G577

Toxicological Profile for
Perfluoroalkyls
Released May 2021
Last Updated March 2020

PERFLUOROALKYLSii

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.

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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 andreviews the key literature that describes a substance's toxicologic properties. Other pertinent literature isalso 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 healtheffects 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 andepidemiologic evaluations on a toxic substance to ascertain the levels of significant
human exposure for the substance due to associated acute, intermediate, and chronic
exposures;(B)

A determination of whether adequate information on the health effects of each substanceis available or in the process of development to determine levels of exposure that present
a significant risk to human health of acute, intermediate, and chronic health effects; and(C)

Where appropriate, identification of toxicologic testing needed to identify the types orlevels 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, andlocal levels; interested private sector organizations and groups; and members of the public.
This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been
peer-reviewed through September 2018. New studies were added in 2019 following public comment, and
NHANES data were updated. Staff from 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 anongovernmental panel and was made available for public review. Final responsibility for the contents
and views expressed in this toxicological profile resides with ATSDR.

Patrick N. Breysse, Ph.D., CIH
Director, National Center for Environmental Health andAgency for Toxic Substances and Disease RegistryCenters for Disease Control and Prevention

PERFLUOROALKYLS*Legislative Background
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 thatpose 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 andmaintain 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 asotherwise necessary to support the site-specific response actions conducted by ATSDR.

iv

PERFLUOROALKYLSv

VERSION HISTORY
Date

May 2021
March 2020
June 2018
August 2015
May 2009

Description

Final toxicological profile released
Toxicological profile last updated
Draft for public comment toxicological profile released
Draft for public comment toxicological profile released
Draft for public comment toxicological profile released

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CONTRIBUTORS & REVIEWERSCHEMICAL MANAGER TEAM
Melanie Buser, M.P.H. (Lead)
Dennis Jones, DVM, Ph.D.
Hana R. Pohl, M.D., Ph.D.
Patricia Ruiz, Ph.D.
Franco Scinicariello, M.D., M.P.H.
Selene Chou, Ph.D.
Henry Abadin, M.S.P.H.
ATSDR, Division of Toxicology and Human Health
Sciences, Atlanta, GA

Lisa Ingerman, Ph.D., DABT
Lynn Barber, M.S.
Heather Carlson-Lynch, M.S., DABTMario Citra, Ph.D.
Gary L. Diamond, Ph.D.
Julie Klotzbach, Ph.D.
Fernando T. Llados, Ph.D.
Daniel J. Plewak, B.S.
SRC, Inc., North Syracuse, NY

REVIEWERS
Interagency Minimal Risk Level Workgroup:
Includes ATSDR; National Center for Environmental Health (NCEH); National Institute ofOccupational Health and Safety (NIOSH); U.S. Environmental Protection Agency (EPA); National
Toxicology Program (NTP).
Additional reviews for science and/or policy:
ATSDR, Division of Community Health Investigations; EPA; NCEH, Division of Laboratory Science.

PEER REVIEWERS
1. Abby Benninghoff, Ph.D., Faculty Research Associate, Department of Environmental andMolecular Toxicology, Oregon State University, Corvallis, Oregon
2. Deborah A. Cory-Slechta, Ph.D., Professor of Environmental Medicine, Pediatrics and Public
Health Sciences, Acting Chair, Department of Environmental Medicine, PI, NIEHS Center of
Excellence, Department of Environmental Medicine, University of Rochester Medical Center,
Rochester, New York3. Jamie DeWitt, Ph.D., Associate Professor, Department of Pharmacology & Toxicology, Brody
School of Medicine, East Carolina University, Greenville, North Carolina
4. Edward Emmett, M.D., Professor, Center of Excellence in Environmental Toxicology, Universityof Pennsylvania, Philadelphia, Pennsylvania
5. Lynn R. Goldman, M.D. M.P.H., Professor of Environmental Health Science, John Hopkins
University, Baltimore, Maryland
6. William L. Hayton, Ph.D., Professor Emeritus, College of Pharmacy, Ohio State University,
Columbus, Ohio
7. David A. Savitz, Ph.D., Professor of Epidemiology, Professor of Obstetrics and Gynecology,
Brown University, Providence, Rhode Island

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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 finalcontent. The responsibility for the content of this profile lies with ATSDR.

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CONTENTSDISCLAIMER .............................................................................................................................................. ii
FOREWORD ............................................................................................................................................... iii
VERSION HISTORY ................................................................................................................................... v
CONTRIBUTORS & REVIEWERS ........................................................................................................... vi
CONTENTS ............................................................................................................................................... viii
LIST OF FIGURES ..................................................................................................................................... xi
LIST OF TABLES ..................................................................................................................................... xiv
CHAPTER 1. RELEVANCE TO PUBLIC HEALTH ................................................................................ 1
1.1 OVERVIEW AND U.S. EXPOSURES ......................................................................................... 1
1.2 SUMMARY OF HEALTH EFFECTS ........................................................................................... 4
1.3 MINIMAL RISK LEVELS (MRLs) ............................................................................................ 15
CHAPTER 2. HEALTH EFFECTS ........................................................................................................... 22
2.1 INTRODUCTION ........................................................................................................................ 22
2.2 DEATH ...................................................................................................................................... 115
2.3 BODY WEIGHT ........................................................................................................................ 119
2.4 RESPIRATORY ......................................................................................................................... 141
2.5 CARDIOVASCULAR ............................................................................................................... 145
2.6 GASTROINTESTINAL ............................................................................................................. 167
2.7 HEMATOLOGICAL ................................................................................................................. 170
2.8 MUSCULOSKELETAL ............................................................................................................ 174
2.9 HEPATIC ................................................................................................................................... 182
2.10 RENAL ....................................................................................................................................... 244
2.11 DERMAL ................................................................................................................................... 261
2.12 OCULAR.................................................................................................................................... 262
2.13 ENDOCRINE ............................................................................................................................. 264
2.14 IMMUNOLOGICAL ................................................................................................................. 294
2.15 NEUROLOGICAL ..................................................................................................................... 352
2.16 REPRODUCTIVE ...................................................................................................................... 359
2.17 DEVELOPMENTAL ................................................................................................................. 410
2.18 OTHER NONCANCER ............................................................................................................. 499
2.19 CANCER .................................................................................................................................... 523
2.20 MECHANISM OF TOXICITY .................................................................................................. 539
2.20.1 Cellular Mechanisms of Toxicity ........................................................................................ 540
2.20.2 Hepatic Toxicity Mechanisms............................................................................................. 547
2.20.3 Developmental Toxicity Mechanisms ................................................................................. 550
2.20.4 Immunotoxicity Mechanisms .............................................................................................. 551
2.20.5 Endocrine Mechanisms ....................................................................................................... 551
2.20.6 Cancer Mechanisms ............................................................................................................ 552
2.21 GENOTOXICITY ...................................................................................................................... 554
CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICALINTERACTIONS ..................................................................................................................................... 558
3.1 TOXICOKINETICS ................................................................................................................... 558
3.1.1
Absorption ........................................................................................................................... 559
3.1.2
Distribution ......................................................................................................................... 563
3.1.3
Metabolism.......................................................................................................................... 578
3.1.4
Excretion ............................................................................................................................. 579

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3.1.5
Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 604
3.1.5.1
Loccisano et al. (2012a, 2012b) Rat Models ............................................................... 604
3.1.5.2
Loccisano et al. (2011, 2013) Monkey and Human Models ........................................ 611
3.1.5.3
Rodriguez et al. (2009) Mouse Model ......................................................................... 615
3.1.5.4.
Wambaugh et al. 2013 (Andersen et al. 2006) Model ................................................. 617
3.1.5.5
Harris and Barton (2008) Rat Model ........................................................................... 620
3.1.5.6
Worley and Fisher (2015a, 2015b) Rat Model ............................................................ 622
3.1.5.7
Worley et al. (2017b) Human Model ........................................................................... 623
3.1.5.8
Fàbrega et al. (2014, 2016) Human Model .................................................................. 624
3.1.5.9
Kim et al. (2018) Rat and Human Model..................................................................... 625
3.1.6
Animal-to-Human Extrapolations ....................................................................................... 628
3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ... 629
3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 632
3.3.1
Biomarkers of Exposure ...................................................................................................... 633
3.3.2
Biomarkers of Effect ........................................................................................................... 634
3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 634
CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION .......................................................... 635
4.1 CHEMICAL IDENTITY............................................................................................................ 635
4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................... 635
CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ...................................................................... 647
5.1 OVERVIEW ............................................................................................................................... 647
5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 651
5.2.1
Production ........................................................................................................................... 651
5.2.2
Import/Export ...................................................................................................................... 659
5.2.3
Use ...................................................................................................................................... 660
5.2.4
Disposal ............................................................................................................................... 660
5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 661
5.3.1
Air ....................................................................................................................................... 665
5.3.2
Water ................................................................................................................................... 666
5.3.3
Soil ...................................................................................................................................... 668
5.4 ENVIRONMENTAL FATE ...................................................................................................... 669
5.4.1
Transport and Partitioning................................................................................................... 669
5.4.2
Transformation and Degradation ........................................................................................ 674
5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 677
5.5.1
Air ....................................................................................................................................... 680
5.5.2
Water ................................................................................................................................... 687
5.5.3
Sediment and Soil ............................................................................................................... 698
5.5.4
Other Media ........................................................................................................................ 703
5.6 GENERAL POPULATION EXPOSURE .................................................................................. 712
5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 736
CHAPTER 6. ADEQUACY OF THE DATABASE ............................................................................... 743
6.1 Existing Information on Health Effects ...................................................................................... 743
6.2 Identification of Data Needs ....................................................................................................... 747
6.3 Ongoing Studies ......................................................................................................................... 757
CHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................ 758
CHAPTER 8. REFERENCES ................................................................................................................. 762

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APPENDICESAPPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS .................................................... A-1
APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR PERFLUOROALKYLS ................... B-1
APPENDIX C. USER’S GUIDE ............................................................................................................. C-1
APPENDIX D. QUICK REFERENCE FOR HEALTH CARE PROVIDERS ....................................... D-1
APPENDIX E. GLOSSARY ................................................................................................................... E-1
APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS .................................................. F-1

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LIST OF FIGURES
1-1. Health Effects Found in Animals Following Oral Exposure to PFOA................................................. 8
1-2. Health Effects Found in Animals Following Oral Exposure to PFOS ................................................. 9
1-3. Health Effects Found in Animals Following Oral Exposure to Other Perfluoroalkyls ...................... 10
1-4. Summary of Sensitive Targets of PFOA – Oral ................................................................................. 18
1-5. Summary of Sensitive Targets of PFOS – Oral .................................................................................. 19
2-1. Health Effect Endpoints Examined in Epidemiological Studies ........................................................ 28
2-2. Health Effect Endpoints Examined in Laboratory Animal Studies .................................................... 29
2-3. Overview of the Number of Studies Examining PFOA Health Effects.............................................. 30
2-4. Overview of the Number of Studies Examining PFOS Health Effects .............................................. 31
2-5. Overview of the Number of Studies Examining Other Perfluoroalkyls Health Effects ..................... 32
2-6. Levels of Significant Exposure to PFOA – Inhalation ....................................................................... 35
2-7. Levels of Significant Exposure to Other Perfluoroalkyls – Inhalation ............................................... 37
2-8. Levels of Significant Exposure to PFOA – Oral ................................................................................ 62
2-9. Levels of Significant Exposure to PFOS – Oral ................................................................................. 84
2-10. Levels of Significant Exposure to Other Perfluoroalkyls – Oral .................................................... 108
2-11. Serum Total Cholesterol Levels Relative to Serum PFOA Levels ................................................. 213
2-12. Risk of Abnormal Cholesterol Levels Relative to PFOA Levels (Presented as Adjusted
Ratios) ............................................................................................................................................ 214
2-13. Serum LDL Cholesterol Levels Relative to Serum PFOA Levels ................................................. 215
2-14. Risk of Abnormal LDL Cholesterol Levels Relative to PFOA Levels (Presented as
Adjusted Ratios) ............................................................................................................................. 216
2-15. Serum Total Cholesterol Levels Relative to Serum PFOS Levels ................................................. 229
2-16. Risk of Abnormal Cholesterol Levels Relative to PFOS Levels (Presented as Adjusted
Ratios) ............................................................................................................................................ 230
2-17. Serum LDL Cholesterol Levels Relative to Serum PFOS Levels .................................................. 231
2-18. Risk of Abnormal LDL Cholesterol Levels Relative to PFOS Levels (Presented as
Adjusted Ratios) ............................................................................................................................. 232

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2-19. Risk of Hyperuricemia Relative to PFOA Levels (Presented as Adjusted Odds Ratios) ............... 254
2-20. Risk of Hyperuricemia Relative to PFOS Levels (Presented as Adjusted Odds Ratios)................ 257
2-21. Antibody Responses Relative to Serum PFOA Levels in Epidemiological Studies ...................... 326
2-22. Risk of Asthma Diagnosis Relative to PFOA Levels (Presented as Adjusted Odds Ratios).......... 328
2-23. Antibody Responses Relative to Serum PFOS Levels in Epidemiological Studies ....................... 334
2-24. Risk of Asthma Diagnosis Relative to PFOS Levels (Presented as Adjusted Odds Ratios) .......... 336
2-25. Antibody Responses Relative to Serum PFHxS Levels in Epidemiological Studies ..................... 339
2-26. Risk of Asthma Diagnosis Relative to PFHxS Levels (Presented as Adjusted Odds Ratios) ........ 341
2-27. Antibody Responses Relative to Serum PFNA Levels in Epidemiological Studies ...................... 343
2-28. Risk of Asthma Diagnosis Relative to PFNA Levels (Presented as Adjusted Odds Ratios).......... 345
2-29. Antibody Responses Relative to Serum PFDA Levels in Epidemiological Studies ...................... 347
2-30. Risk of Asthma Diagnosis Relative to PFDA Levels (Presented as Adjusted Odds Ratios).......... 349
2-31. Fecundability Relative to PFOA Levels (Presented as Adjusted Fecundability Ratios) ................ 393
2-32. Infertility Relative to PFOA Levels (Presented as Adjusted Odds Ratios) .................................... 394
2-33. Fecundability Relative to PFOS Levels (Presented as Adjusted Fecundability Ratios) ................. 401
2-34. Infertility Relative to PFOS Levels (Presented as Adjusted Odds Ratios) ..................................... 402
2-35. Risk of Low Birth Weight Infant Relative to PFOA Levels (Presented as Adjusted Odds
Ratios) ............................................................................................................................................ 466
2-36. Risk of Small for Gestational Age Infant Relative to PFOA Levels (Presented as Adjusted
Odds Ratios) ................................................................................................................................... 467
2-37. Risk of Low Birth Weight Infant Relative to PFOS Levels (Presented as Adjusted Odds
Ratios) ............................................................................................................................................ 480
2-38. Risk of Small for Gestational Age Infant Relative to PFOS Levels (Presented as Adjusted
Odds Ratios) ................................................................................................................................... 481
2-39. Diabetes Risk Relative to Serum PFOA Levels (Presented as Adjusted Ratios) ........................... 519
2-40. Diabetes Risk Relative to Serum PFOS Levels (Presented as Adjusted Odds Ratios)................... 521
3-1. Tissue Concentrations of 14C in Male and Female Rats Following a Single Gavage Dose of[14C]PFOA at 1, 5, or 25 mg/kg ........................................................................................................ 567

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3-2. Tissue Concentrations of 14C in Male (Upper Panel) and Female (Lower Panel) Rats
Following Oral Doses of PFOA for 28 Days at Doses of 3, 10, or 30 mg/kg/day ........................... 568
3-3. Structure of PBPK Model of PFOA and PFOS in the Rat................................................................ 605
3-4. PBPK Model Structure for Simulating PFOA and PFOS Exposure During Gestation in theRat (Dam, Left; Fetus, Right) ........................................................................................................... 606
3-5. PBPK Model Structure for Simulating PFOA/PFOS Exposure During Lactation in the Rat(Dam, Left; Pup, Right) .................................................................................................................... 607
3-6. Structure of PBPK Model for PFOA and PFOS in Monkeys and Humans ...................................... 612
3-7. Renal Resorption Pharmacokinetic Model of Gestation and Lactation used in the Analysis of
CD-1 Mice ........................................................................................................................................ 616
3-8. Andersen et al. (2006) Pharmacokinetic Model with Oral Absorption ............................................ 618
3-9. Conceptual Representation of a Physiologically Based Pharmacokinetic Model for PFOS
Exposure in Rats ............................................................................................................................... 621
3-10. Structure of the PBPK Model for PFHxS in Rats and Humans...................................................... 626
5-1. Perfluorinated Compound (PFAS) Sites with ATSDR, State Health Department, U.S.
Environmental Protection Agency, or Department of Defense Involvement ................................... 647
5-2. Timeline of Important Events in the History of Polyfluorinated Compounds.................................. 653
5-3. Geometric Mean Concentrations of PFOA, PFOS, PFHxS, PFNA, and PFDA in U.S.
Residents from 1999 to 2016 ............................................................................................................ 721
6-1. Summary of Existing Health Effects Studies on PFOA by Route and Endpoint ............................. 744
6-2. Summary of Existing Health Effects Studies on PFOS by Route and Endpoint .............................. 745
6-3. Summary of Existing Health Effects Studies on Other Perfluoroalkyls by Route andEndpoint ........................................................................................................................................... 746

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LIST OF TABLES
1-1. Summary of Estimated Elimination Half-lives for Select Perfluoroalkyls ........................................... 5
1-2. Overview of Minimal Risk Levels Derived for Perfluoroalkyls ........................................................ 17
1-3. Minimal Risk Levels (MRLs) for PFOA ............................................................................................ 20
1-4. Minimal Risk Levels (MRLs) for PFOS ............................................................................................ 20
1-5. Minimal Risk Levels (MRLs) for PFHxS .......................................................................................... 21
1-6. Minimal Risk Levels (MRLs) for PFNA ............................................................................................ 21
2-1. Levels of Significant Exposure to PFOA – Inhalation ....................................................................... 33
2-2. Levels of Significant Exposure to Other Perfluoroalkyls – Inhalation ............................................... 36
2-3. Levels of Significant Exposure to PFOA – Oral ................................................................................ 38
2-4. Levels of Significant Exposure to PFOS – Oral ................................................................................. 66
2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral ........................................................ 88
2-6. Levels of Significant Exposure to PFOA – Dermal ......................................................................... 113
2-7. Body Weight Outcomes in Humans ................................................................................................. 120
2-8. Summary of Cardiovascular Outcomes in Humans.......................................................................... 146
2-9. Summary of Skeletal Outcomes in Humans ..................................................................................... 175
2-10. Summary of Liver Disease in Humans ........................................................................................... 183
2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humans ................. 185
2-12. Summary of Serum Lipid Outcomes in Humans ............................................................................ 191
2-13. Summary of Renal Outcomes in Humans....................................................................................... 245
2-14. Summary of Uric Acid Outcomes in Humans ................................................................................ 248
2-15. Summary of Thyroid Outcomes in Humans ................................................................................... 265
2-16. Summary of Immunological Outcomes in Humans ....................................................................... 295
2-17. Summary of Neurological Outcomes in Humans ........................................................................... 353
2-18. Summary of Alterations in Reproductive Hormone Levels in Humans ......................................... 360

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2-19. Summary of Male Reproductive Outcomes in Humans ................................................................. 368
2-20. Summary of Female Reproductive Outcomes in Humans.............................................................. 373
2-21. Summary of Fertility Outcomes in Humans ................................................................................... 380
2-22. Summary of Pregnancy Outcomes in Humans ............................................................................... 411
2-23. Summary of Birth Outcomes in Humans........................................................................................ 418
2-24. Summary of Neurodevelopmental Outcomes in Humans .............................................................. 442
2-25. Summary of Effects on the Development of the Reproductive System in Humans ....................... 458
2-26. Summary of Outcomes Related to Diabetes in Humans................................................................. 500
2-27. Summary of Cancer Outcomes in Humans..................................................................................... 524
2-28. Transactivation of Human and Mouse PPARα in Transfected Cos-1 Cells Exposed to
Perfluoroalkyls (In Order of Decreasing C20max in the Mouse) ....................................................... 543
2-29. Gene Expression Changes Induced by Perfluoroalkyls .................................................................. 545
2-30. Hepatic Effects of Perfluoroalkyls in Wild-Type and PPARα-Null Mice Exposed Orally ............ 548
3-1. Tissue Distribution and Excretion of 14C-Radioactivity from Both Sexes of Rats, Mice,
Hamsters, and Rabbits Dosed with 14C-Labeled APFO ................................................................... 569
3-2. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant Pairs ................................ 572
3-3. Matched Serum (or Plasma) and Breast Milk Concentrations in Humans ....................................... 576
3-4. Excretory Clearance of PFOA and PFOS in Humans ...................................................................... 580
3-5. Summary Elimination Half-Lives for Perfluoroalkyls Estimated in Humans and Experimental
A Animals.............................................................................................................................................. 583
3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated in Experimental Animals ................. 592
3-7. Estimated and Assumed Pharmacokinetic Parameters for the Modified Andersen et al.
(2006) Model for PFOA and PFOS .................................................................................................. 619
4-1. Chemical Identity of Perfluoroalkyls................................................................................................ 636
4-2. Physical and Chemical Properties of Perfluoroalkyls....................................................................... 641

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5-1. Content (ppm) and Percent Reduction of PFOA, PFOA Homologues, or PFOA Precursors in
Products from 2006 and 2013 U.S. Operations of Fluoropolymer/Fluorotelomer Companies ........ 655
5-2. U.S. Production Volume Ranges for Perfluoroalkyls (1986–2002) Reported under the EPA
Inventory Update Rule...................................................................................................................... 659
5-3. Reported Emissions of PFOA, PFOA Homologues, or PFOA Precursors in Products fromthe 2006 and 2013 U.S. Operations of Fluoropolymer/Fluorotelomer Companies .......................... 661
5-4. Global Historical PFCA Production and Emissions Estimates from 1951 to 2004 .......................... 664
5-5. Biological Monitoring of PFOA and PFOS in the Arctic ................................................................. 671
5-6. Lowest Limit of Detection Based on Standards ............................................................................... 677
5-7. Summary of Environmental Levels of Perfluoroalkyls .................................................................... 678
5-8. Perfluoroalkyls Levels in Water, Soil, and Air of National Priorities List (NPL) Sites ................... 678
5-9. Concentrations of Perfluoroalkyl in Outdoor Air ............................................................................. 680
5-10. Concentrations of Perfluoroalkyl in Indoor Air.............................................................................. 684
5-11. Concentrations of Perfluoroalkyls in Indoor Dust .......................................................................... 685
5-12. Concentrations of PFOA and PFOS in Surface Water (ng/L) ........................................................ 687
5-13. Concentrations of Other Perfluoroalkyls in Surface Water ............................................................ 689
5-14. Concentrations of Perfluoroalkyls in Surface Water and Groundwater at Fluorochemical
Industrial Facilities ......................................................................................................................... 692
5-15. Concentrations of PFOA and PFOS in Ocean Water ..................................................................... 694
5-16. Concentrations of Perfluoroalkyls in Soil and Sediment at Fluorochemical Industrial
Facilities ......................................................................................................................................... 699
5-17. Summary of Perfluoroalkyls Detected in Soil, Sediment, Surface Water, and Groundwaterat 10 Military Installations.............................................................................................................. 702
5-18. Detections of PFOA in 31 U.S. Food Items ................................................................................... 704
5-19. Detections of Perfluoroalkyls in Fish from U.S. Lakes and Rivers ................................................ 705
5-20. Fluorotelomer Alcohols Detected in Microwaveable Popcorn Bags Produced in China andthe United States ............................................................................................................................. 710
5-21. Concentrations of PFOA and PFOS in Human Serum Collected in the United States .................. 714

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5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collected in the United States ........... 717
5-23. Percent Detection and Levels of PFOA and PFOS in Children’s Serum ....................................... 723
5-24. Percent Detection and Levels of Other Perfluoroalkyls in Children’s Serum ................................ 726
5-25. Percent Detection and Levels of PFOA and PFOS in Umbilical Cord Blood and Breast Milk ..... 728
5-26. Percent Detection and Levels of Other Perfluoroalkyls in Children’s Umbilical Cord Bloodand Breast Milk .............................................................................................................................. 732
5-27. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for Occupationally Exposed
Individuals ...................................................................................................................................... 736
5-28. Blood Serum Levels for 69,030 Current and Former Residents of Six Water Districts in the
Mid-Ohio Valley (2005–2006) ....................................................................................................... 742
7-1. Regulations and Guidelines Applicable to Perfluoroalkyls .............................................................. 758
7-2. Select State Drinking Water Guidelines for Perfluoroalkyls ............................................................ 760

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CHAPTER 1. RELEVANCE TO PUBLIC HEALTHThis toxicological profile on perfluoroalkyls discusses information on 10 perfluoroalkyls that have beenmeasured in the serum collected from a representative U.S. population 12 years of age and older in the
National Health and Nutrition Examination Survey (NHANES) 2003–2004 (Calafat et al. 2007b), as well
as 2 compounds (PFBA and PFHxA) that have been identified in other monitoring studies. More recent
NHANES monitoring studies have not evaluated additional perfluoroalkyl compounds (CDC 2019). The
perfluoroalkyl compounds discussed in the profile include:
CompoundAcronym

CAS Registry Number

Perfluorobutanoic acid
Perfluorohexanoic acid
Perfluoroheptanoic acid
Perfluorooctanoic acid
Perfluorononanoic acid
Perfluorodecanoic acid
Perfluoroundecanoic acid
Perfluorododecanoic acid
Perfluorobutane sulfonic acid
Perfluorohexane sulfonic acid
Perfluorooctane sulfonic acid
Perfluorooctane sulfonamide

PFBA
PFHxA
PFHpA
PFOA
PFNA
PFDA
PFUnA
PFDoDA
PFBS
PFHxS
PFOS
FOSA

375-22-4
307-24-4
375-85-9
335-67-1
375-95-1
335-76-2
2058-94-8
307-55-1
375-73-5
355-46-4
1763-23-1
754-91-6

Perfluoroalkyls can exist in several ionic forms, most commonly as the anionic form or acidic form. In
the environment, perfluoroalkyls are found in the anionic form (ITRC 2017). The names for the anionicand acidic forms (e.g., perfluorooctanoate and perfluorooctanoic acid) are often used interchangeably
even though there are differences in physical and chemical properties and behavior in the environment,
and the same acronym is used for both forms (e.g., PFOA). ATSDR has opted to the utilize the same
terminology as NHANES (i.e., the acidic form names).
The term “perfluoroalkyls” used throughout the toxicological profile is referring to at least one of these
12 compounds and the information may not be applicable to other perfluoroalkyl compounds.
1.1

OVERVIEW AND U.S. EXPOSURESThe perfluoroalkyls discussed in this profile primarily consist of perfluorinated aliphatic carboxylic acids(PFCAs) and perfluorinated aliphatic sulfonic acids (PFSAs). These substances have been used
extensively in surface coating and protectant formulations due to their unique surfactant properties (Kissa

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2001; Schultz et al. 2003). Major applications have included protectants for paper and cardboard
packaging products, carpets, leather products, and textiles that enhance water, grease, and soil repellency(3M 1999; Hekster et al. 2003; Kissa 2001; Schultz et al. 2003), and in firefighting foams (Schultz et al.
2003). Perfluoroalkyls such as PFOA have also been used as processing aids in the manufacture offluoropolymers such as nonstick coatings on cookware (DuPont 2008; EPA 2008a).

Perfluoroalkyls are human-made substances that do not occur naturally in the environment. The
perfluoroalkyl substances discussed in this profile, especially PFOS and PFOA, have been detected in air,water, and soil in and around fluorochemical facilities. However, these industrial releases have been
declining since eight companies began voluntarily phasing out the production and use of several
perfluoroalkyls in the early 2000s (3M 2007b, 2008a, 2008b; Barton et al. 2007; Davis et al. 2007;
DuPont 2008; EPA 2007a, 2008a, 2016a). PFOA and PFOS may still be produced domestically,
imported, and used by companies not participating in the PFOA Stewardship program. Under the Toxic
Substances Control Act (TSCA), EPA has proposed a significant new use rule (SNUR) for long-chain
perfluoroalkyl carboxylate (LCPFAC) chemical substances and sulfonates to ensure that the manufacture,import, or processing of LCPFAC chemical substances for any discontinued uses cannot begin without
EPA review. EPA essentially excluded the use or import of all LCPFAC chemical substances by
proposing a SNUR for LCPFACs and sulfonates (EPA 2015). Data are becoming more available
regarding current releases of shorter-chain perfluoroalkyls (perfluorinated carboxylic acids with six or
fewer carbons and perfluorosulfonic acids with five or fewer carbons) that are now being used in surface
treatment products or perfluoropolyethers that are used as a replacement for PFOA in emulsion
polymerization. Environmental fate and toxicity research of newer replacement substances is ongoing(De Silva et al. 2016; Gomis et al. 2018; Kabore et al. 2018).

In the environment, some of the perfluoroalkyls discussed in this profile can also be formed fromenvironmental degradation of precursor compounds released during the manufacture and use of consumer
products containing perfluoroalkyls (D’eon and Mabury 2007; D’eon et al. 2009; Martin et al. 2006;
Prevedouros et al. 2006). Under the PFOA Stewardship Program with the U.S. Environmental Protection
Agency (EPA), eight major fluoropolymer producers have phased out PFOA, precursor substances thatcan degrade to long-chain perfluoroalkyls such as PFOA, and higher homologues from emissions andproducts (EPA 2008a, 2016a).

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Due to the strength of the carbon-fluorine bonds, perfluoroalkyls are very stable in the environment andare resistant to biodegradation, photooxidation, direct photolysis, and hydrolysis (3M 2000; EPA 2008a;
OECD 2002, 2007; Schultz et al. 2003). The perfluoroalkyl carboxylic acids and sulfonic acids have very
low volatility due to their ionic nature (Kissa 2001; Prevedouros et al. 2006; SPARC 2008). As a group,
perfluoroalkyls are persistent in soil and water (3M 2000; Prevedouros et al. 2006). Perfluoroalkyls aremobile in soil and leach into groundwater (Davis et al. 2007). Volatile fluorotelomer alcohols may be
broken down into substances like PFOA, and atmospheric deposition can lead to contamination of soils
and leaching into groundwater away from point sources. Perfluoroalkyls have been detected in many
parts of the world, including oceans and the Arctic, indicating that long-range transport is possible(Armitage et al. 2006; Barber et al. 2007; Prevedouros et al. 2006; Wania 2007; Wei et al. 2007a;
Yamashita et al. 2005, 2008).

Perfluoroalkyls have been detected in all environmental media including air, surface water, groundwater(including drinking water), soil, and food. Human exposure may occur from all of these media.
Contaminated drinking water led to increased levels of exposure to PFOA, PFOS, and otherperfluoroalkyls for some populations residing near fluoropolymer manufacturing facilities (ATSDR 2008;
Emmett et al. 2006a; Steenland et al. 2009b). Median PFOA serum levels (measured in 2005–2006) of
45,276 non-occupationally exposed individuals residing in southeastern Ohio and West Virginia who
were exposed to PFOA via contaminated drinking water (Shin et al. 2011b) were approximately 6 times
greater than the median serum PFOA concentration in a representative sample of the U.S. general
population (2005–2006 NHANES data; CDC 2018). Serum levels of PFOA and PFOS in the general
population of the United States have sharply declined in recent years as U.S. production of thesesubstances ceased (CDC 2019). For example, the geometric mean concentrations of PFOA and PFOS in
the general population were 5.2 and 30.4 ng/mL (ppb), respectively, in 1999–2000; in 2015–2016, PFOA
declined by 70% to 1.56 ng/mL and PFOS declined 84% to 4.72 ng/mL (CDC 2018, 2019).

Based on environmental measurements and theoretical models, one study has proposed that the major
exposure pathways for PFOS for the general population in Europe and North America are food and water
ingestion, dust ingestion, and hand-to-mouth transfer from mill-treated carpets (Trudel et al. 2008). For
PFOA, major exposure pathways were proposed to be oral exposure resulting from migration from paper
packaging and wrapping into food, general food and water ingestion, inhalation from impregnatedclothes, and dust ingestion. This includes exposure to 8:2 fluorotelomer alcohol in food packaging andair, which can be broken down into PFOA. PFOS and PFOA exposure pathways are proposed to be
similar for children except that exposure from hand-to-mouth transfer from treated carpets is expected toPERFLUOROALKYLS

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be much greater in children. Based on these exposure pathways, adult uptake doses estimated for highexposure scenarios were approximately 30 and 47 ng/kg/day for PFOS and PFOA, respectively (Trudel etal. 2008). PFOS and PFOA doses estimated for children under the age of 12 under high exposure
scenarios were 101–219 and 65.2–128 ng/kg/day, respectively. Since PFOA and PFOS are no longer
produced or used in the United States, current exposure levels may be lower than those predicted by
Trudel et al. (2008). A study by Vestergren and Cousins (2009) evaluated potential exposure toperfluorocarboxylate homologues for different populations and also concluded that dietary intake was theprimary background exposure pathway for the general population, while inhalation of indoor air was themain exposure pathway for occupationally exposed individuals with estimated intakes >150 ng/kg/day.
Although not well studied, the available absorption data (Fasano et al. 2005; Franko et al. 2012) suggestthat dermal contact may also contribute to the overall perfluoroalkyl body burden.

Perfluoroalkyls have been detected in human breast milk and umbilical cord blood. The reported
maximum concentrations of PFOS and PFOA measured in human breast milk samples from women
living in Massachusetts (samples were collected in 2004) were 0.617 and 0.161 ng/mL, respectively (Taoet al. 2008b). Maximum concentrations of other perfluoroalkyls were <0.06 ng/mL. In most umbilicalcord samples collected in 2004–2005 in Maryland, the maximum concentrations of PFOS and PFOA
were 34.8 and 7.1 ng/mL, respectively (Apelberg et al. 2007a, 2007b). Other perfluoroalkyls have been
detected less frequently.
1.2

SUMMARY OF HEALTH EFFECTS

The toxicity of PFOA and PFOS has been evaluated in a large number of studies of humans andlaboratory animals; less toxicity data are available for other perfluoroalkyls. However, comparison of the
toxicity of perfluoroalkyls across species is problematic due to differences in elimination half-lives, lackof adequate mechanistic data, species differences in the mechanism of toxicity for some endpoints, anddifferences in measurement of exposure levels between epidemiological and experimental studies.
Table 1-1 lists half-lives for PFOA, PFOS, PFHxS, PFNA, PFBS, and PFBA for human, nonhumanprimates, rats, and mice to illustrate some of the species differences. For example, for PFOA, theestimated elimination half-life is measured in years in humans and in hours in female rats.

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Table 1-1. Summary of Estimated Elimination Half-lives for Select
Perfluoroalkylsa
HumansNonhuman primates

Rats

PFOA

2.1–10.1 years

20.1–32.6 days

PFOS
PFHxS

3.3–27 years
4.7–35 years

110–170 days
87–141 days

PFNA

2.5–4.3 years

PFBS
PFBA

665 hours
72–81 hours

Males: 44–322 hours
Females: 1.9–16.2 hours
179–1,968 hours
731–1,027 hours
Males: 382–688 hours
597–643 hours
Females: 1.03–41.28 hours
Males: 710–1,128 hours
619.2–
Females: 33.6–58.6 hours 1,653 hours
2.1–7.42 hours
1.03–9.22 hours
2.79–13.34 hours

8.0–95.2 hours
40.3–41.0 hours

Mice

aSee Table 3-5 for additional information and citations.

The mechanisms of toxicity of perfluoroalkyls have not been fully elucidated. There is strong evidence
that many of the adverse effects observed in laboratory animals involve the activation of peroxisome
proliferator-activated receptor-α (PPARα), which can mediate a broad range of biological responses(Issemann and Green 1990). There are species differences in the activation of PPARα; rats and mice are
the most sensitive species and guinea pigs, nonhuman primates, and humans are less responsive.
Although humans are less responsive to PPARα agonists, they do have functional PPARα. This may
explain some of the species differences in perfluoroalkyl toxicity. PPARα-dependent mechanisms havebeen associated with a variety of effects, including hepatocellular hypertrophy, alterations in lipid
metabolism, decreased pup survival, and some immune effects. However, there is evidence that
PPARα-independent mechanisms are also involved in PFOA and PFOS toxicity, including liver andimmune toxicity; it is not known if species differences exist for these mechanisms. In general,
epidemiological studies use serum perfluoroalkyl levels as a biomarker of exposure, which contrasts withexperimental studies that utilize dose, expressed in mg/kg body weight/day units, or air concentrations as
the dose metric. Although physiologically based pharmacokinetic (PBPK) models have been developed
for rodents and humans, these models are not sufficient to allow for direct comparisons between
administered doses in laboratory animals and serum concentrations in humans.

Effects in Humans. Perfluoroalkyls have been detected in the serum of workers, residents living near
perfluoroalkyl facilities, and the general population. A large number of epidemiological studies haveevaluated possible associations between perfluoroalkyl exposure and a wide range of adverse healthoutcomes. However, most of the studies have focused on PFOA and/or PFOS; fewer studies haveevaluated a smaller number of potential health outcomes for the remaining 10 perfluoroalkyls included inPERFLUOROALKYLS

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this toxicological profile. Most of the epidemiological studies lack exposure monitoring data, and there isa potential for multiple routes of exposure (inhalation and oral); however, most of the studies used serum
perfluoroalkyl level as a biomarker of exposure. The three primary sources of this information areoccupational exposure studies, studies of communities living near a PFOA manufacturing facility withhigh levels of PFOA in the drinking water, and studies of populations exposed to background levels ofperfluoroalkyls (referred to as general population studies). In the studies examined, workers have thehighest potential exposure to a specific perfluoroalkyl, followed by the highly-exposed residents such as
residents in the Mid-Ohio Valley who have elevated levels of PFOA and background levels of otherperfluoroalkyls, and then the general population. In one study of workers at the Washington Works
facility in West Virginia, the arithmetic mean serum PFOA level in 2001–2004 was 1,000 ng/mL (Sakr et
al. 2007a); the arithmetic mean PFOA level in highly-exposed residents (without occupational exposure)near this facility was 423 ng/mL in 2004–2005 (Emmett et al. 2006a). By comparison, the arithmetic
mean concentration of PFOA in the U.S. population was 4.91 ng/mL in 2005–2006 (calculated by
ATSDR from NHANES data reported in CDC 2013). Although a large number of epidemiologicalstudies have examined the potential of perfluoroalkyls to induce adverse health effects, most of thestudies are cross-sectional in design and do not establish causality. Based on a number of factors(described in Section 2.1), the available epidemiological studies suggest associations between
perfluoroalkyl exposure and several health outcomes; however, cause-and-effect relationships have notbeen established for these outcomes:•

Pregnancy-induced hypertension/pre-eclampsia (PFOA, PFOS)•

Increases in serum hepatic enzymes, particularly alanine aminotransferase (ALT), and decreases
in serum bilirubin levels (PFOA, PFOS, PFHxS)•

Increases in serum lipids, particularly total cholesterol and low-density lipoprotein (LDL)cholesterol (PFOA, PFOS, PFNA, PFDA)•

Decreased antibody response to vaccines (PFOA, PFOS, PFHxS, PFDA)•

Small (<20-g or 0.7-ounce decrease in birth weight per 1 ng/mL increase in either PFOA or PFOS
blood level) decreases in birth weight (PFOA, PFOS)

The International Agency for Research on Cancer (IARC 2017) concluded that PFOA is possibly
carcinogenic to humans (Group 2B), and EPA (2016e, 2016f) concluded that there was suggestive
evidence of the carcinogenic potential of PFOA and PFOS in humans. Increases in testicular and kidneycancer have been observed in highly exposed humans.

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There is also some suggestive evidence for associations between perfluoroalkyls and additional healthoutcomes; there is less certainty in these associations due to inconsistencies across studies and/or asmaller number of studies examining a specific outcome. These health outcomes include osteoarthritis in
women under 50 years of age (PFOA, PFOS) and decreased antibody response to vaccines (PFNA,PFUnA, PFDoDA). Additionally, associations between serum PFOA and PFOS and decreases inglomerular filtration rate and increases in serum uric acid levels and between serum PFOA, PFOS,
PFHxS, and PFNA and increased risk of early menopause have been observed; these effects may be due
to reverse causation, where the effect (disease) causes the change in serum perfluoroalkyl levels(exposure).
Effects in Laboratory Animals. Most of the information regarding the effects of perfluoroalkyls inanimals is derived from oral studies; considerably less information is available from inhalation anddermal exposure studies. PFOA and PFOS are the most studied perfluoroalkyls, with considerably lessdata for the other compounds. Of the 233 animal studies reviewed in this toxicological profile, 42%
examined PFOA, 31% examined PFOS, and 27% examined other perfluoroalkyls (8 studies on PFHxS,
17 studies on PFNA, 1 study on PFUnA, 5 studies on PFBS, 6 studies on PFBA, 9 studies on PFDA,
8 studies on PFDoDA, 1 study on FOSA, and 8 studies on PFHxA). The primary effects observed in rats
and mice exposed to perfluoroalkyls are liver toxicity, developmental toxicity, and immune toxicity (seeFigures 1-1, 1-2, and 1-3); not all of these effects have been observed or examined for all perfluoroalkyls.
Based on limited data, the toxicity of perfluoroalkyls does not appear to be specific to the route ofadministration. It should be noted that, for the most part, adverse health effects in studies in animals havebeen associated with exposure concentrations or doses that resulted in blood levels of perfluoroalkyls thatwere significantly higher than those reported in perfluoroalkyl workers or in the general population.
Furthermore, there are profound differences in the toxicokinetics of perfluoroalkyls between humans andexperimental animals. The elimination t1/2 of PFOA is approximately 4 years in humans compared withdays or hours in rodents. These factors, plus issues related to the mode of action of perfluoroalkyls (seebelow), make it somewhat difficult at this time to determine the true relevance of some effects reported inanimal studies to human health.

Liver Effects. Many studies have described morphological and biochemical alterations in the liver fromrodents following acute and longer-term oral exposure to PFOA. Some of the effects observed in rats
include increases in liver weight, hepatocellular hypertrophy, and decreases in serum cholesterol andtriglyceride levels (e.g., Butenhoff et al. 2004b; Liu et al. 1996; Pastoor et al. 1987; Yang et al. 2001; see
Section 2.9 for a complete list of citations). The observed hepatomegaly and hypertrophy are likely due

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Figure 1-1. Health Effects Found in Animals Following Oral Exposure to PFOAPERFLUOROALKYLS

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Figure 1-2. Health Effects Found in Animals Following Oral Exposure to PFOSPERFLUOROALKYLS

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1. RELEVANCE TO PUBLIC HEALTH

Figure 1-3. Health Effects Found in Animals Following Oral Exposure to Other
Perfluoroalkyls

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to expansion of the smooth endoplasmic reticulum and proliferation of peroxisomes, as confirmed byincreased activity of biochemical markers and light and electron microscopy (Pastoor et al. 1987). It is
important to note also that there appear to be different sensitivities for different endpoints. For example,
in male rats dosed with PFOA for 14 days, absolute liver weight and fatty acid β-oxidation activity weresignificantly increased at 2 mg/kg/day, whereas hepatic microsomal concentration of total cytochrome
P450 was significantly increased at 20 mg/kg/day (Liu et al. 1996). In general, longer-term studies withPFOA have shown that the hepatic effects are reversible once dosing ceases and that recovery tends toparallel the decline in blood levels of PFOA (Perkins et al. 2004). Studies in mice have provided similar
results. However, studies in PPARα-null mice suggest that hepatomegaly may also be due to a
PPARα-independent process in mice (Yang et al. 2002b), since PFOA induced hepatomegaly to the same
extent in wild-type mice and PPARα-null mice, but failed to increase acyl-CoA oxidase activity in
PPARα-null mice. PFOA exposure also resulted in increases in absolute liver weight in monkeys treatedwith ≥3 mg/kg/day for 26 weeks, an effect that was partly associated with significant mitochondrial
proliferation, but not peroxisome proliferation (Butenhoff et al. 2002).

Similar to PFOA, PFOS exposure results in increases in liver weight, hepatocellular hypertrophy, anddecreases in serum cholesterol and triglyceride levels in rodents (e.g., Elcombe et al. 2012a, 2012b; Era etal. 2009; Seacat et al. 2003; Thibodeaux et al. 2003). PFOS induced an increase in absolute liver weight,
a decrease in serum cholesterol, and hepatocellular hypertrophy and lipid vacuolation in monkeys in a
26-week study (Seacat et al. 2002). Not unexpectedly, there was no evidence of peroxisome proliferationand no increase in hepatic palmitoyl-CoA oxidase, consistent with the fact that monkeys (and humans)
seem to be refractory to peroxisome proliferative responses (Cattley et al. 1998; Klaunig et al. 2003).

Studies with other perfluoroalkyls have shown that, in general, liver weight and parameters of fatty acid
β-oxidation are more severely affected as the carbon length increases up to about a 10-carbon chain
length (Butenhoff et al. 2009a, 2012a; Goecke-Flora and Reo 1996; Goecke et al. 1992; Kudo et al. 2000,
2006; Permadi et al. 1992, 1993; van Otterdijk 2007a, 2007b). Significant peroxisome activity seems torequire a carbon length >7 (Goecke-Flora and Reo 1996; Goecke et al. 1992), but increases over control
levels have been reported with a four-carbon chain length (Permadi et al. 1993; Wolf et al. 2008a). In an
in vitro study in COS-1 cells transfected with mouse PPARα, PFOA had the lowest effective
concentration needed for PPARα activation followed by PFNA and PFDA, PFHxA, and PFBA (Wolf et
al. 2008a). This pattern was not found for the sulfonates; the lowest effective concentration was for
PFHxS followed by PFOS and PFBS. Wolf et al. (2008a) also found that carboxylate perfluoroalkyls
activated PPARα at lower concentrations than the sulfonate perfluoroalkyls. In COS-1 cells transfectedPERFLUOROALKYLS

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with human PPARα, PFNA had the lowest effective concentration followed by PFOA PFHxA, PFHxS,PFOS, PFBS, PFBA, and PFDA (Wolf et al. 2008a). Studies have shown that the differential activity isalso related to differential accumulation of the perfluoroalkyls in the liver (Kudo and Kawashima 2003;
Kudo et al. 2000, 2006). Hydrophobicity, which increases as carbon length increases, seems to favorbiliary enterohepatic recirculation, resulting in a more protracted toxicity (Goecke-Flora and Reo 1996).
As discussed in greater detail in Section 2.9, the increases in liver weight and hepatocellular hypertrophyobserved in the rat and mouse studies were considered rodent-specific adaptive responses and were notconsidered relevant to humans. However, other liver effects including biliary effects and hepatocellularnecrosis were considered relevant to humans.

Developmental Effects. PFOA and PFOS have induced developmental effects in rodents. Most studies
with PFOA have been conducted in mice. Specific effects reported include prenatal loss, reduced neonate
weight and viability, neurodevelopment toxicity, altered bone development, and delays in mammary
gland differentiation, eye opening, vaginal opening, and first estrus (Abbott et al. 2007; Albrecht et al.
2013; Cheng et al. 2013; Johansson et al. 2008; Koskela et al. 2016; Lau et al. 2006; Macon et al. 2011;
Ngo et al. 2014; Onishchenko et al. 2011; Sobolewski et al. 2014; White et al. 2007, 2009, 2011; Wolf et
al. 2007; Yahia et al. 2010). These effects occurred generally in the absence of overt maternal toxicity.
Some of these effects, such as reduced pup survival from birth to weaning, have been observed in micetreated with as low as 0.6 mg/kg/day PFOA on gestation days (GDs) 1–17 (Abbott et al. 2007). This doselevel resulted in mean serum PFOA concentrations of 5,200 and 3,800 ng/mL in dams and pups,
respectively, on postnatal day (PND) 22. A cross-fostering study in mice showed that in utero, lactation
only, and in utero and lactation exposure resulted in significant decreases in postnatal growth (Wolf et al.
2007). Alterations in spontaneous behavior were reported in 2- or 4-month-old male mice that wereadministered a single gavage dose of PFOA at the age of 10 days (Johansson et al. 2008). Increases inmotor activity were also observed following in utero exposure to PFOA (Cheng et al. 2013; Onishchenko
et al. 2011). Gestational exposure resulted in altered bone morphology and bone mineral density in themature offspring (Koskela et al. 2016). Delays in ossification were found in another gestational exposure
study in mice (Lau et al. 2006). A cross-fostering study showed that the delays in mammary glanddevelopment were observed following in utero exposure and following lactation-only exposure (White etal. 2009); however, the results of a 2-generation study showed that the delayed development did notappear to affect lactational support (White et al. 2011). No fetal toxicity or teratogenicity was reported inoffspring of rabbits exposed to up to 50 mg/kg/day PFOA on GDs 6–18 (Gortner et al. 1982), suggestingthat rabbits are less susceptible than mice to the developmental effects of PFOA, although comparing
administered doses is probably not very informative due to toxicokinetic differences between species.

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There were significant increases in body weight gain in mice aged 10–40 weeks that were exposed to lowlevels of PFOA (0.01–0.3 mg/kg/day) on GDs 1–17 (Hines et al. 2009). Increases in serum insulin andleptin levels were also observed, but there was no change in serum glucose or the response to a glucose
challenge. A comparison of the effects of in utero exposure (GDs 1–17) to adult exposure (17 days at age
8 weeks) demonstrated that in utero exposure resulted in higher body weights, white fat weight, andbrown fat weight at age 18 months (Hines et al. 2009).
Studies conducted with wild-type and PPARα knockout mice showed that PPARα was required for
PFOA-induced postnatal lethality and that the expression of one copy of the gene was sufficient tomediate this effect (Abbott et al. 2007). Strain or PPARα expression did not affect serum PFOA levels.
The mechanism of reduced postnatal viability has not been elucidated. Alterations in gene expression inboth fetal liver and lung have been reported following exposure of mice to PFOA during pregnancy(Rosen et al. 2007). In the liver, PFOA altered the expression of genes linked to fatty acid catabolism,lipid transport, ketogenesis, glucose metabolism, lipoprotein metabolism, cholesterol biosynthesis, steroid
metabolism, bile acid biosynthesis, phospholipid metabolism, retinol metabolism, proteosome activation,and inflammation. In the lung, transcriptional-related changes were predominantly associated with fatty
acid catabolism. Although decreased pup survival appears to be linked to PPARα expression, there areinsufficient data to determine whether other developmental effects observed in rats and mice are PPARαindependent.

PFOS significantly decreased birth weight and survival in neonatal rats exposed in utero (Chen et al.
2012b; Lau et al. 2003; Xia et al. 2011), and cross-fostering exposed pups with unexposed dams failed to
improve survival rates (Lau et al. 2003). PFOS serum levels of pups at birth associated with significant
decreased survival were approximately ≥70,000 ng/mL. In contrast to PFOA, the results of a study inwild-type and PPARα-null mice suggest that the decrease in pup survival was not dependent on PPARα
activation (Abbott et al. 2009). Dosing rats late during gestation (GDs 17–20) caused significantly morelethality than dosing early (GDs 2–5) (Grasty et al. 2003). Since pups had difficulty breathing withinminutes of birth and their lungs showed evidence of delayed lung maturation and other histologicalalterations (Grasty et al. 2003, 2005; Yahia et al. 2008), the possibility that this caused the early death has
been suggested. Other effects included decreases in birth weight or pup body weight, delays in eye
opening, cleft palate, and neurodevelopmental alterations (Butenhoff et al. 2009b; Case et al. 2001; Chenet al. 2012b; Era et al. 2009; Fuentes et al. 2006, 2007a, 2007b; Lau et al. 2003; Luebker et al. 2005a,
2005b; Onishchenko et al. 2011; Thibodeaux et al. 2003; Wang et al. 2015c; Yahia et al. 2008).
Alterations in spontaneous motor activity were observed in mice. A decrease in activity was observed

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when mice were placed in a novel environment (Fuentes et al. 2007a; Onishchenko et al. 2011); anotherstudy found a decrease in motor activity followed by increased activity (Johansson et al. 2009).
Evaluation of immunological parameters in 8-week-old pups from mice exposed to PFOS during
gestation showed reduced natural killer (NK) cell activity, suppressed IgM response to immunization, andalterations in splenic and thymic lymphocyte subpopulations (Keil et al. 2008).

Similar to PFOA and PFOS, increases in fetal mortality were observed in mice exposed to PFDA on GDs
6–15 (Harris and Birnbaum 1989) and decreases in litter size and pup survival were observed in mice
exposed to PFNA (Wolf et al. 2010). In contrast, gestational exposure to PFBA, PFBS, or PFHxS did not
result in alterations in pup survival or pup body weight (Das et al. 2008; Hoberman and York 2003;
Lieder et al. 2009b). Decreases in spontaneous activity followed by an increase in activity were observedin mice exposed to PFHxS on PND 10 (Viberg et al. 2013); no alterations were observed in micesimilarly exposed to PFDA (Johansson et al. 2008).

Immunological Effects. A number of studies have examined the immunotoxicity of perfluoroalkyls inrats and mice; these data suggest that mice are considerably more sensitive than rats. PFOA- andPFOS-induced immunological alterations in adult mice are characterized by thymus and spleen atrophy,
alterations in thymic and splenic lymphocyte phenotypes, and impaired response to T-dependent antigens(DeWitt et al. 2008, 2009; Dong et al. 2009; Guruge et al. 2009; Lefebvre et al. 2008; Loveless et al.
2008; Qazi et al. 2012; Yang et al. 2000, 2002a; Zheng et al. 2009). The lowest lowest-observed-adverseeffect level (LOAEL) for immune effects in mice exposed to PFOA was 3.75 mg/kg/day administered for
15 days; this dosing level resulted in a mean PFOA serum level of 75,000 ng/mL (DeWitt et al. 2008).
For PFOS, several studies identified LOAELs of 0.02–0.8 mg/kg/day (Dong et al. 2009, 2011; Zheng etal. 2009) and one study identified a LOAEL of 0.00166 mg/kg/day for suppressed response to a
T-dependent antigen (Peden-Adams et al. 2008). PFOA applied to the skin of mice increased serum IgElevels following a challenge with ovalbumin relative to mice treated with ovalbumin alone, which led theinvestigators to suggest that PFOA may increase the IgE response to environmental allergens (Fairley etal. 2007). More limited data are available for other perfluoroalkyls. Thymic and/or splenic alterations
were observed in rats and mice administered ≥1 mg/kg/day PFNA (Fang et al. 2008, 2009, 2010). No
histological alterations were observed in rodents exposed to PFHxS (Butenhoff et al. 2009a), PFDA
(Harris et al. 1989), PFBS (3M 2001), or PFBA (3M 2007a; Butenhoff et al. 2012a; van Otterdijk 2007a,
2007b).

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Cancer Effects. PFOA, as many other PPARα agonists, induced hepatocellular adenomas, Leydig celladenomas, and pancreatic acinar cell adenomas in rats (Biegel et al. 2001). An increase in hepatocellularadenomas was also observed in rats chronically exposed to PFOS (Butenhoff et al. 2012b). Liver tumors
induced by PFOA are believed to be mediated largely through PPARα activation, and considered to be oflimited or no relevance to humans (EPA 2016h), based on species differences in response to PPARα
activation. Although Leydig cell tumors are also commonly induced by peroxisome proliferating agents,
the mode of action by which these tumors are induced by PFOA, and thus their relevance to humans, ismuch less clear (Corton et al. 2014; EPA 2016h; Klaunig et al. 2003). One mode of action proposed forthe induction of Leydig cell tumors involves PFOA-induced decreases in circulating testosterone levels,
leading to increased production of gonadotropin releasing hormone and circulating luteinizing hormone(LH), which promotes Leydig cell proliferation. Reduced testosterone levels may occur throughdecreased biosynthesis, or via the conversion of testosterone to estradiol via the enzyme aromatase, bothof which may be related to PPARα activation (EPA 2016h). However, the data supporting a PPARαdependent mode of action for Leydig cell tumors is not sufficiently established to rule out humanrelevance (EPA 2016h). Likewise, the mechanism of PFOA-induced pancreatic acinar cell tumors may
include a PPARα-dependent component, but the mechanism has not been fully elucidated, and relevant
data are limited. A proposed mode of action involves stimulation of PPARα leading to reduced bile flow
and/or changes in bile acid composition with subsequent increase in cholecystokinin (CCK), which
stimulates pancreatic cell proliferation and tumor formation (EPA 2016h). Support for this mode ofaction is limited to information demonstrating increased biliary excretion of PFOA in wild-type andPPARα null mice (Minata et al. 2010) and data showing altered expression of bile acid transporters(OATPs and MRPs) in exposed laboratory animals (Cheng and Klassen 2008a; Maher et al. 2008). The
limitations in available data on the mode of action for pancreatic tumor development preclude a
conclusion regarding the human relevance of PFOA-induced pancreatic tumors (EPA 2016h).
1.3

MINIMAL RISK LEVELS (MRLs)

ATSDR develops MRLs as screening tools to help identify chemicals that may be of concern. An MRL
is an estimate of the daily human exposure to a hazardous substance that is likely to be without
appreciable risk of adverse noncancer health effects over a specified route and duration of exposure.
MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or themost sensitive health effect(s) for a specific duration for a given route of exposure. These substancespecific estimates, which are intended to serve as screening levels, are used by ATSDR health assessors todetermine areas and populations potentially at risk for health effects from exposure to a particular
substance. Exposure above the MRLs does not mean that health problems will occur. Instead, it may act

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1. RELEVANCE TO PUBLIC HEALTH

as a signal to health assessors to look more closely at a particular site where exposures may be identified.
MRLs do not define regulatory or action levels for ATSDR.
ATSDR uses the point of departure (POD)/uncertainty factor approach to derive MRLs. Potential PODs
are no-observed-adverse-effect levels (NOAELs), LOAELs, or the lower limit of the benchmark dose
(BMDL). MRLs are set below levels that, based on current information, might cause adverse healtheffects in the people most sensitive to such substance-induced effects. MRLs are generally based on themost sensitive substance-induced endpoint considered to be of relevance to humans. Serious healtheffects (such as irreparable damage to the liver or kidneys) are not used as a basis for establishing MRLs.
MRLs are derived for acute (1–14 days), intermediate (15–364 days), and chronic (≥365 days) durations
and for the oral and inhalation routes of exposure. ATSDR does not extrapolate across exposure
durations to derive MRLs for durations with limited databases.
Most MRLs contain a degree of uncertainty because of the lack of precise toxicological information on
the people who might be most sensitive (e.g., infants, elderly, nutritionally or immunologicallycompromised) to the effects of hazardous substances. ATSDR uses a conservative (i.e., protective)
approach to address this uncertainty consistent with the public health principle of prevention. Althoughhuman data are preferred, MRLs often must be based on animal studies because relevant human studies
are lacking. In the absence of evidence to the contrary, ATSDR assumes that humans are more sensitive
to the effects of hazardous substance than animals and that certain persons may be particularly sensitive.
Thus, the resulting MRL may be as much as 100-fold below levels that have been shown to be nontoxic
in laboratory animals. ATSDR utilizes uncertainty factors to account for uncertainties associated with:(1) extrapolating from a LOAEL to a NOAEL; (2) extrapolating from animals to humans; and (3) toaccount for human variability. Default values of 10 are used for each of these categories of uncertainty
factors; a value of 1 can be used if complete certainty exists for a particular uncertainty factor category.
A partial uncertainty factor of 3 can be used when chemical-specific data decreases the uncertainty. On acase-by-case basis, ATSDR also utilizes modifying factors to account for MRL-specific database
deficiencies.
Oral MRLs have been derived for several perfluoroalkyls. A summary of the MRLs derived for
perfluoroalkyls is presented in Table 1-2 and detailed discussions of MRLs are provided in Appendix A.
The database was not considered adequate for derivation of inhalation MRLs. Though inhalation data are
available for PFOA and PFNA, these studies examined a limited number of endpoints and the data are notadequate for identifying the most sensitive targets of toxicity or establishing dose-response relationships.
No inhalation data are available for other perfluoroalkyls.

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Table 1-2. Overview of Minimal Risk Levels Derived for Perfluoroalkyls

CompoundAcute

Inhalation MRLs
Intermediate Chronic

Acute

PFOA

Xa

X

X

X

PFOS

X

X

X

X

PFHxS

X

X

X

PFNA

X

X

PFDA
PFUnA
PFHpA
PFBS
PFBA
PFDoDA

X
X
X
X
X
X

PFHxA
FOSA

X
X

Oral MRLs
Intermediate

Chronic

3x10-6 mg/kg/day(Table 1-3)
2x10-6 mg/kg/day(Table 1-4)

XX

2x10-5 mg/kg/day(Table 1-5)

X

X

X

3x10-6 mg/kg/day(Table 1-6)

X

X
X
X
X
X
X

X
X
X
X
X
X

X
X
X
X
X
X

X
X
X
X
X
X

X
X
X
X
X
X

X
X

X
X

X
X

X
X

X
X

X

aX indicates that no MRL was derived.

FOSA = perfluorooctane sulfonamide; PFBA = perfluorobutanoic acid; PFBS = perfluorobutane sulfonic acid;
PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid;
PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid

The oral databases were considered adequate for derivation of intermediate-duration oral MRLs for
PFOA, PFOS, PFHxS, and PFNA based on laboratory animal data. The databases were not consideredadequate for derivation of MRLs for the other perfluoroalkyls. Hepatic, immune, and developmental
endpoints were the most sensitive targets in laboratory animals exposed to PFOA (see Figure 1-4) andPFOS (see Figure 1-5), respectively. The most sensitive targets were hepatic and thyroid endpoints for
PFHxS and body weight and developmental endpoints for PFNA. As discussed in Section 1.2,
toxicokinetic and mechanistic differences exist between humans and laboratory animals, in particulardifferences in elimination rates and the relevance of effects associated with activation of PPARα. The
uncertainties in the relevance of animal data for developing screening levels are decreased by focusing on
health outcomes also reported in epidemiological studies or involving PPARα-independent mechanismsof action and estimating a POD using serum perfluoroalkyl concentrations. The MRL values for PFOA,PFOS, PFHxS, and PFNA are summarized in Tables 1-3, 1-4, 1-5, and 1-6 and discussed in greater detailin Appendix A.

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Figure 1-4. Summary of Sensitive Targets of PFOA – Oral
Developmental endpoints are the most sensitive target of PFOA.
Numbers in circles are the lowest LOAELs for all health effects in animals.

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Figure 1-5. Summary of Sensitive Targets of PFOS – Oral
The immune system and developing organism are the most sensitive targets of PFOS.
Numbers in circles are the lowest LOAELs for all health effects in animals.

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Table 1-3. Minimal Risk Levels (MRLs) for PFOAa
Exposure
duration

MRL

Critical effect

Point ofdeparture

Uncertainty factor Reference

Inhalation exposure
Acute
Inadequate acute-duration study (exposure ≤14 days)
Intermediate Inadequate intermediate-duration study (exposure 15–364 days)
Chronic
Inadequate chronic-duration study (exposure ≥365 days)
Oral exposure (mg/kg/day)
Acute
Inadequate acute-duration study (exposure ≤14 days)
Intermediate 3x10-6 Skeletal effects in mice 0.000821
300(LOAELHED)
Chronic
Inadequate chronic-duration study (exposure ≥365 days)

Koskela et al.
2016

aSee Appendix A for additional information.

HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level; PFOA = perfluorooctanoic acid

Table 1-4. Minimal Risk Levels (MRLs) for PFOSa
Exposure
duration

MRL

Critical effect

Point ofdeparture

Uncertainty andmodifying factors

Inhalation exposure
Acute
Inadequate acute-duration study (exposure ≤14 days)
Intermediate Inadequate intermediate-duration study (exposure 15–364 days)
Chronic
Inadequate chronic-duration study (exposure ≥365 days)
Oral exposure (mg/kg/day)
Acute
Inadequate acute-duration study (exposure ≤14 days)
Intermediate 2x10-6 Delayed eye opening
0.00051530
and decreased pup(NOAELHED)b10
weight in rats
Chronic
Inadequate chronic-duration study (exposure ≥365 days)

Reference

Luebker et
al. 2005a

aSee Appendix A for additional information.

HED = human equivalent dose; NOAEL = no-observed-adverse-effect level; PFOS = perfluorooctane sulfonic acid

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Table 1-5. Minimal Risk Levels (MRLs) for PFHxSa
Exposure
duration

MRL

Critical effect

Point ofdeparture

Uncertainty andmodifying factors

Inhalation exposure
Acute
Inadequate acute-duration study (exposure ≤14 days)
Intermediate Inadequate intermediate-duration study (exposure 15–364 days)
Chronic
Inadequate chronic-duration study (exposure ≥365 days)
Oral exposure (mg/kg/day)
Acute
Inadequate acute-duration study (exposure ≤14 days)
Intermediate 2x10-5 Thyroid follicular
0.004730
epithelial hypertrophy/ (NOAELHED)
10
hyperplasia in rats
Chronic
Inadequate chronic-duration study (exposure ≥365 days)

Reference

Butenhoff et
al. 2009a

aSee Appendix A for additional information.

HED = human equivalent dose; NOAEL = no-observed-adverse-effect level; PFHxS = perfluorohexane sulfonic acid

Table 1-6. Minimal Risk Levels (MRLs) for PFNAa
Exposure
duration

MRL

Critical effect

Point ofdeparture

Uncertainty andmodifying factors

Inhalation exposure
Acute
Inadequate acute-duration study (exposure ≤14 days)
Intermediate Inadequate intermediate-duration study (exposure 15–364 days)
Chronic
Inadequate chronic-duration study (exposure ≥365 days)
Oral exposure (mg/kg/day)
Acute
Inadequate acute-duration study (exposure ≤14 days)
Intermediate 3x10-6 Decreased body weight 0.001
30
and developmental(NOAELHED)
10
delays in mice
Chronic
Inadequate chronic-duration study (exposure ≥365 days)

ReferenceDas et al.
2015

aSee Appendix A for additional information.

HED = human equivalent dose; NOAEL = no-observed-adverse-effect level; PFNOA = perfluorononanoic acid

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CHAPTER 2. HEALTH EFFECTS
2.1

INTRODUCTION

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, andother interested individuals and groups with an overall perspective on the toxicology of perfluoroalkyls.
It contains descriptions and evaluations of toxicological studies and epidemiological investigations andprovides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.
This document discusses information on perfluoroalkyls that have been measured in the serum collectedfrom a representative U.S. population ≥12 years of age in the 2003–2004 NHANES (Calafat et al. 2007b),
as well as two compounds (PFBA and PFHxA) that have been identified in other monitoring studies.
More recent NHANES monitoring studies have not evaluated additional perfluoroalkyl compounds (CDC2019). The perfluoroalkyl compounds discussed in the profile are listed below. They are discussed in the
profile in following order, based on the abundance of epidemiological data:
Perfluorooctanoic acid (PFOA, CAS Registry Number 335-67-1)
Perfluorooctane sulfonic acid (PFOS, CAS Registry Number 1763-23-1)
Perfluorohexane sulfonic acid (PFHxS, CAS Registry Number 355-46-4)
Perfluorononanoic acid (PFNA, CAS Registry Number 375-95-1)
Perfluorodecanoic acid (PFDA, CAS Registry Number 335-76-2)
Perfluoroundecanoic acid (PFUnA, CAS Registry Number 2058-94-8)
Perfluoroheptanoic acid (PFHpA, CAS Registry Number 375-85-9)
Perfluorobutane sulfonic acid (PFBS, CAS Registry Number 375-73-5)
Perfluorobutanoic acid (PFBA, CAS Registry Number 375-22-4)
Perfluorododecanoic acid (PFDoDA, CAS Registry Number 307-55-1)
Perfluorohexanoic acid (PFHxA, CAS Registry Number 307-24-4)
Perfluorooctane sulfonamide (FOSA, CAS Registry Number 754-91-6)
The term perfluoroalkyls used throughout the profile is referring to at least one of these 12 compounds
and may not be applicable to other perfluoroalkyl compounds.
A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.
To help public health professionals and others address the needs of persons living or working near hazardous
waste sites, the information in this section is organized by health effect. These data are discussed in terms ofroute of exposure (inhalation, oral, and dermal) and three exposure periods: acute (≤14 days), intermediate(15–364 days), and chronic (≥365 days).

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2. HEALTH EFFECTS

As discussed in Appendix B, a literature search was conducted to identify relevant studies examining healtheffect endpoints. Figures 2-1, 2-2, 2-3, 2-4, and 2-5 provide an overview of the database of studies inhumans or experimental animals included in this chapter of the profile. These studies evaluate the potential
health effects associated with inhalation, oral, or dermal exposure to perfluoroalkyls, but may not be
inclusive of the entire body of literature. ATSDR’s approach for assessing study quality and weight-ofevidence evaluation is described in the Agency’s Guidance for the Preparation of Toxicological Profile
document (https://www.atsdr.cdc.gov/toxprofiles/guidance/profile_development_guidance.pdf).

Summaries of the epidemiological studies, including details on the study design and results, are presented
in tables in the Supporting Document for Epidemiological Studies for Perfluoroalkyls; briefer summariesof the studies are presented in summary tables for each endpoint. For studies in which the population was
divided into perfluoroalkyl exposure categories, such as quartiles, the risk ratio reported in the summary
table is for the lowest exposure category with a statistically significant association; risk ratios for higher
exposure categories are presented in the Supporting Document for Epidemiological Studies for
Perfluoroalkyls tables. In general, associations were also found for higher exposure categories.

Summaries of experimental studies are separated by exposure route and are presented in Tables 2-1, 2-2,
2-3, 2-4, 2-5, and 2-6. The inhalation data for PFOA and other perfluoroalkyls are presented inTables 2-1 and 2-2, respectively. A large number of experimental studies have evaluated the oral toxicityof PFOA and PFOS, the results of these studies are presented in Tables 2-3 and 2-4, respectively. Lesser
amounts of data are available for the remaining 10 perfluoroalkyl compounds; the study results for thesecompounds are presented in Table 2-5. Table 2-5 is divided by exposure duration and by compound. The
dermal data for PFOA is presented in Table 2-6. In addition, the NOAEL and LOAEL values frominhalation and oral studies are graphically presented in Figures 2-6, 2-7, 2-8, 2-9, and 2-10.

Levels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated infigures. The points in the figures showing NOAELs or LOAELs reflect the actual doses (levels of
exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects.
"Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality(e.g., acute respiratory distress or death). "Less serious" effects are those that are not expected to causesignificant dysfunction or death, or those whose significance to the organism is not entirely clear.
ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether
an endpoint should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that insome cases, there will be insufficient data to decide whether the effect is indicative of significant

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2. HEALTH EFFECTS

dysfunction. However, the Agency has established guidelines and policies that are used to classify these
endpoints (ATSDR 2003). ATSDR believes that there is sufficient merit in this approach to warrant anattempt at distinguishing between "less serious" and "serious" effects. The distinction between "lessserious" effects and "serious" effects is considered to be important because it helps the users of the
profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs
should also help in determining whether or not the effects vary with dose and/or duration, and place into
perspective the possible significance of these effects to human health.

A User's Guide has been provided at the end of this profile (see Appendix C). This guide should aid in
the interpretation of the tables and figures for LSEs and MRLs.

The discussion of the available data for each health effect is divided into several subsections. Each healtheffect section begins with an overview, which contains a brief discussion of the available data andconclusions that can be drawn from the data. Compound-specific discussions follow the overview; theperfluoroalkyls are discussed in the following order: PFOA, PFOS, PFHxS, PFNA, PFDA, PFUnA,
PFHpA, PFBS, PFBA, PFDoDA, PFHxA, and FOSA. It is noted that for most health effects, there are nodata for a number of the perfluoroalkyls. The health effect endpoints examined in epidemiological andexperimental data for each perfluoroalkyl is summarized in Figures 2-1 and 2-2, respectively. The
compound-specific discussions are further divided into Epidemiological Studies and Laboratory AnimalStudies; for data-rich endpoints, a compound-specific summary is also included. Each perfluoroalkyl istreated separately in this chapter. Although there is some evidence of similar health outcomes for somecompounds, there is evidence of qualitative and mechanistic differences (Peters and Gonzalez 2011).

The health effects of perfluoroalkyls have been evaluated in a large number of epidemiological andanimal studies; the literature search framework for identifying these studies is discussed in Appendix B.
As illustrated in Figures 2-3, 2-4, and 2-5, most of the health effects data come from epidemiologicalstudies. For PFOA, PFOS, and other perfluoroalkyls, 74, 76, and 70%, respectively, of the health effectstudies were in humans; it is noted that most epidemiological studies examined more than one
perfluoroalkyl. More than half (52%) of the epidemiological studies were cross-sectional studies, 29%
were prospective studies, and the remainder were retrospective, case-control, cohort, or longitudinalstudies. Three population categories were examined in epidemiological studies: workers at facilities
involved in the production or use of perfluoroalkyls (most of the studies involved workers at two U.S.
facilities and typically involved higher than background exposure to PFOA and PFOS), communities
living near a PFOA manufacturing facility with high levels of PFOA in the drinking water (almost all ofPERFLUOROALKYLS

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2. HEALTH EFFECTS

the studies involved residents living near a PFOA production facility in West Virginia; elevated PFOA
exposure and background exposure to other perfluoroalkyls), and populations exposed to backgroundlevels of perfluoroalkyls (referred to as general population studies). Most of the studies of communities
living near perfluoroalkyl manufacturing facilities are part of the C8 Health Project and C8 Health Study(C8 is a synonym for PFOA). The C8 Health Project was a population study of Ohio and West Virginia
residents living near the DuPont Washington Works facility in West Virginia and was funded by DuPont
as part of a class action settlement agreement. The Washington Works facility began using PFOA in
1951 and peak use was in the late 1990s. At the time of enrollment (2005–2006), blood samples werecollected from over 69,000 participants who lived, worked, or attended school in six contaminated water
districts surrounding the facility for at least 12 months between 1950 and December 2004 (Frisbee et al.
2009); the six water districts were Little Hocking Water Association, Tuppers Plains Chester Water
District, Village of Pomeroy, Lubeck Public Service District, Mason County Public Service District, or
private water sources within these areas. The participants ranged in age from 1.5 to >100 years, with anaverage age of 39.1 years.

Serum perfluoroalkyl levels were used as the biomarker of exposure in almost all of the epidemiologicalstudies since most of the studies did not provide external exposure levels. The highest levels of serum
PFOA were found among workers, followed by the community members, and then the general
population. One study of PFOA workers in 2004–2005 reported an average serum PFOA level of
1,000 ng/mL (Sakr et al. 2007a). A study of community members living near this same facility reported amean serum PFOA level of 423 ng/mL in 2004–2005. In the United States, the mean geometric mean
serum PFOA level in 2005–2006 was 3.92 ng/mL (CDC 2018). In a study of two PFOS facilities, mean
serum PFOS levels in workers were 960–1,400 ng/mL in 2000 (Olsen et al. 2003a); the geometric mean
serum PFOS levels in the U.S. general population in 1999–2000 was 30.4 ng/mL (CDC 2018). Bach etal. (2015b) investigated whether transport of blood samples under ambient temperature conditions andprocessing delays impact serum perfluoroalkyl concentrations. Using the conditions of the Danish
National Birth Cohort study, Bach et al. (2015a) found relative differences between serum samples thatwere transported with processing delays and those processed immediately of 1% (winter sampling) to 3%(summer sampling) for PFOA, -29–2% for PFOS, 12–11% for PFHxS, -5–3% for PFNA, -39–0% for
PFDA, -77 to -7% for PFUnA, and 38–17% for PFHpA. This discrepancy has not been verified for other
Danish National Birth Cohort studies or for other studies.

Most of the epidemiological studies provided a single serum perfluoroalkyl concentration, which has beenshown to be a reliable biomarker of recent exposure; however, it does not provide information on

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2. HEALTH EFFECTS

historical exposure. The lack of historical exposure data is a particular limitation of the occupational andcommunity population studies where past exposures were typically higher than current exposures.

Another limitation of the epidemiological studies involves co-exposure to multiple perfluoroalkyls. A
number of the epidemiological studies have found strong correlations between serum levels of different
perfluoroalkyls. In vitro studies (Carr et al. 2013; Wolf et al. 2014) have shown that at lower
concentrations, binary pairs of perfluoroalkyls demonstrate concentration and response additivity, butdeviate from additivity at higher concentrations (Wolf et al. 2014). These possible interactions (or dose
additivity) complicate the interpretation of the epidemiological data.

Although a large number of epidemiological studies have examined the potential of perfluoroalkyls to
induce adverse health effects, most of the studies are cross-sectional in design and do not establish
causality. ATSDR evaluated the available epidemiological data to assess whether the preponderance ofthe evidence suggested a possible association between perfluoroalkyl exposure and a particular healtheffect. This approach took into consideration the consistency of the findings across studies, the quality ofthe studies, dose-response, and plausibility. It should be noted that although the data may provide
evidence for an association, it does not always imply that the observed effect is biologically relevant
because the magnitude of the change may be within the normal limits or not indicative of an adverse
health outcome. Plausibility depends primarily on experimental toxicology studies that establish a
plausible biological mechanism for the observed effects. ATSDR’s toxicological profile development
guidance (https://www.atsdr.cdc.gov/toxprofiledocs/additional_resources.html/#Profile_Development)
describes in detail the weight-of-evidence approach that includes quality assessment of every study
included in the profile.

The available epidemiological studies suggest associations between perfluoroalkyl exposure and several
health outcomes; however, cause-and-effect relationships have not been established for these outcomes:•

Hepatic effects. Increases in serum enzymes and decreases in serum bilirubin, observed instudies of PFOA, PFOS, and PFHxS, are suggestive of liver alterations. In addition, the results of
epidemiological studies of PFOA, PFOS, PFNA, and PFDA suggest an association between
perfluoroalkyl exposure and increases in serum lipid levels, particularly total cholesterol and LDLcholesterol; see Section 2.9 for detailed discussion and citations.

•

Cardiovascular effects. There is suggestive epidemiological evidence for an association
between serum PFOA and PFOS and pregnancy-induced hypertension and/or pre-eclampsia; see
Section 2.5 for detailed discussion and citations.

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2. HEALTH EFFECTS•

Immune effects. Evidence is suggestive of an association between serum PFOA, PFOS, PFHxS,and PFDA levels and decreased antibody responses to vaccines; there is also limited evidence for
PFNA, PFUnA, and PFDoDA; see Section 2.14 for detailed discussion and citations.

•

Developmental effects. Evidence is suggestive of an association between serum PFOA andPFOS and small decreases in birth weight; the decrease in birth weight is <20 g (0.7 ounces) per
1 ng/mL increase in blood PFOA or PFOS level; see Section 2.17 for detailed discussion andcitations.

As presented in Figures 2-3, 2-4, and 2-5, most of the available literature on the health effects ofperfluoroalkyls in laboratory animals was conducted in oral studies, with a few inhalation and dermal
exposure studies identified. The most commonly examined endpoints were liver, body weight,
developmental, reproductive, and immunological.

The results of the animal studies suggest the following:•

Hepatic effects. Evidence from acute, intermediate, and/or chronic oral studies in rats, mice, andmonkeys indicates that the liver is a sensitive target of PFOA, PFOS, PFHxS, PFNA, PFDA,PFUnA, PFBA, PFBS, PFDoDA, and PFHpA toxicity. The effects include increases in liver
weight, hepatocellular hypertrophy, and decreases in serum lipid levels. These effects wereconsidered specific to rodents and were not considered relevant to humans. Some degenerativeand necrotic effects that are likely relevant to humans have also been observed for PFOA, PFOS,
and PFHpA. See Section 2.9 for detailed discussion and citations.

•

Immune effects. Evidence from acute and intermediate oral studies in mice indicates that
immune endpoints are sensitive targets of PFOA and PFOS toxicity. The most commonly
reported effect was an impaired response to antigens. No alteration in antigen response wasobserved in the one study of PFNA. Immune function has not been tested for the otherperfluoroalkyls examined in this profile. See Section 2.14 for detailed discussion and citations.

•Reproductive effects. Impaired mammary gland development has been observed in mice orally
exposed to PFOA. In general, studies of PFOA and PFOS have not found alterations in fertility.
See Section 2.16 for detailed discussion and citations.

•

Developmental effects. Evidence from acute and intermediate oral studies in rats and/or miceindicates that developmental endpoints are targets of PFOA, PFOS, PFHxS, PFNA, PFDA,PFUnA, and PFBA toxicity. The developmental effects include decreases in pup body weight,
decreases in pup survival, and alterations in locomotor activity. See Section 2.17 for detailed
discussion and citations.

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Figure 2-1. Health Effect Endpoints Examined in Epidemiological Studies

FOSA = perfluorooctane sulfonamide; PFBA = perfluorobutanoic acid; PFBS = perfluorobutane sulfonic acid;
PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid;
PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid

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Figure 2-2. Health Effect Endpoints Examined in Laboratory Animal Studies

FOSA = perfluorooctane sulfonamide; PFBA = perfluorobutanoic acid; PFBS = perfluorobutane sulfonic acid;
PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid;
PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid

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30
2. HEALTH EFFECTS

Figure 2-3. Overview of the Number of Studies Examining PFOA Health Effects*
Developmental, hepatic, and body weight effects of PFOA were the most widely examined potential toxicity outcomesMore studies evaluated health effects in humans than animals (counts represent studies examining endpoint)*Includes studies discussed in Chapter 2. A total of 363 studies (including those finding no effect) have examined toxicity; most animal studies examined multiple
endpoints. In this figure, the number of human studies is referring to the number of publications; most human studies examined multiple endpoints.

PERFLUOROALKYLS

31
2. HEALTH EFFECTS

Figure 2-4. Overview of the Number of Studies Examining PFOS Health Effects*
Developmental, hepatic, and reproductive effects of PFOS were the most widely examined potential toxicity outcomesMore studies evaluated health effects in humans than animals (counts represent studies examining endpoint)*Includes studies discussed in Chapter 2. A total of 301 studies (including those finding no effect) have examined toxicity; most animal studies examined multiple
endpoints. In this figure, the number of human studies is referring to the number of publications; most human studies examined multiple perfluoroalkyls.

PERFLUOROALKYLS

32
2. HEALTH EFFECTS

Figure 2-5. Overview of the Number of Studies Examining Other Perfluoroalkyls Health Effects*
Developmental, hepatic, and body weight effects of other perfluoroalkyls were the most widely examined potential toxicity outcomesMore studies evaluated health effects in humans than animals (counts represent studies examining endpoint)*Includes studies discussed in Chapter 2. A total of 213 studies (including those finding no effect) have examined toxicity; most animal studies examined multiple
endpoints. Most human studies examined multiple perfluoroalkyls; within each publication, the results for each perfluoroalkyl is counted as a study.

PERFLUOROALKYLS

33
2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to PFOA – Inhalation
SpeciesFigure (strain)
Exposure
Doses
keya No./group parameters (mg/m3)
ACUTE EXPOSURE
1

Rat(albino)5 M,F

1 hour(NS)

18,600Parameters
monitored Endpoint

NOAEL(mg/m3)Less
serious
LOAEL(mg/m3)

Serious
LOAEL(mg/m3)

EffectCS, BW, GN, Resp
HP
Ocular

18,600Red nasal discharge; dry rales

18,600Red material around the eyes; lacrimation

Neuro

18,600

Excessive salivation

Griffith and Long 1980
APFO
2

Rat
(CD)
36 M

4 hours

380, 810, CS, HE, BI,
830, 2,200, GN, HP
4,800,
5,700

Death
Bd wt

980 M
380 M

Resp
GastroHepatic

380 M
810

Ocular

380 M

Bd wt

7.6

Resp

84

CardioGastroHematoMusc/skel
Hepatic

84
84
84
84
84

Renal
DermalOcular
Endocr
Neuro
Repro

84
84
84
84
84
84

380 M

810 M

LC50
Weight loss for 1–2 days after exposure(data not shown)
Pulmonary edema
Stomach irritation
Liver enlargement at 810 mg/m3; nohistological alterations
Corneal opacity and corrosion

Kennedy et al. 1986
APFO
3

Rat
(CD)
24 M

2 weeks
0, 1, 7.6,
6 hours/day 84
5 days/week

Kennedy et al. 1986
APFO

CS, HE, BI,
GN, HP84

7% lower body weight on exposure day 5

Increased absolute and relative liver weight;
hepatocellular hypertrophy at 7.6 mg/m3

No histological alterations
No histological alterations

PERFLUOROALKYLS

34
2. HEALTH EFFECTS

Table 2-1. Levels of Significant Exposure to PFOA – Inhalation
SpeciesFigure (strain)
Exposure
Doses
keya No./group parameters (mg/m3)
4Rat(SpragueDawley)
12 F

GDs 6–15
6 hours/day

0, 0.1, 1,
10, 25

Parameters
monitored Endpoint
MX, DX, OW, Death
CS, HP
Bd wt

NOAEL(mg/m3)
1

Hepatic

25

Develop10

Less
serious
LOAEL(mg/m3)10

25

Serious
LOAEL(mg/m3)

Effect25

3/12 deaths on GDs 12, 13, and 17
12% decrease weight gain on GDs 6–15
18% increase absolute liver weight at
25 mg/m3
10% decreased neonatal body weight on
PND 1

Staples et al. 1984
APFO
aThe number corresponds to entries in Figure 2-6.

APFO = ammonium perfluorooctanoate (ammonia salt of PFOA); BI = biochemical changes; BW or Bd wt = body weight; F = female(s); Cardio = cardiovascular;
CS = clinical signs; Develop = developmental; DX = developmental toxicity; Endocr = endocrine; Gastro = gastrointestinal; GD = gestation day; GN = gross
necropsy; HE or Hemato = hematological; HP = histopathology; LC50 = lethal concentration, 50% kill; LE = lethality; LOAEL = lowest-observed-adverse-effectlevel; M = male(s); Musc/skel = musculoskeletal; MX = maternal toxicity; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified;
OW = organ weight; PFOA = perfluorooctanoic acid; PND = postnatal day; Repro = reproductive; Resp = respiratory

PERFLUOROALKYLS

35
2. HEALTH EFFECTS

Figure 2-6. Levels of Significant Exposure to PFOA – Inhalation
Acute (≤14 days)

PERFLUOROALKYLS

36
2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to Other Perfluoroalkyls – Inhalation
SpeciesFigure (strain)
keya
No./group

Exposure
parameters

Doses(mg/m3)

Parameters
monitored Endpoint

NOAEL(mg/m3)Rat
4 hours(CD)
6M
Kinney et al. 1989
Exposure was nose-only.

67–4,600

LE

Death

2

0, 67, 590

BW, OW

Bd wt
Resp

67
67

Hepatic

67

Less
serious
LOAEL(mg/m3)

Serious
LOAEL(mg/m3)

Effect820

14-day LC50ACUTE EXPOSURE
PFNA
1

Rat
(CD)
10 M

4 hours

590
590

Reduced 18% 5 days after exposure
Lung noise; labored breathing during andafter exposure
28% increase in absolute liver weight 5 days
after exposure to ≥67 mg/m3

Kinney et al. 1989
Exposure was nose-only.
aThe number corresponds to entries in Figure 2-7.

BW or Bd wt = body weight; LC50 = lethal concentration, 50% kill; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s);NOAEL = no-observed-adverse-effect level; OW = organ weight; PFNA = perfluorononanoic acid; Resp = respiratory

PERFLUOROALKYLS

37
2. HEALTH EFFECTS

Figure 2-7. Levels of Significant Exposure to Other Perfluoroalkyls – Inhalation
Acute (≤14 days)

PERFLUOROALKYLS

38
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
ACUTE EXPOSURE
1

Monkey(Rhesus)10 M,F
Griffith and Long 1980
APFO

2 weeks(G)0, 3, 10, 30,
100

LE, CS, HE,
BI, GN, HP

Death

2

Rat
(CD)
10 M
Biegel et al. 1995
APFO

14 days
(GW)

0, 25

BI, OW

Repro

3

14 days(GW)0, 1, 10, 25,
50

BW, OW, BI, Bd wt
HP
Hepatic

10

Repro

1

0, 18, 23

Hepatic

23

100, 215,
464, 1,000,
2,150

Death

Rat
(CD)
75 M

100

Unspecified number out of four
died on week 2

25184% increase in serum estradiol

25

14% reduction in final body weight

10

46% increase in relative liver
weight at ≥10 mg/kg/day
63% increase in serum estradiol

50

Cook et al. 1992
APFO
4

Rat
1 or 7 days
(Sprague-Dawley) (F)18 M

Increased liver weight, decreased
serum cholesterol, triglyceride,
hepatocellular hypertrophy at≥18 mg/kg/day

Elcombe et al. 2010
APFO
5

Rat
(albino)25 M,F
Griffith and Long 1980
APFO

Once
(GO)

680 M
430 F

LD50
LD50

PERFLUOROALKYLS

39
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect6

Rat(albino)40 M,F

28 days(F)

M: 0, 3, 10,30, 10, 300,
1,000, 3,000;
F: 0, 3.4,
11.3, 34, 113,
340, 1,130,
3,400

7 daysad lib
(F)

0, 16

Death

1,000 M
1,130 F

5/5 males and 5/5 females died
before end of 1st week of study

Griffith and Long 1980
APFO
7

Rat
(Wistar)8M

BW, OW, BI, Bd wt
EA

16

Hepatic

16

66% increase in absolute liver
weight45% increase in relative liver
weightHaughom and Spydevold 1992
APFO
8

Rat (SpragueDawley)
3M

14 days(F)

0, 20

OW, EA

Hepatic20

14 days(GW)0, 0.5, 5, 50

BW, OW, CS, Bd wt
HE, BI
Hepatic50
50

2-fold increased mean relative liver
weight at 50 mg/kg/day

Immuno50

No alterations in spleen weight or
splenocyte phenotype

Ikeda et al. 1985
PFOA
9Rat (SpragueDawley)
16 M

Iwai and Yamashita 2006APFO

PERFLUOROALKYLS

40
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect10

Rat(Wistar)5–12 M

Once
(GO)

0, 50

BW, FX

BW

50

Neuro

50

BW, OW, EA, Bd wt
HP
Hepatic

38

BW, OW, BC Bd wt

1

No alteration in performance on
novel object recognition test

Kawabata et al. 2017
PFOA
11

Rat
(Wistar)
30 M

1 week(F)

0, 1.2, 2.4,
4.7, 9.5

9.5

Significant increase in absolute andrelative liver weight at≥4.7 mg/kg/day

Kawashima et al. 1995
PFOA
12

Rat
(SD-IGS BR)
10 M

14 days(GW)0, 0.3, 1, 3,
10, 30,Hepatic

30

0, 0.2, 2, 20, BW, OW, EA Bd wt
40
Hepatic

2

3

24% decrease in overall bodyweight gain
Decreased serum cholesterollevels at ≥0.3 mg/kg/day

Loveless et al. 2006
APFO
13

Rat
(CD)
15 M

14 days
(G)

Repro

20

14% lower final body weight2

34% increase in absolute andrelative liver weight at≥2 mg/kg/day
2-fold increase in serum estradiol

50

17% weight loss

40

0.2

Liu et al. 1996
APFO
14

Rat
1, 3, 7 days 0, 50(Sprague-Dawley) (GW)
24 M

Pastoor et al. 1987
APFO

BW, BI, EA,
HP

Bd wt
Hepatic50

2-fold increase in relative andabsolute liver weightPERFLUOROALKYLS

41
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
15

Rat
GDs 6–15(Sprague-Dawley) (GO)12 or 25 F

0, 100DX, MX, BW Bd wt
Develop100
100

33% reduced maternal body weightgain
No alterations in fetal body weightor teratology

Staples et al. 1984
APFO
16

Mouse
(Kunming)
12 F

GDs 1–7 or 0, 2.5, 5, 10
13(GW)

BC, OW, RX Repro

Develop

5

Bd wt

10

Hepatic

10

Immuno7.5

2.5

Decreases in progesterone levels
at ≥5 mg/kg in GD 13 group;
increased serum estradiol level at
10 mg/kg/day on GD 7; decreases
in number of corpora lutea at≥2.5 mg/kg/day in GD 1–7 groups
and at ≥5 mg/kg/day in GD 13
groups10

Increased resorbed embryos at
10 mg/kg/day in GD 13 group

Chen et al. 2017b
PFOA
17

Mouse
7 days(SV129 wild type) (G)
4M

0, 10

BW, HP

Hepatocellular hypertrophy,
steatosis, and increased hepatic
triglyceride levels

Das et al. 2017
PFOA
18

Mouse
(C57BL/6N)
6F
DeWitt et al. 2009
PFOA

10 days(W)0, 3.75, 7.5,
15

FX

15

Altered response to sRBC

PERFLUOROALKYLS

42
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
19

Mouse
(CD)
40 M,F

28 days(F)

M: 0, 5.4,
18.0, 54, 180,
540, 1,800,
5,400; F: 0,
5.8, 19.5, 58,
195, 580,
1,950, 5,800

Death

GDs 6–17(DW)0, 0.5, 1

Bd wt

180 M
195 F

5/5 died before 2nd week of study
5/5 died before 2nd week of study

Griffith and Long 1980
APFO
20

Mouse
(C57BL/6N)
16 F

1

Develop0.5

7–10% decrease in litter weight on
PND 2

Hu et al. 2010
APFO
21

Mouse
Once
0, 0.58, 8.70 CS, OF, DX Develop
0.58
Decreased spontaneous activity(CD-1)(G)and altered response to cholinergic
10 M
stimulant
Johansson et al. 2008
APFO
10-day-old mice were administered a single dose of PFOA; neurodevelopmental testing was conducted when the pups were 2 or 4 months of age
22

Mouse
(CD-1)
5 M,F
Kennedy 1987
APFO

14 days(F)0, 5.3, 54,
537

OW

23

14 days(GW)0, 0.3, 1, 3,
10, 30,

BW, OW, BC Bd wt

Mouse(CD-1)
10 M

Loveless et al. 2006
APFO

Hepatic

Hepatic537

330

123–155% increase in absolute
liver weight in 14 days at≥5.3 mg/kg/day

10

6–12% decreased in body weightgain
Decreased serum cholesterollevels at ≥0.3 mg/kg/dayPERFLUOROALKYLS

43
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
24

Mouse
(C57BL/6N)
3M

2–10 days(F)

0, 78, 390

BW, OW, EA Bd wt
Hepatic

78

25% body weight loss after 10 daysof treatment
74% increase in absolute liver
weight at ≥78 mg/kg/day

78

25% body weight loss after 5 daysof treatment
74% increase in absolute liver
weight in 5 days at ≥78 mg/kg/day390

Permadi et al. 1992
PFOA
25

Mouse
(C57BL/6N)
4M

2–10 days(F)

0, 78, 390

BW, OW, EA Bd wt
Hepatic

390

Bd wt

2

Hemato2

Hepatic

2

Immuno2

Permadi et al. 1993
PFOA
26

Mouse (C57BL/6) 10 days
4M
(F)

0, 2

BW, FI, BC,HP

68% increase in liver weight,
hepatocellular hypertrophy, anddecreased serum cholesterol levels

Qazi et al. 2010a
PFOA
27

Mouse
(BALB/c)
5F

7 days(GW)

20

BW, OW, BC Bd wt
Hepatic
ImmunoVetvicka and Vetvickova 2013
PFOA

20
20

36% decrease in body weight gain
32% increase in relative liver
weight20

Inhibition of T-and B-lymphocyte
proliferation in response to sRBC;
decreased phagocytosis byperipheral blood cells and NK cell
activity; decreased IgM antibody
formation in response to OVA

PERFLUOROALKYLS

44
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
28

Mouse
(CD-1)
14 F
White et al. 2007
APFO

GDs 8–17
GDs 1217
(GW)

0, 5

29

GDs 8–17
(GW)

0, 5

Mouse
(CD-1)56 F

DX, GN

Develop

5

Bd wt

5

Hepatic

5

Altered mammary glanddevelopment in female pups;
reduced pup weight on PND 20

40–120% increased relative liver
weight in lactating dams on
PNDs 1–10

Repro

5

Immature mammary glandmorphology in lactating dams on
PNDs 1–10

Develop

5

Delayed mammary glanddevelopment (30–60%) in female
pups on PNDs 1–10

Develop

5

Delayed mammary glanddevelopment (31–47%) in female
pups on PNDs 22–32 and at
18 months

White et al. 2009
APFO
30

Mouse
(CD-1)
12–14 FGDs 7–17
0, 5
GDs 10–17
GDs 13–17
GDs 15–17

White et al. 2009
APFO
31

Mouse
(CD-1)
6–14 FGDs 7–17, 0, 5, 20
GDs 10–17
GDs 13–17
GDs 15–17(GW)

DX, MX, BW, Bd wt
OW
Hepatic

Develop

Wolf et al. 2007
APFO

20

No alterations in dams dosed on
GDs 15–17

20

Increase in relative liver weight indams dosed on GDs 13–17, 10–17,
or 7–17 at ≥5 mg/kg/day
5

Reduced pup body weight at
weaning, 43% in males and 35% infemalesPERFLUOROALKYLS

45
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
32

Mouse
(C57BL/6N)
8M

7 days(F)

0, 24

CS, BW, OW, Bd wt
BI

24

Hepatic

24

BW, OW, BI, Bd wt
CS
Hepatic30>10% reduced final body weight2-fold increase in absolute liver
weightXie et al. 2003
PFOA
33

Mouse
(C57BL/6N)
8M

10 days
(F)

0, 30

30

17% decrease in final body weight>90% increase in absolute andrelative liver weight

Immuno30

86% reduction in absolute thymus
weight; 30% reduction in absolute
spleen weight

Yang et al. 2000
PFOA
34

Mouse
(C57BL/6N)
8M

10 days(F)0, 1, 3.5,
11.5, 23, 58

CS, BW, OW, Hepatic
OF, BI1

35% increase in absolute liver
weight at ≥1 mg/kg/day

Immuno11.5

40–50% decrease in spleen andthymus weights

Yang et al. 2001
PFOA
35

Mouse
(C57BL/6N)
8–12 M
Yang et al. 2002a
PFOA

7 days(F)

0, 24

CS, BW, BI,OF

Immuno24

Decreased humoral response to
immunization with horse red blood
cells

36

7 daysad lib
(F)

0, 33

BW, OW, BI, Bd wt
OF
Hepatic

33

14% decreased mean body weight

Mouse(C57BL/6N)
16 M

Immuno33

86% increase in absolute liver
weight33

Yang et al. 2002b
PFOA
Experiments with PPARα-null mice suggested PPARα-dependent and -independent immune effects

40% reduction in spleen weight and
79% reduction in thymus weightPERFLUOROALKYLS

46
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect37

Rabbit(New Zealand)
18 F
Gortner et al. 1982
PFOA

GDs 6–18
1 time/day(GW)0, 1.5, 5, 50

CS, MX, DX, DevelopBW500, 3, 10,
30/20

BC, BW, CS, Bd wt
EA, FI, GN, Resp
HE, HP, LE,
OP, OW, UR Cardio
Gastro10

Hemato20

INTERMEDIATE EXPOSURE
38

Monkey(Cynomolgus)
4–6 M

26 weeks
1 time/day(C)

20

12% decrease by week 103

36% increase in absolute liver
weight at ≥3 mg/kg/day; increased
serum triglyceride levels at
30/20 mg/kg/day

10

Significant decrease in serum TT4(27–35%) and FT4 (30–38%)
No histological alterations
No histological alterations
No histological alterations

20
20
20

Musc/skel 20
Hepatic

Butenhoff et al. 2002
APFO

Renal

20

Dermal20

Ocular
Endocr20
3

Immuno
Neuro
Repro

20
20
20

PERFLUOROALKYLS

47
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) EffectMonkey90 days0, 3, 10, 30, LE, CS, HE, Death30
One male and two females died39
(Rhesus)10 M,F

1 time/day
(G)

100

BI, GN, HP

during weeks 7–12
Bd wt

10

Cardio10

Gastro10

Hemato30

Hepatic

10

Renal

10

Immuno30

33% body weight loss by week 630

Emesis

10

30

Neuro

10

30

Atrophy of lymphoid follicles in
spleen and lymph nodes
Hypoactivity and prostration

Repro

100

Bd wt

20

Hemato20

Hepatic

20

Endocr

20

Repro

20

No histological alterations in testes
or ovaries

Griffith and Long 1980
APFO
40

Monkey(Cynomolgus)
8M

Thomford 2001
APFO

30 day1 time/day(C)0, 2, 20

CS, BW, FI,
BI, HE, EA,
GN, HP

No alterations in serum levels of
thyroid hormones and TSH andhistopathology of adrenals
No alterations in serum estradiol,
estriol, or histopathology of thetestesPERFLUOROALKYLS

48
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
41

Rat
(CD)
156 M

1 yearad lib(F)

0, 13.6

CS, BW, FI, Bd wt
OW, GN, HP Hepatic

13.6>10% reduced weight gain

13.6

Repro

Increased relative liver weight
13.6

Significant increase in serum
estradiol at 1, 3, 6, 9, and12 months (~100–180%); prolactin
was decreased at all time points,
but not always significantly

310>11% reduced body weight

1

3

Increased absolute and relative
liver weight in P-generation (36%)
and F1-generation (30%) males;
hepatocellular hypertrophy and lesscommonly necrosis in F1 males(incidence not reported)3

Increased absolute and relative
kidney weight in P-generation(14%) and F1-generation (11%)
males

30

Vacuolation of zona glomerulosa of
adrenal glandNo alteration in reproductive
performance in P0 or F1 generation
Increased number of dead pups on
PNDs 6–8

Biegel et al. 2001
APFO
42

Rat
70–90 days 0, 1, 3, 10, 30 MX, DX, OF, Bd wt(Sprague-Dawley) 1 time/day
BW, GN, HP Hepatic
30 M,F(GW)

Renal

Endocr

10

Repro

30

Develop1030

Butenhoff et al. 2004b
APFO
43

Rat
(Wistar)
5F

Cheng et al. 2013
PFOA

GD 1 toPND 21ad lib(W)0, 1.6Develop1.6

17–18% reduced motor
coordination and increased
locomotor activity in pups on
PNDs 34–35

PERFLUOROALKYLS

49
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
44

Rat
Daily
(Sprague-Dawley) 28 days
10 M
(G)

0, 5, 20

OW, HP

Resp

5

Hepatic

5

Cytoplasmic vacuolization,
necrosis, hypertrophy, increased
liver weight at ≥5 mg/kg/day; fatty
degeneration, angiectasis andcongestion in the hepatic sinusoid
or central vein at 20 mg/kg/day

Neuro

5

Cachexia and lethargy

0, 18Hepatic

18

Increased liver weight (43% on
day 29), decreased serum
cholesterol (39% on day 29) andtriglyceride (73% on day 29),
hepatocellular hypertrophy andhyperplasia

M: 0, 3, 10,
BW, FI, HP
30, 100, 300,
1,000, 3,000;
F: 0, 3.4,
11.3, 34, 113,
340, 1,130,
3,400

Bd wt

10 M

Hepatic

3M

M: 0, 1, 3, 10, CS, BW, FI,
30, 100; F: 0, HE BI, GN,
1.1, 3.4, 11, HP, OW
34, 110

Bd wt

30 M
110 F

Resp

100 F

Cardio110 F

Gastro110 F

Cui et al. 2009
PFOA
45

Rat
28 days(Sprague-Dawley) (F)
10 M

Elcombe et al. 2010
APFO
46

Rat
(CD)
40 M,F

28 daysad lib
(F)

30 M

100 M

30 mg/kg/day: 11% reduction in
final body weight; 100 mg/kg/day:
33% reduction in final body weightHepatocyte hypertrophy

Griffith and Long 1980
APFO
47

Rat
(CD)
30 M,F90 daysad lib
(F)

100 M

33% reduction in final mean bodyweightMusc/skel 110 F
Hepatic

100 M

Renal

110 F

Hepatocyte hypertrophy; 50%
increase in absolute liver weightPERFLUOROALKYLS

50
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) EffectDermal110 F

Ocular
EndocrImmuno
Neuro
Repro

110 F
110 F
110 F
110 F
100 M
110 F

Bd wt

0.96

Hemato29

Hepatic

0.29

Immuno29

No histological alterations
No histological alterations

Griffith and Long 1980
APFO
48

Rat
(CD)
10 M

28 days(G)0, 0.29, 0.96,
9.6, 299.6

10% decrease in final body weight29

34% decrease in serum triglyceride
levels, minimal hepatocellular
hypertrophy at ≥0.29 mg/kg/day;minimal focal necrosis at
29 mg/kg/day

Loveless et al. 2008
APFO
49

Rat
(CD)
55 M

Perkins et al. 2004
APFO

13 weeks
ad lib(F)

0, 0.06, 0.64, CS, BW, FI, Bd wt
1.94, 6.5
OW, GN, HP Resp

6.5
6.5

Hepatic

6.5

Neuro
Repro

6.5
6.5

Minimal to moderate hepatocellular
hypertrophy at ≥0.64 mg/kg/day
No histological alterations
No histological alterations

PERFLUOROALKYLS

51
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
50

Mouse
(129S1/SvlmJ
WT)
17 F

GDs 1–17(GW)0, 0.1, 0.3,
0.6, 1, 3, 5,
10, 20MX, DX, BW Bd wt

10 F

Hepatic20

Develop

0.3

Hepatic

3

Increased absolute and relative
liver weight of dams on PND 22 at≥1 mg/kg/day
0.6

Significantly reduced pup survival(46%) from birth to weaning

Abbott et al. 2007
APFO
Body weight NOAEL is for changes during pregnancy.
51

Mouse
GDs 1–17(wild-type Sv/129) 1 time/day
5–6 F
(GW)

0, 3

28% increased liver weight,
hepatocellular hypertrophy withincreased peroxisomes

Develop3

31.5% reduced pups per litter on
PND 2015

Weight loss (~5%)

