ATSDR Toxicological Profile for Chlorinated Dibenzo-p-Dioxins

[Page 1] l Toxicological Profile for Chlorinated Dibenzo-p-Dioxins Draft for Public Comment October 2024 [Page 2] CDDs ii ***DRAFT FOR PUBLIC COMMENT*** DISCLAIMER Use of trade names is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human Services. This information is distributed solely for the purpose of pre dissemination public comment under applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic Substances and Disease Registry. It does not represent and should not be construed to represent any agency determination or policy. [Page 3] CDDs iii ***DRAFT FOR PUBLIC COMMENT*** FOREWORD This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects information for these toxic substances described therein. Each peer-reviewed profile identifies and reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is also presented, but is described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile begins with a relevance to public health discussion which would allow a public health professional to make a real-time determination of whether the presence of a particular substance in the environment poses a potential threat to human health. The adequacy of information to determine a substance's health effects is described in a health effects summary. Data needs that are of significance to the protection of public health are identified by ATSDR. Each profile includes the following: (A) The examination, summary, and interpretation of available toxicologic information and epidemiologic evaluations on a toxic substance to ascertain the levels of significant human exposure for the substance and the associated acute, intermediate, and chronic health effects; (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine the levels of exposure that present a significant risk to human health due to acute-, intermediate-, and chronic- duration exposures; and (C) Where appropriate, identification of toxicologic testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. The principal audiences for the toxicological profiles are health professionals at the Federal, State, and local levels; interested private sector organizations and groups; and members of the public. ATSDR plans to revise these documents in response to public comments and as additional data become available. Therefore, we encourage comments that will make the toxicological profile series of the greatest use. Electronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for submitting comments. Written comments may also be sent to: Agency for Toxic Substances and Disease Registry Office of Innovation and Analytics Toxicology Section 1600 Clifton Road, N.E. Mail Stop S106-5 Atlanta, Georgia 30329-4027 [Page 4] CDDs iv ***DRAFT FOR PUBLIC COMMENT*** The toxicological profiles are developed under the Comprehensive Environmental Response, Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA Section 104(i)(1) directs the Administrator of ATSDR to “…effectuate and implement the health -related authorities” of the statute. This includes the preparation of toxicological profiles for hazardous substances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that pose the most significant potential threat to human health, as determined by ATSDR and the EPA. Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. In addition, ATSDR has the authority to prepare toxicological profiles for substances not found at sites on the NPL, in an effort to “…establish and maintain inventory of literature, research, and studies on the health effects of toxic substances” under CERCLA Section 104(i)(1)(B), to respond to requests for consultation under Section 104(i)(4), and as otherwise necessary to support the site-specific response actions conducted by ATSDR. This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel and is being made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. Christopher M. Reh, Ph.D. Associate Director Agency for Toxic Substances and Disease Registry Centers for Disease Control and Prevention [Page 5] CDDs v ***DRAFT FOR PUBLIC COMMENT*** VERSION HISTORY Date Description October 2024 Draft for public comment toxicological profile released November 2012 Addendum to the toxicological profile released December 1998 Final toxicological profile released [Page 6] CDDs vi ***DRAFT FOR PUBLIC COMMENT*** CONTRIBUTORS & REVIEWERS CHE MICAL MANAGER TEAM Hana R. Pohl, M.D., Ph.D. (Lead) Lisa Ingerman, Ph.D., D.A.B.T. Brittany Szafran, D.V.M., Ph.D. Gary L. Diamond, Ph.D. Gaston Casillas, Ph.D. Heather Carlson-Lynch, M.S., D.A.B.T. Fahim Atif, Ph.D. Mario Citra, Ph.D. Deborah Herber, Ph.D. Connor McGuire, Ph.D. ATSDR, Office of Innovation and Analytics, Toxicology Section, Atlanta, GA SRC, Inc., North Syracuse, NY R EVIEWERS Interagency Minimal Risk Level Workgroup: Includes ATSDR; National Center for Environmental Health (NCEH); National Institute for Occupational Safety and Health (NIOSH); U.S. Environmental Protection Agency (EPA); National Toxicology Program (NTP). Additional reviews for science and/or policy: ATSDR, Office of Community Health Hazard Assessment; ATSDR, Office of Capacity Development and Applied Prevention Science; ATSDR, Office of Science; NCEH, Division of Laboratory Sciences; NCEH, Division of Environmental Health Science and Practice; EPA, Office of Research and Development; EPA, Office of Water. PEER REVIEWERS 1. Diane B. Re, Ph.D.; Associate Professor; EHS Department, Columbia University; New York, New York 2. Slawo Lomnicki, Ph.D.; Associate Professor; Department of Environmental Sciences; Louisiana State University; Baton Rouge, Louisiana 3. Stuart Harrad, Ph.D.; Professor of Environmental Chemistry; School of Geography, Earth & Environmental Sciences; University of Birmingham; Birmingham, United Kingdom These experts collectively have knowledge of toxicology, chemistry, and/or health effects. All reviewers were selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. ATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the profile based on comments. The peer reviewers’ comments and responses to these comments are part of the administrative record for this compound. The listing of peer reviewers should not be understood to imply their approval of the profile's final content. The responsibility for the content of this profile lies with ATSDR. [Page 7] CDDs vii ***DRAFT FOR PUBLIC COMMENT*** CONTENTS D ISCLAIMER .............................................................................................................................................. ii FOREWORD ............................................................................................................................................... iii VERSION HISTORY ................................................................................................................................... v CONTRIBUTORS & REVIEWERS ........................................................................................................... vi CONTENTS ................................................................................................................................................ vii LIST OF FIGURES ..................................................................................................................................... ix LIST OF TABLES ....................................................................................................................................... xi CHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................. 