maine (2004) Endangered and Threatened Fishes in the Klamath River Basin (2004) Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003) Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002) Biosolids Applied to Land: Advancing Standards and Practices (2002) The Airliner Cabin Environment and Health of Passengers and Crew (2002) Arsenic in Drinking Water: 2001 Update (2001) Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001) Compensating for Wetland Losses Under the Clean Water Act (2001) A Risk-Management Strategy for PCB-Contaminated Sediments (2001) Acute Exposure Guideline Levels for Selected Airborne Chemicals (six volumes, 2000-2008) Toxicological Effects of Methylmercury (2000) Strengthening Science at the U.S. Environmental Protection Agency (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) Ecological Indicators for the Nation (2000) Waste Incineration and Public Health (2000) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (four volumes, 1998-2004) The National Research Council’s Committee on Toxicology: The First 50 Years (1997) vii

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Carcinogens and Anticarcinogens in the Human Diet (1996) Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (five volumes, 1989-1995) Science and Judgment in Risk Assessment (1994) Pesticides in the Diets of Infants and Children (1993) Dolphins and the Tuna Industry (1992) Science and the National Parks (1992) Human Exposure Assessment for Airborne Pollutants (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Copies of these reports may be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu viii

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Preface Risk assessments are often focused on a single chemical. People, however, are exposed to mixtures of chemicals over their lifetime, and many argue that a better way to estimate risk is to assess exposure to mixtures, particularly for mixtures of chemicals that have similar mechanisms of toxicity or that produce similar effects. Because phthalates make up a chemical class that produce simi- lar effects and have similar chemical structures, the U.S. Environmental Protec- tion Agency (EPA) asked the National Research Council (NRC) to evaluate their health risks and determine whether a cumulative risk assessment would be appropriate and, if so, suggest an approach to such an assessment. In this report, the Committee on the Health Risks of Phthalates reviews risk-assessment practices and describes their strengths and weaknesses. The committee reviews the toxicity of and exposure to phthalates, considers the value of conducting a cumulative risk assessment of this chemical class, and provides recommendations for conducting the assessment. Data gaps and re- search needs are also identified, and the applicability of the committee’s rec- ommendations to other chemical classes is discussed. This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures ap- proved by the NRC’s Report Review Committee. The purposes of this inde- pendent review are to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsive- ness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following for their review of this report: Melvin E. Andersen, The Hamner Insti- tutes for Health Sciences; Kenny S. Crump, ENVIRON; Alan R. Boobis, Impe- rial College London; Ronald Breslow, Columbia University; Patricia A. Buffler, University of California, Berkeley; George P. Daston, Proctor & Gamble Com- pany; John M. DeSesso, Noblis; Holger Koch, Institut der Ruhr-Universität Bo- chum; William S. Knowles, Monsanto Company (retired); Rochelle Tyl, RTI International; John Wakefield, University of Washington; Paige Williams, Har- ix

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x Preface vard School of Public Health; Lauren A. Zeise, California Environmental Pro- tection Agency. Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of the report was overseen by the review coordinator, Thomas A. Louis, Johns Hopkins Bloomberg School of Public Health, and the review moni- tor, Donald R. Mattison, National Institutes of Health. Appointed by the NRC, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the committee and the institution. The committee gratefully acknowledges the following for making presen- tations to the committee: Antonia Calafat, Centers for Disease Control and Pre- vention; Raymond David, BASF; James Donald, California Environmental Pro- tection Agency; Earl Gray, EPA; Jane Houlihan, Environmental Working Group; Leo Posthuma, RIVM (National Institute of Public Health and the Envi- ronment), the Netherlands; Peter Preuss, EPA; Jennifer Sass, Natural Resources Defense Council; Richard Sharpe, Medical Research Council, United Kingdom; Michael Shelby, National Toxicology Program; Jamie Strong, EPA; Shanna Swan, University of Rochester School of Medicine and Dentistry; Linda Teuschler, EPA; and Nigel Walker, National Institute of Environmental Health Sciences. The committee especially thanks Rebecca Clewell, of the Hamner Insti- tutes for Health Sciences, who provided information on the toxicokinetics of dialkylphthalates that aided the committee in its development of the exposure- assessment chapter, and Earl Gray, of EPA, who provided individual animal data for several toxicity studies that aided the committee in its evaluation of the cumulative risk posed by phthalates. The committee is also grateful for the assistance of the NRC staff in pre- paring this report. Staff members who contributed to the effort are Ellen Mantus, project director; James Reisa, director of the Board on Environmental Studies and Toxicology; Norman Grossblatt, senior editor; Mirsada Karalic-Loncarevic, manager, Technical Information Center; Heidi Murray-Smith, research associ- ate; John Brown, program associate; and Panola Golson, senior program assis- tant. I would especially like to thank all the members of the committee for their efforts throughout the development of this report. Deborah Cory-Slechta, Chair Committee on the Health Risks of Phthalates