Albrecht et al. 2013
PFOA
52

Mouse
(C57BL/6N)
8F

15 daysad lib(W)0, 0.94, 1.88, BW, OW, OF Bd wt
3.75, 7.5, 15,
Immuno
30

7.5
1.88

3.75

Reduced sRBC-specific response
to IgM antibody titers30

14–20% decrease in body weight inwild-type mice30

16 and 14% reduction in sRBCspecific antibody response in wildtype and PPARα knockout mice,
respectively; 29.8% decrease inrelative spleen weight in wild-type
mice

DeWitt et al. 2008
APFO
53

Mouse
15 days(wild-type(W)
C57BL/6-Tac andPPARα knockout)
8F

DeWitt et al. 2016
PFOA

0, 7.5, 30

BW, OW, BC Bd wt
Immuno7.5

PERFLUOROALKYLS

52
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
54

Mouse
(C57BL/6N)
8F

15 days(W)0, 0.94, 1.88, BW, OW, BC Bd wt
3.75, 7.5
Immuno7.5

10, 13,15 days(W)0, 3.75, 7.5

BC

Bd wt

7.5

GDs 1–17(GW)0, 0.01, 0.1,
0.3, 1, 5

HP

Hepatic

0.3

0.94

1.88

Decrease in DNP-specific IgM
antibody responses; decreases inrelative spleen (17%) and thymus
weights (14%) at 7.5 mg/kg/day

1

Increase in severity of chronic
inflammation at ≥1 mg/kg/day; Itocell hypertrophy and centrilobular
hepatocellular hypertrophy at
5 mg/kg/day

DeWitt et al. 2016
PFOA
55

Mouse
(C57BL/6N)
8F

DeWitt et al. 2016
PFOA
56

Mouse
(CD-1)
6–14 dams; 21–
37 F offspring

Filgo et al. 2015a, 2015b
PFOA
Animals exposed in utero on GDs 1–17 and examined at 18 months of age; the offspring were also examined by Hines et al. 2009
57

Mouse
GDs 1–17
0, 0.1, 0.3,
HP
Hepatic
1
Increased severity of centrilobular(129/Sv WT)(GW)
0.6, 1
hepatocyte hypertrophy at
3–7 dams; 6–10 F≥0.3 mg/kg/day
offspring
Filgo et al. 2015a, 2015b
PFOA
Animals exposed in utero on GDs 1–17 and examined at 18 months of age; the offspring were also examined by Abbott et al. 2007
58

Mouse
GDs 1–17
0, 0.1, 0.3, 1, HP
Hepatic
1
3
Centrilobular hepatocyte(129/Sv PPARα- (GW)3hypertrophy and bile ductknockout)
hyperplasia at 3 mg/kg/day
5–9 dams; 6–10 F
offspring
Filgo et al. 2015a, 2015b
PFOA
Animals exposed in utero on GDs 1–17 and examined at 18 months of age; the offspring were also examined by Abbott et al. 2007

PERFLUOROALKYLS

53
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
59

Mouse (CD-1)
NS F

GDs 1–17(GW)0, 0.1, 0.3, 1 NX

Develop

28 daysad lib(F)

M: 0, 5.4,
BW, FI, HP
18.0, 54, 180,
540, 1,800,
5,400; F: 0,
5.8, 19.5, 58,
195, 580,
1,950, 5,800

Death

Develop

0.3

1

Increased ambulatory activity anddecreased methamphetamineinduced activity

Goulding et al. 2017
PFOA
60

Mouse
(CD)
40 M,F

Bd wt

Hepatic

5.4 M

18

54 M
58 F

4/5 died before end of 4th week
5/5 died before 4th week of study

5.8 F

Males: final body weight 20% lower
than controls; females: final bodyweight 25% lower than controls
3-fold or greater increased absoluteand relative liver weight andhepatocellular hypertrophy at ≥5.4
mg/kg/day

Griffith and Long 1980
APFO
61

Mouse
(CD-1)
5–14F
Hines et al. 2009
APFO

GDs 1–17(GW)0, 0.01, 0.1,
0.3, 1, 3, 562

21 daysad lib(F)

0, 0.0018,
OW
0.0054,0.018, 0.054,
0.18, 0.54,
1.8, 5.4

Mouse(CD-1)
5 M,F

BW FX

Hepatic

5F

5.4

Decreased birth weight(approximately 8%) and bodyweight at weaning (24%)

39–41% increase in absolute liver
weight at ≥5.4 mg/kg/day

Kennedy 1987
APFO
63

Mouse
GDs 1–21
0.3(C57BL/6)(F)
10 F
Koskela et al. 2016
PFOA
Offspring were examined at 13 and 17 months of age

BW, DX

Develop

0.3b

Altered femur and tibial bonemorphology, decreased tibial
mineral density

PERFLUOROALKYLS

54
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
64

Mouse
(CD-1)
9–45 MGDs 1–17
1 time/day(GW)0, 1, 3, 5, 10, MX, DX, BW, Bd wt
20, 40OW
Hepatic

510

1Develop32% reduced weight gain during
pregnancy
38% increase in absolute liver
weight at ≥1 mg/kg/day

1

5

Reduced ossification of proximal
phalanges and advanced preputial
separation at ≥1 mg/kg/day; 20%
decrease in pup body weight on
PND 23 at ≥3 mg/kg/day; increased
number of dams with full litter
resorptions, decrease in neonatal
survival, tail and limb defects, delay
in eye opening, and delay in first
estrus at ≥5 mg/kg/day

9.6

Weight loss (86% of controls)

Lau et al. 2006
APFO
65

Mouse
(CD)
20 M

28 days(G)0, 0.29, 0.96,
9.6, 29

Bd wt

0.96

Hepatic

0.29

0.96

Mild hepatocellular hypertrophy at≥0.29, moderate to severe
hypertrophy and single cell
necrosis at ≥0.96 mg/kg/day;decreased serum cholesterol (31%)
and triglyceride (53%) at ≥9.6
mg/kg/day

Immuno0.96 M

9.6 M

Decreased response to sRBC,
decreased number of splenic andthymic lymphocytes

0.3

Impaired development of mammary
glands in offspring

Loveless et al. 2008
APFO
66

Mouse
(CD-1)
13 F
Macon et al. 2011
PFOA

GDs 1–17(G)0, 0.3, 1.0,
3.0

DXDevelopPERFLUOROALKYLS

55
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
67

Mouse
(CD-1)
13 F
Macon et al. 2011
PFOA

GDs 10–17 0, 0.01, 0.1,
(G)
1.0

DX

Develop

68

Mouse(C57BL/6JApc+/+)
20–21 F
Ngo et al. 2014
PFOA

GDs 1–17(GW)0, 0.01, 0.1,
3.0

BC, BW, FI,
HE, OW

Develop69

GDs 1–21
ad lib(F)

0, 0.3

Mouse(C57BL/6/
Bk1)
6 M, 10 F

0.01

Developmental delays in mammary
gland development3

Decrease in number of successful
birthsDevelop

0.3

Altered exploratory behavior inadult offspring (increased in males
and decreased in females);increased global activity in males

Hepatic

0.01

Increased severity of hepatocellular
hypertrophy at PND 91 andperiportal inflammation on PND 21
at ≥0.01 mg/kg/day (incidence was
not reported); decreased serum
total cholesterol, LDL, and HDLlevels in high-fat fasted animals on
PND 91 at ≥0.3 mg/kg/day

0.1

Onishchenko et al. 2011
PFOA
70

Mouse
GDs 1–17(CD-1)(GW)
17–21 F dams; 4–
6 M,F pups

0, 0.01, 0.1,
0.3, 1

BI, BW, HP,
OF, OW

Quist et al. 2015a, 2015b
PFOA
Subgroup of female offspring were fed a high-fat diet (50% calories from diet) for 6 weeks
71

Mouse
(C57BL/6)
6 M,F

Rebholz et al. 2016
PFOA

6 weeks(F)

0.55

BC, BW, FI,OWHepatic

0.55

66–67% increase in relative liver
weight in males; increased plasmacholesterol levels in males (35%)
and females (70%)

PERFLUOROALKYLS

56
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
72

Mouse
(BALB/c)
6 M,FRebholz et al. 2016
PFOA

6 weeks(F)

0.55

BC, BW, FI,OWHepatic

73

GD 7 toPND 21(F)

0, 0.1

BH, BW

Develop

21 daysad lib(W)0, 0.5, 2.6,
18, 47

BW, OW, GN, Bd wt
HP
Hepatic

Mouse(C57BL/6)
6F

0.55

54–65% increase in relative liver
weight; 20% increase in plasmacholesterol in males

0.1

Increased horizontal andambulatory locomotor activity anddecreased resting time in males;
decrease in novel object
recognition in males and females

Sobolewski et al. 2014
PFOA
74

Mouse
(ICR)
10 M

Renal

2.6
18

18

17% decrease in weight gain

47

27% increase in relative liver
weight at ≥0.5 mg/kg/day;increases in ALT at≥2.6 mg/kg/day; hepatocytomegalyat 18 mg/kg/day; necrosis at
47 mg/kg/day

47

Son et al. 2008
APFO
75

Mouse
(ICR)
10 M
Son et al. 2009
PFOA

21 days(W)0, 0.49, 2.64, FX HP
17.63, 47.21

Immuno47.21

Marked hyperplasia in spleen white
pulp and thymic atrophy

76

3 weeks(F)0, 5

Hepatic

5

Hepatocellular hypertrophy anddegeneration

Mouse(C57BL/6N)
7–8 M
Tan et al. 2013
PFOA

HP

PERFLUOROALKYLS

57
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
77

Mouse
(CD-1)
4–12 F
Tucker et al. 2015
PFOA

GDs 1–17(GW)0, 0.01, 0.1,
0.3, 1.0

BW, DX, OW Develop

78

Mouse
(C57BL/6)
2–6 F
Tucker et al. 2015
PFOA

GDs 1–17(GW)0, 0.01, 0.1,
0.3, 1.0

BW, DX, OW Develop

79

GDs 1–17
0, 5
GDs 8–17
1 time/day
GDs 12–17(GW)

MX, DX, GN, Repro
HP

80

Mouse
(CD-1)
14 F
White et al. 2007
APFO

GDs 1–17
1 time/day
(GW)

0, 5

DX, GN81

Mouse(CD-1)
28–48 FWhite et al. 2009
APFO

GDs 1–17
1 time/day(GW)0, 3, 5Develop

3

Delayed mammary glanddevelopment in female pups on
PNDs 22–63 and at 18 months82

GDs 1–17
1 time/day(GW)0, 1, 5

Repro

1

Delayed mammary glandlactational differentiation in dams
on PND 22

Mouse(CD-1)
14–16 F

0.1

0.01

Developmental delays in the
mammary glands on PNDs 35(26%) and 56 (30%)

0.3Developmental delays in the
mammary glands on PNDs 21(38%) and 61 (25%)

5Delayed mammary glanddifferentiation

White et al. 2007
APFO

Mouse
(CD-1)
10–12 F

Develop

DevelopWhite et al. 2011
APFO

5

1

5

Increased prenatal loss; 40%
reduced neonatal body weight on
PNDs 5 and 10

323% increased prenatal loss,
16.7% decreased live fetuses,
24.3% decreased neonatal survival

PERFLUOROALKYLS

58
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
83

Mouse
(CD-1)
10–12 FGDs 1–17
0, 0.0024,
1 time/day 1.0024(GW)
GD 7 toPND 22(W);
3-generation
study

Repro

0.0024

Delayed mammary glandlactational differentiation in dams
on PND 22

Develop

0.0024

Delayed mammary glanddevelopment in female pups on
PNDs 22–63

White et al. 2011
APFO
84

Mouse
(CD-1)
28–48 FGDs 1–17
1 time/day(GW)0, 3, 5CS, BW, MX, Bd wt
DX, OW
Hepatic

55Develop

Significant increase in relative andabsolute maternal liver weight on
PND 22 at ≥3 mg/kg/day
3

5

3 mg/kg/day: reduced weight gain
through lactation (14.8% in males
and 20.6% in females); delayed
eye opening and hair growth at≥3 mg/kg/day; decreased pup
survival from birth to weaning at
5 mg/kg/day

Wolf et al. 2007
APFO
85

Mouse
(ICR)
5–10 F

Yahia et al. 2010
PFOA

GDs 0–17 or 0, 1, 5, 10
GDs 0–18(GW)

BW, FI, WI, Hepatic
OW, HP, DX

1

Renal

1

Develop1

10

35% increased maternal relative
liver weight with hepatocellular
hypertrophy at ≥1 mg/kg/day;single cell necrosis and mild
calcification at 10 mg/kg/day
35% increased maternal relative
kidney weight with renal
hypertrophy
514% increased neonatal mortality,
9.5% reduced fetal body weightPERFLUOROALKYLS

59
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect86

Mouse (BALB/c)
5F

5 days/week 0, 1, 5, 10
4 weeks
starting at
PND 21(GW)

BW, OW, HP Bd wt

Mouse (C57BL/6)) 5 days/week 0, 1, 5, 10
5F
4 weeks
starting at
PND 21(GW)

BW, OW, HP Bd wt

Hepatic

510

10Develop13% decrease in body weight gain
Increases in liver weight andhepatocellular hypertrophy at≥1 mg/kg

1

Delay in vaginal opening at
1 mg/kg and mammary gland
growth inhibition at 5 and 10 mg/kg

1010% decrease in body weight gain

Yang et al. 2009
PFOA
87

5

Hepatic10Develop

1

Increases in liver weight andhepatocellular hypertrophy at≥1 mg/kg
5

Delay in vaginal opening at
5 mg/kg and mammary gland
growth stimulation a 5 mg/kg andinhibition at 10 mg/kg

Yang et al. 2009
PFOA
88

Mouse (C57BL/6)) 5 days/week 0, 5
2–5 F
4 weeks(GW)
Zhao et al. 2010
PFOA

BC

Repro

5

Increased progesterone levels

Mouse (PPARαknockout)
NR F
Zhao et al. 2010
PFOA

HP

Develop5

Mammary gland growth stimulation89

5 days/week 0, 5
4 weeks(GW)

PERFLUOROALKYLS

60
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
CHRONIC EXPOSURE
90

Rat
(CD)
156 M

2 years
ad lib(F)

0, 13.6

CS, BW, FI, Bd wt
OW, GN, HP
Hepatic

13.6>10% reduction in weight gain
most of the study

13.6

Increased relative liver weight

Repro

13.6

Increased incidence of Leydig cell
hyperplasia; elevated serum LH at
18 months

Othernoncancer

13.6

Increased incidence of acinar cell
hyperplasia in pancreas

Cancer

13.6

CEL: testicular Leydig celladenomas and pancreatic acinar
cell adenomas

Biegel et al. 2001
APFO
91

Rat
2 years(Sprague-Dawley) ad lib
50–65 M, 50–65 F (F)0, 1.5, 15

CS, FI, BW,
OW, HE, BI,
GN, HP

Bd wt
Resp

1.5 F
15

Cardio15

Gastro15

Hemato15

Hepatic

1.5

Renal

15

Ocular15

EndocrImmuno
Neuro

15
15
15

15 F

10.3% lower terminal body weight

15

Increased serum ALT and AST at≥1.5 mg/kg/day; hepatocellular
hypertrophy at 15 mg/kg/day;hepatocellular necrosis at
15 mg/kg/day only at 1 yearPERFLUOROALKYLS

61
2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to PFOA – Oral
Less
serious
SeriousFigure Species (strain) Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
Repro
Other
noncancer
Cancer

1.5 M
15 F

15 M

Vascular mineralization in thetestesInflammation of the salivary gland

1.5 M
15

CEL: testicular Leydig celladenomas

3M 1983; Butenhoff et al. 2012c
APFO
aThe number corresponds to entries in Figure 2-8.
bUsed to derive an intermediate-duration oral MRL of 3x10-6 mg/kg/day based on the predicted TWA serum PFOA level of 8.29 µg/mL at the LOAEL dose and an
empirical clearance model to estimate a HED. The LOAELHED of 0.000821 mg/kg/day was divided by an uncertainty factor of 300 (10 for the use of a LOAEL,
3 for extrapolation from animals to humans with dosimetric adjustment, and 10 for human variability).

ad lib = ad libitum; ALT = alanine aminotransferase; APFO = ammonium perfluorooctanoate (ammonium salt of PFOA); AST = aspartate aminotransferase;
BC = biochemistry; BI = biochemical changes; BW or Bd wt = body weight; C = capsule; Cardio = cardiovascular; CS = clinical signs; Develop = developmental;
DW = drinking water; DX = developmental toxicity; EA = enzyme activity; Endocr = endocrine; (F) = feed; F = female(s); FI = food intake; FT4 = free thyroxine;
FX = fetal toxicity; G = gavage; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GO = gavage in oil vehicle; GW = gavage in water vehicle;
HDL = high-density lipoprotein; HE or Hemato = hematological; HED = human equivalent dose; HP = histopathology; Immuno = immunotoxicological;
LD50 = lethal dose, 50% kill; LE = lethality; LDL = low-density lipoprotein; LH = luteinizing hormone; LOAEL = lowest-observed-adverse-effect level; M = male(s);MRL = Minimal Risk Level; Musc/skel = musculoskeletal; MX = maternal toxicity; Neuro = neurological; NK = natural killer; NOAEL = no observed-adverse-effectlevel; NX = neurotoxicity; OF = organ function; OP = ophthalmology; OW = organ weight; PFOA = perfluorooctanoic acid; PND = postnatal day;
PPARα = peroxisome proliferator-activated receptor-α; Repro = reproductive; Resp = respiratory; RX = reproductive toxicity; sRBC = sheep red blood cell;
TSH = thyroid-stimulating hormone; TT4 = total thyroxine; TWA = time-weighted average; UR = urinalysis; W = water; WI = water intake

PERFLUOROALKYLS

62
2. HEALTH EFFECTS

Figure 2-8. Levels of Significant Exposure to PFOA – Oral
Acute (≤14 days)

PERFLUOROALKYLS

63
2. HEALTH EFFECTS

Figure 2-8. Levels of Significant Exposure to PFOA – OralIntermediate (15–364 days)

PERFLUOROALKYLS

64
2. HEALTH EFFECTS

Figure 2-8. Levels of Significant Exposure to PFOA – OralIntermediate (15–364 days)

PERFLUOROALKYLS

65
2. HEALTH EFFECTS

Figure 2-8. Levels of Significant Exposure to PFOA – Oral
Chronic (≥365 days)

PERFLUOROALKYLS

66
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
Less
Species
serious
SeriousFigure (strain)
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
keya No./groupparameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
ACUTE EXPOSURE
1

Monkey(cynomolgus)
4–6M, 4–6F

Once or3 times in
315 days(G)0, 9,13.3 (M),
14 (F)

BW, BC

Bd wt

13.3 M
14 F

Hepatic

13.3 M
14 F

Decrease in HDL cholesterol; values
still within normal range

Endocr

13.3 M
14 F

Decreased serum T4; values still within
normal range

Endocr15

Transient decrease in serum TT4 (24,38, and 53% after 2, 6, and 24 hours,
respectively)

Renal

13.3 M
14 F

Chang et al. 2017
PFOS potassium salt
2

Rat
Once
(Sprague(GW)
Dawley)5–15 F
Chang et al. 2008b
PFOS potassium salt

0, 15

3

Rat
1 day
(Sprague(F)Dawley)30 M
Elcombe et al. 2012a
PFOS potassium salt

0, 1.97, 10.3 HP

40, 0, 1.72,
8.17

Rat
(SpragueDawley)
30 M

7 day
(F)

BI, OF

HP

Hepatic

10.3

Endocr

10.3

Hepatic

8.17

Endocr

8.17

Hepatic

8.96

Endocr

8.96

Decreased serum cholesterol (38%)
and triglyceride (55%) levels at
8.17 mg/kg/day

Elcombe et al. 2012a
PFOS potassium salt
5

Rat
(SpragueDawley)
10 M

Elcombe et al. 2012b
PFOS potassium salt

7 day
(F)

0, 1.79, 8.96 HP

Hepatocellular hypertrophy, increased
liver weight, decreased serum
cholesterol at ≥1.79 mg/kg/dayPERFLUOROALKYLS

67
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./groupLess
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

6

Rat
2 day
0, 25, 50(SpragueGDs 19–20
Dawley)1 time/day
NS F
(GW)
Grasty et al. 2003
PFOS potassium salt

BW, MX, DX Develop

25

Decreased neonatal survival (82% of
controls on PND 1)

7MX, DX

Bd wt

25

Weight loss during treatment whentreated on GDs 2–5 (22%) or 6–9(17%)

Develop25

Decreased neonatal survival (90%survival on GDs 2–5; 30% survival on
GDs 17–20)

Develop

25

Increased neonatal mortality

Rat(SpragueDawley)
NS F

4 days0, 25
GDs 2–5, 6–
9, 10–13,
14–17, or
17–20
(GW)

Grasty et al. 2003
PFOS potassium salt
8

Rat
(SpragueDawley)
NS F

2 days0, 25, 50
GDs 19–20
1 time/day(G)

Grasty et al. 2005
PFOS potassium salt
9Rat
7 days(Wistar)ad lib8M(F)
Haughom and Spydevold 1992
PFOS potassium salt
10

0, 15

Mouse
GDs 15–18 0, 4.5, 6.5,
(wild-type
1 time/day 8.5, 10.5
129S1/Svlm) (GW)
8–20 F
Abbott et al. 2009
PFOS potassium salt

BW, OW, BI, Hepatic
EA

DX

Develop15

40% increase in absolute liver weight

4.5

31% reduced percentage of live pups
per litter on PND 15

PERFLUOROALKYLS

68
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./group
11

Mouse
(ICR)
5–7 F

Less
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
GDs 11–15 0, 50
1 time/day(GW)

BW, OW, DX Hepatic50

GDs 6–18
1 time/day(GW)

MX, DX, BW, Bd wt
CS, OW
Hepatic

6
6

21% increase in absolute liver weight at≥3 mg/kg/day

Endocr6

No alterations in serum T3 or T4 levels

Develop6

CS, BW, BH, Bd wt
MX, DX
Develop

6

Develop103% increased maternal relative liver
weight50

6.1% increased cleft palate and 12.7%
reduced body weight in fetuses

Era et al. 2009
PFOS potassium salt
12

Mouse
(CD-1)
10–11 F0, 1.5, 3, 6

Fuentes et al. 2006
PFOS potassium salt
13

Mouse
(CD-1)
8–10 FGDs 12–18 0, 6
(GW)

6Reduced body weight of pups on
PNDs 4 and 8

6

Decreased distance traveled in open
field test at 3 months of age

11.3

Altered spontaneous behavior (≤60,
87.5, or 60% changes in total activity,
rearing, and locomotion)

0.75 M

24% decreased total spontaneous
activity at 2 months of age; nosignificant alteration at 4 months

Fuentes et al. 2007b
PFOS potassium salt
14

Mouse
GDs 12–18 0, 6
(CD-1)(GW)
8–10 F
Fuentes et al. 2007a
PFOS potassium salt

DX

15

BH, BW, OF Develop

Mouse(NMRI)
12 M pups
Hallgren et al. 2015
PFOS
16

Single dose 0, 11.3
(GO)

Mouse
Once
(CD-1)(G)
10 M pups
Johansson et al. 2008
PFOS potassium salt

0, 0.75, 11.3 CS, OF, DX

Develop

DevelopPERFLUOROALKYLS

69
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./group
17

Mouse
(CD-1)10 F

Lessserious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
GDs 11–16 0, 0.5, 2.0,(G)
8.0

BC, BW, DX, Bd wt
HP

8.0

21% reduction in maternal body weightgain on GDs 14–17

Repro

0.5

Develop

0.5

Decreases in mean fetal placental
weight and placental capacity
Post-implantation losses at≥0.5 mg/kg/day; 24 and 35% reduction
fetal body weight and 31 and 52%
reduction in the number of live fetuses
at 2.0 and 8.0 mg/kg/day

2.0

Lee et al. 2015a
PFOS
18

Mouse
(C57BL/6)
4M

10 days(F)0, 6

BW FI BC HP Bd wt

6

Hemato6

Hepatic

6

Immuno6

41% increase in liver weight,
hepatocellular hypertrophy, anddecreased serum cholesterol levels

Qazi et al. 2010a
PFOS
19

Mouse
(BALB/c)
5F

7 days(GW)

20

BW, OW, BC Bd wt
Hepatic

20
20

Immuno41% decreased body weight gain
59% increase in relative liver weight

20

Inhibition of T lymphocyte proliferationin response to sRBC; decreased
phagocytosis by peripheral blood cells
and NK cell activity; decreased IgM
antibody formation in response to OVA

Vetvicka and Vetvickova 2013
PFOS
20

Mouse
(CD-1)
4M

Wan et al. 2011
PFOS potassium salt

14 days
1 time/day(GO)0, 1, 5, 10

Bd wt

10

Hepatic

10

Repro

10

~70% increased absolute liver weightat ≥5 mg/kg/dayPERFLUOROALKYLS

70
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./groupLess
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

21

Mouse
(C57BL/6)
10 M
Xing et al. 2016
PFOS

1 day
(GO)

0, 300, 400, BW, CS, HP, Death
500, 600, 700 LE

22

7 days(G)0, 5, 20, 40

FX

0, 0.1, 1.0,
2.5, 3.75

MX, DX, BW, Bd wt
CS

Mouse
(C57BL/6N)
12 M
Zheng et al. 2009
PFOS
23

RabbitGDs 6–20(New Zealand) 1 time/day
22 F
(GW)

579

ImmunoDevelop

5

0.1

LD50

Impaired response to T-cell mitogens;suppressed response to sRBC

1F

21% decreased mean maternal bodyweight gain on GDs 7–21; no effect onfood consumption

3.75

Decreased fetal body weight; 10% at
2.5 mg/kg/day and 24% at
3.75 mg/kg/day; 10/22 does aborted
between GD 22 and 28 at
3.75 mg/kg/day

1

2.5

0.15 M
0.75 F0.75 M

13.5% reduction in final body weight

0.75

47–55% increased absolute liver
weight; 50–60% decreased serum
cholesterol; hepatocellular hypertrophy,
mild bile stasis, and lipid vacuolation at
0.75 mg/kg/day

Case et al. 2001
PFOS potassium salt

INTERMEDIATE
24

Monkey26 weeks(Cynomolgus) 1 time/day
4–6 M, 4–6 F (C)0, 0.03, 0.15, CS, BW, OW, Bd wt
0.75
HE, BI, GN,HP
Resp
Cardio0.75
0.75

Gastro0.75
Hemato0.75
Musc/skel 0.75
Hepatic
0.15

Renal
Dermal0.75
0.75

PERFLUOROALKYLS

71
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./groupLess
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) EffectOcular
EndocrImmuno
Neuro
Repro

0.75
0.15
0.75
0.75
0.15

0.75

Increased TSH and decreased total T3

0.75 MNo histological alterations
Significant decrease in serum estradiol
on days 62 (48%), 91 (42%), and 182(96%); no histological alterations

Seacat et al. 2002
PFOS potassium salt

25

Monkey4 weeks(Cynomolgus) 1 time/day
6 M,F
(C)

0, 0.02, 2

CS, BW, FC, Bd wt
HE, BI, GN,
Resp
HP, EA
Hemato2

Hepatic

2

Renal

2

Ocular2

Endocr2

Immuno2

No histological alteration

Repro

2

No histological alterations

Repro

1

Develop0.3

2
2

Thomford 2002a
PFOS potassium salt

26

Rat
(SpragueDawley)
25 F

GD 0 toPND 20
1 time/day(GW)0, 0.1, 0.3, 1

GD 0 toPND 20
1 time/day(GW)0, 0.1, 0.3, 1

1~30% increased locomotor activity andconcurrent failure to habituate to test
environment in male pups on PND 171

2.1-fold increased fetal thyroid cellproliferation on GD 20

Butenhoff et al. 2009b
PFOS potassium salt

27

Rat
(SpragueDawley)
25 F

Chang et al. 2009
PFOS potassium salt

DevelopPERFLUOROALKYLS

72
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./group
Rat
28(SpragueDawley)
10 F
Chen et al. 2012b
PFOS

29

Rat
(SpragueDawley)
10 M

Less
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
GDs 1–21
1 time/day(GW)0, 0.1, 2

Daily
28 days(G)0, 5, 20Develop

HP

0.1

Death

2

~5-fold increased postnatal mortality
and severe lung histopathology in pups

20

100% by day 26

Resp

5

Pulmonary congestion

Hepatic

5

Hepatocellular hypertrophy and focal
necrosis at ≥5 mg/kg/day; fatty
degeneration at 20 mg/kg/day

Neuro

5

Cachexia and lethargy

7.01 F

Decreased red blood cells (8.9%),
hemoglobin (10%), hematocrit (8.8%)

Cui et al. 2009
PFOS
30

Rat
(SpragueDawley)
15M, 15F

Daily
28 days(F)

M: 0, 0.13,
1.23, 2.98,
5.89
F: 0, 0.14,
1.33, 3.47,
7.01

Cardio5.89 M

Hemato3.47 F

Hepatic

5.89 M

Renal

5.89 M

Endocr

0.14

Hepatic

7.34

Endocr

7.34

Increased relative liver weight;
hepatocellular hypertrophy in males at
5.89 mg/kg/day
1.23

Decreased T4 level (82% in males;
48% in females)

Curran et al. 2008
PFOS potassium salt
31

Rat
(SpragueDawley)
30 M

Elcombe et al. 2012a
PFOS potassium salt

28 days(F)0, 1.54, 7.34 HP

Hepatocellular hypertrophy anddecreased serum cholesterol levels at≥1.54 mg/kg/dayPERFLUOROALKYLS

73
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./groupLess
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

32

Rat
Daily
(Wistar)28 days
5–6 M(G)Kawamoto et al. 2011
PFOS

0, 0.12, 0.5,
2.0, 8.5

33

Rat
GDs 2–21(Sprague(GW)
Dawley)NS
Lau et al. 2003
PFOS potassium salt

0, 1, 2, 3, 5,
1034

M: 0, 0.14,
1.33, 3.21,
6.34; F: 0,0.15, 1.43,
3.73, 7.58

Rat
(SpragueDawley)
15M, 15F

28 days(F)

FX

OW, BW

Neuro

2

Develop

1

Bd wt

1.33 M

Hepatic

6.34 M

Immuno6.34 M

8.5

Tonic convulsions in response tostimuli2

3.21 M

Reduced serum T4 in pups at
1 mg/kg/day; approximately 60%
survival at weaning versus 80% in
controls at 2 mg/kg/day

12% decrease in terminal body weight
Increased relative liver weight at≥0.14 mg/kg/day

Lefebvre et al. 2008
PFOS
35

Rat
(SpragueDawley)
10 dams; 12–13 pups
Li et al. 2016
PFOS
36

GDs 12–18 0, 5, and 20(GO)

Rat (Sprague- 21 days
Dawley)(G)
5M

Li et al. 2018
PFOS

0, 5, 10

BC, BW, DX, Bd wt
OW
Develop5

20

30% reduction in body weight of dams

520

13% reduction in body weight of malepups

BW, BC, OW, Bd wt
HP
Repro

10
5

Delayed maturation of testicular Leydig
cells, decreased seminal vesicle
weight, decreased epididymal sperm
count, decreased serum testosterone
levelsPERFLUOROALKYLS

74
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./group
37

Rat(SpragueDawley)
19 M

Less
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
28 days(GO)0, 0.5, 1.0,
3.0, 6.0

BC, BW, HP, Neuro
OF, OW

0.5

1

Degeneration of gonadotropic cells of
the pituitary gland at ≥1.0 mg/kg/day;dense chromatin, condensed
ribosomes, loss of morphology in the
hypothalamus at ≥3.0 mg/kg/day

Repro

0.5

1

Loss/degeneration of spermatozoids,
marked edema in the testes

MX, DX, BW, Bd wt
OW, OF, GN, Repro
HP, FC

1.6

3.2>10% reduction in body weight

Lopez-Doval et al. 2014
PFOS
38

Rat
(SpragueDawley)
35 M,F84 days0, 0.1, 0.4,
(6 weeks
1.6, 3.2
prior tomating GD 0
to PND 21)
1 time/day(GW)

Develop

3.2
0.1b

No alterations in mating and fertility
parameters
0.4

1.6

Delayed eye opening and transient
decrease in F2 pup body weight (13%)
on LDs 7–14 at ≥0.4 mg/kg/day;decreased pup survival to postpartum
day 21 at ≥1.6 mg/kg/day

1.6

Increased pup mortality during
PNDs 1–4

Luebker et al. 2005a
PFOS potassium salt
39

Rat
90 day(Sprague1 time/day
Dawley)50 F
Luebker et al. 2005a
PFOS potassium salt
Cross-foster study
40

Rat(SpragueDawley)
20 F

0, 1.6

MX, DX, BW,
OW, OF, GN

Develop

62–67 days 0, 0.4, 0.8, 1, MX, DX, BW, Bd wt
42 days
1.2, 1.6, 2
CS, BIprior tomatingHepatic
through
GD 20 or
PND 4(G)Endocr
Repro

1.6

2

2

16% reduction in serum totalcholesterol on PND 5 at
≥0.4 mg/kg/day; increased liver weightin dams at ≥0.8 mg/kg/day
0.4

2

22% reduction in body weight gain
during premating; food consumption
reduced 5.8%

46% reduction in total T4 on PND 5
No alteration in fertility

PERFLUOROALKYLS

75
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./groupLess
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) EffectDevelop

0.4

1.6>10% decrease in mean pup weight
per litter on PND 5 at ≥0.4 mg/kg/day;~50% decrease mean pup survival per
litter on PND 5 at ≥1.6 mg/kg/day

Endocr

0.5

Decreases in serum corticosterone(~58%) and ACTH levels (~11%),decrease in corticotrophin releasing
hormone levels in hypothalamus (~8%);decrease in relative adrenal weight(~43%),

0.5

10

17% decrease in body weight

0.5

10

Decreases in sperm concentration,
serum testosterone levels; vacuolationin testicular spermatogonia,
spermatocyte, and Leydig cells

18.75

Reduced body weight in dams;
approximately 98% on GD 8 and 33%
on GD 20

18.75

Decreased birth weight in females only
(approximately 11%); increased
systolic blood pressure in maleoffspring at 7 and 52 weeks and infemale offspring at 37 and 65 weeks;
reduced nephron endowment

Luebker et al. 2005b
PFOS potassium salt
41

Rat
(SpragueDawley)
10 M

25 days(GW)0, 0.5, 1.0,
3.0 and 6.0

OF, OW

5 weeks(GO)0, 0.5, 10

BW, OW, HP, Bd wt
RX
Repro

GDs 2–6(G)0, 18.75

Pereiro et al. 2014
PFOS
42

Mouse (C57)
12 M

Qu et al. 2016
PFOS
43

Rat
(SpragueDawley)
21 dams; 10–
12 M,F
pups/litter

Rogers et al. 2014
PFOS

BW, OF, OW Bd wt

DevelopPERFLUOROALKYLS

76
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./group44

Less
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

Rat(SpragueDawley)
7M
Salgado et al. 2015
PFOS

28 days(GW)0, 3.0, and
6.0

BI, BW, OW

45

4 weeks
ad lib(F)

M: 0, 0.05,
0.18, 0.37,
1.51; F: 0,0.05, 0.22,
0.47, 1.77

CS, CO, OW, Bd wt
HE, BI, GN, Hemato
HP
Hepatic

Rat(SpragueDawley)
25 M,F

Bd wt

6

Endocr3

Decreased serum prolactin (~78%) andestradiol concentrations (~18%)

1.77 F1.77 F1.77 F

Renal

1.77 F

Ocular

1.77 F

Immuno1.77 FNo histological alterations

Neuro1.77 FNo histological alterations

Repro

1.51 M
1.77 FNo histological alterations

Seacat et al. 2003
PFOS potassium salt
46

Rat
(SpragueDawley)
25 M,F

Seacat et al. 2003
PFOS potassium salt

14 weeks
ad lib(F)

M:0, 0.03,
0.13, 0.34,
1.33; F:0,
0.04, 0.15,
0.4, 1.56

CS, CO, OW, Bd wt
HE, BI, GN, HematoHP1.56 F

Hepatic

1.33 M

Renal

1.56 F

Ocular

1.56 F

Endocr

1.56 F

ImmunoNeuro
Repro

1.56 F1.56 F1.33 M
1.56 F

0.34 M

1.33 M

45% increase in non-segmented
neutrophils
Increased absolute and relative liver
weight; increased serum ALT;
hepatocyte hypertrophy andvacuolation at 1.33/1.55 mg/kg/day

No histological alterations
No histological alterations
No histological alterations

PERFLUOROALKYLS

77
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./group
47

Rat(SpragueDawley)25–50 F

Less
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
GDs 2–20(GW)0, 1, 2, 3, 5,
10

MX, DX, BW, Bd wt
FI, WI, OW,BI

2Decreased mean body weight gain,
10% at 2 mg/kg/day and 33% at
5 mg/kg/day

Endocr1

Reduced total and free T4 and T3

Develop10

Increased incidences of cleft palate

Develop

0.8

Decreased spatial learning ability inprenatally or postnatally exposed
offspring at ≥0.8 mg/kg/day and in
offspring exposure pre- and postnatallyat 2.4 mg/kg/day; decreased memory
ability in offspring exposure pre- andpostnatally at 2.4 mg/kg/day

Hepatic

1

10

Thibodeaux et al. 2003
PFOS potassium salt
48

Rat
GD 1 to0, 0.8, 2.4(Wistar)PND 1,
10 or 15 dams; PNDs 1–7
6–10 M,F pups or 35,
or GD 1 to
PND 7 or 35

DX

Wang et al. 2015c
PFOS
49

Rat
(SpragueDawley)
10 F
Xia et al. 2011
PFOS

GDs 2–21
1 time/day(GW)0, 0.1, 0.6, 2

Develop50

91 days(W)0, 0.27, 0.79, BC
2.37

Endocr

0.27 M

42% decrease in total T4 levels

Develop3.2 F

19–36% reduced serum T4 levels inpups on PNDs 21–35 after gestationand/or postnatal-only exposure

Rat(SpragueDawley)
8–10 M

Yu et al. 2009a
PFOS potassium salt

0.6

25-fold increased neonatal mortality on
PNDs 1–3

PERFLUOROALKYLS

78
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./group
51

Mouse
(E3L CETP)
6–8 M

Less
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
4–6 weeks
(F)

0, 3

BW, FI, BC,
OW

Bd wt

3

Hepatic

3

60 days(G)0, 0.00833,
0.08333,
0.41667,
0.83333,
2.0833

FX

Immuno0.00830.0833

Impaired response to sRBC

60 days(G)0, 0.00833,
0.0167,0.0833,0.4167,0.8333

FX

Immuno0.01670.0833

Impaired response to sRBC

GDs 1–17
1 time/day
(GW)

0, 20

Bd wt

20

35% reduced maternal body weight

Develop20

89% increased cleft palate, 25%
reduced body weight in fetuses

CS, BW, BH, Develop
MX, DX

3

Impaired retention of the task in thewater maze test

0.025

Decreased host resistance to influenza
virus

Decreased plasma triglyceride, totalcholesterol, non-HDL cholesterol, andHDL cholesterol levels; increased
hepatic triglyceride levels, increased
liver weight

Bijland et al. 2011
PFOS
52

Mouse
(C57BL/6N)
10 M

Dong et al. 2009
PFOS potassium salt
53

Mouse
(C57BL/6N)
12 M

Dong et al. 2011
PFOS potassium salt
54

Mouse
(ICR)
6–8 F

Era et al. 2009
PFOS potassium salt
55

Mouse (CD-1) 4 weeks
10 M
(GW)
Fuentes et al. 2007c
PFOS potassium salt

0, 3, 6

56

0, 0.005,
0.025

Mouse
(B6C3F1)
30 F
Guruge et al. 2009PFOS

21 days(G)

Immuno0.005

PERFLUOROALKYLS

79
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./groupLess
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

57

Mouse
GDs 1–17(B6C3F1)
1 time/day
10–12 F
(GW)
Keil et al. 2008
PFOS potassium salt

0, 0.1, 1, 5

MX, DX, BW, Develop
CS, OF58

GDs 1–17
1 time/day(GW)0, 1, 5, 10,
15, 20DX, OW, BI

DevelopGDs 1–17(GO)

3

BC, EA, OF

Hepatic

Mouse(CD-1)
21–22 F0.1

11

42.5% reduced NK cell activity in malepups at 8 weeks of age

10

1 mg/kg/day: delayed eye opening at≥1 mg/kg/day, ~ 0% postnatal survival
at weaning versus 90% in controls at
10 mg/kg/day

Lau et al. 2003
PFOS potassium salt
59

Mouse
(CD-1)
4 dams;8 fetuses

3

DevelopNo alteration in maternal hepatic lipid
levels3

Significant increase in cholesterollevels in fetal livers

2.15

Impaired spatial learning and memory

10 M~15% reduction in body weight during
the recovery period~36% decrease in spleen index during
recovery; ~15% inhibition in Con Ainduced T-cell proliferation during
treatment; 32% increase in CD3+ cells
after recovery; ~60% increase in
CD3+CD8+ cells and ~56% increase in
CD3+CD4+ cells on week 2; 15%
inhibition in Con A-induced T-cellproliferation during recovery

Lee et al. 2015b
PFOS
60

Mouse
(C57BL/6)
15 M,FLong et al. 2013
PFOS

Daily
3 months(G)0, 0.43, 2.15, FX
10.75

61

3 weeks

0, 2.5, 5 and BW, OF, OW Bd wt
10
ImmunoMouse(BALB/c)
28 M

Lv et al. 2015
PFOS

Neuro

0.43

2.5 M

5M

PERFLUOROALKYLS

80
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./group
62

Mouse
(C57BL/6JApc+/+)
20–21 F

Less
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
GDs 1–17(GW)0, 0.01, 0.1,
3.0

BC, BW, FI,
HE, OW

Develop

0.1

3

Decrease in number of successful
births0.3

Decreased locomotion, muscle
strength, and motor coordination in
adult offspring

0.00166 M

Suppressed response to sRBC (~60%)

0.2

21% reduction in body weight

Ngo et al. 2014
PFOS
63

Mouse
GDs 1–21(C57BL/6/
ad libBk1)
6F
Onishchenko et al. 2011
PFOS, potassium salt

0, 0.3Develop64

0, 0.000166, OW, FX
0.00166,
0.00331,0.0166,
0.0331, 0.166

Immuno

0.20

Bd wt

Mouse
(B6C3F1)
5M, 5F

28 days(G)

0.000166 M

Peden-Adams et al. 2008
PFOS potassium salt
65

Mouse
(B6C3F1)
5M

28 days(F)

NS

Immuno0.2

No alterations in thymic lymphocyte
phenotypes, response to sRBC, or IgM
antibodies to LPS

Develop5

Peroxisome proliferation in fetal liver at≥5 mg/kg/day

BW, OW, BI, Bd wt
DX
Hepatic

20

Endocr15

Qazi et al. 2010b
PFOS
66

Mouse
GDs 1–17(CD-1)
1 time/day
5F(GW)
Rosen et al. 2009
PFOS potassium salt

0, 5, 1067

0, 1, 5, 10,
15, 20

Mouse(CD-1)
60–80 FGDs 1–17(GW)

20

Increase in absolute and relative liver
weight and decreased serum
triglycerides at ≥5 mg/kg/day
20

Decreased total T4 on GD 6PERFLUOROALKYLS

81
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./groupLess
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) EffectDevelop1

5

20

Increased incidences of sternal defects
at ≥5 mg/kg/day; reduced percentage
of live fetuses (9%) at 20 mg/kg/day

BW, BI, OW, Bd wt
HP
Hepatic

5

10

Repro

5

BW, OF, OW Hepatic

3~24% increase in relative liver weight indams at 3 mg/kg/day

Develop3

Increase in relative liver weight at
3 mg/kg/day in male and female pups
on PND 21 (~20–32%), in male STDfed adults (~11%), and in male HDFfed adults (~33%)

Thibodeaux et al. 2003
PFOS potassium salt
68

Mouse
(CD-1)
4M

21 days
1 time/day(GO)0, 1, 5, 10

10~15% reduced body weight
Increased absolute liver weight at≥5 mg/kg/day

10~17% reduced serum testosterone,~38% reduced epididymal sperm count

Wan et al. 2011
PFOS potassium salt
69

Mouse
(CD-1)
6 F (dams)

GD 3 toPND 21 or
GD 3 toPND 63(GO)0, 0.3, 3

Develop

Other
3F
noncancer

Wan et al. 2014b
PFOS

0.3

In PND 63 offspring fed a high fat diet,increased serum glucose levels at≥0.3 mg/kg/day in females (~40%) and
3 mg/kg/day in males (~8%); increased
serum insulin in males (~109%) andfemales (~85%); increased response tooral glucose tolerance test, increased
HOMA-IR index, and 33% increased
relative liver weight at 3 mg/kg/day
No significant alteration in fasting
serum insulin or glucose levels;
significant increase in HOMA-IR index
at 0.3 and 3 mg/kg/dayPERFLUOROALKYLS

82
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./group
70

Mouse
(C57BL/6)
10 M

Less
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
30 days(GO)0, 2.5, 5, 10

BW, HP, OF, Bd wt
OW
Hepatic

Renal

10

Hepatic

20

10

31% reduction in body weight(correlated with 68% reduction in feed
consumption)

2.5

Increased liver weight (35%) andserum AST(~12%) and GGT levels(~98%) at ≥2.5 mg/kg/day; increases in
ALT (~45%) and ALP (~36%) at≥5 mg/kg/day; cytoplasmic vacuolation,
focal or flake-like necrosis, andhepatocellular hypertrophy observed,
but no incidence data provided

Xing et al. 2016
PFOS
71

Mouse
(ICR)
5F

GDs 0–17
GDs 0–18(GW)0, 1, 10, 20

Develop60% increased absolute liver weight at≥10 mg/kg/day
1

Develop20

GDs 0–17: 15.8% increased sternal
defects in fetuses at ≥1 mg/kg/day;
8.8% decrease in number of live
fetuses at 20 mg/kg/day

10

GDs 0–18: decreased survival (55.2%)
at 10 mg/kg/day on PND 4, decreased
neonatal BW, intracranial blood vessel
dilatation, lung atelectasis

Yahia et al. 2008
PFOS potassium salt
CHRONIC EXPOSURE
72
Rat
104 weeks(Spraguead lib
Dawley)(F)
70 M,F0, 0.025,
0.10, 0.25,
1.04

CS, BW, FC, Bd wt
GN, HP, BI

0.25 F

Resp

1.04

Cardio1.04

Gastro1.04

Hemato1.04

Musc/skel 1.04

1.04 F

14% reduction in final body weightPERFLUOROALKYLS

83
2. HEALTH EFFECTS

Table 2-4. Levels of Significant Exposure to PFOS – Oral
SpeciesFigure (strain)
keya No./groupLess
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) EffectHepatic

0.25 M

Renal
DermalOcular
EndocrImmuno
Neuro
Repro

1.04
1.04
1.04
1.04
1.04
1.04
1.04

1.04 M

Hepatocellular hypertrophy at≥0.1 mg/kg/day; single cell necrosis
and cystic degeneration at
1.04 mg/kg/day

No histological alterations
No histological alterations
No histological alterations

Butenhoff et al. 2012b; Thomford 2002b
PFOS potassium saltaThe number corresponds to entries in Figure 2-9.
bUsed to derive an intermediate-duration oral MRL of 2x10-6 mg/kg/day based on the predicted TWA serum PFOA level of 29.7 µg/mL at the NOAEL dose and an
empirical clearance model to estimate a HED. The NOAELHED of 0.000515 mg/kg/day was divided by an uncertainty factor of 30 (3 for extrapolation from animals
to humans with dosimetric adjustment and 10 for human variability) and a modifying factor of 10 for concern that immunotoxicity may be a more sensitive endpoint
than developmental toxicity.

ad lib = ad libitum; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BC = biochemistry; BH = behavioral;
BI = biochemical changes; BW or Bd wt = body weight; C = capsule; Cardio = cardiovascular; CS = clinical signs; Develop = developmental; DX = developmental
toxicity; EA = enzyme activity; Endocr = endocrine; (F) = feed; F = female(s); FX = fetal toxicity; FI = food intake; FX = fetal toxicity; G = gavage;
Gastro = gastrointestinal; GD = gestation day; GGT = gamma-glutamyl transferase; GN = gross necropsy; GO = gavage in oil vehicle; GW = gavage in water
vehicle; HDL = high-density lipoprotein; HE or Hemato = hematological; HED = human equivalent dose; HOMA IR = Homeostatic Model Assessment of Insulin
Resistance; HP = histopathology; Immuno = immunotoxicological; LD = lactation day; LD50 = lethal dose, 50% kill; LE = lethality; LOAEL = lowest-observedadverse-effect level; LPS = lipopolysaccharide; M = male(s); MRL = Minimal Risk Level; Musc/skel = musculoskeletal; MX = maternal toxicity;
Neuro = neurological; NK = natural killer; NOAEL = no observed-adverse-effect level; NS = not specified; OF = organ function; OP = ophthalmology; OW = organ
weight; PFOS = perfluorooctane sulfonic acid; PND = postnatal day; Repro = reproductive; Resp = respiratory; RX = reproductive toxicity; sRBC = sheep red
blood cell; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; TT4 = total thyroxine; TWA = time-weighted average; W = water

PERFLUOROALKYLS

84
2. HEALTH EFFECTS

Figure 2-9. Levels of Significant Exposure to PFOS – Oral
Acute (≤14 days)

PERFLUOROALKYLS

85
2. HEALTH EFFECTS

Figure 2-9. Levels of Significant Exposure to PFOS – OralIntermediate (15–364 days)

PERFLUOROALKYLS

86
2. HEALTH EFFECTS

Figure 2-9. Levels of Significant Exposure to PFOS – OralIntermediate (15–364 days)

PERFLUOROALKYLS

87
2. HEALTH EFFECTS

Figure 2-9. Levels of Significant Exposure to PFOS – Oral
Chronic (≥365 days)

PERFLUOROALKYLS

88
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
Exposure Doses
Parameters
keya No./group parameters (mg/kg/day) monitored Endpoint
ACUTE EXPOSURE
PFHxS
1

Mouse
7 days(SV129 WT (G)and PPARα
null)
4M

0, 10
PFHxS

BW, HP

Less
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

Bd wt

10

Hepatic10Develop

6.1

9.2

Altered spontaneous behavior andhabituation in adults exposed asneonates

1

3

Decreases in body weight at 3 and5 mg/kg/day (18 and 39%)1

24% increase in relative thymus weightat 1 mg/kg/day; 20% decrease in thymus
weight at 3 or 5 mg/kg/day, increases inthymic cortex:medulla ratios, alterations
in cytokine levels at ≥3 mg/kg/day

5

Decreased relative spleen weight andincreases in cytokine levels

Hepatocellular hypertrophy, steatosis,
and increased hepatic triglyceride levels

Das et al. 2017
2

Mouse
(NMRI)
14–18 M,F
Viberg et al. 2013

PND 10Once(GO)0, 0.61, 6.1,
9.2
PFHxS

14 days(GW)0, 1, 3, 5
PFNA

PFNA
3

Rat
(SpragueDawley)
10 M

BC, BW, OW Bd wt
ImmunoFang et al. 2009
4

Rat
(SpragueDawley)
10 M
Fang et al. 2010

14 days(GW)0, 1, 3, 5
PFNA

BC, OW

Immuno3

5

14 days(GW)0, 0.2, 1, 5
PFNA

BC

Hepatic

5

14 days(GW)0, 0.2, 1, 5
PFNA

HP

Rat
(SpragueDawley)
6M

Other
0.2
noncancer(glucose)

Decreased HDL levels at ≥1 mg/kg/day
1

Increased serum glucose levels(1.11-fold at 1 mg/kg/day and 1.16-fold at
5 mg/kg/day)Fang et al. 2012a
6

Rat(SpragueDawley)
6M
Fang et al. 2012b

Hepatic

5

Hepatocellular vacuolation and lipid
accumulation at 5 mg/kg/dayPERFLUOROALKYLS

89
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group
7

Rat(SpragueDawley)
6M

Exposure Doses
Parametersparameters (mg/kg/day) monitored EndpointLess
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

14 days(GW)0, 1, 3, 5
PFNA

BC, HP

Repro

3

5

85.4% decrease in serum testosterone
and 105% increase in estradiol levels at
5 mg/kg/day; atrophy of seminiferous
tubule epithelium

14 days(GW)0, 1, 3, 5
PFNA

HP

Repro

3

5

Large vacuoles between testicular Sertoli
cells and spermatogonia

14 days(GO)
8 or 10M

0, 0.0125,
0.25, 5PFNA

BI, BW, OW, Bd wt
GN, HP

5

Decreased body weight; magnitude ofeffect was not reported

Endocr5

Decreased androstenedione andtestosterone concentrations (data notshown)

Mouse
7 days(SV129 WT (G)and PPARαnull)
4M
Das et al. 2017

0, 10
PFNA

BW, HP11

14 days(G)0, 1, 3, 5
PFNA

FX

Immuno14 days(F)0, 0.5, 1.8,
5.3, 54, 537
PFNA

LE, OW

Death

Feng et al. 20098

Rat
(SpragueDawley)
6M

Feng et al. 2010
9

Rat
(Wistar)Hadrup et al. 2016
10

Mouse
(BALB/c)
6M

Bd wt

10

Hepatic10

Hepatocellular hypertrophy, steatosis,
and increased hepatic triglyceride levels

1

Decreases in the percentages of F4/80+
and CD49b+ cells in the spleen; noalteration in the response of splenic
lymphocytes to ConA at ≤5 mg/kg/day

Fang et al. 2008
12

Mouse
(CD-1)
5 M,F

Kennedy 1987

Hepatic

54
5.3

100% mortality before day 14
50–70% increase in absolute liver weightat ≥0.5 mg/kg/dayPERFLUOROALKYLS

90
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group
13

Mouse
(BALB/c)
8M

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint
14 days(G)0, 0.2, 1, 5
PFNA

BW, OW, BC Bd wt

Once
(GO)

0, 50
PFDA

BW, FX

Hepatic

Less
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect1

5~25% decrease in body weight

1

5

Increases in liver weight (~160%) andincreases in hepatic triglyceride (~66%)
and cholesterol levels (~26%) at≥0.2 mg/kg/day; decreases in serum
triglyceride (~67%) and cholesterol levels(~32%) and increases in serum ALT(~900%) and AST (~280%) levels at
5 mg/kg/day

Wang et al. 2015a

PFDA
14

Rat
(Wistar)5–12 M

BW

50

Neuro

50

BE, OW, EA Bd wt

4.7

8% weight loss was observed 10-days
post-exposure
No alteration in performance on novel
object recognition test

Kawabata et al. 2017
15

Rat
(Wistar)
25 M

1 week(F)

0, 1.2, 2.4,
4.7, 9.5PFDA

9.5~32% weight loss

Hepatic

9.5

Increases in liver weight at≥2.4 mg/kg/day; increases in hepaticcholesterol at 9.5 mg/kg/day

Hepatic

160

Increase in hepatic lipids and liver weight
2 days post-exposure at 40 mg/kg/day

Kawashima et al. 1995
16

Mouse
Once
(C57BL/6N) (GO)4F

0, 40, 80,
OW, EA
100, 120, 160
PFDA

Brewster and Birnbaum 1989
17

Mouse
GDs 6–15(C57BL/6N) (GO)
12–14 F

Harris and Birnbaum 1989

0, 0.03, 0.1, MX, DX, BW, Bd wt
0.3, 1, 3, 6.4, OW
12.8
PFDA
Develop

3

6.4

12.8

No weight gain at 6.4 mg/kg/day andweight loss at 12.8 mg/kg/day (netchange of -2.4)

0.3

1

12.8

18–22% decreases in fetal weight per
litter at ≥1 mg/kg/day; decreases in live
fetuses per litter at 12.8 mg/kg/day(4.6 versus 7.2 in controls)PERFLUOROALKYLS

91
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group18

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint

Mouse
Once
(C57BL/6N) (GO)10 F

0, 20, 40, 80, BW, OW,
160, 320
GN, HPPFDA

Lessserious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

Death

120
80

LD50 in 30-day observation period

Bd wt

40

12% decreased body weight 30 days
post-exposure

Cardio80

No histological alterations in the heart
30 days post-exposure; decreased
relative heart weight at 80 mg/kg/day

Hepatic80

Increases in liver weight and pancellular
hypertrophy at ≥20 mg/kg/day 30 days
post-exposure

Renal

80

No histological alterations 30 days postexposure

Endocr40

80

Immuno40

80Develop10.8

2-fold increase in T3 and 4-fold increasein T4 levels 30 days post-exposure
160

28% decrease in relative spleen weightat 80 mg/kg/day; atrophy and lymphoiddepletion in thymus and spleen at
160 mg/kg/day

Harris et al. 1989
19

Mouse
Once on(CD-1)
PND 10
10 M(G)Johansson et al. 2008

0, 0.72, 10.8 CS, DX
PFDA

20

0, 78
PFDA

Mouse
10 days(C57BL/6N) (F)
4M
Permadi et al. 1992, 1993

BW, OW, EA Bd wt

78

Hepatic

78

0, 18, 58, 184 CS, BW, OW, Bd wt
PFBA
HE, BI, GN, Resp
HP
Cardio184

Gastro184

Hemato184

Musc/skel

184

Hepatic

184

Renal

184

PFBA
21

Rat
(SpragueDawley)
3 M,F

5 days1 time/day(GW)

No alteration in spontaneous activity or
habituation at 2–4 months of age

184
184

33% weight loss
36% increase in liver weightPERFLUOROALKYLS

92
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group

Exposure Doses
Parametersparameters (mg/kg/day) monitored EndpointLess
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

Endocr184

Immuno184

No histological alterations

Neuro

184

No histological alterations

Repro

184

No histological alterations

Hepatic20

Biochemical and ultrastructural evidenceof peroxisome proliferation

3M 2007a
22

Rat(SpragueDawley)
3M
Ikeda et al. 1985

14 daysad lib
(F)

0, 20
PFBA

OW, EA

Mouse
10 days(C57BL/6N) (F)
4M
Permadi et al. 1992, 1993

0, 78
PFBA

BW, OW, EA Bd wt

0, 5, 20, 50
PFDoDA

BW, FX

23

Hepatic

78
78

63% increase in absolute liver weight

PFDoDA
24

Rat(Wistar)5–12 M

Once
(GO)

BW

50

Neuro

50

44% decrease in body weight gain
(measured 10-days post-exposure)
Impaired performance on novel object
recognition test

Kawabata et al. 2017
25

Rat
(Wistar)
10 M

Once
(GO)

0, 50
PFDoDA

FX

Neuro

50

No alterations in open field activity

0, 50
PFDoDA

FX

Neuro

50

No alterations in tests of working memory
or depressive behavior

Kawabata et al. 2017
26

Rat
(Wistar)
8M

Once
(GO)

Kawabata et al. 2017

PERFLUOROALKYLS

93
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group
27

Rat(SpragueDawley)
10 M

Shi et al. 2007
28
Rat
(SpragueDawley)
10 M
Zhang et al. 2008

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint
14 days
1 time/day(GW)

14 days
1 time/day(GW)0, 1, 5, 10
PFDoDA

BW, OW, BI

Lessserious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

Bd wt

1

Hepatic

10

Repro

1

5

25% reduction in final body weight
35% increase in total serum cholesterolat 10 mg/kg/day

5

Decreased serum testosterone (38%)
and estradiol (~38%), and ultrastructural
alterations in testes at ≥5 mg/kg/day;decreased testicular weight at
10 mg/kg/day (22%)

0, 1, 5, 10
PFDoDA

OW, BI, HP

Hepatic

10

Increased liver weight, increased hepatic
triglyceride and cholesterol levels at≥5 mg/kg/day; increased serum
triglyceride levels at 10 mg/kg/day

0, 5
FOSA

BW, OW

Bd wt

5

Hepatic

50, 100, 350,
500
PFHxA

CS, DX

Develop100

350

12.5% decrease in birth weight anddelayed eye opening at ≥350 mg/kg/day;increased pup mortality (PND 0–3) anddecreased pup survival at 500 mg/kg/day

Mouse
GDs 6–18
(CD1)
(GW)
20 F
Iwai and Hoberman 2014

0, 7, 35, 175 CS, DX
PFHxA

Develop35

175

Increase in stillborn pups and 12.5%
decrease in birth weight

32

175, 550,
LE, CS, BW
1,550, 5,000
NaPFHx

Death

1,750

1/4 died at 1,750 mg/kg/day; 3/3 died at
5,000 mg/kg/day

Neuro

175

Abnormal gait, salivation, ataxia, lethargy

FOSA
29

Rat
Once
(Sprague(G)Dawley)15 M
Seacat and Luebker 2000

No alterations in liver weight

PFHxA
30

Mouse
(CD1)
20 F

GDs 6–18(GW)

Iwai and Hoberman 201431

Rat (Crl:CD Once
(SD))
(GW)
NS F

Loveless et al. 2009

PERFLUOROALKYLS

94
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
Exposure Doses
Parameters
keya No./group parameters (mg/kg/day) monitored Endpoint
INTERMEDIATE EXPOSURE
PFHxS
33

Rat
(SpragueDawley)
15 M,F

42–56 days 0, 0.3, 1, 3,
1 time/day 10
(GW)
PFHxS

CS, BW, MX, Bd wt
DX, OW, OF, Resp
BI, HE, GN,
CardioHP, FI
GastroLessserious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

10
10
10
10

Hemato

10 F

0.3 M

6% increase in prothrombin time in males
at ≥0.3 mg/kg/day; decreases inhemoglobin (4%), hematocrit (3%), andRBC levels (2.4%) in males at≥3 mg/kg/day

Hepatic

10

Renal

3M

10 M

31% increase in BUN in males

Endocr

1b M
10 F

3M

Hypertrophy and hyperplasia of thyroid
follicular cells in males

Immuno10

No histological alterations

Neuro

10

No histological alterations

Repro

10

No histological alterations or effects on
fertility

Increased liver weight; centrilobular
hepatocellular hypertrophy in males at≥3 mg/kg/day

Develop
10 F
Butenhoff et al. 2009a (results also reported in Hoberman and York 2003)
34

Rat (Wistar) GDs 7–22
8F(GO)0, 25, 45
PFHxS

CS, BW, BC, Bd wt
DX, OW
EndocrDevelopRamhøj et al. 201845
25

60% decreases in serum T4 levels in
dams

25

40% decrease in serum T4 levels in pups
on PND 16

PERFLUOROALKYLS

95
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group
35

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint

Rat (Wistar) GDs 7–22
16–20F(GO)0, 0.05, 5, 25 CS, BW, BC, Bd wt
PFHxS
DX, OW
EndocrLess
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
25
0.05

5

20–30% decreases in serum T4 levels in
dams

Develop0.05

520% decrease in serum T4 levels in pups
on PND 16/17

Bd wt

6

Hepatic

6

Ramhøj et al. 2018
36

Mouse
4–6 weeks(E3L CETP) (F)
6–8 M

0, 6
PFHxS

BW, FI, BC,OW

Decreased plasma triglyceride,cholesterol, non-HDL cholesterol, andHDL cholesterol levels; increased hepatic
triglyceride levels, increased liver weight

Bijland et al. 2011
37

Mouse
(CD-1)
30 M, 30 F

M: 42 days 0, 0.3, 1, 3
F: 14 days PFHxS
premating,mating,gestation,lactation (G)CS, BW, FI, Bd wt
HE, BC, GN, Resp
HP, FX, RX,
CardioDX
GastroHematoMusc/skel
Hepatic

Renal
Endocr
Neuro
Repro
Develop

Chang et al. 2018

3
3
3
3
3
3
1

3

Single cell necrosis and microvascular
fatty changes at 3 mg/kg/day;
centrilobular hepatocellular hypertrophyat ≥0.3 mg/kg/day in F0 mice and at
3 mg/kg/day in F1 mice

3
3
3
3
0.3

1

Decrease in number of pups per litterwith no change in pup to implantationsite ratioPERFLUOROALKYLS

96
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group
PFNA
38

Rat
(SpragueDawley)
18 dams;
10–12 M,F
pups/litter

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint
GDs 1–20
(GW)

5
PFNA

Less
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

BW, OF, OW Bd wt

Develop

5

Reduced maternal body weight;
approximately 33% on GD 7 and 10% on
GD 20

5

Decreased birth weight in female pups
only (approximately 11%); increased
systolic blood pressure in 10-week-old
male and female offspring; reduced
nephron endowment

Rogers et al. 2014
39

Mouse
(CD-1)
8–10 FGDs 1–17(GW)0, 1, 3, 5, 10 BC, DX, FX,
PFNAMX, OW

Bd wt

10

Hepatic10Develop1c

BW, OW, BC Bd wt
HP, RX
Hepatic

0.5
0.5
0.2

43% maternal weight loss at GD 13
Increases in absolute and relative liver
weights in dams on GD 17 and on postweaning day 28 at ≥1 mg/kg/day

3

5

Delayed postnatal development [eyeopening, preputial separation and vaginal
opening] and decreased body weightgain persisting in males up to PND 287
at ≥3 mg/kg/day; decreased postnatal
survival between PND 2 and 10 with 80%
mortality at ≥5 mg/kg/day; full litter
resorptions at 10 mg/kg/day

Das et al. 2015
40

Mouse
(Parkes)
14 M

90 days(GW)

Singh and Singh 2018

0, 0.2, 0.5
PFNA

Repro

0.5

33% decrease in serum cholesterol
Decreased sperm motility, viability, andnumber; degenerative changes inseminiferous tubules; decreased littersize

PERFLUOROALKYLS

97
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group
41

Mouse
(129S1/
Svlm)
8F

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint
GDs 1–18(G)0, 0.83, 1.1,
1.5, 2.0
PFNA

BW, OW, DX Bd wt

Less
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
2.0

No alterations in maternal body weight or
gestational weight gain

Hepatic

2.0

Increase in dam liver weight at≥0.83 mg/kg/day

Develop

0.83

1.1

Decreased number of live births (36 and
31%) and pup survival at 1.1 and
2.0 mg/kg/day, but not 1.5 mg/kg/day;decreased number of live pups per litterand decreased pup body weight gain infemales at 2 mg/kg/day; increased pup
liver weight at ≥0.83 mg/kg/day

Wolf et al. 2010
42

Mouse
(PPARαknockout)
8F

Wolf et al. 2010

GDs 1–18(G)0, 0.83, 1.1,
1.5, 2.0
PFNA

BW, OW, DX Bd wt

2.0

No alterations in maternal body weight or
gestational weight gain

Hepatic

2.0

Increases in liver weight at≥1.5 mg/kg/day non-pregnant adults, but
not in the dams

Develop2.0

No alterations in the number of live pups
per litter, birth weight, pup survival, dayof eye opening, or pup body weight gain;
no increases in pup liver weight wereobserved

PERFLUOROALKYLS

98
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group

Exposure Doses
Parametersparameters (mg/kg/day) monitored EndpointLess
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

28 days

0.5

PFDA
43

Rat
(SpragueDawley)
8F

0, 0.125,
BW, HE, OW, Bd wt
0.25, 0.5, 1, 2 HP, IX
Resp
PFDA
Gastro1

Decreased body weight gain (21%)

0.5
0.5

Hemato

0.125

0.25

Decreased MCH and MCHC

Hepatic

0.25

0.5

Single cell necrosis

Hepatic
Renal
EndocrImmuno

0.5
0.5
0.5
0.125

0.25

Decreased phagocytosis by fixed tissue
macrophages in the liver

5
5
5
5
5
5
5
0.625

1.25

Decreases in splenic T-cells, T-cell
subsets, and macrophages

0.3

1.0

Decreased body weight (~10%) in males
during exposure and recovery and insatellite females during dosing (~23% on
day 40) and recovery (~10%)

0.3

1.0

Main study males: decreased MCV (5%),
MCH (5%), APTT (25%), and fibrinogen(33%) and increased platelet counts(7%); satellite males: increased WBC(52%) and decreased APTT (16%) andfibrinogen (19%); main study females:
increased MCV (10%) and MCH (10%)
and decreased fibrinogen (32%)

Frawley et al. 2018
44

Mouse
1 time/week 0, 0.325,(B6C3F1/N) 4 weeks
0.625, 1.25,
8F
2.5, 5PFDA

BW, HE, OW, Bd wt
HP, IX
Resp
GastroHematoHepatic
Renal
EndocrImmunoFrawley et al. 2018

PFUnA
45

Rat
41–46 days 0, 0.1, 0.3,
(Crl:CD[SD]) (GO)1.0
12 M,F
PFUnA(main);
5 M,F(other)

BH, BW, CS, Bd wt
HP, OF, OW,
UR
HematoPERFLUOROALKYLS

99
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group

Exposure Doses
Parametersparameters (mg/kg/day) monitored EndpointLess
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) EffectHepatic

1.0

Renal

0.3

1.0

Develop

0.3 F

1.0 F

Bd wt

900

Resp
CardioGastroHematoMusc/Skel
Hepatic

900
900
900
900
900
900

Renal
Ocular
EndocrImmuno
Neuro
Repro

900
900
900
900
900
900

LT, BW, OW, Resp
GN, HP, BC, Cardio
CS, BI, BH,
Gastro
HE

600
600
200

600

Hemato

60 M

200 M

Musc/skel

600

Increased absolute and relative liver
weight and centrilobular hypertrophy at
1.0 mg/kg/day
Increased BUN (61%) and ALP (140%);decreased total protein (11%) andalbumin (7%) in main group males
Decreased body weight in pups on
PNDs 0 and 4 (13–19% in males and
12–16% in females)

Takahashi et al. 2014

PFBS
46

Rat
(SpragueDawley)

28 days
1 time/day(GO)0, 100, 300,
900
PFBS

CS, BW, FI,
HE, BI, GN,
HP, OF

Increased absolute and relative liver
weight at 900 mg/kg/day

No histological alterations
No histological alterations
No histological alterations

3M 2001
47

Rat(SpragueDawley)
10 NS

90 days(G)

0, 60, 200,
600
PFBS

Necrosis of individual squamous cells inforestomach and hyperplasia andhyperkeratosis of limiting ridge
Decreased hemoglobin (4.9%) andhematocrit (5.2%)

PERFLUOROALKYLS

100
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group

Exposure Doses
Parametersparameters (mg/kg/day) monitored EndpointLess
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) EffectHepatic

600

Renal

200

Endocr

600

Neuro

600

600

Hyperplasia of medullary and papillary
tubules and medullary ducts and focal
papillary edema

Lieder et al. 2009a (data also reported in York 2003b)
48

Rat(SpragueDawley)

P0: starting 0, 30, 100,70 days
300, 1,000
PFBS
prior tomating;F1: startingat weaning(G)

BW, OW, FI, Bd wt
GN, HP, FX, Hepatic
MX, DX, TG

1,000
1,000

Increased liver weight in males at≥300 mg/kg/day

Renal

100

300

Medullary/papillary tubular and ductal
hyperplasia in P0 and F1

Repro

1,000

Develop

1,000

Bd wt

30

Hepatic30

BW, BC, OW, Bd wt
DX
Endocr

500
50

200

Decreased maternal total thyroxine, freethyroxine, and total triiodothyronine andincreased TSH

Develop50

200

Decreases in pup body weight; delays ineye opening, vaginal opening, and first
estrous; decreases in ovarian follicles;
decreases in uterine endometrial andmyometrial thickness; alterations in
reproductive hormone levels; decreases
in total T4 and total T3 and increases in
TSH

Lieder et al. 2009b (data also reported in York 2003c)
49

Mouse
4–6 weeks(E3L CETP) (F)
6–8 M

0, 30
PFBS

BW, FI, BC,OW

Decreased plasma triglyceride levels

Bijland et al. 2011
50

Mouse
(ICR)
30 F

Feng et al. 2017

GDs 1–20(G)

0, 50, 200,
500
PFBS

PERFLUOROALKYLS

101
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group51

Exposure Doses
Parametersparameters (mg/kg/day) monitored EndpointRat
GDs 6–20(Crl:CD(SD) (GW)
25 F

York 2002
52
Rat
GDs 6–20(Crl:CD(SD) (GW)
8F

0, 100, 300,
1,000
PFBS

BW FI DX0, 100, 300, BW FI DX
1,000, 2,000
PFBS

Less
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

Bd wt

300

1,000

31% decrease in maternal body weightgain

Develop

300

1,000

Decreases in fetal body weight (9%) anddelays in hindlimb ossification

Bd wt

1,000

2,000

12% decrease in maternal body weight

Develop

1,000

2,000

12–13% decrease in fetal body weights

York 2003a
PFBA
53

Rat
(SpragueDawley)
10 M,F

28 days
1 time/day

0, 6, 30, 150 CS, BW, OW, Bd wt
PFBA
FI, BI, HE,
GN, HP, OF Resp

150

Cardio150

Gastro150

Hemato150

Musc/skel

150

Hepatic

150

Renal

150

DermalOcular
Endocr150
150
6M

Immuno
Neuro
Repro

150
30 M
150

Butenhoff et al. 2012a; van Otterdijk 2007a150

Increased absolute and relative liver
weight and decreased serum cholesterolin males at ≥30 mg/kg/day;hepatocellular hypertrophy in males at
150 mg/kg/day

30 M

150 M

Hyperplasia/hypertrophy of follicularepithelium of the thyroid
No histological alterations
Delayed pupillary reflex
No histological alterations

PERFLUOROALKYLS

102
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group
54

Rat(SpragueDawley)
10 M,F

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint
90 days
1 time/day

0, 1.2, 6, 30
PFBA

CS, BW, FI,
OW, BI, HE,
GN, HP

Less
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

Bd wt

30

Resp

30

Cardio30

Gastro30

Hemato6

Musc/skel

30

Hepatic

30

Renal
DermalOcular
Endocr

30
30
30
6M

Immuno
Neuro
Repro

30
30
30

BW, MX, DX Hepatic

350

30 M

Reduced erythrocyte counts (3.8%),
hemoglobin (5.7%), and hematocrit(4.5%)
Diffuse panlobular hepatocyte
hypertrophy at 30 mg/kg/day in males

30 M

Hypertrophy/hyperplasia of follicularepithelium of the thyroid glandNo histological alterations
No histological alterations
No histological alterations

Butenhoff et al. 2012a; van Otterdijk 2007b
55

Mouse
(CD-1)

18 daysGDs 1–17
1 time/day(GW)

0, 35, 175,
350
PFBA

Develop
Das et al. 2008

Significant increase in absolute andrelative liver weight at ≥175 mg/kg/day

35

Eye opening delayed approximately
1 day

PERFLUOROALKYLS

103
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group
PFDoDA
56

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint

Rat (Crl:CD 42–47 days 0, 0.1, 0.5,(SD)) 12 M, (G)2.5
PFDoDA
17 F

Lessserious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) EffectCS, BW, BC, Death
HE, OW, HP, Bd wt
NX, RX, DX
Cardio0.5

2.5 F

Gastro2.5

Hemato58% mortality

2.5

Decreased body weight gain (20–30%)

0.5

2.5

Decreased mean corpuscular volume
and reticulocytes and increased mean
corpuscular hemoglobin concentration in
males

Hepatic

0.5 F

2.5 F

Single cell necrosis in females;
hepatocellular hypertrophy in males andfemales at 2.5 mg/kg/day; bile duct
proliferation at 2.5 mg/kg/day in females
in recovery group

Renal
Endocr

2.5
0.5

2.5

Neuro

0.5

2.5

Repro

0.5

2.5 F

Develop0.5

2.5

Pancreas: edema in the interstitium infemales and decrease in zymogen
granules in males; thymus: atrophy of thecortex in females; adrenals: atrophy ofthe cortex in males
Decreased forelimb grip in males andmotor activity in females during recovery
periodHemorrhage at the implantation site;
continuous diestrus in nonmated rats
Decreases in pup body weight (onlyone litter had live pups)

Endocr1

3

2.5

Kato et al. 2015
57

Rat
(SpragueDawley)
8F
Shi et al. 2009b

28 days0, 0.5, 1.5, 3
PNDs 24–72 PFDoDA(GW)

40% reduced serum estradiol in pubertal
femalesPERFLUOROALKYLS

104
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral

Exposure Doses
Parametersparameters (mg/kg/day) monitored EndpointLess
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

110 days
GW0, 0.02. 0.05, BW, BI, OW, Bd wt
0.2, 0.5
HP
Repro
PFDoDA

0.5
0.05

Rat (Crl:CD 90 days
(SD))
(GW)
10 M, 10 F

0, 10, 50, 200 CS, BW, FI, Bd wt
PFHxAHE, BC, UR, Resp
OP, NX, OW,
CardioGN, HP
Gastro200

Hemato50

Musc/skel

200

Hepatic200

Renal
Ocular
Endo
Neuro
Repro

200
200
200
200
200

SpeciesFigure (strain)
keya No./group
58

Rat(SpragueDawley)
6M
Shi et al. 2009a

0.2

Decreased serum testosterone (44%)

200

Slight decreases in RBC, hemoglobin,
and hematocrit and increases inreticulocytes

PFHxA
59

Chengelis et al. 2009b

200
200
200

Centrilobular hepatocellular hypertrophy
at 200 mg/kg/dayPERFLUOROALKYLS

105
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group60

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint

Rat
32–44 days
(CRL:CD(S (GW)D))
10–15 M,
10–15 F0, 50, 150,
315 (TWA
dose), 450(4 days)PFHxACS, BW, FI, Death
HE, BC, RX,
DX, OW, GN, Bd wt
HP
GastroLessserious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect450

8/30 deaths (includes rats sacrificed in
extremis) during first 4 days of exposure

315
315

Hemato50 M
315 F

Hepatic

315

Renal

315

Immuno

150 F
315 M

Repro

315

Develop315

Stomach erosions/ulceration in dying or
sacrificed in extremis rats administered
450 mg/kg/day for 4 days
150 M

Decreased hemoglobin levels; increased
reticulocytes at 315 mg/kg/day
Increased relative liver weight at≥150 mg/kg/day; hepatocellular
hyperplasia and decreased serum
cholesterol observed at 315 mg/kg/day

315 F

Thymic atrophy in 3/9 females

200 M

500 M

19% decrease in body weight gain

20

100

Degeneration/atrophy of nasal olfactory
epithelium at ≥100 mg/kg/day andrespiratory metaplasia at 500 mg/kg/day

Hemato100

500

Hepatic500

Decreased RBC, hemoglobin, andhematocrit; increased reticulocytes;
erythroid hypertrophy in bone marrowand extramedullary hematopoiesis inspleenHepatocellular hypertrophy in males at≥100 mg/kg/day and females at
500 mg/kg/dayOcular
Endocr
Neuro

500
100 F
500

500 F

Thyroid follicular epithelial hypertrophy

Kirkpatrick 2005
61

Rat
(CRL:CD(SD)
30 M, 30 F

Loveless et al. 2009

92–93 days 0, 20, 100,(GW)
500
NaPFHxCS, BW, FI, Bd wt
OP, BC, HE, Resp
UR, OW, GN,
HP, NXPERFLUOROALKYLS

106
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./group
62

Rat(CRL:CD(SD)
20M, 20F

Exposure Doses
Parametersparameters (mg/kg/day) monitored Endpoint110–
126 days;
70 daysprior tomating andduringmatinggestation,lactation(GW)

0, 20, 100,500
NaPFHxRat
GDs 1–20(CRL:CD
(GW)
(SD)
22 F
Loveless et al. 2009

0, 20, 100,500
NaPFHxCS, BW, FI,
RX, DX

Less
serious
Serious
NOAEL
LOAEL
LOAEL
(mg/kg/day) (mg/kg/day) (mg/kg/day) Effect

Bd wt

20 M
100 F

100 M
500 F

Decreased weight gain (12%);decreased maternal weight gain during
GDs 0–7 and increased maternal weightgain during lactation

Repro

500

Develop100

500

Decreased pup body weight (17–18%)
during lactation period

Bd wt

100

500

Decreased maternal weight gain (19%)

Develop100

500

Decreased fetal weight (10%)

Loveless et al. 2009
63

BW, FI, DX

CHRONIC EXPOSURE

PFHxA
64

Rat
104 weeks(Sprague(GW)
Dawley)60 or 70 M,F

M: 0, 2.5, 15, BC, BW, CS, Death
100 F: 0, 5, GN, HP, LE,
30, 200
OP, OW, UR
PFHxA
Bd wt
HematoHepatic

200 F

100 M
200 F
100 M

100 M
30F

200 F

200 F

36, 43, 33, and 22% survival rate infemales at 0, 5, 30, and 200 mg/kg/day,
respectively

8.1% reduction in mean RBC count and5.2% reduction in hemoglobin at 51
weeks; 23.6 and 53.6% increase in
reticulocyte counts at weeks 25 and 51,
respectively
Males: 42% decrease in triglycerides,
19% decrease in free fatty acids in males
at 100 mg/kg/day; hepatocellularnecrosis; 66% increase in triglycerides,
44% decrease in non-HDL cholesterol infemales at 200 mg/kg/dayPERFLUOROALKYLS

107
2. HEALTH EFFECTS

Table 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
SpeciesFigure (strain)
keya No./groupLess
serious
Serious
Exposure Doses
Parameters
NOAEL
LOAEL
LOAEL
parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effect
Renal

100 M

Neuro

100 M
200 F

200 F

Mild renal tubular degeneration and mild
to severe papillary necrosis; increased
mean urine volume (109%) and reduced
specific gravity (0.96%)

Klaunig et al. 2015
aThe number corresponds to entries in Figure 2-10.

bUsed to derive an intermediate-duration oral MRL of 2x10-5 mg/kg/day for PFHxS based on a measured serum PFHxS level of 89.12 µg/mL at the NOAEL doseand an empirical clearance model to estimate a HED. The NOAELHED of 0.0047 mg/kg/day was divided by an uncertainty factor of 30 (3 for extrapolation fromanimals to humans with dosimetric adjustment and 10 for human variability) and a modifying factor of 10 for database deficiencies.
cUsed to derive an intermediate-duration oral MRL of 3x10-6 mg/kg/day for PFNA based on a measured serum PFNA level of 8.91 µg/mL at the NOAEL dose andan empirical clearance model to estimate a HED. The NOAELHED of 0.001 mg/kg/day was divided by an uncertainty factor of 30 (3 for extrapolation from animals
to humans with dosimetric adjustment and 10 for human variability) and a modifying factor of 10 for database deficiencies.

ad lib = ad libitum; ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BC = biochemistry;
BH = behavioral; BI = biochemical changes; BUN = blood urea nitrogen; BW or Bd wt = body weight; Cardio = cardiovascular; CI = confidence interval;
CS = clinical signs; Develop = developmental; DX = developmental toxicity; EA = enzyme activity; Endocr = endocrine; (F) = feed; F = female(s); FI = food intake;
FOSA = perfluorooctane sulfonamide; FX = fetal toxicity; G = gavage; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; GO = gavage in oil
vehicle; GW = gavage in water vehicle; HDL = high-density lipoprotein; HE or Hemato = hematological; HP = histopathology; Immuno = immunotoxicological;
IX = immunotoxicity; LD50 = lethal dose, 50% kill; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MCH = mean corpuscularhemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; Musc/skel = musculoskeletal; MX = maternal toxicity;
NaPFHx = sodium perfluorohexanoate; Neuro = neurological; NOAEL = no observed-adverse-effect level; NS = not specified; NS = neurotoxicity; OF = organfunction; OP = ophthalmology; OW = organ weight; PFBA = perfluorobutanoic acid; PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoic acid;
PFDoDA = perfluorododecanoic acid; PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFUnA = perfluoroundecanoic acid; PPARα = peroxisome proliferator-activated receptor-α; RBC = red blood cell; Repro = reproductive; Resp = respiratory;
RX = reproductive toxicity; T3 = triiodothyronine; T4 = thyroxine; TG = teratogenicity; TSH =thyroid stimulating hormone; TWA = time-weighted average;
UR = urinalysis

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Figure 2-10. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
Acute (≤14 days)

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Figure 2-10. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
Acute (≤14 days)

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Figure 2-10. Levels of Significant Exposure to Other Perfluoroalkyls – OralIntermediate (15–364 days)

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Figure 2-10. Levels of Significant Exposure to Other Perfluoroalkyls – OralIntermediate (15–364 days)

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Figure 2-10. Levels of Significant Exposure to Other Perfluoroalkyls – Oral
Chronic (≥365 days)

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Table 2-6. Levels of Significant Exposure to PFOA – Dermal
Species(strain)No./group

Exposure
parameters Doses

Parameters
monitored EndpointLess
serious
LOAEL

Serious
LOAEL

EffectDeath

7,000 M

14-day LD50

Bd wt
Dermal3,000 M F 5,000 M F

3,000 M F 5–7% transient weight loss
Mild skin irritation

Bd wt

20 M

200 M

Resp

2,000 M

Cardio2,000 M

GastroHematoHepatic
Renal
DermalOcular
EndocrImmunoNeuro
Repro

2,000 M
2,000 MNOAELACUTE EXPOSURE

Rat
(CD)
15 M,F

Once

3,000, 5,000,
7,500 mg/kg

CS, LE

Kennedy 1985
APFO
LD50 in females was >7,500 mg/kg
Rat
(CD)
60 M

2 weeks
0, 20, 200,
CS, BW,
6 hours/day 2,000 mg/kg/day HE, BI,
5 days/week
GN, HP

20 M
2,000 M
20 M
2,000 M
2,000 M
2,000 M
2,000 M
2,000 M

200 M

14% weight loss

Foci of coagulative necrosis
2,000 M

Skin irritation; acute necrotizing dermatitis

Kennedy 1985
APFO
The immunological NOAEL is for histopathology of the spleen, thymus, and lymph nodes. The neurological NOAEL is for histopathology of the brain. The
reproductive NOAEL is for histopathology of the testes.
Mouse
4 days0, 0.25, 2.5,
BW, OW, Bd wt
50 F(BALB/c)
1 time/day 6.25, 12.5, 25,OF
Hepatic
2.5 F
6.25 F
52% increase in absolute liver weight
35 F
50 mg/kg/day
Fairley et al. 2007
PFOA

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Table 2-6. Levels of Significant Exposure to PFOA – Dermal
Species(strain)No./group

Exposure
parameters Doses

Parameters
monitored EndpointMouse
4 days(BALB/c)
1 time/day
35 F
Fairley et al. 2007
PFOA

0, 12.5, 18.8, 25, BW, OW,
50 mg/kg/day
OF

ImmunoRabbitOnce(albino)(NS)
6 NS
Griffith and Long 1980
APFO

100 mgCS

Ocular

Rabbit24 hours(albino)(NS)
6 NS
Griffith and Long 1980
APFO

500 mgCS

DermalRabbitOnce(New Zealand)
17 M

1,500, 3,000,
5,000,
7,500 mg/kg

CS, LE

Death

NOAEL

Less
serious
LOAEL

12.5

18.8

Increased serum IgE following ovalbuminchallenge

100

Moderate eye irritation

4,300

14-day LD50

Serious
LOAEL

Effect500

Kennedy 1985
APFO
APFO = ammonium perfluorooctanoate; BI = biochemical changes; BW or Bd wt = body weight; Cardio = cardiovascular; CS = clinical signs; Endocr = endocrine;
F = female(s); Gastro = gastrointestinal; GN = gross necropsy; HE or Hemato = hematological; HP = histopathology; Immuno = immunotoxicological; LD50 = lethaldose, 50% kill; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); Neuro = neurological; NOAEL = no-observed-adverse-effect level;
NS = not specified; OF = organ function; OW = organ weight; PFOA = perfluorooctanoic acid; Repro = reproductive; Resp = respiratory

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2.2

DEATH

Overview. There are limited data regarding the lethality of perfluoroalkyls in humans; the available dataprimarily come from cohort mortality studies in workers; data were only available for PFOA and PFOS.
These studies did not find increases in deaths from all causes associated with PFOA and PFOS, althoughsome increases in disease-specific mortalities were observed. Laboratory animal studies have measured
LC50 and LD50 values and reported deaths following inhalation, oral, or dermal exposure toperfluoroalkyls. Increases in mortality have also been observed in repeated-exposure studies. These data
are presented in Tables 2-1, 2-2, 2-3, 2-4, 2-5, and 2-6 and Figures 2-6, 2-7, 2-8, 2-9, and 2-10. No
laboratory animal data were available for PFHxS, PFUnA, PFHpA, PFBS, PFBA, or FOSA.

PFOA

Epidemiological Studies. Five occupational exposure studies at two PFOA manufacturing facilities haveexamined the possible associations between PFOA exposure and increases in mortality from all causes
and have not found associations (Gilliland and Mandel 1993; Leonard 2006; Leonard et al. 2008; Lundin
et al. 2009; Raleigh et al. 2014; Steenland and Woskie 2012). Some increases in disease-specificmortality have been observed; these data are discussed in subsequent sections of this chapter(Sections 2.5, 2.8, 2.10, 2.18, and 2.19).

Laboratory Animal Studies. Limited data are available regarding death in animals following inhalation
exposure to perfluoroalkyls. Exposure of male and female rats to 18,600 mg/m3 ammonium
perfluorooctanoate (APFO) dusts for 1 hour did not result in deaths during exposure or during a 14-day
observation period (Griffith and Long 1980); APFO is the ammonium salt of PFOA. An LC50 of
980 mg/m3 was reported in male CD rats exposed head-only to APFO dusts for 4 hours (Kennedy et al.
1986). Deaths occurred at all exposure levels (380–5,700 mg/m3) and all deaths occurred within 48 hours
of exposure. Rats dying during exposure had hyperinflated lungs. A similar LC50 value of 820 mg/m3
was calculated for male CD rats exposed nose-only to APFO dusts for 4 hours (Kinney et al. 1989).
Unlike the Kennedy et al. (1986) study, one death was observed at 590 mg/m3 and no deaths occurred at
620 mg/m3. In a developmental study with APFO, whole-body exposure of 12 pregnant rats to 25 mg/m3,
6 hours/day during GDs 6–15 resulted in three deaths on GDs 12, 13, and 17 compared with no deaths ingroups exposed to ≤10 mg/m3 (Staples et al. 1984). The cause of death was not reported.

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Oral LD50 values of 680 and 430 mg/kg were reported for male and female albino rats, respectively,
administered single gavage doses of APFO and observed for 14 days (Griffith and Long 1980); allanimals at the highest dose of 2,150 mg/kg died on day 1. Nonlethal signs observed included ptosis,
piloerection, hypoactivity, decreased limb tone, ataxia, and corneal opacity. All signs were intermittent
and there was no apparent dose-response relationship. In a 28-day dietary study with APFO in rats, allrats (males and females) in groups receiving approximately 1,000–1,130 mg/kg/day APFO died before
the end of the first week (Griffith and Long 1980). In a similar study in mice, all mice receiving doses ofapproximately 180–195 mg/kg/day died before the second week of the study (Griffith and Long 1980). In
this study, doses of approximately 54–58 mg/kg/day APFO were lethal to 4/5 male and 5/5 female mice
before the 4th week of the study.

In a 90-day gavage study, treatment of Rhesus monkeys with 100 mg/kg/day APFO by gavage resulted in
the death of an unspecified number of animals (group size was 10/sex) on week 2 (Griffith and Long
1980). Doses of approximately 30 mg/kg/day were lethal to one male and two females during weeks 7–
12. All animals that died in the 30 and 100 mg/kg/day groups had anorexia, emesis, black stool, pale faceand gums, swollen face and eyes, hypoactivity, and prostration. Microscopic examination of tissues
showed marked diffuse lipid depletion in the adrenals, slight to moderate hypocellularity of the bonemarrow, moderate atrophy of the lymphoid follicles of the spleen, and moderate atrophy of the lymphoidfollicles of the lymph nodes. No deaths occurred at 10 mg/kg/day. Deaths were also reported inintermediate-duration studies in Cynomolgus monkeys (Butenhoff et al. 2002). One monkey exposed to
30/20 mg/kg/day PFOA (12 days of exposure to 30 mg/kg/day, 10 days with no exposure, 23 weeks of
exposure to 20 mg/kg/day) was sacrificed in moribund condition; the animal had a body weight loss of
12.5%, was notably hypoactive, and was cold to the touch (Butenhoff et al. 2002). The investigators
noted that the death was likely due to the high toxicity of the 30 mg/kg/day dose. It is unclear if these
deaths were compound-related; one monkey had pulmonary necrosis with a severe acute recurrence ofpulmonary inflammation and the cause of morbidity for the second monkey was likely hyperkalemia.
Neither effect was observed in the surviving animals.

The dermal LD50 values for APFO were 7,000 mg/kg in male CD rats and >7,500 mg/kg in female rats
(Kennedy 1985). The protocol consisted of application of PFOA (as an aqueous paste) to a clipped areaof the skin, which immediately was covered with gauze pads and wrapped with rubber sheeting aroundthe trunk. The contact period was 24 hours, at which time the application site was washed with water andthe rats were observed for clinical signs for 14 days. Using the same protocol, the dermal LD50 in male
rabbits was 4,300 mg/kg (Kennedy 1985). Rabbits treated with 1,500 mg/kg showed skin irritation with

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formation of a large crusty area at the application site. No deaths occurred at 1,500 mg/kg. Rabbits
treated with 3,000 mg/kg were lethargic and a single death occurred 7 days after treatment. At
5,000 mg/kg, deaths occurred in 3–4 days. These rabbits also showed nasal discharge, pallor, diarrhea,
weakness, severe weight loss, and severe skin irritation along with areas of necrosis.

PFOS

Epidemiological Studies. One occupational exposure study evaluated the potential of PFOS to increaselethality; the study did not find increases in deaths from all causes in workers at a PFOS manufacturing
facility (Alexander et al. 2003). Alterations in disease-specific mortality are discussed in subsequent
sections of this chapter.

Laboratory Animal Studies. Unpublished information summarized by the Organization for Economic
Co-operation and Development (OECD) (2002) indicates that an LC50 of 5,200 mg/m3 was calculated for
PFOS in male and female Sprague-Dawley rats exposed to airborne concentrations of PFOS dusts from1,890 to 45,970 mg/m3 for 1 hour. All rats exposed to 24,090 mg/m3 died by day 6.

Unpublished information summarized by OECD (2002) indicate that LD50 values of 233 and 271 mg/kg
were calculated for male and female CD rats, respectively, following administration by gavage of single
doses of up to 1,000 mg/kg of powdered PFOS suspended in an acetone/oil mixture and observed for
14 days. All rats (5/sex/dose group) dosed with ≥464 mg/kg PFOS died before the end of the study. The
signs most frequently observed were hypoactivity, decreased limb tone, and ataxia. Gross necropsy
showed stomach distension and signs of irritation of the glandular mucosa, and lung congestion. OECD
(2002) also reported that a different study estimated that the acute oral LD50 for PFOS by gavage in waterin Sherman-Wistar albino rats was >50 and <1,500 mg/kg. An oral LD50 value of 579 mg/kg/day wasreported for male C57/BL/6 mice administered single gavage doses of PFOS and observed for 14 days
(Xing et al. 2016). Mortality occurred within 3 hours of dosing, and moribund mice displayed signs ofneurotoxicity (abdominal breathing, hind limb spasticity, tics, and urinary incontinence).

In a 26-week study, 2/6 male Cynomolgus monkeys administered 0.75 mg/kg/day PFOS via a capsuledied or were sacrificed due to morbidity (Seacat et al. 2002). The cause of death in one monkey waspulmonary inflammation; the cause of morbidity in the second monkey was not determined, but the
animal did have hyperkalemia.

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PFNA
Laboratory Animal Studies. A LC50 of 820 mg/m3 was identified in rats exposed to airborne PFNA for
4 hours (Kinney et al. 1989). In a 14-day dietary exposure study, all mice administered approximately
54 mg/kg/day PFNA died before the study period ended; no deaths occurred at 5.3 mg/kg/day (Kennedy1987).
PFDA

Laboratory Animal Studies. An LD50 of 120 mg/kg was estimated for PFDA in female C57BL/6N miceadministered single doses between 20 and 320 mg/kg/day PFDA by gavage in corn oil and observed for
30 days (Harris et al. 1989). All mice receiving 160 or 320 mg/kg were dead by 14 days; no mice died at≤80 mg/kg PFDA. Early death was associated with mural thrombosis in the left ventricle of the heart.
Without providing any details, George and Andersen (1986) reported that the 30-day oral LD50 for PFDA
in male Fischer-344 rats was 57 mg/kg.
PFDoDA

Laboratory Animal Studies. Increases in mortality were observed in pregnant rats administered
2.5 mg/kg/day for 14 days prior to mating and throughout gestation; 4/12 dams between GD 18 and 22
and another 3 dams were sacrificed during the period due to morbidity (Kato et al. 2015). No deaths wereobserved in males or nonpregnant females exposed to 2.5 mg/kg/day (Kato et al. 2015).

PFHxA

Laboratory Animal Studies. In a single exposure gavage study, deaths occurred in rats administered
1,750 or 5,000 mg/kg sodium perfluorohexanoate (NaPFHx) (Loveless et al. 2009). Decreased survival
was observed in female Sprague-Dawley rats administered 200 mg/kg/day PFHxA via gavage in a
104-week study (Klaunig et al. 2015). There was no significant effect on survival rates of males.
Mortality and morbidity were observed in male and female rats administered 450 mg/kg/day PFHxA via
gavage for 4 days (Kirkpatrick 2005). The cause of death was determined to be renal papillary necrosis
and/or stomach erosion/ulceration.

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2.3

BODY WEIGHT

Overview. Epidemiological studies have examined the possible associations between in utero and/or
early life exposure to perfluoroalkyls and body weight, body mass index (BMI; measure of body fat basedon body weight and height), etc. Other studies have examined possible associations between serum
perfluoroalkyl levels in older children or adults and body weight, adiposity markers, and the risk of being
overweight or obese. The results of the epidemiological studies are summarized in Table 2-7, with moredetailed descriptions presented in the Supporting Document for Epidemiological Studies for
Perfluoroalkyls, Table 1. No epidemiological data were available for PFHpA, PFBS, PFBA, PFDoDA,or PFHxA. Animal studies have evaluated changes in body weight, including maternal body weight, in
response to inhalation, oral, or dermal exposure to perfluoroalkyls; these data are summarized inTables 2-1, 2-2, 2-3, 2-4, 2-5, and 2-6 and Figures 2-6, 2-7, 2-8, 2-9, and 2-10. No laboratory animalstudies examining body weight were identified for PFHpA.

Overall, the evidence from epidemiological studies does not suggest an association between in utero
and/or early life exposure to perfluoroalkyls and alterations in growth (body weight or length), bodycomposition (e.g., BMI), or the risk of being overweight or obese in children for PFOA, PFOS, PFHxS,or PFNA. Conclusions cannot be drawn for PFDA, PFUnA, PFDoDA, or FOSA because of the small
number of studies (less than 5 studies for each compound) examining potential body weight endpoints. A
small number of studies examined potential associations between PFOA and body weight effects in adults
and only one study examined PFOS, PFHxS, PFNA, and PFDA associations; these data were consideredinadequate for assessing potential associations in adults.

Studies in laboratory animals exposed to PFOA, PFOS, PFNA, PFDA, PFUnA, PFDoDA, or PFHxA
have consistently shown decreases in body weight or decreases in body weight gain. Studies with PFOA
suggest that the decrease in body weight gain does not appear to be associated with alterations in foodconsumption and the mechanism may involve PPARα as studies in PPARα null have not found decreases
in body weight gain. The small number of studies examining PFHxS, PFBS, PFBA, and FOSA have notreported decreases in body weight; although decreases in maternal body weight gain were observed for
PFBS.