1 1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1 1.2 SUMMARY OF HEALTH EFFECTS........................................................................................... 2 1.3 MINIMAL RISK LEVELS (MRLs) .............................................................................................. 8 CHAPTER 2. HEALTH EFFECTS ................................ ............................................................................ 15 2.1 INTRODUCTION ........................................................................................................................ 15 2.2 DEATH ...................................................................................................................................... 129 2.3 BODY WEIGHT ........................................................................................................................ 133 2.4 RESPIRATORY ........................................................................................................................ 137 2.5 CARDIOVASCULAR ............................................................................................................... 140 2.6 GASTROINTESTINAL ............................................................................................................. 150 2.7 HEMATOLOGICAL ................................................................................................................. 154 2.8 MUSCULOSKELETAL ............................................................................................................ 157 2.9 HEPATIC ................................................................................................................................... 159 2.10 RENAL ...................................................................................................................................... 172 2.11 DERMAL ................................................................................................................................... 173 2.12 OCULAR ................................................................................................................................... 180 2.13 ENDOCRINE ............................................................................................................................. 181 2.14 IMMUNOLOGICAL ................................................................................................................. 193 2.15 NEUROLOGICAL..................................................................................................................... 216 2.16 REPRODUCTIVE ..................................................................................................................... 223 2.17 DEVELOPMENTAL ................................................................................................................. 242 2.18 OTHER NONCANCER ............................................................................................................. 321 2.19 CANCER .................................................................................................................................... 322 2.20 GENOTOXICITY ...................................................................................................................... 338 2.21 MECHANISMS OF TOXICITY ............................................................................................... 345 CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS ......................................................................................... 351 3.1 TOXICOKINETICS................................................................................................................... 351 3.1.1 Absorption ........................................................................................................................... 351 3.1.2 Distribution ......................................................................................................................... 356 3.1.3 Metabolism .......................................................................................................................... 362 3.1.4 Excretion ............................................................................................................................. 366 3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 380 3.1.6 Animal-to-Human Extrapolations ....................................................................................... 396 3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE .......................................................................................................................... 401 3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 413 3.3.1 Biomarkers of Exposure ...................................................................................................... 414 [Page 8] CDDs viii ***DRAFT FOR PUBLIC COMMENT*** 3.3.2 Biomarkers of Effect ........................................................................................................... 415 3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 415 CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ........................................................... 420 4.1 CHEMICAL IDENTITY ........................................................................................................... 420 4.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................................................ 424 CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ....................................................................... 429 5.1 OVERVIEW .............................................................................................................................. 429 5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 433 5.2.1 Production ........................................................................................................................... 433 5.2.2 Import/Export ...................................................................................................................... 