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Contents SUMMARY ........................................................................................................ 3 1 INTRODUCTION ............................................................................ 13 Phthalates, 13 The Committee’s Task and Approach, 17 Organization of the Report, 18 References, 18 2 PHTHALATE EXPOSURE ASSESSMENT IN HUMANS .......... 21 Phthalate Sources and Routes of Exposure, 21 Biomarkers of Exposure, 22 Metabolism, Pharmacokinetics, and Implications for Possible Susceptibility, 26 Pharmacokinetic Models of Phthalates, 30 Amniotic Fluid: The Fetal Compartment, 32 Conclusions, 33 References, 33 3 TOXICITY ASSESSMENT.............................................................. 39 Male Sexual Differentiation in Mammals, 40 Early Teratology Findings, 42 Reproductive Effects, 43 The Phthalate Syndrome of Effects on Male Reproductive Development, 45 Agents That Produce Similar Effects on Reproductive Development, 51 Cancer, 56 Conclusions, 58 References, 58 4 CURRENT PRACTICE IN RISK ASSESSMENT AND CUMULATIVE RISK ASSESSMENT............................................ 68 Current Risk-Assessment Approaches and Practices, 68 The Evolution of Guidance on Cumulative Risk Assessment, 90 xi

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xii Contents Current Environmental Protection Agency Examples and Case Studies of Cumulative Risk Assessment, 95 Strengths and Weaknesses of Current Approaches or Practices, 99 Application to Phthalates, 100 References, 100 5 CUMULATIVE RISK ASSESSMENT OF PHTHALATES AND RELATED CHEMICALS..................................................... 106 Criteria for Choosing Dose Addition or Independent Action as a Default Evaluation Method, 107 Similar or Dissimilar Action: A Default Concept for Cumulative Risk Assessment of Phthalates and Other Antiandrogens? 108 Experimental Evidence of Cumulative Effects of Combinations of Phthalates and Other Antiandrogens, 111 Combined Effects of Low Doses of Phthalates and Other Antiandrogens, 115 Non-Dose-Additive Combined Effects of Phthalates and Other Antiandrogens, 123 Cumulative Risk Assessment of Phthalates and Other Antiandrogens: Basic Issues, 123 Stepped Approaches to Cumulative Risk Assessment of Phthalates and Other Antiandrogens, 130 Standard-Setting, 133 Conclusions, 133 References, 134 6 DATA GAPS AND RESEARCH NEEDS ..................................... 138 Exposure Assessment, 138 Toxicity Assessment, 139 Cumulative Risk Assessment, 140 Data Resources for Cumulative Risk Assessment, 140 APPENDIX A: Statement of Task................................................................. 141 APPENDIX B: Biographic Information on the Committee on Health Risks of Phthalates................................................................ 142 APPENDIX C: Analysis of a Mixture of Five Phthalates: A Case Study ..... 147 APPENDIX D: Evaluating Multiple End Points Simultaneously in a Mixture of Three Antiandrogens: A Case Study .................. 160