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb
PFOA
Barry et al. 2014
Community (C8) (n=8,764 20–40-year-olds)
Alkhalawi et al. 2016

Serum perfluoroalkyl level Outcome evaluatedResultc

164.6 and 194.3 ng/mL(estimated early life [first
3 years] median PFOA)

OR 0.9 (0.7–1.1), males
OR 0.9 (0.7–1.1), females

Overweight or obesity at
age 20–40 years

2.43 ng/mL (maternal
geometric mean serum
General population (n=156 mother-child pairs) PFOA)NS (p>0.05)

Andersen et al. 2010

Inverse association (p<0.05)*, boys
NS (p>0.05), girls
Inverse association (p<0.05)*, boys
NS (p>0.05), girls
NS (p>0.05), boys
NS (p>0.05), girls
NS (p>0.05)
NS (p>0.05)

General population (n=1,010 infants)

Andersen et al. 2013
General population (n=811 children aged
7 years)
Braun et al. 2016a, 2016b

Body weight at 1, 4, 6, and12 months of age
Body length at 1, 4, 6, and12 months of age
5.21 ng/mL (maternal median Body weight (age 5 and
PFOA)
12 months)
BMI (age 5 and 12 months)
Height (age 5 and12 months)
5.25 ng/mL (maternal median BMI
PFOA)
Waist circumference

5.3 ng/mL (maternal median
PFOA)

General population (n=204 children)

Cao et al. 20181.59 ng/mL (mean cord
serum PFOA)

General population (n=337 infants)de Cock et al. 2014
General population (n=89 infants aged 1–
11 months)

0.9402 ng/mL (cord blood
mean PFOA)NS (p>0.05)

Changes in BMI scores
between 2 and 8 years ofage
Overweight/obesity risk

Association (p=0.03)*

Body weight at 19 months

NS (p=0.57)

Length at 19 months
Head circumference at
19 months
WeightHeightBMIHead circumference

NS (p=0.16)
NS (p=0.94)

RR 1.54 (0.77–3.07), 3rd tertile

NS (p=0.350)
NS (p=0.045)
NS (p=0.813)
NS (p=0.774)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Halldorsson et al. 2012

3.7 and 5.8 ng/mL (maternal BMI
median PFOA and 4th quartile Waist circumference
median)Overweight risk

Association (p=0.001)*, females
Association (p=0.006)*, females
RR 3.1 (1.4–6.9)*, females
4th quartile
RR 3.0 (1.3–6.8)*, females
4th quartile
NS (p=0.20)
NS (p=0.05)

General population (n=665 20-year-olds)

High waist circumference
Hartman et al. 2017
General population (n=359 girls aged 9 years)

3.7 ng/mL (maternal median
PFOA)

Total body fatness
Trunk fatness

BMI
Høyer et al. 2015b
2.2–5.1 and 1.1–9.8 ng/mL
Overweight(maternal 3rd tertile PFOA for
Greenland cohort
Ukraine cohort
General population (n=1,122 children aged 5– Greenland and Ukraine
9 years; n=531 for Greenland cohort andcohorts)
Waist-to-height ratio >0.5
n=491 for Ukraine cohort)Greenland cohort
Ukraine cohort
Karlsen et al. 20171.37 ng/mL (maternal
BMI score, 18 months
geometric mean serum
BMI score, 5 years
General population (n=444 children)
PFOA)
Risk of being overweight
18 months
Risk of being overweight
5 years
Karlsen et al. 20172.22 ng/mL (child geometric BMI scoremean serum PFOA)
Risk of being overweight
General population (n=444 children aged
5 years)

NS (p=0.05)

Koshy et al. 2017

OR 0.98 (0.90–1.13)

General population (WTCHR, n=180 children;
n=222 children in comparison group)

1.81 and 1.39 ng/mL (median Risk of being overweight
serum PFOA in WTCHR
group and comparison group)

RR 1.23 (0.87–1.74), 3rd tertile
RR 0.78 (0.47–1.29), 3rd tertile
RR 1.18 (0.80–1.74), 3rd tertile
RR 1.11 (0.48–2.57), 3rd tertile
NS (p>0.05)
NS (p>0.05)
RR 1.14 (0.92–1.4)
RR 1.50 (1.01–2.24, p<0.05)*
Inverse association (p<0.05)*
RR 0.68 (0.38–1.22)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Liu et al. 2018a

4.5 ng/mL (median serum
PFOA)

NS (p=0.73, trend)
NS (p=0.16, trend)
NS (p=0.78, trend)
Association (p=0.007, trend)*

General population (n=621 adults in weightloss clinical trial)

Manzano-Salgado et al. 2017b
General population (n=1,230 children)2.32 ng/mL (maternal
geometric mean serum
PFOA)

Mora et al. 2017

5.6 ng/mL (maternal medianplasma PFOA in early
General population (n=1,006 at median age of childhood group)
3.2 years and n=876 at median age of
7.7 years)

Mora et al. 2017

5.6 ng/mL (maternal medianplasma PFOA in late
General population (n=1,006 at median age of childhood group)
3.2 years and n=876 at median age of
7.7 years)

Weight loss
Weight regain
Males
Females
Resting metabolic rate
Weight loss period
Weight regain period
Weight gain until 6 monthsof age
BMI at 4 years of age
BMI at 7 years of age
Waist circumference at
4 years of age
Waist circumference at
7 years of age
BMI
Waist circumference

NS (p=0.48, trend)
Association (p=0.03, trend)*
β 0.04 (-0.04–0.12)
β 0.04 (-0.04–0.13)
β 0.03 (-0.08–0.13)
β 0.00 (-0.09–0.10)
β -0.02 (-0.11–0.06)

Risk of being overweight
Risk of being obese
BMI
Total fat mass index

β 0.09 (-0.02–0.19),
β 0.31 (0.04–0.57)*, boys and girls
β 0.50 (0.06–0.93)*, boys only
β 0.14 (-0.18–0.47), girls only
RRR 1.05 (0.87–1.26)
RRR 1.03 (0.80–1.32)
β 0.13 (-0.10–0.35)
β 0.13 (0.02–0.29)

Waist circumference
Risk of being overweight
Risk of being obese

β 0.20 (-0.39–0.80)
RRR 1.02 (0.88–1.29)
RRR 1.10 (0.88–1.37)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Timmermann et al. 2014

9.3 ng/mL (mean PFOA)NS (p>0.05), per 10 ng/mL PFOA
increase

Adiposity markers

General population (n=499 8–10-year-old
children)
Wang et al. 2016
General population (n=117 boys and 106 girls
examined at 2, 5, 8, and 11 years of age)
PFOS
Alkhalawi et al. 20162.37 and 2.34 ng/mL (median Growth during childhood
maternal PFOA for boys andgirls)NS (p>0.05)

9.04 ng/mL (maternal
geometric mean serum
General population (n=156 mother-child pairs) PFOS)
Andersen et al. 2010
General population (n=1,010 infants)

Andersen et al. 2013
General population (n=811 children aged
7 years)
Braun et al. 2016a, 2016b
General population (n=204 children)

Body weight at 1, 4, 6, and NS (p>0.05)
12 months of age
Body length at 1, 4, 6, and NS (p>0.05)
12 months of age
33.8 ng/mL (maternal median Body weight (age 5 months) NS (p>0.05), boys
PFOS)
NS (p>0.05), girls
Body weight (ageInverse association (p<0.05)*, boys
12 months)
NS (p>0.05), girls
BMI (age 5 months)
NS, boys
NS (p>0.05), girls
BMI (age 12 months)
Inverse association (p<0.05)*, boys
NS (p>0.05), girls
Height (age 5 andNS (p>0.05), boys
12 months)
NS (p>0.05), girls
33.8 ng/mL (maternal median BMI
NS (p>0.05)
PFOS)
Waist circumference
NS (p>0.05)

13 ng/mL (maternal median
PFOS)

Changes in BMI scores
between 2 and 8 years ofage
Overweight/obesity risk

NS (p>0.23)

RR 1.08 (0.59–1.95), 3rd tertilePERFLUOROALKYLS

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Cao et al. 2018

1.43 ng/mL (mean cord
serum PFOS)

NS (p=0.72)
NS (p=0.91)
NS (p=0.63)

General population (n=337 infants)
Halldorsson et al. 2012
General population (n=665 20-year-olds)
Høyer et al. 2015b

Body weight at 19 months
Length at 19 months
Head circumference at
19 months
21.5 and 5.8 ng/mL (maternal BMI
median PFOS)
Waist circumference

23.9–87.3 and 5.9–
18.1 ng/mL (maternal 3rdGeneral population (n=1,122 children aged 5– tertile PFOS for Greenland
9 years; n=531 for Greenland cohort andand Ukraine cohorts)
n=491 for Ukraine cohort)
Hartman et al. 2017
General population (n=359 girls aged 9 years)
Karlsen et al. 2017
General population (n=444 children)

Karlsen et al. 2017
General population (n=444 children aged
5 years)
Koshy et al. 2017
General population (WTCHR, n=180 children;
n=222 children in comparison group)

Overweight
Greenland cohort
Ukraine cohort
Waist-to-height ratio >0.5
Greenland cohort
Ukraine cohort
19.7 ng/mL (maternal median Total body fatness
PFOS)
Trunk fatness
BMI
8.04 ng/mL (maternal
BMI score, 18 months
geometric mean serum
BMI score, 5 years
PFOS)
Risk of being overweight
18 months
Risk of being overweight
5 years
4.68 ng/mL (child geometric BMI scoremean serum PFOS)
Risk of being overweight

3.72 and 2.78 ng/mL (median Risk of being overweight
serum PFOS in WTCHR
group and comparison group)

NS (p>0.56)
NS (p>0.56)
RR 0.84 (0.61–1.14), 3rd tertile
RR 0.89 (0.57–1.37), 3rd tertile
RR 1.22 (0.86–1.74), 3rd tertile
RR 1.44 (0.62–3.31), 3rd tertile
NS (p=0.12)
Inverse association (p=0.02)
Inverse association (p=0.03)*
Association (p<0.05)
NS (p>0.05)
RR 1.29 (1.01–1.64)*
RR 1.01 (0.58–1.75)
NS (p>0.05)
RR 0.68 (0.36–1.29)

OR 1.00 (0.90–1.07)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Liu et al. 2018a24.5 ng/mL (median serum
PFOS)

Weight loss
Weight regain
Males
Females
Resting metabolic rate
Weight loss period
Weight regain period
19.6 ng/mL (median maternal Body weight at 20 months
PFOS)(adjusted for birth weight)

NS (p=0.27, trend).
Association (p=0.009, trend)*
NS (p=0.34, trend)
Association (p=0.001, trend)*

5.80 ng/mL (maternal
geometric mean serum
PFOS)

β -0.02 (-0.11–0.07)

General population (n=621 adults in weightloss clinical trial)

Maisonet et al. 2012
General population (n=447 girls)
Manzano-Salgado et al. 2017b
General population (n=1,230 children)

Weight gain until 6 monthsof age

BMI at 4 years of age
BMI at 7 years of age
Waist circumference at
4 years of age
Waist circumference at
7 years of age
Mora et al. 201724.8 ng/mL (maternal median BMI
plasma PFOS in early
General population (n=1,006 at median age of childhood group)
3.2 years and n=876 at median age ofWaist circumference
7.7 years)
Risk of being overweight
Risk of being obese
Mora et al. 201724.7 ng/mL (maternal median BMI
plasma PFOS in late
Total fat mass index
General population (n=1,006 at median age of childhood group)
Waist circumference
3.2 years and n=876 at median age of
7.7 years)

Risk of being overweight
Risk of being obese

Association (p<0.001, trend)*
Association (p<0.001, trend)*
Significant trend (p<0.0001) when
adjusted for birth weight andheightβ 0.04 (-0.05–0.13)
β 0.03 (-0.08–0.14)
β -0.03 (-0.13–0.07)
β 0.00 (-0.09–0.09)
β 0.04 (0.05–0.12)*, boys and girls
β 0.02 (-0.11–0.15), boys only
β 0.04 (-0.08–0.16), girls only
β 0.05 (-0.17–0.27)
RRR 1.07 (0.92–1.24)
RRR 0.97 (0.76–1.23)
β 0.16 (-0.04–0.36)
β 0.11 (-0.03–0.25)
β 0.34 (-0.19–0.87),
RRR 1.15 (0.95–1.40)
RRR 1.12 (0.99–1.47)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Timmermann et al. 201441.5 ng/mL (mean PFOS)

Adiposity markers

NS (p>0.05), per 10 ng/mL PFOS
increase

Body weight at 1, 4, 6, and12 months of age
Body weight (longitudinal
analysis)
Body length at 1, 4, 6, and12 months of age
Body length (longitudinal
analysis)
Changes in BMI scores
between 2 and 8 years ofage
Overweight/obesity risk

NS (p>0.05)

0.16 ng/mL (mean cord
serum PFHxS)

Body weight at 19 months
Length at 19 months

NS (p=0.96)
NS (p=0.31)

1.6 ng/mL (maternal median
PFHxS)

Total body fatness

NS (p=0.47)

Trunk fatness
BMI
BMI score, 18 months
BMI score, 5 years
Risk of being overweight
18 months
Risk of being overweight
5 years

NS (p=0.77)
NS (p=0.37)
NS (p>0.05)
NS (p>0.05)
RR 1.12 (0.97–1.30)

General population (n=499 8–10-year-old
children)
PFHxSAlkhalawi et al. 2016

0.62 ng/mL (maternal
geometric mean serum
General population (n=156 mother-child pairs) PFHxS)

Braun et al. 2016a, 2016b

1.4 ng/mL (maternal median
PFHxS)

General population (n=204 children)
Cao et al. 2018
General population (n=337 infants)
Hartman et al. 2017
General population (n=359 girls aged 9 years)
Karlsen et al. 2017
General population (n=444 children)

0.19 ng/mL (maternal
geometric mean serum
PFHxS)

β -5.270 (-9.591 to -0.950)*
NS (p>0.05)
β 4.516 (1.368–7.664)*
NS (p>0.23)

RR 1.48 (0.75–2.96), 3rd tertile

RR 1.11 (0.77–1.59)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Karlsen et al. 20170.34 ng/mL (child geometricmean serum PFHxS)BMI score
Risk of being overweight

NS (p>0.05)
RR 0.73 (0.44–1.23)

0.67 and 0.53 ng/mL (median Risk of being overweight
serum PFHxS in WTCHR
group and comparison group)

OR 1.04 (0.97–1.11)

3.6 ng/mL (median serum
PFHxS)

Weight loss
Weight regain
Males
Females
Resting metabolic rate
Weight loss period
Weight regain period
Body weight at 20 months

NS (p=0.45, trend).
NS (p=0.49, trend)
NS (p=0.17 trend)
Association (p=0.009, trend)*

Weight gain until 6 monthsof age
BMI at 4 years of age
BMI at 7 years of age
Waist circumference at
4 years of age
Waist circumference at
7 years of age

β -0.06 (-0.15–0.02)

General population (n=444 children aged
5 years)
Koshy et al. 2017
General population (WTCHR, n=180 children;
n=222 children in comparison group)
Liu et al. 2018a
General population (n=621 adults in weightloss clinical trial)

Maisonet et al. 2012
General population (n=447 girls)
Manzano-Salgado et al. 2017b
General population (n=1,230 children)

1.6 ng/mL (maternal median
PFHxS)
0.61 ng/mL (maternal
geometric mean serum
PFHxS)

Association (p=0.04, trend)*
Association (p=0.02, trend)*
NS (p=0.4375 for trend)

β -0.02 (-0.10–0.07)
β -0.04 (-0.14–0.06)
Β -0.04 (0.14–0.15)
NS β -0.04 (-0.12–0.04)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedMora et al. 2017

2.4 ng/mL (maternal medianplasma PFHxS in early
General population (n=1,006 at median age of childhood group)
3.2 years and n=876 at median age of
7.7 years)

BMI
Waist circumference
Subscapular and triceps
skinfold thickness

Mora et al. 2017

Risk of being overweight
Risk of being obese
BMI

2.3 ng/mL (maternal medianplasma PFHxS in late
General population (n=1,006 at median age of childhood group)
3.2 years and n=876 at median age of
7.7 years)

Total fat mass index
Waist circumference
Subscapular to triceps
skinfold thickness ratio
Risk of being overweight
Risk of being obese

PFNA
Braun et al. 2016a, 2016b

0.9 ng/mL (maternal median
PFNA)

General population (n=665 20-year-olds)
Hartman et al. 2017
General population (n=359 girls aged 9 years)

β 0.11 (-0.03–0.25)
β 0.11 (-0.22–0.43)
β 0.02 (-0.02–0.06), boys and girls
β -0.50 (-1.70–0.71), boys only
β 1.61 (0.58–2.65)*, girls only
RRR 1.04 (0.92–1.17)
RRR 1.07 (0.94–1.22)
NS (p>0.23)

0.3 ng/mL (maternal medianPFNA)
0.5 ng/mL (maternal median
PFNA)

Total body fatness
Trunk fatness

NS (p=0.26)
NS (p=0.97)

BMI

NS (p=0.68)

0.13 ng/mL (mean cord
serum PFNA)

General population (n=337 infants)
Halldorsson et al. 2012

β 0.01 (-0.05–0.06)
β 0.03 (-0.10–0.16)
β 0.16 (0.01–0.31)*, boys and girls
β 0.15 (-0.09–0.38), boys only
β 0.18 (-0.03–0.38, girls only
RRR 1.03 (0.94–1.13)
RRR 1.02 (0.89–1.17)
β 0.04 (-0.08–0.17)

Changes in BMI scores
between 2 and 8 years ofage
Overweight/obesity risk
Body weight at 19 months
Length at 19 months
Head circumference at
19 months
BMI
Waist circumference

General population (n=204 children)
Cao et al. 2018

Resultc

RR 1.26 (0.64–2.48), 3rd tertile
NS (p=0.88)
NS (p=0.15)
NS (p=0.62)
NS (p>0.56)
NS (p>0.56)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Karlsen et al. 20170.67 ng/mL (maternal
geometric mean serum
PFNA)

BMI score, 18 months
BMI score, 5 years
Risk of being overweight
18 months
Risk of being overweight
5 years
BMI score
Risk of being overweight

NS (p>0.05)
NS (p>0.05)
RR 1.02 (0.79–1.31)

0.61 and 0.49 ng/mL (median Risk of being overweight
serum PFNA in WTCHR
group and comparison group)

OR 1.01 (0.92–1.13)

1.5 ng/mL (median serum
PFNA)

NS (p=0.28, trend).
Association (p=0.01, trend)*
NS (p=0.48 trend)
Association (p=0.006, trend)*

General population (n=444 children)

Karlsen et al. 2017
General population (n=444 children aged
5 years)
Koshy et al. 2017
General population (WTCHR, n=180 children;
n=222 children in comparison group)
Liu et al. 2018a1.12 ng/mL (child geometricmean serum PFNA)

General population (n=621 adults in weightloss clinical trial)

Manzano-Salgado et al. 2017b
General population (n=1,230 children)

0.61 ng/mL (maternal
geometric mean serum
PFNA)

Weight loss
Weight regain
Males
Females
Resting metabolic rate
Weight loss period
Weight regain period
Weight gain until 6 monthsof age
BMI at 4 years of age
BMI at 7 years of age
Waist circumference at
4 years of age
Waist circumference at
7 years of age

RR 1.15 (0.67–1.98)
Inverse association (p<0.05)*
RR 0.67 (0.45–1.00)

Association (p<0.001, trend)*
Association (p=0.03, trend)*
β 0.0 (-0.07–0.09)
β 0.05 (-0.03–0.13)
β 0.06 (-0.04–0.16)
β 0.02 (-0.07–0.10)
β -0.02 (-0.07–0.10)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedMora et al. 2017

0.6 ng/mL (maternal medianplasma PFNA in early
General population (n=1,006 at median age of childhood group)
3.2 years and n=876 at median age of
7.7 years)
Mora et al. 2017
0.6 ng/mL (maternal medianplasma PFNA in late
General population (n=1,006 at median age of childhood group)
3.2 years and n=876 at median age of
7.7 years)

BMI
Waist circumference
Risk of being overweight
Risk of being obese

β 0.02 (-0.07–0.12)
β 0.01 (-0.23–0.22),
RRR 1.12 (0.96–1.30)
RRR 0.97 (0.75–1.27)

BMI

β 0.17 (-0.03–0.36)

Total fat mass index
Waist circumference
Subscapular and triceps
skinfold thickness

β 0.08 (-0.07–0.23)
β 0.31 (-0.19–0.82)
β 0.62 (0.01–1.22)*, boys and girls
β 0.13 (0.74–1.01), boys only
β 1.01 (0.16–1.86)*, girls only
β 1.78 (0.57–2.98)*, boys and girls
β 1.23 (-0.58–3.03), boys only
β 2.17 (0.52–3.83)*, girls only

Subscapular to triceps
skinfold thickness ratio

Wang et al. 2016
General population (n=117 boys and 106 girls
examined at 2, 5, 8, and 11 years of age)
PFDA
Cao et al. 2018

Risk of being overweight
Risk of being obese
1.55 and 1.58 ng/mL (median Growth during childhood
maternal PFNA for boys andgirls)

RRR 1.06 (0.85–1.32)
RRR 1.21 (0.99–1.47)
NS (p>0.05)

0.12 ng/mL (mean cord
serum PFDA)

NS (p=0.57)
NS (p=0.18)
NS (p=0.94)

General population (n=337 infants)
Karlsen et al. 2017
General population (n=444 children)

Resultc

0.26 ng/mL (maternal
geometric mean serum
PFDA)

Body weight at 19 months
Length at 19 months
Head circumference at
19 months
BMI score, 18 months
BMI score, 5 years
Risk of being overweight
18 months
Risk of being overweight
5 years

NS (p>0.05)
NS (p>0.05)
RR 1.14 (0.91–1.43)
RR 1.02 (0.61–1.70)

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Karlsen et al. 20170.33 ng/mL (child geometricmean serum PFDA)

Inverse association (p<0.05)*
RR 0.64 (0.46–0.90)*

General population (n=444 children aged
5 years)
Koshy et al. 2017
General population (WTCHR, n=180 children;
n=222 children in comparison group)
Liu et al. 2018a
General population (n=621 adults in weightloss clinical trial)

Wang et al. 2016
General population (n=117 boys and 106 girls
examined at 2, 5, 8, and 11 years of age)
PFUnA
Cao et al. 2018
General population (n=337 infants)

BMI score
Risk of being overweight

0.14 and 0.11 ng/mL (median Risk of being overweight
serum PFDA in WTCHR
group and comparison group)

OR 0.98 (0.93–1.03)

0.37 ng/mL (median serum
PFDA)

Weight loss
Weight regain
Males
Females
Resting metabolic rate
Weight loss period
Weight regain period
0.46 and 0.43 ng/mL (median Growth during childhood
maternal PFDA for boys andWeightgirls)HeightNS (p=0.45, trend).
NS (p=0.16, trend)
NS (p=0.75 trend)
Association (p=0.03, trend)*

0.06–0.11 ng/mL (2nd quartile Body weight at 19 months
cord serum PFUnA)
Length at 19 months

NS (p=0.88)
β 1.19 (-0.68–3.07, p<0.05)*,
2nd quartile
NS (p=0.60)

Head circumference at
19 months
Koshy et al. 20170.12 and 0.04 ng/mL (median Risk of being overweight
serum PFUnA in WTCH
General population (World Trade Center Health group and comparison group)
Registry, n=180 children; n=222 children incomparison group)

Association (p=0.01, trend)*
Association (p=0.05, trend)*
Inverse association (p<0.05)*, girls
Inverse association (p<0.05)*, girls

OR 0.95 (0.91–0.99)*

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Table 2-7. Body Weight Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Wang et al. 2016

3.52 and 3.31 ng/mL (median Growth during childhood
maternal PFUnA for boys and Weight
girls)HeightInverse association (p<0.05)*, girls
Inverse association (p<0.05)*, girls

0.04 ng/mL (mean cord
serum PFDoDA)

Body weight at 19 months
Head circumference at
19 months
0.37 and 0.37 ng/mL (median Growth during childhood
maternal PFDoDA for boys
Weightand girls)
HeightNS (p=0.74)
NS (p=0.97)

1.1 ng/mL (maternal median
FOSA)

NS (p>0.56)
NS (p>0.56)

General population (n=117 boys and 106 girls
examined at 2, 5, 8, and 11 years of age)
PFDoDACao et al. 2018
General population (n=337 infants)
Wang et al. 2016
General population (n=117 boys and 106 girls
examined at 2, 5, 8, and 11 years of age)
FOSA
Halldorsson et al. 2012
General population (n=665 20-year-olds)

BMI
Waist circumference

Inverse association (p<0.05)*, girls
Inverse association (p<0.05)*, girls

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 1 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living
near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.
BMI = body mass index; FOSA = perfluorooctane sulfonamide; HR = hazard ratio; NR = not reported; NS = not significant; OR = odds ratio;
PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid; RR = relative risk; WTCHR = World Trade Center
Health Registry1

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PFOA

Epidemiological Studies. Mixed results were found in studies of monitoring infant growth from 1 to
12 months of age. Andersen et al. (2010) found an inverse association between maternal serum PFOA
and body weight and BMI in male infants at 5 and 12 months of age; no associations were found in girls.
Other studies of infants less than 19 months of age did not find associations between maternal serum
PFOA (Alkhalawi et al. 2016; Manzano-Salgado et al. 2017b) or cord blood PFOA (Cao et al. 2018; deCock et al. 2014) levels and weight, length, head circumference, or BMI. One study of children (Braun etal. 2016a) found an association between changes in BMI scores between ages 2 and 8 years and maternal
PFOA levels; however, there was no increase in the risk of being overweight or obese. Another study ofyoung children (median age 3.2 years) found an association between maternal PFOA and waist
circumference (Mora et al. 2017); when the children were segregated by sex, the association was only
found in boys. This study did not find associations between maternal PFOA and waist circumference
when the children were older (median age 7.7 years). Other studies in children (2–11 years of age) foundno associations between maternal PFOA or cord blood PFOA and growth during childhood (Wang et al.
2016), risk of being overweight or obese (Andersen et al. 2013; Braun et al. 2016a; Høyer et al. 2015b;
Mora et al. 2017), waist circumference (Manzano-Salgado et al. 2017b), BMI (Hartman et al. 2017;
Karlsen et al. 2017; Manzano-Salgado et al. 2017b; Mora et al. 2017), body fatness (Hartman et al. 2017),
or risk of having a waist-to-height ratio of >0.5 (Høyer et al. 2015b). In a study of children aged 8–
10 years, no associations were found between plasma PFOA levels and markers of adiposity (BMI,
skinfold thickness, waist circumference, adiponectin levels, and leptin levels) (Timmermann et al. 2014).
Similarly, in a study of children in the World Trade Center Health Registry, no association was foundbetween serum PFOA and risk of being overweight (Koshy et al. 2017). In contrast, a study of 5-year-old
children found an inverse association between the child’s serum PFOA levels and BMI score, but noassociation with the risk of being overweight (Karlsen et al. 2017). Overall, the available epidemiological
data do not suggest a connection between serum PFOA levels and body weight or risk of being
overweight/obese in children.

Two studies in adults have not found associations between PFOA and body weight gain. A general
population study of 20-year-old females found associations between maternal PFOA levels and BMI andwaist circumferences, and increases in the risk of being overweight and having a high waist
circumference (Halldorsson et al. 2012); these associations were not observed in males. No increases in
the risk of being overweight or obese were observed in male or female C8 participants (20–40 years ofage) when estimated early life PFOA exposure was used as the exposure metric (Barry et al. 2014). In a

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study of participants in a weight loss study, no association between weight loss and PFOA levels wasfound; however, PFOA was associated with weight gain in females, but not males (Liu et al. 2018a).
PFOA was also associated with a lower increase in resting metabolic rate in all participants during theweight regain period of the study.
Laboratory Animal Studies. Male rats that survived a 4-hour inhalation exposure to 380 mg/m3 APFO
dusts lost weight for 1–2 days after exposure, but resumed normal weight gain thereafter (Kennedy et al.
1986). Male rats exposed via inhalation intermittently to 84 mg/m3 APFO dusts for 2 weeks lost
approximately 7% of their body weight by day 5 of exposure (250 g at start of study, 237 g on day 5)(Kennedy et al. 1986), but recovered by day 16 after exposure ceased. Nose-only exposure of male CD
rats to 590 mg/m3 ammonium perfluorononanoate dusts for 4 hours resulted in 18 and 36% reductions inbody weight 5 and 12 days after exposure, respectively (Kinney et al. 1989). Inhalation exposure to67 mg/m3 had no significant effect on body weight. In a developmental study, inhalation exposure ofpregnant rats to 25 mg/m3 APFO dusts during GDs 6–15 induced a 37% reduction in maternal bodyweight gain relative to controls during the exposure period (Staples et al. 1984); in a pair-fed group, thereduction of weight gain during the same period was 61% relative to ad libitum controls.

Reductions in body weight or body weight gain are typical, although not particularly sensitive, responsesof rodents to oral exposure to perfluoroalkyls. In many cases, this effect is not associated with reduced
food intake, and in some cases, exposed animals have shown an increase in relative food consumption(grams of food/grams of body weight) relative to controls. For example, administration of 50 mg/kg/day
APFO for 7 days resulted in 17% weight loss; a similar decrease was observed in a pair-fed group(Pastoor et al. 1987). In mice, doses of approximately 25–30 mg/kg/day PFOA in the food for 7 days
reduced terminal body weight by >10% relative to controls without a significant reduction in food intake(Xie et al. 2003; Yang et al. 2000, 2002a, 2002b). However, administration of the same dose to PPARαnull mice did not cause a reduction in weight gain, suggesting that the effect on body weight is a specificeffect of peroxisome proliferators possibly due to increased fat utilization (Yang et al. 2002b). In general,body weight recovered once treatment ceased.

Intermediate-duration oral studies in rats have also reported reduced body weight gain with doses≥10 mg/kg/day APFO (Butenhoff et al. 2004b; Griffith and Long 1980). In the former study, mean
absolute food consumption was decreased, but mean relative food consumption was increased. In a
2-year bioassay, body weight gain in rats dosed with 15 mg/kg/day PFOA was reduced >10% relative tocontrols at the 1-year mark and at termination (Biegel et al. 2001). Similar observations have been made

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in mice dosed with approximately ≥18 mg/kg/day APFO for 28 days (Griffith and Long 1980), or
10 mg/kg 5 days/week for 4 weeks (Yang et al. 2009), and in pregnant mice dosed with ≥10 mg/kg/day
APFO during GDs 1–17 (Lau et al. 2006). A study comparing wild-type mice and PPARα knockout mice
(DeWitt et al. 2016) found a decrease in body weight gain in the wild-type mice, but not in the knockout
mice. A 90-day and a 26-week study in monkeys also reported significant reductions in body weight gain
or weight loss associated with decreased food consumption at dose levels in the range of 20–
30 mg/kg/day APFO (Butenhoff et al. 2002; Griffith and Long 1980), but a 4-week study in monkeys
dosed with 20 mg/kg/day PFOA did not (Thomford 2001).

Transient weight loss was reported in rats applied 3,000 mg/kg APFO to the shaven skin for 24 hours(Kennedy 1985). In the 2-week study, rats in the 200 and 2,000 mg/kg/day groups lost weight during thetreatment period (14 and 24%, respectively, on test day 10), but body weights were comparable tocontrols after 42 days of recovery. No changes in body weight were reported in mice applied up to
50 mg/kg/day PFOA daily for 4 days on the dorsal surface of the ears (Fairley et al. 2007).

PFOS

Epidemiological Studies. General population studies have evaluated body weight, height, and BMI in
infants, children, and adults to assess whether there were associations between growth and maternal
serum PFOS levels. Andersen et al. (2010) found that maternal PFOS levels were inversely related tobody weight and BMI in 12-month-old male infants; no associations were found in females at 12 monthsof age or in males and females at 5 months of age. The magnitude of the effect on body weight in theboys was small, 9 g per 1 ng/mL increase in maternal serum PFOS level. Other studies have not foundassociations between maternal PFOS or cord blood PFOS and body weight, length, or head circumference
in infants <2 years of age (Alkhalawi et al. 2016; Cao et al. 2018; Manzano-Salgado et al. 2017b).
Hartman et al. (2017) also found an inverse association between maternal serum PFOS and trunk bodyfatness in 9-year-old girls, but no associations with total body fatness or BMI. Karlsen et al. (2017) foundassociations between maternal PFOS levels and BMI and risk of being overweight at 18 months of age,
but not at 5 years of age. Maisonet et al. (2012) found that at 20 months of age, girls whose mothers had
serum PFOS levels in the 3rd tertile weighed 438 g more than those in the first tertile. Studies in children(Andersen et al. 2013; Braun et al. 2016a; Høyer et al. 2015b; Koshy et al. 2017; Manzano-Salgado et al.
2017b; Mora et al. 2017) or young adults (Halldorsson et al. 2012) did not find associations between
maternal PFOS levels and BMI, waist circumference, and/or risk of being overweight. No associations
between plasma PFOS and markers of adiposity (BMI, skinfold thickness, waist circumference,PERFLUOROALKYLS

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adiponectin levels, and leptin levels) were found in a study of children aged 8–10 years (Timmermann etal. 2014). Similarly, a study of 5-year-old children found no association between child serum PFOS
levels and BMI score or risk of being overweight (Karlsen et al. 2017). Overall, the epidemiologicalstudies do not suggest a connection between serum PFOS and body weight or the risk of being
overweight/obese.

In a study of weight loss programs, PFOS did not influence weight loss, but was associated with greater
weight regain in women (Liu et al. 2018a). PFOS was also associated with greater declines in resting
metabolic rate in all participants during the weight loss period of the study and lower increases in resting
metabolic rate during the weight regain period.

Laboratory Animal Studies. Dietary treatment of rats with 15 mg/kg/day PFOS (only dose level tested)for 7 days did not significantly alter body weight (Haughom and Spydevold 1992). Oral treatment ofpregnant rats with 25 mg/kg/day PFOS on GDs 2–5 or 6–9 resulted in maternal weight loss during
treatment, whereas treatment on GDs 10–13, 14–17, or 17–20 resulted in significant reductions inmaternal weight gain (Grasty et al. 2003). In pregnant mice, oral dosing with up to 6 mg/kg/day PFOS on
GDs 6–18 or 12–18 did not significantly affect body weight (Fuentes et al. 2006, 2007b). Decreases inmaternal body weight were observed in rats administered 20 mg/kg/day on GDs 12–18 (Li et al. 2016).
Pregnant rabbits appeared to be more sensitive as oral doses of 1 mg/kg/day on GDs 6–20 caused a
21% reduction in weight gain during treatment without altering food consumption (Case et al. 2001).

Alterations in body weight have also been observed following intermediate- or chronic-duration exposure.
Reductions in body weight gain of >10% have been reported in intermediate-duration studies in rats
dosed with ≥2 mg/kg/day PFOS associated with reductions in mean absolute and relative foodconsumption (Luebker et al. 2005a, 2005b). In a developmental toxicity study, treatment of pregnant rats
with ≥2 mg/kg/day PFOS on GDs 2–20 resulted in significant reductions in body weight gain, which wereassociated with significant reductions in mean absolute food and water consumption (Thibodeaux et al.
2003). In a 4-week study, treatment of Cynomolgus monkeys with up to 2 mg/kg/day, administered via acapsule, did not affect body weight gain (Thomford 2002a). In a 26-week study in Cynomolgus
monkeys, the highest dose of PFOS tested, 0.75 mg/kg/day, produced a 13.5% reduction in final bodyweight, at which time the mean concentration of PFOS in serum was 172 µg/mL (Seacat et al. 2002). In a
2-year dietary study in rats, final mean body weight of females that received doses of approximately
1.04 mg/kg/day PFOS was 14% lower than controls; this could have been due, in part, to a tendency of
decreased food consumption during weeks 28 through 104 of the study (Butenhoff et al. 2012b;

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Thomford 2002b). No significant effect (<10% difference with controls) was seen in females dosed with
≤0.25 mg/kg/day PFOS.
PFHxS

Epidemiological Studies. Nine studies have evaluated the influence of in utero PFHxS exposure on
childhood growth and found no associations between maternal PFHxS levels and body weight in infants<2 years of age (Alkhalawi et al. 2016; Cao et al. 2018; Maisonet et al. 2012; Manzano-Salgado et al.
2017b), body fatness or BMI at 9 years of age (Hartman et al. 2017), BMI or waist circumference at 3 or
7 years of age (Mora et al. 2017), changes in BMI scores between 2 and 8 years of age (Braun et al.
2016a), BMI at 18 months or 5 years of age (Karlsen et al. 2017), BMI at 4 or 7 years of age (ManzanoSalgado et al. 2017b), or the risk of childhood overweight/obesity (Braun et al. 2016a; Karlsen et al.
2017; Mora et al. 2017). Similarly, no associations were found between serum PFHxS levels in 5-yearold children and their BMI score or risk of being overweight (Karlsen et al. 2017) or between serum
PFHxS and risk of being overweight in children in the World Trade Center Healthy Registry (Koshy et al.
2017). Alkhalawi et al. (2016) found no associations between maternal PFHxS levels and infant bodyweight or length at 1, 4, 6, or 12 months of age; however, longitudinal analysis of growth during thisperiod showed an inverse association for body weight and an association for length.

In a clinical trial of weight loss programs, PFHxS was not associated with weight loss during the first
6 months of the study, but was associated with weight regain in females during the last 18 months of thestudy (Liu et al. 2018a). PFHxS was also associated with greater declines in resting metabolic rate in allparticipants during the weight loss period and lower increases in resting metabolic rate during the weightregain period.

Laboratory Animal Studies. Administration of PFHxS by gavage for 40–60 days did not significantly
affect body weight in rats at ≤10 mg/kg/day PFHxS (Butenhoff et al. 2009a) or mice at ≤3 mg/kg/day(Chang et al. 2018); the mean terminal body weights were within 10% of the body weight of the control
group (Butenhoff et al. 2009a).
PFNA

Epidemiological Studies. Several studies have examined the influence of maternal serum PFNA levels
on childhood growth. These studies did not find associations between maternal PFNA levels and growthPERFLUOROALKYLS

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during childhood (Cao et al. 2018; Wang et al. 2016), BMI (Braun et al. 2016a; Halldorsson et al. 2012;
Hartman et al. 2017; Karlsen et al. 2017; Manzano-Salgado et al. 2017b; Mora et al. 2017), body fatness(Hartman et al. 2017), or overweight/obesity risk (Braun et al. 2016a; Karlsen et al. 2017; Mora et al.
2017). However, when the child’s serum PFNA levels at age 5 years were used as the exposure
biometric, an inverse association was found for BMI, but not for the risk of being overweight (Karlsen etal. 2017). Koshy et al. (2017) found no associations between serum PFNA and the risk of being
overweight in children enrolled in the World Trade Center Health Registry.

PFNA was associated with greater weight regains in a study of participants in a 2-year weight loss clinical
trial, but was not associated with weight loss during the first 6 months of the study (Liu et al. 2018b).
PFNA also affected resting metabolic rate in all participants; it was associated with a greater decline
during the weight loss period of the study and a lower increase during the weight regain period.

Laboratory Animal Studies. Decreases in body weight gain have been observed in rats administered≥3 mg/kg/day for 14 days (Fang et al. 2009, 2010; Hadrup et al. 2016) and in mice administered
5 mg/kg/day for 14 days (Wang et al. 2015a). The NOAEL for body weight effects was 1 mg/kg/day forboth species. In intermediate-duration developmental toxicity studies, decreases in body weight wereobserved at 5 mg/kg/day in rats (Rogers et al. 2014) and weight loss was observed in mice at
10 mg/kg/day (Das et al. 2015). No alterations in maternal weight gain were observed in mice at
2.0 mg/kg/day (Wolf et al. 2010).
PFDA

Epidemiological Studies. Four studies examined the effect of PFDA levels on childhood growth. Cao etal. (2018) did not find associations between cord blood PFDA and body weight, length, or headcircumference in 19-month-old infants. Wang et al. (2016) reported decreases in weight and height ingirls associated with increasing maternal serum PFDA levels. Inverse associations between serum PFDA
levels in 5-year-old children and BMI and the risk of being overweight were reported by Karlsen et al.
(2017). When using maternal serum PFDA levels (measured 2 weeks after childbirth) as the biomarker of
exposure, no associations were found with BMI or the risk of being overweight in children aged
18 months or 5 years (Karlsen et al. 2017). In a study of children in the World Trade Center HealthRegistry, no association between serum PFDA and risk of being overweight was found (Koshy et al.
2017).

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In a study of adult participants in a 2-year weight loss clinical trial, PFDA was not associated with weightloss but was associated with weight regain in females during the last 18 months of the study (Liu et al.
2018a). PFDA also was associated with greater declines in resting metabolic rate during the weight loss
period and lower increases in resting metabolic rate during the weight regain period of the study.

Laboratory Animal Studies. Ten days following administration of a single gavage dose of 50 mg/kg,
weight loss was observed in rats (Kawabata et al. 2017). In a 1-week study, exposure to 9.5 mg/kg/day
PFDA in the diet resulted in a 32% weight loss in rats (Kawashima et al. 1995); the NOAEL was
4.7 mg/kg/day. Rats administered 1 mg/kg/day PFDA for 28 days exhibited a 21% decrease in bodyweight gain (Frawley et al. 2018).

Body weight of female C57BL/6N mice administered a single gavage dose of 80 mg/kg PFDA was
reduced 12% relative to controls 30 days post dosing (Harris et al. 1989); no significant effect was seen at
40 mg/kg PFDA. In a developmental study, pregnant mice dosed with 6.4 mg/kg/day PFDA on GDs 6–
15 gained 92% less weight (adjusted for the weight of the gravid uterus) on GDs 6–18 than controls; mice
dosed with 12.8 mg/kg/day lost weight (Harris and Birnbaum 1989). Weight loss was also observed in
C57BL/6N mice exposed to 78 mg/kg/day PFDA in the diet for 10 days (Permadi et al. 1992, 1993).
PFUnA

Epidemiological Studies. Cao et al. (2018) found an association between cord blood PFUnA levels andlength at 19 months of age, but found no associations for body weight or head circumference. Wang et al.
(2016) found an inverse association between maternal serum PFUnA levels and weight and height ingirls. Koshy et al. (2017) also found an inverse association between the serum PFUnA levels and the riskof being overweight in children enrolled in the World Trade Center Health Registry.

Laboratory Animal Studies. Decreases in body weight gain (10% in males and 23% in females) wereobserved in rats exposed to 1.0 mg/kg/day in a 41–46-day developmental toxicity study (Takahashi et al.
2014).
PFBS

Laboratory Animal Studies. No significant alterations in body weight gain were observed in SpragueDawley rats administered ≤900 mg/kg/day PFBS via gavage for 28 days (3M 2001) or in Sprague-PERFLUOROALKYLS

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Dawley rats administered ≤1,000 mg/kg/day PFBS via gavage for at least 70 days (Lieder et al. 2009b).
Two studies did report decreases in maternal body weight gain in rats administered 1,000 or
2,000 mg/kg/day (York 2002, 2003a).
PFBA

Laboratory Animal Studies. Alterations in body weight do not appear to be a sensitive outcome of PFBA
exposure in rats or mice. No alterations in body weight gain were observed in Sprague-Dawley rats
administered 184 mg/kg/day PFBA via gavage for 5 days (3M 2007a), C57BL/6 mice exposed to78 mg/kg/day PFBA in the diet for 10 days (Permadi et al. 1992, 1993), Sprague-Dawley rats
administered 150 mg/kg/day PFBA via gavage for 28 days (Butenhoff et al. 2012a; van Otterdijk 2007a),or Sprague-Dawley rats administered 30 mg/kg/day PFBA via gavage for 90 days (Butenhoff et al. 2012a;
van Otterdijk 2007b).

PFDoDA

Epidemiological Studies. Cao et al. (2018) found no association between cord blood PFDoDA and bodyweight or head circumference at 19 months of age. In contrast, Wang et al. (2016) found an inverse
association between maternal serum PFDoDA levels and growth (weight and height) in girls.

Laboratory Animal Studies. Dosing of Sprague-Dawley rats with 5 mg/kg/day PFDoDA by gavage for
14 days resulted in a 25% reduction in final body weight relative to a control group or 7% loss of bodyweight compared with the starting body weight (Shi et al. 2007). Decreases in body weight gain
(measured 10 days postexposure) were also observed in rats administered a single gavage dose of
50 mg/kg PFDoDA (Kawabata et al. 2017). Gavage administration of 2.5 mg/kg/day for 42 days resulted
in approximately 30% decreases in male rats; the decreases in body weight gain persisted during a 14-day
recovery period (Kato et al. 2015). An approximately 20% decrease in body weight gain was also
observed in pregnant and nonpregnant females similarly exposed to 2.5 mg/kg/day (Kato et al. 2015).
The decreases in body weight gain were accompanied by decreases in food intake in males and females.
In a longer duration study (110 days), no alterations in body weight gain were observed in rats
administered 0.5 mg/kg/day (Shi et al. 2009a).

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PFHxALaboratory Animal Studies. Gavage administration of up to 315 mg/kg/day did not result in alterations
in body weight gain in rats exposed for 32–44 days (Kirkpatrick 2005), 90 days (Chengelis et al. 2009b),
92–93 days (Loveless et al. 2009), or 2 years (Klaunig et al. 2015). A 19% decrease in body weight gain
was observed in rats administered 500 mg/kg/day NaPFHx for 92–93 days (Loveless et al. 2009) and a
19% decrease in maternal body weight gain was observed in rats administered 500 mg/kg/day on GDs 1–
20 (Loveless et al. 2009). In contrast to these findings, a 110–126-day study found a 12% decrease inmale rats administered 100 mg/kg/day NaPFHx (Loveless et al. 2009).
FOSA

Epidemiological Studies. Halldorsson et al. (2012) did not find associations between maternal serum
FOSA levels and BMI or waist circumference in 20-year-olds.

Laboratory Animal Studies. No alterations in body weight were observed in Sprague-Dawley rats
following a single gavage dose of 5 mg/kg FOSA in 2% Tween 80 vehicle (Seacat and Luebker 2000).
2.4

RESPIRATORY

Overview. A small number of epidemiological studies have examined the potential of PFOA to damage
the respiratory tract; detailed descriptions of these studies are presented in Table 2 in the Supporting
Document for Epidemiological Studies for Perfluoroalkyls. Epidemiological studies examining
respiratory endpoints were not identified for the other perfluoroalkyls. These studies were primarily
conducted in PFOA workers or in residents of nearby communities. The possible associations between
perfluoroalkyl exposure and asthma are discussed along with other immune effects in Section 2.14.
Studies in laboratory animals have examined the potential for perfluoroalkyls to induce histologicallesions in the lungs following inhalation (see Tables 2-1 and 2-2) or oral exposure (see Tables 2-3, 2-4,
and 2-5). No laboratory animal studies examining potential respiratory tract effects were identified for
PFUnA, PFHpA, PFDoDA, or FOSA.

Epidemiological studies examining respiratory effects are only available for PFOA. No alterations inlung function were observed in workers at a PFOA facility but increases in respiratory illnesses wereobserved in residents living near the PFOA facility.

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Inhalation exposure to PFOA, PFOS, or PFNA dusts have resulted in nasal discharge, rales, and/or
labored breathing in laboratory animals. Oral exposure studies in laboratory animals have not foundconsistent evidence of histological alterations for PFOA, PFOS, PFHxS, PFBS, or PFBA. An oral study
with PFHxA reported nasal lesions in rats, however, a second study did not find these effects at higher
doses.
PFOA

Epidemiological Studies. There are limited data on the potential of PFOA to damage the respiratory
tract. Pulmonary function tests and chest roentgenograms conducted on workers potentially exposed to
PFOA at the Washington Works fluoropolymers production facility were within normal limits (Sakr et al.
2007b); the serum PFOA levels ranged from 5 to 9,550 ng/mL. Another study of workers at this facility
did not find an association between estimated cumulative serum PFOA levels and the risk of chronic
obstructive pulmonary disease (Steenland et al. 2015). In contrast, a study of residents living near thisfacility found an increase in the risk of chronic bronchitis (standard prevalence ratio [SPR] of 3.60, 95%
confidence interval [CI] 2.92–4.44) and shortness of breath (SPR 2.05, 95% CI 1.70–2.46) (AndersonMahoney et al. 2008); it is noted that results were based on health surveys, and some of the subjects also
worked at the facility. Summaries of these studies are presented in the Supporting Document for
Epidemiological Studies for Perfluoroalkyls, Table 2.
Laboratory Animal Studies. Inhalation exposure of male and female rats to 18,600 mg/m3 APFO dusts
for 1 hour induced a red nasal discharge and dry rales (Griffith and Long 1980). Necropsy conducted
14 days after exposure showed bilateral mottling of the lungs in 8 out of 10 rats. Head-only exposure for
4 hours to 380 mg/m3 APFO dusts, a concentration that was lethal to some rats, produced pulmonary
edema, which disappeared within 1 week of exposure (Kennedy et al. 1986). Examination of the lungs
and trachea from rats exposed head-only to up to 84 mg/m3 APFO dusts 6 hours/day, 5 days/week for
2 weeks showed no significant gross or microscopic alterations (Kennedy et al. 1986). Male CD rats
exposed nose-only to ≥590 mg/m3 ammonium perfluorononanoate dusts for 4 hours exhibited lung noiseand labored breathing during exposure and throughout a 12-day recovery period (Kinney et al. 1989).
Oral dosing of male and female CD rats with ≤110 mg/kg/day APFO did not induce gross or microscopicchanges in the lungs (Griffith and Long 1980; Perkins et al. 2004). Dosing for 2 years with 15 mg/kg/day
APFO increased the incidence of lung hemorrhage in males (3M 1983; Butenhoff et al. 2012c). The

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incidences were 10/50, 14/50, and 22/50 for groups receiving doses of 0, 1.5, and 15 mg/kg/day,
respectively. Pair-wise comparison between controls and high-dose groups revealed a statisticallysignificant difference (p<0.05). The investigators suggested that pulmonary lesions were not related to
PFOA based on lower incidence of interstitial pneumonia in the 15 mg/kg/day males. In a study inmonkeys administered up to 20 mg/kg/day APFO, administered via a capsule, for 26 weeks, no signs ofrespiratory problems were observed during the study and no gross or microscopic alterations in the lungs
and trachea were observed at termination (Butenhoff et al. 2002).

No gross or microscopic alterations were found in the lung and trachea from male CD rats following
application of up to 2,000 mg/kg/day APFO as an aqueous paste to an area of the shaven back(approximately 15% of the total body surface) 6 hours/day, 5 days/week for 2 weeks (Kennedy 1985).
PFOS

Laboratory Animal Studies. Unpublished data summarized by OECD (2002) indicate that inhalation
exposure of rats to concentrations of PFOS dust between 1,890 and 45,970 mg/m3 for 1 hour induced dryrales and other breathing disturbances.

Dosing of Cynomolgus monkeys with up to 2 mg/kg/day PFOS, administered in a capsule, for 4 weeks
had no effect on the gross or microscopic morphology of the lungs (Thomford 2002a). Administration ofdoses of up to 0.75 mg/kg/day of PFOS (potassium salt) administered via a capsule to Cynomolgus
monkeys for 26 weeks did not produce any gross or microscopic alterations in the lungs or the trachea(Seacat et al. 2002). Dosing rats with up to 1.04 mg PFOS/kg/day in the diet for 104 weeks did not
induce significant gross or microscopic alterations in the lungs or trachea (Butenhoff et al. 2012b;
Thomford 2002b).
PFHxSLaboratory Animal Studies. Examination of the respiratory tract of rats administered ≤10 mg/kg/day
PFHxS or mice administered ≤3 mg/kg/day by gavage in a reproductive study (40–60 days of dosing)showed no treatment-related effects (Butenhoff et al. 2009a; Chang et al. 2018).

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PFNA

Laboratory Animal Studies. Labored breathing during and after a 4-hour nose-only exposure to590 mg/m3 PFNA dust was reported in rats (Kinney et al. 1989).

PFDA

Laboratory Animal Studies. No histological alterations were observed in the respiratory tract of rats
administered 0.5 mg/kg/day for 28 days or mice administered 5 mg/kg once a week for 4 weeks (Frawley
et al. 2018).
PFBS
Laboratory Animal Studies. Administration of PFBS at gavage doses of ≤900 mg/kg/day for 28 days
(3M 2001) or 600 mg/kg/day for 90 days (Lieder et al. 2009a) had no significant effect on the gross or
microscopic morphology of the lungs or trachea in rats; no increases in nasal lesions were observed in the
90-day study (Lieder et al. 2009a).
PFBA
Laboratory Animal Studies. Administration of PFBA to rats by gavage in doses ≤184 mg/kg/day for
5 days (3M 2007a), ≤150 mg/kg/day for 28 days (Butenhoff et al. 2012a; van Otterdijk 2007a), or≤30 mg/kg/day for 90 days (Butenhoff et al. 2012a; van Otterdijk 2007b) did not cause morphologicalalterations in the respiratory tract.
PFHxALaboratory Animal Studies. Degeneration/atrophy of the nasal olfactory epithelium was observed in rats
administered via gavage 100 mg/kg/day NaPFHx for 92–93 days (Loveless et al. 2009); at
500 mg/kg/day, respiratory metaplasia was observed in the nasal cavity. A second study did not reporthistological alterations in the nasal cavity of rats administered up to 200 mg/kg/day NaPFHx for 90 days
(Chengelis et al. 2009b).

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2.5

CARDIOVASCULAR

Overview. Epidemiological and laboratory animal studies have evaluated the toxicity of perfluoroalkyls
to the cardiovascular system. The epidemiological studies evaluated several cardiovascular outcomes
including ischemic heart disease, cerebrovascular disease, stroke, cardiovascular disease, myocardial
infarction, hypertension, and pregnancy-induced hypertension. The results of these studies are
summarized in Table 2-8, with more detailed descriptions presented in the Supporting Document for
Epidemiological Studies for Perfluoroalkyls, Table 3. The available occupational, community, andgeneral population studies have not consistently found increases in the risk of heart disease or stroke thatwere associated with serum PFOA levels. Considerably less epidemiological data are available for otherperfluoroalkyls; general population studies for PFOS, PFHxS, PFNA, PFDA, PFHpA, and PFDoDA havenot consistently found increases in the risk of cardiovascular disease, although single studies for PFUnA,PFBS, PFHxA, and FOSA have found associations. Most of the available epidemiological studies did not
find an association between serum PFOA and hypertension. A small number of studies (three or less foreach compound) have examined potential associations with hypertension for other perfluoroalkyls. Thesestudies found associations (PFBA), no associations (PFHxS, PFDA, PFUnA, PFHpA, PFBS, PFDoDA),or mixed results (PFOS, PFNA).

Several studies have evaluated the possible associations between serum perfluoroalkyls and pregnancyinduced hypertension and pre-eclampsia. Pregnancy-induced hypertension, also referred to as gestational
hypertension, is the onset of hypertension after the 20th week of pregnancy. Pre-eclampsia is pregnancyinduced hypertension accompanied by signs of damage to another organ system, such as the kidney orliver; elevated levels of protein in the urine are often present. While the two diseases are distinct, they
can be inaccurately reported in studies that relied on self-reporting or use of birth certificates (birthcertificates often only have an option for pregnancy-induced hypertension; thus, pre-eclampsia may bereported as pregnancy-induced hypertension). Due to possibility of misreporting, ATSDR has opted togroup these two outcomes together. Although mixed results were found in studies of highly exposed
community residents, the strongest methodological study (Darrow et al. 2013) found an increased risk ofpregnancy-induced hypertension that was associated with serum PFOA levels. Increases in the risk ofpregnancy-induced hypertension associated with serum PFOS levels were also found in two community
studies. General population studies have not found associations between serum PFHxS or PFDA and preeclampsia; one study on PFUnA found an inverse association.

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Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb
PFOA
Leonard 2006
Occupational (n=6,027)

Lundin et al. 2009
Occupational (n=3,993)

Raleigh et al. 2014
Occupational (n=9,027)

Sakr et al. 2009
Occupational (n=4,747)

Serum perfluoroalkyl level Outcome evaluatedResultc

5–9,550 ng/mL (PFOA
range)

SMR 110 (98–123)
SMR 86 (60–120)

Heart disease deaths
Cerebrovascular disease
deathsIschemic heart disease
deaths2,600–5,200 ng/mL (range of Heart disease deaths
definite exposure group)
Cerebrovascular disease
deathsIschemic heart disease
deathsCerebrovascular disease
risk

Cumulative PFOA exposure Ischemic heart disease
deathsCerebrovascular disease
Ischemic heart disease
risk
Cerebrovascular diseaserisk
NRIschemic heart diseaserisk

SMR 109 (96–124)
SMR 0.7 (0.5–1.3)
SMR 1.6 (0.5–3.7)
SMR 0.8 (0.5–1.4)
HR 4.6 (1.3–17.0)* workers withdefinite exposure of ≥6 months
HR 2.1 (1.0–4.6)* workers withdefinite exposure ≥5 years
SMR 0.84 (0.74–0.95)*
SMR 0.81 (0.61–1.05)
HR 0.89 (0.66–1.21), 4th quartile
HR 0.98 (0.53–1.81), 4th quartile
NS (p=0.16 for trend)

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Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Steenland et al. 2015

Estimated cumulative PFOA Coronary artery disease
exposurerisk
Hypertension

NS (p=0.78 for trend), no lag
NS (p=0.75 for trend), 10-year lag
NS (p=0.95 for trend), no lag
NS (p=0.54 for trend), 10-year lag
NS (p=0.35 for trend), no lag
NS (p=0.64 for trend), 10-year lag
SMR 0.93 (0.72–1.19), no lag

Occupational (n=3,713)

StrokeSteenland and Woskie 2012
Occupational (n=1,084)
Anderson-Mahoney et al. 2008
Community (n=566)

Darrow et al. 2013
Community (C8) (n=1,330)
Nolan et al. 2009
Community (C8) (n=1,555 women)
Savitz et al. 2012a

7,800 ng/mL-years (meanIschemic heart disease
estimated cumulative PFOA deaths
exposure)
NR
Cardiovascular disease(self-reported)
Angina (self-reported)
Myocardial infarction
StrokeHypertensionnd
6.9–<11.1 ng/mL (2 PFOA Pregnancy-induced
quintile)
hypertension

SPR 4.29 (3.47–5.29)*
SPR 8.07 (6.54–9.95)*
SPR (1.91 (1.40–2.62)*
SPR 2.17 (1.47–3.21)*
SPR 1.18 (0.97–1.43)
OR 2.39 (1.05–5.46)* (2nd quintile)

NR

Pregnancy-induced
hypertension
LHWA residents
OR 1.2 (0.7–2.0), unadjusted
Partial LHWA residents OR 0.8 (0.5–1.4), unadjusted
6.8–<16.6 ng/mL (2nd PFOA Pre-eclampsia
OR 1.2 (1.0–1.5)*
quartile, estimated)

Community (C8) (n=11,737 pregnant women)
Savitz et al. 2012b
Community (C8) (n=224 cases of pregnancyinduced hypertension)

21.0–717.6 ng/mL (5th PFOA Pregnancy induced
quintile, estimated)
hypertension

OR 1.0 (0.7–1.3), 5th quintile

PERFLUOROALKYLS

148
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Savitz et al. 2012b

21.0–717.6 ng/mL (5th PFOA Pregnancy induced
quintile, estimated)
hypertension

OR 1.1 (0.8–1.5)>178–319 ng/mL(cumulative, estimated
2nd PFOA quintile)

StrokeOR 1.39 (1.11–1.76)*, 2nd quintile

120.6–894.4 ng/mL(4th PFOA quartile)

Pre-eclampsia

OR 0.9 (0.5–1.8)

Community (C8) (n=4,547 pregnant women)
Simpson et al. 2013
Community (C8) (n=28,541; 11% also had
occupational exposure)
Stein et al. 2009
Community (C8) (n=5.262 pregnant women)
Winquist and Steenland 2014aCommunity (C8) (n=28,541; 11% also had
occupational exposure)
Bao et al. 2017
General population (n=1,612 adults)

Geiger et al. 2014a
General population (NHANES) (n=1,655
adolescents)
Huang et al. 2018
General population (NHANES, n=10,859 adults)≥3,579 ng/mL (cumulative,
Hypertension
estimated 5th PFOA quintile) Coronary artery disease

HR 0.98 (0.91–1.06), 5th quintile
HR 1.07 (0.93–1.23), 5th quintile

6.19 ng/mL (median serum Risk of hypertension
PFOA in males and females); Systolic blood pressure
6.59 and 5.08 ng/mL (medianserum PFOA in males andfemales, respectively)

OR 1.12 (0.97–1.30)
β-0.06 mm Hg (-1.70–1.59), males
β 2.91 mm Hg (0.10–5.72)*, females
β 1.69 mm Hg (0.25–3.13)*,
combined

Diastolic blood pressure

β 1.48 mm Hg (0.60–2.35)*, males
β 1.34 mm Hg (-0.14–3.05), females
β 2.12 mm Hg (1.33–2.90)*,
combined
OR 0.69 (0.41–1.17), 4th quartile>5.4 ng/mL (4th quartile
PFOA)

Hypertension

3.17 ng/mL (median serum
PFOA)

Risk of cardiovasculardiseaseOR 1.25 (0.91–1.70), 4th quartilePERFLUOROALKYLS

149
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Koshy et al. 20171.81 and 1.39 ng/mL (median Arterial wall stiffness
serum PFOA in WTCHR
Arterial pulse wave
group and comparison group, velocity
respectively)

Association (p=0.03)*
NS (p=0.39)

3.49 ng/mL (median PFOA)

Carotid intima media
thickness

NS (p=0.285 for trend)

NR

Intima media thickness in NS (p=0.58)
common carotid artery
Echogenicity of intima
NS (p=0.80), males
media complex
NS (p=0.25), females
Blood pressure at 4 years β -0.06 (-0.16–0.04)
of ageBlood pressure at 7 years β -0.02 (-0.11–0.07)
of ageCoronary artery disease OR 0.88 (0.50–1.55), 4th quartile

General population (n=180 children enrolled in
the WTCHR; n=222 children in comparisongroup)
Lin et al. 2013a, 2013b
General population (n=644)
Lind et al. 2017b
General population (n=1,016, 70-year-old
adults)Manzano-Salgado et al. 2017b2.32 ng/mL (maternal
geometric mean PFOA)

General population (n=1,230 children)
Mattsson et al. 2015

4.2 and 4.0 ng/mL (median
PFOA in cases and controls)

General population (n=231 cases with CHD,
231 controls)
Melzer et al. 2010

10.39 and 9.47 ng/mL (mean Coronary artery disease, OR 1.08 (0.70–1.69, p=0.715), 4th
4th quartile PFOA)
angina, and/or heart
quartile
General population (NHANES) (n=3,966 adults)
attackMin et al. 2012
General population (NHANES) (n=2,208)
Shankar et al. 2012
General population (NHANES) (n=1,216)

4.00 ng/mL (geometric mean Systolic blood pressure
PFOA)
Hypertension risk

Association (p=0.0004)*
OR 1.71 (1.23–2.36)*, 4th quartile

4.0–5.6 and 4.4–6.1 ng/mL(females and males,
3rd PFOA quartile)>5.6 and >6.1 ng/mL(females and males,
4th PFOA quartile)

Cardiovascular disease

OR 1.77 (1.04–3.02)*, 3rd quartile

Peripheral arterial
diseaseOR 1.78 (1.03–3.08)*, 4th quartile

Coronary heart disease
StrokeOR 2.24 (1.02–4.94)*, 4th quartile
OR 4.26 (1.84–9.89)*, 4th quartilePERFLUOROALKYLS

150
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Starling et al. 2014b2.78 ng/mL (median PFOA)

HR 0.89 (0.65–1.22), per ln unit

General population (n=976 pregnant women)
PFOS
Darrow et al. 2013
Community (C8) (n=1,330)
Stein et al. 2009

Pre-eclampsia

12.1–<15.9 ng/mL (3rd PFOS Pregnancy-induced
quintile)
hypertension

OR 2.71 (1.33–5.52)* (3rd quintile)

23.2–83.4 ng/mL (4th PFOS
quartile)

OR 1.6 (1.2–2.3)*

Pre-eclampsia

Community (C8) (n=5,262 pregnant women)
Bao et al. 2017
General population (n=1,612 adults)

24.22 ng/mL (median serum Risk of hypertension
PFOS in males and females);27.39 and 14.05 ng/mL(median serum PFOS in
Systolic blood pressure
males and females,
respectively)
Diastolic blood pressure

Geiger et al. 2014a
General population (NHANES)(n=1,655 adolescents)
Huang et al. 2018>25.5 ng/mL (4th PFOS
quartile)

Hypertension

12.40 ng/mL (median serum Risk of cardiovascular
PFOS)
diseaseGeneral population (NHANES, n=10,859 adults)
Koshy et al. 20173.72 and 2.78 ng/mL (median Arterial wall stiffness
serum PFOS in WTCHR
Arterial pulse wave
General population (n=180 children enrolled in group and comparison group, velocity
respectively)
the WTCHR; n=222 children in comparisongroup)

OR 1.08 (0.90–1.29), males
OR 1.63 (1.24–2.13)*, females
OR 1.24 (1.08–1.44)*, combined
Β 1.50 mm Hg (-0.17–3.18), males
β 6.65 mm Hg (4.32–8.99)*, females
β 4.84 mm Hg (3.55–6.12)*,
combined
β 0.45 mm Hg (-0.47–4.36), males
β 2.86 mm Hg (1.51–4.20)*, females
β 2.70 mm Hg (1.98–3.42)*,
combined
OR 0.77 (0.37–1.61), 4th quartile

OR 1.25 (0.92–1.69), 4th quartile

NS (p=0.06)
NS (p=0.51)

PERFLUOROALKYLS

151
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Lin et al. 2013a, 2013b8.65 ng/mL (median PFOS)

Association (p<0.001 for trend)*

General population (n=644)
Lind et al. 2017b

NR

General population (n=1,016, 70-year-old
adults)Manzano-Salgado et al. 2017b
General population (n=1,230 children)
Mattsson et al. 2015
General population (n=231 cases with CHD,
231 controls)
Melzer et al. 2010

Carotid intima media
thickness

Intima media thickness in NS (p=0.72)
common carotid artery
Echogenicity of intima
NS (p=0.40), males
media complex
NS (p=0.56), females
5.80 ng/mL (maternal
Blood pressure at 4 years β 0.00 (-0.09–0.10)
geometric mean PFOS)
of ageBlood pressure at 7 years β -0.05 (-0.15–0.06)
of age22.8 and 22.0 ng/mL (median Coronary artery disease OR 1.07 (0.60–1.92), 4th quartile
PFOS in cases and controls)

Coronary artery disease, OR 0.91 (0.570–1.64, p=0.745),
angina, and/or heart
4th quartile
General population (NHANES) (n=3,966 adults)
attackStarling et al. 2014b
12.87 ng/mL (median PFOS) Pre-eclampsia
HR 1.13 (0.84–1.52), per ln unit
General population (n=976 pregnant women)
PFHxS
Bao et al. 2017
General population (n=1,612 adults)
Huang et al. 2018
General population (NHANES, n=10,859 adults)

57.73 and 50.96 ng/mL(mean 4th quartile PFOS)

0.71 ng/mL (median serum
PFHxS in males andfemales)

Risk of hypertension
Systolic blood pressure
Diastolic blood pressure

OR 0.99 (0.95–1.03)
β 0.10 mm Hg (-0.30–0.51)
β 0.12 mm Hg (-0.11–0.35)

1.60 ng/mL (median serum
PFHxS)

Risk of cardiovasculardiseaseOR 0.96 (0.68–1.37), 4th quartilePERFLUOROALKYLS

152
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Koshy et al. 20170.67 and 0.53 ng/mL (median Arterial wall stiffness
serum PFHxS in WTCHR
Arterial pulse wave
group and comparison group, velocity
respectively)

NS (p=0.69)
NS (p=0.89)

General population (n=180 children enrolled in
the WTCHR; n=222 children in comparisongroup)
Lind et al. 2017b
General population (n=1,016, 70-year-old
adults)Manzano-Salgado et al. 2017b
General population (n=1,230 children)
Mattsson et al. 2015
General population (n=231 cases with CHD,
231 controls)
Starling et al. 2014b
General population (n=976 pregnant women)
PFNA
Bao et al. 2017
General population (n=1,612 adults)

NR

Intima media thickness in NS (p=0.90)
common carotid artery
Echogenicity of intima
NS (p=0.40), males
media complex
NS (p=0.95), females
0.61 ng/mL (maternal
Blood pressure at 4 years β -0.01 (-0.10–0.09)
geometric mean PFHxS)of ageBlood pressure at 7 years β 0.04 (-0.04–0.13)
of age
1.6 ng/mL (median PFHxS in Coronary artery disease OR 0.95 (0.54–1.67), 4th quartile
cases and controls)

0.69 ng/mL (median PFHxS) Pre-eclampsia

HR 0.91 (0.72–1.14), per ln unit

1.96 ng/mL (median serum Risk of hypertension
PFNA in males and females);2.19 and 1.31 ng/mL (medianserum PFNA in males andSystolic blood pressure
females, respectively)

OR 1.08 (0.92–1.26), males
OR 1.49 (1.16–1.92)*, females
OR 1.19 (1.04–1.36)*, combined
Β -0.12 mm Hg (-1.62–1.39), males
β 5.70 mm Hg (3.55–7.85)*, females
β 3.01 mm Hg (1.79–4.23)*, combined
β 0.94 mm Hg (0.12–1.76)*, males
β 2.74 mm Hg (1.51–3.97)*, females
β 2.48 mm Hg (1.80–3.16)*,
combined

Diastolic blood pressurePERFLUOROALKYLS

153
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Huang et al. 2018

0.98 ng/mL (median serum
PFNA)

Risk of cardiovasculardiseaseOR 1.30 (0.99–1.72), 4th quartile
OR 1.42 (1.07–1.88)*, 4th quartile withadjustment for serum total proteinsand eGFR

Risk of coronary heartdiseaseOR 1.89 (1.29–2.76)*, 4th quartile

Risk of heart attack
0.61 and 0.49 ng/mL (median Arterial wall stiffness
serum PFNA in WTCHR
Arterial pulse wave
group and comparison group, velocity
respectively)

OR 1.51 (1.02–2.23)*, 3rd quartile
Association (p=0.04)*
NS (p=0.14)

Lin et al. 2013a, 2013b0.38 ng/mL (median PFNA)

Carotid intima media
thickness

Inverse association (p=0.014 fortrend)*

General population (n=644)
Lind et al. 2017b

NR

Intima media thickness in NS (p=0.76)
common carotid artery
Echogenicity of intima
NS (p=0.66), males
media complex
Association (p=0.01)*, females
Blood pressure at 4 years β -0.01 (-0.10–0.08)
of ageBlood pressure at 7 years β 0.00 (-0.08–0.09)
of ageCoronary artery disease OR 0.68 (0.39–1.20), 4th quartile

General population (NHANES, n=10,859 adults)

Koshy et al. 2017
General population (n=180 children enrolled in
the WTCHR; n=222 children in comparisongroup)

General population (n=1,016, 70-year-old
adults)Manzano-Salgado et al. 2017b

0.66 ng/mL (maternal
geometric mean PFNA)

General population (n=1,230 children)
Mattsson et al. 2015
General population (n=231 cases with CHD,
231 controls)
Starling et al. 2014b
General population (n=976 pregnant women)

0.5 ng/mL (median PFNA incases and controls)

0.54 ng/mL (median PFNA)

Pre-eclampsia

HR 0.90 (0.70–1.16), per ln unitPERFLUOROALKYLS

154
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb
PFDA
Bao et al. 2017
General population (n=1,612 adults)

Huang et al. 2018

Serum perfluoroalkyl level Outcome evaluatedResultc

0.86 ng/mL (median serum Risk of hypertension
PFNA in males and females) Systolic blood pressure

OR 0.96 (0.85–1.09)
β -0.19 mm Hg (-1.39–1.02)
β 0.81 mm Hg (0.08–1.54)*, males
β 0.61 mm Hg (-0.81–2.04), females
β 1.19 mm Hg (0.52–1.37)*,
combined
OR 1.32 (0.99–1.78), 4th quartile
OR 1.43 (1.06–1.92)*, 4th quartile withadjustment for serum total proteinsand eGFR
NS (p=0.10)
NS (p=0.39)

Diastolic blood pressure

0.20 ng/mL (median serum
PFDA)

Risk of cardiovasculardiseaseGeneral population (NHANES, n=10,859 adults)
Koshy et al. 2017
General population (n=180 children enrolled in
the WTCHR; n=222 children in comparisongroup)
Lind et al. 2017b

0.14 and 0.11 ng/mL (median Arterial wall stiffness
serum PFDA in WTCHR
Arterial pulse wave
group and comparison group, velocity
respectively)

NR

General population (n=1,016, 70-year-old
adults)Mattsson et al. 2015

0.2 ng/mL (median PFDA incases and controls)

Intima media thickness in NS (p=0.85)
common carotid artery
Echogenicity of intima
NS (p=0.84), males
media complex
NS (p=014), females
Coronary artery disease OR 0.92 (0.53–1.60), 4th quartile

General population (n=231 cases with CHD,
231 controls)
Starling et al. 2014b0.10 ng/mL (median PFDA)

Pre-eclampsia

HR 0.88 (0.75–1.04), per ln unit

0.5 ng/mL (median serum
PFUnA in males andfemales)

Risk of hypertension
Systolic blood pressure
Diastolic blood pressure

OR 0.95 (0.90–1.01)
β -0.49 mm Hg (-1.04–0.05)
β -0.11 mm Hg (-0.41–0.20)

General population (n=976 pregnant women)
PFUnA
Bao et al. 2017
General population (n=1,612 adults)

PERFLUOROALKYLS

155
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Huang et al. 20180.20 ng/mL (median serum
PFUnA)

Risk of cardiovasculardiseaseGeneral population (NHANES, n=10,859 adults)
Risk of coronary heartdiseaseRisk of angina pectoris
Koshy et al. 20170.12 and 0.04 ng/mL (median Arterial wall stiffness
serum PFUnA in WTCHR
Arterial pulse wave
General population (n=180 children enrolled in group and comparison group, velocity
respectively)
the WTCHR; n=222 children in comparisongroup)

OR 1.58 (1.17–2.12)*, 2nd quartile

Lin et al. 2013a, 2013b

NS (p=0.953 for trend)

General population (n=644)
Lind et al. 2017b
General population (n=1,016, 70-year-old
adults)Mattsson et al. 2015
General population (n=231 cases with CHD,
231 controls)
Starling et al. 2014b
General population (n=976 pregnant women)

6.59 ng/mL (median PFUnA) Carotid intima media
thickness

OR 1.57 (1.00–2.46)*, 2nd quartile
OR 1.97 (1.09–3.55)*, 3rd quartile
NS (p=0.97)
NS (p=0.41)

NR

Intima media thickness in NS (p=0.96)
common carotid artery
Echogenicity of intima
NS (p=0.09), males
media complex
NS (p=0.14), females
0.2 ng/mL (median PFUnA in Coronary artery disease OR 0.88 (0.51–1.51), 4th quartile
cases and controls)

0.17 ng/mL (median PFUnA) Pre-eclampsia

HR 0.78 (0.66–0.92)*, per ln unitPERFLUOROALKYLS

156
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb
PFHpA
Bao et al. 2017
General population (n=1,612 adults)

Huang et al. 2018

Serum perfluoroalkyl level Outcome evaluatedResultc

0.01 ng/mL (median serum
PFHpA in males andfemales); 0.01 and0.01 ng/mL (median serum
PFHpA in males andfemales, respectively)

Risk of hypertension
Systolic blood pressure

0.20 ng/mL (median serum
PFHpA)

Risk of cardiovasculardiseaseOR 1.02 (0.89–1.16)
β 1.84 mm Hg (0.43–3.25)*, males
β 0.34 mm Hg (-2.47–3.15), females
β 1.50 mm Hg (0.21–2.80)*,
combined
β 0.79 mm Hg (0.02–1.55)*, males
β 0.14 mm Hg (-1.45–1.73), females
β 0.66 mm Hg (0.05–1.40), combined
OR 1.16 (0.71–1.91), 4th quartile

NR

Intima media thickness in NS (p=0.78)
common carotid artery

Diastolic blood pressure

General population (NHANES, n=10,859 adults)
Lind et al. 2017b
General population (n=1,016, 70-year-old
adults)Mattsson et al. 2015
General population (n=231 cases with CHD,
231 controls)
PFBS
Bao et al. 2017
General population (n=1,612 adults)
Huang et al. 2018
General population (NHANES, n=10,859 adults)

0.06 and 0.04 ng/mL(median PFHpA in cases andcontrols)

Echogenicity of intima
media complex
Coronary artery disease

0.01 ng/mL (median serum Risk of hypertension
PFBS in males and females) Systolic blood pressure
0.07 ng/mL (median serum
PFBS)

Diastolic blood pressure
Risk of cardiovasculardiseaseNS (p=0.53), males
NS (p=0.13), females
OR 2.58 (1.39–4.78)*, 3rd quartile
OR 1.73 (0.94–3.16), 4th quartile

OR 0.94 (0.78–1.12)
β -0.69 mm Hg (-2.49–1.11)
β -0.41 mm Hg (-1.42–0.60)
OR 1.34 (1.05–1.723)*, 2nd quartilePERFLUOROALKYLS

157
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb
PFBA
Bao et al. 2017
General population (n=1,612 adults)

PFDoDA
Bao et al. 2017
General population (n=1,612 adults)

Huang et al. 2018

Serum perfluoroalkyl level Outcome evaluatedResultc

0.15 ng/mL (median serum Risk of hypertension
PFBA in males and females);0.17 and 0.12 ng/mL (medianserum PFBA in males andSystolic blood pressure
females, respectively)

OR 1.09 (1.02–1.16)*, males
OR 1.16 (1.04–1.29)*, females
OR 1.10 (1.04–1.17)*, combined
β 0.66 mm Hg (0.03–1.28)*, males
β 0.77 mm Hg (-0.27–1.80), females
β 0.80 mm Hg (0.25–1.34)*,
combined

Diastolic blood pressure

β 0.09 mm Hg (-0.22–0.40), combined

0.12 ng/mL (median serum
PFDoDA in males andfemales); 0.17 and0.12 ng/mL (median serum
PFDoDA in males andfemales, respectively)

Risk of hypertension
Systolic blood pressure

0.14 ng/mL (median serum
PFDoDA)

Risk of cardiovasculardiseaseRisk of congestive heart
failureRisk of angina pectoris

OR 1.02 (0.93–1.11)
β -0.74 (-1.71–0.22), males
β 1.89 mm Hg (0.21–3.56*, females
β 0.30 mm Hg (-0.56–1.16), combined
β 0.13 mm Hg (-0.40–0.66), males
β 1.02 mm Hg (0.07–1.97)*, females
β 0.59 mm Hg (0.12–1.07)*,
combined
OR 1.53 (1.14–2.04)*, 4th quartile

General population (NHANES, n=10,859 adults)

Mattsson et al. 2015
General population (n=231 cases with CHD,
231 controls)

0.02 ng/mL (median
PFDoDA in cases andcontrols)

Diastolic blood pressure

Coronary artery disease

OR 1.55 (1.07–2.25)*, 3rd quartile
OR 1.64 (1.06–2.54)*, 4th quartile
OR 0.63 (0.35–1.11), 4th quartilePERFLUOROALKYLS

158
2. HEALTH EFFECTS

Table 2-8. Summary of Cardiovascular Outcomes in Humansa
Reference and study populationb
FOSA
Huang et al. 2018

Serum perfluoroalkyl level Outcome evaluatedResultc

0.07 ng/mL (median serum
FOSA)

OR 1.29 (1.01–1.65)*, 2nd quartile

General population (NHANES, n=10,859 adults)
Lind et al. 2017b
NR
General population (n=1,016, 70-year-old
adults)Risk of cardiovasculardiseaseIntima media thickness in NS (p=0.35), males
common carotid artery
Association (p=0.004)*, females
Association (p=0.01)*, combined
Echogenicity of intima
NS (p=0.84), males
media complex
NS (p=0.78, females

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 3 for more detailed descriptions of studies.

bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.

cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

CHD = coronary heart disease; FOSA = perfluorooctane sulfonamide; HR = hazard ratio; LHWA = Little Hocking Water Authority; NHANES = National Health andNutrition Examination Survey; NR = not reported; NS = not significant; OR = odds ratio; PFBA = perfluorobutanoic acid; PFBS = perfluorobutane sulfonic acid;
PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid;
PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid; SMR = standardizedmortality ratio; SPR = standard prevalence ratio; WTCHR = World Trade Center Health RegistryPERFLUOROALKYLS

159
2. HEALTH EFFECTS

Examination of the cardiovascular system in laboratory animals primarily consists of inhalation, oral, anddermal studies examining the heart for morphological alterations (see Tables 2-1, 2-3, 2-4, 2-5, and 2-6).
No studies in laboratory animals were identified for PFNA, PFUnA, PFHpA, or FOSA.

The laboratory animal studies did not find increases in the incidence of histological alterations in the heart
following exposure to PFOA, PFOS, PFHxS, PFDA, PFBS, PFBA, PFDoDA, or PFHxA.
PFOA

Epidemiological Studies—Heart Disease. Possible associations between PFOA exposure and increased
risk of heart disease have been examined in cohort mortality studies of workers, community members
living near a PFOA facility, and the general population. Occupational exposure studies have not foundincreases in deaths from all heart disease, cerebrovascular disease, or ischemic heart disease whencompared to U.S. general populations, state populations, and/or a population of workers at other company
facilities (Leonard 2006; Lundin et al. 2009; Raleigh et al. 2014; Steenland and Woskie 2012). One
occupational exposure study found an increase in the risk of cerebrovascular disease in workers withdefinite exposure for at least 6 months compared to an internal referent group (Lundin et al. 2009).
However, other studies have not found increased risks of ischemic heart disease (Raleigh et al. 2014; Sakr
et al. 2009), cerebrovascular disease (Raleigh et al. 2014), or coronary artery disease (Steenland et al.
2015). In another occupational exposure study, the investigators noted that electrocardiograms (EKGs)
were within normal limits (Sakr et al. 2007b).

Studies of residents living near the Washington Works facility in West Virginia reported increased risksof self-reported cardiovascular disease (Anderson-Mahoney et al. 2008), angina (Anderson-Mahoney etal. 2008), myocardial infarction (Anderson-Mahoney et al. 2008), and stroke (Anderson-Mahoney et al.
2008; Simpson et al. 2013). It is noted that the Anderson-Mahoney et al. (2008) study did not measureserum PFOA levels; the incidences of self-reported diseases were compared to NHANES rates. Anothercommunity study of residents in this area did not find an increased risk of coronary artery disease(Winquist and Steenland 2014a). Seven general population studies have examined possible associations
between serum PFOA and heart disease risks. A case-control study did not find increases in the risk ofcoronary artery disease in subjects with median serum PFOA levels of 4.2 ng/mL (cases) or 4.0 ng/mL(controls) (Mattsson et al. 2015). Utilizing the NHANES data set, Shankar et al. (2012) found increases
in the risk of peripheral arterial disease, coronary heart disease, or stroke in participants with serum PFOA
levels in the 4th quartile (>5.6 and >6.1 ng/mL in females and males, respectively) and for cardiovascularPERFLUOROALKYLS

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disease in participants with serum PFOA levels in the 3rd and 4th quartiles (>4.0 and >4.4 ng/L for females
and males, respectively). In contrast, two other NHANES studies did not find associations between
serum PFOA and physician-diagnosed coronary artery disease, angina, and/or heart attack (Melzer et al.
2010) or total cardiovascular heart disease (Huang et al. 2018). Two general population studies did not
find associations between serum PFOA levels and carotid intima media thickness (Lin et al. 2013a; Lind
et al. 2017b). Another study did not find associations with arterial wall stiffness or arterial pulse wave
velocity (Koshy et al. 2017).

Epidemiological Studies—Hypertension. Occupational, community, and general population exposurestudies have investigated the possible association between PFOA and blood pressure, the risk ofhypertension, and the risk of pregnancy-induced hypertension and/or pre-eclampsia. A study by Min etal. (2012) utilizing NHANES data found an increase in hypertension risk among participants with serum
PFOA levels in the 4th quartile. Another general population study did not find an association between
serum PFOA and the risk of hypertension, but did find associations between serum PFOA and systolicand diastolic blood pressure (Bao et al. 2017). In contrast, no increases in the risk of hypertension wereobserved in workers at the Washington Works facility (Steenland et al. 2015), adult community members
living near this facility (Winquist and Steenland 2014a), or adolescent NHANES participants (Geiger et
al. 2014a). Additionally, Manzano-Salgado et al. (2017b) did not find associations between maternal
serum PFOA levels and blood pressure in children at ages 4 or 7 years. There is some epidemiologicalevidence suggesting that an elevated uric acid level is a risk factor for hypertension (Johnson et al. 2003;
Sündstrom et al. 2005). Several occupational, community, and general population studies have foundincreases in uric acid levels and increased risks of hyperuricemia; these data are discussed in Section 2.10.
Overall, the results of these studies are suggestive of a connection between serum PFOA and increased
risk of hyperuricemia.

Several studies have examined the possible associations between PFOA and pregnancy-induced
hypertension/pre-eclampsia. Four studies have evaluated the community living near the Washington
Works facility using different approaches to assess PFOA exposure. Savitz et al. (2012a, 2012b) used
residential history and environmental dispersion of PFOA to estimate serum PFOA levels over time.
Stein et al. (2009) used serum PFOA levels measured in 2005–2006 to assess the risk of pre-eclampsia
occurring prior to the blood sampling. Darrow et al. (2013) primarily used serum PFOA levels measured
in 2005–2006 to assess the association with pregnancy-induced hypertension occurring after the blood
samples were collected. Savitz et al. (2012a) found an increased risk of self-reported pre-eclampsia in C8
Health Project participants with elevated PFOA levels and Darrow et al. (2013) found significant

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increases in the odds ratios (ORs) for self-reported pregnancy-induced hypertension in women withhigher PFOA (≥6.9 ng/mL) levels. A third study of highly exposed residents reported a weak association
between serum PFOA and self-reported pre-eclampsia in subjects whose serum PFOA levels were above
the median (Stein et al. 2009); however, there was no dose-response gradient. Using birth record data andserum PFOA levels predicted from addresses, Savitz et al. (2012b) found no consistent associations
between serum PFOA and the occurrence of pregnancy-induced hypertension in participants in the C8
Health Project. Similarly, Stein et al. (2009) did not find increases in the odds of self-reported preeclampsia among C8 Health Project participants categorized by serum PFOA levels. Another study ofresidents of this area did not find increases in the risk of pregnancy-induced hypertension among residents
living in an area where PFOA-contaminated water was supplied by the Little Hocking Water Authority(Nolan et al. 2010). A general population study did not find an association between plasma PFOA andthe risk of pre-eclampsia (Starling et al. 2014a).

Laboratory Animal Studies. A small number of laboratory animal studies have evaluated the
cardiovascular toxicity of PFOA. These studies focused on potential histological alterations in the heart;none of the available studies evaluated endpoints related to hypertension. No histopathological alterations
were seen in the heart from rats exposed intermittently head-only to up to 84 mg/m3 APFO dusts for
2 weeks (Kennedy et al. 1986). Administration of APFO in the diet at doses up to approximately 100–110 mg/kg/day to male and female CD rats or 10 mg/kg/day by gavage to Rhesus monkeys did not cause
gross or microscopic alterations in the heart or aorta (Griffith and Long 1980). Similar negative findings
were reported in Cynomolgus monkeys administered up to 20 mg/kg/day APFO by capsule for 26 weeks(Butenhoff et al. 2002) and in male and female Sprague-Dawley rats that received doses of up to
15 mg/kg/day APFO for 2 years (3M 1983; Butenhoff et al. 2012c). No morphological alterations wereseen in the heart from male rats dermally exposed to ≤2,000 mg/kg APFO for 2 weeks (Kennedy 1985).
Summary. Cardiovascular toxicity as assessed by deaths from heart disease, risk of heart disease, andrisk of hypertension has been evaluated in workers, community members living near a PFOA facility, andthe general population. In general, occupational exposure studies have not found increases in the risks ofdeaths from heart disease or in the risks of ischemic heart disease, cerebrovascular disease, or coronary
disease. Inconsistent results have been found in a small number of studies examining residents living inareas with high PFOA drinking water contamination or the general population. Studies of hypertension
have also not found associations between serum PFOA and hypertension risk. However, studies of highly
exposed residents provide some suggestive evidence of an association between serum PFOA andPERFLUOROALKYLS

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increased risks of pregnancy-induced hypertension/pre-eclampsia. Studies in laboratory animals did not
find histological alterations in the heart following acute-, intermediate-, or chronic-duration oral exposure.
PFOS

Epidemiological Studies—Heart Disease. Three studies have evaluated the possible association between
PFOS and heart disease. Melzer et al. (2010) did not find an association between serum PFOS and therisk of physician-diagnosed coronary artery disease, angina, and/or heart attack among NHANES
participants; Huang et al. (2018) did not find increases in the risk of cardiovascular disease among
NHANES participants. In a case-control study (Mattsson et al. 2015), no alterations in the risk ofcoronary artery disease were observed. Lin et al. (2013a) found an association between serum PFOS
levels and carotid intima media thickness in a general population study. When the subjects were divided
into subpopulations, associations between PFOS and carotid intima media thickness were found forfemales, nonsmokers, subjects 12–19 years of age, BMI <24, and those with an apolipoprotein E
genotype of E2 carrier or E3/E3. A second study of 70-year-old subjects did not find associations
between serum PFOS and the intima media thickness of the common carotid artery (Lind et al. 2017b).
Similarly, no alterations in arterial wall stiffness or pulse wave velocity were found in children enrolled in
the World Trade Center Health Registry (Koshy et al. 2017).

Epidemiological Studies—Hypertension. An increased risk of hypertension associated with serum PFOS
levels were observed in adults; when categorized by sex, the association was only found in females (Baoet al. 2017). The study also found associations for systolic and diastolic blood pressure in males andfemales combined and in females only. No increases in the risk of hypertension associated with serum
PFOS levels were observed in adolescent NHANES participants (Geiger et al. 2014a). Similarly, no
associations between maternal serum PFOS levels and blood pressure were found in children at ages
4 and 7 years (Manzano-Salgado 2017b). Two studies found increases in the risk of self-reported
pregnancy-induced hypertension (Darrow et al. 2013) or self-reported pre-eclampsia (Stein et al. 2009)
associated with serum PFOS levels among C8 participants. No increase in the risk of pre-eclampsia wasobserved in a general population study (Starling et al. 2014b).

Laboratory Animal Studies. Studies in laboratory animal studies have evaluated the cardiovascular
toxicity of PFOS but have not evaluated endpoints related to hypertension. Administration of doses of up
to 0.75 mg/kg/day PFOS (potassium salt) via capsule to Cynomolgus monkeys for 26 weeks did not cause
any significant gross or microscopic alterations in the heart or aorta (Seacat et al. 2002). Rats that

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received up to approximately 1.04 mg/kg/day of PFOS in the diet for 2 years had no significant gross or
microscopic changes in the heart (Butenhoff et al. 2012b; Thomford 2002b).
PFHxS

Epidemiological Studies. Eight general population studies examined possible cardiovascular outcomes
associated with PFHxS exposure. No increases in the risk of coronary artery disease (Mattsson et al.
2015) or cardiovascular disease (Huang et al. 2018) were found. Serum PFHxS levels were notassociated with arterial wall stiffness (Koshy et al. 2017) or carotid artery intima media thickness (Lind etal. 2017b). Studies examining blood pressure have not found associations in adults (Bao et al. 2017) or
children (Manzano-Salgado et al. 2017b). Additionally, no association between serum PFHxS and preeclampsia were found (Starling et al. 2014b).
Laboratory Animal Studies. Dosing of rats with≤10 mg/kg/day PFHxS or mice with ≤3 mg/kg/day by
gavage for 40–60 days did not cause morphological alterations in the heart (Butenhoff et al. 2009a; Changet al. 2018).
PFNA

Epidemiological Studies. In a general population study, an inverse association between serum PFNA
levels and carotid intima media thickness was observed (Lin et al. 2013a). The investigators suggested
that this finding may be secondary to an interaction between higher serum PFOS levels and lower serum
PFNA levels in the study population. Associations were only found in subjects with serum PFOS higher
than the 50th percentile regardless of whether the serum PFNA was higher or lower than the 60th
percentile. A second study did not find an association between serum PFNA and intima media thickness(Lind et al. 2017b), but did find an association with the echogenicity of the intima media complex, an
indicator of early changes in the carotid artery. Koshy et al. (2017) also found an association between
serum PFNA and arterial wall stiffness in children enrolled in the World Trade Center Health Registry.
Increased risks of cardiovascular disease, coronary heart disease, and heart attack were found in
NHANES participants (Huang et al. 2018). In contrast, another general population study did not findincreases in the risk of coronary heart disease (Mattsson et al. 2015). An association between serum
PFNA and hypertension risk and systolic and diastolic blood pressure was found in a general population
study (Bao et al. 2017). Manzano-Salgado et al. (2017b) did not find associations between maternalPERFLUOROALKYLS

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serum PFNA and blood pressure in children aged 4 or 7 years, and Starling et al. (2014b) did not findassociations between serum PFNA and pre-eclampsia (Starling et al. 2014b).
PFDA

Epidemiological Studies. In a study of NHANES participants, Huang et al. (2018) found an increased
risk of any type of cardiovascular disease among participants with the highest serum PFDA levels when
the statistical analyses adjusted for serum total protein levels and estimated glomerular filtration rate;
however, no associations were found for specific types of cardiovascular disease. In another general
population study, Mattsson et al. (2015) found no association between serum PFDA and the risk ofcoronary artery disease. Studies examining carotid artery intima media thickness or arterial wall stiffnessof the brachial artery did not find associations with serum PFDA levels (Koshy et al. 2017; Lind et al.
2017b). Although Bao et al. (2017) did not find an association between serum PFDA levels and the riskof hypertension or systolic blood pressure levels, associations were found in diastolic blood pressurelevels in males only and in males and females combined. No association was found between serum
PFDA and pre-eclampsia (Starling et al. 2014b).

Laboratory Animal Studies. Death in female C57BL/6N mice following administration of a single lethal
dose of 160 or 320 mg/kg PFDA by gavage was associated with mural thrombosis of the left ventricle ofthe heart (Harris et al. 1989). Doses ≤80 mg/kg did not cause gross or microscopic alterations in theheart, assessed 30 days after dosing, but 80 mg/kg significantly decreased relative heart weight (Harris etal. 1989).

PFUnA

Epidemiological Studies. Serum PFUnA levels were associated with increased risks of any type of
cardiovascular disease, coronary heart disease, and angina pectoris in NHANES participants (Huang et al.
2018). No associations between serum PFUnA levels and the risk of hypertension of systolic or diastolicblood pressure were observed (Bao et al. 2017). Starling et al. (2014b) found an inverse association
between serum PFUnA levels and the risk of pre-eclampsia in pregnant women. No associations between
serum PFUnA levels and carotid intima artery thickness (Lin et al. 2013a; Lind et al. 2017b) or brachialartery wall stiffness (Koshy et al. 2017) were observed in general population studies. Another general
population study (Mattsson et al. 2015) did not find an increase in the risk of coronary artery diseaseassociated with serum PFUnA levels.

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PFHpA

Epidemiological Studies. Mattsson et al. (2015) found an increase in the risk of coronary artery disease
in individuals with serum PFHpA levels in the 3rd quartile; however, the risk was not increased for thosewith serum levels in the 4th quartile. A study of NHANES participants did not find an association
between the serum PFHpA levels and any type of cardiovascular disease or a specific type of heartdisease (Huang et al. 2018). No associations between serum PFHpA and the thickness of the intima
media of the common carotid artery were observed in a general population study of 70-year-old adults(Lind et al. 2017b). Bao et al. (2017) did not find an association between serum PFHpA levels and therisk of hypertension; the study did find associations for systolic and diastolic blood pressure levels inmales only.
PFBS

Epidemiological Studies. Two general population studies have evaluated the potential associations
between serum PFBS and cardiovascular effects. Huang et al. (2018) found increased risks ofcardiovascular disease (all types combined) in NHANES participants with serum PFBS levels in the
2nd quartile and higher; however, no associations were found for specific disease types. Bao et al. (2017)
did not find associations between serum PFBS levels and the risk of hypertension or systolic or diastolicblood pressure levels among adults.

Laboratory Animal Studies. No morphological alterations were reported in the heart or aorta from rats
dosed with ≤900 mg/kg/day PFBS by gavage for 28 days (3M 2001) or ≤600 mg/kg/day PFBS for
90 days (Lieder et al. 2009a).
PFBA

Epidemiological Studies. Only one epidemiological study examined potential cardiovascular healthoutcomes. Bao et al. (2017) found increases in the risk of hypertension in male and female adults, which
was associated with serum PFBA levels. Systolic blood pressure levels were also associated with serum
PFBA levels in males and females combined or in males only; no associations were found for diastolicblood pressure.

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Laboratory Animal Studies. PFBA administered to rats by gavage in doses of up to 184 mg/kg/day for
5 days, 150 mg/kg/day for 28 days, or 30 mg/kg/day for 90 days did not induce gross or microscopic
alterations in the heart (3M 2007a; Butenhoff et al. 2012a; van Otterdijk 2007a, 2007b).
PFDoDA

Epidemiological Studies. No increase in the risk of coronary heart disease associated with serum
PFDoDA levels was found in a general population study (Mattsson et al. 2015). In contrast, Huang et al.
(2018) found increased risks of cardiovascular disease (any type), congestive heart failure, or angina
pectoris in NHANES participants with higher serum PFDoDA levels. Bao et al. (2017) reported
associations between serum PFDoDA levels in systolic and diastolic blood pressure levels among women,
but there was no association with the risk of hypertension.

Laboratory Animal Studies. No histological alterations were observed in male rats administered
2.5 mg/kg/day for 42 days (Kato et al. 2015).
PFHxA

Epidemiological Studies. An increased risk of cardiovascular disease (any type) was found in NHANES
participants with higher serum PFHxA levels (Huang et al. 2018). A study of 70-year-old adults reported
increases in the intima media thickness in the common carotid artery that was associated with serum
PFHxA levels (Lind et al. 2017b).

Laboratory Animal Studies. No histological alterations were observed in the heart of rats administered
up to 500 mg/kg/day NaPFHx for 90–93 days (Chengelis et al. 2009b; Loveless et al. 2009).

FOSA

Epidemiological Studies. Serum FOSA levels were associated with an increased risk of cardiovasculardisease (any type) in a study of NHANES participants (Huang et al. 2018). Increases in the intima media
thickness in the common carotid artery was associated with serum FOSA levels in a study of 70-year-old
men and women (Lind et al. 2017b).

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2.6

GASTROINTESTINAL

Overview. Available epidemiological data on the potential of perfluoroalkyls to induce gastrointestinal
effects are limited to two studies of workers at a PFOS facility that found mixed results on the possible
association between PFOS and colon polyps; summaries of these studies are presented in the Supporting
Document for Epidemiological Studies for Perfluoroalkyls, Table 4. Epidemiological studies examining
potential gastrointestinal effects were not identified for the other perfluoroalkyls. Studies examining
ulcerative colitis are discussed in Section 2.14, Immunological. Laboratory animal studies have examined
the gastrointestinal tract for morphological alterations following inhalation, oral, or dermal exposure to
PFOA (Tables 2-1, 2-3, and 2-6), oral exposure to PFOS (Table 2-4), and oral exposure to otherperfluoroalkyls (Table 2-5); the NOAELs and LOAELs are presented in Figures 2-6, 2-8, and 2-9. No
laboratory animal studies were identified for PFNA, PFUnA, PFHpA, or FOSA. Studies on PFOA andPFBS have reported some signs of gastrointestinal irritation following gavage administration. Most
studies did not report histological alterations in the gastrointestinal tract following exposure to PFOA,PFOS, PFHxS, PFDA, PFBA, PFDoDA, or PFHxA.
PFOALaboratory Animal Studies. The available data in rats and monkeys do not suggest that thegastrointestinal tract is a sensitive target of toxicity, although two studies did report some signs of
irritation. Stomach irritation was reported in male rats exposed head-only to ≥380 mg/m3 APFO dusts for
4 hours (Kennedy et al. 1986). No histopathological alterations were seen in the stomach, small intestine,or large intestine from male rats exposed intermittently nose-only to up to 84 mg/m3 APFO dusts for
2 weeks (Kennedy et al. 1986).

No significant gross or microscopic alterations of the gastrointestinal tract were observed in male orfemale rats exposed to approximately 100–110 mg/kg/day APFO through the diet for 90 days (Griffith
and Long 1980). Similar observations were reported in male and female rats exposed to 15 mg/kg/day
APFO via the diet for 2 years (3M 1983; Butenhoff et al. 2012c). The same investigators also reported
that emesis occurred in Rhesus monkeys exposed to lethal doses (30 and 100 mg/kg/day) of APFO bygavage for 90 days (Griffith and Long 1980). In another intermediate-duration study in which
Cynomolgus monkeys were exposed to up to 20 mg/kg/day APFO administered via a capsule forPERFLUOROALKYLS

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26 weeks, no treatment-related alterations in the gastrointestinal tract were observed at termination(Butenhoff et al. 2002).

Intermittent application of up to 2,000 mg/kg/day APFO to the skin of male rats for up to 2 weeks did not
result in gross or microscopic alterations in the gastrointestinal tract (Kennedy 1985).

PFOS

Epidemiological Studies. There are limited data available on the potential of PFOS to induce
gastrointestinal damage. A study of current, retired, or former workers employed for at least 1 year at a
PFOS-based fluorochemical manufacturing facility in Decatur, Alabama found no association between
self-reported incidence of gastric ulcer or colon polyps and having worked in a job with either low(estimated serum PFOS levels of 390–890 ng/mL) or high (estimated PFOS serum levels of 1,300–
1,970 ng/mL) exposure to PFOS, as compared to workers with no direct workplace exposure (estimatedserum PFOS levels of 110–290 ng/mL) (Grice et al. 2007). A second study of workers at the Decatur
facility found an increase in the risk ratio episodes of care for benign colonic polyps in workers with highpotential exposure to PFOS (Olsen et al. 2004a).

Laboratory Animal Studies. Unpublished data summarized by OECD (2002) indicate that distension of
the small intestine was observed in rats exposed to lethal concentrations of airborne PFOS dusts (1,890–
45,970 mg/m3) for 1 hour. Treatment of rats with up to approximately 1.04 mg/kg/day PFOS via the dietfor 2 years did not induce morphological alterations in the gastrointestinal tract (Butenhoff et al. 2012b;
Thomford 2002b).

PFHxSLaboratory Animal Studies. No morphological alterations were observed in the gastrointestinal tract ofrats administered ≤10 mg/kg/day or mice administered ≤3 mg/kg/day PFHxS via gavage for 40–60 days
(Butenhoff et al. 2009a; Chang et al. 2018).

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PFDA

Laboratory Animal Studies. Administration of 0.5 mg/kg/day PFDA to rats for 28 days or 5 mg/kg tomice for 4 weeks (once/week) did not result in histological alterations in the gastrointestinal tract(Frawley et al. 2018).

PFBS

Laboratory Animal Studies. Necrosis of individual squamous cells and hyperplasia and hyperkeratosis
were observed in the limiting ridge of the forestomach of male and female rats administered
600 mg/kg/day PFBS via gavage for 90 days (Lieder et al. 2009a); these lesions were likely due toirritation from the repeated gavage administration with PFBS. In another study, no morphologicalalterations were observed in the gastrointestinal tract of rats administered ≤900 mg/kg/day PFBS via
gavage for 28 days (3M 2001).

PFBA

Laboratory Animal Studies. Administration of PFBA to rats by gavage in doses of up to 184 mg/kg/day
for 5 days, 150 mg/kg/day for 28 days, or 30 mg/kg/day for 90 days did not cause morphologicalalterations in the gastrointestinal tract (3M 2007a; Butenhoff et al. 2012a; van Otterdijk 2007a, 2007b).
PFDoDA

Laboratory Animal Studies. No histological alterations were observed in the gastrointestinal tract ofmale rats receiving gavage administration of 2.5 mg/kg/day for 42 days or in male and female rats
administered 42 mg/kg/day for 42 days and allowed to recover for 14 days (Kato et al. 2015).
PFHxA

Laboratory Animal Studies. Rat administered 200 mg/kg/day NaPFHx for 90 days did not exhibit
histological alterations in the gastrointestinal tract (Chengelis et al. 2009b). Erosions/ulcerations wereobserved in the glandular or nonglandular stomach of rats receiving gavage doses of 450 mg/kg/day
PFHxA for 4 days; all animals exhibiting these lesions died early or were sacrificed in extremis

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2. HEALTH EFFECTS(Kirkpatrick 2005). No gastrointestinal lesions were observed in rats administered a time-weighted
average (TWA) dose of 315 mg/kg/day for 32–44 days (Kirkpatrick 2005).
2.7

HEMATOLOGICAL

Overview. A small number of epidemiological studies have evaluated hematological endpoints inworkers exposed to PFOA or PFOS and in a community exposure study; these studies did not findalterations in hematological indices; epidemiological data were not identified for the otherperfluoroalkyls. Details of these studies are presented in the Supporting Document for EpidemiologicalStudies for Perfluoroalkyls, Table 5. Laboratory animal studies have evaluated potential alterations inhematological endpoints for a variety of perfluoroalkyls (Tables 2-1, 2-3, 2-4, 2-5, and 2-6). No studies
examining hematological endpoints were identified for PFNA, PFHpA, or FOSA. Some laboratory
animal studies have reported alterations in hematological indices following exposure to higher doses of
PFOA, PFOS, PFHxS, PFDA, PFUnA, PFBS, PFBA, PFDoDA, or PFHxA.
PFOA

Epidemiological Studies. Information on effects on hematological parameters is available from a studyof residents in the Little Hocking water district in southeastern Ohio where there was significant
environmental exposure to PFOA via the water supply (Emmett et al. 2006b). No significant correlations
between any of the hematology parameters evaluated (including hemoglobin, hematocrit, red blood cell
indices, white cell count, and platelet count) and serum PFOA were observed, whether the analysis
included all of the individuals as a group or separate analyses were done for adults or children. In an
occupational study, the investigators reported no alterations in blood counts in workers, with a range ofserum PFOA levels of 5–9,550 ng/mL (Sakr et al. 2007b). A second occupational exposure study foundan inverse association between serum fluorine (used as a measure of PFOA exposure) and hemoglobin
levels (Gilliland 1992); no alterations in mean corpuscular hemoglobin or volume were found. Although
no associations were found for total leukocyte counts, an inverse association with lymphocyte count andassociation with monocyte counts was found.

Laboratory Animal Studies. No treatment-related hematological alterations were reported in male rats
exposed intermittently nose-only to up to 84 mg/m3 APFO dusts for 2 weeks (Kennedy et al. 1986). The
specific parameters evaluated included erythrocyte counts, hemoglobin concentration, hematocrit, anddifferential leukocyte counts.

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No significant hematological alterations were reported in male and female rats orally dosed withapproximately 100–110 mg/kg/day APFO in diet for 90 days (Griffith and Long 1980). Similar results
were reported in Cynomolgus monkeys treated daily with up to 20 mg/kg/day APFO administered via acapsule (Butenhoff et al. 2002; Thomford 2001) or in Rhesus monkeys dosed daily by gavage with up to
30 mg/kg/day (Griffith and Long 1980). In a 2-year dietary study in rats dosed with 1.5 or 15 mg/kg/day
APFO, hematology tests performed at various times during the study showed changes in treated groups
consisting of decreases in red blood cell counts, hemoglobin concentration, and hematocrit that were notalways dose-related or consistent among sexes and were within acceptable ranges for the rat (3M 1983;
Butenhoff et al. 2012c).

Hematology tests (erythrocyte count, hemoglobin concentration, hematocrit, total and differential
leukocyte count, and red cell indices) conducted in blood from rats following intermittent dermal
exposure to ≤2,000 mg/kg/day APFO for 2 weeks showed inconsistent alterations or changes of unlikely
biological significance (Kennedy 1985).
PFOS

Epidemiological Studies. Two occupational exposure studies (Olsen et al. 1998a, 2003a) have examined
the potential association between serum PFOS and hematological parameters (including hematocrit,hemoglobin, red blood cells, white blood cells, and platelets) in workers at 3M facilities in Decatur,
Alabama and Antwerp, Belgium; mean measured levels of serum PFOS ranged from 800 to 2,440 ng/mL.
No consistent alterations in hematological parameters were observed at either facility or at the different
measuring time points.

Laboratory Animal Studies. Treatment of male and female rats with approximately 1.5–1.8 mg/kg/day
PFOS (potassium salt) in the diet for 4 weeks did not result in significant alterations in hematologicalparameters (Seacat et al. 2003). Oral dosing with 1.3–1.6 mg/kg/day for 14 weeks resulted in asignificant increase (45%) in non-segmented neutrophils (Seacat et al. 2003). The biological significanceof this finding was not discussed by the investigators. In a 4-week study, oral administration of up to
2 mg/kg/day PFOS to Cynomolgus monkeys had no effect on hematological parameters (Thomford
2002a). In Cynomolgus monkeys dosed with 0, 0.03, 0.15, or 0.75 mg/kg/day PFOS (potassium salt)
administered via a capsule for 26 weeks and subjected to comprehensive hematological tests during thestudy, the only significant effect was a 9% decrease in hemoglobin in 0.75 mg/kg/day males at

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termination (Seacat et al. 2002). The investigators considered this a treatment-related effect, but notbiologically significant given that the value was within the published range and there was no evidence ofblood in the stools. No significant hematological effects were reported in a 2-year study in rats dosedwith approximately 1.04 mg/kg/day PFOS in the diet (Butenhoff et al. 2012b; Thomford 2002b).

PFHxSLaboratory Animal Studies. Treatment of male rats with doses ≥0.3 mg/kg/day PFHxS by gavage for atleast 42 days significantly increased prothrombin time (Butenhoff et al. 2009a). Doses ≥1 mg/kg/day
significantly decreased hemoglobin concentration, whereas ≥3 mg/kg/day decreased erythrocyte countand hematocrit; the decrease in hemoglobin (<5%) was not considered adverse at 1 mg/kg/day. Oral
treatment of female rats with up to 10 mg/kg/day PFHxS did not significantly alter hematologicalparameters (Butenhoff et al. 2009a). No alterations in hematological parameters were observed in miceadministered up to 3 mg/kg/day prior to mating and during mating, gestation, and lactation (Chang et al.
2018).
PFDA

Laboratory Animal Studies. Significant decrease in mean corpuscular hemoglobin and mean corpuscularhemoglobin concentration were observed in rats administered 0.25 or 0.5 mg/kg/day for 28 days (Frawley
et al. 2018). No other alterations in hematological parameters were observed. Hematological alterations
were also not observed in mice receiving once weekly doses of 5 mg/kg PFDA for 4 weeks (Frawley et al.
2018).

PFUnALaboratory Animal Studies. Treatment of rats with 1.0 mg/kg/day PFUnA via gavage for 41–46 days
resulted in significant hematological changes (Takahashi et al. 2014). Effects in males included
decreased mean corpuscular volume (MCV) (5%), mean corpuscular hemoglobin (MCH) (5%), activatedpartial thromboplastin time (APTT) (16–25%), and fibrinogen (19–33%), and increased platelet counts(13%) and white blood cells (7%). In females, there were increases in MCV (10%) and MCH (10%) anda decrease in fibrinogen (32%). The NOAEL was 0.3 mg/kg/day.