437 5.2.3 Use ...................................................................................................................................... 437 5.2.4 Disposal ............................................................................................................................... 437 5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 441 5.3.1 Air ....................................................................................................................................... 441 5.3.2 Water ................................................................................................................................... 446 5.3.3 Soil ...................................................................................................................................... 446 5.4 ENVIRONMENTAL FATE ...................................................................................................... 448 5.4.1 Transport and Partitioning ................................................................................................... 448 5.4.2 Transformation and Degradation ........................................................................................ 461 5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 467 5.5.1 Air ....................................................................................................................................... 470 5.5.2 Water ................................................................................................................................... 477 5.5.3 Sediment and Soil ............................................................................................................... 481 5.5.4 Other Media ........................................................................................................................ 487 5.6 GENERAL POPULATION EXPOSURE.................................................................................. 512 5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 574 CHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 579 6.1 INFORMATION ON HEALTH EFFECTS ............................................................................... 579 6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 579 6.3 ONGOING STUDIES ................................................................................................................ 595 CHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 597 CHAPTER 8. REFERENCES .................................................................................................................. 600 APPEN DICES APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1 APPENDIX B. UPDATE TO THE ATSDR POLICY GUIDELINE FOR DIOXINS AND DIOXIN- LIKE COMPOUNDS IN RESIDENTIAL SOIL ........................................................... B-1 APPENDIX C. LITERATURE SEARCH FRAMEWORK FOR CDDs ................................................ C-1 APPENDIX D. FRAMWORK FOR ATSDR’S SYSTEMIC REVIEW OF HEALTH EFFECTS DATA FOR CDDs .......................................................................................................... D-1 APPENDIX E. USER’S GUIDE ............................................................................................................. E-1 APPENDIX F. QUICK REFERENCE FOR HEALTH CARE PROVIDERS ......................................... F-1 APPENDIX G. GLOSSARY ................................................................................................................... G-1 APPENDIX H. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ................................................. H-1 [Page 9] CDDs ix ***DRAFT FOR PUBLIC COMMENT*** LIST OF FIGURES 1-1. Basic Chemical Structure of Chlorinated Dibenzo-p-Dioxins (CDDs), Chlorodibenzofurans (CDFs), and Polychlorinated Biphenyls (PCBs) .................................................................................. 3 1-2. Health Effects Found in Animals Following Oral Exposure to 2,3,7,8-Tetrachlorodibenzo- p-Dioxin (2,3,7,8-TCDD) ..................................................................................................................... 5 1-3. Health Effects Found in Animals Following Oral Exposure to Other Chlorinated Dibenzo- p-Dioxins (CDDs)................................................................................................................................. 6 1-4. Summary of Sensitive Targets of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) – Oral ....................................................................................................................................................... 8 1-5. Summary of Sensitive Targets of 2,7-Dichlorodibenzo-p-Dioxin (2,7-DCDD) – Oral ....................... 9 1-6. Summary of Sensitive Targets of 2,3,7-Trichlorodibenzo-p-Dioxin (2,3,7-TrCDD) – Oral................ 9 1-7. Summary of Sensitive Targets of 1,2,3,7,8-Pentachlorodibenzo-p-Diox in (1,2,3,7,8- PeCDD) – Oral ................................................................................................................................... 10 1-8. Summary of Sensitive Targets of 1,2,4,7,8-Pentachlorodibenzo-p-Dioxin (1,2,4,7,8- PeCDD) – Oral ................................................................................................................................... 10 1-9. Summary of Sensitive Targets of 1,2,3,4,7,8-Hexachlorodibenzo-p-Dioxin (1,2,3,4,7,8-HxCDD) – Oral ............................................................................................................... 11 1-10. Summary of Sensitive Targets of 1,2,3,6,7,8-Hexachlorodibenzo-p-Dioxin (1,2,3,6,7,8-HxCDD) – Oral ............................................................................................................. 11 1-11. Summary of Sensitive Targets of 1,2,3,4,6,7,8-Heptachlorodibenzo-p-Dioxin (HpCDD) – Oral ................................................................................................................................................... 12 1-12. Summary of Sensitive Targets of Octachlorodibenzo-p-Dioxin (OCDD) – Oral ............................ 12 2-1. Overview of the Number of Studies Examining Chlorinated Dibenzo-p-Dioxins (CDDs) Human Health Effects ........................................................................................................................ 26 2-2. Overview of the Number of Animal Studies Examining 2,3,7,8-Tetrachlorodibenzo- p-Dioxin (2,3,7,8-TCDD) Health Effects ........................................................................................... 27 2-3. Overview of the Number of Animal Studies Examining Other Chlorinated Dibenzo- p-Dioxins (CDDs) Health Effects ....................................................................................................... 