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Contents xiii BOXES, FIGURES AND TABLES BOXES 4-1 EPA Definitions for Toxicity Values, 72 4-2 Derivation of the Dose-Additive Multiple-Dose-Response Relationship, 82 4-3 Hypothetical Example Represented in Figure 4-2, 84 4-4 Procedure for Segregation of Hazard Indexes by Effect, 89 4-5 Information Sources for Segregation of Hazard Indexes, 89 FIGURES S-1 Relationship of phthalate syndrome in rats to effects associated with agents that perturb androgen action and produce androgen insufficiency and to the hypothesized testicular dysgenesis syndrome in humans, 6 S-2 Illustration of a hypothetical mixture experiment with chemicals that all exhibit the same dose-response curve, 8 S-3 Multiple exposures leading to common adverse outcomes, 11 1-1 General chemical structure of an o-phthalate, 14 2-1 Phthalate metabolism, 28 2-2 DEHP metabolism, 29 3-1 Stages of testicular descent, 41 3-2 Comparison of periods of male reproductive development in rat and human, 42 3-3 Effect of DBP given over 3 days on reproductive tract malformations, 46 3-4 Fetal androgen insufficiency and common adverse outcomes, 52 3-5 Relationship of phthalate syndrome in rats to that noted for agents that perturb androgen action to produce androgen insufficiency and to the hypothesized testicular dysgenesis syndrome in humans, 53 4-1 Isobole for a defined electroencephalographic threshold in anesthesia for mixtures of flurazepam and hexobarbital, 80 4-2 Hypothetical example of two-component mixture dose-response curve, 83 5-1 The committee’s reanalysis of the combined effects of five phthalates on suppression of testosterone production, 113 5-2 Illustration of a “sham” mixture experiment with chemicals that all exhibit the same dose-response curve, 118 5-3 Low-dose combined effects of three AR antagonists with changes in AGD as the end point, 121 5-4 Low-dose combined effects of phthalates with suppression of testosterone synthesis as the end point, 122

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xiv Contents 5-5 Schematic to illustrate the derivation of a point of departure for a mixture dose, here the lower confidence limit of a benchmark dose, 127 5-6 Aggregation for cumulative effects and animal-to-human extrapolation, 131 C-1 Average testosterone concentration (as percent of control) per pup (*) vs dose of five single chemicals with maximum likelihood dose- response curves used in additivity model, 157 C-2 (A) Observed (*) and model-predicted dose-response curves for mixture of five phthalates based on the nonlinear logistic model for the mixture data (solid curve) and as predicted under additivity (dashed curve). The mixing ratio of the five phthalates was 3:3:3:3:1 for BBP, DBP, DEHP, DIBP, and DPP, that is, 0.23, 0.23, 0.23, 0.23, and 0.08 of the mixture. (B) For comparison, the prediction using an independent-action model based on percentage of response, 158 D-1 Desirability curves for AGD, NR, and organ weights (ventral prostate, seminal vesicle, and LABC), 171 D-2 Profile plots for individual pups (connected line segment) in each dose group of mixture data, 174 D-3 Average calculated toxicity index (composite desirability score) per litter vs dose of three single chemicals and mixture, 176 D-4 Profile plots from the single chemical dose-response data, 186 TABLES 1-1 Phthalate Parent Compounds and Selected Metabolites, 15 2-1 Common Phthalates and Examples of Uses, 23 2-2 Urinary Phthalate Metabolites in Large Studies in United States and Germany, 24 2-3 Urinary Phthalate Metabolite Concentrations after Exceptional Exposures and Comparison Medians from Available NHANES or European Union Data, 27 3-1 Reproductive and Developmental Effects of DBP in the National Toxicology Program Reproductive Assessment by Continuous Breeding Study (1991), 45 3-2 Comparison of Human Male Reproductive Effects of Concern with Effects of in Utero Phthalate Exposure in Rats, 47 3-3 Effect of in Utero Phthalate Exposure on Male Rat Reproductive Outcomes, 49 3-4 Effects of Agents That Can Produce Androgen Insufficiency by Different Pharmacologic Activities of Mechanisms and the Most Common Resulting Malformation after in Utero Exposure of Pregnant Rats during Sexual Differentiation, 55 3-5 Summary of Hepatocarcinogenic Effects of Phthalates, 56 4-1 Summary of EPA’s Toxicity Values for Phthalates, 75

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Contents xv 4-2 Summary of Stated Purposes of Guidance Documents, Definition of Cumulative in the Context of Risk Assessment, and the Default Approach Taken to the Toxicity of Mixtures of Chemicals, 91 4-3 Summary of Cumulative Health Risk Assessment Applications to Evaluation of Chemical Exposures, 96 5-1 Mixture Studies of Phthalates and Other Antiandrogens, 116 5-2 Examples of Chemicals That Should Be Considered for Cumulative Risk Assessment of Phthalates and Other Antiandrogens According to a Physiologically Based Grouping Approach, 124 C-1 Estimated BMDs Associated with 5% BMR for Single Chemicals and Mixture Data Based on Nonlinear Logistic Model and Estimated with Mixed-Effects Model Accounting for Intralitter Correlated Data, 152 C-2 Three Mixtures to Illustrate an Approach to Calculating Adjusted Critical Doses for Single Chemicals in a Mixture, 153 D-1 Demonstration of Calculation of Toxicity Index for Three Rats in Control Group and Two Mixture Dose Groups, 165 D-2 Parameter Estimates Based on Nonlinear Logistic Model, 167