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PFBS

Laboratory Animal Studies. A 90-day exposure to PFBS resulted in significant decreases in hemoglobin
and hematocrit levels in males orally administered 200 or 600 mg/kg/day, and a decrease in erythrocyte
levels was observed in males administered 600 mg/kg/day; the NOAEL was 60 mg/kg/day (Lieder et al.
2009a). In contrast, no hematological alterations were observed in rats administered 900 mg/kg/day
PFBS for 28 days (3M 2001).
PFBA

Laboratory Animal Studies. Administration of PFBA by gavage to rats in doses of up to 184 mg/kg/day
for 5 days (3M 2007a) or up to 150 mg/kg/day for 28 days (Butenhoff et al. 2012a; van Otterdijk 2007a)
did not result in significant alterations in hematological parameters. Oral doses of 30 mg/kg/day, but not
6 mg/kg/day, for 90 days resulted in significant reductions in red blood cell counts, hemoglobin, andhematocrit, and an increase in red cell distribution width in male rats (Butenhoff et al. 2012a; vanOtterdijk 2007b). This dose level also caused a reduction in MCH and reduced MCH concentration inmale rats. The lower hemoglobin and hematocrit observed in males were still detected at the end of a
3-week recovery period. These hematological effects were considered minor and not evidence of an
adverse effect on red blood cell turnover by the investigator based on lack of alterations in bone marrowor the spleen.
PFDoDA

Laboratory Animal Studies. Gavage administration of 2.5 mg/kg/day for 42 days resulted in decreases inmean corpuscular volume and reticulocytes and increases in mean corpuscular hemoglobin concentrationin male rats (Kato et al. 2015). In animals allowed to recover for 14 days, decreases in red blood cells,
hemoglobin, hematocrit, and leukocyte levels and increases in reticulocytes were observed. In females
administered 2.5 mg/kg/day for 42 days and allowed to recover for 14 days, decreases in hemoglobin,
hematocrit, and mean corpuscular hemoglobin and increases in neutrophil levels were observed (Kato etal. 2015).

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PFHxALaboratory Animal Studies. Several studies in rats have identified the hematological system as a target
of PFHxA toxicity. Decreases in red blood cell counts, hemoglobin levels, and/or hematocrit levels andincreases in reticulocyte levels have been observed in rats administered 315 mg/kg/day PFHxA for 32–
44 days (Kirkpatrick 2005), 200 mg/kg/day NaPFHx for 90 days (Chengelis et al. 2009b), 500 mg/kg/day
NaPFHx for 92–93 days (Loveless et al. 2009), or 200 mg/kg/day PFHxA for 104 weeks (Klaunig et al.
2015). A decrease in hemoglobin levels was also observed in rats administered 150 mg/kg/day PFHxA
for 32–44 days (Kirkpatrick 2005). Hematological alterations were not observed at doses≤100 mg/kg/day. Hematological alterations were only observed in female rats in the Klaunig et al. (2015)
study and only in males in the Kirkpatrick (2005) study; sex-specific differences were not observed in theChengelis et al. (2009b) or Loveless et al. (2009) intermediate-duration studies.
2.8

MUSCULOSKELETAL

Overview. Several epidemiological studies have evaluated possible associations between perfluoroalkyls
and bone mineral density, risk of bone fractures, and risk of osteoarthritis; the results of these studies are
summarized in Table 2-9, with more detailed descriptions presented in the Supporting Document for
Epidemiological Studies for Perfluoroalkyls, Table 6. Several cross-sectional community and general
population studies have found associations between serum PFOA and the risk of osteoarthritis,
particularly in participants under the age of 55 years. However, associations were not found in a study ofmostly male workers. Mixed results were found in studies of PFOS, with studies finding a decreased riskof osteoarthritis, increased risk in women under 50 years of age, or no association. One general
population study found increased risks of osteoarthritis associated with serum PFHxS and PFNA. The
data provide some suggestive evidence of a relationship between serum perfluoroalkyls and osteoarthritis.
Assessing whether there is an association between perfluoroalkyl exposure and osteoarthritis iscomplicated by the lack of mechanistic data to support this association and it is noted that there are anumber of factors that contribute to the osteoarthritis risk, and that some of these factors may be affectedby perfluoroalkyls, including elevations in uric acid levels. Epidemiological information on bone mineraldensity is limited to a study of women and a study of children both examining PFOA, PFOS, PFHxS, and
PFNA; the database was not considered adequate for assessing possible associations. No epidemiologicalstudies evaluating musculoskeletal outcomes were identified for PFDA, PFUnA, PFHpA, PFBS, PFBA,
PFDoDA, PFHxA, or FOSA. No morphological alterations were noted in bone or skeletal muscle inPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-9. Summary of Skeletal Outcomes in Humansa
Reference and study populationb
PFOA
Steenland et al. 2015

Serum perfluoroalkyl level Outcome evaluatedResultc

Estimated cumulative
exposure

Osteoarthritis risk

NS (p=0.92 for trend), no lag
NS (p=0.13 for trend), 10-year lag

13.6–28.0 ng/mL (2nd PFOA
quartile)

Osteoarthritis risk
(physician diagnosed)

Occupational (n=3,713 workers)
Innes et al. 2011
Community (C8) (n=49,432 adults)
Khalil et al. 2016

3.7 ng/mL (mean PFOA)

General population (NHANES)(n=1,914 participants)
Khalil et al. 2018

0.99 ng/mL (mean serum
PFOA)

OR 1.16 (1.03–1.31)*, 2nd quartile
OR 1.22 (1.02–1.45)*, 2nd quartile
participants <55 years of age
Total femur neck mineral β -0.017 (-0.033 to -0.001)*, womendensityβ 0.001 (-0.025–0.022), men
Osteoporosis risk
OR 1.84 (1.17–2.90; p=0.008)*, per ln(women)
PFOA increase
Bone mineral density
NS (p>0.05)

General population (n=48 obese 8–12-year-old
children)
Lin et al. 2014
General population (NHANES)(n=2,339 participants)

4.70 and 3.31 ng/mL(geometric mean PFOA in
males and females)

Total lumbar spine bonemineral density

NS (p>0.01), premenopausal women,
postmenopausal women, men

Total hip bone mineraldensity

NS (p>0.01), premenopausal women,
postmenopausal women, men

All fracture types

OR 0.98 (0.75–1.28), premenopausal
women
OR 1.53 (0.63–3.74), postmenopausal
women
OR 0.84 (0.67–1.07), men
OR 1.59 (0.57–4.46), premenopausal
women
OR 0.48 (0.06–4.16), postmenopausal
women
OR 0.64 (0.39–1.06), men

Hip fracturePERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-9. Summary of Skeletal Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedWrist fracture

Spine fracture

Uhl et al. 2013

Community (C8) (n=49,432 adults)
Khalil et al. 2016

Osteoarthritis risk (selfreported)≥29.4 ng/mL (4th PFOS
quartile)

Osteoarthritis risk
(physician diagnosed)

OR 0.76 (0.68–0.85)*, 4th quartile

12.7 ng/mL (mean PFOS)

Total femur neck mineraldensity
Osteoporosis risk
(women)Bone mineral density

β -0.016 (-0.029 to -0.002)*, women
β -0.013 (-0.024 to -0.002)*, men
OR 1.14 (0.68–1.94; p=0.619), per
ln-PFOS increase
NS (p>0.05)

Total lumbar spine bonemineral density

β -0.022 (-0.038 to -0.007)*,
premenopausal women
NS (p>0.01), postmenopausal women
NS (p>0.01), men

General population (NHANES)(n=1,914 participants)
Khalil et al. 2018

OR 1.07 (0.65–1.77), premenopausal
women
OR 1.21 (0.46–3.13), postmenopausal
women
OR 1.12 (0.75–1.70), men
OR 1.83 (0.59–5.61), premenopausal
women
OR 0.84 (0.46–1.53), postmenopausal
women
OR 1.54 (0.85–2.79), men
OR 1.98 (1.24–3.19)*, 4th quartiles
females
OR 0.82 (0.40–1.70), 4th quartile males
OR 4.95 (1.27–19.4)*, 4th quartile
women 20–49 years of age
OR 1.33 (0.82–1.16), 4th quartile
women 50–84 years of age>5.89 ng/mL (4th PFOA
quartile)

General population (NHANES) (n=1,888 maleand 1,921 female adults)

PFOS
Innes et al. 2011

Resultc

2.79 ng/mL (mean serum
PFOS)

General population (n=48 obese 8–12-year-old
children)
Lin et al. 2014
General population (NHANES)(n=2,339 participants)

19.23 and 12.09 ng/mL(geometric mean PFOS inmales and females)PERFLUOROALKYLS

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Table 2-9. Summary of Skeletal Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedTotal hip bone mineraldensity
All fracture types

Hip fracture

Wrist fracture

PFHxS
Khalil et al. 2016

2.5 ng/mL (mean PFHxS)

General population (NHANES)(n=1,914 participants)
Khalil et al. 2018
General population (n=48 obese 8–12-year-old
children)

1.09 ng/mL (mean serum
PFHxS)

Resultc
NS (p>0.01), premenopausal women,
postmenopausal women, men
OR 0.97 (0.75–1.24), premenopausal
women
OR 1.59 (0.88–2.86), postmenopausal
women
OR 0.92 (0.73–1.16), men
OR 1.12 (0.62–2.03), premenopausal
women
OR 0.83 (0.23–3.00), postmenopausal
women
OR 1.07 (0.76–1.52), men
OR 1.04 (0.63–1.72), premenopausal
women
OR 1.22 (0.61–2.45), postmenopausal
women
OR 1.09 (0.72–1.66), men

Spine fracture

OR 0.52 (0.15–1.86), premenopausal
women
OR 1.12 (0.26–4.78), postmenopausal
women
OR 1.27 (0.67–2.42), men

Total femur bone mineraldensity
Osteoporosis risk
(women)Bone mineral density

β -0.014 (-0.074 to -0.014)*, women
β -0.026 (-0.065–0.013), men
OR 1.64 (1.14–2.38; p=0.008)*, per
ln-PFHxS increase
NS (p>0.05)

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Table 2-9. Summary of Skeletal Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

PFNA
Khalil et al. 2016

1.9 ng/mL (mean PFNA)

β -0.040 (-0.077 to -0.003)*, women
β 0.007 (-0.031–0.045), men
OR 1.45 (1.02–2.05; p=0.001)*, per
ln-PFNA increase.
Inverse association (p<0.05)*
NS (p>0.05) after adjustment for
multiple testing

General population (NHANES)(n=1,914 participants)
Khalil et al. 20180.24 ng/mL (mean serum
PFNA)

General population (n=48 obese 8–12-year-old
children)

Total femur bone mineraldensity
Osteoporosis risk
(women)Bone mineral density

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 6 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

NHANES = National Health and Nutrition Examination Survey; NS = not significant; OR = odds ratio; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

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laboratory animals following exposure to PFOA, PFOS, PFHxS, PFBS, PFBA, or PFHxA; these data aresummarized in Tables 2-1, 2-3, 2-4, and 2-5 and Figures 2-6, 2-8, 2-9, and 2-10. No laboratory animal
data were available for PFNA, PFDA, PFUnA, PFHpA, PFDoDA, or FOSA.
PFOA

Epidemiological Studies. Several studies have examined the possible association between serum PFOA
levels and the risk of osteoarthritis; the possible mechanisms associated with these findings have not been
elucidated. In an occupational study (80% male), no association between estimated cumulative serum
PFOA levels and the risk of osteoarthritis was found (Steenland et al. 2015). Innes et al. (2011) examined
adult participants in the C8 Health Project and found that the odds of reporting osteoarthritis were higher
in participants with serum PFOA levels in the 2nd, 3rd, and 4th quartiles compared to participants in the
1st quartile. When segregated by age and BMI, the strongest associations between serum PFOA levels
and osteoarthritis were found in subjects under 55 years of age and in nonobese (BMI <30) subjects.
Increases in the risk of osteoarthritis associated with serum PFOA levels were observed in female
NHANES participants (Uhl et al. 2013); there were no associations in men. When stratified by age, theassociations were found in women 20–49 years of age, but not in older women (50–84 years old) (Uhl etal. 2013). An association between increases in risk of osteoporosis and serum PFOA levels was found inanother study of female NHANES participants (Khalil et al. 2016). Two studies of adult NHANES
participants found no associations between serum PFOA and bone mineral density of the total femur(Khalil et al. 2016), hip (Lin et al. 2014), or lumbar spine (Khalil et al. 2016; Lin et al. 2014); however, an
inverse association was found in the neck portion of the femur in the Khalil et al. (2016) study. A study
in obese children did not find an association between serum PFOA levels and measures of bone mineraldensity (Khalil et al. 2018). Additionally, Lin et al. (2014) did not find associations between serum
PFOA levels and the risk of bone fractures (total fractures, hip fractures, wrist fractures, or spine
fractures) in premenopausal women, postmenopausal women, or men.
Laboratory Animal Studies. In male rats exposed head-only to up to 84 mg/m3 APFO dusts for up to
2 weeks, examinations of the sternebrae were unremarkable (Kennedy et al. 1986). Similarly, no gross or
microscopic alterations were reported in the sternum from rats following dietary exposure to 100–110 mg/kg/day APFO for 90 days (Griffith and Long 1980) or in the femur, sternum, or thigh skeletal
muscle from Cynomolgus monkeys dosed with up to 20 mg/kg/day APFO administered via a capsule for
26 weeks (Butenhoff et al. 2002). In utero exposure to 0.3 mg/kg/day PFOA resulted in morphometricalalterations in the femur (increases in the periosteal area) and decreases in bone mineral density in the tibia

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of 13- or 17-month-old mice (Koskela et al. 2016). No alterations in biomechanical properties were
found.
PFOS

Epidemiological Studies. Several epidemiological studies have evaluated the potential of PFOS to
induce skeletal damage. In the participants of the C8 Health Study, a decreased risk of osteoarthritis wasfound in participants with serum PFOS levels in the 2nd, 3rd, and 4th quartiles (Innes et al. 2011). In
contrast, Uhl et al. (2013) found an increased risk of osteoarthritis in NHANES participants with serum
levels of >20.97 ng/mL. When categorized by sex and age, the osteoarthritis risk was approximately
5 times higher in women aged 20–49 years with serum PFOS levels in the 4th quartile. Another study of
NHANES participants (Khalil et al. 2016) did not find an increased risk of osteoporosis in women.
However, the study did find an inverse association between serum PFOS and femur neck bone mineraldensity, but no associations with total femur or lumbar spine bone mineral density. No associations
between serum PFOS levels and measures of bone mineral density were observed in a study of obese
children (Khalil et al. 2018).

Laboratory Animal Studies. Treatment of monkeys with up to 0.75 mg/kg/day PFOS (potassium salt)
administered via a capsule for 26 weeks had no significant effect on the gross or microscopic appearanceof the femur, sternum, or thigh skeletal muscle (Seacat et al. 2002). Similar observations were made inrats treated with up to 1.04 mg/kg/day PFOS in the diet for 2 years (Butenhoff et al. 2012b; Thomford
2002b).

PFHxS

Epidemiological Studies. A study of NHANES participants found an increase in the risk of osteoporosis
among women that was associated with serum PFHxS levels (Khalil et al. 2016). An inverse association
between serum PFHxS (fourth quartile) and total femur bone mineral density was also found in women.
There were no associations between serum PFHxS and femur neck or lumbar spine bone mineral density(Khalil et al. 2016). In contrast, no association between serum PFHxS levels and bone mineral density
were observed in obese children (Khalil et al. 2018).

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Laboratory Animal Studies. No histological alterations were observed in bone or muscle of miceadministered up to 3 mg/kg/day prior to mating and during mating, gestation, and lactation periods(Chang et al. 2018).
PFNA

Epidemiological Studies. Khalil et al. (2016) found an increase in the risk of osteoporosis in women
NHANES participants that was associated with serum PFNA levels. Increasing serum PFNA levels did
not result in alterations in bone mineral density of the lumbar spine or femur neck, but was inversely
associated with total femur bone mineral density in women with serum PFNA levels in the fourth quartile.
A study of 48 obese children found an inverse association between serum PFNA levels and bone mineraldensity; however, the association was no longer significant after adjusting for multiple testing (Khalil etal. 2018).

PFBS

Laboratory Animal Studies. Treatment of rats with up to 900 mg/kg/day PFBS by gavage for 28 days
(3M 2001) or 90 days (Lieder et al. 2009a) did not induce morphological alterations in skeletal muscle.
PFBA

Laboratory Animal Studies. PFBA administered to rats by gavage in doses of up to 184 mg/kg/day for
5 days did not induce morphological alterations in skeletal muscle (3M 2007a). Administration of
150 mg/kg/day PFBA for 28 days or 30 mg/kg/day for 90 days did not induce gross or microscopic
alterations in bone (femur and sternum) or skeletal muscle (Butenhoff et al. 2012a; van Otterdijk 2007a,
2007b).
PFHxALaboratory Animal Studies. An intermediate-duration gavage study did not find histological alterationsin the bone or muscle of rats administered up to 200 mg/kg/day NaPFHx for 90 days (Chengelis et al.
2009b).

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2.9

HEPATIC

Overview. Epidemiological studies on perfluoroalkyls have examined three potential hepatic outcomes: liverdisease, alterations in serum enzyme and bilirubin levels, and alterations in serum lipid levels. Summaries ofthe epidemiological studies examining these outcomes are presented in Tables 2-10, 2-11, and 2-12, withmore detailed descriptions presented in the Supporting Document for Epidemiological Studies for
Perfluoroalkyls, Table 7. There are limited epidemiological data on potential associations between serum
perfluoroalkyls and risk of liver disease. Occupational exposure and community studies did not findincreased risk of liver disease associated with PFOA or PFOS. As assessed by serum enzyme and bilirubinlevels, the epidemiological studies provide suggestive evidence of liver damage. Increases in aspartate
aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) levels anddecreases in serum bilirubin levels have been reported in occupational, community, and/or general population
studies. These increases in serum enzyme levels, particularly ALT, are associated with increasing levels of
PFOA, PFOS, and PFHxS; it is noted that there is considerable variability across studies and not all of thestudies adjusted for potential confounders. No consistent results were found for PFNA. The results ofavailable epidemiological studies suggest associations between increases in serum lipids, particularly totalcholesterol and LDL cholesterol, and serum PFOA, PFOS, PFNA, and PFDA. For PFHxS, PFUnA, PFHpA,
PFBS, PFBA, and PFDoDA, there are too few studies or the results are too inconsistent to determine if theyalso would affect serum lipid levels at environmental exposure levels. No epidemiological studies examining
hepatic endpoints were identified for PFHxA or FOSA.

Numerous animal studies have evaluated the hepatotoxicity of perfluoroalkyls following inhalation, oral,
and dermal exposure; summaries of these studies are presented in Tables 2-1, 2-2, 2-3, 2-4, 2-5, and 2-6
and the NOAEL and LOAEL values are graphically presented in Figures 2-6, 2-7, 2-8, 2-9, and 2-10. No
laboratory animal studies were identified for PFHpA.

The results of these studies provide strong evidence that the liver is a sensitive target of PFOA, PFOS,
PFHxS, PFNA, PFDA, PFUnA, PFBS, PFBA, PFDoDA, and PFHxA toxicity. Observed effects inrodents include increases in liver weight; hepatocellular hypertrophy, hyperplasia, and necrosis; anddecreases in serum cholesterol and triglyceride levels. As discussed in greater detail in Section 2.20,
these effects are believed to be initiated by PPARα; however, studies in PPARα-null mice suggest that
other mechanisms are also involved. Increases in liver weight have also been observed in monkey studies
for PFOA and PFOS; these studies have also found alterations in serum lipid levels and hepatocellular
hypertrophy (PFOS only).

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Table 2-10. Summary of Liver Disease in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

PFOA
Anderson-Mahoney et al. 2008

NR

Liver problems (selfreported)

SPR 1.01 (0.64–1.59)

Estimated cumulative
16.5 ng/mL (median
2005/2006)

Liver disease

HR 0.97 (0.92–1.03), no lag per lnincrease in PFOA
HR 0.98 (0.93–1.04), 10-year lag
HR 0.97 (0.91–1.04), no lag per lnincrease in PFOA
HR 1.00 (0.94–1.07), 10-year lag

Community (n=566)
Darrow et al. 2016
Community (C8) (n=28,831)

Enlarged liver, fatty liver,or cirrhosis
Steenland et al. 2015

Estimated cumulative

Non-hepatitis liver disease NS (p=0.86), no lagrisk
NS (p=0.40), 10-year lag

NRLiver cirrhosis deaths

SMR 0.81 (0.10–2.94)

1,300–1,970 ng/mL (highpotential workers)

Liver disease
Cholelithiasis

OR 1.21 (0.56–2.60)
OR 0.91 (0.57–1.46)

Cholecystitis

OR 1.15 (0.65–2.06)

Occupational (n=3,713)
PFOS
Alexander et al. 2003
Occupational (n=2,083)
Grice et al. 2007
Occupational (n=1,400)

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2. HEALTH EFFECTS

Table 2-10. Summary of Liver Disease in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Olsen et al. 2004aNR

Cholelithiasis or acutecholecystitis

RREpC 8.6 (1.1–>100)*
RREpC 25 (2.1–>100)*, workers with
≥10 years high exposure potential
RREpC 1.2 (0.2–8.6)
RREpC 1.6 (0.8–2.9)
RREpC 2.6 (1.2–5.5)*, workers with
≥10 years high exposure potential

Occupational (n=652 exposed, n=659 for nonexposed)

Liver disease
Biliary duct disorders

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 7 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living near

PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

HR = hazard ratio; NR = not reported; NS = not significant; OR = odds ratio; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; RREpC = risk ratio
episode of care; SMR = standardized mortality ratio; SPR = standard prevalence ratioPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa
Reference and study populationb
PFOA
Costa et al. 2009
Occupational (n=37 current workers;
n=16 former workers; n=107 non-exposed
workers)

Serum perfluoroalkyl level

Outcome evaluatedResultc

12,930 ng/mL (mean PFOA
current workers)
6,810 ng/mL (mean former
workers)

AST
ALT

NS (p>0.05) (34 current workers)
NS (p>0.05) (34 current workers)
Association (p<0.01)* (56 current,
former, non-exposed workers)
NS (p>0.05) (34 current workers)
Association (p<0.01)* (56 current,
former, non-exposed workers)
Inverse association (p<0.01)*(56 current, former, non-exposed
workers)
NS (p=0.32)
NS (p=0.80)
NS (p=0.81)
NS (p=0.82, 0.30, 0.73) differences
between exposure groups for eachmeasurement period
NS (p=0.33, 0.45, 0.83) differences
between exposure groups for eachmeasurement period
NS (p=0.24, 0.41, 0.78) differences
between exposure groups for eachmeasurement period

GGT

Total bilirubin

Gilliland 1992; Gilliland and Mandel 1996 NR (serum fluorine levels usedas surrogate for serum PFOA)
Occupational (n=115)
Olsen et al. 2000
Occupational (n=111, 80, and 74 in 1993,
1995, and 1997)

5,000, 6,400, and 6,400 ng/mL(mean PFOA in 1993, 1995, and1997)
Workers divided into threegroups: 0–<1,000, 1,000–<10,000, and ≥10,000 ng/mL

ALT
AST
GGT
ALT

AST

GGT

Total bilirubin

Direct bilirubin

NS (p=0.48, 0.11, 0.58) differences
between exposure groups for eachmeasurement period
NS (p=0.82, 0.05, 0.74) differences
between exposure groups for eachmeasurement periodPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Olsen and Zobel 2007

2170 ng/mL (mean 8th PFOA
GGT
decile)Elevated GGT12,150 ng/mL (mean 10th PFOA Total bilirubin
decile)ALT
Elevated ALT
AST1,130 ng/mL (mean PFOA)
Total bilirubin
AST

Occupational (n=552)

Sakr et al. 2007aOccupational (n=454)

Sakr et al. 2007b

Occupational (n=55)
Darrow et al. 2016
Community (C8) (n=28,831)

Resultc
Association (p=0.05)*
OR 1.0 (0.3–2.9), 10th decile
Inverse association (p=0.001)*
NS (p=0.06)
OR 1.2 (0.5–3.4), 10th decile
NS (p=0.55)
Association (p=0.006)*
Association (p=0.009)*

ALT
GGT
GGT
AST
ALT
Bilirubin

NS (p>0.05)
NS (p>0.05)
Association (p=0.016)*
NS (p=0.317)
NS (p=0.124)
NS (p=0.590)

2,157.74 ng/mL (mean PFOA)

AST
ALT

Association (p=0.02)*
NS (p=0.38)

Estimated cumulative
16.5 ng/mL (median PFOA in
2005/2006)

ALT

Association (p<0.0001 for trend)*,estimated cumulative levels
Association (p<0.0001 for trend)*,2005/2006 levels
NS (p=0.1021), cumulative levels
NS (p=0.1552), 2005/2006 levels
Inverse association (p=0.0029 fortrend)*, estimated cumulative levels
Inverse association (p=0.0036 fortrend)*, 2005/2006 levels

428 ng/mL (mean PFOA)

Occupational (n=1,025)

Wang et al. 2012

Outcome evaluated

GGT
Bilirubin

PERFLUOROALKYLS

187
2. HEALTH EFFECTS

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Emmett et al. 2006b

354 ng/mL (median PFOA)

ALT
Abnormal ALT
AST
Abnormal AST
GGTAbnormal GGT
ALTAbnormal ALT
GGT
Abnormal GGT
Direct bilirubin
Abnormal bilirubin
ALT
AST

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Inverse association (p=0.03)*
NS (p>0.05)
NS (p>0.05)
Correlation (p<0.001)*
OR 1.19 (1.03–1.37)*, 3rd decile
Correlation (p<0.001)*
NS (p=0.213 for trend)
NS (p>0.05)
NS (p=0.496 for trend)
NS (p=0.05)
NS (p=0.22)

ALT
Elevated ALT
AST
Elevated AST
GGTElevated GGTAssociation (p<0.001)*
Association (p=0.007 for trend)*
Association (p<0.01)*
NS (p=0.058 for trend).
Association (p<0.01)*
Association (p=0.042 for trend)*

Community (n=371)

Gallo et al. 2012

NR

Community (C8) (n=46,452)

Wang et al. 2012

378.30 ng/mL (mean PFOA)

Community (n=132)
Gleason et al. 2015

3.7 ng/mL (median PFOA)

General population (NHANES) (n=4,333)

Lin et al. 2010
General population (NHANES) (n=2,216)
Yamaguchi et al. 2013
General population (n=608)

Total bilirubin
Elevated bilirubin
5.05 and 4.06 ng/mL (geometric ALT
mean PFOA in males and
GGT
females)
Total bilirubin
2.1 ng/mL (mean PFOA)
ALT
AST
GGT

Association (p<0.01)*
Association (p<0.001 for trend)*
Association (p=0.005)*
Association (p=0.019)*
NS (p=0.645)
Association (p=0.02)*
Association (p=0.001)*
Association (p=0.03)*

PERFLUOROALKYLS

188
2. HEALTH EFFECTS

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa
Reference and study populationb
PFOS
Grice et al. 2007
Occupational (n=1,400)
Olsen et al. 1999
Occupational (n=178 in 1995; n=149 in
1997)

Olsen et al. 2003a

Serum perfluoroalkyl level

Outcome evaluatedResultc

1,300–1,970 ng/mL (highpotential workers)

Cholelithiasis
Cholecystitis

OR 0.91 (0.57–1.46)
OR 1.15 (0.65–2.06)

2,440 and 1,930 ng/mL (meanPFOS in 1995 in Decatur andAntwerp)1,960 and 1,480 ng/mL (meanPFOS in 1997 in Decatur andAntwerp)

AST

2460 ng/mL (median 4th PFOS
quartile)

AST
ALT

Risk of abnormal GGTNS (p=0.14 for trend), 1995
NS (p=0.67 for trend), 1997
NS (p=0.38 for trend), 1995
NS (p=0.46 for trend), 1997
NS (p=0.71 for trend), 1995
NS (p=0.34 for trend), 1997
NS (p>0.05), no adjustments
Higher levels (p<0.05)*, males onlywith no adjustments
OR 2.1 (0.6–7.3)
Difference (p<0.05)*, females onlywith no adjustments
OR 2.0 (0.7–5.8)

ALT
Abnormal ALT

Correlation (p<0.001)*
OR 1.19 (1.04–1.37)*, 5th decile

GGT
Abnormal GGTNS (p>0.05)
Association (p=0.047 for trend)*

Direct bilirubin
Abnormal bilirubin

Correlation (p<0.001)*
Association (p=0.015 for trend)*

Occupational (n=518)

ALT
GGT

Risk of abnormal ALT
GGT

Gallo et al. 2012
Community (C8) (n=46,452)

NR

PERFLUOROALKYLS

189
2. HEALTH EFFECTS

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Gleason et al. 2015

11.3 ng/mL (median PFOS)

ALTElevated ALT
AST
Elevated AST

NS (p>0.01)
NS (p=0.370 for trend)
NS (p>0.01)
NS (p=0.438 for trend)

General population (NHANES) (n=4,333)

Lin et al. 2010
General population (NHANES) (n=2,216)
Yamaguchi et al. 2013
General population (n=608)
PFHxS
Gleason et al. 2015
General population (NHANES) (n=4,333)

Lin et al. 2010
General population (NHANES) (n=2,216)

GGT
Elevated GGT
Total bilirubin
Elevated bilirubin
27.39 and 22.20 ng/mL
ALT(geometric mean PFOS in males GGTand females)
Total bilirubin
5.8 ng/mL (mean PFOS)
ALT
AST
GGT

NS (p>0.01)
NS (p=0.654 for trend)
NS (p>0.01)
Association (p=0.028 for trend)*
NS (p=0.066)
NS (p=0.808)

1.8 ng/mL (median PFHxS)

ALTElevated ALT

Association (p<0.01)*
NS (p=0.484 for trend)

AST
Elevated AST
GGTElevated GGT
Total bilirubin
Elevated bilirubin

Association (p<0.001)*
NS (p=0.230 for trend)
NS (p>0.01)
NS (p=0.415 for trend)
Association (p<0.01)*
Association (p=0.041 for trend)*

2.29 and 1.72 ng/mL (geometric ALT
mean PFHxS in males and
GGT
females)
Total bilirubin

NS (p=0.223)
Association (p=0.03)*
Association (p=0.01)*
Association (p=0.03)*

NS (p=0.691)
NS (p=0.898)
NS (p=0.063)

PERFLUOROALKYLS

190
2. HEALTH EFFECTS

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

PFNA
Mundt et al. 2007

NR

ALT
AST
GGT

NS, longitudinal analysis
NS, longitudinal analysis
NS, longitudinal analysis

Bilirubin
ALT
Elevated ALT
AST
Elevated AST
GGT

NS, longitudinal analysis
Association (p<0.001)*
NS (p=0.042 for trend)
NS (p>0.01)
NS (p=0.516 for trend)
Association (p<0.01)*

Occupational (n=592)

Gleason et al. 2015

1.4 ng/mL (median PFNA)

General population (NHANES) (n=4,333)

Lin et al. 2010
General population (NHANES) (n=2,216)

Elevated GGT
Total bilirubin
Elevated bilirubin
0.89 and 0.72 ng/mL (geometric ALT
mean PFNA in males and
GGT
females)
Total bilirubin

NS (p=0.126 for trend)
NS (p>0.01)
NS (p=0.614 for trend)
NS (p=0.131)
NS (p=0.857)
NS (p=0.053)

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 7 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyl transferase; OR = odds ratio; NHANES = National Health andNutrition Examination Survey; NR = not reported; NS = not significant; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

PERFLUOROALKYLS

191
2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

PFOA
Costa 2004

NR

Association (p=0.03)*
Association (p=0.03)*
NS (p>0.05)

Occupational (n=35)

Costa et al. 2009
Occupational (n=37 current workers; n=16
former workers; n=107 non-exposed workers)

Gilliland 1992; Gilliland and Mandel 1996
Occupational (n=115)
Olsen et al. 2000
Occupational (n=111, 80, and 74 in 1993,
1995, and 1997)

Total cholesterol
Non-HDL cholesterol
HDL cholesterol

LDL cholesterol
Total triglycerides
12,930 ng/mL (mean PFOA in Total cholesterol
current workers)
6,810 ng/mL (mean PFOA in
former workers)

NR (serum fluorine levels
used as surrogate for serum
PFOA)

HDL cholesterol
Triglycerides
Total cholesterol
Total LDL
Total HDL

5,000, 6,400, andTotal cholesterol
6,400 ng/mL (mean PFOA in
1993, 1995, and 1997)
LDL cholesterol
Workers divided into threegroups: 0–<1,000, 1,000–<10,000, and ≥10,000 ng/mL
HDL cholesterol

Triglycerides

NS (p>0.05)
NS (p>0.05)
Association (p=0.005)* (current
workers)
Association (p<0.05)* (56 current,
former, non-exposed workers)
NS (p>0.05) (34 current workers)
NS (p>0.05)
NS (p=0.62)
NS (p=0.87)
NS (p=0.66)
NS (p=0.45, 0.48, 0.08) differences
between exposure groups for eachmeasurement period
NS (p=0.84, 0.96, 0.11) differences
between exposure groups for eachmeasurement period
NS (p=0.32, 0.70, 0.40) differences
between exposure groups for eachmeasurement period
NS (p=0.77, 0.07, 0.13) differences
between exposure groups for eachmeasurement periodPERFLUOROALKYLS

192
2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Olsen and Zobel 2007

2,170 ng/mL (mean of
8th PFOA decile)
12,150 ng/mL (mean of
10th PFOA decile)

Total cholesterol
Elevated total cholesterol
LDL cholesterol
Elevated LDL cholesterol

NS (p=0.20)
OR 1.1 (0.5–2.6), 10th decile
NS (p=0.81)
OR 1.2 (0.5–2.8), 10th decile

HDL cholesterol
Decreased HDLcholesterol
Triglycerides
Elevated triglycerides
Total cholesterol
LDL cholesterol
HDL cholesterol

Association (p=0.01)*
OR 1.8 (0.7–4.8), 10th decile

Triglycerides
Total bilirubin
Total cholesterol
LDL cholesterol
VLDL cholesterol
HDL cholesterol
Triglycerides

NS (p>0.05)
Association (p=0.006)*
Association (p=0.002)*
Association (p=0.008)*
Association (p=0.031)*
NS (p=0.680)
NS (p=0.384)

Estimated cumulative PFOA

Elevated cholesterol

NS (p=0.56), no lag
NS (p=0.62), 10-year lag

2,157.74 ng/mL (mean
PFOA)

Total cholesterol

NS (p=0.36)

LDL cholesterol
HDL cholesterol
Triglycerides
Total cholesterol
Abnormal cholesterol

NS (p=0.43)
Inverse association (p=0.01)*
NS (p=0.37)
NS (p>0.05)
NS (p>0.05)

Occupational (n=552)

Sakr et al. 2007a

1,130 ng/mL (mean PFOA)

Occupational (n=454)

Sakr et al. 2007b

428 ng/mL (mean PFOA)

Occupational (n=1,025)

Steenland et al. 2015
Occupational (n=3,713)
Wang et al. 2012
Occupational (n=55)

Emmett et al. 2006b
Community (n=371)

354 ng/mL (median PFOA)

Association (p=0.0001)*
OR 1.8 (0.8–4.4), 10th decile
Association (p=0.011)*
NS (p>0.05)
NS (p>0.05)

PERFLUOROALKYLS

193
2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Fitz-Simon et al. 2013

140.1 and 68.2 ng/mL (mean Total cholesterol
PFOA at first and second
examinations)
LDL cholesterol-1.65% (-0.32 to -2.97)*, 50%
decrease in PFOA
-3.58% (-1.47 to -5.66)*, 50%
decrease in PFOA
-1.33% (0.21 to -2.85), 50% decreasein PFOA
0.78% (5.34 to -3.58), 50% decreasein PFOAAssociation (p<0.001)*, children
5th quintile
Association (p<0.001)*, adolescents
5th quintile

Community (C8) (n=560 adults)

HDL cholesterol
Triglycerides
Frisbee et al. 2010
Community (C8) (n=12,476 children andadolescents)

77.7 ng/mL (mean PFOA in
children)
61.8 ng/mL (mean PFOA in
adolescents)

Total cholesterol

Abnormal cholesterol

OR 1.1 (1.0–1.3), 2nd quintile

LDL cholesterol

Total cholesterol
Abnormal cholesterol

Association (p=0.001)*, children
5th quintile
Association (p=0.004)*, adolescents
5th quintile
OR 1.2 (1.0–1.5), 2nd quintile
NS (p=0.88), children 5th quintile
NS (p=0.20), adolescents 5th quintile
NS (p=0.1), children 5th quintile
NS (p=0.1), adolescents 5th quintile
Association (p<0.001 for trend)*
OR 1.21 (1.12–1.31)*, 2nd quartile

LDL cholesterol
HDL cholesterol
Triglycerides

Association (p<0.05 for trend)*
NS (p>0.05)
Association (p<0.05 for trend)*

Abnormal LDL levels
HDL cholesterol
Triglycerides
Steenland et al. 2009b
Community (C8) (n=46,294)

80.3 ng/mL (mean PFOA)
13.2–26.5 ng/mL (2nd PFOA
quartile)PERFLUOROALKYLS

194
2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Wang et al. 2012
Community (n=132)

378.30 ng/mL (mean PFOA)

Total cholesterol
LDL cholesterol
Triglycerides
HDL cholesterol

NS (p=0.85)
NS (p=0.97)
NS (p=0.73)
NS (p=0.39)

Winquist and Steenland 2014a142–<234 ng/mL (estimated
2nd quintile for cumulative
PFOA)
7.1 ng/mL (mean PFOA)Hypercholesterolemia

HR 1.24 (1.15–1.33)*, 2nd quintile for
estimated cumulative exposure

Total cholesterol

Association (p=0.01)*

2.46 ng/mL (mean PFOA)

Total cholesterol
High cholesterol levels

NS (p=0.22)
OR 1.5 (0.86–2.62), 4th quartile

Non HDL cholesterol
LDL cholesterol
HDL cholesterol
Total cholesterol
Elevated cholesterol
LDL cholesterol
Elevated LDL

NS (p=0.13)
NS (p=0.63)
NS (p=0.96)
Association (p=0.015)*
OR 0.55 (0.09–3.31)
Association (p=0.022)*
OR 0.71 (0.14–3.49)

HDL cholesterol
Elevated HDL
Triglycerides
Elevated triglyceride

NS (p=0.260)
OR 0.67 (0.13–3.51)
NS (p=0.298)
OR 1.97 (0.59–6.55)

Community (C8) (n=28,541)
Eriksen et al. 2013
General population (n=753)
Fisher et al. 2013
General population (n=2,368)

Fu et al. 2014a
General population (n=133)

1.43 ng/mL (median PFOA)PERFLUOROALKYLS

195
2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Geiger et al. 2014b

4.2 ng/mL (mean PFOA)LDL cholesterol
Elevated LDL
HDL cholesterol
Decreased HDL

Association (p=0.0170 for trend)*
OR 1.44 (1.11–1.88, p=0.0253 fortrend)*, log transformed PFOA
Association (p=0.0027 for trend)*
NS (p=0.0539 for trend)
NS (p=0.1769 for trend)
NS (p=0.1493 for trend)

Triglycerides
Elevated triglycerides
Total cholesterol
LDL cholesterol
Triglycerides

NS (p=0.9943 for trend)
NS (p=0.5975 for trend)
β -2.256 (-11.490–6.978, p=0.630)
β 3.899 (-4.810–12.608, p=0.377)
β 0.020 (-0.134–0.175, p=0.796)

General population (NHANES) (n=815 12–18-year-old adolescents)

Kang et al. 20181.88 ng/mL (median serum
PFOA)

General population (n=150 children ages 3–
18 years)
Koshy et al. 2017
General population (WTCHR, n=180 children;
n=222 children in comparison group)
Liu et al. 2018b
General population (NHANES, n=1,871 adults)

Maisonet et al. 2015a
General population (n=111 for 7-year-old andn=88 for 15-year-old girls

Total cholesterol
Elevated cholesterol

1.81 and 1.39 ng/mL (median Total cholesterol
serum PFOA in WTCHR
LDL cholesterolgroup and comparison group)
HDL cholesterol
Triglycerides
1.86 ng/mL (geometric mean Total cholesterol
serum PFOA)LDL cholesterol
HDL cholesterol
1.1–3.1, 3.2–4.4, and 4.5–
16.4 ng/mL (maternal PFOA
for 1st, 2nd, and 3rd tertiles)

Triglycerides
Total cholesterol in
7-year-olds

β 0.09 mg/dL (0.04–0.14, p<0.001)*
β 0.11 mg/dL (0.03–0.19, p=0.006)*
β 0.04 mg/dL (-0.04–0.12, p=0.34)
β 0.14 mg/dL (0.02 to 0.27, p=0.03)*
Association (p<0.05)
NS (p>0.05)
Association (p<0.01)
NS (p>0.05)
Association (β 13.75, 0.05–27.45)*,
1st tertile
NS, 2nd and 3rd tertiles

Association (β 17.19, 0.405–33.93)*,
1st tertile
NS, 2nd and 3rd tertiles
LDL cholesterol in 7-year- Association (β 14.01, 3.26–24.76)*,olds
1st tertile
NS, 2nd and 3rd tertiles
Total cholesterol in
15-year-olds

PERFLUOROALKYLS

196
2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedTotal cholesterol
LDL cholesterol
HDL cholesterol

Association (β 14.261, 0.25–28.26)*,
1st tertile
NS, 2nd and 3rd tertiles
NS (β -0.40, -1.82–1.01), 3rd tertile
7-year-olds
NS (β -0.520, -2.10–1.06), 3rd tertile
15-year-olds
NS (β -0.020, -0.068–0.029),
3rd tertile, 7-year-olds
NS (β -0.013, -0.051–0.025),
3rd tertile, 15-year-olds
β -0.02 (-0.10–0.15)
β 0.03 (-0.12–0.21)
β -0.04 (-0.15–0.08)

Triglycerides

β -0.01 (-0.17–0.16)

Total cholesterol

NS (p=0.07)

LDL cholesterol
Non-HDL cholesterol

NS (p=0.84)
Association (p=0.05)*
β 1.38 (0.12–2.65), per ng/mL
increase in PFOAHDL cholesterol
Total cholesterol

NS (p=0.34)
Association (p=0.01 for trend)*

LDL cholesterol in
15-year-olds
HDL cholesterol

Triglycerides

Manzano-Salgado et al. 2017b2.32 ng/mL (maternal
geometric mean PFOA)

General population (n=1,230 children; evaluatedat 4 years of age)
Nelson et al. 2010

4.6 ng/mL (mean PFOA)

General population (NHANES) (n=860)

Skuladottir et al. 2015
General population (n=854 pregnant women)

4.1 ng/mL (mean PFOA)

ResultcPERFLUOROALKYLS

197
2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Starling et al. 2014a2.25 ng/mL (50th PFOA
percentile)

NS (β 2.58; -4.32–9.47), per ln-unit
increase in PFOANS (β 0.35 -3.97–8.48), per ln-unit
increase in PFOA
Association (β 3.42 0.56–6.28)*,
4th quartile
NS (β 0.00 (-0.07–0.06), per ln-unit
increase in PFOANS (p=0.91), normal weight children
Association (p=0.002)*, obese
children

General population (n=854 pregnant women)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

Timmermann et al. 2014

9.3 ng/mL (median PFOA)

Triglycerides

1.90 ng/mL (median serum
PFOA)

HDL cholesterol
Triglycerides

β 0.15 (-0.17–0.46)
β 2.3 (0.77–8.38)*

1.1 and 0.92 ng/mL (mean
PFOA in boys and girls)

Total cholesterol
LDL cholesterol
HDL cholesterol

Association (p=0.001)*
Association (p=0.002)*
NS (p=0.06)

Triglycerides

Association (p<0.001)*

General population (n=499 children, 8–10 years
old)Yang et al. 2018
General population (n=148 men; 81 diagnosed
with metabolic syndrome)
Zeng et al. 2015
General population (n=225 adolescents, 12–15 years old)
PFOS
Olsen et al. 1999
Occupational (n=178 in 1995; n=149 in 1997)

2,440 and 1,930 ng/mL
Total cholesterol(mean PFOS in 1995 in
Decatur and Antwerp)
1,960 and 1,480 ng/mL
LDL cholesterol(mean in 1997 in Decatur andAntwerp)
HDL cholesterol

Triglycerides

NS (p=0.96 for trend), 1995
Association (p=0.006 for trend)*,1997
NS (p=0.87 for trend), 1995
Association (p=0.01 for trend)*,1997
Inverse association (p=0.04 fortrend)*, 1995
NS (p=0.34) 1997
NS (p=0.35 for trend), 1995
NS (p=0.67 for trend), 1997

PERFLUOROALKYLS

198
2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Olsen et al. 2003a2,460 ng/mL (median 4th
PFOS quartile)

NS (p>0.05), no adjustments
Association (p=0.04)*, withadjustments
NS (p>0.05), no adjustments
Higher levels (p<0.05)*, males onlywith no adjustments
Association (p=0.01)*, withadjustments

Total cholesterol

Occupational (n=518)
HDL cholesterol
Triglycerides

Frisbee et al. 2010
Community (C8) (n=12,476 children andadolescents)

23.6 ng/mL (mean PFOS inchildren)
21.9 ng/mL (mean PFOS inadolescents)

Total cholesterol

Abnormal cholesterol
LDL cholesterol

Abnormal LDL levels
HDL cholesterol

Triglycerides
Steenland et al. 2009b
Community (C8) (n=46,294)

22.4 ng/mL (mean PFOS)
Total cholesterol
13.3–19.5 ng/mL (2nd quartile) Abnormal cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

Association (p<0.001)*, children
5th quintile
Association (p<0.001)*, adolescents
5th quintile
OR 1.3 (1.1–1.4)*, 2nd quintile
Association (p=0.002)*, children
5th quintile
Association (p<0.001)*, adolescents
5th quintile
OR 1.2 (1.0–1.5)*, 2nd quintile
Association (p=0.007)*, children
5th quintile
Association (p=0.001)*, adolescents
5th quintile
NS (p=0.1), children 5th quintile
NS (p=0.1), adolescents 5th quintile
Association (p<0.001 for trend)*
OR 1.14 (1.05–1.23)*, 2nd quartile
Association (p<0.05 for trend)*
NS (p>0.05)
Association (p<0.05 for trend)*PERFLUOROALKYLS

199
2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Châtaeu-Degat et al. 201025.7 ng/mL (mean PFOS)

Eriksen et al. 201336.1 ng/mL (mean PFOS)

Total cholesterol

NS (p=0.086)
NS (p=0.242)
Association (p<0.001)*, men
Association (p=0.001)*, women
NS (p=0.162), men
Inverse association (p=0.040)*,
women
Association (p=0.02)*

General population (n=753)
Fisher et al. 20138.04 ng/mL (mean PFOS)

Total cholesterol
High cholesterol levels
Non HDL cholesterol
LDL cholesterol

NS (p=0.35)
OR 1.36 (0.87–2.12), 4th quartile
NS (p=0.14)
NS (p=0.42)

HDL cholesterol
Total cholesterol
Elevated cholesterol
LDL cholesterol
Elevated LDL
HDL cholesterol
Elevated HDL

NS (p=0.33)
NS (p=0.287)
OR 2.27 (0.47–10.92)
NS (p=0.357)
OR 2.27 (0.50–10.37)
NS (p=0.260)
OR 0.29 (0.06–1.50)

Triglycerides
Elevated triglycerides
Total cholesterol
Elevated cholesterol

NS (p=0.711)
OR 1.26 (0.41–3.90)
NS (p=0.0512 for trend)
OR 1.35 (1.11–1.64, p=0.0183 fortrend)*, log transformed PFOS
Association (p=0.0081 for trend)*
OR 1.48 (1.15–1.90, p=0.0178 fortrend)*, log transformed PFOS

General population (n=723)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

General population (n=2,368)

Fu et al. 2014a1.47 ng/mL (median PFOS)

General population (n=133)

Geiger et al. 2014b
General population (NHANES) (n=815 12–18-year-old adolescents)

17.7 ng/mL (mean PFOS)LDL cholesterol
Elevated LDLPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Kang et al. 2018
General population (n=150 children ages 3–
18 years)
Koshy et al. 2017
General population (WTCHR, n=180 children;
n=222 children in comparison group)
Liu et al. 2018b
General population (NHANES, n=1,871 adults)

Maisonet et al. 2015b
General population (n=111 for 7-year-old andn=88 for 15-year-old girls)

Serum perfluoroalkyl level Outcome evaluated

5.68 ng/mL (median serum
PFOS)

Resultc

HDL cholesterol
Decreased HDL
Triglycerides
Elevated triglycerides

NS (p=0.9703)
NS (p=0.9873 for trend)
NS (p=0.1104 for trend)
NS (p=0.2418 for trend)

Total cholesterol
LDL cholesterol
Triglycerides

β -0.450 (-10.667–9.768, p=0.931)
β 2.507 (-6.879–11.893, p=0.598)
β -0.020 (-0.186–0.146, p=0.809)

3.72 and 2.78 ng/mL (median Total cholesterol
serum PFOS in WTCHR
LDL cholesterolgroup and comparison group)
HDL cholesterol
Triglycerides
5.28 ng/mL (geometric mean Total cholesterol
serum PFOS)LDL cholesterol
HDL cholesterol
Triglyceridesrd
23.5–94.5 ng/mL (3 tertile
Total cholesterolmaternal PFOS)LDL cholesterol

HDL cholesterol
Triglycerides

β 0.08 mg/dL (0.05–0.12, p<0.001)*
β 0.10 mg/dL (0.05–0.16, p<0.001)*
β 0.06 mg/dL (0.003–0.13, p=0.04)*
β 0.04 mg/dL (0.05–0.13, p=0.36)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (β -0.10, -0.73–0.54), 7-year-olds
Association (β -0.77, -1.40
to -0.13)*, 15-year-olds
NS (β 0.02, -0.48–0.53), 7-year-olds
Association (β -0.54, -1.08
to -0.003)*, 15-year-olds
NS (β -0.04, -0.33–0.25), 7-year-olds
NS (β -0.18, -0.47–0.12), 15-year-olds
NS (β -0.004, -0.015–0.006), 7-yearolds
NS (β -0.004, -0.011–0.004), 15-yearolds

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Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Manzano-Salgado et al. 2017b5.80 ng/mL (maternal
geometric mean PFOS)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

β -0.02 (-0.10–0.15)
β 0.02 (-0.12–0.15)
β -0.03 (-0.14–0.09),
β 0.05 (-0.06–0.17)

25.3 ng/mL (mean PFOS)

Total cholesterol

Association (p=0.01)*

22.3 ng/mL (mean PFOS)LDL cholesterol
Non-HDL cholesterol
HDL cholesterol
Total cholesterol

NS (p=0.27)
Association (p=0.02)*
NS (p=0.78)
Association (p=0.01 for trend)*

13.03 ng/mL (50th PFOS
percentile)

Total cholesterol
LDL cholesterol

Association (p<0.05)*
NS (β 6.48, -0.07–13.03), per ln-unit
increase in PFOS
Association (β 4.39, 2.37–6.42)*, per
ln-unit increase in PFOSNS (β -0.02, -0.09–0.04), per ln-unit
increase in PFOS
NS (p=0.78), normal weight children
Association (p=0.002)*, obese
children

General population (n=1,230 children; evaluatedat 4 years of age)
Nelson et al. 2010
General population (NHANES) (n=860)

Skuladottir et al. 2015
General population (n=854 pregnant women)
Starling et al. 2014a
General population (n=854 pregnant women)

HDL cholesterol
Triglycerides
Timmermann et al. 201441.5 ng/mL (median PFOS)

Triglycerides

3.00 ng/mL (median serumPFOS)

HDL cholesterol
Triglycerides

β 0.02 (-0.17–0.2)
β 0.3 (-0.63–1.22)

32.4 and 34.2 ng/mL (meanPFOS in boys and girls)

Total cholesterol
LDL cholesterol

Association (p<0.001)*
Association (p<0.001)*

HDL cholesterol
Triglycerides

NS (p=0.72)
Association (p=0.05)*

General population (n=499 children, 8–10 years
old)Yang et al. 2018
General population (n=148 men; 81 diagnosed
with metabolic syndrome)
Zeng et al. 2015
General population (n=225 children, 12–15 years old)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

PFHxS
Fisher et al. 20132.18 ng/mL (mean PFHxS)

Total cholesterol
High cholesterol levels
Non HDL cholesterol

Association (p=0.005)*
OR 1.27 (1.11–1.45)*, 4th quartile
Association (p=0.002)*

LDL cholesterol
HDL cholesterol
Total cholesterol
LDL cholesterol
Triglycerides

Association (p=0.02)*
NS (p=0.67)
β 0.989 (-9.526–11.503, p=0.853)
β -4.222 (-13.979–5.534, p=0.393)
β 0.081 (-0.092–0.253, p=0.355)

0.67 and 0.53 ng/mL (median Total cholesterol
serum PFHxS in WTCHR
LDL cholesterol
General population (WTCHR, n=180 children;group and comparison group)
HDL cholesterol
n=222 children in comparison group)
Triglycerides
Manzano-Salgado et al. 2017b0.61 ng/mL (maternal
Total cholesterol
geometric mean PFHxS)LDL cholesterol
General population (n=1,230 children; evaluated
HDL cholesterolat 4 years of age)

β 0.04 mg/dL (0.04–0.06, p=0.01)*
β 0.05 mg/dL (0.01–0.09, p=0.02)*
β 0.03 mg/dL (-0.02–0.07, p=0.26)
β 0.04 mg/dL (-0.02–0.11, p=0.20)
β 0.02 (-0.09–0.12)
β -0.01 (-0.12–0.09)
β -0.01 (-0.11 to 0.10)

General population (n=2,368)

Kang et al. 2018

0.793 ng/mL (median serum
PFHxS)

General population (n=150 children ages 3–
18 years)
Koshy et al. 2017

Nelson et al. 2010
General population (NHANES) (n=860)

2.6 ng/mL (mean PFHxS)

Triglycerides

β 0.11 (0.01–0.21)*

Total cholesterol
LDL cholesterol
Non-HDL cholesterol
HDL cholesterol

NS (p=0.07)
NS (p=0.10)
Association (p=0.04)*
NS (p=0.11)

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Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Starling et al. 2014a0.60 ng/mL (50th PFHxS
percentile)

3.80 ng/mL (median serum
PFHxS)

HDL cholesterol
Triglycerides

NS (β 3.00, -1.75–7.76), per ln-unit
increase in PFHxS
NS (β 1.92, -2.50–6.33), per ln-unit
increase in PFHxSAssociation (β 1.46; 0.19–2.73)*, per
ln-unit increase in PFHxS
NS (β -0.01, -0.05–0.03), per ln-unit
increase in PFHxS
β 0.22 (0 to 0.43, p<0.05)*
β 1.18 (0.12–2.25, p<0.05)*

2.1 and 2.1 ng/mL (meanPFHxS in boys and girls)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

NS (p=0.23)
NS (p=0.17)
NS (p=0.54)
NS (p=0.15)

PFNA
Mundt et al. 2007

NR

Occupational (n=592)
Fu et al. 2014a

Total cholesterol
Triglycerides

NS, longitudinal analysis
NS, longitudinal analysis

0.37 ng/mL (median PFNA)

Total cholesterol
Elevated cholesterol
LDL cholesterol

Association (p=0.002)*
OR 1.03 (0.24–4.46)
Association (p=0.004)

Elevated LDL
HDL cholesterol
Lowered HDL
Triglycerides
Elevated triglycerides

OR 2.51 (0.59–10.74)
NS (p=0.191)
OR 1.06 (0.20–5.57)
NS (p=0.460)
OR 0.80 (0.26–2.49)

General population (n=854 pregnant women)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

Yang et al. 2018
General population (n=148 men; 81 diagnosed
with metabolic syndrome)
Zeng et al. 2015
General population (n=225 children, 12–15 years old)

General population (n=133)

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2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Kang et al. 2018

0.938 ng/mL (median serum
PFNA)

Total cholesterol
LDL cholesterol
Triglycerides

β -1.624 (-10.218–6.970, p=0.709)
β 2.304 (-6.558–11.167, p=0.607)
β 0.065 (-0.092–0.221, p=0.820)

0.61 and 0.49 ng/mL (median Total cholesterol
serum PFNA in WTCHR
LDL cholesterolgroup and comparison group)
HDL cholesterol
Triglycerides
0.66 ng/mL (maternal
Total cholesterol
geometric mean PFNA)LDL cholesterol

β 0.05 mg/dL (0.01–0.09, p=0.01)*
β 0.07 mg/dL (0.01–0.14, p=0.01)*
β 0.05 mg/dL (0.02–0.12, p=0.13)
β -0.07 mg/dL (0.11–0.01, p=0.89)
β-0.00 (-0.11–0.12)
β 0.01 (-0.10–0.12)

General population (n=150 children ages 3–
18 years)
Koshy et al. 2017
General population (WTCHR, n=180 children;
n=222 children in comparison group)
Manzano-Salgado et al. 2017b
General population (n=1,230 children; evaluatedat 4 years of age)
Nelson et al. 2010

1.3 ng/mL (mean PFNA)

General population (NHANES) (n=860)

Starling et al. 2014a0.39 ng/mL (50th PFNA
percentile)

General population (n=854 pregnant women)

HDL cholesterol
Triglycerides

β -0.03 (-0.14–0.08),
β 0.03 (-0.07–0.14)

Total cholesterol
LDL cholesterol
Non-HDL cholesterol
HDL cholesterol
Total cholesterol

Association (p=0.04)*
NS (p=0.08)
Association (p=0.04)*
NS (p=0.31)
NS (β 0.01, -5.98–6.00), per ln-unit
increase in PFNANS (β -2.15, -7.31–3.02), per ln-unit
increase in PFNA
Association (β 2.84; 0.97–4.71)*, per
ln-unit increase in PFNANS (β -0.02, -0.07–0.03), per ln-unit
increase in PFNA
β 0.3 (0.05–0.56)*
β 1.54 (0.27–2.8)*

LDL cholesterol
HDL cholesterol
Triglycerides

Yang et al. 2018
General population (n=148 men; 81 diagnosed
with metabolic syndrome)

0.50 ng/mL (median serum
PFNA)

HDL cholesterol
Triglycerides

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Zeng et al. 2015

0.8 and 0.9 ng/mL (mean
PFNA in boys and girls)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

Association (p=0.04)*
Association (p=0.05)*
NS (p=0.37)
Association (p=0.007)*

0.19 ng/mL (median PFDA)

Total cholesterol
Elevated cholesterol
LDL cholesterol
Elevated LDL
HDL cholesterol

Association (p=0.048)*
OR 3.84 (0.87–16.95)
NS (p=0.251)
OR 2.17 (0.52–9.04)
Association (p=0.007)*General population (n=225 children, 12–15 years old)
PFDA
Fu et al. 2014a
General population (n=133)

Kang et al. 2018
General population (n=150 children ages 3–
18 years)
Koshy et al. 2017
General population (WTCHR, n=180 children;
n=222 children in comparison group)
Starling et al. 2014a
General population (n=854 pregnant women)

Elevated HDL
Triglycerides
Elevated triglycerides
0.0592 ng/mL (median serum Total cholesterolPFDA)
LDL cholesterol
Triglycerides

OR 2.21 (0.49–10.07)
NS (p=0.317)
OR 0.51 (0.17–1.58)
β -3.330 (-7.484–0.824, p=0.115)
β -1.858 (-5.694–1.979, p=0.339)
β -0.036 (-0.103–0.032, p=0.302)

0.14 and 0.11 ng/mL (median Total cholesterol
serum PFDA in WTCHR
LDL cholesterolgroup and comparison group)
HDL cholesterol
Triglyceridesth
0.09 ng/mL (50 PFDA
Total cholesterol
percentile)
LDL cholesterol

β 0.04 mg/dL (0.02–0.06, p<0.001)*
β 0.04 mg/dL (0.02–0.06, p=0.03)*
β 0.05 mg/dL (0.02–0.09, p=0.003)*
β -0.01 mg/dL (-0.047–0.057,p=0.85)
NS (β 1.84, -2.12–5.79), per ln-unit
increase in PFDA
NS (β 0.19, -3.30–3.69), per ln-unit
increase in PFDA
Association (β 2.54, 1.22–3.87)*, per
ln-unit increase in PFDA
NS (β -0.03, -0.07–0.01), per ln-unit
increase in PFDA

HDL cholesterol
Triglycerides

PERFLUOROALKYLS

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Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Yang et al. 20180.40 ng/mL (median serumPFDA)

HDL cholesterol
Triglycerides

β 0.24 (0.04–0.52)
β 0.64 (-0.77–2.05)

1.0 and 1.0 ng/mL (meanPFDA in boys and girls)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

NS (p=0.74)
NS (p=0.85)
NS (p=0.47)
NS (p=0.92)

0.26 ng/mL (median PFUnA) Total cholesterol

NS (p=0.184)

General population (n=148 men; 81 diagnosed
with metabolic syndrome)
Zeng et al. 2015
General population (n=225 children, 12–15 years old)
PFUnA
Fu et al. 2014a

Elevated cholesterol
LDL cholesterol
Elevated LDL
HDL cholesterol
Elevated HDL
Triglycerides
Elevated triglycerides

OR 3.70 (0.76–18.03)
NS (p=0.270)
OR 4.16 (0.96–18.00)
NS (p=0.279)
OR 0.54 (0.11–2.57)
NS (p=0.755)
OR 0.74 (0.25–2.21)

Total cholesterol
LDL cholesterol
Triglycerides

β 7.906 (2.681–13.131, p=0.003)*
β 7.101 (2.448–11.754, p=0.003)*
β 0.043 (-0.042–0.129, p=0.317)

0.12 and 0.04 ng/mL (median Total cholesterol
serum PFUnA in WTCHR
LDL cholesterolgroup and comparison group)
HDL cholesterol
Triglycerides

β 0.02 mg/dL (0–0.04, p=0.06)
β 0.01 mg/dL (-0.02–0.04, p=0.49)

General population (n=133)

Kang et al. 2018
General population (n=150 children ages 3–
18 years)
Koshy et al. 2017
General population (WTCHR, n=180 children;
n=222 children in comparison group)

0.652 ng/mL (median serum
PFUnA)

β 0.04 mg/dL (0.01–0.07, p=0.01)*
β -0.04 mg/dL (-0.09–0.003, p=0.07)

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Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Starling et al. 2014a0.22 ng/mL (50th PFUnA
percentile)

NS (β 0.89, -3.28–5.06), per ln-unit
increase in PFUnA
NS (β -2.36, -5.97–1.25), per ln-unit
increase in PFUnAAssociation (β 4.05, 2.75–5.35)*, per
ln-unit increase in PFUnA
NS (β -0.04, -0.08–0.00), per ln-unit
increase in PFUnA
β 0.11 (-0.11–0.34)
β 0.61 (-0.48–1.7)

General population (n=854 pregnant women)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

Yang et al. 20180.30 ng/mL (median serum
PFUnA)

General population (n=148 men; 81 diagnosed
with metabolic syndrome)
PFHpA
Fu et al. 2014a
General population (n=133)

Yang et al. 2018
General population (n=148 men; 81 diagnosed
with metabolic syndrome)
PFBS
Zeng et al. 2015
General population (n=225 children, 12–15 years old)

HDL cholesterol
Triglycerides

0.04 ng/mL (median PFHpA) Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides
0.20 ng/mL (median serum
HDL cholesterol
PFHpA)
Triglycerides

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
β -0.33 (-0.77–0.11)
β -0.92 (-3.12–1.28)

0.5 and 0.4 ng/mL (meanPFBS in boys and girls)

Total cholesterol
LDL cholesterol
HDL cholesterol

Association (p=0.04)*
NS (p=0.14)
NS (p=0.15)

Triglycerides

NS (p=0.81)

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Table 2-12. Summary of Serum Lipid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

PFBA
Fu et al. 2014a0.11 ng/mL (median PFBA)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

4.5 and 4.4 ng/mL (meanPFDoDA in boys and girls)

Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides

NS (p=0.37)
NS (p=0.44)
NS (p=0.68)
NS (p=0.40)

General population (n=133)
PFDoDA
Zeng et al. 2015
General population (n=225 children, 12–15 years old)aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 7 for more detailed descriptions of studies.

bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.

cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

HDL = high density lipoprotein; LDL = low density lipoprotein; NHANES = National Health and Nutrition Examination Survey; NR = not reported; NS = notsignificant; OR = odds ratio; PFBA = perfluorobutanoic acid; PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoic acid;
PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid; VLDL = very low-density lipoprotein; WTCHR = World
Trade Center Health RegistryPERFLUOROALKYLS

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To address concern over the relevance of liver enlargement in rodents to human health risk, the European
Society of Toxicologic Pathology (ESTP) convened an expert panel to define what constitutes an adverse
hepatic effect and whether hepatic effects induced by nuclear hormone receptors such as PPARα,constitutive androstane receptor (CAR), or pregnane X receptor (PXR) are rodent-specific adaptive
reactions; the findings of the panel are summarized by Hall et al. (2012). As discussed by Hall et al.
(2012), criteria were established for determining whether increases in liver organ weight and liver cell
hypertrophy observed in studies of rodents exposed to agents inducing enzyme induction can beconsidered adaptive responses and of little relevance to humans. According to the ESTP criteria,
increases in liver weight without histological evidence, such as (1) degenerative or necrotic changes
including hepatocyte necrosis, inflammation, and steatotic vascular degeneration; (2) biliary/oval cellproliferation, degeneration, fibrosis, and cholestasis; or (3) necrosis and degeneration of other resident
cells within the liver, are not considered adverse or relevant for human risk assessment. In the absence ofhistological changes, increases in liver organ weight are not considered relevant for human risk
assessment unless at least two of the following three parameters are present: (1) at least 2–3 times
increase in ALT levels; (2) biologically significant change in other biomarkers of hepatobiliary damage(alkaline phosphatase, AST, GGT, etc.); or (3) biologically significant change in another clinicalpathology marker indicating liver dysfunction (albumin, bilirubin, bile acids, coagulation factors,
cholesterol, triglycerides, etc.). ATSDR has adopted the criteria from Hall et al. (2012) for determining
the adversity of the liver effects reported in the rodent perfluoroalkyl studies. Doses associated withincreases in liver weight and hepatocellular hypertrophy were not considered adverse effect levels unlesshepatocellular degenerative or necrotic changes or evidence of biliary or other liver cell damage were alsopresent. The lowest doses associated with the liver weight increases and hepatocellular hypertrophy are
noted in the LSE tables even though the dose levels are considered NOAELs.

PFOA

Epidemiological Studies—Liver Disease. Three studies of highly exposed populations have examinedpossible associations between PFOA and increased risk of liver disease. In workers, no association
between estimated cumulative serum PFOA levels and the risk of non-hepatitis liver disease was observed(Steenland et al. 2015). Similarly, two studies of residents living near the Washington Works PFOA
facility reported no increases in liver disease. In a study by Anderson-Mahoney et al. (2008), no
significant increases in self-reported liver problems were found in residents primarily served by the
Lubeck Public Water Service District or Little Hocking Water District; the study did not measure serum
PFOA levels. In a C8 Health Project study that included workers at the Washington Works facility,

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estimated cumulative serum PFOA levels were not associated with any liver disease or enlarged liver,fatty liver, or cirrhosis (Darrow et al. 2016).

Epidemiological Studies—Hepatic Serum Enzymes and Bilirubin Levels. The possible association
between PFOA exposure and hepatic enzymes has been examined in seven occupational exposure studies
that have found inconsistent results. A small study of Italian perfluoroalkyl workers did not findassociations between serum PFOA and ALT, AST, or GGT activities when only current workers were
examined (Costa et al. 2009). In analysis of all workers (current, former, and non-exposed workers),
associations between serum PFOA levels and ALT and GGT activities were found; total bilirubin was
also inversely associated with serum PFOA. Another small study of workers at a fluorochemical facility
in China found an association between serum PFOA and AST activity, but not ALT activity (Wang et al.
2012). Gilliland and Mandel (1996; data also reported in Gilliland 1992) did not find associations
between serum fluorine levels (used as a surrogate for serum PFOA) and ALT, AST, or GGT levels inworkers. In a follow-up study of this facility, there were no differences between AST, ALT, GGT, or
total bilirubin levels between workers in three exposure groups (Olsen et al. 2000); the mean serum
PFOA levels in this study ranged from 5,000 to 6,400 ng/mL at three time points and the serum PFOA
levels in the lowest exposure group ranged from 0 to <1,000 ng/mL. Increases in GGT and decreases intotal bilirubin levels associated with increases in serum PFOA were observed in a study of workers
exposed to high levels of PFOA and PFOS (Olsen and Zobel 2007); ALT activity was not affected. In across-sectional study of active workers at a PFOA facility, a modest but statistically significant positive
association between serum PFOA and GGT activity was found (Sakr et al. 2007b). No associations were
found for bilirubin levels or ALT and AST activities.

The possible associations between serum PFOA and serum enzyme and bilirubin levels were examined in
two longitudinal occupational exposure studies. Sakr et al. (2007a) examined the relationship between
serum PFOA and liver enzymes in a longitudinal study of 454 workers who had two or moremeasurements of serum PFOA from 1979 until the study was conducted. The average length of
employment among workers with multiple PFOA measurements was 11 years, and, on average,
10.8 years elapsed between their first and last serum PFOA measurement. The means of the first and last
PFOA measurement were 1,040 and 1,160 ng/mL, respectively. After adjustment for potential
confounders, serum PFOA was associated with AST activity, but not ALT, GGT, or total bilirubin. The
second study included 179 workers involved in the demolition of 3M perfluoroalkyl manufacturing
facilities examined over a mean period of 164 days (Olsen et al. 2012). In workers with prior exposure toPERFLUOROALKYLS

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2. HEALTH EFFECTSPFOA who had a decrease in serum PFOA levels during the study period, there was a significant increasein ALT levels. An increase in serum PFOA levels did not significantly alter AST or total bilirubin levels.

Community and general population exposure studies have also examined possible associations between
serum PFOA levels and alterations in serum hepatic enzyme and bilirubin levels. As with theoccupational exposure studies, several studies of populations living near PFOA facilities have foundinconsistent results. Darrow et al. (2016) found associations between ALT and bilirubin (inverse
association) and estimated cumulative and 2005/2006 serum PFOA levels in participants of the C8 Health
Project (6.5% of the participants also worked at the facility); there were no associations with GGTactivity. Gallo et al. (2012) also reported a significant correlation between serum PFOA levels and ALT
activity in C8 Health Project participants. Unlike the Darrow et al. (2016) study, a significant correlation
between serum PFOA levels and GGT activity, but no correlation with direct bilirubin levels, was found.
An earlier study of residents in the same area, as well as a study of residents near a facility in China, did
not find associations between serum PFOA and ALT, AST, or GGT (Emmett et al. 2006b; Wang et al.
2012).

More consistent results were found in three general population studies. In studies utilizing data fromNHANES, Gleason et al. (2015) and Lin et al. (2010) reported associations between serum PFOA levels
and ALT, AST, and GGT activities; total bilirubin was also found to be associated with serum PFOA in
the Gleason et al. (2015) study, but not in the Lin et al. (2010) study. A general population study
conducted in Japan (Yamaguchi et al. 2013) also found associations between serum PFOA levels and
AST, ALT, and GGT activities.

Although a number of epidemiological studies have found associations between serum PFOA and serum
hepatic enzyme and bilirubin levels, many of the investigators noted that liver biomarker levels weretypically within the normal range. Four studies examining the risk of having biomarker levels outside of
the normal range provide useful information for evaluating the health impact of the enzyme level
alterations. For ALT, Gallo et al. (2012) and Gleason et al. (2015) found increased risks of abnormal
levels in C8 and NHANES participants, respectively. In contrast, Olsen and Zobel (2007) and Emmett etal. (2006b) did not find increased risks of abnormal ALT levels in workers and C8 participants,
respectively. No alterations in the risk of abnormal AST levels associated with elevated serum PFOA
levels were observed in NHANES participants (Gleason et al. 2015). Emmett et al. (2006b) found a
decrease in the risk of abnormal AST levels with increasing serum PFOA levels in community members.
Associations between the risk of elevated GGT and serum PFOA were found in the study conducted by

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Gleason et al. (2015), but not in the Olsen and Zobel (2007), Gallo et al. (2012), or Emmett et al. (2006b)
studies. Similarly, Gleason et al. (2015) reported an association between serum PFOA and the risk ofelevated bilirubin levels, whereas Gallo et al. (2012) did not find this association in the higher exposed
population.

One limitation to the interpretation of the serum hepatic enzyme data is confounding factors that should
be considered in analyses; these include age, body mass index (BMI), serum lipid levels (triglycerides andtotal cholesterol), alcohol consumption, smoking, physical activity, and glucose levels (Deb et al. 2018;
Kim et al. 2008). Although many of the studies accounted for age, BMI, smoking, and alcohol
consumption, none of the studies adjusted for all of these potential confounders.

Epidemiological Studies—Serum Lipids. Occupational, community, and general population studies haveexamined the possible associations between serum PFOA levels and serum lipid levels; the results ofthese studies are presented in Table 2-12. Summaries of the changes in serum total cholesterol and LDLcholesterol levels, as well as the risk associated with elevated serum cholesterol and LDL cholesterollevels, are presented in Figures 2-11, 2-12, 2-13, and 2-14.

A study of workers at a manufacturing facility in Italy found higher total cholesterol and non-high-density
lipoprotein (HDL)-cholesterol levels (non-HDL cholesterol was estimated by subtracting HDL cholesterol
from total cholesterol) in the PFOA-exposed workers, as compared to levels in workers who were notexposed to PFOA (Costa 2004). A second study at this facility (Costa et al. 2009) also found an
association between serum PFOA levels and total cholesterol levels, but no association with HDLcholesterol levels. No associations were found for HDL cholesterol or triglyceride levels. In anothersmall study of workers at a fluorochemical facility in China (Wang et al. 2012), no associations between
serum PFOA and total cholesterol, LDL cholesterol, or triglyceride levels were observed; the study did
find an inverse association between serum PFOA and HDL cholesterol levels.

Several studies have examined workers at 3M facilities in Cottage Grove, Minnesota, Decatur, Alabama,
and/or Antwerp, Belgium; workers at these facilities were also exposed to high levels of PFOS. Gilliland
and Mandel (1996; data also reported in Gilliland 1992) examined workers at the Cottage Grove facility
in 1990 and found no associations between serum fluorine levels (used as a surrogate for PFOA) and totalcholesterol, LDL cholesterol, or HDL cholesterol. In a follow-up to this study, Olsen et al. (2000)
examined workers in 1993, 1995, and 1997; only 17 workers were examined at all three time periods,

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Figure 2-11. Serum Total Cholesterol Levels Relative to Serum PFOA Levels(Presented as percent change in cholesterol levels)

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Figure 2-12. Risk of Abnormal Cholesterol Levels Relative to PFOA Levels (Presented as Adjusted Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Figure 2-13. Serum LDL Cholesterol Levels Relative to Serum PFOA Levels(Presented as percent change in LDL cholesterol levels)

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Figure 2-14. Risk of Abnormal LDL Cholesterol Levels Relative to PFOA Levels (Presented as Adjusted Ratios)PERFLUOROALKYLS

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21 workers were examined in 1995 and 1997, and 68 workers were examined in 1993 and 1995. The
study did not adjust for the use of cholesterol-lowering medication. When workers were categorized byblood PFOA levels (0–<1,000, 1,000–<10,000, and >10,000 ng/mL), no significant differences in serum
cholesterol, LDL cholesterol, HDL cholesterol, or triglyceride levels were found at any of the monitoring
periods. A study in workers at the three 3M facilities, most of whom were not taking cholesterollowering medications, did not find associations between serum PFOA levels and total cholesterol or LDL
cholesterol levels; however, serum PFOA levels were associated with elevated triglyceride levels andinversely associated with HDL cholesterol levels (Olsen and Zobel 2007). The study did not findincreases in the risk of elevated total cholesterol (≥200 mg/dL), elevated LDL cholesterol (≥130 mg/dL),elevated triglyceride (≥150 mg/dL), or decreased HDL cholesterol (≤40 mg/dL) levels in workers withserum PFOA levels in the highest deciles. In addition to these cross-sectional studies, two longitudinalstudies were conducted at these facilities. Using data for 174 workers with medical surveillance data in2000 and 1997 and/or 1995, Olsen et al. (2003a) found that serum PFOA was a significant predictor ofcholesterol and triglyceride levels, which was primarily due to 21 workers at the Antwerp facility (meanserum level 8,400 ng/mL) whose serum PFOA levels increased over time. In a longitudinal study, Olsenet al. (2012) examined workers (none of the subjects reported using cholesterol-lowering medication)
involved in the demolition of 3M perfluoroalkyl manufacturing facilities; serum PFOA and lipid levels
were measured prior to the demolition and after demolition (mean time interval of 164 days). The meanbaseline serum PFOA levels were 881 ng/mL in 14 3M workers with prior PFOA or PFOS exposure and28.9 ng/mL in the remaining 165 workers. Among the 119 workers whose serum PFOA/PFOS levels(mean increase 50.9 ng/mL) increased during the observation period, there was a significant increase in
HDL cholesterol levels, but no change in total cholesterol or non-HDL cholesterol levels. No significant
alterations in serum lipid levels were observed in the 55 workers whose serum PFOA/PFOS levels
decreased during the observation period. In workers whose baseline levels of PFOA and PFOS were
<15 and <50 ng/mL, respectively, there were no significant differences between pre- and post-exposureserum lipid levels.

Investigators have also examined workers at the DuPont Washington Works facility in West Virginia. In
a cross-sectional study, Sakr et al. (2007b) found associations between serum PFOA levels and totalcholesterol, LDL cholesterol, and very-low-density lipoprotein (VLDL) cholesterol levels in all subjects
and in a subset of subjects not taking cholesterol-lowering medication. The study did not find any
association between serum PFOA and HDL cholesterol or triglyceride levels. In a second study,
Steenland et al. (2015) did not find an association between estimated serum PFOA levels and theoccurrence of elevated cholesterol levels that required medication. In a longitudinal study of workers

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who had at least two serum PFOA measurements between 1979 and 2004, Sakr et al. (2007a) found apositive association between serum PFOA and total cholesterol levels; no associations with triglycerides,
LDL cholesterol, or HDL cholesterol were found. Total cholesterol levels increased 1.06 mg/dL for each
1,000 ng/mL increase in serum PFOA.

Several studies have been conducted of residents living near the Washington Works facility. A study byEmmett et al. (2006b) of adults and children living in a community serviced by the Little Hocking Water
Authority did not find an association between serum PFOA levels and total cholesterol levels; the study
included an adjustment for the use of cholesterol-lowering medication. Four larger-scale studies ofparticipants in the C8 Science Panel studies found associations between serum PFOA levels and serum
lipid levels (Fitz-Simon et al. 2013; Frisbee et al. 2010; Steenland et al. 2009b; Winquist and Steenland
2014a). Positive associations between serum PFOA levels and total cholesterol and LDL cholesterol
were found in a study of over 12,000 children and adolescents, with mean serum PFOA levels of
32.6 ng/mL in children (aged 1.0–11.9 years) and 26.3 ng/mL in adolescents (aged 12.0–17.9 years)(Frisbee et al. 2010). Serum PFOA was also positively associated with triglyceride levels. Additionally,
there was an increased risk of elevated cholesterol (≥170 mg/dL) in subjects with serum PFOA levels in
the 4th or 5th quintiles. Increased odds of high LDL cholesterol (≥110 mg/dL) were also observed for the
5th PFOA quintile (OR 1.4, 95% CI 1.2–1.7). The investigators noted that the dose-response relationshipbetween serum PFOA and serum lipids was nonlinear, with greater increases in lipids observed at thelower serum PFOA levels. Similar findings were reported in a study of >46,000 adults with a medianserum PFOA level of 26.6 ng/mL; the study excluded subjects who reported taking cholesterol-lowering
medication (Steenland et al. 2009b). Associations were found between serum PFOA levels and totalcholesterol, LDL cholesterol, and non-HDL cholesterol; a positive association between serum PFOA andtriglycerides was also found. No associations between serum PFOA levels and HDL cholesterol levels
were found. Increased risks of having high total cholesterol (≥240 mg/dL) were found in subjects withserum PFOA levels in the 2nd, 3rd, and 4th quartiles. The investigators noted that the odds of high totalcholesterol from the 1st to the 5th quartile were approximately 40% for PFOA, which may be important
given that the Framingham study found that the risk of coronary heart disease was about 1.8 times higher
in subjects with total cholesterol levels >240 mg/dL as compared to subjects with levels <200 mg/dL.
Steenland et al. (2009b) also found an association between serum PFOA levels and total cholesterol levels
in a study of 10,746 adults taking cholesterol-lowering medication. Using both groups of subjects (taking
or not taking cholesterol-lowering medication), the investigators analyzed whether taking cholesterollowering medication was associated with lower serum PFOA levels, which may be indicative of reverse
causality. Although serum PFOA levels were significantly lower in subjects taking cholesterol-lowering

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medication, the difference between the groups was low (4%). Using estimated cumulative serum PFOA
levels as the exposure metric, Winquist and Steenland (2014a) found increased risks of hypercholesterolemia at estimated cumulative exposure levels ≥142 ng/mL. In a longitudinal study by FitzSimon et al. (2013), adults participating in the C8 Health Project and not taking cholesterol-lowering
medication were examined twice, with an average of 4.4 years between examinations. Mean serum
PFOA levels were 74.8 ng/mL at the first examination and 30.8 ng/mL at the second examination. In
subjects whose serum PFOA levels halved between examinations, there was a 3.6% decrease in LDLcholesterol levels and 1.7% decrease in total cholesterol levels. However, there were very small changes
in LDL cholesterol and total cholesterol levels in subjects whose serum PFOA levels decreased by >64%
and there were slight increases in LDL cholesterol and total cholesterol levels in subjects whose serum
PFOA levels fell by <50%. Changes in PFOA levels were not associated with changes in HDLcholesterol or triglyceride levels. Similarly, Wang et al. (2012) found no associations between serum
PFOA levels and total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides in a study of adults
living near a PFOA manufacturing facility in China; the mean serum PFOA level was 378.30 ng/mL anddid not include an adjustment for the use of cholesterol-lowering medication.

General population studies were conducted in the United States, Canada, Denmark, Norway, Spain,
Japan, Korea, China, and Taiwan; these studies have examined possible associations between serum
PFOA levels and serum lipid levels in children, adolescents, pregnant women, and adults. In a study of
8–10-year-old children (median serum PFOA of 9.3 ng/mL), Timmermann et al. (2014) found an
association between serum PFOA and triglyceride levels among obese children; this association was notfound among normal weight children. In a study of adolescents (12–18 years of age) participating in
NHANES (mean serum PFOA level of 4.2 ng/mL), Geiger et al. (2014b) found associations between
serum PFOA and total cholesterol and LDL cholesterol levels; no associations were found for HDLcholesterol or triglycerides. The study also found increased risks of elevated total cholesterol levels(>170 mg/dL) associated with serum PFOA levels. No alterations in the risk of elevated LDL cholesterol
or triglycerides or decreased HDL cholesterol were found. Associations between serum total cholesterol,
LDL cholesterol, and triglycerides have also been observed in a study of Taiwanese adolescents (12–15 years of age, median PFOA level of 9.3 ng/mL) (Zeng et al. 2015); no association was found for HDLcholesterol. A fourth study found associations between maternal PFOA levels and total cholesterol and
LDL cholesterol in 7- and 15-year-old girls, but no associations for girls whose maternal PFOA levels
were in the 2nd or 3rd tertiles (Maisonet et al. 2015b). No associations were found for HDL cholesterol or
triglyceride levels. A study of children enrolled in the World Trade Center Health Registry foundassociations between serum PFOA levels and elevated serum cholesterol, LDL cholesterol, andPERFLUOROALKYLS

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triglyceride levels, but no association with HDL cholesterol (Koshy et al. 2017). Another study ofchildren aged 3–18 years found no associations between serum PFOA levels and total cholesterol, LDL
cholesterol, or triglycerides (Kang et al. 2018). Manzano-Salgado et al. (2017b) found no association
between maternal serum PFOA levels and serum lipid levels in 4-year-old children.

Studies in adults have found mixed results for serum lipids. Using NHANES data for adults not taking
cholesterol-lowering medication (mean serum PFOA level of 4.6 ng/mL), Nelson et al. (2010) found an
association between serum PFOA levels and non-HDL cholesterol levels; no associations were found for
total cholesterol, LDL cholesterol, or HDL cholesterol. Another study of NHANES participants thatstatistically adjusted for use of cholesterol-lowering medication found no associations between serum
PFOA and total cholesterol, LDL cholesterol, HDL cholesterol, or triglyceride levels (Liu et al. 2018b).
Associations between serum PFOA levels and total cholesterol levels were also found in a study ofDanish adults not taking cholesterol-lowering medication (mean serum PFOA level of 7.1 ng/mL)(Eriksen et al. 2013). A study in Chinese adults (median PFOA level of 1.43 ng/mL) also foundassociations between serum PFOA and total cholesterol and LDL cholesterol, with no associations for
HDL cholesterol or triglycerides (Fu et al. 2014a). This study did not find increased risks of elevatedtotal cholesterol, LDL cholesterol, or triglycerides or decreased HDL cholesterol associated with serum
PFOA. A second study of Chinese men found an association between serum PFOA and triglyceride
levels, but no association with HDL cholesterol levels (Yang et al. 2018). A study of pregnant women in
Denmark also found an association between serum PFOA (mean serum PFOA level of 4.1 ng/mL atgestation week 30) and total cholesterol levels (Skuladottir et al. 2015). No associations between serum
PFOA levels and total cholesterol, LDL cholesterol, or non-HDL cholesterol levels were found in
Canadian adults not taking cholesterol-lowering medication with a geometric mean serum PFOA level of
2.46 ng/mL (Fisher et al. 2013). In a second study of pregnant women (median PFOA level of
2.25 ng/mL at gestation week 18), no associations between plasma PFOA and total cholesterol, LDL
cholesterol, or triglycerides were found (Starling et al. 2014a). The study did find an association between
plasma PFOA and HDL cholesterol.

A number of epidemiological studies have reported associations between serum PFOA levels and serum
lipid levels; the most consistently found alteration was for increased serum total cholesterol levels.
Associations between serum PFOA and serum cholesterol levels have been observed in occupational(Costa 2004; Costa et al. 2009; Sakr et al. 2007a, 2007b), community (Fitz-Simon et al. 2013; Frisbee etal. 2010; Steenland et al. 2009b; Winquist and Steenland 2014a), and general population (Eriksen et al.
2013; Fu et al. 2014a; Geiger et al. 2014b; Skuladottir et al. 2015; Zeng et al. 2015) studies, whereas

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other investigators have not found associations in worker populations (Gilliland and Mandel 1996; Olsenet al. 2000; Olsen and Zobel 2007; Steenland et al. 2015; Wang et al. 2012), community populations(Emmett et al. 2006b; Wang et al. 2012), or general populations (Fisher et al. 2013; Nelson et al. 2010;
Starling et al. 2014a). Longitudinal studies conducted in workers and highly exposed residents strengthen
the interpretation of this association between serum PFOA and serum lipid levels. Serum PFOA levels
were found to be a significant predictor of serum cholesterol levels in workers examined at least twice ina ≥5-year period (Olsen et al. 2003a; Sakr et al. 2007a). Similarly, a study of highly-exposed residents
examined twice with approximately 4 years between examinations found that there was a 1.7% decrease
in serum total cholesterol levels in subjects whose serum PFOA levels decreased by 50% between
examinations (Fitz-Simon et al. 2013). As noted in Steenland et al. (2010a), there is considerable
variation in the strength of the association between PFOA and serum cholesterol, with the greatest
changes in serum cholesterol occurring at lower PFOA levels. The change in cholesterol levels per
ng/mL change in serum PFOA ranged from 0.0007, calculated from data from the Olsen et al. (2000)
occupational exposure study, to 2.0 calculated from data from the Nelson et al. (2010) general population
study; the mean serum PFOA levels in these studies were ~22,000 and 4 ng/mL respectively. In a clinical
trial, administration of APFO to patients with advanced solid tumors at doses of 50–1,200 mg weekly for
6 weeks resulted in decreases in serum cholesterol levels; the marked decreases in serum cholesterollevels were observed at serum PFOA concentrations of 175,000–230,000 ng/mL (Convertino et al. 2018).
These results are similar to those observed in laboratory animals, suggesting that the dose-response curve
may be biphasic. Steenland et al. (2010a) and Frisbee et al. (2010) suggested that this may be due to asteep dose-response curve at low PFOA levels, which flattens out at higher PFOA levels and may be
indicative of saturation. A similar pattern was also observed in the risks of elevated cholesterol per
increases in serum PFOA levels (Figure 2-14). Several investigators have explored whether PFOA andcholesterol could be jointly affected or whether the associations were due to reverse causality (i.e.,
increased cholesterol resulted in increased serum PFOA levels). Butenhoff et al. (2012c) explored theissues of whether PFOA distributes into serum lipoprotein fractions, and whether increases in serum
lipoproteins would result in increases in serum PFOA. They concluded that there was limited distribution
to plasma lipoproteins, and did not consider it a non-causal factor. The Steenland et al. (2009b) study
found slightly lower serum PFOA levels (4%) among individuals taking cholesterol medication, as
compared to those not taking medication and noted that this was primarily a function of the large sample
size. This finding does not support reverse causality.

Laboratory Animal Studies. Information from inhalation studies in animals is limited. Head-only
exposure of male rats to 810 mg/m3 APFO dusts for 4 hours caused liver enlargement, but

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microscopically, the liver tissue appeared normal (Kennedy et al. 1986). Exposure head-only of male rats
to 0, 1, 7.6, or 84 mg/m3 APFO dusts 6 hours/day, 5 days/week for 2 weeks resulted in significant
increases in absolute and relative liver weight at 7.6 and 84 mg/m3 on exposure day 10; in rats from the84 mg/m3 group, absolute and relative liver weights were still significantly increased 28 days after
exposure ceased (Kennedy et al. 1986). The activities of serum enzymes markers of liver function wereunremarkable except for alkaline phosphatase, which was significantly increased in the 7.6 and 84 mg/m3
groups immediately after exposure on day 10 and remained elevated in the 84 mg/m3 group on day 14 ofrecovery. Histopathological changes were restricted to the 7.6 and 84 mg/m3 groups and consisted of
panlobular and centrilobular hepatocellular hypertrophy and necrosis. Panlobular hepatocellular
hypertrophy was seen only after the 10th exposure, but was limited to the centrilobular hepatocytes 14 or
28 days after exposure terminated, and was absent 42 days following cessation of exposure. Inhalation
exposure of pregnant rats to 25 mg/m3 APFO dusts 6 hours/day during GDs 6–15 induced an 18%
increase in absolute liver weight (Staples et al. 1984); no significant effect was reported in rats exposed to≤10 mg/m3.
Nose-only exposure of male CD rats to 67 mg/m3 ammonium perfluorononanoate dusts for 4 hours
induced significant increases (28–37%) in absolute and relative liver weight, assessed 5 and 12 days after
exposure (Kinney et al. 1989). Histopathological examinations were not conducted in this study.

The liver is the main target organ for perfluoroalkyls in animals following short- or long-term oral
exposures. The hepatic response to exposure to many perfluoroalkyls, particularly in rodents, is initiatedby the activation of the nuclear hormone receptor, PPARα, which triggers a characteristic sequence ofmorphological and biochemical events characterized by liver hypertrophy and alteration of a wide range
of enzymes, particularly those involved in lipid metabolism. It appears that PFOA can also damage theliver via a method independent of PPARα resulting in increases in liver weight, hepatocellular
hypertrophy, microvesicular steatosis, and cholangiopathy (Abbott et al. 2007; Das et al. 2017; Minata etal. 2010; Wolf et al. 2008a; Yang e al. 2002b).

The most sensitive liver effect observed in rats and mice after acute oral exposure to PFOA is an increasein liver weight (Cook et al. 1992; Das et al. 2017; Eldasher et al. 2013; Haughom and Spydevold 1992;
Ikeda et al. 1985; Iwai and Yamashita 2006; Kawashima et al. 1995; Kennedy 1987; Liu et al. 1996;
Loveless et al. 2006; Pastoor et al. 1987; Permadi et al. 1992, 1993; Qazi et al. 2012; White et al. 2009;
Wolf et al. 2007, 2008a; Xie et al. 2003; Yahia et al. 2010; Yang et al. 2001, 2002b). In rats orally
administered 50 mg/kg/day PFOA for 1, 3, or 7 days, a 10% increase in liver weight was observed afterPERFLUOROALKYLS

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the first dose; however, the relative liver weight was not significantly different from controls (Pastoor etal. 1987). After 3 days of exposure, the relative liver weight was significantly higher (36%) than controls.
Similarly, in mice, exposure to 390 mg/kg/day PFOA in the diet resulted in a significant increase in liver
weight after 5 days of exposure, but not after 2 days of exposure (Permadi et al. 1992). The lowest
LOAELs for increased relative liver weight in rats were 4.7 mg/kg/day in a 7-day study (Kawashima et al.
1995) and 2 mg/kg/day in a 14-day study (Liu et al. 1996); these studies also identified NOAELs of
2.4 and 0.2 mg/kg/day, respectively. In mice, the lowest LOAEL for increases in liver weight was
1 mg/kg/day PFOA administered in the diet for 10 days (Yang et al. 2001) or administered via gavage for7 days (Eldasher et al. 2013; Wolf et al. 2008a). Pastoor et al. (1987) noted that oral administration of
50 mg/kg/day PFOA to rats for 7 days resulted in a 2-fold increase in absolute and relative liver weight,
but no significant change in total deoxyribonucleic acid (DNA), indicating that the hepatomegaly
represented hypertrophy rather than hyperplasia. Few acute-duration studies included histologicalexaminations of the liver. Centrilobular and midzonal hypertrophy was observed in mice administered
1 or 3 mg/kg/day PFOA via gavage for 7 days; panlobular hypertrophy with cytoplasmic vacuolation wasobserved at 10 mg/kg/day (Wolf et al. 2008a). Qazi et al. (2010a) reported hepatocellular hypertrophy inmice exposed to 3.5 mg/kg/day PFOA in the diet for 10 days. Elcombe et al. (2010) reported
hepatocellular hypertrophy in rats orally exposed to 18 mg/kg/day for 7 days, but not after 1 day of
exposure. Increases in steatosis and triglyceride levels were observed in the livers of mice administered
10 mg/kg/day for 7 days (Das et al. 2017). A related liver effect was the finding of reduced serum
cholesterol and triacylglycerol levels in rats administered 16 mg/kg/day PFOA in the diet for 7 days
(Haughom and Spydevold 1992) and decreases in serum cholesterol and triglyceride levels in rats
administered 18 mg/kg/day PFOA via gavage for 7 days (Elcombe et al. 2010).

Similar to the acute-duration studies, intermediate-duration oral exposure to PFOA resulted in increases inabsolute and relative liver weights in rats (Biegel et al. 2001; Butenhoff et al. 2004b; Griffith and Long
1980; Perkins et al. 2004) and mice (Abbott et al. 2007; Ahmed and Abd Ellah 2012; Albrecht et al. 2013;
Griffith and Long 1980; Kennedy 1987; Lau et al. 2006; Son et al. 2008; Wolf et al. 2007; Yang et al.
2009). The lowest dose resulting in increases in liver weight in rats was 0.96 mg/kg/day, observed
following gavage administration of APFO for 28 days (Loveless et al. 2008); the lowest dose in mice was
0.5 mg/kg/day, observed in two 28-day studies using APFO (Kennedy 1987; Son et al. 2008). No
significant alterations in liver weight were observed in rats administered 0.29 mg/kg/day for 28 days
(Loveless et al. 2008) or in mice exposed to 0.2 mg/kg/day for 21 days (Kennedy 1987). Hepatocellular
hypertrophy was the predominant histopathological alteration in rats (Cui et al. 2009; Griffith and Long
1980; Loveless et al. 2008; Perkins et al. 2004) and mice (Albrecht et al. 2013; Filgo et al. 2015a; Griffith

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and Long 1980; Loveless et al. 2008; Tan et al. 2013); the severity of the hypertrophy was dose-related(Filgo et al. 2015a; Loveless et al. 2008). At higher doses, focal necrosis was observed (LOAEL of
29 mg/kg/day in rats and 0.96 mg/kg/day in mice exposed for 28 days) (Loveless et al. 2008). Fattychanges were observed in rats administered 20 mg/kg/day for 28 days (Cui et al. 2009) and miceadministered 9.6 mg/kg/day (Loveless et al. 2008). No significant alterations in liver weight or
histopathology were observed in rats allowed to recover for 8 weeks following a 13-week exposure to
0.6–6.5 mg/kg/day (Perkins et al. 2004). Intermediate-duration exposure to PFOA also resulted indecreases in serum HDL cholesterol levels in rats and mice administered ≥0.29 or 0.96 mg/kg/day,
respectively, for 28 days (Loveless et al. 2008). Serum cholesterol levels were decreased in rats
administered 0.29 or 0.96 mg/kg/day (no changes were observed at higher doses) and in miceadministered 9.6 or 29 mg/kg/day (Loveless et al. 2008). Similarly, serum triglyceride levels weredecreased in rats administered 0.29–9.6 mg/kg/day and in mice administered 9.6 or 29 mg/kg/day(Loveless et al. 2008). In a study of mice fed a western-type diet, increases in plasma cholesterol levels
were observed after 6 weeks of dietary exposure to 0.55 mg/kg/day in BALB/c or C57BL/6 mice
(Rebholz et al. 2016). The results of this study suggest that diet (fat intake and/or cholesterol levels) may
influence the response to PFOA and may account for some of the differences observed in humans and rats
fed a standard diet, which is typically low in fat.

Chronic exposure of rats to PFOA resulted in hepatocellular hypertrophy, hepatocellular necrosis, andportal mononuclear cell infiltration after a 1-year exposure to a LOAEL of 15 mg/kg/day in the diet (3M
1983; Butenhoff et al. 2012c). A 2-year exposure to 15 mg/kg/day resulted in hepatocellular hypertrophy,
cystoid degeneration, and portal mononuclear cell infiltration (3M 1983; Butenhoff et al. 2012c). The
study also found significant increases in ALT and AST levels in male rats exposed to 1.5 mg/kg/day. A
second chronic exposure study found significant increases in relative liver weight in rats exposed to13.6 mg/kg/day in the diet for 2 years; no non-neoplastic lesions were noted in the liver (Biegel et al.
2001).

Studies in monkeys suggest that longer-term exposure may also result in liver effects. Significant
increases in absolute and relative liver weight were observed in Cynomolgus monkeys exposed to
20/30 mg/kg/day administered via capsules for 26 weeks (Butenhoff et al. 2002). A significant increasein absolute, but not relative, liver weight was also observed in monkeys administered 3 or 10 mg/kg/day.
However, no histological alterations were observed in the livers at the doses tested. Similarly, no
histological alterations were observed in the livers of Cynomolgus monkeys administered 2 or
20 mg/kg/day via capsules for 30 days (Thomford 2001) or Rhesus monkeys administered 3 orPERFLUOROALKYLS

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10 mg/kg/day via gavage for 90 days (Griffith and Long 1980). Significant increases in serum
triglyceride levels were observed in the 10 and 20/30 mg/kg/day groups; the increases were statisticallysignificant at only some of the time points (Butenhoff et al. 2002). At 10 mg/kg/day, increases in serum
triglyceride levels at 4, 10, and 14 weeks of exposure were significantly higher than pre-treatment levels.
Increases in cholesterol levels were only observed in the 20/30 mg/kg/day group after 13 weeks of
exposure, but not after 26 weeks. No alterations in serum cholesterol or triglyceride levels were observedin the Thomford (2001) study.
Several studies have examined PPARα-null mice to assess whether PFOA-induced liver effects can also
occur via a mechanism independent of PPARα-receptor activation. Similar to wild-type mice, exposure
to PFOA resulted in significant increases in liver weight (Abbott et al. 2007; Das et al. 2017; Minata et al.
2010; Wolf et al. 2008a; Yang e al. 2002b). Abbott et al. (2007) found that the effect level was slightly
higher in PPARα-null mice than wild-type mice (3 versus 1 mg/kg/day) following oral exposure on
GDs 1–17 (liver weights measured at weaning). Wolf et al. (2008a) and Minata et al. (2010) reported thesame effect level (1 or 5 mg/kg/day, respectively) in PPARα-null mice and wild-type mice administered
PFOA via gavage for 7 days or 4 weeks. Wolf et al. (2008a) found dose-related increases inhepatocellular cytoplasmic vacuoles at ≥1 mg/kg/day and suggested that the increase in liver weight wasdue to the accumulation of PFOA in the hepatocytes rather than a toxic response. Hepatocyte
proliferation was also observed at 10 mg/kg/day. Unlike the Wolf et al. (2008a) study, the Minata et al.
(2010) 4-week study reported hepatocellular hypertrophy and microvesicular steatosis in the PPARα-nullmice (no incidence data were provided and it is unclear at what dose levels these effects were found);cytoplasmic vacuolation was also reported in the hepatocytes. Filgo et al. (2015a) also reported
hepatocellular hypertrophy in PPARα-null mice; the LOAEL was 3 mg/kg/day, which was higher than the
LOAEL of 0.3 mg/kg/day found in wild-type mice. Minata et al. (2010) also reported cholangiopathy inboth the wild-type and PPARα-null mice, but noted that the effect was more intensive in the PPARα-nullmice. No significant alterations in steatosis or triglyceride accumulation were observed in PPARα-nullmice administered 10 mg/kg/day for 7 days, but were observed in wild-type mice (Das et al. 2017).
Additionally, significant decreases in serum total cholesterol levels at 5.2 and 10.2 mg/kg/day andincreases at 20.7 mg/kg/day were observed in the PPARα-null mice; significant decreases in totalcholesterol were observed in the wild-type mice at 10.2 and 20.7 mg/kg/day doses. Serum triglyceride
levels were increased in both strains at 5.2 and 10.2 mg/kg/day doses and in the PPARα-null mice at
20.7 mg/kg/day (Minata et al. 2010).

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Intermittent application of 20, 200, or 2,000 mg/kg APFO to the skin of rats for 2 weeks resulted in thepresence of one or more foci of coagulative necrosis in the livers from all treated groups (Kennedy 1985).
The Kupffer cells within the foci of hepatocellular necrosis contained large vesicular nuclei and weremarkedly increased in number. At 2,000 mg/kg/day, these changes were seen in three out of five rats
killed on the 10th day of exposure, in three out of five rats killed on recovery day 14, and in one out offive rats killed on recovery day 42. This lesion occurred in two out of five rats from the 20 mg/kg/day
dose group killed on day 10 of exposure. Serum ALT activity appeared elevated at termination of
exposure in a dose-related manner, but without achieving statistical significance. A similar trend wasseen for AST activity, but achieving statistical significance in the high-dose group. The bloodconcentrations of organofluorine on the 10th day of exposure were 10.2, 52.4, 79.2, and 117.8 µg/mL in
the control, low-, mid-, and high-dose groups, respectively. A study in mice reported that application of
6.25 mg/kg/day PFOA on the dorsal surface of each ear for 4 days resulted in a 52% increase in absolute
liver weight (Fairley et al. 2007); no significant effect occurred after application of 2.5 mg/kg/day.

Summary. Epidemiological studies examining the hepatotoxicity of PFOA have examined threeoutcomes—risk of liver disease, evidence of hepatocellular damage (as measured by alterations in serum
hepatic enzymes and bilirubin levels), and alterations in serum lipid levels (total cholesterol, LDL
cholesterol, HDL cholesterol, and triglycerides)—among workers, residents living near a PFOA
manufacturing facility with high levels of drinking water contamination, and the general population.
Exposure to PFOA does not appear to be associated with increased risks of liver disease in workers or
highly exposed community members. The epidemiological studies have found associations between
serum PFOA levels and increases in serum ALT, AST, and GGT enzyme levels and decreases in serum
bilirubin levels. However, the results have not been consistently found, and serum enzyme levels weretypically within the normal range. Four studies examined the risk of serum enzyme levels outside of thenormal range; the results were mixed for the risk of elevated ALT, with two studies finding an increased
risk and two studies finding no association. A number of occupational, community, and general
population studies have found associations between serum PFOA levels and serum total cholesterollevels; several studies have also found no associations. Studies examining the change in cholesterollevels per change in serum PFOA levels have found greater increases in serum cholesterol levels
associated with serum PFOA levels at the lower range of PFOA levels and the dose-response curve
suggests a biphasic relationship. Positive associations have also been observed for LDL cholesterol,
although associations have not been consistently found. In general, no consistent associations were foundbetween serum PFOA and HDL cholesterol or triglyceride levels.

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Studies in laboratory animals have found strong associations between PFOA exposure and hepatotoxicity.
Liver effects have been observed in rats exposed to airborne APFO dusts; in rats, mice, and monkeys
following oral exposure for acute-, intermediate-, or chronic-durations; and in rats following dermal
exposure. The observed effects typically include increases in liver weight, hepatocellular hypertrophy,
and decreases in serum cholesterol and triglyceride levels. Other effects that have been observed include
hyperplasia, necrosis, and fatty degeneration. Available evidence suggests that the increased liver weight,
hypertrophy, and serum lipid alterations are likely due to PPARα initiation and therefore, may not be
relevant to humans. However, other mechanisms of liver toxicity are also involved, as evidenced by liver
effects observed in PPARα-null mice (Das et al. 2017; Minata et al. 2010; Wolf et al. 2008a). In contrast
to the results observed in epidemiological studies, a clinical trial study in humans with advanced solid
tumors exposed to very large doses of PFOA (Convertino et al. 2018) and human exposure to other
PPARα agonists, such as fibrates (Staels et al. 1998), suggest that hypolipidemic effects, similar to thoseobserved in rodents, may occur in humans exposed to PFOA, although humans may not be as sensitive as
rodents.