28 2-4. Levels of Significant Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) – Oral ..................................................................................................................................................... 79 2-5. Levels of Significant Exposure to Other Chlorinated Dibenzo-p-Dioxins (CDDs) – Oral .............. 114 3-1. A Generalized Scheme of Pathways for the Biotransformation of CDDs Based on Information from In Vivo Mammalian Studies ................................................................................. 365 5-1. Number of NPL Sites with Chlorinated Dibenzo-p-Dioxin (CDD) Contamination ......................... 429 [Page 10] CDDs x ***DRAFT FOR PUBLIC COMMENT*** 6-1. Summary of Existing Human Health Effects Studies on Chlorinated Dibenzo-p-Dioxins (CDDs) by Route and Endpoint ........................................................................................................ 580 6-2. Summary of Existing Animal Health Effects Studies on 2,3,7,8-Tetrachlorodibenzo- p-Dioxin (2,3,7,8-TCDD) by Route and Endpoint ........................................................................... 581 6-3. Summary of Existing Health Effects Animal Studies on Other Chlorinated Dibenzo- p-Dioxins (CDDs) by Route and Endpoint ....................................................................................... 582 [Page 11] CDDs xi ***DRAFT FOR PUBLIC COMMENT*** LIST OF TABLES 1-1. Minimal Risk Levels (MRLs) for 2,3,7,8-Tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) ................. 13 1-2. Minimal Risk Levels (MRLs) for Other CDD Congeners ................................................................. 14 2-1. Summary of World Health Organization (WHO) 1998, 2005, and 2022 Toxic Equivalency Factors (TEFs) .................................................................................................................................... 18 2-2. Levels of Significant Exposure to 2,3,7,8-Tetrachloroibenzo-p-Dioxin – Oral ................................. 29 2-3. Levels of Significant Exposure to Other Chlorinated Dibenzo-p-Dioxins (CDDs) – Oral .............. 103 2-4. Levels of Significant Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) – Dermal .............................................................................................................................................. 125 2-5. Levels of Significant Exposure to Other Chlorinated Dibenzo-p-Dioxins (CDDs) – Dermal ......... 128 2-6. LD50 Values in Laboratory Animals Following a Single Oral Dose of 2,3,7,8-TCDD .................... 130 2-7. LD50 Values in Laboratory Animals Following a Single Oral Dose of Other CDD Congeners ...... 132 2-8. Alterations in Body Weight in Animals Orally Exposed to Other CDD Congeners ........................ 137 2-9. Cardiovascular Effects in Humans Exposed to TCDD/CDDs .......................................................... 142 2-10. Gastrointestinal Effects in Humans Exposed to TCDD/CDDs....................................................... 151 2-11. Hepatic Effects in Humans Exposed to TCDD/CDDs ................................................................... 161 2-12. Hepatic Clinical Chemistry in Rats and Mice Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) .................................................................. 166 2-13. Histopathological Alterations in the Liver of Experimental Animals Resulting From Oral Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) .............................................. 168 2-14. Endocrine Effects in Humans Exposed to TCDD/CDDs ............................................................... 182 2-15. Results of Studies Evaluating Thyroid Outcomes in Laboratory Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) .................................................................. 190 2-16. Immunological Effects in Humans Exposed to TCDD/CDDs ....................................................... 195 2-17. Results of Studies Evaluating Immunosuppression in Laboratory Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) .............................................................. 204 2-18. Numbers of Aryl Hydrocarbon Receptor Responsive Elements (AhREs) in Genes Regulating T Helper Cell Differentiation ....................................................................................... 215 2-19. Neurological Effects in Humans Exposed to TCDD/CDDs ........................................................... 217 2-20. Reproductive Effects in Humans Exposed to TCDD/CDDs .......................................................... 225 [Page 12] CDDs xii ***DRAFT FOR PUBLIC COMMENT*** 2-21. Effects on Reproductive Hormone Levels in Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) .................................................................. 235 2-22. Reproductive Effects in Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) .............................................................................................................................. 237 2-23. Developmental Effects in Humans Exposed to TCDD/CDDs ....................................................... 244 2-24. Structural Anomalies in Laboratory Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) .................................................................. 290 2-25. Systemic Effects Observed in the Offspring of Laboratory Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) .................................................................. 292 2-26. Immunological Effects in the Offspring of Laboratory Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) .................................................................. 297 2-27. Impaired Development of Reproductive System in Offspring of Laboratory Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) ............................................... 305 2-28. Functional Alterations in the Reproductive System of Male Offspring of Laboratory Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) ..................... 309 2-29. Functional Alterations in the Reproductive System of Female Offspring of Laboratory Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) ..................... 311 2-30. Alterations in Reproductive Hormones in the Male Offspring of Laboratory Animals Orally Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (2,3,7,8-TCDD) ............................................... 314 2-31. Cancer Effects in Humans Exposed to TCDD/CDDs .................................................................... 323 2-32. Occupational Cohort Studies Examining the Carcinogenicity of Chlorinated Dibenzo- p-Dioxins (CDDs) .......................................................................................................................... 331