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Abbreviations AGD anogenital distance AhR aryl hydrocarbon receptor AR androgen receptor ATSDR Agency for Toxic Substances and Disease Registry B[a]P benzo[a]pyrene BBP butyl benzyl phthalate BMD benchmark dose BMDL lower confidence limit of BMD BMR benchmark response CDC Centers for Disease Control and Prevention CERCLA Comprehensive Environmental Response, Compensation, and Liability Act CERHR Center for the Evaluation of Risks to Human Reproduction CHO Chinese hamster ovary CRPF cumulative relative potency factor CSF cancer slope factor CSL cranial suspensory ligament CT central tendency DA dose addition DBP di-n-butyl phthalate DCHP dicyclohexyl phthalate DDT dichloro-diphenyl-trichloroethane DEHP di(2-ethylhexyl) phthalate DEP diethyl phthalate DHT dihydrotestosterone DIBP diisobutyl phthalate DIDP diisodecyl phthalate DINP diisononyl phthalate DMP dimethyl phthalate DMT dimethyl terephthalate or dimethyl-p-phthalate DOP di-n-octyl phthalate DPHP di(2-propylheptyl) phthalate DPP dipentyl phthalate ECAO Environmental Criteria and Assessment Office effective dose at x response level EDx xvii

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xviii Abbreviations EPA U.S. Environmental Protection Agency EU European Union FSH follicle-stimulating hormone GD gestation day Gub gubernaculum HI hazard index HQ hazard quotient IA independent action insl3 insulin-like factor 3 IQ intelligence quotient IQR interquartile range IRIS Integrated Risk Information System LABC levator ani/bulbocavernosus muscles LC Leydig cell LOAEL lowest observed-adverse-effect level LOD limit of detection LOEL lowest observed-effect level MADL maximum allowable dose level MBP monobutyl phthalate MBZP monobenzyl phthalate MCHP monocyclohexyl phthalate MCINP mono(carboxyisononyl) phthalate MCIOP mono(carboxyisooctyl) phthalate MCPHP mono(carboxypropylheptyl) phthalate MCPP mono-3-carboxypropyl phthalate MECPP mono(2-ethyl-5-carboxypentyl) phthalate MEHHP mono(2-ethyl-5-hydroxyhexyl) phthalate MEHP mono(2-ethylhexyl) phthalate MEOHP mono(2-ethyl-5-oxohexyl) phthalate MEP monoethyl phthalate MHIDP mono(hydroxyisodecyl) phthalate MHINP mono(hydroxyisononyl) phthalate MHPHP mono(hydroxypropylheptyl) phthalate MIBP monoisobutyl phthalate MIDP monoisodecyl phthalate MINP monoisononyl phthalate MIS Mullerian inhibiting substance MMP monomethyl phthalate MOIDP mono(oxoisodecyl) phthalate MOINP mono(oxoisononyl) phthalate MOP mono-n-octyl phthalate MOPHP mono(oxopropylheptyl) phthalate MPHP monopropylheptyl phthalate MRL minimal risk level NATA National Air Toxics Assessment

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Abbreviations xix NHANES National Health and Nutrition Examination Survey NOAEL no-observed-adverse-effect level NOEL no-observed-effect level NR nipple retention NRC National Research Council NTP National Toxicology Program p,p′-DDE p,p′-dichlorodiphenyl dichloroethylene PAH polycyclic aromatic hydrocarbon PBDE polybrominated diphenyl ethers PBPK physiologically based pharmacokinetic PCB polychlorinated biphenyls PCDD polychlorinated dibenzo-p-dioxins PCDF polychlorinated dibenzo-p-furans POD point of departure PPARα peroxisome-proliferator-activated receptor-α PPRTV provisional peer reviewed toxicity value RAGS Risk Assessment Guidance for Superfund RfC reference concentration RfD reference dose RME reasonable maximum exposure S.V. seminal vesicles STSC Superfund Health Risk Technical Support Center TCDD tetrachlorodibenzo-p-dioxin TCP/TAL Contract Laboratory Program Target Compound and Target Analyte List TDS testicular dysgenesis syndrome TEF toxicity equivalence factor TEQ toxic equivalence UR unit risk

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