PFOS

Epidemiological Studies—Liver Disease. Several studies have examined the possible association
between PFOS exposure and liver diseases. No increases in deaths from cirrhosis of the liver were foundin workers at the 3M facility in Decatur, Alabama (Alexander et al. 2003). Another study of workers at
this facility found no significant alterations in the episodes of care for all liver disorders or all biliary ductdisorders (Olsen et al. 2004a). However, among workers with at least 10 years of high potential exposure
to PFOS, there were significant increases in episodes of care for cholelithiasis or acute cholecystitis andfor all biliary tract disorders. A third study of workers at a PFOS facility in Decatur, Alabama did not
find increases in cholelithiasis, cholecystitis, or liver disease (including cirrhosis and hepatitis) (Grice etal. 2007).

Epidemiological Studies—Hepatic Serum Enzymes and Bilirubin Levels. A series of studies conductedby Olsen and associates evaluated liver function (as assessed by serum liver enzymes) in workers atseveral 3M facilities involved in PFOS production. Using health data collected in 1995 and 1997, Olsenet al. (1999) did not find associations between serum PFOS and serum ALT, AST, or GGT enzymes at
PFOS levels <6,000 ng/mL; a positive association with total bilirubin levels was found. No conclusions
were drawn from the few workers with serum PFOS ≥6,000 ng/mL due to their small number (seven in
1995 and five in 1997 data). Similarly, no association of ALT, AST, or GGT and serum PFOA levels

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were observed in groups of workers at these facilities examined in 1993 (111 subjects), 1995
(80 subjects), and/or 1997 (74 subjects) (Olsen et al. 2000). A subsequent evaluation of workers from thesame plants, but that included women and a longitudinal analysis of the workers, reported that, after
adjusting for potential confounding factors, there were no substantial changes in hepatic parameters(Olsen et al. 2003a). GGT levels in females and ALT levels in males with PFOS levels in the 4th quartile
were significantly elevated in comparisons between individuals with serum PFOS levels in the 4th quartile
to those with levels in the 1st quartile; however, there were no statistical adjustments for potential
confounders. In contrast to these findings in workers, Gallo et al. (2012) reported significant increases in
the risks of elevated ALT, GGT, and bilirubin levels in a study of C8 participants. Conflicting results
have been found in general populations studies. Studies using the NHANES data set (Gleason et al. 2015;
Lin et al. 2010) did not find associations between serum PFOS and ALT, AST, GGT, or total bilirubinlevels. No increases in the risk of elevated levels of ALT, AST, or GGT were found (Gleason et al.
2015), although there was an increased risk of elevated total bilirubin levels. In a study of adults in Japan(Yamaguchi et al. 2013), significant correlations between serum PFOS and ALT, AST, and GGT levels
were found.

Epidemiological Studies—Serum Lipids. Occupational, community, and general population studies haveexamined possible associations between serum PFOS levels and serum lipids; these data are summarizedin Table 2-12. A graphical presentation of differences in total cholesterol and LDL cholesterol levels
relative to serum PFOS levels and the risks of elevated total cholesterol and LDL cholesterol arepresented in Figures 2-15, 2-16, 2-17, and 2-18.

In the Olsen occupational studies, significantly higher serum total cholesterol levels were found inworkers with serum PFOS levels between 3,000 and 6,000 ng/mL (Olsen et al. 1999, 2003a). However,the studies found mixed results for associations between serum PFOS and other serum lipids, with one
study finding an association with LDL cholesterol (Olsen et al. 1999) and the other finding an association
with triglycerides (Olsen et al. 2003a). Longitudinal analysis was conducted using data for 174 workers
with medical surveillance data in 2000 and 1997 and/or 1995 (Olsen et al. 2003a). No significant
differences in serum PFOS levels were observed across the three time periods, and serum PFOS levels
were not a significant predictor of cholesterol or triglyceride levels.

Two large-scale studies of participants in the C8 Science Panel studies found associations between serum
PFOS levels and serum lipid levels (Frisbee et al. 2010; Steenland et al. 2009b). Associations between
serum PFOS levels and total cholesterol, LDL cholesterol, and HDL cholesterol were found in a study ofPERFLUOROALKYLS

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Figure 2-15. Serum Total Cholesterol Levels Relative to Serum PFOS Levels(Presented as percent change in cholesterol levels)

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Figure 2-16. Risk of Abnormal Cholesterol Levels Relative to PFOS Levels (Presented as Adjusted Ratios)PERFLUOROALKYLS

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Figure 2-17. Serum LDL Cholesterol Levels Relative to Serum PFOS Levels(Presented as percent change in LDL cholesterol levels)

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Figure 2-18. Risk of Abnormal LDL Cholesterol Levels Relative to PFOS Levels (Presented as Adjusted Ratios)PERFLUOROALKYLS

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over 12,000 children and adolescents; the mean serum PFOS levels were 20.7 ng/mL in children (aged
1.0–11.9 years) and 19.3 ng/mL in adolescents (aged 12.0–17.9 years) (Frisbee et al. 2010). Similarfindings were reported in a study of adults with a median serum PFOS level of 19.6 ng/mL; the study
excluded subjects who reported taking cholesterol-lowering medication (Steenland et al. 2009b).

Associations were found between serum PFOS and total cholesterol, LDL cholesterol, and triglyceride
levels, but not with HDL cholesterol. Participants with serum PFOS levels in the 2nd, 3rd, and 4th quartiles
also had elevated risks of high cholesterol levels. Steenland et al. (2009b) noted that the odds of highcholesterol from the 1st to the 5th quintile was approximately 50% for PFOS, which may be important
given that the Framingham study found that the risk of coronary heart disease was about 1.8 times higher
in subjects with total cholesterol levels >240 mg/dL as compared to subjects with levels <200 mg/dL.

Steenland et al. (2009b) also examined over 10,000 participants who were taking cholesterol-lowering
medication; an association between serum PFOS and total cholesterol levels was found in this group.
Using both groups of subjects (taking or not taking cholesterol-lowering medication), the investigators
analyzed whether taking cholesterol medication was associated with lower serum PFOA or PFOS levels,
which may be indicative of reverse causality; no differences in serum PFOS levels were found between
the two groups.

General population studies were conducted in the United States, Canada, and several European and Asian
countries; these studies have found mixed results for associations between serum PFOS levels and serum
lipids. Some studies have found associations between serum PFOS levels and serum total cholesterol(Nelson et al. 2010; Skuladottir et al. 2015; Starling et al. 2014a) and HDL cholesterol (Châtaeu-Degat etal. 2010); inverse associations between serum PFOS and HDL cholesterol (Starling et al. 2014a) andtriglycerides (Châtaeu-Degat et al. 2010) were also found. However, other studies in adults have notfound associations between serum PFOS and total cholesterol (Châtaeu-Degat et al. 2010; Eriksen et al.
2013; Fisher et al. 2013; Fu et al. 2014a; Liu et al. 2018b), non-HDL cholesterol (Fisher et al. 2013), LDL
cholesterol (Châtaeu-Degat et al. 2010; Fisher et al. 2013; Fu et al. 2014a; Liu et al. 2018b; Starling et al.
2014a), HDL cholesterol (Fisher et al. 2013; Fu et al. 2014a; Liu et al. 2018b; Yang et al. 2018), or
triglycerides (Fu et al. 2014a; Starling et al. 2014a; Liu et al. 2018b; Yang et al. 2018). Additionally, twostudies did not find increased risks of elevated cholesterol levels (Fisher et al. 2013; Fu et al. 2014a).
Several of these studies controlled for use of cholesterol-lowering medication (Châtaeu-Degat et al. 2010;
Eriksen et al. 2013; Fisher et al. 2013; Nelson et al. 2010; Liu et al. 2018b). Overall, studies of children
and adolescents have found associations for serum lipid levels. Geiger et al. (2014b) found increases inPERFLUOROALKYLS

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the risk of elevated cholesterol and LDL cholesterol in children and adolescents aged 12–18 years; anassociation between serum PFOS and LDL cholesterol levels was also found. Zeng et al. (2015) foundassociations between serum PFOS and serum total cholesterol, LDL cholesterol, and triglyceride levels inchildren aged 12–15 years. Koshy et al. (2017) found an association between serum PFOS levels andserum total cholesterol, LDL cholesterol, and HDL cholesterol in children enrolled in the World Trade
Center Health Registry. Timmermann et al. (2014) also found an association between serum PFOS andtriglycerides only in obese Danish children (8–10 years of age), but not in normal weight children. In
contrast, Maisonet et al. (2015b) found an inverse association between maternal serum PFOS and totalcholesterol and LDL cholesterol in 15-year-old girls; no association was found when the girls were
7 years of age. Kang et al. (2018) did not find an association between serum PFOS and cholesterol, LDL
cholesterol, or triglyceride levels in children aged 3–18 years, and Manzano-Salgado et al. (2017b) did
not find associations between maternal serum PFOS and cholesterol, LDL cholesterol, HDL cholesterol,
or triglyceride levels in 4-year-old children.

Laboratory Animal Studies. Unpublished data summarized by OECD (2002) indicate that inhalation
exposure of rats to lethal concentrations (1,890–45,970 mg/m3) of PFOS dusts for 1 hour resulted invarying discoloration of the liver.

Consistent with the results for PFOA, acute-duration oral exposure of rats to PFOS resulted in increases
in liver weight (Elcombe et al. 2012b; Era et al. 2009; Haughom and Spydevold 1992), hepatocellular
hypertrophy (Elcombe et al. 2012b), and decreases in serum cholesterol and/or triglyceride levels(Elcombe et al. 2012a, 2012b; Haughom and Spydevold 1992). The lowest adverse effect level forincreased liver weight, hypertrophy, and decreased serum cholesterol was 1.79 mg/kg/day in rats exposed
to PFOS in the diet for 7 days (Elcombe et al. 2012b); however, a similar study by this group did not findsignificant alterations in liver weight or ALT, AST, or serum cholesterol levels after 7 days of exposure to
1.72 mg/kg/day (Elcombe et al. 2012a). Likewise, in mice, increases in liver weight (Fuentes et al. 2006;
Qazi et al. 2009b, 2010a; Wan et al. 2011), hepatocellular hypertrophy (Qazi et al. 2010a), and decreases
in serum cholesterol levels (Qazi et al. 2010a) were observed following acute exposure to PFOS. The
lowest LOAEL for liver weight was 3 mg/kg/day in mice administered PFOS via gavage on GDs 6–18
(Fuentes et al. 2006); no effects were observed at 1.5 mg/kg/day. The only acute-duration mouse study
that included histopathological examination of the liver and measurement of serum cholesterol levels
identified a LOAEL of 8.5 mg/kg/day in mice exposed to PFOS in the diet for 10 days (Qazi et al. 2010a).

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Intermediate-duration exposure to PFOS resulted in increased liver weight in rats (Cui et al. 2009; Curran
et al. 2008; Elcombe et al. 2012a; Seacat et al. 2003; Thibodeaux et al. 2003) and mice (Bijland et al.
2011; Thibodeaux et al. 2003; Wan et al. 2011, 2014b; Xing et al. 2016; Yahia et al. 2008), hepatocellular
hypertrophy in rats (Cui et al. 2009; Curran et al. 2008; Elcombe et al. 2012a; Seacat et al. 2003),
decreased serum cholesterol levels in rats (Curran et al. 2008; Elcombe et al. 2012a; Luebker et al. 2005b;
Seacat et al. 2003), decreased total cholesterol, triglyceride, non-HDL cholesterol, and HDL cholesterollevels in mice (Bijland et al. 2011), and increased serum AST and GGT levels in mice (Xing et al. 2016).
A mouse study (Bijland et al. 2011) also showed dramatic decreases in the hepatic production of VLDLand HDL (Bijland et al. 2011). Another mouse study (Lee et al. 2015b) did not find increases in hepatic
lipid levels in dams, although there were alterations in fetal livers. Only one of the intermediate-duration
mouse studies included histopathological examination of the liver. Xing et al. (2016) reported
cytoplasmic vacuolization, focal necrosis, and hepatocellular hypertrophy in mice exposed to PFOS via
gavage for 30 days; however, the study did not report incidence; the lowest dose tested was
2.5 mg/kg/day. The lowest adverse effect level for liver effects in rats was 0.14 mg/kg/day for asignificant increase in relative liver weight in female rats, but not male rats, exposed to PFOS in the dietfor 28 days (Curran et al. 2008). This study also found significant decreases in serum cholesterol levels
and increases in absolute and relative liver weights in males and females at 2.98 mg/kg/day andhepatocellular hypertrophy at 5.89 mg/kg/day. Seacat et al. (2003) reported increases in liver weight,
hepatocellular hypertrophy, and decreased serum cholesterol levels in rats following a 14-week dietary
exposure to 1.33 mg/kg/day; however, no significant alterations in liver weight or liver histopathology
were observed in rats exposed to 1.77 mg/kg/day PFOS in the diet for 4 weeks (Seacat et al. 2003). In
contrast, Elcombe et al. (2012a) reported increases in liver weight, hepatocellular hypertrophy, anddecreased serum cholesterol in rats exposed to 1.54 mg/kg/day PFOS in the diet for 28 days.

Data on the chronic toxicity of PFOS to the liver in rodents are limited to a study in rats (Butenhoff et al.
2012b; Thomford 2002b). Hepatotoxicity characterized by centrilobular hypertrophy, centrilobulareosinophilic hepatocytic granules, and centrilobular hepatocytic vacuolation was noted in rats exposed to
PFOS in the diet for 2 years. Among rats sacrificed at the end of the study, significant increases in theincidence of centrilobular hepatocellular hypertrophy were observed in male and female rats exposed to≥0.25 mg/kg/day (Thomford 2002b). When animals sacrificed at interim periods (14 or 52 weeks) andunscheduled deaths were included with animals sacrificed at exposure termination, the incidence ofcentrilobular hepatocellular hypertrophy was also increased in males exposed to 0.1 mg/kg/day. At≥0.1 mg/kg/day, significant increases in the incidences of eosinophilic clear cell altered foci and cystic
hepatocellular degeneration were observed in male rats. An increase in cystic degeneration was observed

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in male rats exposed to ≥0.025 mg/kg/day. However, this was mainly due to a high incidence inunscheduled deaths; among animals sacrificed at exposure termination, the incidence was only increasedin males exposed to 1.04 mg/kg/day. An increased incidence of single cell necrosis was observed inmales and females at 1.04 mg/kg/day (all groups combined). Observations made in a group of rats
exposed to 1.17 mg/kg/day PFOS for 52 weeks and allowed to continue on the control diet for an
additional year showed that hepatotoxicity was not a persistent response, as hepatotoxicity was generally
absent at the end of the recovery period. At termination, electron microscopy showed mild to moderatesmooth endoplasmic reticulum hyperplasia and minimal to mild hepatocellular hypertrophy primarily inrats dosed with 1.5 mg/kg/day PFOS, the highest dose tested.

In a study of Cynomolgus monkeys administered via gavage three doses of PFOS over 315 days,
decreases in HDL cholesterol levels were found; the investigators noted that the levels were still within
the normal variation (Chang et al. 2017). No alterations in other serum clinical chemistry parameters
were found. Treatment of Cynomolgus monkeys with up to 2 mg/kg/day PFOS administered via acapsule for 4 weeks did not induce gross or microscopic morphological alterations in the liver and did notincrease cell proliferation (Thomford 2002a). In a 26-week study in Cynomolgus monkeys, exposure to0.75 mg/kg/day PFOS, administered via a capsule resulted in increased absolute liver weight after
183 days of treatment (Seacat et al. 2002). Significant decreases in serum total cholesterol were also
observed at 0.75 mg/kg/day after 91, 153, and 182 days of exposure. On day 182, total cholesterol
decreased to 35 and 53% of predosing values in males and females, respectively. The HDL cholesterollevels were significantly lower in males at 0.03 and 0.75 mg/kg/day on days 153 and 182 and in females
at 0.15 and 0.75 mg/kg/day on days 153 and 182; the lack of pre-treatment HDL cholesterol
measurements precludes within-group comparisons. Serum bilirubin was significantly lower in males at
0.75 mg/kg/day on days 91, 153, and 182. Light microscopy of liver sections showed centrilobularvacuolation, hypertrophy, and mild bile stasis in some monkeys exposed to 0.75 mg/kg/day. Electron
microscopy showed lipid-droplet accumulation in some males and females exposed to 0.75 mg/kg/day.
Increased glycogen content was also noted at this dose level. No histological alterations were observed in
the livers of monkeys exposed to 0.75 mg/kg/day for 26 weeks and allowed to recover for 7 months or
1 year. Similarly, serum cholesterol returned to pretreatment levels 36 days post exposure and HDLcholesterol levels returned to pretreatment levels after 61 days of recovery.

Summary. Epidemiological studies have examined the possible associations between PFOS exposure andliver disease in workers and hepatocellular damage and alterations in serum lipid levels in workers andthe general population. The available occupational exposure studies or general population studies do notPERFLUOROALKYLS

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consistently suggest an association between PFOS exposure and increases in the risk of liver disease orbiliary tract disorders. A small number of occupational exposure studies have not found associations
between serum PFOS levels and increases in ALT, AST, or GGT levels. Overall, the epidemiologicalstudies suggest an association between serum PFOS levels and increases in serum total cholesterol levels
and possibly serum LDL cholesterol levels. Studies of workers at a PFOS manufacturing facility foundelevated serum total cholesterol levels in workers with high serum PFOS levels; however, a longitudinal
analysis at the same facility did not find that serum PFOS was a significant predictor of cholesterol levels.
Studies of residents living in an area with very high PFOA water levels found increases in serum totalcholesterol levels associated with elevated serum PFOS levels in children, adolescents, and adults. Mixed
results have been found for associations between serum PFOS and increases in serum total cholesterollevels in general population studies. Associations have been found between serum PFOS levels andserum LDL-cholesterol levels among non-occupational populations.

In laboratory animals, oral exposure to PFOS results in increases in liver weight, hepatocellular
hypertrophy, and decreases in serum lipid levels. A small number of studies also reported focal necrosis
and centrilobular hepatocytic vacuolization. The proposed mechanism of action for the increased liver
weight, hepatocellular hypertrophy, and decreased serum lipid levels involves PPARα receptor activation.
Due to species differences for this mechanism, these effects observed in rodents are not considered
relevant to humans. The applicability of the hepatic hypertrophy and serum lipid alterations observed inrodent studies to humans has been questioned due to species differences in the presumed mechanism ofaction for these effects in rodents.
PFHxS

Epidemiological Studies—Hepatic Serum Enzymes and Bilirubin Levels. Lin et al. (2010) did not findassociations between serum ALT and GGT levels with serum PFHxS levels in a general population study
using the NHANES data set.

Epidemiological Studies—Serum Lipids. Eight studies have evaluated the potential association between
serum PFHxS levels and serum lipids in the general population. A study utilizing the NHANES data set
for adults not taking cholesterol-lowering medication reported an association between serum PFHxS andnon-HDL cholesterol, but no associations with total cholesterol, LDL cholesterol, or HDL cholesterol(Nelson et al. 2010). In a study of Canadian adults not taking cholesterol-lowering medication with ageometric mean serum PFHxS level of 2.16 ng/mL, associations were found for total cholesterol, LDLPERFLUOROALKYLS

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cholesterol, and non-HDL cholesterol (Fisher et al. 2013). The study also found increased odds of having
a high cholesterol level with increasing PFHxS levels. Associations between serum PFHxS levels and
HDL cholesterol and triglyceride levels were found in a study of Chinese men (Yang et al. 2018). In
pregnant women in Norway with median serum PFHxS levels of 0.60 ng/mL, serum PFHxS levels wereassociated with serum HDL cholesterol, but not with total cholesterol, LDL cholesterol, or triglycerides(Starling et al. 2014a). No associations between serum PFHxS and total cholesterol, LDL cholesterol,
HDL cholesterol, or triglyceride levels were found in a study of Taiwanese children aged 12–15 years(mean serum PFHxS of 2.1 ng/mL) (Zeng et al. 2015) or Korean children aged 3–18 years (mean serum
PFHxS of 0.793 ng/mL) (Kang et al. 2018). A study of Spanish children aged 4 years found an
association between maternal serum PFHxS and triglyceride levels, but not with cholesterol, LDL
cholesterol, or HDL cholesterol (Manzano-Salgado et al. 2017b). A fourth study in children reported
associations between serum PFHxS levels and serum cholesterol and LDL cholesterol, but not HDLcholesterol or triglycerides, in World Trade Center Health Registry enrollees (Koshy et al. 2017).

Laboratory Animal Studies. Acute-duration gavage administration of PFHxS resulted in increases inliver weight, steatosis, and increases in hepatic triglyceride levels in mice; increases in liver weight andsteatosis were also observed in similarly exposed PPARα-null mice (Das et al. 2017). An intermediateduration study with PFHxS in rats reported that gavage doses of ≥3 mg/kg/day induced a significant
increase in absolute and relative liver weight in males (Butenhoff et al. 2009a). Light microscopy
revealed minimal to moderate enlargement of centrilobular hepatocytes. Clinical chemistry tests showeda significant decrease in serum cholesterol at ≥0.3 mg/kg/day and decreased serum triglycerides at
10 mg/kg/day. None of these alterations were observed in female rats. Centrilobular hepatocellular
hypertrophy was observed in mice administered ≥0.3 mg/kg/day PFHxS for 42–60 days (Chang et al.
2018); at 3 mg/kg/day single cell necrosis and microvascular fatty changes were also observed. In malemice, dietary exposure to PFHxS in a western-type diet resulted in >50% decreases in plasma triglyceride,
total cholesterol, non-HDL cholesterol, and HDL cholesterol levels and approximately 75% decreases in
the hepatic production of VLDL (Bijland et al. 2011). Increases in liver weight and hepatic triglyceride
levels were also observed.
PFNA

Epidemiological Studies—Hepatic Serum Enzymes and Bilirubin Levels. A health evaluation ofworkers at a U.S. polymer production facility using PFNA did not find alterations in ALT, AST, GGT, orbilirubin levels related to increases in exposure intensity score in a longitudinal analysis (Mundt et al.

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2007). Associations between serum PFNA and ALT and GGT levels were observed in a NHANES data
study (Gleason et al. 2015); however, another study (Lin et al. 2010) utilizing the NHANES data did not
find associations between serum PFNA and these enzymes. Neither study found associations for AST or
total bilirubin.

Epidemiological Studies—Serum Lipids. Longitudinal analysis of serum lipid levels in the occupational
exposure study (Mundt et al. 2007) did not find significant differences in serum total cholesterol or
triglycerides over time. In general population studies, associations have been observed between serum
PFNA levels and total cholesterol levels in adults (Fu et al. 2014a; Nelson et al. 2010) and children(Koshy et al. 2017; Zeng et al. 2015). No associations with cholesterol were found in a study in pregnant
women (Starling et al. 2014a) or studies in children (Kang et al. 2018; Manzano-Salgado et al. 2017b).
Several studies have also found associations with LDL cholesterol (Fu et al. 2014a; Koshy et al. 2017;
Zeng et al. 2015) or non-HDL cholesterol (Nelson et al. 2010), but others did not find associations for
LDL cholesterol (Nelson et al. 2010; Kang et al. 2018; Starling et al. 2014a). Most studies did not find an
association between serum PFNA and HDL cholesterol (Fu et al. 2014a; Nelson et al. 2010; Koshy et al.
2017; Manzano-Salgado et al. 2017b; Zeng et al. 2015) or triglycerides (Fu et al. 2014a; Kang et al. 2018;
Koshy et al. 2017; Manzano-Salgado et al. 2017b;Starling et al. 2014a). Exceptions were the Starling etal. (2014a) study of pregnant women, which found a positive association for HDL cholesterol, Yang et al.
(2018) study of men, which found associations for HDL cholesterol and triglycerides, and Zeng et al.
(2015), which found an association with triglycerides in children. Fu et al. (2014a) did not find increased
risks of elevated cholesterol, LDL cholesterol, or triglyceride levels or lowered HDL cholesterol levels in
adults.

Laboratory Animal Studies. Ten studies have evaluated the hepatic toxicity of PFNA. The observed
effects are consistent with effects observed for other perfluoroalkyls. Alterations in serum lipid levels
consisted of decreases in serum HDL cholesterol levels in rats administered via gavage ≥1 mg/kg/day
PFNA for 14 days (Fang et al. 2012a), decreases in serum triglyceride and cholesterol levels in micereceiving gavage doses of ≥1 mg/kg/day PFNA (Wang et al. 2015a), and decreases in serum cholesterollevels in mice administered 0.5 mg/kg/day PFNA (Singh and Singh 2018). Increases in liver weight wereobserved in rats nose-only exposed to ≥67 mg/m3 PFNA (Kinney et al. 1989), in mice administered via
gavage 10 mg/kg/day PFNA for 7 days (Das et al. 2017), in mice exposed to 0.5 mg/kg/day PFNA in thediet for 14 days (Kennedy 1987), in mice administered ≥0.2 mg/kg/day PFNA via gavage for 14 days
(Wang et al. 2015a), and in the offspring of mice administered via gavage ≥0.83 mg/kg/day PFNA on
GDs 1–17 or 1–18 (Das et al. 2015; Wolf et al. 2010). The increases in liver weight, hepatocellularPERFLUOROALKYLS

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2. HEALTH EFFECTS

hypertrophy, and deceases in serum lipid levels are considered adaptive and not relevant to humans (Hallet al. 2012). Hepatocellular vacuolation was observed in mice administered via gavage 5 mg/kg/day
PFNA for 14 days (Fang et al. 2012b). In PPARα-null mice, increases in liver weight were observed in
non-pregnant mice administered via gavage ≥1.5 mg/kg/day PFNA for 18 days, but were not found in
pregnant animals (Wolf et al. 2010). Das et al. (2017) found increases in liver weight, steatosis, andincreases in liver triglyceride levels in PPARα-null mice administered 10 mg/kg/day PFNA for 10 days.
PFDA

Epidemiological Studies—Serum Lipids. Six general population studies have evaluated the potential
relationships between serum PFDA and serum lipids and reported inconsistent results. Fu et al. (2014a)
found an association between serum PFDA and total cholesterol in adults and Koshy et al. (2017) foundassociations between serum PFDA and total cholesterol in children. A study of men did not findassociations between serum PFDA and HDL cholesterol or triglycerides (Yang et al. 2018). Studies inpregnant women (Starling et al. 2014a) and other studies in children (Kang et al. 2018; Zeng et al. 2015)
did not find associations. Fu et al. (2014a), Starling et al. (2014a), and Koshy et al. (2017) found positive
associations with HDL cholesterol; this was not found in the Zeng et al. (2015) study. Koshy et al. (2017)
also found an association with LDL cholesterol. The other studies did not find associations between
serum PFDA and LDL cholesterol (Fu et al. 2014a; Starling et al. 2014a; Zeng et al. 2015), and none
found association with triglycerides (Fu et al. 2014a; Kang et al. 2018; Koshy et al. 2017; Starling et al.
2014a; Zeng et al. 2015). Only the Fu et al. (2014a) study looked for alterations in the risk of elevatedcholesterol, LDL cholesterol, or triglyceride levels or decreased HDL cholesterol levels, but the study did
not find significant increases in the risk.

Laboratory Animal Studies. Hepatic effects observed in laboratory animals exposed to PFDA include
alterations in liver weight and morphology. Increases in liver weight have been observed in micefollowing a single gavage dose of PFDA; the alterations were observed 2 days after exposure to40 mg/kg/day (Brewster and Birnbaum 1989) or 30 days after exposure to ≥20 mg/kg/day (Harris et al.
1989). Repeated dietary exposure to 2.4 mg/kg/day PFDA for 1 week (Kawashima et al. 1995) or
78 mg/kg/day for 10 days (Permadi et al. 1992, 1993) also resulted in increases in liver weight. Oraldoses ≥9.5 mg/kg/day also resulted in increases in hepatic cholesterol levels in rats (Kawashima et al.
1995) and hepatic lipids in mice (Brewster and Birnbaum 1989). These acute doses were also associatedwith hepatocellular hypertrophy and evidence of peroxisome proliferation. Thirty days after a single
gavage dose of ≥20 mg/kg/day PFDA, effects included periportal to panlobular hepatocellularPERFLUOROALKYLS

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2. HEALTH EFFECTS

hypertrophy characterized by swollen hepatocytes with abundant granular eosinophilic cytoplasm andenlarged and hyperchromatic nuclei (Harris et al. 1989).

In intermediate-duration exposure studies, an increased incidence of minimal single cell hepatocellularnecrosis were observed in rats administered 0.5 mg/kg/day PFDA for 28 days (Frawley et al. 2018).

PFUnA

Epidemiological Studies—Serum Lipids. Of the five studies evaluating potential associations between
serum PFUnA and serum lipids, only a study by Kang et al. (2018) in children found an association
between serum PFUnA and total cholesterol and LDL cholesterol. The other studies did not findassociations between serum PFUnA and total cholesterol or LDL cholesterol (Fu et al. 2014a; Koshy etal. 2107; Starling et al. 2014a) or with HDL cholesterol or triglycerides (Yang et al. 2018). None of thestudies found associations with triglyceride levels. Starling et al. (2014a) and Koshy et al. (2017) foundassociations of serum PFUnA levels with HDL cholesterol levels; Fu et al. (2014a) did not find an
association for this parameter. No alterations in the risk of abnormal serum lipid levels were found in theadults examined by Fu et al. (2014a).

Laboratory Animal Studies. Only one animal study was identified that examined the liver following oral
exposure to PFUnA. In an intermediate-duration study of rats administered PFUnA via gavage, increases
in relative liver weight were observed in males at 0.3 mg/kg/day and in females at 1.0 mg/kg/day, andmild to moderate centrilobular hepatocellular hypertrophy was observed in males and females at
1.0 mg/kg/day (Takahashi et al. 2014).

PFHpA

Epidemiological Studies—Serum Lipids. Epidemiological data on PFHpA are limited to a study inadults conducted by Fu et al. (2014a), which found no associations between serum PFHpA and totalcholesterol, LDL cholesterol, HDL cholesterol, or triglyceride levels and a study in men conducted by
Yang et al. (2018), which found no associations between serum PFHpA and HDL cholesterol or
triglycerides.

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PFBS

Epidemiological Studies—Serum Lipids. In the only epidemiological study examining serum lipids andpossible associations with serum PFBS, Zeng et al. (2015) found an association with total cholesterollevels in children. No associations were found between serum PFBS and LDL cholesterol, HDL
cholesterol, or triglycerides.

Laboratory Animal Studies. Treatment of male rats with 900 mg/kg/day PFBS by gavage for 28 days
induced a significant increase in absolute and relative liver weight (25–30%) relative to controls, which
was no longer detected following a 14-day recovery period (3M 2001). Clinical chemistry tests of liverfunction were unremarkable and there were no chemical-related microscopic alterations. No alterations inliver weight, serum chemistry parameters (ALT, AST, cholesterol), or liver morphology were observed inrats administered gavage doses as high as 600 mg/kg/day PFBS for 90 days (Lieder et al. 2009a).
Significant increases in liver weight were observed at 300 and 1,000 mg/kg/day in a 2-generation study(Lieder et al. 2009b); the alterations were only observed in male rats. An increase in hepatocellular
hypertrophy was also observed in the male P0 and F1 rats administered via gavage 1,000 mg/kg/day.
Dietary exposure to mice resulted in decreases in plasma triglyceride levels and hepatic cholesterol levels,
but no alterations in liver weight or plasma cholesterol, HDL cholesterol, or non-HDL cholesterol(Bijland et al. 2011).
PFBA

Epidemiological Studies—Serum Lipids. Only one epidemiological study examined hepatic outcomes;
this study (Fu et al. 2014a) did not find any associations between serum PFBA levels and totalcholesterol, LDL cholesterol, HDL cholesterol, or triglycerides in adults.

Laboratory Animal Studies. Treatment of rats with up to 184 mg/kg/day PFBA by gavage for 5 days did
not affect liver weight, nor did it cause gross or microscopic morphological alterations in the liver (3M
2007a). In addition, clinical chemistry tests did not indicate altered liver function. Similarly,
administration of approximately 20 mg/kg/day PFBA in the diet to male rats for 2 weeks did not
significantly affect relative liver weight, but the same dose of PFOA induced a 45% increase in liver
weight (Ikeda et al. 1985). Dietary administration of doses of approximately 78 mg/kg/day PFBA to malemice for 10 days induced a 63% increase in absolute liver weight (Permadi et al. 1992, 1993).

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PFBA intermediate-duration studies have consistently found increases in liver weight and histologicalalterations. Dosing rats with PFBA by gavage for 28 days resulted in significant increases in absolute andrelative liver weight and decreases in serum cholesterol at ≥30 mg/kg/day and hepatocellular hypertrophy
at 150 mg/kg/day (Butenhoff et al. 2012a; van Otterdijk 2007a). Administration of 150 mg/kg/day PFBA
induced hepatocyte hypertrophy. These liver effects were no longer detected after a 21-day recovery
period. In a similar 90-day study, administration of 30 mg/kg/day PFBA resulted in increased absolute
liver weight and panlobular hepatocyte hypertrophy (Butenhoff et al. 2012a; van Otterdijk 2007b); noliver effects were observed at 6 mg/kg/day. None of the liver alterations were observed after a 21-day
recovery period.
PFDoDA

Epidemiological Studies—Serum Lipids. A general population study of adolescents (Zeng et al. 2015)
did not find any associations between serum PFDoDA and total cholesterol, LDL cholesterol, HDL
cholesterol, or triglyceride levels.

Laboratory Animal Studies. Dosing of male Sprague-Dawley rats with 10 mg/kg/day PFDoDA bygavage for 14 days induced a 35% increase in total serum cholesterol; doses of 1 or 5 mg/kg/day had no
significant effect (Shi et al. 2007). In a subsequent study, the same group of investigators reported that inrats dosed via gavage with 1 or 5 mg/kg/day PFDoDA, there was a trend for decreased serum
triglycerides, but the differences with controls were not statistically significant (Zhang et al. 2008); at
10 mg/kg/day, serum triglyceride levels were significantly increased. Liver triglyceride and livercholesterol levels were increased at ≥5 mg/kg/day. Absolute liver weight was significantly reduced in the
5 mg/kg/day group (19%) relative to controls, but this may have been due to a marked reduction in bodyweight (shown in Shi et al. [2007], but not in Zhang et al. [2008]).

In a 42-day PFDoDA gavage administration study, increases in relative liver weight were observed inmales at ≥0.5 mg/kg/day and hepatocellular hypertrophy was observed at 2.5 mg/kg/day (Kato et al.
2015). The study also found decreases in serum cholesterol at 0.1 and 0.5 mg/kg/day, but not at 2.5
mg/kg/day. In pregnant females (most dying before the end of the study), single cell hepatocyte necrosis
was observed at 2.5 mg/kg/day (Kato et al. 2015). Prebiliary infiltration of inflammatory cells (males),disposition of bilirubin (females), and hepatocellular hypertrophy (females) were observed in males andnonpregnant females administered 2.5 mg/kg/day PFDoDA for 42 days followed by a 42-day recovery
period (Kato et al. 2015).

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PFHxALaboratory Animal Studies. Increases in liver weight, decreases in serum cholesterol levels, andcentrilobular hepatocellular hypertrophy have been observed in rats administered 315 mg/kg/day PFHxA
for 32–44 days (Kirkpatrick 2005) or ≥100 mg/kg/day NaPFHx for 90–93 days (Chengelis et al. 2009b;
Loveless et al. 2009). In a chronic-duration study, gavage administration of 200 mg/kg/day for 2 years
resulted in increases in the incidence of hepatocellular necrosis in female rats (Klaunig et al. 2015). At
100 mg/kg/day, decreases in triglyceride levels were observed in male rats.
FOSA

Laboratory Animal Studies. In the only study examining hepatic effects, Seacat and Luebker (2000)
reported no alterations in liver weight in rats receiving a single gavage dose of 5 mg/kg FOSA.

2.10 RENAL
Overview. Epidemiological and laboratory animal studies have evaluated the potential of perfluoroalkyls
to be renal toxicants. Human studies have evaluated the risk of kidney disease, alterations in renal
function, damage to the kidney, and alterations in uric acid levels. The results of epidemiological studies
evaluating kidney disease and renal function are summarized in Table 2-13; Table 2-14 contains thestudies evaluating alterations in uric acid levels. More detailed descriptions of these studies can be foundin the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 8. Although there area couple of studies finding associations between PFOA exposure and kidney disease, the results are notconsistent across study populations. However, there is some indication that perfluoroalkyls may affectrenal function. Decreases in estimated glomerular filtration rate and increases in uric acid levels
associated with serum PFOA or PFOS have been reported in a number of epidemiological studies.
However, these alterations may be due to reverse causality (i.e., increases in serum perfluoroalkyl levels
could be due to a decrease in glomerular filtration and shared renal transporters for perfluoroalkyls anduric acid). Based on the small number of epidemiological studies or the inconsistency of the results,
possible associations between other perfluoroalkyls (PFHxS, PFNA, PFDA, PFBS, PFDoDA, or PFHxA)
and renal functions cannot be assessed. No studies were available for PFUnA, PFHpA, PFBA, or FOSA.

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2. HEALTH EFFECTS

Table 2-13. Summary of Renal Outcomes in Humansa
Reference and study populationb
PFOA
Costa et al. 2009

Serum perfluoroalkyl level Outcome evaluatedResultc

12,930 ng/mL (mean PFOA
in current workers)

Serum urea
Serum creatinine
Total proteins

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

α1 globulins, α2globulins, β globulins, or
γ globulins
α2 globulins

NS (p>0.05)

Occupational(n =53)

Lundin et al. 2009

NR

Nephritis and nephrosis
deathsOccupational (n=3,992)
Raleigh et al. 2014

NR

Chronic kidney disease
deathsOccupational (n=9,027)
Steenland et al. 2015

Association (p<0.01), current,
former and non-exposed workers.
SMR 5.2 (0.6–18.9)

HR 0.73 (0.21–2.48), 4th quartile

Estimated cumulative PFOA Chronic kidney diseaserisk

NS (p=0.92), no lag
NS (p=0.99), 10-year lag

7,800 ng/mL-year (mean
PFOA)

Chronic kidney disease
deathsSMR 3.79 (1.03–9.71)*, 2nd quartile

Anderson-Mahoney et al. 2008

NR

Kidney disease (selfreported)SPR 2.26 (1.45–3.51)*

Community (n=566)
Dhingra et al. 2016b

Estimated cumulative PFOA Chronic kidney disease

Occupational (n=3,713)
Steenland and Woskie 2012
Occupational (n=1,084)

Community (C8) (n=28,541)
Emmett et al. 2006b
Community (n=371)

354 ng/mL (median PFOA)

Serum creatinine
BUN
Total serum proteins

NS (p=0.80 for trend), no lag
NS (p=0.81 for trend), 5-year lag
NS (p=0.88 for trend), 10-year lag
NS (p=0.30 for trend), 20-year lag
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

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2. HEALTH EFFECTS

Table 2-13. Summary of Renal Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Watkins et al. 201328.3 ng/mL (median PFOA)GFRInverse association (p=0.02)*≥4.7 ng/mL (4th PFOA
quartile)

GFR

Inverse association (p<0.01)*,
4th quartile
Association (p<0.01)*

Community (C8) (9,660 children)
Kataria et al. 2015
General population (NHANES)(n=1,960 adolescents)
Shankar et al. 2011a

Serum uric acid
>5.9 ng/mL (4th PFOA
quartile)

General population (NHANES) (n=4,587)
PFOS
Olsen et al. 1998aOccupational (n=178 in 1995; n=149 in 1997)

Watkins et al. 2013
Community (C8) (9,660 children)
Kataria et al. 2015
General population (NHANES)(n=1,960 adolescents)
Shankar et al. 2011aGeneral population (NHANES) (n=4,587)
PFHxS
Watkins et al. 2013
Community (C8) (9,660 children)

2,440 and 1,930 ng/mL(mean PFOS in 1995 in
Decatur and Antwerp)
1,960 and 1,480 ng/mL(mean in 1997 in Decaturand Antwerp)
20.0 ng/mL (median PFOS)

GFR
Chronic kidney disease

Inverse association (p<0.001 fortrend)*
OR 1.73 (1.04–2.88)*, 4th quartile

Serum creatinine
BUN

Association (p<0.06)*, 1997 only
NS (p>0.1)

GFR

Inverse association (p=0.0001)*

7.9–12.8 ng/mL (2nd PFOS
GFR
quartile)≥19.4 ng/mL (4th PFOS
quartile)>29.5 ng/mL (4th PFOS
GFR
quartile)
11.2–17.8 ng/mL (2nd PFOS Chronic kidney disease
quartile)

Inverse association (p<0.05)*,
2nd quartile

5.2 ng/mL (median PFHxS)

Inverse association (p=0.003)*

GFR

Inverse association (p<0.001 fortrend)*
OR 1.82 (1.02–3.27)*, 4th quartilePERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-13. Summary of Renal Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Kataria et al. 2015

≥4 ng/mL (4th PFHxSquartile)

GFR

NS (p>0.05)

NR

BUN
Creatinine

Small, but not clinically significant

1.5 ng/mL (median PFNA)

GFRInverse association (p=0.002)*≥1.5 ng/mL (4th PFNA
quartile)

GFR

NS (p>0.05)

General population (NHANES)(n=1,960 adolescents)
PFNA
Mundt et al. 2007
Occupational (n=592)
Watkins et al. 2013
Community (C8) (9,660 children)
Kataria et al. 2015
General population (NHANES)(n=1,960 adolescents)
aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 8 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

BUN = blood urea nitrogen; GFR = glomerular filtration rate; HR = hazard ratio; NHANES = National Health and Nutrition Examination Survey;
NR = not reported; NS = not significant; OR = odds ratio; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid; SMR = standardized mortality ratioPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-14. Summary of Uric Acid Outcomes in Humansa
Reference and study populationb
PFOA
Costa et al. 2009
Occupational (n=53)
Sakr et al. 2007b

Serum perfluoroalkyl level Outcome evaluatedResultc

12,930, ng/mL (mean PFOA Serum uric acidin current workers)

Association (p=0.039)*

490 ng/mL (median PFOA)

Association (reported byinvestigator)*

Serum uric acidOccupational (n=1,025)
Steenland et al. 2010b
Community (n=54,591)
Gleason et al. 2015
General population (NHANES) (n=4,333)
Geiger et al. 2013
General population (NHANES)(n=1,772 adolescents and adults)
Kataria et al. 2015
General population (NHANES)(n=1,960 adolescents)
Qin et al. 2016

11.5–20.6 ng/mL (2nd quintile Hyperuricemia risk
PFOA)

OR 1.33 (1.24–1.43)* (2nd quintile)

3.7 ng/mL (median PFOA)

Serum uric acid

Association (p<0.001)*

Hyperuricemia risk

Association (p<0.001)*

4.3 ng/mL (mean PFOA),>5.4 ng/mL (4th PFOA
quartile)

Serum uric acid
Hyperuricemia risk

Association (p=0.0001)*
OR 1.62 (1.10–2.37)* (4th quartile)≥4.7 ng/mL (4th PFOA
quartile)

Serum uric acid

Association (p<0.01)*

0.5 ng/mL (median PFOA)

Serum uric acid

Association (p<0.05)*

Hyperuricemia risk

OR 2.16 (1.29–3.61)* (full cohort)
OR 2.76 (1.37–5.56)* (boys only)

Serum uric acid
Hyperuricemia risk

Association (p<0.0001)*
OR 1.90 (1.35–2.69)*, 3rd quartile

17.5–23,26 ng/mL (3rd PFOS Hyperuricemia risk
quintile)

OR 1.11 (1.04–1.20)* (3rd quintile)

General population (n=225 adolescents)
Shankar et al. 2011b
General population (NHANES) (n=3,883 adults)
PFOS
Steenland et al. 2010b
Community (n=54,591)

3.5–5.1 ng/mL (3rd PFOA
quartile)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-14. Summary of Uric Acid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Gleason et al. 2015

11.3 ng/mL (median PFOS) Serum uric acid
Hyperuricemia risk

Association (p<0.01)*
NS (p=0.502)

18.4 ng/mL (mean PFOS),>25.5 ng/mL (4th PFOS
quartile)

Serum uric acid
Hyperuricemia risk

NS (p=0.0575)
OR 1.65 (1.10–2.49)* (4th quartile)≥19.4 ng/mL (4th PFOS
quartile)

Serum uric acid

Association (p<0.05)*

General population (NHANES, n=4,333)
Geiger et al. 2013
General population (NHANES)(n=1,772 adolescents and adults)
Kataria et al. 2015
General population (NHANES)(n=1,960 adolescents)
Qin et al. 201628.9 ng/mL (median PFOS) Serum uric acid
Hyperuricemia risk

NS (p>0.05)
OR 1.35 (0.95–1.93) (full cohort)

11.2–17.8 ng/mL (2nd PFOS Serum uric acidquartile)
Hyperuricemia risk

Association (p=0.0018)*
OR 1.46 (1.11–1.91)*, 2nd quartile

1.8 ng/mL (median PFHxS)

Serum uric acid
Hyperuricemia risk

NS (p>0.01)
NS (p=0.110 for trend)≥4 ng/mL (4th PFHxSquartile)

Serum uric acid

NS (p>0.05)

General population (NHANES)(n=1,960 adolescents)
Qin et al. 2016

1.3 ng/mL (median PFHxS)

General population (n=225 adolescents)
PFNA
Mundt et al. 2007

Serum uric acid
Hyperuricemia risk

Association (p<0.05)*
OR 1.39 (0.93–2.07)

NR

Serum uric acid

Small, but not clinically significant

General population (n=225 adolescents)
Shankar et al. 2011b
General population (NHANES) (n=3,883 adults)
PFHxS
Gleason et al. 2015
General population (NHANES) (n=4,333)
Kataria et al. 2015

Occupational (n=592)

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2. HEALTH EFFECTS

Table 2-14. Summary of Uric Acid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Gleason et al. 2015

1.4 ng/mL (median PFNA)

Serum uric acid
Hyperuricemia risk

Association (p<0.001)*
NS (p=0.42 for trend)≥1.5 ng/mL (4th PFNA
quartile)

Serum uric acid

NS (p>0.05)

General population (NHANES)(n=1,960 adolescents)
Qin et al. 2016

0.8 ng/mL (median PFNA)

General population (n=225 adolescents)
PFDA
Qin et al. 2016

Serum uric acid
Hyperuricemia risk

NS (p>0.05)
OR 1.28 (0.83–1.96)

0.9 ng/mL (median PFDA)

General population (n=225 adolescents)
PFBS
Qin et al. 2016

Serum uric acid
Hyperuricemia risk

NS (p>0.05)
OR 1.26 (0.82–1.92)

0.5 ng/mL (median PFBS)

Serum uric acid
Hyperuricemia risk

NS (p>0.05)
OR 1.23 (0.86–1.75)

2.7 ng/mL (median
PFDoDA)

Serum uric acid
Hyperuricemia risk

NS (p>0.05)
OR 0.93 (0.65–1.34)

General population (NHANES) (n=4,333)
Kataria et al. 2015

General population (n=225 adolescents)
PFDoDAQin et al. 2016
General population (n=225 adolescents)

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Table 2-14. Summary of Uric Acid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

PFHxA
Qin et al. 2016

0.2 ng/mL (median PFHxA)

Serum uric acid

NS (p>0.05)

Hyperuricemia risk

OR 1.08 (0.77–1.61)

General population (n=225 adolescents)

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 8 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

NHANES = National Health and Nutrition Examination Survey; NR = not reported; NS = not significant; OR = odds ratio; PFBS = perfluorobutane sulfonic acid;
PFDoDA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid

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Laboratory animal studies have primarily evaluated kidney morphology; these studies are summarized inTables 2-1, 2-3, 2-4, 2-5, and 2-6. The NOAEL and LOAEL values for these studies are illustrated in
Figures 2-6, 2-8, 2-9, and 2-10. In general, the laboratory animal studies have not found evidence ofimpaired renal function or morphological damage following exposure to PFOA, PFOS, PFHxS, PFDA,PFUnA, PFBS, PFBA, PFDoDA, or PFHxA. No laboratory animal studies examining renal endpoints
were available for PFNA, PFHpA, or FOSA.
PFOA

Epidemiological Studies—Kidney Disease. Several epidemiological studies have examined the possible
association between PFOA exposure and increased risk of kidney disease. In a cohort mortality study ofworkers at the DuPont PFOA facility in West Virginia, Steenland and Woskie (2012) found an increase indeaths from chronic renal disease when compared to DuPont workers at other regional facilities. Whenestimated cumulative PFOA exposure was estimated based on the worker’s job history and data from abiomonitoring survey conducted from 1979 to 2004, there was a significant positive trend fornonmalignant kidney disease when the workers were divided in estimated cumulative exposure quartiles.
Two studies of workers at the 3M APFO facility in Cottage Grove, Minnesota did not find increases indeaths from chronic kidney disease (Raleigh et al. 2014) or nephritis and nephrosis (Lundin et al. 2009) ascompared to mortality rates for the state of Minnesota. Similar results were found when chronic kidneydisease deaths were compared to those in a cohort of workers in St. Paul Minnesota who worked at a nonAPFO facility (Raleigh et al. 2014). An occupational exposure study (Steenland et al. 2015) and C8
community study (Dhingra et al. 2016b) found no associations between estimated cumulative PFOA
exposure and the risk of chronic kidney disease. Another study of the community living near the
Washington Works facility found a higher prevalence of self-reported kidney disease as compared to rates
reported in NHANES (Anderson-Mahoney et al. 2008).

Epidemiological Studies—Biomarkers of Renal Function. Several biomarkers of renal function havebeen evaluated in epidemiological studies; these include BUN, serum creatinine, glomerular filtration
rate, and uric acid levels (discussed in the following section). Kidney function, assessed by levels of
BUN and serum creatinine, was not associated with exposure to PFOA in the occupational exposurestudies by Olsen et al. (2003a) or Costa et al. (2009) or a community exposure study by Emmett et al.
(2006b).

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Three studies have found inverse associations between serum PFOA and glomerular filtration rate. Using
the NHANES data for the 1999–2008 cycles, Shankar et al. (2011a) found an inverse association between
serum PFOA levels and estimated glomerular filtration rate in adults. The likelihood of chronic kidneydisease, defined as a glomerular filtration rate of <60 mL/minute/1.73 m2, was significantly higher in
adults with the highest serum PFOA (>5.9 ng/mL, OR 1.73, 95% CI 1.04–2.88) levels than in adults withserum PFOA levels in the lowest quartile. The study also investigated whether the association between
serum PFOA levels and chronic kidney disease was due to reverse causality (i.e., decreased glomerular
filtration leads to a decrease in perfluoroalkyl filtration) and found a stronger negative correlation
between estimated glomerular filtration rate and serum PFOA levels in subjects without chronic kidneydisease, suggesting that it was not due to reverse causality. In another study utilizing NHANES data, aninverse association was found in adolescents with serum PFOA levels in the 4th quartile (Kataria et al.
2015). Similarly, an inverse association between serum PFOA and glomerular filtration rate was found inchildren participating in the C8 Health Project (Watkins et al. 2013). Unlike Shankar et al. (2011a),
Watkins et al. (2013) suggested that the association between serum perfluoroalkyl levels and estimatedglomerular filtration rates may be a consequence of reverse causation because no associations were foundbetween estimated serum PFOA levels 3 or 10 years prior to enrollment in the study or at the time of
study enrollment and estimated glomerular filtration rates; predicted serum PFOA levels were based on
environmental PFOA levels, self-reported residential history, and PBPK modeling.

Epidemiological Studies—Alterations in Uric Acid Levels. Associations between serum PFOA levels
and serum uric acid levels have been found in several occupational, community, and general population
studies. Costa et al. (2009) and Sakr et al. (2007b) reported associations between serum PFOA levels andserum uric acid levels in workers with high serum PFOA levels. In adult participants of the C8 Health
Project, positive linear trends between serum uric acid levels and serum PFOA levels were found(Steenland et al. 2010b). When the subjects were categorized by PFOA levels, significantly increased
risks of hyperuricemia (>6.0 mg/dL for women, >6.8 mg/dL for men) were observed for subjects withserum PFOA levels in the 2nd, 3rd, 4th, and 5th quintiles (≥11.5 ng/mL). Four studies utilizing NHANES
data have found associations between serum PFOA and serum uric acid levels in adults (Gleason et al.
2015; Shankar et al. 2011b) and adolescents (Geiger et al. 2013; Kataria et al. 2015). A study in
Taiwanese adolescents also found this association between PFOA and uric acid (Qin et al. 2016). Several
studies have also found increases in the risk of hyperuricemia in a highly exposed population (Steenland
et al. 2010b) and the general population (Gleason et al. 2015; Geiger et al. 2013; Qin et al. 2016; Shankar
et al. 2011b). The ORs for the risk of hyperuricemia in these studies are summarized in Figure 2-19.

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Figure 2-19. Risk of Hyperuricemia Relative to PFOA Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Laboratory Animal Studies. No gross or microscopic alterations were observed in the kidneys from malerats following head-only inhalation exposure to up to 84 mg/m3 APFO dusts for 2 weeks (Kennedy et al.
1986). Significantly elevated absolute and relative kidney weight was reported in male rats dosed with
≥3 mg/kg/day PFOA by gavage in water for 70 days (Butenhoff et al. 2004b), but histological evaluationof the kidney was not conducted in this study. Rats that received much higher doses (100–110 mg/kg/day) of APFO for 90 days in the diet showed no significant morphological alterations in thekidneys, and BUN and the urinalysis were unremarkable (Griffith and Long 1980). Also, male mice
dosed with up to 47 mg/kg/day APFO in the drinking water for 21 days showed no morphologicalalterations in the kidneys, and BUN and serum creatinine levels were not significantly affected (Son et al.
2008). Treatment of Cynomolgus monkeys with daily doses of up to 20 mg/kg/day APFO, administered
via a capsule, for 26 weeks (Butenhoff et al. 2002) or Rhesus monkeys dosed with up to 10 mg/kg/day by
gavage for 90 days (Griffith and Long 1980) did not cause morphological alterations in the kidneys, andblood chemistries and urinalyses provided no evidence of alterations in kidney function. In a 2-year
dietary study in rats, relative kidney weight from males dosed with 15 mg/kg/day APFO was significantly
elevated (14%) at the 1-year interim evaluation relative to controls, but gross and microscopic appearance(at 1 year and at termination), BUN, and urinalyses (several times during the study) were not significantly
affected (3M 1983; Butenhoff et al. 2012c). No gross or microscopic alterations were seen in the kidneys
from rats that received dermal applications of up to 2,000 mg/kg/day APFO to the shaven skin for
2 weeks (Kennedy 1985).

Summary. Epidemiological studies have examined possible associations between exposure to PFOA andincreases in the risk of kidney disease and alterations in renal function. Mixed results for associations
between serum PFOA and risks of kidney disease have been reported in occupational exposure studies
and studies of highly exposed residents with more studies not finding associations. Several general
population and community studies have found inverse associations between serum PFOA andglomerular filtration rate; however, there is suggestive evidence that this association may be due toreverse causation rather than a direct effect. Associations between serum PFOA levels and serum uricacid levels have been consistently observed in occupational, community, and general populations.
Laboratory animal studies have not found evidence of alterations in renal function or histologicalalterations.

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PFOS

Epidemiological Studies—Biomarkers of Renal Function. Three studies have found inverse
associations between serum PFOS levels and glomerular filtration rate in adults (Shankar et al. 2011a),adolescents (Kataria et al. 2015), and children (Watkins et al. 2013). In the Watkins et al. (2013) study of
C8 Health Project participants, a concentration-related linear trend between decreasing estimatedglomerular filtration rates and increases in serum PFOS levels was observed in children and adolescents
1–<18 years old. In adolescents 12–19 years of age participating in NHANES, the estimated glomerular
filtration rate was lower in participants with serum PFOA levels in the 2nd, 3rd, and 4th quartiles than thosewith levels in the 1st quartile (Kataria et al. 2015). In addition to the inverse association between serum
PFOS and estimated glomerular filtration rate observed in adult NHANES participants, Shankar et al.
(2011a) also found increased risks of chronic kidney disease (defined as a glomerular filtration rate of<60 mL/minute/1.73 m2) in participants with serum PFOS levels in the 4th quartile.

Epidemiological Studies—Alterations in Uric Acid Levels. In a study of C8 Health Project participants,
a linear trend between serum uric acid levels and serum PFOS levels was found (Steenland et al. 2010b).
When the subjects were categorized by serum PFOS levels, increased risks of hyperuricemia (>6.0 mg/dL
for women, >6.8 mg/dL for men) were observed for subjects with serum PFOS levels in the 3rd, 4th, and5th quintiles. Similar findings were found in NHANES adult participants (Shankar et al. 2011b). A studyof adolescent NHANES participants found associations between serum PFOS and serum uric acid levels(Kataria et al. 2015); a second study did not find an association (Geiger et al. 2013). The Geiger et al.
(2013) study did find an increased risk of hyperuricemia for adolescents with serum PFOS levels in the
4th quartile. A study of Taiwanese adolescents did not find associations between serum PFOS and uricacid or an increased risk of hyperuricemia (Qin et al. 2016). The ORs for the risk of hyperuricemia inthese studies are summarized in Figure 2-20.

Laboratory Animal Studies. No significant morphological alterations or clinical evidence of impaired
kidney function was reported in male and female rats dosed with up to 1.77 mg/kg/day PFOS (potassiumsalt) (Seacat et al. 2003) or 5.89 mg/kg/day (Curran et al. 2008) for 4 weeks. Extending the treatment to
14 weeks resulted in an increase in BUN in male (23% increase) and female rats (41% increase), but
histopathology of the kidneys and urinalyses were unremarkable (Seacat et al. 2003). The NOAEL values
were 0.34 and 0.4 mg/kg/day in males and females, respectively. Gavage administration of three doses of
PFOS to Cynomolgus monkeys over 315 days did not result in alterations in BUN or serum creatinine orPERFLUOROALKYLS

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Figure 2-20. Risk of Hyperuricemia Relative to PFOS Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

total protein levels (Chang et al. 2017). Treatment of Cynomolgus monkeys with up to 0.75 mg/kg/day
PFOS (potassium salt) administered via a capsule for 26 weeks did not cause morphological alterations in
the kidneys, nor did it affect BUN, serum creatinine, or urinary parameters (Seacat et al. 2002). Similar
results were reported in a 4-week study in monkeys dosed with up to 2 mg/kg/day PFOS (Thomford
2002a). A mild increase in BUN was reported in rats treated with approximately 0.25 or 1.04 mg/kg/day
PFOS in the diet for 53 weeks in a 2-year study (Butenhoff et al. 2012b; Thomford 2002b). However,there were no significant gross or microscopic alterations in the kidneys at week 53 or at termination.
PFHxS

Epidemiological Studies—Biomarkers of Renal Function. A small number of epidemiological studies
have evaluated biomarkers of renal function. In a study of C8 Health Project child participants (aged 1–<18 years), an inverse association between serum PFHxS and estimated glomerular filtration rate wasobserved (Watkins et al. 2013). A study of adolescent participants in NHANES did not find thisassociation (Kataria et al. 2015). It is noted that the reported median PFHxS level in the Watkins et al.
(2013) study (5.2 ng/mL) exceeded the lower end of the 4th quartile serum PFHxS level in the Kataria etal. (2015) study (≥4 ng/mL).
Epidemiological Studies—Alterations in Uric Acid Levels. In NHANES participants ≥12 years of age(Gleason et al. 2015) and adolescent NHANES participants (Kataria et al. 2015), no associations between
serum PFHxS levels and serum uric acid levels or risk of hyperuricemia (Gleason et al. 2015) were found.
A study of Taiwanese adolescents found an association between serum PFHxS levels and serum uric acidlevels, but did not find increased risks of hyperuricemia (Qin et al. 2016).

Laboratory Animal Studies. Male rats treated by gavage with 10 mg/kg/day PFHxS for at least 42 days
showed a significant increase in BUN levels, but there were no significant gross or microscopic
alterations in the kidneys (Butenhoff et al. 2009a); the NOAEL was 3 mg/kg/day. No significant effecton BUN was reported in female rats. No histological alterations were observed in the kidneys of micefollowing intermediate-duration administration of ≤3 mg/kg/day PFHxS (Chang et al. 2018).
PFNA

Epidemiological Studies—Biomarkers of Renal Function. Two epidemiological studies have evaluatedthe possible associations between serum PFNA and alterations in renal function biomarkers. In a study ofPERFLUOROALKYLS

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children participating in the C8 Health Project, an inverse association between serum PFNA andestimated glomerular filtration rate was observed, but not in adolescents participating in NHANES(Watkins et al. 2013). Mundt et al. (2007) noted that there were small, but not clinically significant,alterations in BUN, creatinine, and serum uric acid levels in workers exposed to PFNA.

Epidemiological Studies—Alterations in Uric Acid Levels. Gleason et al. (2015) found an association
between serum PFNA and serum uric acid levels in NHANES participants; this association was not foundin studies of adolescents (Kataria et al. 2015; Qin et al. 2016). Studies by Gleason et al. (2015) and Qin etal. (2016) did not find increases in the risk of hyperuricemia associated with serum PFNA levels.
PFDA

Epidemiological Studies—Alterations in Uric Acid Levels. Epidemiological studies examining renal
outcomes are limited to a study of Taiwanese adolescents that found no association between serum PFDA
levels and serum uric acid levels and did not find increased risks of hyperuricemia (Qin et al. 2016).

Laboratory Animal Studies. Administration of a single dose of up to 80 mg/kg PFDA to female
C57BL/6N mice by gavage did not induce gross or microscopic changes in the kidneys (Harris et al.
1989). However, 2 out of 10 mice that died following administration of a dose of 320 mg/kg showed
mild acute necrosis of the proximal convoluted tubules. No histological alterations were observed in thekidneys of rats administered 0.5 mg/kg/day PFDA for 28 days or mice receiving weekly gavage doses of
5 mg/kg for 4 weeks (Frawley et al. 2018).

PFUnA

Laboratory Animal Studies. Treatment of male and female rats with 1.0 mg/kg/day PFUnA via gavagefor 41–46 days resulted in significant increases in BUN levels (35–61% in males, 19–45% in females)
and alkaline phosphatase activity (86–140% in males, 83% in females) and significant decreases in total
protein (11% in males, 10–13% in females) and albumin (7% in males) levels (Takahashi et al. 2014); the
NOAEL was 0.3 mg/kg/day.

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PFBS

Epidemiological Studies—Alterations in Uric Acid Levels. Serum PFBS levels were not associated withserum uric acid levels or increases in the risk of hyperuricemia in a study of adolescents in Taiwan (Qin etal. 2016).

Laboratory Animal Studies. Treatment of female rats with 900 mg/kg/day PFBS by gavage for 28 days
caused a significant increase (9–11%) in absolute and relative kidney weight, but caused no significant
alterations in the microscopic appearance of the kidneys (3M 2001). The weight of the kidneys returned
to control levels following a recovery period of approximately 14 days; the NOAEL for kidney weighteffects was 900 mg/kg/day PFBS. In a 90-day rat study, PFBS did not result in alterations in kidneyweights, but did result in hyperplasia of the medullary and papillary tubular and ductal epithelial cells in
the inner medullary region at 600 mg/kg/day, but not at 200 mg/kg/day (Lieder et al. 2009a). Minimal tomoderate papillary epithelial tubular/acinar hyperplasia was also observed in a 2-generation rat study at
300 mg/kg/day; the study identified a NOAEL of 100 mg/kg/day (Lieder et al. 2009b).
PFBA

Laboratory Animal Studies. No alterations in renal morphology or clinical indications of impaired renal
function were reported in rats treated with PFBA in doses of up to 184 mg/kg/day for 5 days (3M 2007a),
150 mg/kg/day for 28 days (Butenhoff et al. 2012a; van Otterdijk 2007a), or 30 mg/kg/day by gavage for
90 days (Butenhoff et al. 2012a; van Otterdijk 2007b).

PFDoDA

Epidemiological Studies—Alterations in Uric Acid Levels. In adolescents, no associations between
serum PFDoDA levels and serum uric acid levels or the risk of hyperuricemia were observed (Qin et al.
2016).

Laboratory Animal Studies. No histopathological alterations were observed in rats administered up to
2.5 mg/kg/day PFDoDA for 42–47 days (Kato et al. 2015).

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PFHxA

Epidemiological Studies—Alterations in Uric Acid Levels. In adolescents, no associations between
serum PFHxA levels and serum uric acid levels or the risk of hyperuricemia were observed (Qin et al.
2016).

Laboratory Animal Studies. Renal papillary necrosis was determined to be one of the causes of death inrats administered 450 mg/kg/day PFHxA for 4 days (Kirkpatrick 2005). No increases in renal lesions
were observed in surviving rats administered a TWA dose of 315 mg/kg/day for 32–44 days (Kirkpatrick2005). No histological alterations were observed in the kidneys of rats administered up to 200 mg/kg/day
NaPFHx for 90 days (Chengelis et al. 2009b). In a 2-year gavage study, treatment of female rats with
200 mg/kg/day PFHxA resulted in mild renal tubular degeneration and mild to severe papillary necrosis(Klaunig et al. 2015); the NOAEL was 100 mg/kg/day. In addition, urinalysis revealed an increased
mean urine volume and reduced specific gravity. There were no histological alternations in the kidneysof males.
2.11 DERMAL
Overview. No studies were located regarding dermal effects in humans. Studies in laboratory animals
have not found dermal effects following head-only inhalation exposure to PFOA (see Table 2-1) or oral
exposure to PFOA, PFOS, or PFBA (see Tables 2-3, 2-4, and 2-5). Dermal exposure to PFOA has
resulted in skin damage (see Table 2-6).
PFOA

In an inhalation head-only exposure study, no histopathological alterations were observed in theabdominal skin of male rats exposed to ≤84 mg/m3 APFO dusts for 2 weeks (Kennedy et al. 1986).
No microscopic alterations were observed in the skin following oral exposure of rats to ≤100–
110 mg/kg/day APFO via the diet for 90 days (Griffith and Long 1980) or monkeys exposed to up to
20 mg/kg/day PFOA or 0.75 mg/kg/day PFOS for 26 weeks (Butenhoff et al. 2002; Seacat et al. 2002).

Application of a single dose of 5,000 mg/kg of an aqueous paste of APFO to a clipped area of the skin ofrats, and left in place covered for 24 hours produced mild skin irritation (Kennedy 1985); no irritation was

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apparent with a dose of 3,000 mg/kg. In a 2-week dermal exposure study, skin irritation was observed inrats exposed to 200 mg/kg/day (Kennedy 1985). Acute necrotizing dermatitis was observed in two out offive rats exposed to 2,000 mg/kg/day; this lesion was observed after the 10th treatment. Application of
500 mg/kg APFO to the intact or abraded skin of young rabbits and left covered for 24 hours was nonirritating, as scored according to the Draize procedure immediately after removal of the cover and48 hours later (Griffith and Long 1980).
PFOS

Administration of up to approximately 1.04 mg/kg/day PFOS to rats in the diet for 2 years did not induce
morphological alterations in the skin (Butenhoff et al. 2012b; Thomford 2002b).
PFBA

There were no significant gross or microscopic alterations in the skin of rats receiving gavage doses of≤150 mg/kg/day PFBA for 28 days or ≤30 mg/kg/day PFBA for 90 days (Butenhoff et al. 2012a; vanOtterdijk 2007a, 2007b).
2.12 OCULAR
Overview. No information was located regarding ocular effects in humans. Ocular irritation has been
observed in laboratory animals following exposure to airborne APFO dust or instillation of PFOA into theeye (see Tables 2-1 and 2-6). However, ocular effects have not been found following oral exposure to
PFOA, PFOS, PFBS, PFBA, or PFHxA (see Tables 2-3, 2-4, and 2-5).
PFOA
Rats exposed to 18,600 mg/m3 APFO dusts for 1 hour exhibited a red material around the eyes andlacrimation during exposure (Griffith and Long 1980). Male rats exposed to ≥810 mg/m3 APFO dusts for
4 hours showed corneal opacity and corrosion, which was confirmed by fluorescein staining (Kennedy etal. 1986). Examination of the eyes of male rats exposed intermittently to up to 84 mg/m3 APFO for
2 weeks using a bright light and a slit-lamp biomicroscope on days 5 and 9 of exposure did not reveal any
significant exposure-related alterations (Kennedy et al. 1986). Microscopic examination of the eyes fromthese rats at termination and following a recovery period of up to 42 days was unremarkable.

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In oral exposure studies, examination of the eyes from rats exposed to approximately 100–110 mg/kg/day
APFO in the diet for 90 days did not reveal any significant gross or microscopic alterations (Griffith andLong 1980). Similar results were reported in rats that received dietary doses up to 15 mg/kg/day APFO
for 2 years (3M 1983; Butenhoff et al. 2012c) and in monkeys dosed with up to 20 mg/kg/day APFO for
26 weeks (Butenhoff et al. 2002).

No significant gross alterations were observed in the eyes of rats following repeated dermal exposure to
APFO (Kennedy 1985). Microscopic examination of the eyes also did not reveal treatment-relatedchanges. In a study in rabbits, 0.1 g APFO was instilled once in the conjunctival sac of the right eye andexaminations were conducted after 1, 24, 48, and 72 hours and 5 and 7 days after the application (Griffith
and Long 1980). APFO produced moderate irritation of the eye characterized by iridal and conjunctival
effects. The effects were most pronounced 1 hour after instillation. The irritation was persistent, but by
day 7, it had subsided. In a different experiment in which 0.1 g APFO was instilled for 5 or 30 seconds
before washing with 200 mL of water, there was limited conjunctival irritation, but the effects wereimmediate and persistent.
PFOS
No gross or microscopic alterations were observed in the eyes from rats exposed to ≤1.77 mg/kg/day
PFOS in the diet for 4 weeks or ≤1.56 mg/kg/day for 14 weeks (Seacat et al. 2003). Similar findings werereported in monkeys dosed daily with up to 2 mg/kg/day PFOS administered via a capsule for 4 weeks(Thomford 2002a) or up to 0.75 mg/kg/day PFOS administered via a capsule for 26 weeks (Seacat et al.
2002), and in rats dosed with up to 1.04 mg/kg/day in the diet for 2 years (Butenhoff et al. 2012b;
Thomford 2002b).
PFBS
No gross or microscopic alterations were observed in the eyes of rats administered ≤900 mg/kg/day PFBS
via gavage for 28 days (3M 2001).

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PFBA
Examination of the eyes of rats orally exposed to ≤150 mg/kg/day PFBA for 28 days or ≤30 mg/kg/day
for 90 days did not reveal any significant alterations in the eyes (Butenhoff et al. 2012a; van Otterdijk
2007a, 2007b).

PFHxA

No ophthalmological alterations were observed in rats administered up to 500 mg/kg/day NaPFHx for
90–93 days (Chengelis et al. 2009b; Loveless et al. 2009).
2.13 ENDOCRINE
Overview. Epidemiological studies have examined a number of endocrine targets including thyroid glandand hormones, reproductive hormones, and insulin levels. A discussion of the thyroid effects is includedin this section; the reproductive hormone effects are discussed in Section 2.16, Reproductive, and theinsulin effects (as well as other effects associated with glucose metabolism and utilization) are discussed
in Section 2.18, Other Noncancer. Summaries of results of epidemiological studies evaluating thyroid
outcomes are presented in Table 2-15; more in-depth summaries of the studies are presented in the
Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 9. Although someassociations between serum PFOA, PFOS, PFHxS, PFNA, PFDA, and PFUnA and thyroid stimulating
hormone (TSH), triiodothyronine (T3), or thyroxine (T4) levels or thyroid disease have been found, theresults are not consistent across studies and a larger number of studies have not found associations. A
small number of studies have evaluated PFDoDA and most studies have not found consistent associations
between serum perfluoroalkyl levels and thyroid hormone levels. No epidemiological studies examining
endocrine health outcomes were identified for PFHpA, PFBS, PFBA, PFHxA, or FOSA.

Laboratory animal studies have primarily evaluated potential morphological alterations in endocrine
tissues following oral exposure; these studies are summarized in Tables 2-3, 2-4, and 2-5. Somealterations in thyroid hormone levels have been observed in laboratory animals exposed to PFOA, PFOS,
PFHxS, or PFDA. Histopathological alterations have been observed in the thyroid of some laboratory
animal studies for PFHxS, PFBA, and PFHxA; the investigators noted that these effects were likely
secondary to the hepatocellular hypertrophy, although the mechanism has not been established for thesecompounds. In general, the pituitary, parathyroid, thyroid, and adrenal glands do not appear to be

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Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb
PFOA
Gilliland 1992
Occupational (n=115)
Olsen et al. 1998b

Serum perfluoroalkyl level Outcome evaluatedResultc

NR (serum fluorine levels
TSH
used as surrogate for serum
PFOA)
10,000–<30,000 ng/mL
TSH(PFOA range)

Association (p=0.004)*

428 ng/mL (mean PFOA)

The investigators noted that the levels
were within the reference range

NS (p=0.09 for trend), 1993 group
Association (p=0.002), 1995 group

Occupational (n=111 in 1993 and n=80 in 1995)
Sakr et al. 2007b
Occupational (n=1,025)
Steenland et al. 2015

TSH
T4
T3
Estimated cumulative PFOA Thyroid disease risk

Occupational (n=3,713)

Olsen and Zobel 2007

2,210 ng/mL (mean PFOA)

Occupational (n=552)

Anderson-Mahoney et al. 2008

Free T4
T4
T3

NS (p=0.98 for trend) no lag, males
NS (p=0.55 for trend) 10-year lag,males
NS (p=0.97 for trend) no lag, females
NS (p=0.27 for trend) 10-year lag,females
Association (p=0.01)*
NS (p=0.29)
Association (p=0.05)*

NR

TSH
Self-reported thyroid
problems

NS (p=0.08)
SPR 1.56 (1.22–1.98)*

354 ng/mL (median PFOA)

TSH

NS (p>0.05)

Community (n=566)
Emmett et al. 2006b
Community (n=371)

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Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Knox et al. 2011a52.6, 91.0, 98.6, andT4
124.3 ng/mL (mean PFOA in
women ≤50 years, men≤50 years, women>50 years, men >50 years, T3 uptake
respectively)

Association (p≤0.0001)*, women≤50 years
Association (p<0.001), men andwomen >50 years
Inverse association (p=0.0001)*
women ≤50 years
Inverse association (p=0.005)*,
women >50 years
Inverse association (p=0.037)*, men>50 years
OR 1.44 (1.02–2.03)*, perinterquartile shift
OR 1.54 (1.00–2.37)*, perinterquartile shift
OR 0.98 (0.86–1.15), per interquartileshift
OR 0.81 (0.58–1.15), per interquartile
shift

Community (n=50,113 adults ≥20 years of age)

Lopez-Espinosa et al. 2012
Community (n=10,725 children aged 1–
17 years)

29.3 and 67.7–2,071 ng/mL(median and 4th quartile
PFOA)

Thyroid disease
Hypothyroidism
Subclinicalhypothyroidism
Subclinicalhyperthyroidism

Winquist and Steenland 2014b
Community (C8 and occupational) (n=28,541)

114.7–<202.2 ng/mL-year(2nd quintile estimatedcumulative PFOA)

TSH
Total T4
Functional thyroid
diseaseβ -1.1 (-5.3–3.4), 4th quartile
β -0.1 (-1.7–1.4), 4th quartile
HR 1.24 (1.02–1.51;p=0.031)*(women), retrospective analysis
HR 1.01 (0.94–1.07 per log linear
increase in PFOA, p=0.853) (men),
retrospective analysis
NS (p=0.549) (women), prospective
analysis
NS (p=0.087) (men), prospective
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Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedHyperthyroidism

Hypothyroidism

Berg et al. 2017
General population (n=370 pregnant women)

Bloom et al. 2010
General population (n=31)
Chan et al. 2011
General population (n=94 women withhypothyroxinemia and 175 matched controls)

1.53 ng/mL (medianmaternal serum PFOA)

Total T4
Free T4
Total T3
Free T3
TSH
Thyroxine binding
capacity
1.33 ng/mL (geometric mean TSH
PFOA)Free T4
1.28 and 1.37 ng/mL(geometric mean PFOA incases and controls)

Hypothyroxinemia risk

Resultc
NS (p=0.074) (women), retrospective
analysis
NS (p=0.858) (men), retrospective
analysis
NS (p=0.268) (women), prospective
analysis
NS (p=0.760) (men), prospective
analysis
NS (p=0.076) (women), retrospective
analysis
NS (p=0.684) (men), retrospective
analysis
NS (p=0.247) (women), prospective
analysis
HR 1.24 (1.03–1.49)* (men),prospective analysis
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p=0.871)
NS (p=0.896)
OR 0.94 (0.74–1.18)

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Crawford et al. 20172.79 ng/mL (geometric mean Total T4serum PFOA)Free T4

NS (p=0.07)
NS (p=0.11)
Association (β 6.05, p=0.03)*
NS (p=0.37)
OR 4.42 (1.23–21.14)*, 4th quartile

General population (n=99 30–44-year-old
women)
Dufour et al. 2018
General population (n=214 pregnant women)
Jain 2013
General population (NHANES) (n=1,525)

Ji et al. 2012
General population (n=633)
Kang et al. 2018

T3
TSH
Hypothyroidism

0.80 ng/mL (cord blood
mean PFOA); 0.44–
TSH in infants
0.68 ng/mL (2nd quartile cord
blood PFOA)
NR
Total T3
TSH
Free T3

General population (NHANES) (n=1,682)

Association (p=0.013)*
NS (p>0.05)
NS (p>0.05)

Free T4
Total T4
Thyroglobulin
TSH
T4

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p=0.4055)
NS (p=0.2221)

1.88 ng/mL (median serum
PFOA)

Free T4
TSH

NS (p=0.075)
NS (p=0.565)

1.42–2.55 ng/mL (range of
median PFOA for different
age groups)

TSH

Association (p<0.05)*, 12–20-yearold females

Free T4

Association (p<0.05)*, 20–<40-yearold females

Total T4
Free T3

NS (p>0.05)
Association (p<0.05)*, 60–80-yearold females
Association (p<0.05)*, 60–80-yearold females

2.74 ng/mL (median PFOA)

General population (150 children, 3–18 years)
Lewis et al. 2015

NS (p=0.196)

Total T3

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Melzer et al. 2010

9.47 and 10.39 ng/mL(4th PFOA quartile mean inwomen and men)

OR 1.64 (1.09–2.46)*, females
OR 1.58 (0.74–3.39), males

General population (NHANES) (n=3,966)
Preston et al. 2018
General population (n=732 mothers and
480 infants)
Raymer et al. 2012
General population (n=256)
Shah-Kulkarni et al. 2016
General population (n=279 pregnant women)
Shrestha et al. 2015
General population (n=87 with thyroid disease)

Tsai et al. 2017
General population (n=118 mother-infant pairs)
Wang et al. 2013a
General population (n=903 pregnant women)
Wang et al. 2014
General population (n=285 pregnant women)

Thyroid disease risk

5.6 ng/mL (maternal median Total T4serum PFOA)Free T4
TSH
Neonatal T4
10.4 ng/mL (mean PFOA)
TSH
T3

β 0.09 (-0.08–0.27)
β -1.87 (-3.40 to -0.31)*
β 0.28 (-9.26–10.8)
β -1.1 (-2.1 to -0.1)*, 4th quartile
NS (p>0.05)
NS (p>0.05)

T4
0.91 ng/mL (cord blood
Cord blood T4
median PFOA)
Cord blood T3
Cord blood TSH
9.17 ng/mL (geometric mean TSH
PFOA)Free T4
T4

NS (p>0.05)
NS (p=0.99)
NS (p=0.99)
NS (p=0.24)
NS (p=0.176)
NS (p=0.536)
NS (p=0.097)

T3
3.14 ng/mL (mean cord
Cord blood T4
blood PFOA)
Cord blood T3
Cord blood TSH
2.13 ng/mL (geometric mean TSH
PFOA)
Elevated TSH risk

NS (p=0.208)
β -0.031 (-0.414–0.342)
β 0.025 (-0.054–0.103)
β 0.059 (-0.136–0.254)
NS (p>0.05)
NS (p>0.05)

2.39 ng/mL (median PFOA)

TSHFree T4
Total T4

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Total T3

NS (p>0.05)

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Webster et al. 2016

4.2 ng/mL (geometric mean
PFOA)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*
NS (p<0.05)

General population (NHANES) (n=1,525)

Wen et al. 20134.15 ng/mL (geometric mean TSH
PFOA)General population (NHANES) (n=1,181)

Yang et al. 2016a
General population (n=157 pregnant women)

PFOS
Olsen et al. 1998aOccupational (n=327)
Olsen et al. 2003aOccupational (n=518)

TSHFree T4
Total T4
Free T3
Total T3

NS (p=0.916), men
NS (p=0.732), women

Total T4

NS (p=1.0), men
NS (p=0.705), women

Total T3

NS (p=0.673), men
Association (p=0.035)*, women

Thyroglobulin

NS (p=0.226), men
NS (p=0.341), women

Subclinicalhypothyroidism risk
Subclinicalhyperthyroidism risk
TSH

OR1.29 (0.40–4.10), men
OR 7.42 (1.14–48.12, p<0.05), women
OR 0.38 (0.16–0.95, p<0.05)*, men
OR 0.99 (0.13–7.59), women
NS (p>0.05)

Free T4
Total T4
Free T3
Total T3

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

1,480–2,440 ng/mL (range of TSH
mean PFOS)
Cortisol

NS (p=0.95)

1,320 and 800 ng/mL (mean T3
PFOS at the Decatur andAntwerp facilities,
respectively)

Association (p=0.04)*

1.95 ng/mL (mean PFOA)NS (p=0.45)

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Knox et al. 2011a

17.3, 24.8, 25.7, and29.1 ng/mL (mean PFOA in
women ≤50 years, men≤50 years, women>50 years, men >50 years,
respectively)

T4

20.0 ng/mL (median PFOS)

Thyroid disease

Subclinicalhypothyroidism
Subclinicalhyperthyroidism
TSH
Total T4

Association (p<0.0001)*, women ≤50
or >50 years
Association (p=0.0001)*, men ≤50 or>50 years
Inverse association (p<0.0001)*
women ≤50 years
Inverse association (p=0.0001)*,
women >50 years
Inverse association (p=0.009)*, men≤50 years
Inverse association (p=0.0001)*,
men >50 years
OR 0.8 (0.62–1.08), per interquartileshift
OR 0.91 (0.63–1.31), per interquartileshift
OR 0.99 (0.86–1.13), per interquartileshift
OR 0.80 (0.62–1.02), per interquartileshift
β -1.0 (-0.3–2.3), per interquartile shift
β 1.1 (0.6–1.5), per interquartile shift

TSH

Association (p=0.03)*, 3rd quartile

Community (n=50,113 adults ≥20 years of age)

Lopez-Espinosa et al. 2012
Community (n=10,725 children aged 1–
17 years)

Berg et al. 2015
General population (n=391)

T3 uptake

Hypothyroidism

8.1–11.0 ng/mL (3rd PFOS
quartile)PERFLUOROALKYLS

272
2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Berg et al. 20178.03 ng/mL (medianmaternal serum PFOS)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*
NS (p<0.05) after adjustment for otherperfluoroalkyls or persistent organic
pollutants
NS (p>0.05)

General population (n=370 pregnant women)

Bloom et al. 2010
General population (n=31)
Chan et al. 2011
General population (n=94 women withhypothyroxinemia and 175 matched controls)
Crawford et al. 2017
General population (n= 99 30–44-year-old
women)
Dallaire et al. 2009
General population (n=623)

Dufour et al. 2018
General population (n=214 pregnant women)

19.57 ng/mL (geometricmean PFOS)
7.59 and 7.08 ng/mL(geometric mean PFOS incases and controls)

Total T4
Free T4
Total T3
Free T3
TSH

Thyroxine binding
capacity
TSH
Free T4
Hypothyroxinemia risk

9.29 ng/mL (geometric mean Total T4serum PFOS)
Free T4

18.28 ng/mL (geometricmean PFOS)

T3
TSH
TSH
T3
T4-binding globulin
Free T4
Hypothyroidism

0.88 ng/mL (cord blood
mean PFOS); 0.73–
1.01 ng/mL (3rd quartile cord TSH in infants
blood PFOS)

NS (p=0.896)
NS (p=0.623)
OR 0.88 (0.63–1.24)

NS (p=0.28)
NS (p=0.42)
NS (p=0.19)
NS (p=0.98)
Inverse association (p≤0.05)*
Inverse association (p≤0.05)*
Inverse association (p≤0.01)*
Association (p≤0.05)*
OR 3.22 (1.08–10.92)*, 3rd quartile
OR 2.95 (0.98–10.07), 4th quartile
NS (p=0.679)

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Jain 2013

NR

TSH
Free T3
Total T3
Free T4
Total T4

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

7.96 ng/mL (median PFOS)

Thyroglobulin
TSH
T4

NS (p>0.05)
NS (p=0.3537)
NS (p=0.1134)

5.68 ng/mL (median serum
PFOS)

Free T4
TSH

NS (p=0.987)
NS (p=0.628)

3.76–11.1 ng/mL (range of
median PFOS for different
age groups)

TSH

NS (p>0.05)

Free T4

Association (p<0.05)*, 20–<40-yearold females
NS (p>0.05)

General population (NHANES) (n=1,525)

Ji et al. 2012
General population (n=633)
Kang et al. 2018
General population (150 children, 3–18 years)
Lewis et al. 2015
General population (NHANES) (n=1,682)

Total T4

Melzer et al. 2010
General population (NHANES) (n=3,966)

Preston et al. 2018
General population (n=732 mothers and
480 infants)

57.73 and 50.96 ng/mL(4th PFOS quartile mean inwomen and men)

24.0 ng/mL (maternal
median serum PFOS)

Free T3
Total T3
Thyroid disease risk

Total T4

NS (p>0.05)
NS (p>0.05)
OR 1.15 (0.7–1.91, p=0.568), females
OR 1.58 (0.72–3.47, p=0.251), males
OR 2.68 (1.03–6.98, p=0.043)*, males
4th quartile versus combined 1st and2nd quartiles
β 0.01 (-0.14–0.16)

Free T4TSH

β -1.04 (-2.36–0.29)
β 0.90 (-7.27–9.80)
β-16.4 (-29.8 to -0.38)*, TPOAb
positive mothers

Neonatal T4

β -1.1 (-2.1 to -0.1)*, 4th quartile.

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Raymer et al. 201237.4 ng/mL (mean PFOS)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p=0.10)
NS (p=0.37)

General population (n=256)
Shah-Kulkarni et al. 2016
General population (n=279 pregnant women)
Shrestha et al. 2015
General population (n=87 with thyroid disease)

Tsai et al. 2017
General population (n=118 mother-infant pairs)
Wang et al. 2013a
General population (903 pregnant women)
Wang et al. 2014
General population (285 pregnant women)

Webster et al. 2016
General population (NHANES) (n=1,525)

0.66 ng/mL (cord blood
median PFOS)

TSH
T3
T4
Cord blood T4
Cord blood T3

Cord blood TSH
31.6 ng/mL (geometric mean TSH
PFOS)Free T4
T4
T3
7.24 ng/mL (mean cord
Cord blood T4
blood PFOS)
Cord blood T3
12.77 ng/mL (geometricmean PFOS)

Cord blood TSH
TSH
Elevated TSH risk

NS (p=0.73)
NS (p=0.094)
Association (p=0.044)*
Association (p=0.001)*
NS (p=0.287)
β -0.458 (-0.916 to -0.001, p<0.05)*
β 0.027 (-0.072–0.125)
β 0.346 (0.101–0.591, p<0.05)*
Association (p=0.03)*
NS (p>0.05)

12.73 ng/mL (median PFOS) TSH
Free T4
Total T4
Total T3
13.9 ng/mL (geometric mean TSH
PFOS)Free T4

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Total T4
Free T3
Total T3

NS (p>0.05)
NS (p>0.05)
NS (p<0.05)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Wen et al. 201314.2 ng/mL (geometric mean TSH
PFOS)
Total T4

NS (p=0.931), men
NS (p=0.358), women
NS (p=0.840), men
NS (p=0.433), women
NS (p=0.404), men
NS (p=0.384), women
NS (p=0.342), men
NS (p=0.061), women
OR 1.98 (1.19–3.28, p<0.05)*, men
OR 3.03 (1.14–8.07, p<0.05)*, women
OR 0.92 (0.19–4.46), men
OR 1.90 (0.33–6.80), women
Inverse association (p<0.01)*
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

General population (NHANES) (n=1,181)

Total T3
Thyroglobulin

Yang et al. 2016a5.08 ng/mL (mean PFOS)

General population (n=157 pregnant women)

Subclinicalhypothyroidism risk
Subclinicalhyperthyroidism risk
TSH
Free T4
Total T4
Free T3
Total T3

PFHxSBerg et al. 2017
General population (n=370 pregnant women)

0.44 ng/mL (medianmaternal serum PFHxS)

Total T4
Free T4
Total T3
Free T3
TSH
Thyroxine binding
capacity

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Bloom et al. 2010

0.75 ng/mL (geometric mean TSH
PFHxS)
Free T4

NS (p=0.956)
NS (p=0.567)

1.28 and 1.37 ng/mL(geometric mean PFHxS incases and controls)

OR 1.12 (0.89–1.41)

General population (n=31)
Chan et al. 2011
General population (n=94 women withhypothyroxinemia and 175 matched controls)
Crawford et al. 2017
General population (n= 99 30–-44-year-old
women)
Dufour et al. 20181.59 ng/mL (geometric mean Total T4serum PFHxS)Free T4

0.18 ng/mL (cord blood
mean PFHxS)

General population (n=214 pregnant women)
Jain 2013
General population (NHANES) (n=1,525)

Ji et al. 2012
General population (n=633)
Kang et al. 2018
General population (150 children, 3–18 years)

Hypothyroxinemia risk

NR

T3
TSH
Hypothyroidism
TSH in infants
TSH
Free T3
Total T3
Free T4

NS (p=0.50)
NS (p=0.84)
NS (p=0.22)
NS (p=0.71)
OR 1.92 (95% CI 0.87–4.25),detectedversus non-detected
NS (p=0.894)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Total T4
Thyroglobulin
1.51 ng/mL (median PFHxS) TSH
T4

NS (p>0.05)
NS (p>0.05)
NS (p=0.8144)
NS (p=0.5147)

0.793 ng/mL (median serum Free T4
PFHxS)TSH

NS (p=0.308)
NS (p=0.901)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Lewis et al. 2015

0.69–1.81 ng/mL (range of
median PFHxS for different
age groups)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

General population (NHANES) (n=1,682)

Preston et al. 2018
General population (n=732 mothers and
480 infants)
Shah-Kulkarni et al. 2016
General population (n=279 pregnant women)
Wang et al. 2013a
General population (n=903 pregnant women)
Wang et al. 2014

2.4 ng/mL (maternal median Total T4serum PFHxS)Free T4
TSH
Neonatal T4
0.38 ng/mL (cord blood
Cord blood T4
median PFHxS)
Cord blood T3

β -0.05 (-0.14–0.04)
β -0.60 (-1.39–0.19)
β 2.89 (-2.12–8.17)
β -1.1 (-2.1 to -0.1)*, 4th quartile
NS (p=0.83)
NS (p=0.15)

Cord blood TSH
0.62 ng/mL (geometric mean TSH
PFHxS)
Elevated TSH risk

NS (p=0.15)
NS (p>0.05)
NS (p>0.05)

0.81 ng/mL (median PFHxS) TSH

Association (p<0.05)

General population (n=285 pregnant women)

Webster et al. 2016
General population (NHANES) (n=1,525)

TSH
Free T4
Total T4
Free T3
Total T3

1.9 ng/mL (geometric mean
PFHxS)

Free T4
Total T4
Total T3
TSH
Free T4
Total T4

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Free T3
Total T3

NS (p>0.05)
NS (p>0.05)

PERFLUOROALKYLS

278
2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Wen et al. 2013

2.0 ng/mL (geometric mean
PFHxS)NS (p=0.608), men
NS (p=0.720), women
NS (p=0.641), men
Association (p=0.022)*, women
NS (p=0.917), men
Association (p<0.001)*, women
NS (p=0.455), men
NS (p=0.725), women
OR 1.57 (0.76–3.25), men
OR 3.10 (1.22–7.86, p<0.05)*, women
OR 0.56 (0.24–1.20.92), men
OR 12.27 (1.07–4.80.90)*,women
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

General population (NHANES) (n=1,181)

TSH
Total T4
Total T3
Thyroglobulin

Yang et al. 2016a

0.63 ng/mL (mean PFHxS)

General population (n=157 pregnant women)

Subclinicalhypothyroidism risk
Subclinicalhyperthyroidism risk
TSH
Free T4
Total T4
Free T3
Total T3

PFNA
Mundt et al. 2007

NR

Occupational (n=592)
Lopez-Espinosa et al. 2012
Community (n=10,725 children aged 1–
17 years)

1.5 ng/mL (median PFNA)

TSH
T4
T3
Thyroid disease
Hypothyroidism
Subclinicalhypothyroidism
Subclinicalhyperthyroidism

Investigators noted differences
between groups was small and notclinically relevant
OR 1.05 (0.78–1.41), per interquartileshift
OR 1.11 (0.77–1.60), per interquartileshift
OR 0.99 (0.88–1.12), per interquartileshift
OR 0.78 (0.61–1.01), per interquartileshift

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluated
TSH

Berg et al. 2017
General population (n=370 pregnant women)

Bloom et al. 2010
General population (n=31)
Crawford et al. 2017
General population (n= 99 30–44-year-old
women)
Dufour et al. 2018
General population (n=214 pregnant women)
Jain 2013
General population (NHANES) (n=1,525)

0.56 ng/mL (medianmaternal serum PFNA)

Total T4
Total T4
Free T4
Total T3
Free T3

Resultc
β -1.1 (CI 0.7–1.5), per interquartileshift
Β 0.8 (-0.4–2.0), per interquartile shift
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

TSH
Thyroxine binding
capacity
0.79 ng/mL (geometric mean TSH
PFNA)Free T4

NS (p>0.05)
NS (p>0.05)

0.84 ng/mL (geometric mean Total T4serum PFNA)
Free T4

NS (p=0.34)
Association (β 0.08, p<0.01)*
Association (β 5.65, p=0.02)*
NS (p=0.91)
OR 1.17 (0.37–3.92), 4th quartile
NS (p=0.064)

T3
TSH
Hypothyroidism
TSH in infants

0.18 ng/mL (cord blood
mean PFNA), 0.23–
0.68 ng/mL (4th quartile cord
blood PFNA)
NR
TSH
Free T3
Total T3
Free T4
Total T4

Thyroglobulin

NS (p=0.789)
NS (p=0.424)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Ji et al. 2012

2.09 ng/mL (median PFNA)NS (p=0.1354)
NS (p=0.7436)

General population (n=633)
Kang et al. 2018
General population (150 children, 3–18 years)
Preston et al. 2018
General population (n=732 mothers and
480 infants)
Shah-Kulkarni et al. 2016
General population (n=279 pregnant women)
Tsai et al. 2017
General population (n=118 mother-infant pairs)
Wang et al. 2013a
General population (n=903 pregnant women)
Wang et al. 2014

0.938 ng/mL (median serum Free T4
PFNA)
TSH

β 0.052 (0.007–0.097, p=0.025)*
NS (p=0.840)

0.6 ng/mL (maternal median Total T4serum PFNA)
Free T4
TSH
Neonatal T4
0.2 ng/mL (cord blood
Cord blood T4
median PFNA)
Cord blood T3
Cord blood TSH

β -0.05 (-0.16–0.05)

7.55 ng/mL (mean cord
blood PFNA)

Cord blood T4
Cord blood T3
Cord blood TSH
0.37 ng/mL (geometric mean TSH
PFNA)
Elevated TSH risk

β -0.067 (-0.252–0.009)
β -0.03 (0.069–0.103)
β 0.045 (-0.051–0.142)
NS (p>0.05)
NS (p>0.05)

1.51 ng/mL (median PFNA)

TSH
Free T4
Total T4
Total T3
TSH

NS (p>0.05)
Inverse association (p<0.001)*
Inverse association (p<0.001)*
NS (p>0.05)
NS (p>0.05)

Free T4
Total T4
Free T3
Total T3

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

General population (n=285 pregnant women)

Webster et al. 2016
General population (NHANES) (n=1,525)

TSH
T4

1.5 ng/mL (geometric meanPFNS)

β -0.57 (-1.52–0.40)
β -0.27 (-6.19–6.03)
β 0.05 (-0.29–0.39)
NS (p=0.70)
NS (p=0.93)
NS (p=0.14)

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Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Wen et al. 2013

1.54 ng/mL (geometric mean TSH
PFNA)
Total T4

Subclinicalhypothyroidism risk
Subclinicalhyperthyroidism risk
TSH
Free T4
Total T4
Free T3
Total T3

NS (p=0.973), men
NS (p=0.407), women
NS (p=0.097), men
NS (p=0.632), women
NS (p=0.063), men
NS (p=0.258), women
NS (p=0.537), men
NS (p=0.395), women
OR 1.30 (0.65–2.60), men
OR 2.54 (0.40–16.05), women
OR 2.41 (0.48–12.04), men
OR 1.91 (0.83–4.38), women
Inverse association (p<0.05)*
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

T3

Association (p=0.03) (4th quartile)

General population (NHANES) (n=1,181)

Total T3
Thyroglobulin

Yang et al. 2016a0.52 ng/mL (mean)

General population (n=157 pregnant women)

PFDA
Berg et al. 2015
General population (n=391 pregnant women)
Berg et al. 2017
General population (n=370 pregnant women)

0.31–2.34 ng/mL (4th PFDA
quartile)

0.23 ng/mL (median
Total T4
maternal serum PFNA) and Free T4
0.32–2.34 ng/mL (4th quartile
Total T3
serum PFNA)
Free T3
TSH
Thyroxine binding
capacity

NS (p>0.05)
NS (p>0.05)
β -0.02 (-0.044 to -0.005, p<0.05)*
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

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Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Bloom et al. 2010

0.21 ng/mL (geometric mean TSH
PFDA)Free T4

NS (p=0.365)
NS (p=0.107)

NR

TSH
Free T3
Total T3
Free T4
Total T4
Thyroglobulin

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

0.91 ng/mL (median PFDA)

TSH
T4

NS (p=0.2721)
NS (p=0.2176)

0.0592 ng/mL (medianserum PFDA)

Free T4

NS (p=0.153)

TSH

NS (p=0.420)

0.1 ng/mL (cord blood
median PFDA)

Cord blood T4
Cord blood T3
Cord blood TSH

NS (p=0.40)
NS (p=0.07)
NS (p=0.22)

General population (n=31)
Jain 2013
General population (NHANES) (n=1,525)

Ji et al. 2012
General population (n=633)
Kang et al. 2018
General population (150 children, 3–18 years)
Shah-Kulkarni et al. 2016
General population (n=279 pregnant women)
Wang et al. 2013a
General population (903 pregnant women)
Wang et al. 2014

0.09 ng/mL (geometric mean TSH
PFDA)
Elevated TSH risk

NS (p>0.05)
NS (p>0.05)

0.46 ng/mL (median PFDA)

TSH

NS (p>0.05)

Free T4
Total T4
Total T3
TSH
Free T4
Total T4

NS (p>0.05)
NS (p>0.05)
Association (p<0.01)*
Inverse association (p<0.01)*
NS (p>0.05)
NS (p>0.05)

Free T3
Total T3

NS (p>0.05)
NS (p>0.05)

General population (285 pregnant women)

Yang et al. 2016a
General population (n=157 pregnant women)

0.45 ng/mL (mean PFDA)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb
PFUnA
Berg et al. 2015
General population (n=391)
Berg et al. 2017
General population (n=370 pregnant women)

Serum perfluoroalkyl level Outcome evaluatedResultc

0.4–0.96 ng/mL (4th PFUnA
quartile)

Association (p=0.00)*, 4th quartile

Free T3

0.26 ng/mL (median
Total T4
maternal serum PFUnA) and Free T4
0.39–1.46 (4th quartile serum
Total T3
PFUnA)
Free T3
TSH
Thyroxine binding
capacity

Bloom et al. 2010
General population (n=31)
Ji et al. 2012
General population (n=633)
Kang et al. 2018
General population (150 children, 3–18 years)
Shah-Kulkarni et al. 2016

General population (n=118 mother-infant pairs)
Wang et al. 2013a
General population (n=903 pregnant women)

NS (p>0.05)

0.20 ng/mL (geometric mean TSH
PFUnA)
Free T4

NS (p=0.527)
NS (p=0.204)

1.75 ng/mL (median PFUnA) TSH
T4

NS (p=0.5368)
NS (p=0.0642)

0.0652 ng/mL (medianserum PFUnA)

Free T4
TSH

NS (p=0.581)
NS (p=0.510)

0.26 ng/mL (cord blood
median PFUnA)

Cord blood T4
Cord blood T3
Cord blood TSH
Cord blood T4

NS (p=0.86)
NS (p=0.35)
NS (p=0.37)
β 0.045 (-0.223–0.313)

General population (n=279 pregnant women)
Tsai et al. 2017

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
β -0.02 (-0.033 to -0.003, p<0.05)
NS (p>0.05)

15.94 ng/mL (mean cord
blood PFNA)

Cord blood T3
Cord blood TSH
0.20 ng/mL (geometric mean TSH
PFUnA)
Elevated TSH risk

β 0.048 (-0.008–0.104)
β 0.077 (0.063–0.216)
NS (p>0.05)
NS (p>0.05)

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Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Wang et al. 20143.26 ng/mL (median PFUnA) TSH
Free T4
Total T4
Total T3
0.45 ng/mL (mean PFUnA) TSH

NS (p>0.05)
Inverse association (p<0.001)*
Inverse association (p<0.001)*
NS (p>0.05)
Inverse association (p<0.05)*

General population (n=285 pregnant women)

Yang et al. 2016aFree T4
Total T4
Free T3
Total T3

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

0.92 ng/mL (median
PFDoDA)TSH

NS (p=0.6925)

T4

NS (p=0.7153)

0.08 ng/mL (cord blood
median PFDoDA)

Cord blood T4
Cord blood T3
Cord blood TSH

NS (p=0.69)
NS (p=0.30)
NS (p=0.20)

0.36 ng/mL (median
PFDoDA)

TSH
Free T4
Total T4
Total T3
TSH
Free T4

NS (p>0.05)
Inverse association (p<0.001)*
Inverse association (p<0.01)*
NS (p>0.05)
Inverse association (p<0.01)*
Inverse association (p<0.05)*

Total T4
Free T3
Total T3

Inverse association (p<0.05)*
Inverse association (p<0.01)*
Inverse association (p<0.01)*

General population (n=157 pregnant women)

PFDoDAJi et al. 2012
General population (n=633)
Shah-Kulkarni et al. 2016
General population (n=279 pregnant women)
Wang et al. 2014
General population (285 pregnant women)

Yang et al. 2016a
General population (n=157 pregnant women)

0.046 ng/mL (meanPFDoDA)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-15. Summary of Thyroid Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Me-FOSA-AcOH
Jain 2013

NR

TSH
Free T3
Total T3
Free T4

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Total T4
Thyroglobulin

NS (p>0.05)
NS (p>0.05)

General population (NHANES) (n=1,525)

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 9 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

HR = hazard ratio; NHANES = National Health and Nutrition Examination Survey; NR = not reported; NS = not significant; OR = odds ratio;
PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid
stimulating hormone

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2. HEALTH EFFECTS

sensitive targets following exposure to PFOA, PFOS, PFDA, PFBS, or PFBA. Endocrine effects havenot been examined in laboratory animal studies on PFNA, PFUnA, PFHpA, or FOSA.
PFOA

Epidemiological Studies. A number of epidemiological studies have examined the potential of PFOA todamage the thyroid. Steenland et al. (2015) did not find an association between serum PFOA and the riskof thyroid disease in male or female workers at the Washington Works facility. The occupational
exposure studies do not suggest an association between serum PFOA and alterations in thyroid hormone
levels. One study (Olsen and Zobel 2007) reported associations between serum PFOA levels and free T4
and T3 levels in workers at 3M facilities; it is noted that the investigators did not consider the results
clinically relevant since the levels were within the normal range. A study reported an association between
serum PFOA and TSH, but this was only observed at one time point (Olsen et al. 1998b); another study ofthe 3M Cottage Grove facility, reported an association between serum fluorine levels and TSH levels(Gilliland 1992). A fifth occupational study reported that TSH, T4, and T3 levels were within thereference range (Sakr et al. 2007b).

Three studies of the community affected by the Washington Works facility reported increases in selfreported thyroid disease (Anderson-Mahoney et al. 2008), any type of functional thyroid disease (LopezEspinosa et al. 2012; Winquist and Steenland 2014b), or hypothyroidism (Lopez-Espinosa et al. 2012).
No associations between estimated cumulative serum PFOA and hyperthyroidism or hypothyroidism
were found in retrospective analysis (Winquist and Steenland 2014b). However, in prospective analysis,
an association between estimated cumulative serum PFOA and hypothyroidism was found in men(Winquist and Steenland 2014b). Consistent with the occupational exposure data, no association between
serum PFOA and TSH levels was found (Emmett et al. 2006b; Knox et al. 2011a; Lopez-Espinosa et al.
2012). Increases in serum PFOA were also associated with increases in T4 levels and decreases in T3
uptake in adults (Knox et al. 2011a).

A number of studies have examined the thyroid outcomes associated with serum PFOA levels in thegeneral population. An association between serum PFOA and thyroid disease risk was found in female
NHANES participants, but not in males (Melzer et al. 2010). Another study utilizing NHANES data
(Wen et al. 2013) found an increased risk of subclinical hypothyroidism among women, but not men, anda decreased risk of subclinical hyperthyroidism among men, but not women. An increased risk ofhypothyroidism was also observed in a study of pregnant women (DuFour et al. 2018). A case-control

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study of women did not find that serum PFOA levels were associated with the risk of hypothyroxinemia(Chan et al. 2011). Although five studies found associations between serum PFOA and T3 levels(Crawford et al. 2017; Jain 2013; Lewis et al. 2015; Webster et al. 2016; Wen et al. 2013), five otherstudies did not find these associations (Berg et al. 2017; Raymer et al. 2012; Shrestha et al. 2015; Wang etal. 2014; Yang et al. 2016a). No associations between serum PFOA and TSH or T4 levels were found in
the general population studies (Berg et al. 2017; Bloom et al. 2010; Crawford et al. 2017; Jain 2013; Ji etal. 2012; Kang et al. 2018; Raymer et al. 2012; Shrestha et al. 2015; Wang et al. 2013a, 2014; Webster et
al. 2016; Wen et al. 2013; Yang et al. 2016a), with the exception of two studies which found an
association for TSH and T4 levels (Lewis et al. 2015) or free T4 (Preston et al. 2018).

Studies examining possible relationships between cord blood PFOA and cord blood thyroid hormone
levels have not found associations for T4, T3, or TSH (Dufour et al. 2018; Shah-Kulkarni et al. 2016;
Tsai et al. 2017). Preston et al. (2018) found an inverse association between maternal serum PFOA andneonatal T4 levels.

In a clinical trial of patients with advanced solid tumors administered 50–1,200 mg APFO (approximately
0.10–2.4 mg/kg/day) for 6 weeks, increases in free T4 levels were observed with no apparent alterations
in TSH (Convertino et al. 2018).
Laboratory Animal Studies. Repeated intermittent head-only exposure of male rats to up to 84 mg/m3
APFO dusts for 2 weeks did not result in significant gross or microscopic alterations in the thyroid or
adrenal gland (Kennedy et al. 1986).

In a 2-generation study in rats, daily treatment of the parental generation with 0, 1, 3, 10, or 30 mg/kg/day
APFO by gavage in water for 70–90 days produced an increased incidence of hypertrophy and/or
vacuolation of the zona glomerulosa of the adrenal gland from high-dose males (Butenhoff et al. 2004b).
The respective incidences were 0/10, 0/10, 0/10, 2/10, and 7/10. This effect was also observed in
F1 generation males treated with the same dose level. No explanation was apparent for this finding. In
rats dosed with up to 15 mg/kg/day APFO in the diet for 2 years, there were no significant morphologicalalterations in the adrenals (3M 1983; Butenhoff et al. 2012c). A study in monkeys treated with APFO
also reported effects on the adrenal glands. Griffith and Long (1980) reported diffuse lipid depletion in
the adrenals from Rhesus monkeys dosed daily for 90 days with 30 mg/kg/day APFO by gavage. Thisdose level was lethal to some monkeys; no such effect was seen in monkeys dosed with 10 mg/kg/day.

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For the most part, morphological evaluations of other endocrine glands in animals treated with PFOA
have been negative. For example, male and female rats dosed via the diet with approximately 100–110 mg/kg/day APFO for 90 days showed no gross or microscopic alterations in the pituitary or thyroid
glands (Griffith and Long 1980). Similar observations were reported in the pituitary, thyroid, andparathyroid glands from male and female rats dosed with up to 15 mg/kg/day APFO in the diet for 2 years(Butenhoff et al. 2012c; 3M 1983).

Administration of up to 20 mg/kg/day PFOA administered via a capsule to Cynomolgus monkeys for
4 weeks did not significantly alter free T4, total T4, free T3, total T3, or TSH (Thomford 2001). SerumT4 and total T4 were significantly reduced in Cynomolgus monkeys dosed with 10 mg/kg/day APFO
administered via a capsule for up to 6 months, but were still within the normal range (Butenhoff et al.
2002). No significant changes were seen on serum free T3, total T3, or TSH, or thyroid histology.

The only relevant dermal information is that no morphological alterations were observed in the thyroid ofrats following dermal application of up to 2,000 mg/kg/day APFO for 2 weeks in the Kennedy (1985)
study.
PFOS

Epidemiological Studies. A number of epidemiological studies have examined the risk of thyroid disease
and alterations in thyroid hormone levels to evaluate whether the thyroid gland is a target of PFOS
toxicity. In studies of NHANES participants, no increases in the risk of thyroid disease were observed inmen or women (Lewis et al. 2015; Melzer et al. 2010). Melzer et al. (2010) did find an increase in therisk of having thyroid disease and currently taking thyroid medication among men, and Wen et al. (2013)
found increased risks of subclinical hypothyroidism among men and women. Dufour et al. (2018) also
found an association between cord blood PFOS and risk of maternal hypothyroidism. Although somestudies have found alterations in thyroid hormone levels, the results are not consistent across studies.
Associations between serum PFOS and TSH levels were observed in three general population studies(Berg et al. 2015, 2017; Wang et al. 2014); however, one of the studies (Berg et al. 2017) found that theassociation was no longer significant after adjustments for exposure to other perfluoroalkyls andpersistent organic compounds. In contrast, two other studies found inverse associations for TSH (Dallaire
et al. 2009; Yang et al. 2016a). A third study also found an inverse association with TSH but only among
pregnant women who were positive for thyroid peroxides antibodies (Preston et al. 2018). An
occupational exposure study (Olsen et al. 1998a) and ten general population studies (Bloom et al. 2010;

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Crawford et al. 2017; Jain 2013; Ji et al. 2012; Kang et al. 2018; Lewis et al. 2015; Raymer et al. 2012;
Shrestha et al. 2015; Wang et al. 2014; Wen et al. 2013) did not find associations between serum PFOS
and TSH levels. Conflicting results were also reported for T3 levels, with some studies reporting
associations (Olsen et al. 2003a), inverse associations (Dallaire et al. 2009), or no association (Berg et al.
2017; Crawford et al. 2017; Jain 2013; Lewis et al. 2015; Raymer et al. 2012; Shrestha et al. 2015; Wanget al. 2014; Webster et al. 2016; Wen et al. 2013; Yang et al. 2016a). Most studies did not find an
association with T4 levels (Berg et al. 2017; Crawford et al. 2017; Jain 2013; Ji et al. 2012; Kang et al.
2018; Lewis et al. 2015; Raymer et al. 2012; Preston et al. 2018; Wang et al. 2014; Webster et al. 2016;
Wen et al. 2013; Yang et al. 2016a), but three studies did find associations between T4 levels and serum
PFOS (Dallaire et al. 2009; Lewis et al. 2015; Shrestha et al. 2015). In NHANES participants with two
indicators of thyroid stress (low iodine levels and high thyroid peroxidase antibody), serum PFOS levels
were significantly (p<0.05) associated with increases in free and total T3, decreases in free T4, andincreases in TSH levels (Webster et al. 2016).

Conflicting results were also found in studies using cord blood PFOS as the biomarker of exposure. Tsaiet al. (2017) found an inverse association with cord blood T4 and a positive association with cord blood
TSH; no association was found for T3. Shah-Kulkarni et al. (2016) found no associations for cord blood
T4, T3, or TSH. It is noted that cord blood serum PFOS levels were much higher in the Tsai et al. (2017)
study compared to the Shah-Kulkarni et al. (2016) study.

Laboratory Animal Studies. Chang et al. (2008b) conducted a study of thyroid function in rats exposed
to PFOS (potassium salt). Administration of a single dose of 15 mg/kg by gavage in water (only doselevel tested) reduced serum total T4 significantly at 2, 6, and 24 hours after dosing. This effect was
attributed to a PFOS-induced transient increase in tissue availability of thyroid hormones and turnover of
T4 with a resulting reduction in serum total T4. Chang et al. (2008b) concluded that PFOS did not inducea classical hypothyroid state or alter the hypothalamic-pituitary-thyroid axis. In another acute-duration
study, dosing of pregnant mice with 6 mg/kg/day PFOS (potassium salt) on GDs 6–18 did not affectmaternal serum levels of free or total T3 or T4 (Fuentes et al. 2006).

Changes in thyroid hormones have also been reported following intermediate-duration exposure to PFOS.
For example, in a 2-generation gavage study in which dosing of rats started before mating and continued
through gestation, doses ≥0.4 mg/kg/day (the lowest dose tested) caused a significant and dose-related
reduction in total T4 in maternal serum on postpartum day 5 (Luebker et al. 2005b). Free T4 and TSH
were not significantly affected. Exposure of pregnant rats to ≥1 mg/kg/day PFOS on GDs 2–20 induced

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significant reductions in total T4 and free T4 and less marked reductions in T3 during pregnancy,
particularly on GD 7 (Thibodeaux et al. 2003); however, serum TSH values were not significantly altered.
A similar study in pregnant mice reported a decrease in total T4 on GD 6 in mice dosed with
20 mg/kg/day PFOS on GDs 1–17 (Thibodeaux et al. 2003). No alterations in total T4 were reported inmice dosed with 15 mg/kg/day. No information was provided regarding other thyroid hormones.
Decreases in T4 levels were observed in male and female rats exposed to PFOS in the diet for 28 days
(Curran et al. 2008); T3 levels were decreased in female rats exposed to 50 or 100 mg/kg/day and in malerats at 100 mg/kg/day. No histological alterations were observed in the thyroid. Another study withPFOS found no thyroid histological effects in rats exposed to 10.3 mg/kg/day for 1 day, 8.17 mg/kg/day
for 7 days, or 7.34 mg/kg/day for 28 days (Elcombe et al. 2012a). Exposure of rats to ≥0.27 mg/kg/day
PFOS in drinking water for 91 days resulted in decreases in total T4 levels (Yu et al. 2009a), but nochanges in T3 or TSH levels (highest dose tested was 2.37 mg/kg/day). Curran et al. (2008) suggested
that the apparent decreases in T4 levels, in the absence of TSH alterations and histological alterations in
the thyroid, may be a result of measurement error when analog assays (chemiluminometric immunoassay
and radioimmunoassay) are used due to binding interference. A decrease in serum total T4 levels wasobserved in Cynomolgus monkeys administered three doses of PFOS (average dose of 13.3 mg/kg in
males and 14 mg/kg in females) over 315 days (Chang et al. 2017). The investigators did not consider
this an adverse effect because the values were within the normal variation and there were not changes infree T4 levels or TSH levels. In another study in Cynomolgus monkeys, T3 was numerically lower thancontrols in one female and one male monkey dosed with 2 mg/kg/day PFOS by capsule for 4 weeks(Thomford 2002a). However, it is difficult to determine whether the effect was treatment-related basedon only two animals. In a 26-week study in Cynomolgus monkeys, the highest dose of PFOS tested,
0.75 mg/kg/day, induced a significant increase in serum TSH (approximately twice control value, but still
within the reference range) and a decrease in total T3 at termination, but not at earlier time points;
variations in other thyroid hormones, including T4, were inconsistent regarding dose and over time
(Seacat et al. 2002). The clinical relevance of the lowered total T3 values was not apparent since there
was no indication of a clinical hypothyroid response, and thyroid histology was not altered by treatment
with PFOS.

Examination of the adrenal glands from rats dosed with up to 1.77 mg/kg/day PFOS via the diet for 4 or
14 weeks did not show any significant gross or microscopic alterations (Seacat et al. 2003). No
significant gross or microscopic lesions were reported in the adrenals, thyroid and parathyroid, or
pituitary gland from rats dosed with up to 1.04 mg/kg/day PFOS in the diet for 2 years (Butenhoff et al.
2012b; Thomford 2002b).

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PFHxS

Epidemiological Studies. Fifteen general population studies have evaluated possible associations
between serum PFHxS levels and alterations in thyroid hormone levels. With the exception of a study ofpregnant women, which found an association between serum PFHxS levels and TSH levels (Wang et al.
2014), and a study of NHANES participants, which found associations between serum PFHxS and total
T4 and T3 in women (Wen et al. 2013), the epidemiological studies did not find associations for TSH, T3,
or T4 (Berg et al. 2017; Bloom et al. 2010; Crawford et al. 2017; Jain 2013; Ji et al. 2012; Kang et al.
2018; Lewis et al. 2015; Preston et al. 2018; Wang et al. 2013a, 2014; Webster et al. 2016; Yang et al.
2016a). No associations were also found between cord blood PFHxS levels and cord blood T4, T3, or
TSH (Shah-Kulkarni et al. 2016). Chan et al. (2011) did not find an increase in the risk ofhypothyroxinemia associated with serum PFHxS levels. Wen et al. (2013) found increases in the risk of
subclinical hypothyroidism and subclinical hyperthyroidism among women, but not men and Dufour et al.
(2018) did not find an association between cord blood PFHxS levels and risk of hypothyroidism inpregnant women.

Laboratory Animal Studies. Hypertrophy and hyperplasia of the follicular cells were observed in the
thyroids of male rats treated with ≥3 mg/kg/day PFHxS for at least 42 days (Butenhoff et al. 2009a). The
NOAEL was 1 mg/kg/day. The investigators noted that the observed changes in rats are consistent withthe known effects of inducers of microsomal enzymes where the hepatocellular hypertrophy results in acompensatory hypertrophy and hyperplasia of the thyroid due to an increase in plasma turnover of T4 andassociated stimulation of TSH. Neither thyroid hormones nor TSH were measured in the study. In
studies of pregnant rats, 20–30 and 60% decreases in serum thyroxine were observed in the dams
administered 5 mg/kg/day or 25 mg/kg/day PFHxS on GD 7–22 (Ramhøj et al. 2018). In miceadministered up to 3 mg/kg/day PFHxS prior to mating and during mating, gestation, and lactation, no
alterations in TSH were observed in the parental males or females (Chang et al. 2018); this study also
found no histological alterations in the thyroid gland.
PFNA

Epidemiological Studies. Inverse associations between serum PFNA levels and T4 levels (Wang et al.
2014) and TSH levels (Yang et al. 2016a) have been reported in general population studies. However,
several other studies have not found alterations in TSH, T4, or T3 levels associated with serum PFNAPERFLUOROALKYLS

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levels (Berg et al. 2017; Bloom et al. 2010; Jain 2013; Ji et al. 2012; Lopez-Espinosa et al. 2012; Preston
et al. 2018; Wang et al. 2013a; Webster et al. 2016; Wen et al. 2013; Yang et al. 2016a). The
investigators for an occupational exposure study reported that differences in TSH, T4, and T3 levels were
small and clinically insignificant in groups of workers exposed to low levels, high levels, or no PFNA
(Mundt et al. 2007). Preston et al. (2018) found an inverse association between serum PFNA levels andTSH levels, but only in pregnant women who were positive for maternal thyroid peroxides antibodies.
Crawford et al. (2017) found associations between serum PFNA and free T4 and T3 levels in women, but
no associations with total T4 or TSH. No associations between cord blood PFNA levels and cord blood
T4, T3, or TSH were found in two studies (Shah-Kulkarni et al. 2016; Tsai et al. 2017). No associations
were found for thyroid disease, hypothyroidism, or subclinical hypo- or hyperthyroidism among residents
living near the Washington Works PFOA facility (Lopez-Espinosa et al. 2012), in NHANES participants(Wen et al. 2013), or in pregnant women (Dufour et al. 2018).
PFDA

Epidemiological Studies. Most general population studies did not find associations between serum
PFDA levels and TSH, T3, or T4 levels (Berg et al. 2017; Bloom et al. 2010; Ji et al. 2012; Kang et al.
2018; Wang et al. 2013a, 2014; Yang et al. 2016a). The exceptions were studies in pregnant women thatfound positive associations (Berg et al. 2015; Wang et al. 2014) or inverse associations with T3 (Berg etal. 2017), or an inverse association with TSH levels (Yang et al. 2016a). No associations between cord
blood PFDA and cord blood T4, T3, or TSH were found in a study by Shah-Kulkarni et al. (2016).

Laboratory Animal Studies. Administration of a single dose of 80 mg/kg PFDA to female C57BL/6N
mice by gavage resulted in 2- and 4-fold increases in serum T3 and T4, respectively, relative to controls
30 days after dosing (Harris et al. 1989). No alterations were observed in the adrenal glands of rats
administered 0.5 mg/kg/day PFDA for 28 days or mice receiving weekly gavage doses of 5 mg/kg for
4 weeks (Frawley et al. 2018).
PFUnA

Epidemiological Studies. Inverse associations between serum PFUnA and serum TSH (Yang et al.
2016a) T4 (Wang et al. 2014), or T3 (Berg et al. 2015, 2017) have been reported in pregnant women.
However, other general population studies have not found association between PFUnA and TSH, T4, orT3 levels (Bloom et al. 2010; Ji et al. 2012; Kang et al. 2018; Wang et al. 2013a, 2014; Yang et al. 2016a)

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or between cord blood PFUnA and cord blood T4, T3, or TSH (Shah-Kulkarni et al. 2016; Tsai et al.
2017).
PFBS

Laboratory Animal Studies. Treatment of rats with up to 900 mg/kg/day PFBS by gavage for 28 days
did not alter the gross or microscopic appearance of the adrenal, pituitary, or thyroid/parathyroid glands(3M 2001). Levels of thyroid hormones in serum were not available in this study. A study in pregnant
mice administered ≥200 mg/kg/day PFBS on GDs 1–20 found decreases in maternal levels of total T4,
free T4, and total T3 and increases in TSH levels (Feng et al. 2017).
PFBA

Laboratory Animal Studies. Treatment of rats with up to 184 mg/kg/day PFBA by gavage for 5 days did
not affect the gross or microscopic morphology of the adrenal, thyroid, or pituitary glands (3M 2007a).
Treatment with ≥30 mg/kg/day for 28 or 90 days significantly increased the incidence of hyperplasia/
hypertrophy of the follicular epithelium of the thyroid gland (Butenhoff et al. 2012a; van Otterdijk 2007a,
2007b). These changes were not observed following a 3-week recovery period. Van Otterdijk (2007a,
2007b; Butenhoff et al. 2012a) suggested that the thyroid lesion likely reflected an increase in T4
producing follicular cells in response to feedback mechanisms from the increased turnover of T4 by thehypertrophic hepatocytes. None of these studies measured thyroid hormones or TSH in serum.
PFDoDA

Epidemiological Studies. Four general population studies have evaluated the effect of PFDoDA on
thyroid hormone levels. Wang et al. (2014) reported inverse associations between serum PFDoDA andfree T4 and total T4 in pregnant women; no associations were found for TSH or total T3. In anotherstudy of pregnant women (Yang et al. 2016a), inverse associations were found for TSH, free T4, total T4,
free T3, and total T3. The third study (Ji et al. 2012) found no associations between serum PFDoDA andTSH or T4. Shah-Kulkarni et al. (2016) did not find associations between cord blood PFDoDA levels andcord blood T4, T3, or TSH levels.

Laboratory Animal Studies. Histological alterations were observed in the pancreas, adrenal gland, and/or
thymus of rats administered 2.5 mg/kg/day PFDoDA for 42–47 days (Kato et al. 2015). Decreases inPERFLUOROALKYLS

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zymogen granules were observed in the pancreas of male rats and edema of the pancreas interstitium wasobserved in females (most female rats died before the end of the study). Atrophy of the adrenal cortex
was observed in males and in females exposed for 42 days and allowed to recover for 14 days. Atrophyof the thymic cortex was observed in females (most dying before the end of the study). A 28-day study
found a 40% reduction in serum estradiol levels in pubertal female rats administered 3 mg/kg/day for
28 days (Shi et al. 2009b).
PFHxALaboratory Animal Studies. An increased incidence of thyroid follicular epithelial hypertrophy wasobserved in female rats administered 500 mg/kg/day NaPFHx for 93 days (Loveless et al. 2009). No
alterations were observed in male rats in this study or in a second 90-day study in which male and female
rats were administered doses as high as 200 mg/kg/day NaPFHx.

2.14 IMMUNOLOGICAL
Overview. Epidemiological studies have evaluated three categories of altered immune response related to
exposure to perfluoroalkyls: immunosuppression (altered antibody response, infectious disease
resistance), hypersensitivity (asthma, wheezing, eczema, atopic dermatitis, allergies), and autoimmunity.
A summary of epidemiological studies evaluating immunological endpoints is presented in Table 2-16;
more detailed descriptions of individual studies are presented in the Supporting Document for
Epidemiological Studies for Perfluoroalkyls, Table 10. Epidemiological data evaluating potential
immunological effects are available for all perfluoroalkyls except PFBA. In general, the epidemiologicalstudies identify the immune system as a target of perfluoroalkyl toxicity. The strongest evidence of theimmunotoxicity of perfluoroalkyls in humans comes from epidemiological studies finding associations
evaluating the antibody response to vaccines. Associations have been found for PFOA, PFOS, PFHxS,and PFDA. There is also some limited evidence for decreased antibody response for PFNA, PFUnA, andPFDoDA, although many of the studies did not find associations for these compounds. In general,
decreases in disease resistance have not been found for PFOA, PFOS, PFHxS, or PFNA. There is
marginal evidence for associations between PFOA, PFOS, PFHxS, PFNA, PFDA, PFBS, and PFDoDA
and increased risk of asthma; the evidence was considered marginal due to the small number of studies
evaluating the outcome and/or conflicting study results. There are limited data of effects on

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

PFOA
Anderson-Mahoney et al. 2008

NR

AsthmaSPR 1.82 (1.47–2.25)*

Community (n=566 adults)
Ashley-Martin et al. 2015

NR

IL-33/TSLP (cord blood)
IgE (cord blood)

OR 1.1 (0.6–1.8)
OR 1.1 (0.6–1.9)

General population (1,258 women)
Buser and Scinicariello 2016

3.59 and 3.27 ng/mL
Food allergies(geometric mean 2005–2006 Food sensitization
General population (NHANES) (n=637 and and 2007–2010)
701 adolescents in 2005–2006 and 2007–2010)>4.47 ng/mL (4th quartile)
Dalsager et al. 2016
2.04–10.12 ng/mL (maternal Risk of number of days
3rd tertile PFOA)
above the median
Fever
General population (n=359 1–4-year-old
Coughchildren)Nasal discharge
Diarrhea
Vomiting
Risk of number of days
Fever
Cough
Nasal discharge
Diarrhea
Vomiting
Dong et al. 2013
1.5 and 1.0 ng/mL (mean
Asthma diagnosis
serum PFOA levels in the
IgE
General population (n=231 asthmatic and asthmatic and non-asthmatic
225 non-asthmatic children)
children, respectively; serum
Absolute eosinophil counts
levels were not reported forThis is the same group of children
full cohort)
Eosinophil cationic protein
evaluated by Zhu et al. (2016)

OR 9.09 (3.52–24.90)*, 4th quartile
NS (p=0.74 for trend)

OR 1.97 (1.07–3.62)*, 3rd tertile
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
OR 1.12 (0.82–1.54), 3rd tertile
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
OR 2.67 (1.49–4.79)*, 3rd quartile
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedFei et al. 2010

5.6 ng/mL (maternal PFOA)

General population. (n=1,400 pregnant
women and young children)
Goudarzi et al. 2016a

Resultc

Risk of hospitalization for
IRR 0.96 (0.87–1.06) for trend
infectious disease in young IRR 1.21 (1.04–1.42)* for trend, girls
children
IRR 0.83 (0.73–0.95)* for trend, boys

2.713 ng/mL (mean maternal Prevalence of allergic
plasma PFOA)
diseasePrevalence of wheezing

OR 0.830 (0.591–1.16), 4th quartile

2.713 ng/mL (mean maternal Risk of total infectious
serum PFOA)
diseases

OR 1.11 (0.806–1.54), 4th quartile,
p=0.393 for trend.

Grandjean et al. 2012; Mogensen et al.
2015a

4.1 and 4.4 ng/mL (median
PFOA at age 5 and 7 years)

NS, maternal PFOA
NS, PFOA at age 5

General population (n=456 andn=464 children 5 and 7 years of age)

3.20 ng/mL (geometric mean Tetanus antibody levels atmaternal PFOA)
age 7

General population (n=1,558 4-year-old
children)
Goudarzi et al. 2017

OR 1.09 (0.729–1.65), 4th quartile

General population (n=1,558 mother-childpairs); children examined up to 4 years ofage
Tetanus antibody levels atage 5

Diphtheria antibody levels
at age 5
Diphtheria antibody levels
at age 7

NS, maternal PFOA
β -35.8% (-51.9 to -14.2)*, per 2-foldincrease in PFOA levels at age 5
NS, PFOA at age 7
NS, maternal PFOANS (p=0.69), PFOA at age 5
NS, maternal PFOA
β -25.2% (-42.9 to -2.0)*, per 2-foldincrease in PFOA levels at age 5
β -25.4% (-40.9 to -5.8)*, per 2-foldincrease in PFOA levels, PFOA at
age 7

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Grandjean et al. 2017

4.4 and 2.0 ng/mL (median
Tetanus antibody levels at
PFOA at age 7 and 13 years) age 13
Diphtheria antibody levels
at age 13

NS (p=0.637), PFOA at age 7
NS (p=0.856), PFOA at age 13
Full cohort
NS (p=0.742), PFOA at age 7
NS (p=0.129), PFOA at age 13
Cohort restricted to children without
possible unscheduled booster vaccines
NS (p=0.480), PFOA at age 7
Association (p=0.029)*, PFOA at
age 13

1.1 ng/mL (mean maternal
PFOA)

Inverse association (p=0.001)*
NS (p>0.05)

General population (n=516 children
examined at age 7 and 13 years)

Granum et al. 2013
General population (n=56 children age
3 years)

Humblet et al. 2014
General population (NHANES)(n=1,877 adolescents)

4.3 and 4.0 ng/mL (median
PFOA in asthmatics andnonasthmatics)

Rubella antibody levels
Hemophilus influenza typeB antibody levels
Tetanus antibody levels
Asthma diagnosis
Atopic eczema

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Eczema and itchiness
NS (p>0.05)
Number of episodes of otitis NS (p>0.05)
media
Number of episodes of
Association (p<0.001)*
common cold
Number of episodes of
Association (p=0.048)*
gastroenteritis
Asthma episode in last
OR 1.18 (1.01–1.39)*, per doubling
12 months
PFOA
Current asthma
Wheezing

NS (p=0.26)
NS (p=0.98)

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedImpinen et al. 2018

Exposure: level 1.8 ng/mL(mean cord PFOA)

General population (n=641 infants followed
through age 10)

Kielsen et al. 2016
General pop. (n=12 adults)
Looker et al. 2014
Community (C8) (n=411)

Okada et al. 2012
General population (n=343 pregnant
women)

1.69 ng/mL (median PFOA)

Number of common colds NS (p=0.089)(0–2 years of age)
Number of lower respiratory β 0.28 (0.22–0.35; p=<0.0001)*
infections (0–10 years ofage)
Rhinitis
Rhinoconjunctivitis
Asthma diagnosis
Current asthma
Asthma everAllergic sensitization

NS
NS
NS
NS
NS
NS

Diphtheria antibody levels
Tetanus antibody levels

NS (p=0.250), unadjusted
NS (p=0.970), unadjusted.

33.74 ng/mL (geometric
Seroprotection frommean)
influenza A H3N2 virus
13.8–31.5 ng/mL (2nd quartile) Seroprotection frominfluenza A H1N1 virus
Seroprotection frominfluenza type B virus
Cold or flu infection
Frequency of colds
1.3 ng/mL (maternal median
PFOA)

Resultc

OR 0.34 (0.14–0.83)*, 2nd quartile
NS (p=0.02)
NS (p=0.68)
NS (p>0.05)
NS (p>0.05)

Cord IgE levels
Males
FemalesInfant food allergy

NS (p>0.05)
Inverse association (p<0.05)*
OR 1.67 (0.52–5.37)

EczemaWheezing
Otitis media

OR 0.96 (0.23–4.02)
OR 1.27 (0.27–6.05)
OR 1.51 (0.45–5.12)

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedOkada et al. 20142.67 ng/mL (maternal mean
PFOA)

General population (n=2,603 infants)

Qin et al. 2017
General population (n=132 children aged
10–15 years and 168 matched controls)
Smit et al. 2015
General population (n=1,024 children)

Steenland et al. 2013

EczemaMales
Females
1.02 and 0.50 ng/mL (median Asthma
serum PFOA in cases andcontrols)
0.97 and 1.79 ng/mL(maternal mean PFOA in
Ukraine and Greenland
cohorts)

Estimated cumulative

Community (C8) (28,441)

Steenland et al. 2015

Risk of allergic diseases
Males
Females

Estimated cumulative

Resultc
OR 0.63 (0.63–1.37), 4th quartile
OR 0.64 (0.42–0.97)*, 4th quartile
OR 0.75 (0.48–1.18), 4th quartile
OR 0.65 (0.39–1.09), 4th quartile
OR 2.76 (1.82–4.17)*

Ever having asthma
Ever having eczema
Current eczema

OR 0.80 (0.62–1.04), whole cohort
OR 0.97 (0.81–1.17), whole cohort
OR 1.01 (0.79–1.29), whole cohort

Ever having wheezing
Current wheezing
Ulcerative colitis
Rheumatoid arthritis
Crohn’s disease
Type I diabetes
Lupus

OR 0.91 (0.76–1.10), whole cohort
OR 0.97 (0.71–1.33), whole cohort
OR 1.76 (1.04–2.99)*, 2nd quartile
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Multiple sclerosis
AsthmaNS (p>0.05)
NS (p=0.27), with no lag
NS (p=0.53), with 10-year lag
Positive categorical trend (p=0.05)*,
with no lag
RR 6.57 (1.47–29.40)*, with 10-year lag

Occupational (n=3,713)
Ulcerative colitis
Rheumatoid arthritis

Positive categorical trend (p=0.04)*,
with no lag

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Stein et al. 2016a

4.13 ng/mL (geometric mean) Measles antibody titers
Mumps antibody titers

NS (95% CI included unity)
NS (95% CI included unity), whole cohort
β -6.6% (-11.7 to -1.5)*, per 2-foldincrease in PFOA levels, seropositive
subcohortRubella antibody titers

NS (95% CI included unity), whole cohort
β -8.9% (-14.6 to -2.9)*, per 2-foldincrease in PFOA levels, seropositive
subcohort
OR 1.35 (1.10–1.66)*
OR 1.28 (0.81–2.04)

General population (NHANES)(n=1,191 adolescents)

Stein et al. 2016a
General population (NHANES)(n=640 adolescents)

Stein et al. 2016b
General population (n=78 adults receiving
influenza vaccine)

3.59 ng/mL (geometric mean) Rhinitis
Current asthma
WheezeAllergy
Allergic sensitization
PlantsDust mites
Pets
Cockroach or shrimp
Rodents
Mold
Food
2.28 ng/mL (geometric mean) Seroconversion
Hemagglutinin
Immunohistochem.

OR 0.94 (0.51–1.73)
OR 1.12 (0.85–1.47)
OR 0.88 (0.67–1.15)
OR 0.93 (0.75–1.16)
OR 1.17 0.81–1.68)
OR 0.79 (0.55–1.13)
OR 1.65 (0.59–4.60
OR 1.21 (0.85–1.72)
OR 1.02 (0.60–1.73)

Serum cytokine levels
Serum chemokine levels
Nasal cytokine levels
Nasal chemokine levels
Serum IgA levels

NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)

NS (p=0.07 for trend)
NS (p=0.27 for trend)

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Wang et al. 20111.71 ng/mL (median cord
PFOA)

NS (p=0.870)
Association (p=0.047)*
NS (p>0.05)

General population (n=244 children aged
2 years)
Zhu et al. 2016
General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Dong et al. (2013)

PFOS
Ashley-Martin et al. 2015
General population (1,258 women)
Buser and Scinicariello 2016

Serum IgE levels
Cord blood IgE levels
Atopic dermatitis

1.51 and 1.00 ng/mL (mean in Asthma diagnosis
asthmatics and nonasthmatics)
T-helper cytokines
IL-4
IL-5
IFN-γ
IL-2
Serum IgE

OR 4.24 (1.91–9.42)*, males 4th quartile
OR 3.68 (1.43–9.48)*, females 4thquartileNR

1.1 (0.6–1.9)
OR 1.1 (0.6–1.9)

IL-33/TSLP (cord blood)
IgE (cord blood)

14.98 and 8.74 ng/mL
Food allergies(geometric mean PFOS
General population (NHANES) (n=637 and 2005–2006 and 2007–2010) Food sensitization
701 adolescents in 2005–2006 and 2007–
9.17–13.75 ng/mL
2010)(3rd quartile)
Dalsager et al. 201610.19–25.10 ng/mL (maternal Risk of number of days
3rd tertile PFOS)
above the median
Fever
General population (n=359 1–4-year-old
Coughchildren)Nasal discharge
Diarrhea
Vomiting

Association (p=0.001 for trend)*
Association (p=0.004 for trend)*
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)

OR 2.43 (1.05–5.59)*, 3rd quartile(trend not significant, p=0.27)
NS (p=0.49 for trend)

OR 2.35 (1.34–4.11)*, 3rd tertile
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Dong et al. 2013
General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Zhu et al. (2016)

Fei et al. 2010
General population (n=1,400 pregnant
women and young children)
Goudarzi et al. 2016a

Serum perfluoroalkyl level Outcome evaluatedResultc

Risk of number of days
Fever
Cough
Nasal discharge
Diarrhea
Vomiting
45.5 and 33.4 ng/mL (mean Asthma diagnosis
serum PFOS levels in the
Asthma severity
asthmatic and non-asthmaticchildren, respectively; serum IgElevels were not reported for
Absolute eosinophil counts
full cohort)

OR 1.65 (1.24–2.18)*, 3rd tertile
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
OR 2.63 (1.48–4.69)*, 4th quartile
Association (p=0.045 for trend)*
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Eosinophil cationic protein Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
35.3 ng/mL (maternal PFOS) Risk of hospitalization for
IRR 1.00 (0.91–1.09) for trend
infectious disease in young IRR 1.18 (1.03–1.36)* for trend, girls
children
IRR 0.90 (0.80–1.12) for trend, boys
5.456 ng/mL (mean maternal Prevalence of allergic
plasma PFOS)
diseasePrevalence of wheezing

OR 0.815 (0.596–1.11), 4th quartile

5.456 ng/mL (mean maternal Risk of total infectious
serum PFOS)
diseases

OR 1.44 (1.06–1.96)*, 2nd quartile;
p=0.008 for trend

General population (n=1,558 mother-childpairs); children examined up to 4 years ofage
Grandjean et al. 2012; Mogensen et al.
2015a17.3 and 15.5 ng/mL (median Tetanus antibody levels at
PFOS at age 5 and 7 years) age 5

General population (n=456 andn=464 children 5 and 7 years of age)

27.3 ng/mL (geometric mean Tetanus antibody levels atmaternal PFOS)
age 7

NS, maternal PFOS
β -28.5% (-45.5 to -6.1)*, per 2-foldincrease in PFOS levels at age 5
NS, maternal PFOS
NS, PFOS at ages 5 and 7

General population (n=1,558 4-year-old
children)
Goudarzi et al. 2017

OR 0.770 (0.526–1.12), 4th quartilePERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Grandjean et al. 2017

Serum perfluoroalkyl level Outcome evaluated15.3 and 6.7 ng/mL (medianat age 7 and 13 years)

Diphtheria antibody levels
at age 5

NS, maternal PFOS
NS, PFOS at age 5

Diphtheria antibody levels
at age 7

β -27.6% (-45.8 to -3.3)*, per 2-foldincrease in PFOS levels at age 5
β -30.3% (47.3 to -7.8)*, per 2-foldincrease in PFOS levels at age 7
Full cohort
NS (p=0.240), PFOS at age 7
NS (p=0.237), PFOS at age 13
Cohort restricted to children without
possible unscheduled booster vaccines
Association (p=0.043)*, PFOS atage 7
NS (p=0.144), PFOS at age 13
NS (p=0.07), age 7
NS (p=0.454), age 13
Inverse association (p=0.007)*NS (p>0.05)

Tetanus antibody levels atage 13General population (n=516 children
examined at age 7 and 13 years)

Granum et al. 2013
General population (n=56 children age
3 years)

5.6 ng/mL (mean maternal
PFOS)

Resultc

Diphtheria antibody levels
at age 13
Rubella antibody levels
Hemophilus influenza
type B antibody levels
Tetanus antibody levels
Asthma diagnosis
Atopic eczema

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Eczema and itchiness
NS (p>0.05)
Number of episodes of otitis NS (p>0.05)
media
Number of episodes ofNS (p=0.501)
common cold
Number of episodes ofNS (p=0.367)
gastroenteritis

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Humblet et al. 2014

17.0 and 16.8 ng/mL (median Asthma episode in last
NS (p=0.13), per doubling PFOSPFOS in asthmatics and non- 12 months
General population (NHANES)
asthmatics)
Current asthma
NS (p=0.24)(n=1,877 adolescents)
Wheezing
NS (p=0.08)
Impinen et al. 2018
5.6 ng/mL (mean cord PFOS) Number of common colds NS (p=0.173)(0–2 years of age)
General population (n=641 infants followed
Number of lower respiratory β 0.50 (0.42–0.57; p=<0.0001)*
through age 10)
infections (0–10 years ofage)
Rhinitis
NS
Rhinoconjunctivitis
NS
Asthma diagnosis
NS
Current asthma
NS
Asthma everAllergic sensitization
Diphtheria antibody levels

Kielsen et al. 20169.52 ng/mL (median PFOS)

General population (n=12 adults)

Tetanus antibody levels
8.32 ng/mL (geometric mean Response to influenza A
PFOS)
H3N2 virus vaccine
Response to influenza A
H1N1 virus vaccine
Response to influenza
type B virus vaccine
Cold or flu infection
Frequency of colds

Looker et al. 2014
Community (C8) (n=411)

NS
NS
Inverse association (p=0.044)*,
unadjusted
NS (p=0.420), unadjusted
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Okada et al. 2012

5.2 ng/mL (maternal median
PFOS)

Cord IgE levels
Infant food allergy
EczemaWheezing
Otitis media

NS (p>0.05)
OR 3.72 (0.81–17.10)
OR 0.87 (0.15–5.08)
OR 2.68 (0.39–18.30)
OR 1.40 (0.33–6.00)

5.56 ng/mL (maternal mean
PFOS)

Risk of allergic diseases
Males
FemalesEczemaMales
Females
AsthmaGeneral population (n=343 infants)

Okada et al. 2014
General population (n=2,603 infants)

Qin et al. 2017
General population (n=132 children aged
10–15 years and 168 matched controls)
Smit et al. 2015
General population (n=1,024 children)

Stein et al. 2016a
General population (NHANES)(n=1,191 adolescents)

31.51 and 28.83 ng/mL(median serum PFOS incases and controls)
4.88 and 20.6 ng/mL(maternal mean PFOS in
Ukraine and Greenland
cohorts)

Ever having asthma
Ever having eczema
Current eczema
Ever having wheezing
Current wheezing

20.8 ng/mL (geometric mean Measles antibody titers
PFOS)
Mumps antibody titers

Rubella antibody titers

OR 0.95 (0.65–1.37), 4th quartile
OR 0.79 (0.53–1.17), 4th quartile
OR 0.98 (0.63–1.53), 4th quartile
OR 0.84 (0.51–1.38), 4th quartile
OR 1.30 (1.00–1.69)*

OR 0.86 (0.67–1.10), whole cohort
OR 0.98 (0.88–1.18), whole cohort
OR 1.05 (0.82–1.33), whole cohort
OR 0.83 (0.69–1.00), whole cohort
OR 0.60 (0.38–0.92)*, Ukraine cohort
OR 0.91 (0.62–1.36) Greenland
OR 0.76 (0.56–1.01), whole cohort
NS (95% CI included unity)
β -7.4% (-12.8 to -1.7)*, per 2-foldincrease in PFOS levels, whole cohort
β -5.9% (-9.9 to -1.6)*, per 2-foldincrease in PFOS levels, seropositive
subcohort
NS (95% CI included unity), whole cohort
β -13.3% (-19.9–6.2)*, per 2-foldincrease in PFOS levels, seropositive
subcohortPERFLUOROALKYLS

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Stein et al. 2016a15.0 ng/mL (geometric mean) Rhinitis
Current asthma
WheezeAllergy
Allergic sensitization
PlantsDust mites
Pets
Cockroach or shrimp
Rodents
Mold
Food
5.22 ng/mL (geometric mean) Seroconversion
Hemagglutinin
Immunohistochemistry
Serum cytokine levels
Serum chemokine levels
Nasal cytokine levels

OR 1.16 (0.90–1.50)
OR 1.20 (0.88–1.63)
OR 0.76 (0.45–1.19)
OR 1.05 (0.80–1.37)

General population (NHANES)(n=640 adolescents)

Stein et al. 2016b
General population (n=78 adults receiving
influenza vaccine)

Wang et al. 2011
General population (n=244 children aged
2 years)
Zhu et al. 2016
General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Dong et al. (2013)5.50 ng/mL (median cord
PFOS)

Nasal chemokine levels
Serum IgA levels
Serum IgE levels
Cord blood IgE levels
Atopic dermatitis

45.86 and 33.9 ng/mL (mean Asthma diagnosis
in asthmatics and nonasthmatics)
T-helper cytokines
IL-4
IL-5
IFN-γ
IL-2
Serum IgE

OR 0.17 (0.53–0.97)*
OR 1.00 (0.73–1.38)
OR 0.83 (0.56–1.22)
OR 0.67 (0.48–0.93)*
OR 0.85 (0.29–2.45)
OR 1.33 (1.06–1.69)*
OR 0.74 (0.39–1.40)
NS (p=0.81 for trend)
NS (p=0.12 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p=0.179)
Association (p=0.017)*
NS (p>0.05)
OR 4.38 (2.02–9.50)*, males 4th quartile
NS (p=0.899 for trend), females
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

PFHxS
Ashley-Martin et al. 2015

NR

1.0 (0.7–1.4)
OR 1.0 (0.7–1.4)

General population (1,258 women)
Buser and Scinicariello 2016

IL-33/TSLP (cord blood)
IgE (cord blood)

2.09 and 2.19 ng/mL
Food allergies(geometric mean 2005–2006
General population (NHANES) (n=637 and and 2007–2010)
Food sensitization
701 adolescents in 2005–2006 and 2007–>4.00 ng/mL (4th quartile)
2010)
Dalsager et al. 2016
General population (n=359 1–4-year-old
children)

Dong et al. 2013
General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Zhu et al. (2016)

0.32 ng/mL (maternal median Risk of number of days
PFHxS)
above the median
Fever
Cough
Nasal discharge
Diarrhea
Vomiting
Risk of number of days
Fever
Cough
Nasal discharge
Diarrhea
Vomiting
3.9 and 2.1 ng/mL (mean
Asthma diagnosis
serum PFHxS levels in the
Asthma severity
asthmatic and non-asthmaticchildren, respectively; serum IgElevels were not reported for
Absolute eosinophil counts
full cohort)
Eosinophil cationic protein

OR 3.06 (1.35–6.93)*, 4th quartile (trend
not significant, p=0.11)
NS (p=0.72 for trend)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
OR 2.94 (1.65–5.25)*, 3rd quartile
NS (p=0.722 for trend)
NS (p>0.05), asthmatics
NS (p>0.05), non-asthmatics
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Goudarzi et al. 2016a

0.322 ng/mL (mean maternal Prevalence of allergic
plasma PFHxS)
diseasePrevalence of wheezing

OR 0.841 (0.615–1.151), 4th quartile

0.322 ng/mL (mean maternal Risk of total infectious
serum PFHxS)
diseases

OR 0.957 (0.7.3–1.41), 4th quartile,
p=0.928 for trend

General population (n=1,558 4-year-old
children)
Goudarzi et al. 2017
General population (n=1,558 mother-childpairs); children examined up to 4 years ofage

Females only:
OR 1.81 (1.14–2.88)*, 3rd quartile;
p=0.045 for trend

Grandjean et al. 2012; Mogensen et al.
2015a

0.6 and 0.5 ng/mL (median
Tetanus antibody levels at
PFHxS at age 5 and 7 years) age 5

General population (n=456 and n=464
children 5 and 7 years of age)

4.41 ng/mL (geometric mean Tetanus antibody levels atmaternal PFHxS)
age 7

Grandjean et al. 2017
General population (n=516 children
examined at age 7 and 13 years)

OR 0.728 (0.497–1.06), 4th quartile

0.5 and 0.4 ng/mL (median
PFHxS at age 7 and13 years)

Diphtheria antibody levels
at age 5
Diphtheria antibody levels
at age 7
Tetanus antibody levels atage 13Diphtheria antibody levels
at age 13

Males only:
p=0223 for trend
NS, maternal PFHxS-19.0% (-29.8 to -6.6)*, per 2-foldincrease in PFHxS levels at age 5
NS, maternal PFHxS
β -19.7% (-31.6 to -5.7)*, per 2-foldincrease PFHxS levels at age 5
β -22.3% (-36.3 to -5.2)*, per 2-foldincrease PFHxS levels at age 7
NS, maternal PFHxSNS, PFHxS at age 5
NS, maternal PFHxSNS, PFHxS at age 5 or 7
NS (p=0.334), PFHxS at age 7
NS (p=0.568), PFHxS at age 13
NS (p=0.264), PFHxS at age 7
NS (p=0.583), PFHxS at age 13

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Granum et al. 2013

0.3 ng/mL (mean maternal
PFHxS levels)

Inverse association (p=0.008)*
NS (p>0.05)

General population (n=56 children age
3 years)

Rubella antibody levels
Hemophilus influenza
type B antibody levels
Tetanus antibody levels
Asthma diagnosis
Atopic eczema
Eczema and itchiness

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Number of episodes of otitis NS (p>0.05)
media

Humblet et al. 2014
General population (NHANES)(n=1,877 adolescents)
Impinen et al. 2018
General population (n=641 infants followed
through age 10)

2.2 and 2.0 ng/mL (median
PFHxS in asthmatics andnonasthmatics)
0.3 ng/mL (mean cord
PFHxS)

Number of episodes ofcommon cold

NS (p=0.078)

Number of episodes ofgastroenteritis

Association (p=0.007)*

Asthma episode in last
12 months
Current asthma

NS (p=0.66), per doubling PFHxS
NS (p=0.99)

Wheezing
NS (p=0.92)
Number of common colds NS (p=0.530)(0–2 years of age)
Number of lower respiratory NS (p=0.119)
infections (0–10 years ofage)
Rhinitis
Rhinoconjunctivitis
Asthma diagnosis
Current asthma
Asthma everAllergic sensitization

NS
NS
NS
NS
NS
NS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Kielsen et al. 2016

0.37 ng/mL (median PFHxS)

NS (p=0.055), unadjusted
NS (p=0.390), unadjusted

General population (n=12 adults)
Okada et al. 2014
General population (n=2,603 infants)

Qin et al. 2017
General population (n=132 children aged
10–15 years and 168 matched controls)
Smit et al. 2015
General population (n=1,024 children)

Stein et al. 2016a
General population (NHANES)(n=1,191 adolescents)

Diphtheria antibody levels
Tetanus antibody levels

0.324 ng/mL (maternal mean Risk of allergic diseases
PFHxS)
Males
FemalesEczemaMales
Females
2.38 and 1.07 ng/mL (median Asthma
serum PFHxS in cases andcontrols)
1.53 and 2.14 ng/mL(maternal mean PFHxS in
Ukraine and Greenland
cohorts)

Ever having asthma
Ever having eczema
Current eczema
Ever having wheezing
Current wheezing

2.47 ng/mL (geometric mean Measles antibody titers
PFHxS)
Mumps antibody titers
Rubella antibody titers

OR 0.81 (0.56–1.16), 4th quartile
OR 1.13 (0.75–1.69), 4th quartile
OR 0.78 (0.51–1.19), 4th quartile
OR 0.82 (0.49–1.36), 4th quartile
OR 2.14 (1.48–3.11)*

OR 0.91 (0.69–1.18), whole cohort
OR 1.03 (0.86–1.24), whole cohort
OR 0.93 (0.73–1.20), whole cohort
OR 0.96 (0.79–1.17), whole cohort
OR 0.93 (0.68–1.27), whole cohort
NS (95% CI included unity)
NS (95% CI included unity)
NS (95% CI included unity), whole cohort
β -6.0% (-9.6 to -2.2)*, per 2-foldincrease PFHxS levels, seropositive
subcohortPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Stein et al. 2016a

2.09 ng/mL (geometric mean Rhinitis
PFHxS)
Current asthma
WheezeAllergy
Allergic sensitization
PlantsDust mites
Pets
Cockroach or shrimp
Rodents
Mold
Food
1.1 ng/mL (geometric mean Seroconversion
PFHxS)
Hemagglutinin
Immunohistochem.
Serum cytokine levels
IFN-γ
IFN-α2
TNF-α
IP-10

OR 0.81 (0.57–1.16)
OR 0.98 (0.51–1.87)
OR 0.99 (0.68–1.44)
OR 0.83 (0.59–1.17)

General population (NHANES)(n=640 adolescents)

Stein et al. 2016b
General population (n=78 adults receiving
influenza vaccine)Serum chemokine levels
Nasal cytokine levels
Nasal chemokine levels
Serum IgA levels

OR 0.93 (0.62–1.39)
OR 1.01 (0.84–1.22)
OR 0.96 (0.71–1.30)
OR 0.72 (0.56–0.93)
OR 0.81 (0.54–1.21)
OR 0.98 (0.65–1.47)
OR 1.03 (0.74–1.42)
NS (p=0.22 for trend)
NS (p=0.34 for trend)
Association (p=0.05 for trend)*
NS (p=0.09 for trend)
Association (p=0.04 for trend)*
NS (p=0.59 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)

PERFLUOROALKYLS

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Zhu et al. 20163.86 and 2.10 ng/mL (meanPFHxS in asthmatics andnon-asthmatics)

OR 2.97 (1.33–6.64)*, males 4th quartile
OR 5.02 (2.05–12.30)*, females
4th quartile

General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Dong et al. (2013)

PFNA
Buser and Scinicariello 2016

0.93 and 1.13 ng/mL(geometric mean PFNA
General population (NHANES) (n=637 and 2005–2006 and 2007–2010)
701 adolescents in 2005–2006 and 2007–>1.36 ng/mL (4th quartile)
2010)
Dalsager et al. 2016
General population (n=359 1–4-year-old
children)

Asthma diagnosis

T-helper cytokines
IL-4
IL-5
IFN-γ
IL-2
Serum IgE

NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)

Food allergies

NS (p=0.28 for trend)

Food sensitization

OR 0.51 (0.28–0.92)*, 4th quartile (trend
not significant, p=0.15)

0.56–0.81 and 0.82–
Risk of number of days
3.64 ng/mL (maternal 2nd and above the medianFever
3rd tertile PFNA)
Cough
Nasal discharge
Diarrhea
Vomiting
Risk of number of days
Fever
Cough
Nasal discharge
Diarrhea
Vomiting

NS (p>0.05)
NS (p>0.05)
OR 0.53 (0.31–0.92)*, 2nd tertile
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
OR 1.12 (0.84–1.49), 3rd tertile
NS (p>0.05)
NS (p>0.05)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluated

Dong et al. 2013

1.1 and 0.9 ng/mL (meanserum PFNA levels in theasthmatic and non-asthmaticchildren, respectively; serum
levels were not reported forfull cohort)

General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Zhu et al. (2016)

Goudarzi et al. 2016a
General population (n=1,558 4-year-old
children)
Goudarzi et al. 2017
General population (n=1,558 mother-childpairs); children examined up to 4 years ofage
Grandjean et al. 2012
General population (n=456 andn=464 children 5 and 7 years of age)Grandjean et al. 2017
General population (n=516 children
examined at age 7 and 13 years)

Resultc

OR 2.56 (1.41–4.65)*, 4th quartile
NS (p=0.217 for trend)
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Absolute eosinophil counts Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Eosinophil cationic protein Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
1.402 ng/mL (mean maternal Prevalence of allergic
OR 0.873 (0.562–1.35), 4th quartile
plasma PFNA)
diseasePrevalence of wheezing
OR 1.11 (0.760–1.63), 4th quartile
Asthma diagnosis
Asthma severity
IgE

1.402 ng/mL (mean maternal Risk of total infectious
serum PFNA)
diseases

OR 0.918 (0.672–1.25), 4th quartile,
p=0.748 for trend

1.00 ng/mL (geometric mean Tetanus antibody levels at
PFNA at age 5 years)
age 5
Tetanus antibody levels at
0.60 ng/mL (geometric mean age 7
PFNA at age 7 years)
Diphtheria antibody levels
at age 5

NS, maternal PFNA
NS, PFNA at age 5
NS, maternal PFNA
NS, PFNA at age 5
NS, maternal PFNA
β -16.1% (-28.8 to -1.0)*, per 2-foldincrease PFNA levels at age 5
NS, maternal PFNA
NS, PFNA at age 5
NS (p=0.075), PFNA at age 7
NS (p=0.394), PFNA at age 13
NS (p=0.243), PFNA at age 7
NS (p=0.693), PFNA at age 13

Diphtheria antibody levels
at age 7
1.1 and 0.7 ng/mL (median
Tetanus antibody levels at
PFNA at age 7 and 13 years) age 13
Diphtheria antibody levels
at age 13

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedGranum et al. 2013

0.3 ng/mL (mean maternal
PFNA levels)

Resultc

Rubella antibody levels
Inverse association (p=0.007)*
Hemophilus influenza
NS (p>0.05)
General population (n=56 children age
type B antibody levels
3 years)
Tetanus antibody levels
NS (p>0.05)
Asthma diagnosis
NS (p>0.05)
Atopic eczema
NS (p>0.05)
Eczema and itchiness
NS (p>0.05)
Number of episodes of otitis NS (p>0.05)
media
Number of episodes of
Association (p=0.035)*
common cold
Number of episodes ofNS (p=0.883)
gastroenteritis
Humblet et al. 2014
0.9 and 0.8 ng/mL (median
Asthma episode in last
NS (p=0.92), per doubling PFNA
PFNA in asthmatics and
12 months
General population (NHANES)
nonasthmatics)
Current asthma
NS (p=0.97)(n=1,877 adolescents)
Wheezing
NS (p=0.94)
Impinen et al. 2018
0.2 ng/mL (mean cord PFNA) Number of common colds NS (p=0.983)(0–2 years of age)
General population (n=641 infants followed
Number of lower respiratory β 0.0.09 (0.03–0.14;p=0.001)*
through age 10)
infections (0–10 years ofage)
Rhinitis
NS
Rhinoconjuctivitis
NS
Asthma diagnosis
Current asthma
Asthma everAllergic sensitization

NS
NS
NS
NS

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Kielsen et al. 2016

0.66 ng/mL (median PFNA)

Inverse association (p=0.004)*,
unadjusted
NS (p=0.250), unadjusted

General population(n=12 adults)
Okada et al. 2014

Tetanus antibody levels
1.36 ng/mL (maternal mean
PFNA)

General population (n=2,603 infants)

Qin et al. 2017
General population (n=132 children aged
10–15 years and 168 matched controls)
Smit et al. 2015
General population (n=1,024 children)

Stein et al. 2016a
General population (NHANES)(n=1,191 adolescents)

Diphtheria antibody levels

Risk of allergic diseases
Males
FemalesEczemaMales
Females

OR 0.95 (0.66–1.38), 4th quartile
OR 0.55 (0.36–0.82)*, 4th quartile
OR 0.96 (0.61–1.52), 4th quartile
OR 0.63 (0.38–1.02), 4th quartile

2.00 and 0.80 ng/mL (median Asthma
serum PFNA in cases andcontrols)

OR 1.61 (1.12–2.31)*

0.62 and 0.73 ng/mL(maternal mean PFNA in
Ukraine and Greenland
cohorts)

Ever having asthma
Ever having eczema
Current eczema
Ever having wheezing
Current wheezing
Measles antibody titers
Mumps antibody titers

OR 0.90 (0.70–1.14), whole cohort
OR 0.94 (0.78–1.14), whole cohort
OR 1.03 (0.82–1.30), whole cohort
OR 0.91 (0.75–1.09), whole cohort
OR 0.90 (0.66–1.23), whole cohort
NS (95% CI included unity)
NS (95% CI included unity)

Rubella antibody titers

NS (95% CI included unity)

0.765 ng/mL (geometricmean)

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Stein et al. 2016a

0.929 ng/mL (geometricmean)

OR 1.24 (0.97–1.60)
OR 1.26 (0.79–2.01)
OR 0.99 (0.58–1.68)
OR 1.12 (0.85–1.47)

General population (NHANES)(n=640 adolescents)

Stein et al. 2016b
General pop. (n=78 adults receiving
influenza vaccine)

Wang et al. 2011
General population (n=244 children aged
2 years)
Zhu et al. 2016
General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Dong et al. (2013)

RhinitisCurrent asthma
WheezeAllergy
Allergic sensitization
PlantsDust mites
Pets
Cockroach or shrimp
Rodents
Mold
Food
0.77 ng/mL (geometric mean Seroconversion
PFNA)
Hemagglutinin
Immunohistochem.
Serum cytokine levels
Serum chemokine levels
Nasal cytokine levels

2.30 ng/mL (median cord
PFNA)

Nasal chemokine levels
Serum IgA levels
Serum IgE levels
Cord blood IgE levels
Atopic dermatitis

1.07 and 0.87 ng/mL (mean Asthma diagnosis
PFNA in asthmatics and nonasthmatics)
T-helper cytokines
IL-4
IL-5
IFN-γ
IL-2
Serum IgE

OR 0.96 (0.74–1.23)
OR 1.05 (0.78–1.41)
OR 1.26 (0.85–1.87)
OR 0.86 (0.60–1.24)
OR 2.25 (0.83–6.10)
OR 1.31 (0.83–2.06)
OR 0.91 (0.55–1.50)
NS (p=0.33 for trend)
NS (p=0.40 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p=0.837)
NS (p=0.908)
NS (p>0.05)
OR 3.33 (1.46–7.58)*, males 4th quartile
NS (p=0.142 for trend), females
Association (p=0.031 for trend)*
Association (p=0.011 for trend)*
NS (p>0.05 for trend)
NS (p>0.05 for trend)
Association (p=0.008 for trend)*PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb
PFDA
Dalsager et al. 2016

Serum perfluoroalkyl level Outcome evaluatedResultc

0.27 ng/mL (median maternal Symptoms of infection
serum PFDA level)

NS (p>0.05)

General population (n=359 children aged
1–4 years)
Dong et al. 2013
General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Zhu et al. (2016)

Goudarzi et al. 2016a
General population (n=1,558 4-year-old
children)
Goudarzi et al. 2017
General population (n=1,558 mother-childpairs); children examined up to 4 years ofage
Grandjean et al. 2012
General population (n=456 andn=464 children 5 and 7 years of age)

OR 3.22 (1.75–5.94)*, 4th quartile
Association (p=0.005 for trend)*
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Absolute eosinophil counts Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Eosinophil cationic protein Association (p<0.05)*, asthmatics
Association (p<0.05)*, non-asthmatics
0.575 ng/mL (mean maternal Prevalence of allergic
OR 0.906 (0.663–1.23), 4th quartile
plasma PFDA)
diseasePrevalence of wheezing
OR 0.879 (0.602–1.28), 4th quartile
1.2 and 1.0 ng/mL (meanserum PFDA levels in theasthmatic and non-asthmaticchildren, respectively; serum
levels were not reported forfull cohort)Asthma diagnosis
Asthma severity
IgE

0.575 ng/mL (mean maternal Risk of total infectious
serum PFDA)
diseases

OR 0.799 (0.588–1.08), 4th quartile,p=0.114 for trend

0.28 ng/mL (geometric mean Tetanus antibody levels at
PFDA at age 5 years)
age 5

NS, maternal PFDA
β -19.9% (-33.1 to -3.9), per 2-foldincrease PFDA levels at age 5
NS, maternal PFDA
β -22.3 (-35.8 to -5.8), per 2-foldincrease PFDA levels at age 5
NS, maternal PFDA
NS, PFDA at age 5
NS, maternal PFDA
NS, PFDA at age 5

0.28 ng/mL (geometric mean Tetanus antibody levels atmaternal PFDA)
age 7
Diphtheria antibody levels
at age 5
Diphtheria antibody levels
at age 7

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Grandjean et al. 2017

0.4 and 0.3 ng/mL (median at Tetanus antibody levels atage 7 and 13 years)
age 13Diphtheria antibody levels
at age 130.30 ng/mL (median PFDA)
Diphtheria antibody levels

Association (p=0.022)*, PFDA at age 7
NS (p=0.258), PFDA at age 13
Association (p=0.008)*, PFDA at age 7
NS (p=0.726), PFDA at age 13
Inverse association (p=0.009)*,
unadjusted
NS (p=0.130), unadjusted

General population (n=516 children
examined at age 7 and 13 years)
Kielsen et al. 2016
General population (n=12 adults)
Okada et al. 2014
General population (n=2,603 infants)

Qin et al. 2017
General population (n=132 children aged
10–15 years and 168 matched controls)
Smit et al. 2015
General population (n=1,024 children)

Zhu et al. 2016
General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Dong et al. (2013)

Tetanus antibody levels
0.563 ng/mL (maternal mean Risk of allergic diseases
PFDA)
Males
FemalesEczemaMales
Females
1.13 and 0.93 ng/mL (median Asthma
serum PFDA in cases andcontrols)
0.16 and 0.42 ng/mL(maternal mean PFDA in
Ukraine and Greenland
cohorts)

Ever having asthma
Ever having eczema
Current eczema
Ever having wheezing
Current wheezing
1.24 and 1.02 ng/mL (mean in Asthma diagnosis
asthmatics and nonasthmatics)
T-helper cytokines
IL-4
IL-5
IFN-γ
IL-2
Serum IgE

OR 1.13 (0.78–1.64), 4th quartile
OR 0.70 (0.47–1.04), 4th quartile
OR 0.93 (0.60–1.44), 4th quartile
OR 0.78 (0.49–1.25), 4th quartile
OR 1.24 (0.97–1.58)

OR 0.92 (0.73–1.16), whole cohort
OR 0.88 (0.73–1.06), whole cohort
OR 0.95 (0.75–1.20), whole cohort
OR 0.85 (0.70–1.01), whole cohort
OR 0.76 (0.56–1.04), whole cohort
OR 3.45 (1.51–7.88)*, males 4th quartile
OR 3.68 (1.43–9.48)*, females 4thquartile
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)
Association (p=0.002 for trend)*PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb
PFUnA
Goudarzi et al. 2016a
General population (n=1,558 4-year-old
children)
Goudarzi et al. 2017
General population (n=1,558 mother-childpairs); children examined up to 4 years ofage
Impinen et al. 2018

Serum perfluoroalkyl level Outcome evaluatedResultc

1.534 ng/mL (mean maternal Prevalence of allergic
plasma PFUnA)
diseasePrevalence of wheezing

OR 0.736 (0.538–1.00), 4th quartile

1.534 ng/mL (mean maternal Risk of total infectious
serum PFUnA)
diseases

OR 1.03 (0.764–1.40), 4th quartile,
p=0.786 for trend

0.1 ng/mL (mean cord
PFUnNA)

General population (n=641 infants followed
through age 10)

Kielsen et al. 2016

Okada et al. 2014
General population (n=2,603 infants)

Number of common colds β 0.11 (0.08–0.14; p=<0.0001)*(0–2 years of age)
Number of lower respiratory β 0.18 (0.13–0.23; p=<0.0001)*
infections (0–10 years ofage)
Rhinitis
NS
Rhinoconjunctivitis
NS
Asthma diagnosis
NS
Current asthma
NS
Asthma everNS
Allergic sensitizationNS

0.21 ng/mL (median PFUnA) Diphtheria antibody levels

General population (n=12 adults)

Tetanus antibody levels
1.50 ng/mL (maternal mean
PFUnA)

OR 1.04 (0.714–1.51), 4th quartile

Risk of allergic diseases
Males
FemalesEczemaMales
Females

Inverse association (p=0.036)*,
unadjusted
Inverse association (p=0.039)*,
unadjusted
OR 1.13 (0.79–1.63), 4th quartile
OR 0.58 (0.39–0.86)*, 4th quartile
OR 1.16 (0.75–10.81), 4th quartile
OR 0.50 (0.30–0.81)*, 4th quartilePERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Smit et al. 2015

0.16 and 0.68 ng/mL(maternal mean PFUnA in
Ukraine and Greenland
cohorts)

OR 0.96 (0.77–1.21), whole cohort
OR 0.95 (0.79–1.15), whole cohort
OR 1.07 (0.85–1.34), whole cohort
OR 0.84 (0.70–1.00), whole cohort
OR 0.87 (0.65–1.17), whole cohort

General population (n=1,024 children)

PFHpA
Kielsen et al. 2016
General population (n=12 adults)
Smit et al. 2015
General population (n=1,024 children)

PFBS
Dong et al. 2013
General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Zhu et al. (2016)

Qin et al. 2017
General population (n=132 children aged
10–15 years and 168 matched controls)

Ever having asthma
Ever having eczema
Current eczema
Ever having wheezing
Current wheezing

0.12 ng/mL (median PFHpA) Diphtheria antibody levels
Tetanus antibody levels

NS (p=0.750), unadjusted
NS (p=0.280), unadjusted

0.03 and 0.05 ng/mL(maternal mean PFHpA in
Ukraine and Greenland
cohorts)

Ever having asthma

OR 0.93 (0.71–1.22), whole cohort

Ever having eczema
Current eczema
Ever having wheezing
Current wheezing

OR 0.93 (0.78–1.11), whole cohort
OR 0.90 (0.70–1.15), whole cohort
OR 1.03 (0.84–1.25), whole cohort
OR 0.62 (0.40–0.97)*, Ukraine cohort
OR 1.24 (0.79–1.93), Greenland cohort
OR 0.88 (0.64–1.20), whole cohort

OR 1.90 (1.08–3.37)*, 4th quartile
NS (p=0.092 for trend)
NS (p>0.05), asthmatics
NS (p>0.05), non-asthmatics
Absolute eosinophil counts Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Eosinophil cationic protein NS (p>0.05), asthmatics
NS (p>0.05), non-asthmatics
0.48 and 0.48 ng/mL (median Asthma
OR 1.06 (0.93–1.20)
serum PFBS in cases andcontrols)
0.5 and 0.5 ng/mL (meanserum PFBS levels in theasthmatic and non-asthmaticchildren, respectively; serum
levels were not reported forfull cohort)Asthma diagnosis
Asthma severity
IgE

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Zhu et al. 2016

0.53 and 0.48 ng/mL (meanserum PFBS in asthmatics
and non-asthmatics)

OR 2.59 (1.14–5.87)*, males 4th quartile
NS (p=0.505 for trend), females

General population (n=231 asthmatic and225 non-asthmatic children)
This is the same group of children
evaluated by Dong et al. (2013)

Asthma diagnosis
T-helper cytokines
IL-4
IL-5
IFN-γ
IL-2
Serum IgE

NS (p>0.05 for trend)
Association (p=0.023 for trend)*
NS (p>0.05 for trend)
NS (p>0.05 for trend)
NS (p>0.05 for trend)

PFDoDA
Dong et al. 2013
General population (n=231 asthmatic and225 non-asthmatic children)

Goudarzi et al. 2016a
General population (n=1,558 4-year-old
children)
Goudarzi et al. 2017
General population (n=1,558 mother-childpairs); children examined up to 4 years ofage
Kielsen et al. 2016
General population (n=12 adults)

5.8 and 4.5 ng/mL (meanserum PFDoDA levels in theasthmatic and non-asthmaticchildren, respectively; serum
levels were not reported forfull cohort)

0.191 ng/mL (mean maternal
plasma PFDoDA)

OR 1.81 (1.02–3.23)*, 4th quartile
Association (p=0.024 for trend)*
Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Absolute eosinophil counts Association (p<0.05)*, asthmatics
NS (p>0.05), non-asthmatics
Eosinophil cationic protein Association (p<0.05)*, asthmatics
Association (p<0.05)*, non-asthmatics
Prevalence of allergic
OR 0.621 (0.454–0.847)*, 4th quartile
diseasePrevalence of wheezing
OR 0.999 (0.684–1.45), 4th quartile
Asthma diagnosis
Asthma severity
IgE

0.191 ng/mL (mean maternal
serum PFDoDA)

Risk of total infectious
diseases

OR 1.07 (0.790–1.46), 4th quartile,
p=0.502 for trend

0.039 ng/mL (median
PFDoDA)

Diphtheria antibody levels

Inverse association (p=0.038)*,
unadjusted
Inverse association (p=0.038)*,
unadjusted

Tetanus antibody levels

PERFLUOROALKYLS

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedOkada et al. 2014

0.188 ng/mL (maternal mean
PFDoDA)

Resultc

General population (n=2,603 infants)

Risk of allergic diseases
Males
Females

OR 0.93 (0.65–1.34), 4th quartile
OR 0.58 (0.39–0.85)*, 4th quartile

Smit et al. 2015

EczemaMales
FemalesEver having asthma

OR 1.00 (0.64–1.55), 4th quartile
OR 0.73 (0.45–1.18), 4th quartile
OR 1.03 (0.81–1.30), whole cohort

Ever having eczema
Current eczema
Ever having wheezing
Current wheezing

OR 0.90 (0.75–1.08), whole cohort
OR 0.88 (0.70–1.14), whole cohort
OR 0.97 (0.80–1.16), whole cohort
OR 0.87 (0.64–1.18), whole cohort

Asthma diagnosis

OR 1.60 (0.90–2.86), 4th quartile

Asthma severity
IgE

NS (p=0.854)
NS (p>0.05), asthmatics
NS (p>0.05), non-asthmatics

General population (n=1,024 children)

PFHxA
Dong et al. 2013
General population (n=231 asthmatic and225 non-asthmatic children)

0.04 and 0.13 ng/mL(maternal mean PFDoDA in
Ukraine and Greenland
cohorts)

0.3 and 0.2 ng/mL (meanserum PFHxA levels in theasthmatic and non-asthmaticchildren, respectively; serum
levels were not reported forfull cohort)

Absolute eosinophil counts NS (p>0.05), asthmatics
NS (p>0.05), non-asthmatics
Eosinophil cationic protein

Qin et al. 2017
General population (n=132 children aged
10–15 years and 168 matched controls)

0.20 and 0.18 ng/mL (median Asthma
serum PFHxA in cases andcontrols)

NS (p>0.05), asthmatics
NS (p>0.05), non-asthmatics
OR 0.99 (0.80–1.21)

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Table 2-16. Summary of Immunological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

FOSA
Impinen et al. 2018

0.4 ng/mL (mean cord FOSA) Number of common colds NS (p=0.477)(0–2 years of age)
General population (n=641 infants followed
Number of lower respiratory β 0.10 (0.06–0.14; p=<0.0001)*
through age 10)
infections (0–10 years ofage)
Rhinitis
NS
Rhinoconjunctivitis
NS
Asthma diagnosis
NS
Current asthma
NS
Asthma everNS
Allergic sensitizationNS

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 10 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk and bold indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

CI = confidence interval; IFN-α-2 = interferon-α2; IFN-γ = interferon-γ; IgA = immunoglobulin A; IgE = immunoglobulin E; IP-10 = interferon-γ-inducible protein 10;
IRR= incidence risk ratio; NHANES = National Health and Nutrition Examination Survey; NR = not reported; NS = not significant; OR = odds ratio;
PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid;
PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid;PFUnA = perfluoroundecanoic acid; RR= relative risk; SPR = standard prevalence ratio; TNF-α =tumor necrosis factor-α

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2. HEALTH EFFECTS

autoimmunity; epidemiological studies provide suggestive evidence of an association between serum
PFOA and the risk of ulcerative colitis. The small number of studies investigating immunotoxicity
following exposure to PFHpA and PFHxA did not find associations.

Laboratory animal studies have also evaluated immunosuppression (disease resistance, antibody response,
NK cell activity, delayed-type hypersensitivity response, monocyte phagocytosis), hypersensitivity(airway resistance, local lymph node assay), and autoimmunity. In addition, laboratory animal studies
have examined secondary outcomes (lymphoid organ weights, lymphocyte counts or subpopulations,
lymphocyte proliferation, cytokine levels, serum antibody levels, histological alterations in immune
organs). Summaries of the laboratory animal studies are presented in the LSE tables for PFOA, PFOS,
and other perfluoroalkyls (Tables 2-3, 2-4, 2-5, and 2-6); the NOAEL and LOAEL values are presented in
Figures 2-8, 2-9, and 2-10. No laboratory animal studies were identified for PFUnA, PFHpA, PFDoDA,
or FOSA. Studies in laboratory animals identify the immune system as a sensitive target of toxicity
following exposure to PFOA and PFOS. The observed effects include impaired responses to T-dependent
antigens, impaired response to infectious disease, and secondary outcomes (decreases in spleen andthymus weights and in the number of thymic and splenic lymphocytes). A small number of studies
evaluated the immunotoxicity of other perfluoroalkyls and most did not evaluate immune function. No
alterations in spleen or thymus organ weights or morphology were observed in studies on PFHxS, PFBA,
and PFDA. A study on PFNA found decreases in spleen and thymus weights and alterations in splenic
lymphocyte phenotypes.

The National Toxicology Program (NTP 2016b) concluded that exposure to PFOA or PFOS is presumed
to be an immune hazard to humans based on a high level of evidence that PFOA and PFOS suppressed
the antibody response from animals and a moderate level of evidence from studies in humans. It wasnoted that the strongest evidence is for suppression of the antibody response and increased
hypersensitivity (PFOA only).
PFOA

Epidemiological Studies—Immunosuppression Outcomes. Studies evaluating the immunosuppressive
effects of PFOA have examined disease resistance and antibody responses. One study found associations
between maternal serum PFOA and the number of episodes of the common cold and other respiratory
tract infections and the number of episodes of gastroenteritis with vomiting or diarrhea in 3-year-old
children (Granum et al. 2013). Another study found an association between maternal PFOA and the risk

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2. HEALTH EFFECTS

of having a greater number of days with a fever greater than the median (Dalsager et al. 2016), although
there was no increase in the number of days with a fever. A third study found an increased risk of lower
respiratory tract infections associated cord PFOA from birth to 10 years of age (Impinen et al. 2018).
However, other studies have not found associations between PFOA levels and the frequency of thecommon cold or flu in adults (Looker et al. 2014), between maternal PFOA levels and otitis media in 1.5–
3-year-old children (Granum et al. 2013; Okada et al. 2012), between maternal PFOA and the risk of
hospitalization for infectious diseases in young children (Fei et al. 2010), between maternal PFOA and therisk of number of days with cough, nasal discharge, diarrhea, or vomiting (Dalsager et al. 2016), between
cord PFOA and number of common colds (Impinen et al. 2018), or between maternal serum PFOA andtotal number of infectious diseases between birth and 2 years of age (Goudarzi et al. 2017).

Several studies have evaluated the antibody response to vaccination in adults and children; the changes in
the response to antibody levels relative to serum PFOA levels are graphically presented in Figure 2-21;
the figure does not include data from other studies that used different statistical methods. In adults,
decreases in antibody response against influenza A H3N2 virus were associated with increasing serum
PFOA levels; however, there were no associations with two other strains of influenza virus(influenza A H1N1 and influenza B) (Looker et al. 2014). Another study of adults also did not find analtered immune response to influenza A H1N1 virus (Stein et al. 2016b). A small-scale study of 12 adults
did not find significant alterations in the response to diphtheria or tetanus booster vaccines associatedwith serum PFOA levels (Kielsen et al. 2016). Increasing current serum PFOA levels were associatedwith lower antibody levels for mumps and rubella, but not for measles, in a cross-sectional study ofadolescents (Stein et al. 2016a). A series of prospective studies by Grandjean and associates (Grandjean
et al. 2012, 2017; Mogensen et al. 2015a) evaluated tetanus and diphtheria antibody levels in children at
5, 7, and 13 years of age. Diphtheria antibody levels at age 7 and 13 were inversely associated withserum PFOA levels at age 5 and 7 (Grandjean et al. 2012; Mogensen et al. 2015a) and with serum PFOA
at age 13 (Grandjean et al. 2017), respectively. Decreases in tetanus antibody levels at age 7 wereassociated with increases in serum PFOA levels at age 5, but not at age 7 (Grandjean et al. 2012;
Mogensen et al. 2015a) and tetanus antibody levels were not associated with serum PFOA at age 7 or
13 (Grandjean et al. 2017). In studies comparing maternal serum PFOA with antibody levels in children,no associations were found for tetanus antibodies at age 3 (Granum et al. 2013), age 5 (Grandjean et al.
2012), or age 7 (Grandjean et al. 2012) or for diphtheria at age 5 or 7 (Grandjean et al. 2012). It is notedthat Grandjean and associates also found an inverse association between serum polychlorinated biphenyls(PCBs) and serum antibody concentrations against tetanus and diphtheria in children living in the FaroePERFLUOROALKYLS

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2. HEALTH EFFECTS

Figure 2-21. Antibody Responses Relative to Serum PFOA Levels in Epidemiological Studies(Presented as percent difference in antibody concentration per 2-fold increase in serum PFOA)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Islands (Heilmann et al. 2010). Statistically adjusting for PCB exposure (milk and serum PCB levels) did
not alter the results (Grandjean et al. 2012). Lower levels of rubella antibodies at age 3 were associatedwith increasing maternal PFOA (Granum et al. 2013).

NTP (2016b) concluded that there is moderate confidence that exposure to PFOA is associated with
suppression of the antibody response based on the available human studies. NTP (2016b) also concluded
that there is low confidence that exposure to PFOA is associated with increased incidence of infectious
disease (or lower ability to resist or respond to infectious disease).

Epidemiological Studies—Hypersensitivity Outcomes. Of the different types of hypersensitivity effects,
the most widely studied endpoint is asthma; the possible association between exposure to PFOA andasthma has been studied in occupational, community, and general population studies. Several studies
have found associations between current serum PFOA levels and diagnosis of asthma in children (Dong etal. 2013; Humblet et al. 2014; Qin et al. 2017) and adults (Anderson-Mahoney et al. 2008; Zhu et al.
2016). A case-control study found significantly higher serum PFOA levels in asthmatic adolescents ascompared to adolescents without asthma (Zhou et al. 2017).

However, other studies have found no association between estimated cumulative serum PFOA levels andincidence of asthma being treated with medication in workers (Steenland et al. 2015) or asthma in thegeneral population (Stein et al. 2016a). In children, no associations between maternal serum PFOA levels
and asthma-related health outcomes were observed in 3-year-old children (Granum et al. 2013), 5–9-yearold children (Smit et al. 2015) or 1–10-year-old children (Impinen et al. 2018), or between current PFOA
levels and current asthma in adolescents (Stein et al. 2016a). However, the Stein et al. (2016a) study did
find an association with rhinitis in adolescents. No associations between maternal PFOA and wheezing
were found in infants up to 18 months of age (Okada et al. 2012), infants 12 or 24 months of age (Okada
et al. 2014), children 3 years of age (Granum et al. 2013), children 5–9 years of age (Smit et al. 2015),
children 2–10 years old (Impinen et al. 2018), or between current serum PFOA levels and wheezing in
adults (Stein et al. 2016a). The ORs for asthma diagnosis relative to serum PFOA levels are graphicallypresented in Figure 2-22; studies using different statistical methods are not included. No associations
between maternal PFOA and prevalence of allergic diseases or wheezing were found in 4-year-old
children (Goudarzi et al. 2016a). No associations between maternal PFOA and eczema were found in
infants up to 18 months of age (Okada et al. 2012), children 3 years of age (Granum et al. 2013), or
children 5–9 years of age (Smit et al. 2015). Similarly, no association was found between cord blood
PFOA and atopic dermatitis in children 2 years of age (Wang et al. 2011).

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Figure 2-22. Risk of Asthma Diagnosis Relative to PFOA Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

No associations were found between risks of allergy or allergic sensitization and current serum PFOA
levels in adults (Stein et al. 2016a) or between cord PFOA in 2–10-year-old children (Impinen et al.
2018). Two studies examining the possible association between current serum PFOA levels in adults andfood allergies have found mixed results, with one study finding an association (Buser and Scinicariello2016) and one not finding an association (Stein et al. 2016a); a study in infants did not find an association
between the risk of food allergy and maternal serum PFOA levels (Okada et al. 2012). It is noted that IgElevels, which were used to assess food allergies, is not a sensitive measure of clinical food allergy. No
association was found for food sensitization (Buser and Scinicariello 2016).

Associations between serum PFOA and IgE, eosinophil counts, and eosinophil cationic protein levels
were observed in asthmatic children (9–16 years of age), but not in non-asthmatic children (Dong et al.
2013; Zhu et al. 2016). Significantly higher IL-4 and IL-5 levels were observed in male children withasthma with the highest PFOA levels (Zhu et al. 2016). Two studies found associations between PFOA
and IgE levels in infants. An inverse association was found between maternal PFOA and IgE levels infemale infants but not in male infants (Okada et al. 2012), whereas Wang et al. (2011) found a correlation
between cord blood PFOA and child IgE levels in males only or in males and females combined. A third
study did not find an association between cord blood PFOA and IgE levels in infants (Ashley-Martin etal. 2015). NTP (2016b) concluded that there is low confidence that exposure to PFOA during childhood
is associated with increased hypersensitivity responses.

Epidemiological Studies—Autoimmune Outcomes. There are limited data that can be used to evaluate
the possible association between PFOA exposure and the risk of autoimmune diseases. Significant
increases in the risk of ulcerative colitis were observed in an occupational exposure study (Steenland et al.
2015) and a C8 Science Panel study (Steenland et al. 2013). Although both studies found consistent
results, it should be noted that the community study also included participants with occupational exposure
to PFOA. The occupational study also found an association between PFOA exposure and rheumatoid
arthritis; this was not observed in the community study. The community study (Steenland et al. 2013)
also found no associations for other autoimmune diseases (Crohn’s disease, Type I diabetes, lupus, andmultiple sclerosis). A third study examined neural- and non-neural-specific antibodies and found noassociations with cord blood PFOA or current serum PFOA in 7-year-old children (Osuna et al. 2014).

NTP (2016b) concluded that there is low confidence that exposure to PFOA is associated with ulcerative
colitis.

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Laboratory Animal Studies. The results of several mouse studies support the epidemiological datasuggesting that exposure to PFOA can result in immunosuppression. Significant alterations in IgM levels
in response to T-dependent antigens, such as sheep red blood cells (sRBCs) or horse red blood cells wereobserved in acute and intermediate oral mouse studies (DeWitt et al. 2008, 2009, 2016; Loveless et al.
2008; Yang et al. 2002a); the lowest-adverse-effect level was 3.75 mg/kg/day in mice exposed to PFOA
in the drinking water for 15 days (DeWitt et al. 2008). Rats appear to be less sensitive than mice; noalterations in IgM levels were observed in rats administered PFOA via gavage for 28 days (Loveless et al.
2008). In a mouse developmental toxicity study, exposure to PFOA on GDs 6–17 was not associatedwith alterations in IgM or IgG levels in the offspring (Hu et al. 2010). Limited data suggest thatalterations in NK cells or delayed type hypersensitivity are not sensitive endpoints for PFOA in laboratory
animals. Exposure of male rats to 50 mg/kg/day PFOA by gavage for 14 days did not significantly affectthe numbers of T cells, NK cells, or helper T cells (Iwai and Yamashita 2006), and tests for delayed-type
hypersensitivity response in mice challenged with bovine serum albumin following exposure to30 mg/kg/day PFOA via drinking water for 15 days were negative (DeWitt et al. 2008).
Two studies have evaluated hypersensitivity in mice. Application of ≥18.8 mg/kg/day PFOA to thedorsal surface of the ears of mice and subsequently injected with ovalbumin resulted in a significant
increase in serum total IgE compared to mice exposed only to ovalbumin (Fairley et al. 2007).
Ovalbumin-specific airway hyperreactivity also increased in mice co-exposed to ovalbumin and 25 mg/kg
PFOA relative to mice exposed to ovalbumin alone. The investigators suggested that PFOA exposure
may increase the IgE response to environmental allergens (Fairley et al. 2007). In contrast to the resultsof the dermal study, no increases in airway hyperresponsiveness were observed in ovalbumin-sensitizedmice exposed in utero and post-weaning to PFOA in the diet (Ryu et al. 2014). In nonsensitized mice,
PFOA did induce airway hyperresponsiveness in 12-week-old pups.

Numerous studies have evaluated secondary outcomes in monkeys, rats, and mice. In the spleen andthymus, exposure to PFOA resulted in decreases in organ weight, decreases in the number of cells, and/or
atrophy (DeWitt et al. 2008; Loveless et al. 2008; Qazi et al. 2009a, 2012; Son et al. 2009; Yang et al.
2000, 2001, 2002b). Acute exposure resulted in decreases in absolute thymus weight at 11.5 mg/kg/day(Yang et al. 2001), decreases in spleen weight at 30 mg/kg/day (Qazi et al. 2012; Yang et al. 2000), andsevere thymic atrophy at 30 mg/kg/day (Qazi et al. 2012; Yang et al. 2000). Exposure of male rats to
50 mg/kg/day PFOA by gavage for 14 days did not significantly affect the absolute or relative spleen
weight nor did it alter lymphocyte subsets (Iwai and Yamashita 2006).

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Decreases in relative spleen weight were observed at ≥0.96 mg/kg/day PFOA, and absolute spleen weight
and absolute and relative thymus weights were decreased at 9.6 and 29 mg/kg/day (Loveless et al. 2008).
The lowest-adverse-effect levels for spleen and thymus weight changes identified in mouse intermediatestudies were 3.75 mg/kg/day PFOA for decreases in absolute spleen weight (DeWitt et al. 2008) and9.6 mg/kg/day for decreases in absolute and relative thymus weight (Loveless et al. 2008). In rats, noalterations in spleen weight were observed following chronic exposure to 15 mg/kg/day in the diet (3M
1983; Butenhoff et al. 2012c).

Decreases in the number of splenic and thymic lymphocytes were observed in mice administered via
gavage ≥9.6 mg/kg/day PFOA for 28 days (Loveless et al. 2008). In contrast, administration of
29 mg/kg/day PFOA by gavage for 28 days did not result in alterations in the number of splenic or thymic
lymphocytes in rats (Loveless et al. 2008). A 10-day exposure of mice to 3.0 mg/kg/day PFOA resulted
in decreases in the number of bone marrow B-lymphoid cells (Qazi et al. 2012); a decrease in bonemarrow myeloid cells was also observed at 30 mg/kg/day. Examination of the B-lymphoid cell
subpopulations showed decreases in pro/pre B cells, immature B cells, and early mature B cells, with thegreatest reductions observed for pro/pre B cells. When mice were allowed to recover for 10 days
following a 10-day exposure to 30 mg/kg/day PFOA in the diet, only a partial recovery of B-lymphoidcells was observed. Significant increases in CD4-CD8- and CD4-CD8+ thymic lymphocytes wereobserved in mice exposed to 47.21 mg/kg/day for 21 days; increases in CD4+CD8+ lymphocytes wereobserved at 17.63 and 47.21 mg/kg/day (Son et al. 2009). Similarly, there were decreases in splenic
CD4-CD8- lymphocytes at 47.21 mg/kg/day and CD4-CD8+ lymphocytes at ≥0.49 mg/kg/day andincreases in splenic CD4+CD8- lymphocytes at 17.63 and 47.21 mg/kg/day.

Two studies examined the immune response to mitogens in mice exposed to PFOA. Marked decreases intotal leukocytes, lymphocytes, and neutrophils levels and increases in tumor necrosis factor-α (TNF-α)
and interleukin-6 (IL-6) were observed in the peritoneal cavity, bone marrow, and spleen cells in response
to lipopolysaccharide (LPS) stimulation in mice exposed to approximately 40 mg/kg/day PFOA for
10 days (Qazi et al. 2009a). Exposure of splenic lymphocytes isolated from PFOA-exposed mice toconcavalin A (ConA) or LPS resulted in decreases in lymphocyte proliferation (Yang et al. 2002a).

A number of studies have evaluated the potential of PFOA to induce histological alterations in immune
organs. In monkeys, administration of approximately 20 mg/kg/day PFOA administered via a capsule toCynomolgus monkeys for 4 or 26 weeks did not affect the gross or microscopic morphology of the spleen(Butenhoff et al. 2002; Thomford 2001). Administration via gavage of 30 mg/kg/day PFOA to Rhesus

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monkeys for 90 days induced atrophy of lymphoid follicles in the spleen and lymph nodes and slight tomoderate hypocellularity of the bone marrow (Griffith and Long 1980). No histological alterations wereobserved in the spleen or thymus of rats exposed intermittently to ≤84 mg/m3 APFO dusts for 2 weeks(Kennedy et al. 1986), ≤29 mg/kg/day administered via gavage for 28 days (Loveless et al. 2008), or
dermal doses of ≤2000 mg/kg/day for 2 weeks (Kennedy 1985) or in the spleen and mesenteric lymph
nodes of rats exposed to ≤110 mg/kg/day PFOA in the diet for 90 days (Griffith and Long 1980) or≤15 mg/kg/day PFOA in the diet for 2 years (3M 1983; Butenhoff et al. 2012c).
Studies in wild-type mice and PPARα-null mice demonstrate that PFOA-induced immunomodulation
results from PPARα-dependent and -independent mechanisms (DeWitt et al. 2016; Yang et al. 2002b).
Exposure to 30 or 33 mg/kg/day PFOA resulted in decreases in spleen weight, thymus weight, number of
splenic lymphocytes, number of thymic lymphocytes, and CD4+ and CD8+ splenic and thymic
lymphocytes in wild-type mice. Similar exposures of PPARα knockout mice did not result in alterationsin spleen weight, number of splenic lymphocytes, or their phenotypes. Although decreases in thymus
weight, number of thymic lymphocytes, and their phenotypes were observed in the knockout mice, themagnitudes of the changes were lower in the knockout mice than in the wild-type mice. However, similar
responses were observed in T-cell-dependent antibody responses. Exposure to 30 mg/kg/day PFOA
resulted in 16 and 14% decreases in the response to sRBCs in wild-type and knockout mice, respectively(DeWitt et al. 2016).

In a systematic review of the available laboratory animal data, NTP (2016b) concluded that there is highconfidence that exposure to PFOA is associated with suppression of the antibody response, very low
confidence that PFOA is associated with the ability to respond to infectious disease, and moderateconfidence that PFOA is associated with increased hypersensitivity.

Summary. Epidemiological studies have evaluated several aspects of immunotoxicity including
immunosuppression, hypersensitivity, and autoimmunity. A number of general population studies havefound significant inverse associations between serum PFOA levels and antibody responses to vaccines.
However, no consistent associations were found between serum PFOA and disease resistance, as
measured by episodes of the common cold, cough, fever, or hospitalization for infectious disease. In testsof hypersensitivity, there is some evidence of an association between serum PFOA and asthma diagnosis
in children and adults, although this finding was not consistent across studies; increased risk of allergy orallergic sensitization does not appear to be associated with serum PFOA. Based on the findings of an
occupational exposure and community exposure study, there is some suggestive association between

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serum PFOA and an increased risk of ulcerative colitis, but not for other autoimmune diseases. Animalstudies suggest that the immune system is a sensitive target of PFOA toxicity. A number of studies inmice have demonstrated evidence of immunosuppression and increased hypersensitivity. Laboratory
animal studies have also found secondary immune outcomes in the spleen and thymus, which included
decreases in organ weight and decreases in the number of lymphocytes.

PFOS

Epidemiological Studies—Immunosuppression Outcomes. Several epidemiological studies haveevaluated the potential of PFOS to cause immunosuppression. In studies that evaluated infectious disease
resistance, no alterations in the risk of otitis media were observed in infants monitored through 18 months
or 3 years of age (Granum et al. 2013; Okada et al. 2012), common cold or other upper respiratory
infections (Granum et al. 2013), gastroenteritis with vomiting or diarrhea (Granum et al. 2013),
hospitalizations due to infectious diseases in children (Fei et al. 2010), or symptoms of infection such as
nasal discharge, cough, diarrhea, or vomiting in children (Dalsager et al. 2016). In contrast, other studies
have found associations between PFOS and infectious diseases. Associations between the number ofdays with symptoms of infection and maternal PFOS levels were observed in children (Dalsager et al.
2016) and between maternal serum PFOS and the risk of total infectious disease in early life (age 4 years)(Goudarzi et al. 2017). Associations were also found between cord PFOS levels and the number ofcommon colds from 0 to 2 years of age and the number of lower respiratory tract infections between
0 and 10 years of age (Impinen et al. 2018).

Other studies evaluating immunosuppression found significant alterations in the response to vaccines; thechanges in the response to antibody levels relative to serum PFOS levels are graphically presented in
Figure 2-23; studies utilizing different statistical methods are not included in this figure. In children
receiving a tetanus vaccination at age 5, there were associations between serum PFOS levels at age 5 andtetanus antibody levels at age 5 (Grandjean et al. 2012) and between serum PFOS levels at age 7 andtetanus antibody levels at age 7 when the analysis was restricted to children who were not likely to have
had a booster vaccine after age 5 (Grandjean and Budtz-Jorgensen 2013). However, no associations were
found between tetanus antibody levels at age 5 and maternal PFOS or child PFOS levels (Grandjean et al.
2012), between tetanus antibody levels at age 7 and maternal PFOS or child PFOS levels at age 5 or
7 years (Grandjean et al. 2012; Mogensen et al. 2015a), or between tetanus antibody levels at age 14 andchild PFOS levels at age 13 (Grandjean et al. 2017). Similarly, diphtheria antibody levels at age 7 werePERFLUOROALKYLS

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Figure 2-23. Antibody Responses Relative to Serum PFOS Levels in Epidemiological Studies(Presented as percent difference in antibody concentration per 2-fold increase in serum PFOS)PERFLUOROALKYLS

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2. HEALTH EFFECTS

significantly associated with serum PFOS levels at age 5 and 7 (Grandjean et al. 2012; Mogensen et al.
2015a), but antibody levels at age 5 were not associated with maternal PFOS or child PFOS at age 5 years(Grandjean et al. 2012) and antibody levels at age 13 were not associated with child PFOS levels at age
7 or 13 years (Grandjean et al. 2017). In another study of children (Granum et al. 2013), decreased
rubella antibody levels were associated with higher maternal PFOS levels, but no associations were found
for tetanus or Haemophilus influenza type B antibodies. In adolescents, recent serum PFOS levels wereinversely associated with mumps and rubella antibody levels, but not with measles antibody levels (Steinet al. 2016a). In studies in adults, recent PFOS levels were inversely associated with diphtheria antibody
levels 30 days after booster administration (Kielsen et al. 2016), but not with tetanus antibody levels
30 days after booster administration (Kielsen et al. 2016) or influenza types A H3N2, A H1N1, or
B antibody levels 21 days post-vaccination (Looker et al. 2014).

NTP (2016b) concluded that there is moderate confidence that exposure to PFOS is associated with
suppression of the antibody response and that there is low confidence that exposure to PFOS is associatedwith increased incidence of infectious disease (or lower ability to resist or respond to infectious disease).

Epidemiological Studies—Hypersensitivity Outcomes. Several studies examined the risk ofhypersensitivity associated with serum PFOS in children and adolescents; however, the results areinconsistent. In three case-control studies, increased risks of asthma were observed. Qin et al. (2017)
reported increased risk of asthma in children associated with serum PFOS levels. Dong et al. (2013)
reported an increased risk of asthma diagnosis and increased severity of asthma episodes in children withPFOS levels in the 4th quartile. Zhu et al. (2016) also reported an association between asthma diagnosis
and serum PFOS levels in the 4th quartile; however, the association was only significant in males. A thirdcase-control study found significantly elevated serum PFOS levels in asthmatic adolescents (Zhu et al.
2016). Prospective and cross-sectional studies in children (Granum et al. 2013) did not find an
association between maternal PFOS levels and the risk of asthma diagnosis in 3-year-old children;
between cord PFOS and asthma diagnosis, current asthma, or ever having asthma in 2–10-year-old
children (Impinen et al. 2018); or between maternal PFOS and asthma diagnosis in adolescents (Humblet
et al. 2014; Stein et al. 2016a). Data evaluating associations between serum PFOS and the risk of asthma
diagnosis are presented in Figure 2-24.

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Figure 2-24. Risk of Asthma Diagnosis Relative to PFOS Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

No associations between maternal PFOS or cord PFOS and eczema, atopic dermatitis, or wheezing or
total allergic diseases have been found in children (Goudarzi et al. 2016a; Granum et al. 2013; Impinen etal. 2018; Okada et al. 2012, 2014; Smit et al. 2015; Wang et al. 2011). Similarly, no associations between
recent serum PFOS levels in adolescents and food allergies or sensitizations (Buser and Scinicariello2016; Stein et al. 2016a) or maternal PFOS levels and food allergies in infants (Okada et al. 2012) wereobserved. However, in a cross-sectional study of adolescents, recent PFOS levels were associated withmold allergies and inversely associated with the risk of plant or cockroach or shrimp allergies (Stein et al.
2016a). In related studies, cord blood PFOS levels were associated with an increase in cord IgE levels,
but not in infant serum IgE levels (Wang et al. 2011). Two other studies did not find associations
between maternal PFOS levels and cord IgE levels (Ashley-Martin et al. 2015; Okada et al. 2012).

NTP (2016b) concluded that there is very low confidence that exposure to PFOS is associated withchanges in the hypersensitivity response in children.

Laboratory Animal Studies. A limited number of laboratory animal studies examined PFOS-induced
immunosuppression. Guruge et al. (2009) reported an impaired response to an influenza A virus
challenge in mice administered 0.025 mg/kg/day PFOS via gavage for 21 days (Guruge et al. 2009).
Several studies have found an impaired response to sRBCs (Dong et al. 2009, 2011; Peden-Adams et al.
2008); however, decreases in NK cell activity were observed at higher doses (0.83–2.08 mg/kg/day)(Dong et al. 2009). Qazi et al. (2009a) reported several alterations in parameters associated with theinnate immune system in mice exposed to approximately 40 mg/kg/day PFOS in the diet for 10 days.
These alterations included marked decreases in total leukocyte and lymphocyte levels and increases in
TNF-α and IL-6 levels in the peritoneal cavity and bone marrow in response to LPS stimulation; noalterations were observed in mice exposed to a 20-fold lower dose. As discussed in Section 2.17, adevelopmental toxicity study (Keil et al. 2008) found an altered response to sRBCs in mice exposed to
PFOS in utero.

No alterations in spleen or thymus weights were observed in mice exposed to 0.025 mg/kg/day PFOS
(Guruge et al. 2009); at a higher dose (0.42 mg/kg/day), significant decreases in relative spleen andthymus weights were observed (Dong et al. 2009; Zheng et al. 2009). Decreases in splenic and thymic
cellularity were also observed at ≥0.42 mg/kg/day PFOS (Dong et al. 2009; Qazi et al. 2009b, 2012;
Zheng et al. 2009). Bone marrow cells (B-lymphoid and myeloid cells) were also significantly decreased
in mice exposed to 30 mg/kg/day PFOS for 10 days (Qazi et al. 2012). Within the B-lymphoid cell
population, there were decreases in the number of pro/pre B cells and immature cells (Qazi et al. 2012).

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Significant alterations in all splenic T cell CD4 and CD8 subpopulations were observed at≥0.00331 mg/kg/day PFOS (Peden-Adams et al. 2008) and thymic lymphocyte phenotypes were altered
at 0.42 mg/kg/day PFOS (Dong et al. 2009).

Rats treated with 1.77 mg/kg/day PFOS for 4 weeks, 6.34 mg/kg/day for 28 days, 1.56 mg/kg/day for
14 weeks, or 1.04 mg/kg/day for 2 years did not show significant morphological alterations in the spleen,
thymus, or mesenteric lymph nodes (Butenhoff et al. 2012b; Lefebvre et al. 2008; Seacat et al. 2003;
Thomford 2002b). Similar findings were reported in Cynomolgus monkeys dosed with up to
2 mg/kg/day for 4 weeks or up to 0.75 mg/kg/day PFOS for 26 weeks (Seacat et al. 2002; Thomford
2002a).

In a systematic review of the available laboratory animal data, NTP (2016b) concluded that there is highconfidence that exposure to PFOS is associated with suppression of the antibody response, moderateconfidence that PFOS is associated with the ability to respond to infectious disease, and low confidence
that PFOS is associated with increased hypersensitivity.

Summary. A number of epidemiological studies have examined the potential immunotoxicity of PFOS.
The database provides convincing evidence of an association between serum PFOS levels andimmunosuppression, particularly impaired antibody responses to vaccines in adults and children. Mixed
results have been observed in studies evaluating infectious disease resistance. Similarly, inconsistent
results have been examined in studies evaluating associations between serum PFOS and hypersensitivity
outcomes, such as asthma; no associations were found for eczema, dermatitis, food allergies/
sensitizations. Laboratory animal studies, particularly studies in mice, provide strong evidence of theimmunotoxicity of PFOS. The strongest evidence comes from studies reporting impaired antibody
responses resulting from oral exposure to relatively low doses of PFOS. Other immune effects include
decreased response to infectious disease, decreases in spleen and thymus weights, and decreases insplenic and thymic cellularity and bone marrow cells.
PFHxS

Epidemiological Studies—Immunosuppression Outcomes. Several epidemiological studies haveexamined the potential of PFHxS to suppress the immune system. Altered antibody responses relative toserum PFHxS levels are graphically presented in Figure 2-25. Inverse associations were observed
between tetanus antibody levels in 5- and 7-year-old children and serum PFHxS levels at age 5 or 7 years

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Figure 2-25. Antibody Responses Relative to Serum PFHxS Levels in Epidemiological Studies(Presented as percent difference in antibody concentration per 2-fold increase in serum PFHxS)PERFLUOROALKYLS

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2. HEALTH EFFECTS(Grandjean et al. 2012; Mogensen et al. 2015a); but there were no associations between serum PFHxSlevels at age 7 or 13 and tetanus antibody levels at age 13 (Grandjean et al. 2017). No associations were
found between maternal PFHxS levels and tetanus antibody levels in the children. These studies found noassociations between diphtheria antibody levels at ages 5, 7, or 13 and serum PFHxS levels in the motheror in the children. A study in 3-year-old children found an inverse association between maternal PFHxSlevels and rubella antibody levels, but no association with influenza type B or tetanus antibody levels(Granum et al. 2013). In adolescents, serum PFHxS levels were also inversely associated with rubella
antibody titers in a seropositive subcohort (Stein et al. 2016a); no associations were found for measles or
mumps antibody titers. Another study in adolescents did not find associations between recent serum
PFHxS levels and tetanus or diphtheria antibody levels (Kielsen et al. 2016). A study in adults did not
find associations between PFHxS levels and response to influenza vaccine; some alterations in serum
cytokine levels were observed, but chemokine and IgA levels were not altered (Stein et al. 2016b).

In general, the available studies do not suggest an association between serum PFHxS and decreased
infectious disease resistance. No alterations in the frequency of fever, cough, nasal discharge, otitis
media, diarrhea, or vomiting were observed in children (Dalsager et al. 2016; Granum et al. 2013). Cord
PFHxS levels were not associated with increased prevalence of common colds in children 0–2 years ofage or lower respiratory tract infections in children 0–10 years of age (Impinen et al. 2018). No
association between maternal PFHxS levels and total infectious disease prevalence was found in children
up to the age of 4 years (Goudarzi et al. 2017); however, when boys and girls were analyzed separately,an association was found in girls. An association between maternal PFHxS levels and the number of
episodes of gastroenteritis was found in children (Granum et al. 2013).

Epidemiological Studies—Hypersensitivity Outcomes. Data evaluating associations between serum
PFHxS and the risk of asthma diagnosis are presented in Figure 2-26. No associations were observed
between asthma diagnosis, wheezing, and/or eczema or total allergic diseases in children and maternal
serum PFHxS levels (Goudarzi et al. 2016a; Granum et al. 2013; Smit et al. 2015) or with recent PFHxSlevels in adolescents (Humblet et al. 2014; Okada et al. 2014). In contrast, case-control studies inasthmatic children did find associations between recent PFHxS serum levels and asthma diagnosis (Donget al. 2013; Qin et al. 2017; Zhu et al. 2016), but no association with asthma severity (Dong et al. 2013).
Another case-control study found significantly elevated serum PFHxS levels in adolescents with asthma(Zhu et al. 2016). Dong et al. (2013) also reported associations between serum PFHxS levels andPERFLUOROALKYLS

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Figure 2-26. Risk of Asthma Diagnosis Relative to PFHxS Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

eosinophil counts and eosinophil cationic protein levels in asthmatic children, but not in non-asthmatics.
No associations were found with IgE levels in either case-control study (Dong et al. 2013; Zhu et al.
2016) or in a study measuring cord blood IgE (Ashley-Martin et al. 2015).

An increased risk of food allergies associated with serum PFHxS levels, but not increased sensitivity tofoods, was found in adolescents (Buser and Scinicariello 2016). Another study found no associations
between serum PFHxS levels and allergic sensitization to plants, dust mites, pets, cockroaches/shrimp,
rodents, mold, or food in adolescents (Stein et al. 2016a).

Laboratory Animal Studies. In the only available study evaluating immunotoxicity for PFHxS,
Butenhoff et al. (2009a) did not find histological alterations in the spleen, thymus, or lymph nodes of rats
administered 10 mg/kg/day PFHxS via gavage for 42–56 days.
PFNA

Epidemiological Studies—Immunosuppression Outcomes. Most studies examining a possible
association between serum PFNA levels and immunosuppression have not found associations. No
associations were found between maternal or child PFNA levels and tetanus antibody levels at ages 3, 5,
7, or 13 (Grandjean et al. 2012, 2017; Granum et al. 2013) or in adults (Kielsen et al. 2016). Somestudies have found associations between serum PFNA and diphtheria antibody levels, but the results were
not consistent. Grandjean and associates found a significant inverse association between diphtheria
antibodies levels at age 5 (Grandjean et al. 2012) and serum PFNA levels at age 5, but not for antibody
levels at age 13 and PFNA levels at age 7 or 13 (Grandjean et al. 2017). Kielsen et al. (2016) also
reported an inverse association (unadjusted for potential confounders) between serum PFNA anddiphtheria antibody levels in a small study of adults. An inverse association between maternal serum
PFNA and rubella antibody levels was observed in children (Granum et al. 2013), but there was no
association for influenza type B antibody levels. Similarly, no associations were found between recent
PFNA serum levels and measles, mumps, or rubella antibody titers in adolescents (Stein et al. 2016a).
Data evaluating associations between serum PFNA and altered antibody response are presented in
Figure 2-27.

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Figure 2-27. Antibody Responses Relative to Serum PFNA Levels in Epidemiological Studies(Presented as percent difference in antibody concentration per 2-fold increase in serum PFNA)PERFLUOROALKYLS

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2. HEALTH EFFECTS

The epidemiological data provide mixed results on whether there are associations between decreased
infectious disease resistance and PFNA levels. No alterations in the risk of increased number of days
with fever, cough, nasal discharge, diarrhea, or vomiting were observed in children (Dalsager et al. 2016),
although the study did find a significant increase in the number of days above the median for nasal
discharge. In a prospective study of children to the age of 4 years, no associations between maternal
PFNA levels and prevalence of total infectious diseases were found (Goudarzi et al. 2017). Another study
found that the number of episodes of the common cold in children was associated with maternal serum
PFNA; no associations were found for otitis media or gastroenteritis (Granum et al. 2013). No
associations between cord PFNA levels and the prevalence of common colds were found in children up to
2 years of age (Impinen et al. 2018), but cord PFNA levels were positively associated with the prevalenceof lower respiratory infections in children up to the age of 10 years (Impinen et al. 2018).

Epidemiological Studies—Hypersensitivity Outcomes. Case-control studies of asthmatic children havereported associations between serum PFNA and asthma diagnosis (Dong et al. 2013; Qin et al. 2017; Zhu
et al. 2016), but no association with asthma severity (Dong et al. 2013); another study found significantly
higher serum PFNA levels in adolescents with asthma (Zhu et al. 2016). However, cross-sectional or
retrospective studies (Humblet et al. 2014; Smit et al. 2015; Stein et al. 2016a) have not foundassociations. A prospective study of children to the age of 10, did not find associations between cord
PFNA levels and current asthma, ever having asthma, asthma diagnosis, or wheezing (Impinen et al.
2018). Data evaluating associations between serum PFNA and the risk of asthma diagnosis are presented
in Figure 2-28. Another study found no associations between maternal PFNA levels and prevalence of
total allergic diseases or wheezing (Goudarzi et al. 2016a). No associations were found in adolescents
between PFNA and food allergies (Buser and Scinicariello 2016), allergies (Stein et al. 2016a), or allergic
sensitizations to plants, dust mites, pets, cockroach/shrimp, rodents, mold, or food (Stein et al. 2016a).
However, inverse associations between serum PFNA and food sensitizations were observed inadolescents (Buser and Scinicariello 2016) and between maternal serum PFNA and allergic diseases in
infants (Okada et al. 2014). No increases in the risk of other hypersensitivity effects (wheezing, eczema,
or atopic dermatitis) were observed (Humblet et al. 2014; Okada et al. 2014; Smit et al. 2015; Stein et al.
2016a; Wang et al. 2011).

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Figure 2-28. Risk of Asthma Diagnosis Relative to PFNA Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Laboratory Animal Studies. Administration of PFNA for 14 days resulted in decreases in thymus and/or
spleen weights at ≥3 mg/kg/day in rats and mice (Fang et al. 2008, 2009, 2010); at 1 mg/kg/day, an
increase in thymus weight was observed in rats (Fang et al. 2009). Fang et al. (2009) reported increases
in the ratio of thymic cortex to medulla in rats presumably administered ≥3 mg/kg/day PFNA. In the
spleen, there were decreases in the percentage of F4/80+ and CD49b+ cells at ≥1 mg/kg/day and in
CD11c+ cells at ≥3 mg/kg/day (Fang et al. 2008). Increases in pro-inflammatory cytokines wereobserved in the serum at ≥3 mg/kg/day (Fang et al. 2009) and spleen at 5 mg/kg/day (Fang et al. 2010).
No alterations were observed in the response of splenic T lymphocytes to ConA at 5 mg/kg/day (Fang etal. 2008).

Two weeks after a single intraperitoneal administration of 46 mg/kg PFNA to male and female B57BL/6J
mice, a number of immunological alterations included significant decreases in relative spleen weight andsplenic leukocyte counts, alterations in splenic T-lymphocyte phenotypes (increased ratios of CD4+ andCD8+ cells), a decrease in viable thymic cells, a marked decrease in CD4+CD8+ thymic lymphocytes,
and an increase in CD4+ and CD8+ thymic lymphocytes, and increased levels of tumor necrosis factor-α
in response to exposure to the LPS (Rockwell et al. 2013). Similar effects were observed 4 weeks postexposure (Rockwell et al. 2017). Comparison of the results 2 weeks post-exposure to 4 weeks postexposure showed a partial recovery in spleen weight and specific thymic lymphocyte subpopulations, but
no recovery of the ratio of specific splenic lymphocytes, thymocyte viability, or response to LPS(Rockwell et al. 2017). Some sex-related differences were noted, with females appearing to be moresensitive than males (Rockwell et al. 2017).

PFDA

Epidemiological Studies—Immunosuppression Outcomes. Studies examining possible associations
between serum PFDA levels and response to vaccines have reported mixed results; see Figure 2-29 for agraphical presentation of the antibody response relative to PFDA levels. Inverse associations wereobserved between serum PFDA levels at age 5 and tetanus antibody levels at ages 5 and 7 (Grandjean etal. 2012) and serum PFDA levels at age 7 and antibody levels at age 13 (Grandjean et al. 2017).

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Figure 2-29. Antibody Responses Relative to Serum PFDA Levels in Epidemiological Studies(Presented as percent difference in antibody concentration per 2-fold increase in serum PFDA)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Similarly, diphtheria antibody levels at age 13 were inversely associated with serum PFDA levels at age
7 years (Grandjean et al. 2017), but no associations were observed at other time periods (Grandjean et al.
2012). In adults, diphtheria antibody levels were inversely associated with serum PFDA levels, but there
was no association for tetanus antibody levels (Kielsen et al. 2016); this study did not adjust for potential
confounders. Two studies examined the possible association between serum PFDA levels and infectious
disease resistance, no association was found between maternal serum PFDA levels and symptoms ofinfection in children aged 1–4 years (Dalsager et al. 2016) and the prevalence of total infectious disease inchildren 0–4 years of age (Goudarzi et al. 2017).

Epidemiological Studies—Hypersensitivity Outcomes. In case-control studies, associations between
asthma diagnosis and asthma severity were observed in children (Dong et al. 2013; Zhu et al. 2016);
associations with serum IgE levels, absolute eosinophil counts, and eosinophil cationic protein levels
were also observed. A case-control study in adolescents found significantly higher serum PFDA levels
among the asthmatic cases (Zhu et al. 2016). A fourth case-control study did not find an association
between serum PFDA and asthma risk in children (Qin et al. 2017). A cross-sectional study of children
did not find associations between maternal PFDA levels and asthma, eczema, or wheezing in children(Smit et al. 2015). Another cross-sectional study found no association between allergic diseases or
eczema in infant and maternal PFDA levels (Okada et al. 2014). In a prospective study, the prevalencesof total allergic diseases or wheezing in 4-year-old children were not associated with maternal PFDA
levels (Goudarzi et al. 2016a). Data evaluating associations between serum PFDA and the risk of asthma
diagnosis are presented in Figure 2-30.

Laboratory Animal Studies. A single gavage dose of 80 mg/kg PFDA did not significantly alter relative
thymus weight in female C57BL/6N mice, but it caused a 28% decrease in relative spleen weight 30 days
after dosing (Harris et al. 1989). Lethal doses (160 and 320 mg/kg) induced atrophy and lymphoiddepletion in both the thymus and spleen. No significant alterations in tests of humoral- or cell-mediatedimmunity, or alterations in the number of total splenic cells or splenic B-cells, T-cells, T-cell subsets,natural killer cells or macrophages were observed in rats administered up to 0.5 mg/kg/day for 28 days
(Frawley et al. 2018). In tests of innate immunity, the study found decreases in the specific activity of
fixed tissue macrophages in the liver in rats administered 0.25 or 0.5 mg/kg/day; the investigators
suggested that interpretation of this finding may be confounded by the increased number of hepatocytes.

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Figure 2-30. Risk of Asthma Diagnosis Relative to PFDA Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

In mice receiving weekly doses of PFDA for 4 weeks, decreases in the number of splenic T cells, T-cell
subsets, and macrophages were observed at ≥1.25 mg/kg (Frawley et al. 2018). No alterations inhumoral-mediated or cell-mediated immune tests or host-resistance to the influenza virus were found.
PFUnA

Epidemiological Studies. Six epidemiological studies have evaluated the potential immunotoxicity of
PFUnA in humans. Kielsen et al. (2016) reported inverse associations between serum PFUnA(unadjusted for potential confounders) and diphtheria and tetanus antibody levels in adults. Goudarzi etal. (2017) found no association between maternal PFUnA levels and the risk of total infectious diseases inchildren up to the age of 4 years. However, Impinen et al. (2018) found cord PFUnA levels wereassociated with increases in the prevalence of common colds in children up to 2 years of age and theprevalence of lower respiratory tract infections in children up to the age of 10 years.

No significant associations between maternal PFUnA levels and the risk of asthma diagnosis, eczema, or
wheezing were observed in children (Smit et al. 2015). Similarly, no associations were found between
cord PFUnA levels and risk of current asthma, ever having asthma, asthma diagnosis, or wheezing inchildren up to the age of 10 years (Impinen et al. 2018). Maternal PFUnA levels were not associated withthe prevalences of total allergic diseases or wheezing in 4-year-old children (Goudarzi et al. 2016a).
Okada et al. (2012) found inverse associations between maternal serum PFUnA and risk of allergies or
eczema in female infants, but not in males, and Impinen et al. (2018) found no association between serum
PFUnA and allergic sensitization.

PFHpA

Epidemiological Studies. In general, the two available human immunotoxicity studies did not findassociations between serum PFHpA levels and diphtheria or tetanus antibody levels in adults (Kielsen etal. 2016) or risk of asthma diagnosis, eczema, or wheezing in children (Smit et al. 2015). The Smit et al.
(2015) study did find an inverse association between maternal PFHpA levels and current wheezing in one
subcohort; however, this was not observed in the other subcohort with higher mean maternal PFHpA
levels.

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PFBS

Epidemiological Studies. The epidemiological database for PFBS consists of three case-control studies
in asthmatic children (Dong et al. 2013; Qin et al. 2017; Zhu et al. 2016). Two studies reported increases
in asthma diagnosis, but no association with serum IgE levels (Dong et al. 2013; Zhu et al. 2016); thethird study (Qin et al. 2017) did not find an association between serum PFBS and asthma risk.

Laboratory Animal Studies. No significant histological alterations were observed in spleen, thymus, or
lymph nodes of rats administered via gavage 900 mg/kg/day PFBS for 28 days (3M 2001).
PFBA

Laboratory Animal Studies. No significant gross or microscopic alterations were reported in the spleen,
thymus, or mesenteric lymph nodes from rats dosed with PFBA by gavage in doses of up to
184 mg/kg/day for 5 days, 150 mg/kg/day for 28 days, or 30 mg/kg/day for 90 days (3M 2007a;
Butenhoff et al. 2012a; van Otterdijk 2007a, 2007b).
PFDoDA

Epidemiological Studies. Six epidemiological studies examining potential immunotoxic endpoints wereidentified. Kielsen et al. (2016) found inverse associations between recent serum PFDoDA levels (notadjusted for potential confounders) and diphtheria and tetanus antibody levels in adults. No associations
between maternal PFDoDA levels and the risk of total infectious diseases were found in children up to theage of 4 years (Goudarzi et al. 2017). Associations between serum PFDoDA levels and the risk of asthma
diagnosis, severity of asthma, serum IgE levels, absolute eosinophil counts, and eosinophil cationicprotein levels were observed in a case-control study of asthmatic children (Dong et al. 2013). A crosssectional study of children did not find associations between maternal serum PFDoDA levels and risk ofasthma diagnosis, eczema, or wheezing (Smit et al. 2015). Another study did not find associations
between maternal serum PFDoDA levels and the risk of allergic disease or eczema in infants (Okada et al.
2014). In contrast, a prospective study of 4-year-old children found an inverse association between
maternal PFDoDA levels and the prevalence of mother-reported total allergic diseases, but no association
with the prevalence of wheezing (Goudarzi et al. 2016a).

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PFHxA

Epidemiological Studies. Two epidemiological studies examined potential immunotoxic endpoints.
Dong et al. (2013) found no associations between serum PFHxA levels in asthmatic and nonasthmaticchildren and asthma diagnosis, asthma severity, or IgE levels. Qin et al. (2017) did not find an
association between serum PFHxA levels and asthma risk in children.

Laboratory Animal Studies. Thymic atrophy was observed in 3/9 female rats administered a TWA doseof 315 mg/kg/day PFHxA for 32–44 days (Kirkpatrick 2005). Thymic atrophy and necrosis was also
observed in most male and female rats administered 450 mg/kg/day PFHxA for 4 days; all animals diedearly or were sacrificed in extremis (Kirkpatrick 2005).
FOSA

Epidemiological Studies. The only available epidemiological study found an association between cord
FOSA levels and an increased prevalence of lower respiratory tract infections in children up to the age of
10 years (Impinen et al. 2018); no association was found for common colds in children up to the age of
2 years. This study also found no associations between cord FOSA and current asthma, ever having
asthma, asthma diagnosis, wheezing, or allergic sensitization (Impinen et al. 2018).
2.15 NEUROLOGICAL
Overview. There are limited data on the neurotoxicity of perfluoroalkyls in humans or laboratory
animals; epidemiological data come from three studies examining memory and animal studies primarily
evaluated for morphological alterations; the results of these human studies are summarized in Table 2-17
with more detailed descriptions in the Supporting Document for Epidemiological Studies for
Perfluoroalkyls, Table 11. The epidemiological studies found decreases in the risk of memory loss
associated with serum PFOA, PFOS, PFHxS, and PFNA. The potential to induce neurodevelopmental
effects (including the risk of attention deficit hyperactivity disorder [ADHD]) has been more widely
studied; these data are discussed in Section 2.17, Developmental. No epidemiological studies examining
potential neurological effects were found for PFDA, PFUnA, PFHpA, PFBS, PFBA, PFDoDA, PFHxA,or FOSA.

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Table 2-17. Summary of Neurological Outcomes in Humansa
Reference and study populationb
PFOA
Gallo et al. 2013

Serum perfluoroalkyl level Outcome evaluatedResultc

14.1–27.0 ng/mL (2nd PFOA Memory loss (selfquintile)reported)

OR 0.88 (0.79–0.97)*, 2nd quintile

Community (C8) (n=21,024 older adults;>50 years of age)
Power et al. 2013
General population (NHANES) (n=1,766 older
adults aged 60–<85 years)
Shrestha et al. 20174.08 ng/mL (median PFOA)

Difficulty remembering or OR 0.92 (0.78–1.09)
periods of confusion (selfreported)

8.1 ng/mL (median serum
PFOA)

Memory and learning
Association (p=0.03)*
scoresExecutive function scores Inverse association (p=0.04,
p=0.03)*Visual and spatial
NS (p>0.05)
function scores
Reaction time
NS (p>0.05)
Motor function
NS (p>0.05)

20.5–27.1 ng/mL (3rd PFOS
quintile)

Memory loss (selfreported)

General population (n=126 older adults, aged
55–74 years)

PFOS
Gallo et al. 2013
Community (C8) (n=21,024 older adults;>50 years of age)
Power et al. 2013
General population (NHANES) (n=1,766 older
adults aged 60–<85 years)

OR 0.86 (0.78–0.96)*, 3rd quintile

22.63 ng/mL (median PFOS) Difficulty remembering or OR 0.90 (0.78–1.03)
periods of confusion (selfreported)PERFLUOROALKYLS

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Table 2-17. Summary of Neurological Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluated

Shrestha et al. 201733.7 ng/mL (median serum
PFOS)

General population (n=126 older adults, aged
55–74 years)

PFHxS
Gallo et al. 2013
Community (C8) (n=21,024 older adults;>50 years of age)
Power et al. 2013
General population (NHANES) (n=1,766 older
adults aged 60–<85 years)
PFNA
Gallo et al. 2013
Community (C8) (n=21,024 older adults;>50 years of age)
Power et al. 2013

Resultc

Memory and learning
Association (p=0.04)*
scoresExecutive function scores NS (p>0.05)
Visual and spatial
Association (p=0.05)*
function scores
Reaction time
NS (p>0.05)
Motor function
NS (p>0.05)

5.7–232.6 ng/mL (5th PFHxS Memory loss (selfquintile)reported)

OR 0.89 (0.79–0.99)*, 5th quintile

2.05 ng/mL (median PFHxS) Difficulty remembering or OR 0.93 (0.82–1.06)
periods of confusion (selfreported)

OR 0.86 (0.78–0.96)*, 2nd quintile

1.0–1.2 ng/mL (2nd PFNA
quintile)

Memory loss (selfreported)

1.01 ng/mL (median PFNA)

Difficulty remembering or OR 0.91 (0.79–1.04)
periods of confusion (selfreported)

General population (NHANES) (n=1,766 older
adults aged 60–<85 years)

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 11 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

OR = odds ratio; NHANES = National Health and Nutrition Examination Survey; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

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The results of the laboratory animal studies are presented in Tables 2-1, 2-3, 2-4, 2-5, and 2-6 and in
Figures 2-6, 2-8, 2-9, and 2-10. No morphological alterations in the brain and nerves were observed instudies of PFOA, PFOS, PFBS, or PFBA. No alterations in neurological function tests were observed instudies of PFOA, PFHxS, PFHxA, PFBS, PFBA, or PFDoDA. Impaired learning and memory wereobserved in a study of PFOS and decreases in grip strength were observed in a study of PFUnA. Potential
neurological effects were not examined in animals exposed to PFNA, PFHpA, or FOSA.
PFOA

Epidemiological Studies. Gallo et al. (2013) found a decreased risk of self-reported memory loss in older
adult (>50 years of age) C8 participants with serum PFOA levels in the 2nd, 3rd, 4th, or 5th quintiles. Whenthe participants were categorized by diabetic status, the risk of memory loss was higher among thediabetics than nondiabetics (p=0.014). In sensitivity analyses, the association between serum PFOA
levels and memory impairment was compared within and across water districts. Within a water district,the association between serum PFOA and memory impairment was significant, but there was no
association between the geometric mean concentration of PFOA in a district and memory impairment. A
general population study conducted by Shrestha et al. (2017) of 55–74-year-old participants also foundhigher memory and learning scores (6% increase) and 16–18% decreases in perseverative errors andresponses. In a third study, no association between serum PFOA and self-reported difficulty
remembering or periods of confusion was found in NHANES participants aged 60–<85 years (Power et
al. 2013).
Laboratory Animal Studies. Exposure of rats to 18,600 mg/m3 APFO dusts for 1 hour induced excessive
salivation. Intermittent, head-only exposure of male rats exposed to up to 84 mg/m3 APFO dusts for
2 weeks did not reveal gross or microscopic alterations in the brain (Kennedy et al. 1986).

A small number of studies have examined the potential toxicity of perfluoroalkyls to the nervous system
in animals, but comprehensive testing has not been conducted. No alterations in performance on a novel
recognition test were observed in rats administered a single 50 mg/kg dose of PFOA (Kawabata et al.
2017). No overt signs of neurotoxicity or altered response to stimuli were observed in rats and miceadministered up to 1,000 mg/kg PFOA via gavage and observed for 14 days (Sato et al. 2009). Exposureof rats to up to approximately 110 mg/kg/day PFOA via the diet for 90 days did not induce gross or
microscopic alterations in the brain, spinal cord, or peripheral nerves (Griffith and Long 1980). Similar
results were reported in rats fed a diet that provided approximately 15 mg/kg/day PFOA for 2 years (3MPERFLUOROALKYLS

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2. HEALTH EFFECTS

1983; Butenhoff et al. 2012c). Rhesus monkeys exposed to doses of PFOA that caused lethality(≥30 mg/kg/day by gavage) showed signs of hypoactivity and prostration, but examination of the brain
did not reveal treatment-related alterations (Griffith and Long 1980). Treatment of Cynomolgus monkeys
with doses of up to 20 mg/kg/day PFOA administered via a capsule did not induce morphologicalalterations in the brain or sciatic nerve (Butenhoff et al. 2002).

Similarly, no gross or microscopic alterations were reported in the brain from rats dermally exposed to
APFO in the Kennedy (1985) study.
PFOS

Epidemiological Studies. Three studies have examined the influence of serum PFOS levels on selfreported memory in older adults. Gallo et al. (2013) found an inverse association between serum PFOS
levels and the risk of memory loss in C8 Health Study participants. No association for difficulty
remembering or periods of confusion was found in the second study of NHANES participants (Power et
al. 2013). A second general population study of older adults found associations between serum PFOS
levels and 11% higher scores on tests of visual reproduction delayed recall and 8% higher scores on testsof visual and spatial function (Shrestha et al. 2017), but found no associations on tests of executivefunction, reaction time, affective state, or motor function.

Laboratory Animal Studies. No histological alterations were observed in the brain, spinal cord, and/or
sciatic nerve of rats administered a single gavage dose of up to 500 mg/kg PFOS (Sato et al. 2009), rats
treated with up to 1.6–1.8 mg/kg/day PFOS for 4 or 14 weeks (Seacat et al. 2003), rats exposed to
8.5 mg/kg/day PFOS in the diet for 13 weeks (Kawamoto et al. 2011), rats exposed to 1.04 mg/kg/day
PFOS in the diet for 2 years (Butenhoff et al. 2012b; Thomford 2002b), or Cynomolgus monkeys dosedwith up to 0.75 mg/kg/day PFOS for 26 weeks (Seacat et al. 2002). However, ultrasonic stimulation
resulted in bursts of locomotion immediately followed by tonic convulsions in mice administered
125 mg/kg PFOS and rats administered 250 mg/kg PFOS (Sato et al. 2009); the effect was observed 1–
7 days postexposure and frequently resulted in death. Similarly, tonic convulsions following ultrasonicstimulation were observed in rats exposed to 8.5 mg/kg/day PFOS in the diet for 6 weeks (Kawamoto etal. 2011); this effect was not observed at ≤2.0 mg/kg/day. Impaired spatial learning and memory,
assessed using the Morris water maze test, was observed in mice administered 2.15 or 10.75 mg/kg/day
PFOS, but not 0.43 mg/kg/day, for 3 months (Long et al. 2013). Similarly, impaired performance on
retention tasks, as assessed by the water maze test, was observed in mice administered 3 or 6 mg/kg/dayPERFLUOROALKYLS

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2. HEALTH EFFECTSPFOS for 4 weeks (Fuentes et al. 2007c). Histopathological examination of the hypothalamus in maleSprague-Dawley rats administered PFOS via gavage for 28 days revealed degeneration of gonadotropic
cells of the pituitary gland at ≥1.0 mg/kg/day and dense chromatin, condensed ribosomes, and loss ofmorphology in the hypothalamus at ≥3.0 mg/kg/day (López-Doval et al. 2014).
PFHxS

Epidemiological Studies. A decrease in the risk of self-reported memory loss was observed in older adultparticipants of the C8 Health Study who had serum PFHxS levels in the 5th quintile (Gallo et al. 2013).
No association between serum PFHxS levels and self-reported difficulty remembering or periods ofconfusion was reported in a study of NHANES participants (Power et al. 2013).

Laboratory Animal Studies. In a reproductive study in rats dosed with PFHxS, a functional observational
battery (FOB) and motor activity tests were conducted in males on exposure days 36 and 39 and infemales on postpartum day 17 (Butenhoff et al. 2009a). The battery assessed autonomic functions,reactivity and sensitivity to stimuli, excitability, gait and sensorimotor coordination, limb grip strength,
and abnormal clinical signs. No significant alterations were reported in males or females dosed with up to
10 mg/kg/day PFHxS.
PFNA

Epidemiological Studies. Self-reported memory loss was shown to be inversely associated with serum
PFNA levels in a study of older C8 Health Study participants (Gallo et al. 2013). Another study of
NHANES participants did not find an association with self-reported difficulty remembering or periods ofconfusion (Power et al. 2013).
PFUnA

Laboratory Animal Studies. In the only study located for PFUnA, a decrease in grip strength wasobserved in male and female rats administered 1.0 mg/kg/day PFUnA for 41–46 days and allowed torecover for 14 days (Takahashi et al. 2014). No other alterations in performance on FOB tests were
found.

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PFBS

Laboratory Animal Studies. A significant decrease in tail flick latency to a thermal stimulus wasobserved in all groups of male rats administered via gavage PFBS for 28 days. However, other tests ofsensory reactivity to stimuli, grip strength, and motor activity were not affected (3M 2001), and thesignificance of this isolated finding is difficult to ascertain. Gross and microscopic examination of thebrain, spinal cord, and sciatic nerve did not show any significant alterations. In a 90-day study, no
significant alterations in motor activity or performance on functional observation tests were observed inrats at PFBS doses as high as 600 mg/kg/day (Lieder et al. 2009a).
PFBA

Laboratory Animal Studies. Administration of up to 184 mg/kg/day PFBA by gavage for 5 consecutive
days to rats had no significant effect on the gross or microscopic morphology of the brain or spinal cord
(3M 2007a). In a 28-day gavage study, male rats dosed with 150 mg/kg/day, but not 30 mg/kg/day,showed a delay in bilateral pupillary reflex at the end of the treatment period (Butenhoff et al. 2012a; vanOtterdijk 2007a). Results from other tests, including hearing ability, static righting reflex, grip strength,
and motor activity, were comparable between groups, and histological examinations of the brain(including the optic nerve), spinal cord, and sciatic nerve were unremarkable. In a 90-day study, pupillaryreflex tests conducted in weeks 8 and 12 showed delayed dilation under dark conditions in rats dosed with30 mg/kg/day (2/40 in controls versus 7/39 in high-dose rats; p=0.071 according to the Fisher Exact Test)(Butenhoff et al. 2012a; van Otterdijk 2007b). Since no abnormalities were recorded during a 3-week
recovery period, and there were no histopathological alterations in the eyes, the effect was not consideredbiologically significant by the investigators. Tests for hearing ability, static righting reflex, grip strength,
and motor activity showed no associations with treatment with PFBA. In addition, there were no
significant gross or microscopic alterations in the brain, spinal cord, or sciatic nerve.
PFDoDA

Laboratory Animal Studies. Single-dose administration of 50 mg/kg resulted in impaired performanceon a novel object recognition test, but did not result in alterations in other tests of memory, anxiety, or
open field activity (Kawabata et al. 2017). A second study conducted functional observation tests in rats
administered PFDoDA for 42 days (Kato et al. 2015). No alterations in sensorimotor reactivity, grip
strength, or spontaneous motor activity were observed at 2.5 mg/kg/day. However, in rats allowed toPERFLUOROALKYLS

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recover for 14 days, decreases in forelimb grip strength were observed in males and females at
2.5 mg/kg/day; a decrease in motor activity was also observed in females at 2.5 mg/kg/day but this was
only observed during the first week of recovery (Kato et al. 2015).
PFHxA

Laboratory Animal Studies. Administration of up to 500 mg/kg/day NaPFHx for 92–93 days (Lovelesset al. 2009) or 200 mg/kg/day PFHxA for 104 weeks (Klaunig et al. 2015) had no effect on locomotion or
performance in the FOB test.
2.16 REPRODUCTIVE
Overview. A number of epidemiological studies have evaluated the reproductive toxicity ofperfluoroalkyls; summaries of these studies are presented in the Supporting Document for
Epidemiological Studies for Perfluoroalkyls, Table 12. These studies have evaluated the following
categories of reproductive outcomes: alterations in reproductive hormone levels; effects on sperm; effects
on menopause onset, menstrual cycle length, endometriosis, and breastfeeding duration; and effects on
fertility. Overviews of the studies examining these specific endpoints are presented in Tables 2-18, 2-19,
2-20, and 2-21, respectively. In addition to these reproductive outcomes, several epidemiological studies
have evaluated the influence of perfluoroalkyls on sexual maturation; these data are discussed in
Section 2.17, Developmental. Although some studies examining reproductive hormone levels have foundassociations with PFOA, PFOS, PFHxS, PFNA, PFUnA, PFDoDA, or PFHxA levels, the findings are notconsistent across studies or there are too few studies to interpret the results. Alterations in reproductive
hormone levels have not been found in studies of FOSA. Some associations between serum
perfluoroalkyls (PFOA, PFOS, PFHxS, PFNA, PFDA) levels and sperm parameters have been found;often, only one sperm parameter was altered and it is difficult to assess the adversity of this alteration.
There is some suggestive evidence of an association between serum PFOA, PFOS, PFHxS, or PFNA
levels and an increased risk of early menopause; however, this may be due to reverse causation since anearlier onset of menopause would result in a decrease in the removal of perfluoroalkyls in menstrual
blood. Epidemiological studies provide mixed evidence of impaired fertility (increased risks of longer
time to pregnancy and infertility); there is also some evidence for PFOA, PFOS, PFHxS PFNA, PFHpA,
and PFBS but the results are not consistent across studies or were only based on a single study. The small
number of studies evaluating fertility for PFDA, PFUnA, PFDoDA, and FOSA did not find associations.
Reproductive outcomes have not been evaluated in epidemiological studies on PFBA.

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Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa
Reference and study populationb
PFOA
Gilliland 1992
Occupational (n=115)

Olsen et al. 1998b

Serum perfluoroalkyl level Outcome evaluatedResultc

NR (serum fluorine levels
used as surrogate for serum
PFOA)

Bound testosterone
Free testosterone
Estradiol
LH

Inverse association (p=0.05)*
Inverse association (p=0.03)*
Association (p=0.03)*
NS (p=0.93)

FSH
Prolactin
Prolactin

NS (p=0.91)
Association (p=0.0002)*
Association (p=0.01 for trend)*,1993
NS (p=0.58 for trend), 1995
NS (p=0.66 and 0.56 for trend), 1993
and 1995
NS (p=0.21 and 0.18 for trend), 1993
and 1995
NS (p=0.07 and 0.85 for trend), 1993
and 1995

0–80,000 ng/mL (PFOA
range)

Occupational (n=111 males in 1993 and80 males in 1995)

Estradiol
17α-Hydroxyprogesterone
Bound testosterone

Sakr et al. 2007b
Occupational (n=1,025)
Knox et al. 2011
Community (C8) (n=25,957 women)
Barrett et al. 2015
General population (n=178 women)

Free testosterone.

NS (p=0.15 or 0.82 for trend), 1993
and 1995

428 ng/mL (mean PFOA)

Estradiol
Testosterone

Association (p=0.017)*, males
Association (p=0.034)*, males

11.3–19.8 ng/mL (2nd PFOA
quintile)

Estradiol concentration

NS (p>0.05), menopausal andperimenopausal subgroups

3.61 and 2.31 ng/mL (mean
PFOA in nulliparous andparous women)

Follicular estradiol

NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts
NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts

Luteal progesterone

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Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Joensen et al. 20133.46 ng/mL (mean PFOA)

Total testosterone
Free testosterone
Free androgen index
LH
Estradiol

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

SHBG
FSH
Estradiol
Prolactin
FSH
LH

NS (p>0.05)
NS (p>0.05)
NS (p=0.751)
NS (p=0.349)
NS (p=0.581)
Correlation (p=0.011)*

Free testosterone
Total testosterone
SHBG

Correlation (p=0.015)*
NS (p=0.440)
NS (p=0.39 for trend)

General population (n=247 young men; mean
age 19.6 years)

Raymer et al. 201210.4 ng/mL (mean PFOA)

General population (n=256 men)

Specht et al. 2012

1.3–4.8 (range of PFOA
means of different sites)

General population (n=604 men)
Tsai et al. 20152.74 ng/mL (geometric mean SHBG
PFOA)General population (n=540 adolescents andyoung adults aged 12–30 years)
Vested et al. 2013
General population (n=169 males aged 19–
21 years)

3.8 ng/mL (median maternal
PFOA)

Association (p<0.05)*, females 12–
17 years old

FSH
Testosterone
Testosterone
Estradiol
Inhibin B
SHBG

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Free antigen index
LH
FSH

NS (p>0.05)
Association (p=0.03)*
Association (p=0.01)*

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Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Zhou et al. 2016

0.5 and 0.5 ng/mL (medianserum PFOA in boys andgirls)

β -0.0549 (-0.1186–0.0088), boys
β -0.1627 (-0.1627–0.0233), girls
β 0.0921 (0.0186–0.1656)*, boys
β 0.1015 (-0.0023–0.0033), girls

General population (n=225 adolescents, 13–15 years of age)
PFOS
Olsen et al. 1998aTestosterone
EstradiolOccupational (n=327)

1,480–2,440 ng/mL (range of DHEAS
PFOS means at different time FSH
periods)
17-HP
LH

NS (p=0.60)
NS (p=0.91)
NS (p=0.99)
NS (p=0.69)
NS (p=0.25)
NS (p=0.77)
NS (p=0.90)
NS (p=035)
NS (p=0.14), after removal of 1 outlier

Knox et al. 2011

Prolactin
SHBG
Free testosterone
Bound testosterone
Estradiol
11.9–17.0 and 17.1–
Estradiol concentration
22.4 ng/mL (2nd and 3rd PFOS Perimenopausal
quintiles)
subgroup
Menopausal subgroup
16.44 and 14.18 ng/mL
Follicular estradiol(mean PFOS in nulliparousand parous women)

Community (C8) (n=25,957 women)
Barrett et al. 2015
General population (n=178 women)

Luteal progesterone

Inverse association (p=0.0001)*
Inverse association (p=0.007)*
Inverse association (β -0.013, 95%
CI -0.023 to -0.001)*, whole cohort
Inverse association (β -0.025, 95%
CI -0.043 to -0.007)*, nulliparous
subcohort
NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts

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Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Joensen et al. 20138.46 ng/mL (mean PFOS)

Total testosterone
Free testosterone
Free androgen index
LH
Estradiol

Inverse association (p<0.05)*
Inverse association (p<0.05)*
Inverse association (p<0.05)*
NS (p>0.05)
NS (p>0.05)

SHBG
FSH
Estradiol
Prolactin
FSH
LH

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

General population (n=247 young men; mean
age 19.6 years)

Raymer et al. 2012
General population (n=256 men)

Tsai et al. 2015
General population (n=540 male and female
adolescents and young adults aged 12–30 years)
Vested et al. 2013
General population (n=169 males aged 19–
21 years)Zhou et al. 2016
General population (n=225 adolescents, 13–15 years of age)

37.4 ng/mL (mean PFOS)

Free testosterone
Total testosterone
7.78 ng/mL (geometric mean SHBG
PFOS)
FSH
Testosterone
21.2 ng/mL (median maternal Testosterone
PFOS)
Estradiol
Inhibin B
SHBG
Free antigen index
LH
FSH
29.9 and 28.8 ng/mL (median Testosterone
serum PFOS in boys andgirls)
Estradiol

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Inverse association (p<0.05)*, males
12–17 years old
Inverse association (p<0.05)*,
females 12–17 years old
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
β -0.0029 (-0.0055 to -0.0003)*, boys
β 0.0005 (-0.0018–0.0028), girls
β 0.0024 (-0.0007–0.0055), boys
β 0.0005 (-0.0023–0.0033), girls

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Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa
Reference and study populationb
PFHxS
Barrett et al. 2015
General population (n=178 women)

Serum perfluoroalkyl level Outcome evaluatedResultc

1.22 and 1.65 ng/mL (meanPFHxS in nulliparous andparous women)

NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts
NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts

Follicular estradiol

Luteal progesterone

Joensen et al. 2013

0.81 ng/mL (mean PFHxS)

General population (n=247 young men; mean
age 19.6 years)

Zhou et al. 2016
General population (n=225 adolescents, 13–15 years of age)
PFNA
Barrett et al. 2015
General population (n=178 women)

1.4 and 1.2 ng/mL (medianserum PFHxS in boys andgirls)

0.67 and 0.60 ng/mL (mean
PFNA in nulliparous andparous women)

Total testosterone
Free testosterone
Free androgen index
LH
Estradiol
SHBG

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

FSH
Testosterone

NS (p>0.05)
β 0.0173 (-0.0211–0.0588), boys
β -0.0182 (-0.0451–0.0087), girls

Estradiol

β 0.0462 (0.0020–0.0925)*, boys
β 0.0017 (-0.0154–0.0496), girls

Follicular estradiol

NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts
NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts

Luteal progesterone

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Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Joensen et al. 20131.23 ng/mL (mean PFNA)NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*

General population (n=247 young men; mean
age 19.6 years)

Tsai et al. 2015
General population (n=540 male and female
adolescents and young adults aged 12–30 years)Zhou et al. 2016
General population (n=225 adolescents, 13–15 years of age)
PFDA
Barrett et al. 2015
General population (n=178 women)

Total testosterone
Free testosterone
Free androgen index
LH
Estradiol

SHBG
FSH
1.10 ng/mL (geometric mean SHBG
PFNA)
FSH
Testosterone

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

0.8 and 0.9 ng/mL (medianserum PFNA in boys andgirls)

Testosterone

β -0.4233 (-0.6998 to -0.1467)*, boys
β -0.1018 (-0.2684–0.0648), girls
β 0.3204 (-0.0115–0.6522), boys
β 0.1252 (-0.0758–0.3263), girls

0.25 and 0.24 ng/mL (meanPFDA in nulliparous andparous women)

Follicular estradiol

Estradiol

Luteal progesterone

Joensen et al. 2013
General population (n=247 young men; mean
age 19.6 years)

0.38 ng/mL (mean PFDA)

Total testosterone
Free testosterone
Free androgen index
LH
Estradiol
SHBG
FSH

NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts
NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

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Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Zhou et al. 2016

0.3 and 1.0 ng/mL (medianserum PFDA in boys andgirls)

β -0.2565 (-0.4135 to -0.0994)*, boys
β -0.0626 (-0.1730–0.0477), girls
β 0.0734 (-0.1189–0.2657), boys
β 0.0131 (-0.1208–0.1469), girls

General population (n=225 adolescents, 13–15 years of age)
PFUnA
Barrett et al. 2015
General population (n=178 women)

0.40 and 0.42 ng/mL (mean
PFUnA in nulliparous andparous women)

Testosterone
Estradiol

Follicular estradiol

Luteal progesterone

Tsai et al. 20155.84 ng/mL (geometric mean
PFUnA)

General population (n=540 males and females
aged 12–30 years)
PFBS
Zhou et al. 2016
General population (n=225 adolescents, 13–15 years of age)
PFDoDA
Zhou et al. 2016
General population (n=225 adolescents, 13–15 years of age)
PFHxA
Zhou et al. 2016
General population (n=225 adolescents, 13–15 years of age)

SHBG
FSH
Testosterone

NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts
NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts
NS (p>0.05)
Inverse association (p<0.05)*,
females 12–17 years old
NS (p>0.05)

0.5 and 0.5 ng/mL (median
Testosterone
serum PFBS in boys and girls)
Estradiol

β -0.0387 (-0.3261–0.2487), boys
β 0.1326 (-0.3576–0.6229), girls
β 0.0149 (-0.3216–0.3513), boys
β 0.3129 (-0.2771–0.9028), girls

2.4 and 3.1 ng/mL (medianserum PFDoDA in boys andgirls)

β 0.0056 (-0.0056–0.0168), boys
β -0.0119 (-0.0227 to -0.0010)*, girls
β -0.0007 (-0.0139–0.0124), boys
β 0.0106 (-0.0026–0.0218), girls

Testosterone
Estradiol

0.2 and 0.2 ng/mL (median
Testosterone
serum PFHxA in boys and girls)
Estradiol

β -0.3095 (0.5942 to -0.0248)*, boys
β -0.1896 (-0.4387–0.0595), girls
β 0.0600 (-0.2803–0.4003), boys
β -0.1492 (-0.4515–0.1531), girls

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Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa
Reference and study populationb
FOSA
Barrett et al. 2015
General population (n=178 women)

Serum perfluoroalkyl level Outcome evaluated
0.25 and 0.23 ng/mL (mean
Follicular estradiol
FOSA in nulliparous and parous
women)
Luteal progesterone

Resultc
NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts
NS (95% CI included unity), wholecohort and parous and nulliparous
subcohorts

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 12 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

CI = confidence interval; DHEAS = dihydroepiandrosterone sulfate; FOSA = perfluorooctane sulfonamide; FSH = follicle stimulating hormone; LH = luteinizing
hormone; NS = not significant; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane
sulfonic acid; PFUnA = perfluoroundecanoic acid; SHBG = sex hormone binding globulin

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Table 2-19. Summary of Male Reproductive Outcomes in Humansa
Reference and study populationb
PFOA
Buck Louis et al. 2015
General population (n=96 in Michigan and
366 in Texas)

Joensen et al. 2013

Serum perfluoroalkyl level Outcome evaluated
4.6 and 5.3 ng/mL (median
PFOA in Michigan andTexas)

3.46 ng/mL (mean PFOA)

General population (n=247 young men; mean
age of 19.6 years)

Kvist et al. 2012
General population (n=588 men)
Raymer et al. 2012

1.91–5.19 ng/mL (range of
PFOA means)
10.4 ng/mL (mean PFOA)

General population (n=256 men)

Toft et al. 2012
General population (n=588 males)

3.8 ng/mL (median PFOA)

Resultc

Sperm viability
NS (p>0.05)
Sperm countNS (p>0.05)
Sperm motility↑ curvilinear velocity
Association (p<0.05)*
Other parameters
NS (p>0.05)
Sperm morphology↑ percentage of sperm Association (p<0.05)*
head acrosome area
↓ percentage sperm
Association (p<0.05)*
with coiled tails
Other parameters
NS (p<0.05)
Sperm volume
NS (p>0.05)
Sperm concentration
Sperm count
Percentage progressive
motile sperm
Sperm morphology
Y-X chromosome ratio

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Semen volume
Semen pH
Sperm motility
Sperm concentration↑ percent motile sperm

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*

Sperm concentration
Sperm volume
Sperm count
Sperm morphology

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

NS (p>0.05)
NS (p>0.05)

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Table 2-19. Summary of Male Reproductive Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Vested et al. 2013

3.8 ng/mL (median maternal Sperm concentration
PFOA)
Total sperm countSemen volume
Percentage progressive
spermatozoa
Percentage
morphologically normal
spermatozoa
Mean testicular volume

Inverse association (p=0.01)*
Inverse association (p=0.001)*
NS (p>0.05)
NS (p>0.05)

19.15 and 21.6 ng/mL(median PFOS in Michigan
and Texas)

Sperm viability

NS (p>0.05)

Sperm count
Sperm motility↑ distance travelled
Other parameters
Sperm morphology

NS (p>0.05)

General population (n=169 males aged 19–
21 years)

PFOS
Buck Louis et al. 2015
General population (n=96 in Michigan and
366 in Texas)

Joensen et al. 2013
General population (n=247 young men; mean
age of 19.6 years)

Kvist et al. 2012
General population (n=588 men)
Raymer et al. 2012
General population (n=256 men)

8.46 ng/mL (mean PFOS)

Sperm volume
Sperm concentration
Sperm count
Percentage progressive
motile sperm
8.20–51.65 ng/mL (range of Y-X chromosome ratio
mean PFOS)
51.65 ng/mL (mean forGreenland subcohort)
37.4 ng/mL (mean PFOS)
Semen volume
Semen pH
Sperm motility
Sperm concentration

NS (p>0.05)

NS (p>0.05)

Association (p<0.05)*
NS (p>0.05)
NS (p<0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*, whole cohort
Inverse association (p=0.044 fortrend)*, Greenland subcohort
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

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Table 2-19. Summary of Male Reproductive Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Toft et al. 201218.4 ng/mL (median PFOS)

Percent motile sperm
Sperm concentration
Sperm volume
Sperm count
Percent normal sperm

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Inverse association (p<0.05)*

21.2 ng/mL (medianmaternal PFOS)

Sperm concentration
Total sperm countSemen volume
Percentage progressive
spermatozoa
Percentage
morphologically normal
spermatozoa
Mean testicular volume

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Sperm volume
Sperm concentration
Sperm countNS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Percentage progressive
motile sperm

NS (p>0.05)

Sperm morphology
Percent motile sperm
Sperm concentration
Sperm volume
Sperm count
Percent normal sperm

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Inverse association (p<0.05)*

General population (n=588 males)

Vested et al. 2013
General population (n=169 males aged 19–
21 years)

PFHxS
Joensen et al. 2013

0.81 ng/mL (mean PFHxS)

General population (n=247 young men; mean
age of 19.6 years)

Toft et al. 2012
General population (n=588 males)

1.1 ng/mL (median PFHxS)

NS (p>0.05)

NS (p>0.05)

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2. HEALTH EFFECTS

Table 2-19. Summary of Male Reproductive Outcomes in Humansa
Reference and study populationb
PFNA
Buck Louis et al. 2015
General population (n=96 in Michigan and
366 in Texas)

Joensen et al. 2013
General population (n=247 young men; mean
age of 19.6 years)

Toft et al. 2012
General population (n=588 males)

PFDA
Buck Louis et al. 2015
General population (n=96 in Michigan and
366 in Texas)

Serum perfluoroalkyl level Outcome evaluatedResultc

1.0 and 1.65 ng/mL (median Sperm viability
NS (p>0.05)
PFNA in Michigan andSperm countNS (p>0.05)
Texas)
Sperm motility
NS (p>0.05)
Sperm morphology↑ percentage of normal Association (p<0.05)*
sperm↓ percentage sperm
Association (p<0.05)*
with coiled tails
Other parameters
NS (p<0.05)
1.23 ng/mL (mean PFNA)
Sperm volume
NS (p>0.05)
Sperm concentration
NS (p>0.05)
Sperm countNS (p>0.05)
Percentage progressive NS (p>0.05)
motile sperm
Sperm morphology
NS (p>0.05)
1.2 ng/mL (median PFNA)
Percent motile sperm
NS (p>0.05)
Sperm concentration
NS (p>0.05)

0.3 and 0.5 ng/mL (median
PFDA in Michigan andTexas)

Sperm volume
Sperm count
Percent normal sperm

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Sperm viability
Sperm countNS (p>0.05)
NS (p>0.05)

Sperm motility
Sperm morphology↑ sperm head length↓ percentage spermwith coiled tails
Other parameters

NS (p>0.05)
Association (p<0.05)*
Association (p<0.05)*
NS (p<0.05)

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Table 2-19. Summary of Male Reproductive Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Joensen et al. 2013

0.38 ng/mL (mean PFDA)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

General population (n=247 young men; mean
age of 19.6 years)

Sperm volume
Sperm concentration
Sperm count
Percentage progressive
motile sperm
Sperm morphology

NS (p>0.05)

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 12 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

NS = not significant; PFDA = perfluorodecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid

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Table 2-20. Summary of Female Reproductive Outcomes in Humansa
Reference and study populationb
PFOA
Dhingra et al. 2016aCommunity (C8) (n=8,759; retrospective
analysis)Serum perfluoroalkyl level Outcome evaluatedResultc>2,130 ng/mL∙year (estimated Menopause age
cumulative PFOA exposure
5th quintile)
Early menopause risk

HR 1.11 (0.97–1.26, p=0.14),
5th quintile
NS (p=0.45), 5-year lag
NS (p=0.58), 10-year lag
NS (p=0.57), 15-year lag
NS (p=0.20), 20-year lag>4,670 ng/mL∙year (estimated Menopause age
cumulative PFOA exposure (estimated cumulative)
Community (C8) (n=3,334, prospective analysis) 5th quintile)
Menopause age(measured)>80.8 ng/mL (measured 5th
PFOA quintile)
Knox et al. 2011b
11.3–19.8 ng/mL (2nd PFOA Early menopause risk
quintile)(menopausal subgroup)
Community (C8) (n=25,957)
Early menopause risk
(perimenopausal
subgroup)

HR 1.10 (0.84–1.43, p=0.51),
5th quintile

Buck Louis et al. 2012

OR 1.89 (1.17–3.06)*, without parity
adjustment
OR 1.62 (0.99–2.66), with parity
adjustment
OR 2.58 (1.18–5.64)*, without parity
adjustment
OR 1.86 (0.81–4.24) with parity
adjustment
OR 5.45 (1.19–25.04)*, 3rd quartile
OR 1.33 (0.82–2.17), 4th quartile

Dhingra et al. 2016a

General population (n=473)

2.65 and 2.15 ng/mL(geometric mean PFOA in
women with or without
endometriosis)

Endometriosis

Risk of moderate tosevere endometriosis

Campbell et al. 2016
General population (NHANES) (n=753 women
aged 20–50 years)

2.70–3.99 and 4.00–
20.60 ng/mL (3rd and4th quartile serum PFOA)

Self-reported
endometriosis

HR 1.12 (0.86–1.45, p=0.40),
5th quintile
OR 1.5 (1.1–2.1)*, 2nd quintile
OR 1.4 (1.1–1.8)*, 2nd quintile

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Table 2-20. Summary of Female Reproductive Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Fei et al. 2010

3.91–5.20 ng/mL (2nd quartile Breastfeeding duration
for maternal PFOA)≤3 months
Breastfeeding duration≤6 months
3.1, 3.5, and 3.1 ng/mL
Menstrual cycle length(median serum PFOA in
women with menstrual cyclesof ≤24 days, 25–31 days, or≥32 days
1.5 ng/mL (median PFOA)
Irregular menstrual cycle
Long menstrual cycle

OR 1.98 (1.17–3.24)*, 2nd quartile

General population (n=1,347 pregnant women)
Lum et al. 2017
General population (n=501 women)

Lyngsø et al. 2014
General population (n=1,623 pregnant women)
Romano et al. 2016

5.5–7.6 ng/mL (maternal
3rd quartile PFOA)

General population (n=336 women)
Taylor et al. 2014
General population (n=2,151 women)
Timmermann et al. 2017
General population (n=1,130 woman)
Vagi et al. 2014
General population (n=52 cases and
50 controls)>2.5–4.4 and >4.4 ng/mL(2nd and 3rd PFOA tertiles)

Short menstrual cycle
Breastfeeding duration≤3 months
Breastfeeding duration≤6 months
Menopause
Hysterectomy

OR 1.88 (1.31–2.72)*, 2nd quartile
OR 0.98 (0.96–1.00)

OR 1.4 (0.9–2.2)
OR 1.7 (1.1–2.6)*
OR 0.7 (0.3–1.5)
RR 1.63 (1.16–2.28)*, 3rd quartile
RR 1.38 (1.06–1.79)*, 3rd quartile
HR 1.36 (1.05–1.75)*, 3rd tertile
HR 1.83 (1.31–2.56)*, 2nd tertile

2.40 ng/mL (median maternal Breastfeeding duration (in β -1.3 (-1.9 to -0.7)*, per doubling of
PFOA)
months)serum PFOA levels
Exclusive breastfeeding β -0.5 (-0.7 to -0.3)*, per doubling of(in months)
serum PFOA levels
4.1 and 2.3 ng/mL (geometric Polycystic ovary
OR 6.93 (1.79–29.92, p=0.003)*,mean PFOA for cases andsyndrome risk
3rd tertile
controls)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-20. Summary of Female Reproductive Outcomes in Humansa
Reference and study populationb
PFOS
Knox et al. 2011b
Community (C8) (n=25,957)

Buck Louis et al. 2012
General population (n=473)

Campbell et al. 2016

Serum perfluoroalkyl level Outcome evaluatedResultc

11.9–17.0 and 17.1–
Early menopause risk
22.4 ng/mL (2nd and 3rd PFOS (menopausal subgroup)
quintiles)
Early menopause risk
(perimenopausal
subgroup)
7.20 and 6.11 ng/mL
Endometriosis(geometric mean PFOS inwomen with or without
endometriosis)
Risk of moderate tosevere endometriosis

OR 1.5 (1.1–2.1)*, 2nd quintile

18.20–392.00 ng/mL(4th quartile PFOS)

Self-reported
endometriosis

OR 1.1 (1.1–1.8)*, 3rd quintile

OR 1.39 (0.98–1.98), without parity
adjustment
OR 1.25 (0.87–1.80), with parity
adjustment
OR 1.86 (1.05–3.30)*, without parity
adjustment
OR 1.50 (0.82–2.74) with parity
adjustment
OR 3.48 (1.00–12.00), 4th quartile

General population (NHANES) (n=753 women
aged 20–50 years)
Fei et al. 2010
General population (n=1,347 pregnant women)
Lum et al. 2017
General population (n=501 women)

Lyngsø et al. 2014
General population (n=1,623 pregnant women)

3.91–5.20 ng/mL (2nd quartile Breastfeeding duration
for maternal PFOA)≤3 months

OR 1.89 (1.19–3.01)*, 4th quartile

Breastfeeding duration≤6 months

OR 1.56 (1.10–2.22)*, 2nd quartile

12.3, 12.6, and 11.5 ng/mL
Menstrual cycle length(median serum PFOS inwomen with menstrual cyclesof ≤24 days, 25–31 days, or≥32 days
8.0 ng/mL (median PFOS)
Irregular menstrual cycle
Long menstrual cycle
Short menstrual cycle

OR 1.01 (0.98–1.03), 3rd tertile

OR 1.0 0.6–1.6)
OR 0.7 (0.4–1.2)
OR 0.7 (0.3–1.5)

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2. HEALTH EFFECTS

Table 2-20. Summary of Female Reproductive Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Romano et al. 201613.9 ng/mL (maternal median Breastfeeding duration
PFOS)≤3 months
Breastfeeding duration≤6 months>9–18.4 and >18.4 ng/mL
Menopause(2nd and 3rd PFOS tertiles)
Hysterectomy

NS (p=0.065 for trend)

General population (n=336 women)
Taylor et al. 2014
General population (n=2,151 women)
Timmermann et al. 201719.47 ng/mL (medianmaternal PFOS)

General population (n=1,130 woman)
Vagi et al. 2014
General population (n=52 cases and
50 controls)
PFHxS
Buck Louis et al. 2012
General population (n=473)

General population (NHANES) (n=753 women
aged 20–50 years)
Romano et al. 2016
General population (n=336 women)

HR 1.16 (0.91–1.48), 3rd tertile
HR 1.44 (1.12–1.85)*, 2nd tertile

Breastfeeding duration (in β -1.4 (-2.1 to -0.6)*, per doubling ofmonths)serum PFOS levels
Exclusive breastfeeding(in months)

β -0.3 (-0.6 to -0.1)*, per doubling ofserum PFOS levels

8.2 and 4.9 ng/mL (geometric Polycystic ovary
mean PFOS for cases andsyndrome risk
controls)

OR 5.79 (1.58–24.12, p=0.005)*,
3rd tertile

0.48 and 0.43 ng/mL(geometric mean PFHxS in
women with or without
endometriosis)

OR 1.14 (0.58–2.24), without parity
adjustment
OR 0.85 (0.42–1.73), with parity
adjustment
OR 2.12 (0.85–5.27), without parity
adjustment
OR 1.24 (0.47–3.31) with parity
adjustment

Endometriosis

Risk of moderate tosevere endometriosis

Campbell et al. 2016

NS (p=0.111 for trend)

2.20–19.40 ng/mL (4th quartile Self-reported
PFHxS)
endometriosis

OR 1.47 (0.40–1.41), 4th quartile

1.5 ng/mL (maternal median
PFHxS)NS (p=0.124 for trend)

Breastfeeding duration≤3 months
Breastfeeding duration≤6 months

NS (p=0.087 for trend)

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2. HEALTH EFFECTS

Table 2-20. Summary of Female Reproductive Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Taylor et al. 2014

>0.9–1.8 and >1.8 ng/mL(2nd and 3rd PFHxS tertiles)

HR 1.42 (1.08–7.87)*, 2nd tertile
HR 2.22 (1.66–2.98)*, 2nd tertile

General population (n=2,151 women)
Timmermann et al. 20171.45 ng/mL (median maternal Breastfeeding duration (in β -0.2, (-0.5–0.2), per doubling of
PFHxS)
months)serum PFHxS levels

General population (n=1,130 woman)
Vagi et al. 2014
General population (n=52 cases and
50 controls)
PFNA
Buck Louis et al. 2012
General population (n=473)

Menopause
Hysterectomy

Exclusive breastfeeding(in months)
1.1 and 0.7 ng/mL (geometric Polycystic ovary
mean PFHxS for cases and syndrome risk
controls)

OR 1.20 (0.35–4.07), 3rd tertile

0.69 and 0.58 ng/mL(geometric mean PFNA inwomen with or without
endometriosis)

OR 2.20 (1.02–4.75)*, without parity
adjustment
OR 1.99, 0.91–4.33), with parity
adjustment
OR 1.21 (0.35–4.19), without parity
adjustment
OR 0.99 (0.27–3.65) with parity
adjustment

Endometriosis

Risk of moderate tosevere endometriosis

Campbell et al. 2016
General population (NHANES) (n=753 women
aged 20–50 years)
Lum et al. 2017
General population (n=501 women)

Romano et al. 2016
General population (n=336 women)

β -0.1 (-0.2–0.2), per doubling ofserum PFHxS levels

1.20–15.40 ng/mL (4th quartile Self-reported
PFNA)
endometriosis

OR 3.24 (0.81–12.91), 4th quartile

1.3, 1.2, and 1.1 ng/mL
Menstrual cycle length(median serum PFNA inwomen with menstrual cyclesof ≤24 days, 25–31 days, or≥32 days
0.9 ng/mL (maternal median Breastfeeding duration
PFNA)≤3 months
Breastfeeding duration≤6 months

OR 1.01 (0.99–1.04), 3rd tertile

NS (p=0.591 for trend)
NS (p=0.349 for trend)

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2. HEALTH EFFECTS

Table 2-20. Summary of Female Reproductive Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Taylor et al. 2014

>0.80–1.5 and >1.5 ng/mL(2nd and 3rd PFNA tertiles)

HR 1.47 (1.14–1.90)*, 3rd tertile
HR 1.39 (1.08–1.80)*, 2nd tertile

General population (n=2,151 women)
Timmermann et al. 20170.62 ng/mL (median maternal Breastfeeding duration (in β -1.3, (-2.0 to -0.7)*, per doubling ofPFNA)
months)serum PFNA levels

General population (n=1,130 woman)
Vagi et al. 2014
General population (n=52 cases and
50 controls)
PFDA
Buck Louis et al. 2012
General population (n=473)

Menopause
Hysterectomy

Exclusive breastfeeding(in months)
1.2 and 0.9 ng/mL (geometric Polycystic ovary
mean PFNA for cases andsyndrome risk
controls)

OR 2.25 (0.67–8.00), 3rd tertile

0.20 and 0.18 ng/mL(geometric mean PFDA inwomen with or without
endometriosis)

OR 2.95 (0.72–12.1), without parity
adjustment
OR 2.60 (0.62–10.9), with parity
adjustment
OR 0.72 (0.06–8.09), without parity
adjustment
OR 0.58 (0.04–7.42) with parity
adjustment

Endometriosis

Risk of moderate tosevere endometriosis

Lum et al. 2017
General population (n=501 women)

β -0.2 (-0.5 to -0.0)*, per doubling ofserum PFNA levels

0.4, 0.4, and 0.4 ng/mL
Menstrual cycle length(median serum PFDA inwomen with menstrual cyclesof ≤24 days, 25–31 days, or≥32 days

OR 1.01 (0.99–1.04), 3rd tertilePERFLUOROALKYLS

379
2. HEALTH EFFECTS

Table 2-20. Summary of Female Reproductive Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluated

Timmermann et al. 20170.28 ng/mL (median maternal Breastfeeding duration (in β -0.8 (-1.4 to -0.3) *, per doubling ofPFDA)months)serum PFDA levels
Exclusive breastfeeding β -0.2 (-0.4–0.0), per doubling of(in months)
serum PFDA levels

General population (n=1,130 woman)

Resultc

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 12 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

HR = hazard ratio; OR = odds ratio; NS = not significant; PFDA = perfluorodecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoicacid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; RR = risk ratioPERFLUOROALKYLS

380
2. HEALTH EFFECTS

Table 2-21. Summary of Fertility Outcomes in Humansa
Reference and study populationb
PFOA
Bach et al. 2015a
General population (n=1,372 pregnant women)
Bach et al. 2015c, 2015dGeneral population (n=440 pregnant women)

Bach et al. 2015c, 2015d(re-analysis of Fei et al. 2009, 2012 data)
General population (n=1,161 pregnant women)

Buck Louis et al. 2013
General population (n=501 couples)

Crawford et al. 2017
General population (n=99 30–44-year-old
women)
Fei et al. 2009
General population (n=1,240 pregnant women)

Serum perfluoroalkyl level Outcome evaluatedResultc

2.0 ng/ml (median maternal
PFOA)

Fecundability
Infertility risk

FR 1.00 (0.99–1.01), per 0.1 ng/mL
OR 1.00 (0.98–1.01), per 0.1 ng/mL

5.6–7.7 ng/mL (4th PFOA
quartile)

Fecundability
Parous subgroup
Nulliparous subgroup

FR 0.86 (0.63–1.19), 4th quartile
FR 0.74 (0.48–1.13), 4th quartile
FR 0.99 (0.64–1.54), 4th quartile

Infertility
Parous subgroup
Nulliparous subgroupnd
4.1–5.4 ng/mL (2 PFOA
Fecundability
quartile)
Parous subgroup
Nulliparous subgroup
7.2–41.5 ng/mL (4th PFOA
Infertility
quartile)
Parous subgroup
Nulliparous subgroup
Couples achieving
Fecundability
pregnancy: 3.112 andFemale serum PFOA
5.016 ng/mL or withdrawing
Male serum PFOA
from study or not pregnant
3.101 and 4.749 ng/mL(geometric mean serum
PFOA in females and males)
2.79 ng/mL (geometric mean Fecundability
serum PFOA)

3.91–5.20 ng/mL (2nd PFOA Fecundability
quartile, maternal)
Infertility

OR 1.67 (0.70–4.00), 4th quartile
OR 1.74 (0.46–6.55), 4th quartile
OR 1.56 (0.55–4.42), 4th quartile
FR 0.78 (0.65–0.94)*, 2nd quartile
FR 0.76 (0.59–0.96)*, 2nd quartile
FR 0.74 (0.56–0.98)*, 4th quartile
OR 1.91 (1.16–3.13)*, 2nd quartile
OR 2.30 (1.09–4.87)*, 2nd quartile
OR 1.48 (0.80–2.75), 4th quartile
OR 0.95 (0.82–1.11)
OR 1.01 (0.88–1.17)

FR 1.15 (0.66–2.01)

FOR 0.72 (0.57–0.90)*, 2nd quartile
OR 2.06 (1.22–3.51)*, 2nd quartilePERFLUOROALKYLS

381
2. HEALTH EFFECTS

Table 2-21. Summary of Fertility Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Fei et al. 2012
(re-analysis of Fei et al. 2009 data)

3.91–5.20 and ≥6.97 ng/mL Fecundability(2nd and 4th PFOA quartiles,
Parous subgroup
Nulliparous subgroupmaternal)

FOR 0.61 (0.46–0.80)*, 2nd quartile
FOR 0.63 (0.39–1.04), 4th quartile

General population (n=1,240 pregnant women)

Jørgensen et al. 2014a, 2014b

Infertility
Parous subgroup
Nulliparous subgroup1.65 ng/mL (median PFOA)

General population (n=938 pregnant women)
Lum et al. 2017
General population (501 couples)
Vélez et al. 2015
General population (n=1,743 pregnant women)
Vestergaard et al. 2012

≥4.20 ng/mL (3rd tertile
serum PFOA)

1.7 ng/mL (median maternal Fecundability
PFOA)
Infertility

5.58 and 5.61 ng/mL(median PFOA in women
General population (n=222 nulliparous couples) with no pregnancy andpregnant)
Wang et al. 2017
General population (n=157 women withendometriosis-related infertility and
178 controls)
Whitworth et al. 2012b

Fecundability
Primiparous subgroup
Infertility
Probability of pregnancy

OR 3.39 (1.75–6.53)*, 2nd quartile
OR 1.30 (0.52–3.21; p=0.082 fortrend), 4th quartile
FR1.04 (0.87–1.25)
FR 1.31 (1.03–1.68)*
OR 1.11 (0.74–1.66)
OR 0.7 (0.5–1.1)

FOR 0.89 (0.83–0.94, p<0.001)*
OR 1.31 (1.11–1.53, p=0.001)*

Fecundability
Not becoming pregnant
within first six cycles

OR 1.18 (0.78–1.78)
OR 1.21 (0.67–2.18)>19.6–72.1 ng/mL (3rd tertile Endometriosis-related
serum PFOA)
infertility

OR 1.05 (0.58–1.91)

1.66–2.24, 2.25–3.02, andInfertility
OR 1.6 (1.1–2.3)*, 2nd quartilendrd≥3.02 ng/mL (2 , 3 , andParous subgroup
OR 2.4 (1.4–4.1)*, 3rd quartilethGeneral population (n=416 subfecund pregnant 4 PFOA quartiles)
Primiparous subgroup
OR 0.5 (0.2–1.2), 4th quartile
women and 474 controls)
Whitworth et al. 2016
2.8 ng/mL (maternal median Fecundability
OR 1.0 (0.90–1.2)
serum PFOA)
General population (n=451 primiparous
pregnant women)

PERFLUOROALKYLS

382
2. HEALTH EFFECTS

Table 2-21. Summary of Fertility Outcomes in Humansa
Reference and study populationb
PFOS
Bach et al. 2015a
General population (n=1,372 pregnant women)

Bach et al. 2015c, 2015dGeneral population (n=440 pregnant women)

Bach et al. 2015c, 2015d(re-analysis of Fei et al. 2009, 2012 data)
General population (n=1,161)

Buck Louis et al. 2013
General population (n=501 couples)

Crawford et al. 2017
General population (n=99 30–44-year-old
women)
Fei et al. 2009
General population (n=1,240 pregnant women)

Serum perfluoroalkyl level Outcome evaluatedResultc

8.3 ng/ml (median maternal
PFOS)

FR 1.09 (0.92–1.30), 4th quartile
OR 0.71 (0.47–1.07), 4th quartile

Fecundability
Infertility risk

10.85–36.10 ng/mL(4th PFOS quartile)
36.3–103.8 ng/mL (4th PFOS Fecundability
quartile)
Parous subgroup
Nulliparous subgroup
Infertility
Parous subgroup
Nulliparous subgroup27.0–34.2, 34.3–43.8, andFecundability
43.9–106.7 ng/mL (2nd, 3rd,
Parous subgroup
Nulliparous subgroupand 4th PFOS quartiles)
Infertility
Parous subgroup
Nulliparous subgroup
Couples achieving
Fecundability
pregnancy: 11.764 andFemale serum PFOS
20.867 ng/mL or withdrawing
Male serum PFOS
from study or not pregnant
11.088 and 19.765 ng/mL(geometric mean serum
PFOS in females and males)
9.29 ng/mL (geometric mean Fecundability
serum PFOS)

26.1–33.3 ng/mL (2nd PFOS Fecundability
quartile, maternal)
Infertility

FR 0.96 (0.75–1.24), 4th quartile
FR 1.04 (0.70–1.55), 4th quartile
FR 0.97 (0.62–1.51), 4th quartile
OR 1.03 (0.54–2.00), 4th quartile
OR 0.70 (0.16–3.11), 4th quartile
OR 1.23 (0.452–3.39), 4th quartile
FR 0.79 (0.66–0.95)*, 2nd quartile
FR 0.90 (0.70–1.14), 4th quartile
FR 0.68 (0.52–0.91)*, 3rd quartile
OR 1.65 (1.01–2.68)*, 2nd quartile
OR 1.60 (0.78–3.28), 4th quartile
OR 2.71 (1.38–5.30)*, 3rd quartile
OR 0.99 (0.85–1.17)
OR 0.96 (0.80–1.15)

FR 0.89 (0.49–1.60)

OR 0.70 (0.56–0.87)*, 2nd quartile
OR 1.70 (1.01–2.86)*, 2nd quartilePERFLUOROALKYLS

383
2. HEALTH EFFECTS

Table 2-21. Summary of Fertility Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Fei et al. 2012
(re-analysis of Fei et al. 2009 data)

26.1–33.3 and 33.4–43.2
ng/mL (2nd and 3rd PFOS
quartiles, maternal)

NS (p=0.32 for trend)
FOR 0.63 (0.43–0.91)*, 3rd quartile

General population (n=1,240 pregnant women)

Jørgensen et al. 2014a, 2014b
General population (n=938 pregnant women)
Lum et al. 2017
General population (501 couples)
Vélez et al. 2015
General population (n=1,743 pregnant women)
Vestergaard et al. 2012

Fecundability
Parous subgroup
Nulliparous subgroup
Infertility
Parous subgroup
Nulliparous subgroup10.60 ng/mL (median PFOS) Fecundability
Infertility≥15.20 ng/mL (3rd tertile
serum PFOS)

Probability of pregnancy

4.7 ng/mL (median maternal Fecundability
PFOS)
Infertility

35.75 and 36.29 ng/mL(median PFOS in women
General population (n=222 nulliparous couples) with no pregnancy andpregnant)
Wang et al. 2017>9.36–138 ng/mL (3rd tertile
serum PFOS)
General population (n=157 women withendometriosis-related infertility and
178 controls)
Whitworth et al. 2012b
10.34–16.60 and≥16.61 ng/mL (3rd andGeneral population (n=416 subfecund women
4th PFOS quartile)and 474 controls)
Whitworth et al. 201614.6 ng/mL (maternal
median serum PFOS)
General population (n=451 primiparous
pregnant women)

NS (p=0.26 for trend)
OR 2.50 (1.16–5.37, p=0.36 fortrend)*, 3rd quartile
FR 0.90 (0.76–1.07)
OR 1.39 (0.93–2.07)
OR 0.9 (0.6–1.3)

FOR 0.96 (0.91–1.02, p=0.17)
OR 1.14 (0.98–1.34, p=0.09)

Fecundability

NS (p=0.29)

Not becoming pregnant
within first six cycles

OR 0.98 (0.54–1.77)

Endometriosis-related
infertility

OR 0.66 (0.36–1.21)

Infertility
OR 1.4 (1.0–2.0)*, 3rd quartile
Parous subgroup
OR 2.1 (1.2–3.8)*, 4th quartile
Primiparous subgroup
OR 0.7 (0.4–1.3), 4th quartile
Fecundability

OR 1.00 (0.88–1.1)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-21. Summary of Fertility Outcomes in Humansa
Reference and study populationb
PFHxSBach et al. 2015a
General population (n=1,372 pregnant women)
Crawford et al. 2017
General population (n=99 30–44-year-old
women)
Jørgensen et al. 2014a, 2014b
General population (n=938 pregnant women)
Vélez et al. 2015
General population (n=1,743 pregnant women)
Vestergaard et al. 2012

Serum perfluoroalkyl level Outcome evaluatedResultc

0.5 ng/ml (median maternal
PFHxS)

FR 1.00 (0.99–1.01), per 0.1 ng/mL
OR 0.98 (0.93–1.03), per 0.1 ng/mL

1.59 ng/mL (geometric mean Fecundability
serum PFHxS)

0.84 (0.46–1.54)

1.94 ng/mL (median PFHxS) Fecundability

FR 0.97 (0.85–1.11)

Infertility

OR 0.99 (0.73–1.33)

Fecundability
Infertility

FOR 0.91 (0.86–0.97, p=0.002)*
OR 1.27 (1.09–1.48, p=0.003)*

Fecundability
Not becoming pregnant
within first six cycles

OR 1.33 (1.01–1.75)*
OR 0.67 (0.37–1.20)>0.39–1.69 ng/mL (3rd tertile Endometriosis-related
serum PFHxS)
infertility

OR 0.47 (0.26–0.87)*

7.0 ng/mL (maternal median Fecundability
serum PFHxS)

OR 0.97 (0.90–1.1)

1 ng/mL (median maternal
PFHxS)

1.12 and 1.22 ng/mL(median PFHxS in women
General population (n=222 nulliparous couples) with no pregnancy andpregnant)
Wang et al. 2017
General population (n=157 women withendometriosis-related infertility and
178 controls)
Whitworth et al. 2016
General population (n=450 primiparous
pregnant women)

Fecundability
Infertility risk

PERFLUOROALKYLS

385
2. HEALTH EFFECTS

Table 2-21. Summary of Fertility Outcomes in Humansa
Reference and study populationb
PFNA
Bach et al. 2015a
General population (n=1,372 pregnant women)
Buck Louis et al. 2013
General population (n=501 couples)

Crawford et al. 2017

Serum perfluoroalkyl level Outcome evaluatedResultc

0.8 ng/mL (median maternal) Fecundability
Infertility risk

FR 1.00 (0.98–1.02), per 0.1 ng/mL
OR 0.99 (0.95–1.03), per 0.1 ng/mL

Couples achieving
Fecundability
pregnancy: 1.176 andFemale serum PFNA
1.558 ng/mL or withdrawing
Male serum PFNA
from study or not pregnant
1.112 and 1.422 ng/mL(geometric mean serum
PFNA in females and males)
0.84 ng/mL (geometric mean Fecundability
serum PFNA)

OR 1.00 (0.84–1.19)
OR 1.09 (0.90–1.32)

1.40 (0.79–2.49)

General population (n=99 30–44-year-old
women)
Jørgensen et al. 2014a, 2014b0.64 ng/mL (median PFNA)

Fecundability
Primiparous subgroup
Infertility

FR 0.80 (0.69–0.94)*
FR 0.99 (0.88–1.22)
OR 1.53 (1.08–2.15)*≥1.50 ng/mL (3rd tertile
serum PFNA)

Probability of pregnancy

OR 0.8 (0.6–1.2)

General population (n=938 pregnant women)
Lum et al. 2017
General population (501 couples)
Vestergaard et al. 2012

0.45 and 0.51 ng/mL
Fecundability(median PFNA in womenNot becoming pregnant
General population (n=222 nulliparous couples) with no pregnancy andwithin first six cycles
pregnant)
Wang et al. 2017>1.50–7.10 ng/mL (3rd tertile Endometriosis-related
serum PFNA)
infertility
General population (n=157 women withendometriosis-related infertility and
178 controls)

OR 1.17 (0.88–1.54)
OR 0.67 (0.37–1.25)

OR 0.52 (0.28–0.95)*

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Table 2-21. Summary of Fertility Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Whitworth et al. 2016

0.43 ng/mL (maternal
median serum PFNA)

OR 1.1 (0.92–1.3)

Fecundability

General population (n=451 primiparous
pregnant women)
PFDA
Bach et al. 2015a
General population (n=1,372 pregnant women)
Buck Louis et al. 2013
General population (n=501 couples)

Lum et al. 2017
General population (501 couples)
Vestergaard et al. 2012

0.3 ng/mL (median maternal Fecundability
PFDA)
Infertility risk
Couples achieving
Fecundability
pregnancy: 0.385 andFemale serum PFDA
0.448 ng/mL or withdrawing
Male serum PFDA
from study or not pregnant
0.349 and 0.416 ng/mL(geometric mean serum
PFDA in females and males)≥0.05 ng/mL (3rd tertile
serum PFDA)

0.10 and 0.11 ng/mL(median PFDA in women
General population (n=222 nulliparous couples) with no pregnancy andpregnant)
Wang et al. 2017>1.79–11.2 ng/mL ng/mL(3rd tertile serum PFDA)
General population (n=157 women withendometriosis-related infertility and
178 controls)
Whitworth et al. 20160.11 ng/mL (maternal
median serum PFDA)
General population (n=429 primiparous
pregnant women)

FR 1.00 (0.97–1.03), per 0.1 ng/mL
OR 0.99 (0.92–1.07), per 0.1 ng/mL

OR 1.11 (0.95–1.29)
OR 1.08 (0.93–1.26)

Probability of pregnancy

OR 0.9 (0.6–1.3)

Fecundability
Not becoming pregnant
within first six cycles

OR 1.15 (0.89–1.49)
OR 0.61 (0.33–1.12)

Endometriosis-related
infertility

OR 0.74 (0.40–1.35)

Fecundability

OR 1.00 (0.85–1.2)

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Table 2-21. Summary of Fertility Outcomes in Humansa
Reference and study populationb
PFUnABach et al. 2015a
General population (n=1,372 pregnant women)
Wang et al. 2017
General population (n=157 women withendometriosis-related infertility and
178 controls)
Whitworth et al. 2016
General population (n=447 primiparous
pregnant women)
PFHpA
Wang et al. 2017

Serum perfluoroalkyl level Outcome evaluatedResultc

0.3 ng/mL (median maternal Fecundability
PFUnA)
Infertility risk

FR 1.01 (0.98–1.03), per 0.1 ng/mL
OR 0.98 (0.92–1.04), per 0.1 ng/mL>1.42–5.34 ng/mL (3rd tertile Endometriosis-related
serum PFUnA)
infertility

OR 0.61 (0.33–1.13)

0.23 ng/mL (maternal
median serum PFUnA)

OR 0.93 (0.78–1.1)

Fecundability>0.11–0.66 ng/mL (3rd tertile Endometriosis-related
serum PFHpA)
infertility

OR 0.48 (0.26–0.86)*>0.086–0.094 ng/mL(2nd tertile serum PFBS)

OR 3.74 (2.04—6.84)*

General population (n=157 women withendometriosis-related infertility and
178 controls)
PFBS
Wang et al. 2017
General population (n=157 women withendometriosis-related infertility and
178 controls)
PFDoDA
Wang et al. 2017
General population (n=157 women withendometriosis-related infertility and
178 controls)

Endometriosis-related
infertility>0.27–1.02 ng/mL (2nd tertile Endometriosis-related
serum PFDoDA)
infertility

OR 0.61 (0.34–1.11)

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Table 2-21. Summary of Fertility Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Whitworth et al. 2016

0.04 ng/mL (maternal
median serum PFDoDA)

OR 0.91 (0.77–1.1)

Fecundability

General population (n=410 primiparous
pregnant women)
FOSA
Buck Louis et al. 2013

Couples achieving
Fecundability
pregnancy: 0.110 andFemale serum FOSA
General population (n=501 couples)
0.112 ng/mL or withdrawing
Male serum FOSA
from study or not pregnant
0.126 and 0.129 ng/mL(geometric mean serum
FOSA in females and males)
Vestergaard et al. 2012
0.10 and 0.11 ng/mL
Fecundability(median FOSA in womenNot becoming pregnant
General population (n=222 nulliparous couples) with no pregnancy andwithin first six cycles
pregnant)
Whitworth et al. 2016
0.03 ng/mL (maternal
Fecundability
median serum FOSA)
General population (n=226 primiparous
pregnant women)

OR 0.81 (0.70–0.94)*
OR 0.89 (0.78–1.02)

OR 1.01 (0.86–1.18)
OR 0.81 (0.45–1.46)

OR 0.91 (0.71–1.2)

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 12 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

FOR = fecundability odds ratio; FOSA = perfluorooctane sulfonamide; FR = fecundability ratio (probability of conceiving during a given menstrual cycle);
OR = odds ratio; NS = not significant; PFDA = perfluorodecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid

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Studies in laboratory animals have evaluated the potential histological alterations in reproductive tissues,
alterations in reproductive hormones, and impaired reproductive functions. Summaries of these studies
are presented in Tables 2-1, 2-3, 2-4, 2-5, and 2-6 and in Figures 2-6, 2-8, 2-9, and 2-10. Multigeneration
studies on PFOA, PFOS, and PFBS have not found alterations in reproductive parameters in animals;
similarly, no effect on fertility was observed for PFHxS or PFDoDA. One study found alterations insperm parameters and decreases in fertility in mice exposed to PFNA. An increase in the incidence ofLeydig cell hyperplasia (reclassified as gonadal stromal hyperplasia) has been observed in animals
exposed to PFOA; one study for PFDoDA reported ultrastructural alterations in the testes. Studies on
PFOS, PFHxS, PFBS, and PFBA have not found histological alterations. Delays in mammary glanddevelopment have been observed in mice exposed to PFOA; this effect has also been observed inperinatally exposed mice (see Section 2.17, Developmental). No laboratory animal studies examined
reproductive endpoints for PFDA, PFUnA, PFHpA, or FOSA.
PFOA

Epidemiological Studies—Reproductive Hormone Levels. Three studies have evaluated potential effects
of PFOA exposure on reproductive hormone levels in workers (Gilliland 1992; Olsen et al. 1998b; Sakr et
al. 2007b). Sakr et al. (2007b) found associations between serum PFOA and estradiol and testosterone
levels in male workers at the Washington Works facility. Similarly, Gilliland (1992) found associations
between serum fluorine levels and estradiol and prolactin levels and inverse associations with bound andfree testosterone levels in workers at the 3M Cottage Grove facility. In contrast, Olsen et al. (1998b) did
not find associations between serum PFOA and estradiol or testosterone in male workers at the 3M
Cottage Grove facility. The study did find an association with prolactin levels, but this was only found inworkers examined in 1993, but not in those examined in 1995. In a general population study of men aged
30–66 years of age, correlations were found between serum PFOA levels and free testosterone levels and
LH levels; no correlations were found for estradiol, prolactin, follicle stimulating hormone (FSH), or total
testosterone levels (Raymer et al. 2012). Another study of similar aged men did not find an association
between serum PFOA and sex hormone binding globulin levels (Specht et al. 2012). Studies of youngmen (median age 19 years) (Joensen et al. 2013) or adolescents and young men (12–30 years of age) (Tsaiet al. 2015) did not find associations between serum PFOA and reproductive hormone levels. A third
study (Vested et al. 2013) found an association between LH and FSH levels and maternal serum PFOA
levels in young adult males; other hormones were not affected. A fourth study in adolescents (aged 13–
15 years) found an association between serum PFOA and estradiol levels in boys, but not in girls, and did
not find associations for testosterone levels (Zhou et al. 2016).

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Two studies of women (Barrett et al. 2015; Knox et al. 2011b) did not find associations with estradiol
levels or luteal progesterone levels. A third study of adolescent and young women (Tsai et al. 2015)
found an association between serum PFOA and sex hormone binding globulin levels in adolescents (12–17 years), but not in young adults; no associations with FSH or testosterone were observed in eithergroup.

Epidemiological Studies—Effects on Sperm. Six general population studies have evaluated the potential
alterations in sperm parameters associated with PFOA exposure. Although some associations have beenfound, the results are not consistent across studies. Buck Louis et al. (2015) reported an increase incurvilinear velocity and some alterations in sperm morphology that were associated with serum PFOA
levels. Toft et al. (2012) found a PFOA-related increase in the percentage of motile sperm in men withserum PFOA levels in the 3rd tertile. Vested et al. (2013) reported inverse associations between maternal
serum PFOA levels and sperm concentration and total sperm count in young adults; no alterations inmotility or morphology were observed. Other studies did not find alterations in sperm viability, count,concentration, motility, or morphology (Buck Louis et al. 2015; Joensen et al. 2013; Raymer et al. 2012;
Toft et al. 2012) or the Y-X chromosome ratio (Kvist et al. 2012).

Epidemiological Studies—Effects on Menstrual Cycle Length, Menopause Onset, Endometriosis, andBreastfeeding Duration. Two studies examined possible associations between serum PFOA levels andalterations in menstrual cycle length. An increased risk of a long menstrual cycle (≥32 days) was
observed in women with serum PFOA levels in the 3rd tertile and when serum PFOA was used as acontinuous variable (Lyngsø et al. 2014). No alterations in the risk of having a short menstrual cycle(≤24 days) or irregular menstrual cycles (≥7 days difference between cycles) were observed. The second
study did not find an association between serum PFOA and menstrual cycle length (Lum et al. 2017).

Four studies have evaluated the risk of early menopause. In a study of C8 Health Study participants,
increases in the risk of early menopause was observed in perimenopausal (>42–≤51 years of age) andmenopausal (>51–≤65 years of age) women with serum PFOA levels in the 2nd, 3rd, 4th, and 5th quintiles(Knox et al. 2011b). An increase in menopause risk was also observed in a cross-sectional study of
NHANES participants with serum PFOA levels in the 3rd tertile (Taylor et al. 2014). Taylor et al. (2014)
also found a higher risk of hysterectomy among women with serum PFOA levels in the 2nd and 3rd tertiles.
Findings of higher levels of PFOA (and other perfluoroalkyls) among women with hysterectomies andthat serum PFOA levels increased after menopause provide suggestive evidence that at least part of thePERFLUOROALKYLS

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association may be due to reverse causation (Taylor et al. 2014). In contrast, no alterations in the risk ofearly menopause or age of menopause were associated with estimated cumulative serum PFOA levels in
retrospective and prospective studies of C8 Health Study participants (Dhingra et al. 2016a); age ofmenopause was also not associated with measured serum PFOA levels in the prospective study (Dhingra
et al. 2016a). Cross-sectional analysis also showed that early menopause was associated with measured
serum PFOA levels, but not with modeled serum PFOA levels (Dhingra et al. 2017), providing support
that reverse causation may contribute to the observed association.

Buck Louis et al. (2012) showed that the risk of endometriosis and the risk of moderate-to-severe
endometriosis were associated with serum PFOA levels; however, adjustment for parity resulted inconfidence intervals that included unity. A second study found an increased risk of self-reported
endometriosis in women with serum PFOA levels in the 3rd quartile; for the 4th quartile women, theconfidence intervals included unity (Campbell et al. 2016). A case-control study (Vagi et al. 2014) foundan increased risk of polycystic ovary syndrome among women with serum PFOA levels in the 3rd tertile.

Two studies utilizing pharmacokinetic modeling have investigated whether the observed associations
between PFOA exposure and early onset menopause or risk of endometriosis was due to reverse causation(Ngueta et al. 2017; Ruark et al. 2017). As discussed in Section 3.1.4, menstrual blood loss is a route ofelimination of perfluoroalkyls. Therefore, variability in menstruation such as menarche, menopause, andpharmacological management of menstruation (e.g., use of oral contraceptives) could affect serum
perfluoroalkyl levels, and thereby contribute to observed statistical associations between serum PFOA
levels and early onset menopause (Ruark et al. 2017) or endometriosis (Ngueta et al. 2017) outcomes.

Three studies evaluated a possible association between maternal PFOA levels and breastfeeding duration.
Two studies found increases in the risk of breastfeeding ≤3 or 6 months that were associated withmaternal PFOA levels (Fei et al. 2010; Romano et al. 2016). Timmermann et al. (2017) found an inverse
association between maternal PFOA levels and the duration of breastfeeding and the amount of time thewomen exclusively breastfed. Fei et al. (2010) reported that when the women were segregated by parity,
the associations were only found in multiparous women. In contrast, Timmermann et al. (2017) found nodifferences in duration or breastfeeding exclusiveness between primiparous and multiparous women. It isnoted that a number of factors can influence the duration of breastfeeding including diminished milk
production, inadequate lactation support from health care providers after delivery, use of medication thatis not compatible with breastfeeding, lack of spousal/family support, and individual choice. In general,these studies did not consider whether these factors may have influenced the observed associations.

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Epidemiological Studies—Effects on Fertility. Several general population studies have examined thepossible association between female serum PFOA levels and decreased fertility or infertility; the results
are graphically presented in Figures 2-31 and 2-32, respectively. With the exception of the Buck Louis etal. (2013) and Vestergaard et al. (2012) prospective studies, all of the women were pregnant; thus,
couples with unresolved infertility are underrepresented in these analyses. Maternal transfer of PFOA
during pregnancy and lactation can result in lower serum PFOA levels in women (see Section 3.1.2 foradditional information), as compared to nulliparous women; thus, parity should be considered whenevaluating potential associations between serum PFOA and infertility. The Buck Louis et al. (2013) study
is the only study that used maternal and paternal serum PFOA levels as the biomarkers of exposure. Mostof the studies evaluated two aspects of fertility: fecundability, which is a measure of time to pregnancy,
and risk of infertility, which is typically time to pregnancy of >12 months.

In a study of pregnant women participating in the Danish National Birth Cohort study, a decrease infecundability and an increase in infertility were observed in women with serum PFOA (measured at
gestation week 12) levels in the three highest quartiles (Fei et al. 2009). When the women werecategorized by parity, decreased fecundability OR and increased infertility OR were only found in theparous group; the ORs for the nulliparous women included unity (Fei et al. 2009). A second re-analysisof these data (Bach et al. 2015a) using a different statistical approach confirmed the results of the wholegroup and the parous subgroup; this re-analysis also found a decrease in the fecundability risk among thenulliparous women. In another set of women participating in the Danish National Birth Cohort study(Bach et al. 2015c), no alterations in fecundability or infertility risk were observed in the whole cohort orwhen the women were categorized into parous and nulliparous subcohorts. It was noted that the medianserum PFOA levels in this second study (4.0 ng/mL) were lower than the levels in the larger study(5.4 ng/mL). A decrease in fecundability and an increase in infertility risk were also observed in a
Canadian study of pregnant women (Vélez et al. 2015). An increase in infertility risk was also found in a
Norwegian study of subfecund pregnant women with serum PFOA levels in the three highest quartiles(Whitworth et al. 2012b); when the women were categorized based on parity, the infertility risk was only
elevated in the parous women with serum PFOA levels in the 3rd and 4th quartiles. A multinational study
also found an alteration in fecundability (Jørgensen et al. 2014a); however, this study found that higher
serum PFOA levels resulted in a decrease in the time to pregnancy (fecundability ratio >1) among
primiparous women.

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Figure 2-31. Fecundability Relative to PFOA Levels (Presented as Adjusted Fecundability Ratios)PERFLUOROALKYLS

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Figure 2-32. Infertility Relative to PFOA Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Other studies of pregnant women have not found alterations in fecundability, fertility, and/or infertility(Bach et al. 2015a; Crawford et al. 2017; Jørgensen et al. 2014a; Lum et al. 2017; Wang et al. 2017;
Whitworth et al. 2016). The two prospective studies which followed women intending to get pregnant for
6 months (Vestergaard et al. 2012) or 12 months (Buck Louis et al. 2013) also did not find associations
between serum PFOA levels in women and fecundability; Buck Louis et al. (2013) also found noassociation when male serum PFOA was used as the biomarker of exposure.

Laboratory Animal Studies. Examination of the testes and epididymides of rats exposed intermittently
head-only to up to 84 mg/m3 APFO dusts for 2 weeks did not reveal any gross or microscopic treatmentrelated alterations (Kennedy et al. 1986).

Several studies have been conducted in rats to examine whether induction of Leydig cell tumors could be
due to an endocrine-related mechanism. In a 14-day gavage study in which rats were dosed with up to
50 mg/kg/day PFOA, testes weight was not significantly affected and microscopic examination did notreveal any significant alterations (Cook et al. 1992). However, the weight of the accessory sex organ unit
(ventral and dorsal lateral prostate, seminal vesicles, and coagulating glands) was significantly decreased
in rats dosed with 25 mg/kg/day PFOA (17% decrease) and 50 mg/kg/day PFOA (18% decrease) relative
to controls and to a pair-fed group. There was also a trend for reduced serum and interstitial fluid
testosterone in PFOA-treated rats; serum LH was not altered and estradiol was significantly increased(63%) at ≥10 mg/kg/day. Challenge experiments conducted with human chorionic gonadotropin,
gonadotropin-releasing hormone, or naloxone suggested that the decrease in serum testosterone was due
to a lesion at the level of the testes. Serum levels of progesterone and 17α-hydroxyprogesterone were notaltered by 50 mg/kg/day PFOA, but androstenedione levels were reduced 2-fold. The data suggested thatthe decrease in serum testosterone may be due to a decrease in the conversion of 17α-hydroxyprogesterone to androstenedione, and this could be attributed to the elevated serum levels of estradiol.
The decrease in weight of the accessory sex organ unit could also be attributed to the elevated estradiol
serum levels. In a subsequent study from the same group of investigators, rats dosed with 25 mg/kg/day
PFOA for 14 days showed a significant increase in estradiol in serum and in testicular interstitial fluid
relative to controls (Biegel et al. 1995). Treatment with PFOA for 14 days significantly increased
aromatase activity in the liver (aromatase converts testosterone to estradiol), but not in testes, muscle, or
adipose tissue, suggesting that PFOA increases serum estradiol by inducing aromatase activity in theliver. Treatment with PFOA also increased testicular interstitial fluid transforming growth factor α(TGFα). Collectively, the results were consistent with the hypothesis that increased estradiol levels
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factor secretion. A study of the dose-response relationship for PFOA and serum estradiol reported asignificant increase in serum estradiol in rats dosed with ≥2 mg/kg/day, which was well correlated withtotal hepatic aromatase activity (Liu et al. 1996). Significant increases in serum estradiol were also
reported during the first year of treatment of male rats with 13.6 mg/kg/day PFOA in a 2-year dietary
study (Biegel et al. 2001).

Significant increases in the incidence of Leydig cell hyperplasia were observed in rats exposed to13.6 mg/kg/day PFOA in the diet for 2 years (Biegel et al. 2001). Another 2-year study found anincreased incidence of vascular mineralization in the testes of rats exposed to 15 mg/kg/day PFOA in thediet; no effects were observed at 1.5 mg/kg/day (3M 1983; Butenhoff et al. 2012c). In female rats,
increases in the incidence of tubular hyperplasia of the ovaries were observed following a 2-year exposure
to 1.5 mg/kg/day (3M 1983; Butenhoff et al. 2012c). A peer review of the histological slides from thisstudy (3M 1983; Butenhoff et al. 2012c) concluded that the more current nomenclature for the tubular
hyperplasia was gonadal stromal hyperplasia (Mann and Frame 2004). Additionally, the peer reviewers
substantially disagreed with the incidence of lesions in the 1.5 mg/kg/day group and slightly disagreed
with the incidence in the 15 mg/kg/day group. Based on the incidence reported by the peer reviewers, nostatistically significant increases in the occurrence of gonadal stromal hyperplasia were observed in eithergroup; a significant increase in grade 3 and above lesions were observed in the 15 mg/kg/day group.

In a 2-generation reproduction study in which male and female rats were dosed with up to 30 mg/kg/day
PFOA by gavage in water for 70 days before mating and until sacrifice, there were no effects on estrous
cycling, sperm number and quality, mating and fertility, or histopathology of the reproductive organs
assessed in the parental and F1 generations (Butenhoff et al. 2004b). Intermediate-duration studies of rats
and monkeys also did not find gross or microscopic alterations in the sex organs at termination;
Cynomolgus monkeys were dosed with up to 20 mg/kg/day PFOA for 4 or 26 weeks (Butenhoff et al.
2002; Thomford 2001), Rhesus monkeys with up to 100 mg/kg/day PFOA for 13 weeks (Griffith andLong 1980), and rats with up to approximately 100–110 mg/kg/day PFOA for 13 weeks (Griffith andLong). Serum levels of estradiol and estriol were not significantly altered in the 4-week study conductedby Thomford (2001), but estrone was reduced in monkeys dosed with 2 and 20 mg/kg/day PFOA; no
possible explanation was discussed. In the 26-week study (Butenhoff et al. 2002), no treatment-related
alterations were reported in serum estrone, estriol, estradiol, or testosterone, indicating that the reduced
serum estrone levels in the 4-week study was transitory. In 2-year dietary studies in rats, doses of
13.6 mg/kg/day PFOA significantly increased the incidence of Leydig cell hyperplasia (Biegel et al.
2001), whereas 15 mg/kg/day increased the incidence of vascular mineralization in the testes andPERFLUOROALKYLS

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1.5 mg/kg/day increased the incidence of tubular hyperplasia in the ovaries (3M 1983; Butenhoff et al.
2012c).

A study in pregnant mice dosed with 5 mg/kg/day PFOA (only dose level tested) reported that the
mammary gland showed changes suggesting substantial delay (possibly up to 10 days) in glanddifferentiation on PND 20 and alterations in milk protein gene expression on PND 20 (White et al. 2007).
Subsequent studies by this group support the finding of delayed mammary gland differentiation. On
PND 1, the mammary glands of mice administered 5 mg/kg/day on GDs 8–17 appeared immature; themorphology was similar to that seen in late pregnancy prior to parturition and the initiation of nursing(White et al. 2009). Another study found that the normal weaning-induced mammary gland involution
was compromised on PND 22 in mice exposed to 1 mg/kg/day on GDs 1–17 or 0.001 mg/kg/day
administered on GD 7–PND 22 (White et al. 2011); the investigators noted that the mammary glandstructure was similar to mammary gland tissue at or near the peak of lactation (PND 10). Necrosis wasobserved in the placenta of mice administered via gavage 10 or 25 mg/kg/day PFOA on GDs 11–16 (Suhet al. 2011); no alterations were observed at 2 mg/kg/day.

A study of pregnant mice reported increases in serum estradiol levels, with no changes in progesterone
levels, at 10 mg/kg/day when PFOA was administered on GDs 1–7 (Chen et al. 2017b); however, when
PFOA was administered on GD 13, there were significant decreases in serum progesterone levels at 5 and
10 mg/kg/day with no changes in estradiol levels (Chen et al. 2017b). In peripubertal female mice,administration of 5 mg/kg PFOA 5 days/week for 4 weeks resulted in significant increases in serum
progesterone levels during estrus and preestrus, but no changes in estradiol levels were observed (Zhao et
al. 2010).

No gross or microscopic alterations were reported in the testes from rats dermally exposed to2,000 mg/kg/day APFO (Kennedy 1985).

Summary. Epidemiological studies have examined a several types of reproductive endpoints. Due toinconsistent results, the available data are not suitable for determining whether there are associations
between serum PFOA and reproductive hormones or effects on sperm. There is some suggestive
evidence that increases in serum PFOA levels can result in earlier onset of menopause; however, this isbased on the findings of two studies (a third study did not find an association) and may partially be due toreverse causation. Several general population studies found associations between serum PFOA andimpaired fertility (increased time to pregnancy and/or infertility), while others have not foundPERFLUOROALKYLS

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associations. The available epidemiological data are considered inadequate for determining whether there
is an association between serum PFOA and fertility. The database limitations include inconsistency
across studies, small number of studies including measurements of male serum PFOA levels, findings inparous women but not nulliparous women, and the underrepresentation of couples not becoming
pregnant. The results of a multi-generational study in rats do not suggest that the reproductive system is asensitive target of PFOA toxicity. Additionally, histological alterations have not been observed inmonkeys or rats following intermediate and/or chronic oral exposure.
PFOS

Epidemiological Studies—Reproductive Hormone Levels. In an occupational exposure study of workers
at 3M Decatur and Antwerp facilities (Olsen et al. 1998a) and a general population study (Raymer et al.
2012), no associations between serum PFOS and reproductive hormones were found. Studies inadolescent and young adult males have found inverse associations between serum PFOS levels and total
and free testosterone levels (Joensen et al. 2013), free androgen index (Joensen et al. 2013), and FSH
levels (Tsai et al. 2015). Another study of young men did not find alterations in reproductive hormone
levels (Vested et al. 2013).

In a study of females participating in the C8 Health Studies, serum PFOS levels were inversely associatedwith estradiol levels in both perimenopausal and menopausal women (Knox et al. 2011b). An inverse
association with follicular estradiol levels was also observed in a general population study (Barrett et al.
2015); when segregated by parity, the inverse association was only found in nulliparous women. An
inverse association between serum PFOS levels and testosterone levels was observed in adolescentfemales; no association was found in older females (Tsai et al. 2015). A general population study ofadolescents (aged 13–15 years) found an inverse association between serum PFOS levels and testosterone
levels in boys, but not in girls; the study also found no associations with estradiol levels in boys or girls(Zhou et al. 2016).

Epidemiological Studies—Effects on Sperm. The available general population data do not provide
evidence that PFOS damages sperm. One study (Buck Louis et al. 2015) found an association for one
measure of sperm motility (distance travelled) but not for other measures. Another study (Toft et al.
2012) found an inverse association between serum PFOS levels and percentage of normal sperm. Other
studies have not found alterations in sperm viability, count, motility, volume, or morphology (Buck Louiset al. 2015; Joensen et al. 2013; Raymer et al. 2012; Toft et al. 2012; Vested et al. 2013). A multinationalPERFLUOROALKYLS

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study (Kvist et al. 2012) found a nonlinear association between serum PFOS and Y-X chromosome ratio;
however, when categorized by country, the only significant trend was a negative trend in the Greenland
cohort. It is noted that these are studies of individuals exposed to background levels of PFOS, involved asingle measurement of PFOS, and are not adequate for establishing causality.

Epidemiological Studies—Effects on Menstrual Cycle Length, Menopause Onset, Endometriosis, andBreastfeeding Duration. No alterations in the risk of irregular, short, or long menstrual cycle lengths
associated with serum PFOS levels were observed in a study of pregnant women (Lyngsø et al. 2014).
Similarly, no association between serum PFOS levels and menstrual cycle length was observed in anotherstudy (Lum et al. 2017). A study of C8 Health Study participants found increases in the risk of earlymenopause in perimenopausal and menopausal women with serum PFOS levels in the ≥3rd and≥2nd quintiles, respectively (Knox et al. 2011b). In contrast, a study of NHANES participants did not findan association between serum PFOS and the risk of early menopause (Taylor et al. 2014). The risk ofendometriosis was not associated with serum PFOS levels (Buck Louis et al. 2012; Campbell et al. 2016).
However, there was a greater risk of having moderate to severe endometriosis; adjusting for parity
decreased the risk and the CIs included unity. General population studies found increases in the risk of
having a hysterectomy in women having serum PFOS levels in the 2nd and 3rd tertiles (Taylor et al. 2014)
and the risk of having polycystic ovary syndrome in women with serum PFOS levels in the 3rd tertile(Vagi et al. 2014). Most of these endpoints were only examined in one study and the evidence isinconclusive to determine whether there is an association between PFOS exposure and these female
reproductive outcomes.

Utilizing pharmacokinetic modeling, Ruark et al. (2017) and Ngueta et al. (2017) have investigatedwhether the observed associations between PFOS exposure and early onset menopause or risk ofendometriosis was due to reverse causation. Menstrual blood loss is a route of elimination of
perfluoroalkyls (see Section 3.1.4) and variability in menstruation such as menarche, menopause, andpharmacological management of menstruation (e.g., use of oral contraceptives) could affect serum
perfluoroalkyl levels, and thereby contribute to observed statistical associations between serum PFOS
levels and early onset menopause (Ruark et al. 2017) or endometriosis (Ngueta et al. 2017) outcomes.
Maternal serum PFOS levels have been associated with increases in the risk of breastfeeding for ≤3 or
6 months (Fei et al. 2010; Romano et al. 2016) and inversely associated with the length of breastfeeding
and the length of exclusive breastfeeding (Timmermann et al. 2017). When the women were segregatedby parity, the associations were only found in multiparous women (Fei et al. 2010). In contrast,

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Timmermann et al. (2017) found no significant alterations in breastfeeding length or exclusivenessbetween primiparous women and multiparous women. In general, these studies did not consider whether
other factors such as the duration of breastfeeding including diminished milk production, inadequate
lactation support from health care providers after delivery, use of medication that is not compatible withbreastfeeding, lack of spousal/family support, and individual choice may have influenced the observed
associations. Additionally, the associations between maternal PFOS and breastfeeding duration may be
due to reverse causality since longer breastfeeding would likely result in lower maternal PFOS levels.

Epidemiological Studies—Effects on Fertility. Several general population studies have evaluatedwhether there is a possible association between serum PFOS and time-to-pregnancy (as measured using a
fecundability ratio) or infertility; graphical presentations of potential associations between fecundability
and infertility relative to serum PFOA levels are presented in Figures 2-33 and 2-34, respectively. A
couple of studies have found associations, but most have not found associations. Fei et al. (2009) founddecreases in fecundability and increases in infertility risk among pregnant women with serum PFOS
levels in the top three quartiles. When the women were categorized by parity (Fei et al. 2012), thedecrease in fecundability and increase in infertility risk were only observed in nulliparous women withserum PFOS levels in the 3rd and 4th quartiles; no alterations were observed among parous women. A reanalysis of these data (Bach et al. 2015c) resulted in similar associations between PFOS and fecundability
and infertility. Whitworth et al. (2012b) also found an increased risk of infertility among subfecund
women with serum PFOS levels in the 3rd quartile; categorizing by parity resulted in increases in only
parous women with serum PFOS levels in the 4th quartile. In contrast, other studies have not foundalterations in fecundability or fertility associated with maternal serum PFOS levels (Bach et al. 2015a,
2015c; Buck Louis et al. 2013; Crawford et al. 2017; Jørgensen et al. 2014a; Lum et al. 2017; Vélez et al.
2015; Vestergaard et al. 2012; Wang et al. 2016; Whitworth et al. 2016).

Laboratory Animal Studies. Significant decreases in serum testosterone levels and epididymal sperm
count were observed in mice administered 10 mg/kg/day PFOS for 21 days (Wan et al. 2011), in rats
administered 5 mg/kg/day for 21 days (Li et al. 2018), and in mice administered 10 mg/kg/day for
5 weeks (Qu et al. 2016). No alterations were observed in mice administered 5 mg/kg/day PFOS or inmice administered 5 or 10 mg/kg/day PFOS for 14 days (Wan et al. 2011). No alterations in reproductive
performance (number of litters, gestation length, number of implantation sites, or potential resorptions)were observed in rats administered 1 mg/kg/day PFOS throughout gestation and lactation (Buttenoff et al.
2009b). Lee et al. (2015a) did find a decrease in placental weight and placental capacity (ratio of fetal
weight to placental weight) in mice administered ≥0.5 mg/kg/day PFOS via gavage on GDs 11–16.

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Figure 2-33. Fecundability Relative to PFOS Levels (Presented as Adjusted Fecundability Ratios)PERFLUOROALKYLS

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Figure 2-34. Infertility Relative to PFOS Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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Multigeneration studies with PFOS in rats did not provide indications of reproductive toxicity. Exposureof male and female rats to up to 3.2 mg/kg/day PFOS by gavage before mating and continuing during
gestation did not affect mating or fertility parameters of the parental or F1 generation (Luebker et al.
2005a, 2005b). Dietary exposure of rats to 1.3–1.8 mg/kg/day PFOS for 4 or 14 weeks did not induce
gross or microscopic alterations in the sex organs of males or females (Seacat et al. 2003). A similar
study in Cynomolgus monkeys administered up to 0.75 mg/kg/day PFOS administered via a capsule also
reported no significant morphological alterations in the sex organs, but serum estradiol was significantly
decreased in males on days 62, 91, and 182 of the study (Seacat et al. 2002). In addition, treatment withPFOS had no significant effect on cell proliferation in the testes. Serum estradiol also was lower than incontrols in one male and one female monkey dosed with 2 mg/kg/day PFOS for 4 weeks, but little can beconcluded from results from just two animals (Thomford 2002a). In a 2-year dietary study in rats,
administration of up to 1.04 mg/kg/day PFOS did not induce gross or microscopic alterations in the
reproductive organs (Butenhoff et al. 2012b; Thomford 2002b). Overall, the reproductive system does
not seem to be a sensitive target of PFOS toxicity, although some changes in testosterone and estradiol
levels and decreases in sperm count have been observed.
PFHxS

Epidemiological Studies—Reproductive Hormone Levels. Three general population studies evaluatedpossible effects of PFHxS on reproductive hormone levels. In young men, no associations between serum
PFHxS levels and testosterone, free androgen index, LH, estradiol, sex hormone binding globulin, or FSH
levels were found (Joensen et al. 2013). Similarly, no alterations in follicular estrogen or lutealprogesterone were observed in women (Barrett et al. 2015). An association between serum PFHxS levels
and estradiol levels were observed in adolescent boys, but not in girls; no associations were observed fortestosterone levels (Zhou et al. 2016).

Epidemiological Studies—Effects on Sperm. With the exception of the finding of an inverse association
between serum PFHxS levels and percent normal sperm (Toft et al. 2012), general population studies
have not found associations between PFHxS and sperm parameters (Joensen et al. 2013; Toft et al. 2012);
it is noted that the Joensen et al. (2013) study of young men did not find alterations in sperm morphology.

Epidemiological Studies—Effects on Menstrual Cycle Length, Menopause Onset, Endometriosis, andBreastfeeding Duration. Five general population studies have evaluated possible associations between
serum PFHxS levels and female reproductive outcomes. Taylor et al. (2014) reported increases in the risk

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of earlier menopause in women with serum PFHxS levels in the 3rd tertile and the risk of hysterectomy inwomen with serum PFHxS levels in the 2nd and 3rd tertiles. These findings may be due to reverse
causation in that early menopause may result in higher serum PFHxS levels. Other studies did not findassociations with the risk and severity of endometriosis (Buck Louis et al. 2012; Campbell et al. 2016) or
polycystic ovary syndrome (Vagi et al. 2014).

Romano et al. (2016) did not find associations between maternal PFHxS levels and the risk ofbreastfeeding ≤3 or 6 months. Similarly, Timmermann et al. (2017) did not find associations between
maternal PFHxS levels and the length of breastfeeding or length of exclusive breastfeeding.

Epidemiological Studies—Effects on Fertility. Seven studies have evaluated possible effects on fertility
associated with female serum PFHxS levels. Vélez et al. (2015) found increases in time to pregnancy(measured as a decreased fecundability OR) and risk of infertility, which were associated with serum
PFHxS levels in pregnant women. Vestergaard et al. (2012) reported an increase in the fecundability OR,
indicating a shorter time to pregnancy, when risk was calculated using continuous serum PFHxS;
however, when the subjects were divided into two groups based on serum PFHxS levels above and below
the median level, the fecundability ratio included unity in the above-median group (fecundability ratio
1.29, 95% CI 0.90–1.83), as compared to the below-median group. Wang et al. (2017) found a decreased
risk of endometriosis-related infertility in a case-control study. Studies by Bach et al. (2015a), Crawford
et al. (2017), Jørgensen et al. (2014a), and Whitworth et al. (2016) did not find alterations in time topregnancy, fertility, or the risk of infertility.

Laboratory Animal Studies. Exposure to 10 mg/kg/day PFHxS did not result in alterations in
reproductive organ weights or histopathology in male rats exposed for a minimum of 42 days beginning
14 days prior to cohabitation and female rats sacrificed on lactation day 21 or GD 25 (rats that did notdeliver a litter) (exposure began 14 days prior to cohabitation) (Butenhoff et al. 2009a). Fertility was notaffected by treatment with PFHxS and there were no significant effects on sperm parameters. Also,
estrous cycling was not affected by dosing with PFHxS. A similarly designed study in mice also reported
no alterations in reproductive toxicity parameters (Chang et al. 2018).
PFNA

Epidemiological Studies—Reproductive Hormone Levels. Reproductive hormone alterations associatedwith serum PFNA levels are limited to a finding for estradiol in young men (Joensen et al. 2013); noPERFLUOROALKYLS

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associations with other reproductive hormones were found in this study. In another study of adolescentand young adults, no associations between serum PFNA and sex hormone binding globulin, FSH, or
testosterone were found in males or females (subjects were segregated by sex and age range) (Tsai et al.
2015). Zhou et al. (2016) found an inverse association between serum PFNA and testosterone levels inboys, but not in girls, and did not find associations for estradiol levels. Another study did not findalterations in follicular estradiol or luteal progesterone levels in women (Barrett et al. 2015).

Epidemiological Studies—Effects on Sperm. Buck Louis et al. (2015) found associations between serum
PFNA and increases in the percentage of normal sperm and a decrease in the percentage of sperm withcoiled tails. No associations were found for other sperm parameters (Buck Louis et al. 2015; Joensen etal. 2013; Toft et al. 2012).

Epidemiological Studies—Effects on Menstrual Cycle Length, Menopause Onset, Endometriosis, andBreastfeeding Duration. No association between serum PFNA levels and menstrual cycle length wasobserved in a general population study (Lum et al. 2017). Increases in the risk of earlier menopause andhysterectomy were found in women with serum PFNA levels in the 3rd and ≥2nd serum PFNA tertiles(Taylor et al. 2014). The investigators examined the possibility that these effects may be due to reverse
causation and found that serum PFNA levels increased post-menopause (Taylor et al. 2014). An increasein the risk of endometriosis was associated with serum PFNA levels in a general population study (BuckLouis et al. 2012); however, adjustment for parity resulted in OR CIs that included unity. A second study
did not find an association between serum PFNA and self-reported endometriosis (Campbell et al. 2016).
Vagi et al. (2014) did not find an increased risk of polycystic ovary syndrome that was associated withserum PFNA levels.
No associations between maternal PFNA levels and the risk of breastfeeding ≤3 or 6 months were foundin a general population study (Romano et al. 2016). In contrast, Timmermann et al. (2017) found inverse
associations between maternal PFNA levels and breastfeeding length and the length of exclusive
breastfeeding. The study also found no differences in breastfeeding length or exclusiveness between
primiparous and multiparous women.

Epidemiological Studies—Effects on Fertility. Jørgensen et al. (2014a) found increases in time topregnancy (measured as a decrease in fecundability ratio) and an increase in infertility risk in a study ofpregnant women. In sensitivity analysis, the fecundability ratio for primiparous women was 0.99 and the
95% CI range included unity (0.88–1.22). Wang et al. (2016) found an inverse association between

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serum PFNA levels in women and the risk of endometriosis-induced infertility. Studies by Bach et al.
(2015a), Buck Louis et al. (2013), Crawford et al. (2017), Lum et al. (2017), Vestergaard et al. (2012),
and Whitworth et al. (2016) did not find associations between serum PFNA levels and fecundability ratio,
fertility or risk of infertility.

Laboratory Animal Studies. Two acute-duration studies have evaluated the reproductive toxicity of
PFNA in male rats (Feng et al. 2009, 2010). Gavage administration of 5 mg/kg/day for 14 days resulted
in decreases in serum testosterone and increases in serum estradiol levels and atrophy of the seminiferous
tubules (Feng et al. 2009). Electron microscopic examination of the testes revealed large vacuoles
between the Sertoli cells and spermatogonia at 5 mg/kg/day; these changes as well as increases in serum
Mullerian inhibiting substance and decreases in serum inhibin B cells were suggestive of damage to thesecretory function of the Sertoli cells (Feng et al. 2010). In mice administered 0.5 mg/kg/day PFNA for
90 days, decreases in sperm motility, viability, and count and degenerative changes in the seminiferous
tubules were observed (Singh and Singh 2018). When the mice were mated with unexposed females,significant decreases in litter size were observed at 0.5 mg/kg/day.
PFDA

Epidemiological Studies—Reproductive Hormone Levels. No associations were found between serum
PFDA levels and testosterone, free androgen index, LH, estradiol, sex hormone binding globulin, or FSH
levels in young men (Joensen et al. 2013). Similarly, no alterations in follicular estradiol or lutealprogesterone levels were observed in women (Barrett et al. 2015). In adolescent boys, an inverse
association between serum PFDA and testosterone was found; no association was found in girls (Zhou etal. 2016). This study also found no associations for estradiol levels in boys or girls.

Epidemiological Studies—Effects on Sperm. Two general population studies evaluated potential effects
of PFDA exposure on sperm parameters. Buck Louis et al. (2015) found associations between serum
PFDA levels and increases in sperm head length and decreases in the percentage of sperm with coiled
tails. No alterations were found for sperm viability, count, volume, motility, or other morphologicalalterations (Buck Louis et al. 2015; Joensen et al. 2013).

Epidemiological Studies—Effects on Menstrual Cycle Length, Menopause Onset, Endometriosis, andBreastfeeding. Three studies examined alterations in female reproductive outcomes associated withserum PFDA levels. In two studies, no associations between serum PFDA levels and the risk or severity

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of endometriosis were found (Buck Louis et al. 2012; Lum et al. 2017). In the third study, an inverse
association between maternal PFDA levels and duration of breastfeeding was found (Timmermann et al.
2017). No association was found for the length of exclusive breastfeeding.

Epidemiological Studies—Effects on Fertility. Six studies examined the potential for PFDA to alter
fertility. No alterations in time to pregnancy (measured as fecundability ratio) or risk of infertility wereobserved in pregnant women (Bach et al. 2015a). Additionally, no associations with the probability ofpregnancy (Lum et al. 2017), endometriosis-related infertility (Wang et al. 2017), or fecundability(Whitworth et al. 2016) were observed in other general population studies. Two prospective studies also
found no association between female serum PFDA levels (Buck Louis et al. 2013; Vestergaard et al.
2012) or male serum PFDA levels (Buck Louis et al. 2013) and time to pregnancy.
PFUnA

Epidemiological Studies—Reproductive Hormone Levels. An inverse association between serum
PFUnA levels and FSH levels was observed in adolescent girls (Tsai et al. 2015). The study did not findalterations in sex hormone binding globulins or testosterone levels in adolescent and young adult males or
females. Another study of women did not find alterations in follicular estradiol or luteal progesterone
levels (Barrett et al. 2015).

Epidemiological Studies—Effects on Fertility. Three studies evaluated possible associations between
maternal serum PFUnA levels and fertility. No alterations in time to pregnancy (measured as afecundability ratio) or infertility risk (Bach et al. 2015a), endometriosis-related infertility risk, or
fecundability (Whitworth et al. (2016) were observed.
PFHpA

Epidemiological Studies. Only one study examined potential fertility associations. Wang et al. (2017)
found a decreased risk of endometriosis-related infertility in a case-control study.

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PFBS

Epidemiological Studies—Two studies have evaluated potential association for reproductive outcomes.
Zhou et al. (2016) did not find associations between serum PFBS and testosterone or estradiol levels inadolescent boys or girls. Wang et al. (2017) found an association between serum PFBS levels andendometriosis-related infertility in a case-control study.

Laboratory Animal Studies. Administration of up to 900 mg/kg/day PFBS to rats by gavage for 28 days
did not cause any significant gross or microscopic alterations in primary or secondary sex organs frommales or females (3M 2001). A 2-generation study in which rats were exposed to gavage doses ofpotassium PFBS as high as 1,000 mg/kg/day did not result in alterations in fertility, sperm parameters,
estrus cycling, or histological alterations in reproductive tissues (Lieder et al. 2009b).
PFBA

Laboratory Animal Studies. No significant gross or microscopic alterations were reported in primary andsecondary reproductive organs from rats dosed with PFBA by gavage in doses of up to 184 mg/kg/day for
5 days (3M 2007a), 150 mg/kg/day for 28 days (Butenhoff et al. 2012a; van Otterdijk 2007a), or
30 mg/kg/day for 90 days (Butenhoff et al. 2012a; van Otterdijk 2007b).
PFDoDA

Epidemiological Studies—A study in adolescent boys and girls found an inverse association between
serum PFDoDA levels and testosterone levels in girls only; no associations were found for estradiol levels(Zhou et al. 2016). In the two studies evaluating fertility, no associations were found for endometriosisrelated infertility (Wang et al. 2017) or fecundability (Whitworth et al. 2016).

Laboratory Animal Studies. Treatment of male rats with 1, 5, or 10 mg/kg/day PFDoDA by gavage for
14 days induced a dose-related decrease in testes weight, which achieved statistical significance at
10 mg/kg/day (Shi et al. 2007). Measurement of serum hormone levels showed a significant decrease in
LH at 10 mg/kg/day and in testosterone at 5 and 10 mg/kg/day, no significant effect on FSH levels, and asignificant decrease in serum estradiol only at 5 mg/kg/day. Alterations in the ultrastructure of the testes
were seen in the 5 and 10 mg/kg/day groups and consisted of the presence of large clustered lipid droplets
and enlarged mitochondria in Sertoli cells, large vacuoles, and expanded mitochondria in Leydig andPERFLUOROALKYLS

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spermatogenic cells. Morphological features of apoptosis were seen in cells in the 10 mg/kg/day group.
Assessment of messenger ribonucleic acid (mRNA) expression of genes involved in cholesterol transportand steroidogenesis provided evidence of altered cholesterol transport and steroid hormone synthesis, but
no effects were noted for LH receptor and aromatase mRNA expression. Considering that serum totalcholesterol was unaffected at 5 mg/kg/day and increased at 10 mg/kg/day and that aromatase expression
was unaffected, the decrease in testosterone synthesis probably resulted from decreased steroidogenesis
gene expression. In a longer-duration study (110 days) conducted by these investigators, decreased serum
testosterone levels were observed at 0.2 and 0.5 mg/kg/day (Shi et al. 2009a). A third study (Kato et al.
2015) evaluated reproductive performance and found no alterations in estrous cycling during the first
14 days of exposure and no alterations in fertility, number of corpora lutea, or number of implantationsites in male and female rats administered 2.5 mg/kg/day PFDoDA for 14 days prior to mating and during
gestation. In pregnant females administered 2.5 mg/kg/day, hemorrhages were observed at the
implantation sites; only one female delivered live pups and 58% of the animals died or were sacrificed
early. In females exposed for 42 days and not mated, continuous diestrus was observed at 2.5 mg/kg/day(Kato et al. 2015).
PFHxA

Epidemiological Studies—The only epidemiological study evaluating reproductive outcomes associatedwith PFHxA found an inverse association for testosterone levels in adolescent boys (Zhou et al. 2016) but
did not find this association in girls and found no association with estradiol levels.

Laboratory Animal Studies. No alterations in mating, fertility, or gestation length were observed in rats
administered TWA doses of 315 mg/kg/day PFHxA for 14 days prior to mating and during mating andgestation (Kirkpatrick 2005). Similarly, no alterations in mating, fertility, gestation length, number of
implantation sites, estrous cycling, or sperm parameters were observed in rats administered up to
500 mg/kg/day NaPFHx for 70 days prior to mating, during the mating period, and throughout gestationand lactation (Loveless et al. 2009). A 90-day study did not find histological alterations in reproductive
tissues of male or female rats administered up to 200 mg/kg/day NaPFHx (Chengelis et al. 2009b).
FOSA

Epidemiological Studies. One study examined reproductive hormone levels and did not find an
association between serum FOSA and follicular estradiol or luteal progesterone levels in women (Barrett

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et al. 2015). Two prospective epidemiological studies evaluated the possible association between FOSA
and fertility. Vestergaard et al. (2012) did not find an increase in time to pregnancy, as measured as afecundability ratio, or decrease in the likelihood of becoming pregnant within the first six menstrual
cycles. In contrast, Buck Louis et al. (2013) found an increased time to pregnancy associated with serum
FOSA levels in women, but not in men; the investigators noted that the results should be interpreted
cautiously because only 10% of the blood samples had FOSA levels above the limit of detection.
Another study found no association between maternal FOSA and fecundability (Whitworth et al. 2016).
2.17 DEVELOPMENTAL
Overview. A large number of epidemiological studies have examined the potential of developmental
toxicity of perfluoroalkyls in the general population and in populations living in an area with high PFOA
drinking water contamination. Epidemiological studies are available for 10 of the 12 perfluoroalkyls
discussed in the profile; no developmental data were identified for PFHxA or PFBS. The discussion ofthese developmental outcomes is divided into four categories: pregnancy outcome, birth outcome,neurodevelopment, and sexual maturation. The epidemiological studies examining pregnancy outcome
are summarized in Table 2-22; the pregnancy outcomes include miscarriage, stillbirth, preterm birth, andgestation age. Table 2-23 summarizes the epidemiological studies examining birth outcomes, which
include birth weight, birth size, low birth weight, small for gestational age, birth defects, and sex ratio.
Epidemiological studies examining neurodevelopmental endpoints, particularly risks for ADHD, aresummarized in Table 2-24. Studies evaluating possible associations between serum perfluoroalkyl levels
and development of the reproductive system are summarized in Table 2-25. Further details on thesestudies are presented in the Supporting Document for Epidemiological Studies for Perfluoroalkyls,
Table 13. Studies examining childhood growth and examining the possible relationship between maternal
serum perfluoroalkyl levels and body weight and BMI in children and adults are discussed in Section 2.3,
Body Weight.

In general, the epidemiological studies did not find associations between perfluoroalkyl exposure andadverse pregnancy outcomes (miscarriage, preterm birth, or gestational age) for PFOA, PFOS, PFHxS,
PFNA, PFDA, or PFUnA. Mixed results have been found for birth outcomes, particularly birth weight.
Some epidemiological studies have found associations between maternal PFOA or PFOS exposure anddecreases in birth weight, and meta-analyses of these data have found that increases in maternal PFOA orPFOS were associated with 11–19 g or 1–5 g decreases in birth weight, respectively; accounting formaternal glomerular filtration rates attenuated these results by about 50%. No consistent associations forPERFLUOROALKYLS

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Table 2-22. Summary of Pregnancy Outcomes in Humansa
Reference and study populationb
PFOA
Darrow et al. 2013
Community (C8) (n=1,330 women)
Darrow et al. 2014

Serum perfluoroalkyl level Outcome evaluatedResultc≥37.2 ng/mL (5th PFOA
quintile)

Preterm birth

OR 1.01 (0.55–1.86)>39.4 ng/mL (5th PFOA
quintile)

Miscarriage risk
Parous subgroup
Nulliparous subgroup

OR 1.00 (0.63–1.58), 5th quintile
OR 1.06 (0.57–1.97), 5th quintile
OR 0.81 (0.38–1.71), 5th quintile

63.1–934.3 ng/mL(4th maternal PFOA quartile)

Miscarriage
Stillbirth

OR 0.9 (0.7–1.0)
OR 1.0 (0.5–1.8)

21.0–717.6 ng/mL(5th maternal PFOA quintile)

Stillbirth

OR 0.8 (0.5–1.5)

Preterm birth (<37 weeks)
Preterm birth (<32 weeks)

OR 1.0 (0.9–1.2)
OR 1.0 (0.7–1.3)

83.3–921.3 ng/mL(5th maternal PFOA quintile)

Preterm birth (<37 weeks)
Preterm birth (<32 weeks)

OR 1.2 (0.9–1.6)
OR 1.4 (0.5–3.6)

48.8 ng/mL (maternal mean
PFOA)

Miscarriage
Preterm birth

OR 0.9 (0.5–1.6), >90th percentile
OR 0.9 (0.6–1.5), >90th percentile

1.6 ng/mL (cord serum
median PFOA)

Gestational age

NS (p>0.05)

3.3 ng/mL (median serum
PFOA in women)

Pregnancy loss

HR 0.93 (0.75–1.16)

1.84 ng/mL (cord bloodgeometric mean PFOA)

Gestational age
Preterm birth

NS (p>0.05)
OR 0.64 (0.40–1.02)>2.1–18 ng/mL (maternal
3rd PFOA tertile)

Preterm birth

RR 1.31 (0.38–4.45), 3rd tertile

Community (C8) (n=1,129 women)
Savitz et al. 2012aCommunity (C8) (11,737 singleton infants)
Savitz et al. 2012b
Community (13,243 cases stillbirth, preterm
birth, low birth weight or small for gestationalage)
Savitz et al. 2012b
Community (4,547 infants)
Stein et al. 2009
Community (C8) (n=1,845 pregnancies)
Apelberg et al. 2007b
General population (n=341 singleton births)
Buck Louis et al. 2016
General population (n=332 couples)
Chen et al. 2012a
General population (n=429 infants)
Hamm et al. 2010
General population (n=252 pregnant women)

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Table 2-22. Summary of Pregnancy Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedJensen et al. 2015

1.58 ng/mL (maternal median Miscarriage before gestation OR 0.64 (0.36–1.18)
PFOA)
week 12General population (n=56 cases and336 controls)
Lauritzen et al. 20172.33 ng/mL (median maternal Gestational age
serum PFOA)

General population (n=159 mother-infant pairs)
Lauritzen et al. 20171.62 ng/mL (median maternal Gestational age
serum PFOA)
General population (n=265 mother-infant pairs)
Li et al. 2017
1.2 ng/mL (median cord
Gestational age
serum PFOA)
General population (n=321 mother-infant pairs)
Lind et al. 2017a
1.7 ng/mL (median maternal Gestational length
serum PFOA)
General population (n=649 pregnant women)
Manzano-Salgado et al. 2017a2.35 ng/mL (mean maternal Preterm
serum PFOA)
Gestational age
General population (n=1,202 mother-infant
pairs)
Sagiv et al. 2018
5.8 ng/mL (median maternal Preterm
plasma PFOA)
Gestation length
General population (n=1,645 pregnant women)
Whitworth et al. 2012a≥3.04 ng/mL (maternal
Preterm birth
4th PFOA quartile)
General population (n=901 infants)
Wu et al. 201218.32 and 9.76 ng/mL (mean Gestational age
maternal serum PFOA at
General population (n=167 pregnant women at each hospital)
2 hospitals)

Resultc

NS (p=0.318)

NS (p=0.431)

β 0.16 (-0.02–0.33)

NS (p>0.05)

OR 0.90 (0.60–1.35)
β-0.05 (-0.12–0.08)
OR 1.0 (0.9–1.3)
β -0.05 (-0.16–0.06)
OR 0.1 (0.03–0.6)*, 4th quartile

β -15.99 (-27.72 to -4.25, p<0.01)*

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Table 2-22. Summary of Pregnancy Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

PFOS
Darrow et al. 201315.6 ng/mL (mean PFOS)

Preterm birth

OR 1.07 (0.58–1.95)>23.3 ng/mL (5th PFOS
quintile)

Miscarriage risk
Parous subgroup
Nulliparous subgroup

OR 1.41 (0.88–2.26), 5th quintile
OR 1.12 (0.58–2.17), 5th quintile
OR 2.02 (0.83–4.93), 5th quintile

23.2–83.4 ng/mL(>90th PFOS percentile)

Miscarriage
Preterm birth

OR 0.9 (0.7–1.3), >90th percentile
OR 1.4 (1.1–1.7)*, >90th percentile

12.2 ng/mL (median serum
PFOS in women)

Pregnancy loss

HR 0.81 (0.65–1.00)

5.94 ng/mL (cord bloodgeometric mean PFOS)

Preterm birth

OR 2.45 (1.47–4.08)*

Community (C8) (n=1,330 women)
Darrow et al. 2014
Community (C8) (n=1,129 women)
Stein et al. 2009
Community (C8) (n=5,262 infants)
Buck Louis et al. 2016
General population (n=332 couples)
Chen et al. 2012a
General population (n=429 infants)
Fei et al. 2007, 2008a35.3 ng/mL (maternal median Gestation length
PFOS)
Preterm birth

General population (n=1,400 pregnant women)
Hamm et al. 2010
>10–35 ng/mL (maternal
3rd tertile PFOS)
General population (n=252 pregnant women)
Jensen et al. 2015
General population (n=56 cases and336 controls)
Lauritzen et al. 2017

Preterm birth

NS (p>0.01)
OR 1.43 (0.50–4.11), 4th quartile
RR 1.11 (0.36–3.38), 3rd tertile

8.10 ng/mL (maternal median Miscarriage before gestation OR 1.16 (0.59–1.29)
PFOS)
week 1216.4 ng/mL (median maternal Gestational age
serum PFOS)

General population (n=159 mother-infant pairs)
Lauritzen et al. 20179.74 ng/mL (median maternal Gestational age
serum PFOS)
General population (n=265 mother-infant pairs)

NS (p=0.201)

NS (p=0.952)

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Table 2-22. Summary of Pregnancy Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Li et al. 2017

3.0 ng/mL (median cord
serum PFOS)

Gestational age

β 0.11 (-0.06–0.29)
β 0.29 (0.05–0.53)*, boys only
β -0.07 (-0.35–0.20), girls only

8.1 ng/mL (median maternal
serum PFOS)

Gestational length

NS (p>0.05)

6.05 ng/mL (mean maternal
serum PFOS)

Preterm

OR 1.10 (0.70–1.74)

Gestational age

β-0.06 (-0.19–0.06)

General population (n=321 mother-infant pairs)
Lind et al. 2017a
General population (n=649 pregnant women)
Manzano-Salgado et al. 2017a
General population (n=1,202 mother-infant
pairs)
Sagiv et al. 201825.7 ng/mL (median maternal Preterm
plasma PFOS); 18.9–
Gestation length
General population (n=1,645 pregnant women) 25.6 ng/mL (2nd quartilematernal PFOS)
Whitworth et al. 2012a13.0 and ≥16.59 ng/mL
Preterm birth(maternal median andGeneral population (n=901 infants)
4th quartile PFOS)
PFHxS

OR 2.0 (1.1–3.7)*, 2nd quartile
β -0.08 (-0.17–0.02)

Hamm et al. 2010

RR 0.31 (0.11–0.90)*, 3rd tertile

General population (n=252 pregnant women)
Jensen et al. 2015
General population (n=56 cases and336 controls)
Li et al. 2017

OR 0.3 (0.1–1.0, p=0.03)*,
4th quartile>1.4–43 ng/mL (maternal
3rd tertile PFHxS)

Preterm birth0.298 ng/mL (maternal
median PFHxS)

Miscarriage before gestation OR 1.53 (0.99–2.38)
week 12

3.9 ng/mL (median cord
serum PFHxS)

Gestational age

β 0.12 (-0.03–0.27)

Gestational length

NS (p>0.05)

General population (n=321 mother-infant pairs)
Lind et al. 2017a
0.3 ng/mL (median maternal
serum PFHxS)
General population (n=649 pregnant women)

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Table 2-22. Summary of Pregnancy Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Manzano-Salgado et al. 2017a0.58 ng/mL (mean maternal
serum PFHxS)

Preterm
Gestational age

OR 0.85 (0.63–1.13)
β -0.01 (-0.10–0.09)

2.4 ng/mL (median maternal
plasma PFHxS)

Preterm

OR 1.0 (0.9–1.1)

0.2 ng/mL (median cord
serum PFNA)

Gestational age

β -0.02 (-0.19–0.10)

Gestational length

NS (p>0.05)

Preterm
Gestational age

OR 0.87 (0.62–1.22)
β -0.00 (-0.11–0.11)Preterm
Gestation length

OR 1.2 (1.0–1.4)
β-0.07 (-0.17–0.02)

General population (n=1,202 mother-infant
pairs)
Sagiv et al. 2018

β 0.02 (-0.04–0.07)
General population (n=1,645 pregnant women)
PFNA
Buck Louis et al. 2016
1.2 ng/mL (median serum
Pregnancy loss
HR 0.86 (0.70–1.06)
PFNA in women)
General population (n=332 couples)
Chen et al. 2012a2.36 ng/mL (cord blood
Preterm birth
OR 0.88 (0.71–1.11)
geometric mean PFNA)
General population (n=429 infants)
Jensen et al. 2015
0.72 ng/mL (maternal median Miscarriage before gestation OR 16.46 (7.39–36.62)*
PFNA)
week 12General population (n=56 cases and336 controls)
Li et al. 2017

General population (n=321 mother-infant pairs)
Lind et al. 2017a
0.7 ng/mL (median maternal
serum PFNA)
General population (n=649 pregnant women)
Manzano-Salgado et al. 2017a0.66 ng/mL (mean maternal
serum PFNA)
General population (n=1,202 mother-infant
pairs)
Sagiv et al. 2018
0.7 ng/mL (median maternal
plasma PFNA)
General population (n=1,645 pregnant women)

Gestation length

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Table 2-22. Summary of Pregnancy Outcomes in Humansa
Reference and study populationb
PFDA
Buck Louis et al. 2016
General population (n=332 couples)
Jensen et al. 2015
General population (n=56 cases and336 controls)
Li et al. 2017

Serum perfluoroalkyl level Outcome evaluatedResultc

1.2 ng/mL (median serum
PFDA in women)

HR 0.83 (0.66–1.04)

Pregnancy loss

0.27 ng/mL (maternal median Miscarriage before gestation OR 2.30 (1.18–4.47)*
PFDA)
week 120.1 ng/mL (median cord
serum PFDA)

General population (n=321 mother-infant pairs)
Lind et al. 2017a
0.3 ng/mL (median maternal
serum PFDA)
General population (n=649 pregnant women)
PFUnA
Chen et al. 2012a10.26 ng/mL (cord bloodgeometric mean PFUnA)
General population (n=429 infants)
Li et al. 2017
0.1 ng/mL (median cord
serum PFUnA)
General population (n=321 mother-infant pairs)
PFHpA
Li et al. 2017
0.1 ng/mL (median cord
serum PFHpA)
General population (n=321 mother-infant pairs)
PFBA
Li et al. 2017
0.1 ng/mL (median cord
serum PFBA)
General population (n=321 mother-infant pairs)

Gestational age

β 0.10 (-0.09–0.29)

Gestational length

NS (p>0.05)

Preterm birth

OR 0.87 (0.64–1.16)

Gestational age

β 0.09 (-0.07–0.25)

Gestational age

β 0.14 (-0.17–0.45)

Gestational age

β 0.01 (-0.18–0.20)

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Table 2-22. Summary of Pregnancy Outcomes in Humansa
Reference and study populationb
PFDoDA
Li et al. 2017

Serum perfluoroalkyl level Outcome evaluatedResultc

0.1 ng/mL (median cord
serum PFDoDA)

β 0.07 (-0.24 to 0.39)

Gestational age

General population (n=321 mother-infant pairs)
aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 13 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

OR = odds ratio; NS = not significant; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid;
PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid; RR= risk ratioPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb
PFOA
Darrow et al. 2013
Community (C8) (n=1,330 women)
Nolan et al. 2009

Serum perfluoroalkyl level Outcome evaluatedResultc≥37.2 ng/mL (5th PFOA
quintile)

Birth weight
Low birth weight

NS (p=0.70 for trend)
OR 0.92 (0.44–1.95)

NR

Birth weight
Low birth weight

NS (p>0.05)
OR 0.37 (0.16–0.86)*

NR

Congenital anomalies

OR 1.1 (0.34–3.3)

63.1–934.3 ng/mL(4th maternal PFOA quartile)

Low birth weight

OR 0.37 (0.16–0.86)*

Birth defect

OR 1.0 (0.8–1.3)

7.7 ng/mL (estimatedmaternal median PFOA)

Birth weight

β -14.80 (-42.28–13.68), per
100 ng/mL increase in PFOA
OR 1.0 (0.86–1.15), per 100 ng/mL
increase in PFOA
OR 0.86 (0.67–1.11), per 100 ng/mL
increase in PFOA
OR 1.07 (0.96–1.18), per 100 ng/mL
increase in PFOA
OR 1.08 (1.01–1.16)*, per
100 ng/mL increase in PFOA
OR 0.8 (0.6–1.2), for serum PFOA
levels ≥80th percentile
OR -12.76 (-26.08–0.57), per
100 ng/mL increase in PFOA
OR 0.8 (0.3–1.9), 4th quartile
OR 1.7 (0.8–3.6), 4th quartile

Community (n=1,555 singleton infants)
Nolan et al. 2010
Community (n=1,548 singleton infants)
Savitz et al. 2012aCommunity (C8) (11,737 singleton infants)
Savitz et al. 2012b
Community (13,243 cases stillbirth, preterm
birth, low birth weight, or small for gestationalage)
Savitz et al. 2012b

Low birth weight
Small for gestational age
13.4 ng/mL (estimatedmaternal median PFOA)

Community (4,547 infants)

Low birth weight
Small for gestational age

Birth weight
Stein et al. 2009
Community (C8) (n=1,845 pregnancies)

50.0–<120.6 and 120.6–
894.4 ng/mL (3rd and 4thmaternal PFOA quartile)

Low birth weight
Birth defects

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Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Stein et al. 2014c

61.3 ng/mL (estimated inutero mean PFOA)

OR 2.6 (1.3–5.1), interquartile range
OR 0.7 (0.3–1.4), interquartile range
OR 0.7 (0.3–1.8), interquartile range
OR 0.6 (0.3–1.3), interquartile range
OR 1.1 (0.6–2.1), interquartile range

Community (C8) (n=10,262 infants)

Brain defects
Gastrointestinal defects
Kidney defects
Craniofacial defects
Eye defects

Limb defects
Genitourinary defects
Heart defects
Alkhalawi et al. 20162.43 ng/mL (geometric mean Birth weightmaternal PFOA)
Birth length
General population (n=156 mother-infant pairs)
Ponderal index

OR 1.2 (0.7–2.0), interquartile range
OR 1.0 (0.6–1.7), interquartile range
OR 1.2 (0.8–1.7), interquartile range
NS (p>0.05)
NS (p>0.05)
β -0.412 (-0.788 to -0.037)*

Apelberg et al. 2007b

Birth weight
Birth length
Head circumference
Ponderal index
Gestational weight gain

NS (p>0.05)
NS (p>0.05)
Inverse association (p>0.05)*
Inverse association (p>0.05)*
NS (p>0.1), serum PFOA
OR 1.04 (1.02–1.06)*, cord PFOA

Birth weight
Infant leptin levels
Infant adiponectin levels

β -0.10 (-0.34–0.13)
β 0.01 (-0.15–0.13)
β 0.04 (-0.05–0.12)

Birth weightNS, investigators noted no consistentalterations across PFOA quartiles

Birth length

NS, investigators noted no consistentalterations across PFOA quartiles

Head circumference

NS, investigators noted no consistentalterations across PFOA quartiles

1.6 ng/mL (cord serum
median PFOA)

General population (n=341 singleton births)

Ashley-Martin et al. 20161.70 and 0.39 ng/mL(maternal and cord median
General population (n=1,723 pregnant women) PFOA)
Ashley-Martin et al. 2017
1.7 ng/mL (median maternal
plasma PFOA)
General population (n=1,705 mother-infant
pairs)Bach et al. 2016
General population (n=1,507 nulliparous
women)

2.0 ng/mL (median PFOA)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Bae et al. 2015

5.01 and 4.05 ng/mL andMale birth
5.00 and 2.54 ng/mL(geometric mean PFOA in
male and female nulliparousparents and male and femaleparous parents, respectively)
0.86 ng/mL (median maternal Birth weight
serum PFOA)
Birth length
Head circumference

OR 0.93 (0.68–1.26), maternal PFOA
OR 0.94 (0.72–1.23), paternal PFOA

General population (n=233 couples)

Callan et al. 2016
General population (n=98 pregnant women)

Cao et al. 2018
General population (n=337 newborns)
Chen et al. 2012a1.59 ng/mL (mean cord
serum PFOA); >1.59 ng/mL(3rd tertile cord PFOA)
1.84 ng/mL (cord bloodgeometric mean PFOA)

General population (n=429 infants)

Fei et al. 2007, 2008a

5.6 ng/mL (maternal median
PFOA)

General population (n=1,400 pregnant women)

Govarts et al. 2016
General population (n=202 infants)

1.52 ng/mL (cord bloodgeometric mean PFOA)

β -48 g (-203–108)
β 0.06 (-0.70–0.81)
β -0.40 (-0.96–0.16)

Ponderal index
Birth weight
Birth length
Ponderal index
Birth weight
Birth length
Head circumference

β-0.06 (-0.16–0.05)
NS (p=0.58)
β -0.45 (-0.79 to -0.10)*, 3rd tertile
NS (p=0.21)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Ponderal index
Small for gestational age
Low birth weight
Birth weight
Birth length
Abdominal circumference

NS (p>0.05)
OR 1.24 (0.75–2.05)
OR 0.53 (0.18–1.55)
β -10.63 (-20.79 to -0.47)*
β -0.069 (-0.113 to -0.024)*
β -0.059 (-0.106 to -0.012)*

Head circumference
Low birth weight
Small for gestational age
Birth weight

β-0.030 (-0.064–0.004)
OR 2.44 (0.27–22.25), 4th quartile
OR 0.97 (0.55–1.70), 4th quartile
NS (p=0.473)

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Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Hamm et al. 2010

>2.1–18 ng/mL (maternal
3rd tertile PFOA)

General population (n=252 pregnant women)

Small for gestational age
1.46 ng/mL (maternal median Birth weight
PFOA)
Cord TSH
Cord T3
Cord T4

Change in weight 14.80 (-107.29–
136.89), 3rd tertile
RR 0.99 (0.25–3.92), 3rd tertile
NS (p>0.05)
Association (p<0.05)*
NS (p>0.05)
NS (p>0.05)

Kim et al. 2011
General population (n=44 pregnant women)

Kim et al. 2016aBirth weight

5.398 and 2.12 ng/mL (mean Thyroid stimulating
PFOA in cases and controls) immunoglobulin levels

General population (n=27 infants withcongenital hypothyroidism; n=13 controls)

TSH
T3
T4
Kobayashi et al. 2017
1.6 ng/mL (mean maternal
Birth weight
serum PFOA)
Birth length
General population (n=177 mother-infant pairs)
Ponderal index
Lauritzen et al. 20172.33 ng/mL (median maternal Birth weight
serum PFOA)
Birth length
General population (n=159 mother-infant pairs)
Head circumference
Small for gestational age

Lauritzen et al. 2017
General population (n=265 mother-infant pairs)

Lee et al. 2013
General population (n=59 pregnant women)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
β -49.4 (-130.4–31.6)
β 0.01 (-0.37–0.40)
β -0.44 (-0.99–0.12)
β -359 (-596 to -122; p=0.003)*

Head circumference
Small for gestational age
Birth weight

β -1.3 (-2.3 to -0.3, p=0.010)*
NS (p=0.115)
OR 5.25 (1.68–16.4)*
OR 6.55 (1.14–37.45)*, boys only
OR 4.73 (0.79–28.3), girls only
NS (p=0.590)
NS (p=0.656)
NS (p=0.354)
OR 0.66 (0.33–1.33)
OR 0.54 (0.17–3.03)

Birth length
Ponderal index
Head circumference

OR 0.44 (0.12–1.58)
OR 0.56 (0.16–2.01)
OR 0.82 (0.24–13.65)

1.62 ng/mL (median maternal Birth weight
serum PFOA)
Birth length

2.73 ng/mL (maternal mean
PFOA)

Inverse association (p<0.05)*

PERFLUOROALKYLS

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Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Lee et al. 20161.11 ng/mL (cord blood mean Birth weight
PFOA)

NS (p>0.05)

General population (n=85 infants)
1.84, 0.96, and 2.51 ng/mL(maternal median PFOA for
General population (n=513 infants inGreenland, Ukraine, andGreenland subcohort, n=557 infants in Ukraine Poland subcohorts)
subcohort, and n=180 infants in Poland
subcohort
Li et al. 2017
1.2 ng/mL (median cord
serum PFOA)
General population (n=321 mother-infant pairs)
Lind et al. 2017a
1.7 ng/mL (median maternal
serum PFOA)
General population (n=649 pregnant women)

Birth weight

β -63.77 (-122.83 to -4.71,
p=0.035)*, 2 SD increase in lntransformed PFOA

Birth weightβ -112.7 (-171.9 to -53.5)*

Birth weight

NS (p>0.05)

Maisonet et al. 2012

Birth weight
Birth length

Inverse association (p=0.0120 for
trend)*NS (p=0.0978)

2.35 ng/mL (mean maternal
serum PFOA)

Ponderal index
Body weight at 20 months
Birth weight
Birth length
Head circumference
Small for gestational age

NS (p=0.5920)
NS (p=0.4147)
β -9.33 (-38.81–20.16)
β -0.01 (-0.15–0.14)
β 0.07 (-0.17–0.03)
OR 0.92 (0.72–1.19)

1.4 ng/mL (median maternal
serum PFOA)

Low birth weight
Low birth weight at term
Birth weight
Ponderal index
Cord total adiponectin
Cord leptin

OR 0.90 (0.63–1.29)
OR 0.85 (0.53–1.34)
β -197 (-391 to -3, p=0.047)*
β -1.32 (-2.66–0.02, p=0.054)
NS (p=0.377)
NS (p=0.830)

Lenters et al. 2016a, 2016b

3.7 ng/mL (maternal median
PFOA)

General population (n=447 girls)

Manzano-Salgado et al. 2017a
General population (n=1,202 mother-infant
pairs)

Minatoya et al. 2017
General population (n=168 mother-infant pairs)

PERFLUOROALKYLS

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Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Monroy et al. 2008

1.81 and 1.58 ng/mL(maternal and cord median
PFOA)

Birth weight

NS (p>0.05), maternal serum andcord blood PFOA

3.16 and 5.00 ng/mL(maternal and paternal
geometric mean PFOA)

Birth weight
Birth length
Head circumference
Ponderal index
Birth weight for gestationalage

NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal
β -0.02 (-0.08–0.03)

Birth weight
Birth length
Ponderal index

β 163.28 (-127.66–454.23)
β 0.38 (-0.41–1.17)
β 0.06 (-0.10–0.22)

Birth weightβ -92.4 g (-166.2 to -18.5)*, 3rd
tertileβ -0.97% fat mass (-0.33–0.49),
3rd tertile
NS (p>0.05)

General population (n=101 pregnant women)
Robledo et al. 2015a, 2015b
General population (n=234 couples)

Sagiv et al. 2018

5.8 ng/mL (median maternal
plasma PFOA)

General population (n=1,645 pregnant women)
Shi et al. 20171.097 ng/mL (median cord
serum PFOA)
General population (n= 170 infants)
Starling et al. 2017

1.1 ng/mL (median maternal
serum PFOA); 1.4–
General population (n=604 mother-infant pairs) 17.0 ng/mL (3rd tertilematernal PFOA)
Wang et al. 2016
General population (n=117 boys and 106 girls
examined at 2, 5, 8, and 11 years of age)
Washino et al. 2009
General population (n=428 infants)

Whitworth et al. 2012a
General population (n=901 infants)

Adiposity at birth2.37 and 2.34 ng/mL (median Birth weightmaternal PFOA for boys and Birth length
girls)
Head circumference
Small for gestational age
1.3 ng/mL (maternal median Birth weight
PFOA)
Birth length
Chest circumference
2.2 and ≥3.04 ng/mL(maternal median and4th quartile PFOA)Head circumference
Birth weight
Small for gestational age
Large for gestational age

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p=0.207)
NS (p=0.631)
NS (p=0.460)
NS (p=0.823)
NS (p=0.12)
NS (p=0.92)
NS (p=0.33)

PERFLUOROALKYLS

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Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluated

Wu et al. 201218.32 and 9.76 ng/mL (mean Birth weightmaternal serum PFOA at
General population (n=167 pregnant women at each hospital)
Birth length
2 hospitals)
Ponderal index
PFOS
Grice et al. 2007
1,300–1,970 ng/mL (range of Birth weight
PFOS)
Occupational (n=263 females)
Darrow et al. 201315.6 ng/mL (mean PFOS)
Birth weight
Community (C8) (n=1,330 women)

Stein et al. 2009
Community (C8) (n=5,262 infants)

17.7–<23.2 and 23.2–
83.4 ng/mL (75th–90th and>90th PFOS percentile)

Low birth weight
Low birth weight

Birth defects
Alkhalawi et al. 2016
9.04 ng/mL (geometric mean Birth weightmaternal serum PFOS)
Birth length
General population (n=156 mother-child pairs)
Ponderal index
Apelberg et al. 2007b
5 ng/mL (PFOS cord serum Gestational age
median)Birth weight
General population (n=341 singleton births)
Birth length
Head circumference
Ponderal index
Ashley-Martin et al. 2016
4.60 and 0.15 ng/mL
Gestational weight gain
(maternal and cord PFOS
General population (1,723 pregnant women)
median)Ashley-Martin et al. 2017

4.6 ng/mL (median maternal
plasma PFOS)

Birth weight
Infant leptin levels

Resultc
β -267.30 (-573.27 to -37.18,
p<0.05)*β -1.91 (-3.31 to -0.52, p<0.01)*
β -0.095 (-0.200–0.389)
NS (p=0.15)

NS (p=0.045 for trend), whole cohort
Association (p=0.006), women(n=783) who conceived after blood
sample collection
OR 1.33 (0.60–2.96)
OR 1.6 (1.1–2.3)*, 75th-90th
percentile
OR 1.3 (0.8–2.1)
NS (p>0.05)
NS (p>0.05)
β -0.355 (-0.702 to -0.008)*
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Inverse association (p>0.05)*
Inverse association (p>0.05)*
Association (p<0.1), serum PFOS
in underweight/normal weightsubjects
OR 1.03 (1.00–1.05)*, cord PFOS
β 0.05 (-0.18–0.29)
β -0.09 (-0.23–0.04)

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb
General population (n=1,705 mother-infant
pairs)Bach et al. 2016

Serum perfluoroalkyl level Outcome evaluated

8.3 ng/mL (PFOS median)

General population (n=1,507 nulliparous
women)

Infant adiponectin levels

β 0.02 (-0.11–0.07)

Birth weight

Inverse association reported byinvestigators
NS, investigators noted no consistentalterations across PFOS quartiles
NS, investigators noted no consistentalterations across PFOS quartiles
OR 1.16 (0.88–1.53), maternal PFOS
OR 1.01 (0.78–1.33), paternal PFOS

Birth length
Head circumferenceBae et al. 2015
General population (233 couples)

Callan et al. 2016
General population (n=98 pregnant women)

Cao et al. 201821.7 and 14.5 ng/mL andMale birth21.5 and 10.8 ng/mL(geometric mean PFOS inmale and female nulliparousparents and male and femaleparous parents, respectively)
1.99 ng/mL (median maternal Birth weight
serum PFOS)
Birth length
Head circumference
Ponderal index
1.43 ng/mL (mean cord
serum PFOS)

General population (n=337 newborns)
Chen et al. 2012a
General population (n=429 infants)

5.94 ng/mL (cord bloodgeometric mean PFOS)

Resultc

Birth weight
Birth length
Ponderal index
Gestational age
Birth weight
Birth length
Head circumference
Ponderal index
Small for gestational age
Low birth weightβ -69 g (-231–94)
β -0.22 (-1.0–0.57)
β -0.39 (-0.98–0.20)
β -0.03 (-0.14–0.08)
NS (p=0.84)
NS (p=0.65)
NS (p=0.47)
Inverse association (p<0.001)*
β -110.2 g (-176.0 to -44.5,
p<0.001)*, per ln PFOS
NS (p>0.05)
β -0.25 cm (-0.46–0.05 cm,
p<0.05)*, per ln PFOS
NS (p>0.05)
OR 2.27 (1.25–4.15)*
OR 2.61 (0.185–8.03)

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultcde Cock et al. 2014

1.611 ng/mL (cord blood
mean PFOS)

NS (p=0.802)
NS (p=0.975)
NS (p=0.586)
NS (p=0.649)
β -0.46 (-2.34–1.41)

General population (n=89 infants)

Fei et al. 2007, 2008a
General population (n=1,400 pregnant women)

Govarts et al. 2016
General population (n=202 infants)
Hamm et al. 2010
General population (n=252 pregnant women)
Kim et al. 2011
General population (n=44 pregnant women)

Kim et al. 2016a
General population (n=27 infants withcongenital hypothyroidism; N=13 controls)

Kobayashi et al. 2017
General population (n=177 mother-infant pairs)

WeightHeightBMIHead circumference
35.3 ng/mL (maternal median Birth weight
PFOS)
Birth length
Abdominal circumference
Head circumference
Gestation length
Low birth weight
Small for gestation age

β-0.002 (-0.011–0.006)
β -0.003 (-0.012–0.005)
β 0.000 (-0.006–0.007)
NS (p>0.01)
OR 4.82 (0.56–41.16), 4th quartile
OR 0.98 (0.58–1.65), 4th quartile

2.63 ng/mL (cord bloodgeometric mean PFOS)

Birth weight

NS (p=0.798)>10–35 ng/mL (maternal 3rd
tertile PFOS)

Birth weight

Change in weight 71.25 (54.97–
197.48), 3rd tertile
RR 0.26 (0.10–0.70)*, 3rd tertile
NS (p>0.05)

Small for gestational age
2.93 ng/mL (maternal median Birth weight
PFOS)
Cord TSH
Cord T3
Cord T4
5.326 and 4.05 ng/mL (mean Thyroid stimulating
PFOS in cases and controls) immunoglobulin levels
TSH
T3
T4
5.7 ng/mL (mean maternal
serum PFOS)

Birth weight
Birth length
Ponderal index

NS (p>0.05)
Inverse association (p<0.05)*
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
β -56.0 (-162.8–50.8)
β 0.32 (-0.19–0.82)
β -1.07 (-1.79 to -0.36)*

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Lauritzen et al. 201716.4 ng/mL (median maternal Birth weight
serum PFOS)
Birth length

β -292 (-500 to -84; p=0.006)*
β -1.2 (-2.1 to -0.3, p=0.007)*NS (p=0.073)
OR 2.51 (0.93–6.77)
NS (p=0.167)

General population (n=159 mother-infant pairs)

Lauritzen et al. 2017
General population (n=265 mother-infant pairs)

Lee et al. 2013
General population (n=59 pregnant women)

Lee et al. 2016

Head circumference
Small for gestational age
9.74 ng/mL (median maternal Birth weight
serum PFOS)
Birth length
Head circumference
Small for gestational age
10.77 ng/mL (maternal mean Birth weight
PFOS)
Birth length
Ponderal index
Head circumference
0.87 ng/mL (cord blood mean Birth weight
PFOS)

General population (n=85 infants)
Lenters et al. 2016a, 2016b

NS (p=0.987)
NS (p=0.189)
OR 0.71 (0.42–1.20)
OR 0.98 (0.32–3.03)
OR 0.97 (0.29–3.27)
OR 0.22 (0.05–0.90)*
OR 1.34 (0.20–8.90)
NS (p>0.05)

20.09, 5.04, and 7.81 ng/mL(maternal median PFOS for
General population (n=513 infants inGreenland, Ukraine, andGreenland subcohort, n=557 infants in Ukraine Poland subcohorts)
subcohort, and n=180 infants in Poland
subcohort)
Li et al. 2017
3.0 ng/mL (median cord
serum PFOS)
General population (n=321 mother-infant pairs)

Birth weight

NS (p=0.109)

Birth weightβ -95.0 (-154.0 to -36.0)*
β -150.6 (-225.4 to -75.7)*, boys
only
β -26.6 (-125.1–71.8), girls only

Liew et al. 2014

Congenital cerebral palsy
Boys
Girls

28.90 and 27.50 ng/mL(maternal median PFOS in
General population (n=156 children diagnosed boy and girl cases)
27.60 and 26.20 ng/mL
with congenital cerebral palsy (cases) and(maternal median PFOS in
550 controls)
boy and girl controls)

RR 1.7 (1.0–2.8)*
RR 0.7 (0.4–1.4)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Lind et al. 2017a

8.1 ng/mL (median maternal
serum PFOS)

NS (p>0.05)

Birth weight

General population (n=649 pregnant women)
Maisonet et al. 201219.6 ng/mL (maternal median Birth weight
PFOS)

General population (n=447 girls)

Manzano-Salgado et al. 2017a6.05 ng/mL (mean maternal
serum PFOS)

General population (n=1,202 mother-infant
pairs)

Minatoya et al. 2017

5.1 ng/mL (median maternal
serum PFOS)

General population (n=168 mother-infant pairs)

Monroy et al. 2008
General population (n=101 pregnant women)
Robledo et al. 2015a, 2015b
General population (n=234 couples)

Sagiv et al. 2018
General population (n=1,645 pregnant women)

14.54 and 6.08 ng/mL(maternal and cord medianPFOS)
12.44 and 21.6 ng/mL(maternal and paternal
geometric mean PFOS)

β -140.01 g (-238.14 to -41.89 g,
p=0.0053 for trend)*, 3rd tertile

Birth length

β -0.63 cm (-1.11 to -0.15 cm,
p=0.103 for trend)* 3rd tertile

Ponderal index
Birth weight
Birth length
Head circumference
Small for gestational age
Low birth weight

NS (p=0.1120)
β 0.44 (-32.48–33.36)
β 0.03 (-0.12–0.17)
β -0.00 (-0.10–0.10)
OR 0.92 (0.70–1.22)
OR 1.06 (0.71–1.58)

Low birth weight at term
Birth weight
Ponderal index
Cord total adiponectin
Cord leptin
Birth weight

OR 0.91 (0.55–1.50)
β -29 (-289–232, p=0.828)
β -2.25 (-4.01 to -0.50, p=0.012)*
β 0.12 (0.01–0.22, p=0.028)*
NS (p=0.691)
NS (p>0.05), maternal serum andcord blood PFOA

Birth weight
Birth length
Head circumference

NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal

Ponderal index
25.7 ng/mL (median maternal Birth weight for gestational
plasma PFOS)age

NS (p>0.05), maternal or paternal
β -0.04 (-0.08–0.01)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Shi et al. 20170.974 ng/mL (median cord
serum PFOS)

Birth weight
Birth length
Ponderal index
Birth weight
Adiposity at birth

β 160.45 (-11.85–332.75)
β 0.33 (-0.14–0.79)
β 0.07 (-0.03–0.16)
β -13.8 g (-53.8–26.3)
β 0.8 (-0.33–0.49)

Birth weightMales

β -148.8 g (-297.0 to -0.5 g,
p=0.049)*, per log PFOS unit
NS (p=0.917)
β -269.4 g (-465.7 to -73.0 g,
p=0.007)*, per log PFOS unit

General population (n= 170 infants)
Starling et al. 2017

2.4 ng/mL (median maternal
serum PFOS)

General population (n=604 mother-infant pairs)
Washino et al. 2009
5.2 ng/mL (maternal median
PFOS)
General population (n=428 infants)

Females

Whitworth et al. 2012a
General population (n=901 infants)

13.0 and ≥16.59 ng/mL(maternal median and 4thquartile PFOS)

Birth length
Chest circumference
Head circumference
Birth weight
Small for gestational age
Large for gestational age

NS (p=0.167)
NS (p=0.718)
NS (p=0.488)
NS (p=0.10)
NS (p=0.51)
NS (p=0.33)

PFHxS
Alkhalawi et al. 2016

0.62 ng/mL (geometric mean Birth weightmaternal serum PFHxS)
Birth length
General population (n=156 mother-child pairs)
Ponderal index
Ashley-Martin et al. 2016
1.00 and 0.10 ng/mL
Gestational weight gain
(maternal and cord PFHxSGeneral population (n=1,723 pregnant women) median)
Ashley-Martin et al. 2017
1.0 ng/mL (median maternal Birth weightplasma PFHxS)
Infant leptin levels
General population (n=1,705 mother-infant
Infant adiponectin levels
pairs)NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.1), serum PFHxS
OR 1.01 (10.99–1.03), cord PFHxS
β 0.04 (-0.12–0.20
β 0.01 (-0.08–0.10)
β 0.02 (-0.08–0.04)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Bach et al. 2016

0.5 ng/mL (maternal PFHxS
median)Inverse association reported byinvestigators
NS, investigators noted no consistentalterations across PFHxS quartiles
NS, investigators noted no consistentalterations across PFHxS quartiles
β -103 g (-221–15)
β -0.20 (-0.78–0.38)
β -0.31 (-0.74–0.12)
β -0.05 (-0.13–0.03)
NS (p=0.69)

General population (n=1,507 nulliparous
women)

Birth weight
Birth length
Head circumference

Callan et al. 2016
General population (n=98 pregnant women)

Cao et al. 2018
General population (n=337 newborns)

0.33 ng/mL (median maternal Birth weight
serum PFHxS)
Birth length

0.16 ng/mL (mean cord
serum PFHxS); 0.06–
0.139 ng/mL (2nd tertile cord
PFHxS)

Head circumference
Ponderal index
Birth weight
Birth length
Head circumference
Ponderal index
Birth weight

Hamm et al. 2010

>1.4–43 ng/mL (maternal
3rd tertile PFHxS)

General population (n=252 pregnant women)

Small for gestational age
0.55 ng/mL (maternal median Birth weightPFHxS)
Cord TSH

Kim et al. 2011
General population (n=44 pregnant women)

Kim et al. 2016a
General population (n=27 infants withcongenital hypothyroidism; n=13 controls)

Cord T3
Cord T4
1.228 and 1.17 ng/mL (mean Thyroid stimulating
PFHxS in cases and controls) immunoglobulin levels
TSH
T3
T4

NS (p=0.67)
β 1.33 (0.42–2.26)*, 2nd tertile
NS (p=0.85)
Change in weight (25.99, 95%
CI -95.25–147.23), 3rd tertile
RR 2.35 (0.63–8.72), 3rd tertile
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Lee et al. 20131.35 ng/mL (maternal mean
PFHxS)

OR 0.57 (0.19–1.75)
OR 0.44 (0.12–1.58)
OR 0.64 (0.19–2.23)
OR 0.90 (0.13–6.13)
NS (p>0.05)

General population (n=59 pregnant women)

Lee et al. 2016

Birth weight
Birth length
Ponderal index
Head circumference
0.60 ng/mL (cord blood mean Birth weightPFHxS)

General population (n=85 infants)
Lenters et al. 2016a, 2016b

2.05, 1.56, and 2.28 ng/mL
Birth weight(maternal median PFHxS for
General population (n=513 infants inGreenland, Ukraine, andGreenland subcohort, n=557 infants in Ukraine Poland subcohorts)
subcohort, and n=180 infants in Poland
subcohort)

NS (p=0.801)

Li et al. 2017

Birth weight

β -30.0 (-83.4–23.5)

Congenital cerebral palsy
Boys
Girls

RR 1.2 (0.9–1.7)
RR 1.1 (0.6–1.9)

0.3 ng/mL (median maternal
serum PFHxS)

Birth weight

NS (p>0.05)

1.6 ng/mL (maternal median
PFHxS)

Birth weight

Inverse association (p=0.0314 fortrend)*
Inverse association (p=0.0008 fortrend)*NS (p=0.6802 for trend)

3.9 ng/mL (median cord
serum PFHxS)

General population (n=321 mother-infant pairs)
Liew et al. 20140.96 and 0.90 ng/mL(maternal median PFHxS in
General population (n=156 children diagnosed boy and girl cases)
0.92 and 0.92 ng/mL
with congenital cerebral palsy (cases) and(maternal median PFHxS in
550 controls)
boy and girl controls)
Lind et al. 2017a
General population (n=649 pregnant women)
Maisonet et al. 2012
General population (n=447 girls)

Birth length
Ponderal index

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Manzano-Salgado et al. 2017a0.58 ng/mL (mean maternal
serum PFHxS)

Birth weight
Birth length
Head circumference
Small for gestational age
Low birth weight

β -8.60 (-32.00–14.80)
β -0.06 (-0.17–0.06)
β -0.01 (-0.09–0.07)
OR 0.98 (0.80–1.19)
OR 0.94 (0.71–1.23)

Low birth weight at term
Birth weight

OR 0.97 (0.68–1.41)
NS (p>0.05)

Birth weight for gestationalage

β 0.00 (-0.03–0.02)

Birth weightβ 108.80 (-53.84–271.45)

Birth length
Ponderal index
Birth weight
Adiposity at birth

β 0.38 (-0.06–0.82)
β 0.03 (-0.06–0.12)
β -31.84 g (-105.8–42.2), 3rd tertile
β -0.99% fat mass (-1.75 to -0.23)*,
3rd tertile

Birth weightNS, investigators noted no consistentalterations across PFNA quartiles
NS, investigators noted no consistentalterations across PFNA quartiles
NS, investigators noted no consistentalterations across PFNA quartiles

General population (n=1,202 mother-infant
pairs)

Monroy et al. 2008

1.62 mg/mL (maternal
median PFHxS)

General population (n=101 pregnant women)
Sagiv et al. 2018

2.4 ng/mL (median maternal
plasma PFHxS)

General population (n=1,645 pregnant women)
Shi et al. 20170.157 ng/mL (median cord
serum PFHxS)
General population (n= 170 infants)
Starling et al. 2017

0.8 ng/mL (median maternal
serum PFHxS); 1.1–
General population (n=604 mother-infant pairs) 10.9 ng/mL (3rd tertilematernal PFHxS)
PFNABach et al. 2016
General population (n=1,507 nulliparous
women)

0.8 ng/mL (PFNA median)

Birth length
Head circumferencePERFLUOROALKYLS

433
2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Bae et al. 2015

1.60 and 1.37 ng/mL andMale birth1.55 and 1.09 ng/mL(geometric mean PFNA inmale and female nulliparousparents and male and femaleparous parents, respectively)
0.30 ng/mL (median maternal Birth weight
serum PFNA)
Birth length
Head circumference

OR 0.94 (0.70–1.26), maternal PFNA
OR 0.94 (0.71–1.24), paternal PFNA

General population (233 couples)

Callan et al. 2016
General population (n=98 pregnant women)

Cao et al. 20180.13 ng/mL (mean cord
serum PFNA)

General population (n=337 newborns)
Chen et al. 2012a2.36 ng/mL (cord bloodgeometric mean PFNA)

General population (n=429 infants)

Kim et al. 2016a
General population (n=27 infants withcongenital hypothyroidism; n=13 controls)

Lee et al. 2016
General population (n=85 infants)

1.931 and 0.633 ng/mL(mean PFNA in cases andcontrols)

β 14 g (-169–196)
β 0.20 (-0.68–1.09)
β -0.14 (-0.80–0.52)

Ponderal index
Birth weight
Birth length
Ponderal index
Gestational age
Birth weight
Birth length

β -0.03 (-0.16–0.09)
NS (p=0.19)
NS (p=0.06)
NS (p=0.91)
NS (p>0.05)
NS (p>0.05)
Association (p<0.01)*

Head circumference
Ponderal index
Small for gestational age
Low birth weight
Thyroid stimulating
immunoglobulin levels
TSH
T3

NS (p>0.05)
Inverse association (p<0.05)
OR 0.97 (0.74–1.26)
OR 0.76 (0.47–1.23)
NS (p>0.05)

T4
0.36 ng/mL (cord blood mean Birth weightPFNA)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

PERFLUOROALKYLS

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Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedLenters et al. 2016a, 2016b

0.69, 0.61, and 0.56 ng/mL(maternal median PFNA for
General population (n=513 infants inGreenland, Ukraine, andGreenland subcohort, n=557 infants in Ukraine Poland subcohorts)
subcohort, and n=180 infants in Poland
subcohort)
Li et al. 2017
0.2 ng/mL (median cord
serum PFNA)
General population (n=321 mother-infant pairs)
Liew et al. 20140.46 and 0.39 ng/mL(maternal median PFNA in
General population (n=156 children diagnosed boy and girl cases)
0.44 and 0.41 ng/mL
with congenital cerebral palsy (cases) and(maternal median PFNA in
550 controls)
boy and girl controls)
Lind et al. 2017a
0.7 ng/mL (median maternal
serum PFNA)
General population (n=649 pregnant women)
Manzano-Salgado et al. 2017a0.66 ng/mL (mean maternal
serum PFNA)
General population (n=1,202 mother-infant
pairs)

Monroy et al. 2008
General population (n=101 pregnant women)
Robledo et al. 2015a, 2015b
General population (n=234 couples)

0.69 mg/mL (maternal
median PFNA)
1.211 and 1.566 ng/mL(maternal and paternal
geometric mean PFNA)

Resultc

Birth weight

NS (p=0.065)

Birth weight

β -45.6 (-106.9–15.8)

Congenital cerebral palsy
Boys
Girls

RR 1.2 (0.6–2.5)
RR 0.6 (0.3–1.2)

Birth weight

NS (p>0.05)

Birth weight
Birth length
Head circumference
Small for gestational age

β -10.27 (-38.14–17.61)
β -0.00 (-0.13–0.13)
β -0.04 (-0.13–0.05)
OR 0.85 (0.68–1.07)

Low birth weight
Low birth weight at term
Birth weight

OR 0.86 (0.63–1.17)
OR 0.91 (0.60–1.38)
NS (p>0.05)

Birth weight
Birth length
Head circumference
Ponderal index

NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternalPERFLUOROALKYLS

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Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedSagiv et al. 2018

0.7 ng/mL (median maternal
plasma PFNA); 0.7–
General population (n=1,645 pregnant women) 0.9 ng/mL (3rd quartilematernal PFNA)
Shi et al. 20170.191 ng/mL (median cord
serum PFNA)
General population (n= 170 infants)

Resultc

Birth weight for gestationalage

β -0.20 (-0.33 to -0.06)*, 3rd quartile

Birth weight

β 52.68 (-206.01–311.36)

Birth length
Ponderal index
Starling et al. 2017
0.4 ng/mL (median maternal Birth weight
serum PFNA); 0.5–6.0 ng/mL Adiposity at birth
General population (n=604 mother-infant pairs) (2nd half maternal PFNA)

β 0.13 (-0.57–0.83)
β 0.01 (-0.13–0.15)
β -92.1 g (-150.6 to -33.6)*, 2nd half
β -0.85% fat mass (-1.46 to -0.24)*,
2nd half

Wang et al. 2016

Inverse association (p>0.05)*, girls
only

General population (n=117 boys and 106 girls
examined at 2, 5, 8, and 11 years of age)

PFDA
Bach et al. 2016
General population (n=1,507 nulliparous
women)

1.55 and 1.58 ng/mL (median Birth weightmaternal PFNA for boys andgirls)
Birth length
Head circumference
Small for gestational age
Growth during childhood
0.3 ng/mL (PFDA median)

Birth weight
Birth length
Head circumferenceBae et al. 2015
General population (233 couples)

0.46 and 0.38 ng/mL andMale birth0.49 and 0.46 ng/mL(geometric mean PFDA inmale and female nulliparousparents and male and femaleparous parents, respectively)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS, investigators noted no consistentalterations across PFDA quartiles
NS, investigators noted no consistentalterations across PFDA quartiles
NS, investigators noted no consistentalterations across PFDA quartiles
OR 1.07 (0.81–1.42), maternal PFDA
OR 1.02 (0.78–1.34), paternal PFDAPERFLUOROALKYLS

436
2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Callan et al. 20160.12 ng/mL (median maternal Birth weight
serum PFDA)
Birth length

β 4 g (-161–170)
β 0.36 (-0.44–1.15)
β -0.07 (-0.67–0.53)
β -0.06 (-0.18–0.05)
NS (p=0.26)

General population (n=98 pregnant women)

Cao et al. 2018
General population (n=337 newborns)
Kim et al. 2016a
General population (n=27 infants withcongenital hypothyroidism; n=13 controls)

Lee et al. 2016
General population (n=85 infants)
Lenters et al. 2016a, 2016b0.12 ng/mL (mean cord
serum PFDA)

Head circumference
Ponderal index
Birth weight

Birth length
Ponderal index
0.523 and 0.298 ng/mL
Thyroid stimulating(mean PFDA in cases andimmunoglobulin levels
controls)
TSH
T3
T4
0.14 ng/mL (cord blood mean Birth weight
PFDA)

0.40, 0.16, and 0.22 ng/mL(maternal median PFDA for
General population (n=513 infants inGreenland, Ukraine, andGreenland subcohort, n=557 infants in Ukraine Poland subcohorts)
subcohort, and n=180 infants in Poland
subcohort)
Li et al. 2017
0.1 ng/mL (median cord
serum PFDA)
General population (n=321 mother-infant pairs)
Liew et al. 20140.18 and 0.16 ng/mL(maternal median PFDA in
General population (n=156 children diagnosed boy and girl cases)
0.17 and 0.16 ng/mL
with congenital cerebral palsy (cases) and(maternal median PFDA in
550 controls)
boy and girl controls)

NS (p=0.24)
NS (p=0.55)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Birth weight

NS (p=0.158)

Birth weightβ -47.3 (-112.9–18.2)

Congenital cerebral palsy
Boys
Girls

RR 1.1 (0.7–1.7)
RR 0.6 (0.3–1.1)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Lind et al. 2017a

0.3 ng/mL (median maternal
serum PFDA)

Birth weight

NS (p>0.05)

0.402 and 0.458 ng/mL(maternal and paternal
geometric mean PFDA)

0.075 ng/mL (median cord
serum PFDA)

Birth weight
Birth length
Head circumference
Ponderal index
Birth weight
Birth length

NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal
β -3.04 (-129.67–123.59)
β -0.002 (-0.354–0.34)

0.1 ng/mL (median maternal
serum PFDA)

Ponderal index
Birth weight
Adiposity at birth

β -0.01 (-0.08–0.06)
β 11.5 g (-37.3–60.4)
β 0.06 (-0.45–0.56)

General population (n=649 pregnant women)
Robledo et al. 2015a, 2015b
General population (n=234 couples)

Shi et al. 2017
General population (n= 170 infants)
Starling et al. 2017
General population (n=604 mother-infant pairs)
Wang et al. 2016
General population (n=117 boys and 106 girls
examined at 2, 5, 8, and 11 years of age)

PFUnABach et al. 2016
General population (n=1,507 nulliparous
women)

0.46 and 0.43 ng/mL (median Birth weightmaternal PFDA for boys andgirls)
Birth length

0.3 ng/mL (PFUnA median)Head circumference
Small for gestational age

NS (p>0.05)
OR 3.14 (1.07–9.19)*, girls only

Birth weight

Head circumference

NS, investigators noted no consistentalterations across PFUnA quartiles
NS, investigators noted no consistentalterations across PFUnA quartiles
NS, investigators noted no consistentalterations across PFUnA quartiles
β 102 g (-41–245)
β 0.32 (-0.37–1.02)
β -0.29 (-0.81–0.24)

Ponderal index
Optimal body weight

β 0.01 (-0.09–0.11)
β 5.3 (1.2–9.3)*

Birth length
Head circumference

Callan et al. 2016
General population (n=98 pregnant women)

Inverse association (p>0.05)*, girls
only
NS (p>0.05)

0.08 ng/mL (median maternal Birth weight
serum PFUnA)
Birth length

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Cao et al. 20180.10 ng/mL (mean cord
Birth weight
serum PFUnA); >0.11 ng/mL Birth length(3rd tertile cord PFUnA
Ponderal index
10.26 ng/mL (cord blood
Gestational age
geometric mean PFUnA)
Birth weight

NS (p=0.08)
β 0.41 (0.06–0.77)*, 3rd tertile
NS (p=0.56)
NS (p>0.05)
NS (p>0.05)

General population (n=337 newborns)
Chen et al. 2012a
General population (n=429 infants)

Kim et al. 2016a
General population (n=27 infants withcongenital hypothyroidism; n=13 controls)

Lee et al. 2016

0.982 and 0.438 ng/mL(mean PFUnA in cases andcontrols)

Birth length
Head circumference
Ponderal index
Small for gestational age
Low birth weight
Thyroid stimulating
immunoglobulin levels
TSH

T3
T4
0.22 ng/mL (cord blood mean Birth weight
PFUnA)NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
OR 0.93 (0.65–1.33)
OR 1.01 (0.53–1.91)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

General population (n=85 infants)
Lenters et al. 2016a, 2016b

0.70, 0.16, and 0.13 ng/mL(maternal median PFUnA for
General population (n=513 infants inGreenland, Ukraine, andGreenland subcohort, n=557 infants in Ukraine Poland subcohorts)
subcohort, and n=180 infants in Poland
subcohort)
Li et al. 2017
0.1 ng/mL (median cord
serum PFUnA)
General population (n=321 mother-infant pairs)
Shi et al. 20170.063 ng/mL (median cord
serum PFUnA)
General population (n= 170 infants)

Birth weight

NS (p=0.275)

Birth weight

β -29.7 (-85.7–26.3)

Birth weight
Birth length
Ponderal index

β -28.87 (-128.16–70.42)
β -0.20 (-0.47–0.07)
β 0.01 (-0.04–0.06).

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Wang et al. 2016

3.52 and 3.31 ng/mL (median Birth weightmaternal PFUnA for boys andgirls)
Birth length
Head circumference
Small for gestational age

Inverse association (p<0.05)*, girls
only
NS (p>0.05)
NS (p>0.05)
OR 1.83 (1.01–3.32)*, girls only

0.284 and 0.324 ng/mL(mean PFHpA in cases andcontrols)

NS (p>0.05)

General population (n=117 boys and 106
girls examined at age 2, 5, 8, and 11 yearsof age)
PFHpA
Kim et al. 2016a
General population (n=27 infants withcongenital hypothyroidism; n=13 controls)

Li et al. 2017

0.1 ng/mL (median cord
serum PFHpA)

Thyroid stimulating
immunoglobulin levels
TSH
T3
T4
Birth weight

General population (n=321 mother-infant pairs)
PFBA
Kim et al. 2016a
General population (n=27 infants withcongenital hypothyroidism; n=13 controls)

Li et al. 20170.464 and 0.220 ng/mL(mean PFBA in cases andcontrols)

0.1 ng/mL (median cord
serum PFBA)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
β -103.7 (-211.3–3.8)
β -266.6 (-426.8 to -106.3)*, boys
only
β 15.5 (-134.1–165.1), girls only

Thyroid stimulating
immunoglobulin levels
TSH
T3
T4
Birth weight

NS (p>0.05)

Birth weight
Birth length
Ponderal index

NS (p=0.94)
NS (0.51)
NS (p=0.60)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
β -46.2 (-111.3–19.0)

General population (n=321 mother-infant pairs)
PFDoDACao et al. 2018
General population (n=337 newborns)

0.04 ng/mL (mean cord
serum PFDoDA)PERFLUOROALKYLS

440
2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Lee et al. 20160.14 ng/mL (cord blood mean Birth weight
PFDoDA)NS (p>0.05)

0.13, 0.04, and 0.05 ng/mL(maternal median PFDoDA
for Greenland, Ukraine, andPoland subcohorts)

Birth weight

NS (p=0.440)

0.1 ng/mL (median cord
serum PFDoDA)

Birth weightβ -46.86 (-122.0–28.4)
β 18.4 (-86.8–123.5), boys only
β -130.4 (-239.1 to -21.7)*, girls
only

General population (n=85 infants)
Lenters et al. 2016a, 2016b
General population (n=513 infants inGreenland subcohort, n=557 infants in
Ukraine subcohort, and n=180 infants in
Poland subcohort)
Li et al. 2017
General population (n=321 mother-infant pairs)
Wang et al. 2016
General population (n=117 boys and 106 girls
examined at 2, 5, 8, and 11 years of age)

FOSA
Bae et al. 2015
General population (233 couples)

0.37 and 0.37 ng/mL (median Birth weightmaternal PFDoDA for boys
and girls)
Birth length

Inverse association (p<0.05)*, girls
only

Head circumference

NS (p>0.05)
Inverse association (p<0.05)*, girls
only

Small for gestational age

NS (p>0.05)

0.11 and 0.10 ng/mL andMale birth0.10 and 0.12 ng/mL(geometric mean FOSA inmale and female nulliparousparents and male and femaleparous parents, respectively)

OR 1.07 (0.81–1.41), maternal FOSA
OR 1.14 (0.86–1.51), paternal FOSAPERFLUOROALKYLS

441
2. HEALTH EFFECTS

Table 2-23. Summary of Birth Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedRobledo et al. 2015a, 2015b0.112 and 0.114 ng/mL(maternal and paternal
geometric mean FOSA)

General population (n=234 couples)

Birth weightBoys

Resultc

Girls
Birth length

Inverse association (p<0.05)*,
maternal only
NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternal

Head circumference
Ponderal index

NS (p>0.05), maternal or paternal
NS (p>0.05), maternal or paternalaSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 13 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

BMI = body mass index; FSH = follicle stimulating hormone; FOSA = perfluorooctane sulfonamide; HR = hazard ratio; LH = luteinizing hormone; NS = notsignificant; NR = not reported; OR = odds ratio; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid;
PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid; RR = relative risk;
T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb
PFOA
Stein et al. 2013
Community (C8) (n=320 children 6–12 years
old)
Stein et al. 2014a, 2014b
Community (C8) (n=321 children 6–12 years
old)

Stein and Savitz 2011
Community (C8) (n=10,546 children aged 5–
18 year)Serum perfluoroalkyl level Outcome evaluated115.9 ng/mL (estimated inutero mean PFOA)

Resultc

β 4.61 (0.68–8.54)*, 4th quartileNS
β -8.49 (-16.14 to -0.84)*, 4thquartile
β -6.39 (-11.43 to -1.35)*, 4thquartile boys
β -6.39 (-0.03–8.87), 4th quartile girls
β -6.42 (-13.29–0.45), 4th quartileboys
β -1.92 (-10.39–6.55), 4th quartile
girls
ADHD-like behaviors
β -3.82 (-8.96–1.31), 4th quartile boys
(mother completed survey) β 6.99 (2.47–11.51)*, 4th quartilegirls
β 2.30 (-1.18–5.77), 4th quartile boys
and girls
ADHD-like behaviors
β -9.25 (-18.78–0.27), 4th quartile(teacher completed survey) boys
β -3.65 (-10.85–3.51) 4th quartile girls
β -6.03 (-11.40 to -0.66)*, 4thquartile boys and girls

Full scale IQ
Reading and math skills
Scores on tests of ADHD
(improvement)th
94.1–838.6 ng/mL (4 PFOA Executive function scores
quartile measured 3–4 years (mother completed survey)
prior to behavioral
assessment)
Executive function scores(teacher completed survey)

65.3–2,070.6 ng/mL(4th PFOA quartile)

Behavioral problems andemotional disturbances(mother completed survey)
Behavioral problems andemotional disturbances(teacher completed survey)
ADHD
Learning problems
12–15 years old
5–18 years old

β -1.55 (-5.91–2.82), 4th quartile boys
β 4.63 (0.72–8.53)*, 4th quartile girls
β -2.47 (-8.24–3.30), 4th quartile boys
β -0.91 (-6.19–4.37), 4th quartile girls
OR 0.76 (0.64–0.90)*, 4th quartile
OR 0.96 (0.73–1.26), 4th quartile
OR 0.90 (0.76–1.06), 4th quartilePERFLUOROALKYLS

443
2. HEALTH EFFECTS

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedBraun et al. 2014

5.5 ng/mL (maternal median
PFOA)

General population (n=175 children 4 and5 years old)
Chen et al. 2013

Social responsiveness scale β -2.0 (-4.4–0.4)
score (measure of autistic
behaviors)

2.5 ng/mL (mean cord PFOA) Poor performance on tests

NS OR 0.6 (0.08–4.8), whole test
OR1.3 (0.3–6.2), cognitive tests
OR 0.5 (0.06–4.0), language tests
OR 0.8 (0.1–4.7), gross motor tests
OR 2.8 (0.6–13.5), fine motor tests
OR 0.3 (0.02–2.7), social tests
OR 3.2 (0.7–14.3), self-help tests

5.49 ng/mL (maternal
geometric mean PFOA)NS (p>0.05)
OR 3.79 (1.1–12.8)* per 10-foldincrease in PFOANS (p=0.3533)
OR 1.14 (0.57–2.25)
NS (p>0.05)

General population (239 children 2 years ofage)

Donauer et al. 2015
General population (n=349 infants at 5 weeks
of age)Fei et al. 2008b

5.6 ng/mL (maternal median
PFOA)

General population (n=1,400 infants)

Fei and Olsen 2011

5.4 ng/mL (maternal median
PFOA)

General population (n=526–787 7-year-old
children)
Forns et al. 2015

40 ng/L (median PFOA
breast milk level)

General population (n=843 infants)
Goudarzi et al. 2016b
General population (n=173 infants at 6 months
and 133 at 18 months)

Resultc

1.2 ng/mL (maternal median
PFOA)

Social/easy going
Hypotonic

High arousal/difficult
Apgar scores <10
Motor and mental
development at 6 months
Neurobehavioral milestones NS (p>0.05)
at 18 months
Behavioral problems
NS (p>0.15 for trend)
Motor coordination
NS (p=0.89 for trend)

Risk of an abnormal scoreon neurobehavioral
assessment questionnaire

OR 1.05 (0.77–1.44) at 6 months ofage
OR 1.0 (0.78–1.28) at 24 months ofage
MDI/PDI at 6 months of age NS (p>0.05), boys and girls
Inverse association (p<0.05)*,
females
MDI/PDI at 18 months ofNS (p>0.05)
age

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Gump et al. 20113.23 ng/mL (mean PFOA)NS (p>0.05)

General population (n=83 children aged 9–
11 years)Hoffman et al. 2010

Performance on task
requiring behavioral
inhibition

4.4 ng/mL (median PFOA)ADHD (parent reported)

OR 1.12 (1.01–1.23)*, per 1 ng/mL
PFOA

Motor skills
Abnormal behavior
Hyperactivity

β -0.2 (-1.2–0.9)
OR 2.7 (1.2–6.3)*, 3rd tertile
OR 3.1 (1.3–7.2)*, 3rd tertile

Inattention
Hyperactivity/impulsivity
Emotional symptoms
Conduct problems
Hyperactivity/inattention
Verbal comprehension(15-month-olds)
Vocabulary comprehension
and production (15-montholds)
Nonverbal communication(15-month-olds)
Social development(15-month-olds)
Intelligibility scores(38-month-olds)
Language scores(38-month-olds)
Communicative scores(38-month-olds)

NS (p=0.7758)
NS (p=0.2997)
NS (p=0.691)
NS (p=0.2664)
NS (p=0.774)
NS (p>0.05)

General population (NHANES) (n=571 children
12–15 years)
Høyer et al. 2015a
1.4 and 1.9–9.8 ng/mL(maternal median andGeneral population (n=1,106 children aged 5– 3rd tertile PFOA)
9 years)
Lien et al. 2016
1.55 ng/mL (cord bloodweighted average PFOA)
General population (n=282 children aged
7 years)

Jeddy et al. 2017
General population (n=432 mother-daughter
pairs)

3.7 ng/mL (maternal medianserum PFOA)NS (p>0.05)

NS (p>0.05)
NS (p>0.05)
β -0.04 (-0.08 to -0.01)*
NS (p>0.05)
NS (p>0.05)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Liew et al. 2015

4.06, 3.88, and 4.00 ng/mL
ADHD(maternal median PFOA for Autism
ADHD, autism, and controls)

RR 0.98 (0.82–1.16)
RR 0.98 (0.73–1.31)

General population (n=215, ADHD cases,
213 autism cases, 545 controls)
Ode et al. 2014

1.80 and 1.83 ng/mL (cordADHD
OR 0.98 (0.91–1.02), per 1 ng/mL
blood median PFOA in cases
increase in PFOA
General population (n=206 children with ADHD and controls)and 206 controls; children were 5–17 years old
at time of diagnosis)
Oulhote et al. 20163.19 ng/mL (maternal
Behavioral development
No associations
geometric mean PFOA)
scoresGeneral population (n=567 7-year-old children)
Oulhote et al. 2016
4.09 ng/mL (geometric mean Total behavioral scores and Associations
PFOA in 5-year-old children) higher internalizing
General population (n=567 7-year-old children)
problems, peer relationship,
and autism screening
scores
Oulhote et al. 2016
4.51 ng/mL (geometric mean Behavioral development
No associations
PFOA in 7-year-old children) scores
General population (n=567 7-year-old children)
Quaak et al. 2016
0.9056 ng/mL (cord mean
Score on test evaluating
NS (p=0.72), 3rd tertile
PFOA)
ADHD
Males
General population (n=76 infants 18 months ofNS (p=0.22), 3rd tertile
FemalesNS (p=0.31), 3rd tertile
age)
Scores on test evaluatingexternalizing problem
Males

Strøm et al. 2014
General population (n=876 adults age
20 years)

3.7 ng/mL (median maternal
PFOA)

Females
ADHD
Depression
Scholastic achievement

NS (p=0.31), 3rd tertile
Association (p=0.05 and 0.09)*,
2nd and 3rd tertiles
NS (p=0.74), 3rd tertile
NS (p=0.45 for trend of 3rd tertile)
NS (p=0.28 for trend of 3rd tertile)
NS (p=0.21 for trend of 3rd tertile)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedVuong et al. 2016

5.4 ng/mL (maternal median
PFOA)

Behavioral regulation
β 1.11(-1.22–3.44)
Metacognition
β 0.58 (-1.77–2.93)
Global executive functioning β 1.06 (-1.33–3.45)

2.4 ng/mL (mean serum
PFOA)

Metacognition index score

NS (p>0.05)

Behavior regulation indexscore

NS (p>0.05)

General population (n=256 children aged 5 or
8 years)
Vuong et al. 2018
General population (n=208 8-year-old children)

Resultc

Global executive functioning NS (p>0.05)
score

Wang et al. 2015b
General population (n=120 children age
5 years and 120 children aged 8 years)
Wu et al. 20122.50 and 2.50 ng/mL(maternal median PFOA for
5- and 8-year-old children)

At risk metacognition score
At risk behavior regulationscore
At risk global executivescore
IQ scoreAge 5 years
Age 8 years

18.32 and 9.76 ng/mL (mean 5-minute Apgar scorematernal serum PFOA at
General population (n=167 pregnant women at each hospital)
2 hospitals)
Zhang et al. 2018
5.4 ng/mL (median maternal Reading scores
PFOA)
At 5 years of age
General population (n=167 mother-child pairs)
At 8 years of age
Zhang et al. 2018
5.5 ng/mL (median PFOA in Reading scores
3-year-old children)
At 5 years of age
General population (n=167 mother-child pairs)
At 8 years of age
Zhang et al. 2018
General population (n=167 mother-child pairs)

2.4 ng/mL (median PFOA in
5-year-old children)

Reading scores
At 8 years of age

OR 3.18 (1.17–8.60)*
OR 1.56 (0.49–4.92)
OR 2.69 (0.92–7.90)

NSNS
β -1.37 (-2.42 to -0.32, p<0.05)*

NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*
NS (p>0.05)
Association (p<0.05)*

PERFLUOROALKYLS

447
2. HEALTH EFFECTS

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb
PFOS
Stein and Savitz 2011
Community (C8) (n=10,546 children aged 5–
18 years)
Braun et al. 2014

Serum perfluoroalkyl level Outcome evaluated
14.8–<20.2, 20.22–<27.9,
and 27.9–202.1 ng/mL (2nd,
3rd, and 4th PFOS quartiles)
13 ng/mL (maternal PFOS
median)Resultc

ADHD
OR 0.99 (0.76–1.30), 4th quartile
Learning problems
5–18 years old
OR 0.83 (0.70–0.98)*, 2nd quartile
12–15 years old
OR 0.68 (0.52–0.89)*, 3rd quartile
Social responsiveness scale No association
score (test of autism)

General population (n=175 children 4 and5 years old)
Donauer et al. 2015
General population (n=349 infants)
Fei et al. 2008b
General population (n=1,400 infants)

Fei and Olsen 2011
General population (n=526–787 children)
Forns et al. 201513.25 ng/mL (maternal
geometric mean PFOS)

Neurobehavioral outcomes NS (p>0.05)
Hypotonic
NS (p=0.3996)
High arousal/difficult
NS (p=0.4678)
35.3 ng/mL (maternal median Apgar scores <10
OR 1.20 (0.67–2.14)
PFOS)
Neurobehavioral milestones
Delay in age of sitting
Association (p=0.041 for trend)*
Earlier use of word-like
Association (p=0.039 for trend)*
soundsDelays in using 2-word
Association (p=0.050 for trend)*
sentences
Other milestones
NS (p>0.05)
Motor and mental
NS (p>0.05)
development at 6 months
34.4 ng/mL (maternal median Behavioral health
NS (p>0.39 for trend)
PFOS)
Motor coordination
NS (p=0.41 for trend)
110 ng/L (median PFOS
breast milk level)

General population (n=843 infants)
Goudarzi et al. 2016b
General population (n=173 at 6 months and
133 at 18 months)

5.7 ng/mL (maternal median
PFOS)

Risk of an abnormal scoreon neurobehavioral
assessment questionnaire

OR 0.96 (0.76–1.20) at 6 months ofage
OR 0.93 (0.74–1.17) at 24 months ofage
MDI/PDI at 6 months of age NS (p>0.05)
MDI/PDI at 18 months ofage

NS (p>0.05)

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2. HEALTH EFFECTS

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Gump et al. 20119.90 ng/mL (mean PFOS)

Inverse association (p<0.05)*

General population (n=83 children aged 9–
11 years)Hoffman et al. 2010

Performance on task
requiring behavioral
inhibition

22.6 ng/mL (median PFOS)ADHD (parent reported)

OR 1.03 (1.01–1.05)*, per 1 ng/mL
PFOS

Motor skills
Abnormal behavior
Hyperactivity

β -0.1 (-1.2–1.1)
OR 1.5 (0.5–4.8), 3rd tertile
OR 1.4 (0.4–4.9), 3rd tertile

General population (NHANES) (n=571 children
12–15 years)
Høyer et al. 2015a10.0 and 16.6–87.3 ng/mL(maternal median andGeneral population (n=1,106 children)
3rd tertile PFOS)
Jeddy et al. 201719.8 ng/mL (maternal median Verbal comprehension
serum PFOS)(15-month-olds)

General population (n=432 mother-daughter
pairs)

Lien et al. 2016
General population (n=282 children aged
7 years)

4.79 ng/mL (cord bloodweighted average PFOS)

β 0.03 (0.01–0.05)*

Vocabulary comprehension
and production (15-montholds)
Nonverbal communication(15-month-olds)
Social development(15-month-olds)
Intelligibility scores(38-month-olds)
Language scores(38-month-olds)
Communicative scores(38-month-olds)
Inattention
Hyperactivity/impulsivity

NS (p>0.05)

Emotional symptoms
Conduct problems
Hyperactivity/inattention

NS (p=0.9431)
NS (p=0.4938)
NS (p=0.5226)

NS (p>0.05)
NS (p>0.05)
β -0.01 (-0.01–0.00)*
NS (p>0.05)
NS (p>0.05)
NS (p=0.8508)
NS (p=0.6857)

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2. HEALTH EFFECTS

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedLiew et al. 2015

Resultc

26.80, 25.40, andADHD
27.40 ng/mL (maternal
General population (n=215, ADHD cases,
median PFOS for ADHD,
Autism
213 autism cases, 545 controls)
autism, and controls)
Ode et al. 20146.92 and 6.77 ng/mL (cordADHDblood median PFOS in cases
General population (n=206 children with ADHD and controls)and 206 controls)
Oulhote et al. 201627.42 ng/mL (maternal
Behavioral development
geometric mean PFOS)
scoresGeneral population (n=567 7-year-old children)
Oulhote et al. 201616.75 ng/mL (geometricBehavioral development
mean PFOS in 5-year-old
scoresGeneral population (n=567 7-year-old children) children)
Oulhote et al. 201615.27 ng/mL (geometricBehavioral development
mean PFOS in 7-year-old
scoresGeneral population (n=567 7-year-old children) children)
Quaak et al. 2016
1.5836 ng/mL (cord mean
Score on test evaluating
PFOS)
ADHD
Males
General population (n=76 infants 18 months ofFemalesage)
Scores on test evaluatingexternalizing problem
Males
Females

RR 0.87 (0.74–1.02)
RR 0.79 (0.64–0.98)*, 4th quartile
RR 0.92 (0.69–1.22)

Strøm et al. 2014

NS (p=0.38 for trend of 3rd tertile)
NS (p=0.14 for trend of 3rd tertile)
NS (p=0.59 for trend of 3rd tertile)

General population (n=876 adults age
20 years)

21.4 ng/mL (median maternal ADHD
PFOS)
Depression
Scholastic achievement

OR 0.98 (0.92–1.04), per 1 ng/mL
increase in PFOS

No associations

No associations

No associations

NS (p=0.19), 3rd tertile
NS (p=0.35), 3rd tertile
NS (p=0.43), 3rd tertile
NS (p=0.31), 3rd tertile
NS (p=0.74), 3rd tertile
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Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedVuong et al. 201613.2 ng/mL (maternal median Behavioral regulation
PFOS)
Metacognition

General population (n=256 children 5 or
8 years of age)

Vuong et al. 2018

3.9 ng/mL (mean serum
PFOS)

General population (n=208 8-year-old children)

Wang et al. 2015b
General population (n=120 children age
5 years and 120 children aged 8 years)
Zhang et al. 201813.25 and 12.28 ng/mL(maternal median PFOS for
5- and 8-year-old children)

Resultc

β 3.14 (0.68–5.61)*
β 3.10 (0.62–5.58)*
Global executive functioning β 3.38 (0.86–5.90)*
Global executive functioning OR 2.19 (1.03–4.66)*
composite score >60
Metacognition index score NS (p>0.05)
Behavior regulation index
NS (p>0.05)
score
Global executive functioning NS (p>0.05)
score
At risk metacognition score OR 1.53 (0.67–3.52)
At risk behavior regulationscore

OR 0.40 (0.14–1.14)

At risk global executivescore
IQ scoreAge 5 years
Age 8 years

OR 1.04 (0.41–2.68)

13.0 ng/mL (median maternal Reading scores
PFOS)
At 5 years of age
General population (n=167 mother-child pairs)
At 8 years of age
Zhang et al. 2018
6.6 ng/mL (median PFOS in Reading scores
3-year-old children)
At 5 years of age
General population (n=167 mother-child pairs)
At 8 years of age
Zhang et al. 2018
3.6 ng/mL (median PFOS in Reading scores
5-year-old children)
At 8 years of age
General population (n=167 mother-child pairs)

NS (p>0.05)
NS (p>0.05)

NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*
NS (p>0.05)
Association (p<0.05)*

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Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb
PFHxSStein and Savitz 2011
Community (C8) (n=10,546 children aged 5–
18 years)

Braun et al. 2014

Serum perfluoroalkyl level Outcome evaluatedResultc

2.9–<5.2 and 10.1–
276.4 ng/mL (2nd and4th PFHxS quartiles)

OR 1.27 (1.06–1.52)*, 2nd quartile
OR 1.46 (1.10–1.93)*, 2nd quartileADHD
5–18 years
12–15 years
Learning problems
5–18 years old
12–15 years old

OR 1.19 (1.00–1.41), 4th quartile
OR 1.05 (0.79–1.40), 4th quartile

1.6 ng/mL (maternal PFHxS
median)Social responsiveness scale No association
score (test for autism)

General population (n=175 children 4 and5 years old)
Gump et al. 20116.06 ng/mL (mean PFHxS)

Inverse association (p<0.01)*

General population (n=83 children aged 9–
11 years)Hoffman et al. 2010

Performance on task
requiring behavioral
inhibition

2.2 ng/mL (median PFHxS)

ADHD (parent reported)

OR 1.06 (1.02–1.11)*, per 1 ng/mL
PFOS

Verbal comprehension(15-month-olds)
Vocabulary comprehension
and production (15-montholds)
Nonverbal communication(15-month-olds)
Social development(15-month-olds)
Intelligibility scores(38-month-olds)
Language scores(38-month-olds)

NS (p>0.05)

General population (NHANES) (n=571 children
12–15 years)
Jeddy et al. 2017
1.6 ng/mL (maternal medianserum PFHxS)
General population (n=432 mother-daughter
pairs)NS (p>0.05)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

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Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc
NS (p>0.05)

Liew et al. 2015

Communicative scores(38-month-olds)
0.84. 0.92, and 0.92 ng/mL
ADHD(maternal median PFHxS for Autism
ADHD, autism, and controls)
4.43 ng/mL (maternal
geometric mean PFHxS)

No associations

General population (n=215, ADHD cases,
213 autism cases, 545 controls)
Oulhote et al. 2016

Behavioral developmentscoresRR 0.67 (0.54–0.83)*, 4th quartile
RR 1.10 (0.92–1.33)

General population (n=567 7-year-old children)
Oulhote et al. 2016
0.54 ng/mL (geometric mean Behavioral development
No associations
PFHxS in 5-year-old children) scores
General population (n=567 7-year-old children)
Oulhote et al. 2016
0.53 ng/mL (geometric mean Behavioral development
No associations
PFHxS in 7-year-old children) scores
General population (n=567 7-year-old children)
Vuong et al. 2016
1.5 ng/mL (maternal median Behavioral regulation
β 1.19 (-0.54–5.40)
PFHxS)
Metacognition
β 1.31 (-0.43–3.04)
General population (n=256 children 5 or
Global executive functioning β 1.36 (-0.41–3.12)
8 years of age)
Global executive functioning OR 1.71 (1.05–2.77)*
composite score >60
Vuong et al. 2018
1.4 ng/mL (mean serum
Metacognition index score NS (p>0.05)
PFHxS)
Behavior regulation index
NS (p>0.05)
General population (n=208 8-year-old children)
score
Global executive functioning NS (p>0.05)
score
At risk metacognition score OR 1.10 (0.58–2.09)
At risk behavior regulationscore

OR 0.54 (0.22–1.32)

At risk global executivescore

OR 0.65 (0.32–1.32)

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Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Wang et al. 2015b0.69 and 0.69 ng/mL
IQ score(maternal median PFHxS for
Age 5 years
5- and 8-year-old children)
Age 8 years

NS (p>0.05)
NS (p>0.05)

General population (n=120 children age
5 years and 120 children aged 8 years)
Zhang et al. 2018

Reading scores
At 5 years of age
General population (n=167 mother-child pairs)
At 8 years of age
Zhang et al. 2018
1.9 ng/mL (median PFHxS in Reading scores
3-year-old children)
At 5 years of age
General population (n=167 mother-child pairs)
At 8 years of age
Zhang et al. 2018
1.2 ng/mL (median PFHxS in Reading scores
5-year-old children)
At 8 years of age
General population (n=167 mother-child pairs)
PFNA
Stein and Savitz 2011
1.2–<1.5, 1.5–<2.0, and 2.0– ADHD
24.1 ng/mL (2nd, 3rd, and5–18 years
12–15 years
Community (C8) (n=10,546 children aged 5–
4th PFNA quartiles)
18 years)
Learning problems
5–18 years old
12–15 years old
Braun et al. 2014

1.5 ng/mL (median maternal
PFHxS)NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

OR 0.99 (0.84–1.18), 4th quartile
OR 1.00 (0.75–1.32), 4th quartile
OR 0.81 (0.69–0.95)*, 3rd quartile
OR 0.73 (0.55–0.98)*, 4th quartile

0.9 ng/mL (maternal PFNA
median)Social responsiveness scale No association
score (tests for autism)

General population (n=175 children 4 and5 years old)
Gump et al. 20110.82 ng/mL (mean PFNA)

Inverse association (p<0.05)*

General population (n=83 children aged 9–
11 years)Hoffman et al. 2010

Performance on task
requiring behavioral
inhibition

0.6 ng/mL (median PFNA)ADHD (parent reported)

OR 1.32 (0.86–2.02), per 1 ng/mL
PFNA

General population (NHANES) (n=571 children
12–15 years)

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2. HEALTH EFFECTS

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedJeddy et al. 2017

0.5 ng/mL (maternal medianserum PFNA)

General population (n=432 mother-daughter
pairs)

Resultc

Verbal comprehension
NS (p>0.05)(15-month-olds)
Vocabulary comprehension NS (p>0.05)
and production (15-montholds)
Nonverbal communication(15-month-olds)

NS (p>0.05)

Social development(15-month-olds)

NS (p>0.05)

Intelligibility scores(38-month-olds)

NS (p>0.05)

Language scores(38-month-olds)
Communicative scores(38-month-olds)
Inattention
Hyperactivity/impulsivity

NS (p>0.05)

Emotional symptoms
Conduct problems
Hyperactivity/inattention
ADHD
AutismNS (p=0.1902)
NS (p=0.6931)
Inverse association (p=0.0484)*
RR 0.80 (0.62–1.03)
RR 0.80 (0.58–1.11)

Behavioral developmentscoresNo association

1.01 ng/mL (geometric mean Total behavioral
PFNA in 5-year-old children) development score andGeneral population (n=567 7-year-old children)
higher externalizing
problems score

Association*

Lien et al. 2016

4.49 ng/mL (cord bloodweighted average PFNA)

General population (n=282 children aged
7 years)

Liew et al. 2015
General population (n=215, ADHD cases,
213 autism cases, 545 controls)
Oulhote et al. 2016

0.42, 0.41, and 0.43 ng/mL(maternal median PFNA for
ADHD, autism, and controls)
0.61 ng/mL (maternal
geometric mean PFNA)NS (p>0.05)
Inverse association (p=0.0129)*
NS (p=0.0588)

General population (n=567 7-year-old children)
Oulhote et al. 2016

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Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Oulhote et al. 2016

1.2 ng/mL (geometric mean Behavioral development
PFNA in 7-year-old children) scores

No association

General population (n=567 7-year-old children)
Vuong et al. 2016
General population (n=256 children 5 or
8 years of age)
Vuong et al. 2018

0.9 ng/mL (maternal median
PFNA)

Behavioral regulation
β 2.57 (-0.26–5.40)
Metacognition
β 1.37 (-1.49–4.23)
Global executive functioning β 2.01 (-0.89–4.92)

0.8 ng/mL (mean serum
PFNA)

Metacognition index score β 3.4 (0.4–6.3, p<0.05)*
Behavior regulation index
NS (p>0.05)
score
Global executive functioning Association (p<0.05)*
score
At risk metacognition score OR 2.94 (1.52–5.69)*

General population (n=208 8-year-old children)

Wang et al. 2015b
General population (n=120 children age
5 years and 120 children aged 8 years)
Zhang et al. 20181.59 and 1.44 ng/mL(maternal median PFNA for
5- and 8-year-old children)

0.9 ng/mL (median maternal
PFNA)

General population (n=167 mother-child pairs)
Zhang et al. 2018
1.2 ng/mL (median PFNA in
3-year-old children)
General population (n=167 mother-child pairs)
Zhang et al. 2018
0.7 ng/mL (median PFNA in
5-year-old children)
General population (n=167 mother-child pairs)

At risk behavior regulationscore

OR 2.75 (1.30–5.79)*

At risk global executivescore
IQ score
IQ scores, age 8 years
Full scale IQ
Visual IQ
Performance IQ
Reading scores
At 5 years of age
At 8 years of age
Reading scores
At 5 years of age
At 8 years of age
Reading scores
At 8 years of age

OR 3.07 (1.60–5.90)*
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*
NS (p>0.05)
NS (p>0.05)

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Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

PFDA
Gump et al. 20110.26 ng/mL (mean PFDA)

Inverse association (p<0.05)*

General population (n=83 children aged 9–
11 years)
Liew et al. 2015
General population (n=215, ADHD cases,
213 autism cases, 545 controls)
Oulhote et al. 2016

Performance on task
requiring behavioral
inhibition

0.15, 0.15, and 0.17 ng/mL
ADHD(maternal median PFDA for
ADHD, autism, and controls) Autism

RR 0.76 (0.64–0.91)*
RR 0.53 (0.43–0.66)*, 4th quartile

0.28 ng/mL (maternal
geometric mean PFDA)

No associations

Behavioral developmentscoresRR 0.79 (0.63–1.01)
RR 0.52 (0.35–0.77)*, 4th quartile

General population (n=567 7-year-old children)
Oulhote et al. 20160.28 ng/mL (geometric mean Total behavioral
Associations*
PFDA in 5-year-old children) development score andGeneral population (n=567 7-year-old children)
higher externalizing
problems and hyperactivity/
inattention scores
Oulhote et al. 20160.36 ng/mL (geometric mean Behavioral development
No associations
PFDA in 7-year-old children) scores
General population (n=567 7-year-old children)
Vuong et al. 2016
General population (n=256 children 5 or
8 years of age)
Wang et al. 2015b
General population (n=120 children age
5 years and 120 children aged 8 years)

0.2 ng/mL (maternal medianPFDA)

Behavioral regulation
β 0.70 (-3.31–1.92)
Metacognition
β 1.24 (-3.87–1.39)
Global executive functioning β -1.13 (-3.79–1.54)

0.44 and 0.44 ng/mL(maternal median PFDA for
5- and 8-year-old children)

IQ scoreAge 5 years
Age 8 years

NS (p>0.05)
NS (p>0.05)

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Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa
Reference and study populationb
PFUnA
Lien et al. 2016

Serum perfluoroalkyl level Outcome evaluatedResultc

7.96 ng/mL (cord bloodweighted average PFUnA)

Inattention
Hyperactivity/impulsivity
Emotional symptoms
Conduct problems

NS (p=0.6177)
NS (p=0.3642)
NS (p=0.0517)
NS (p=0.1207)

Hyperactivity/inattention
3.42 and 3.13 ng/mL
IQ score(maternal median PFUnA for IQ scores, age 8 years
5- and 8-year-old children)
Full scale IQ
Visual IQ
Performance IQ

NS (p=0.9991)
NS (p>0.05)

General population (n=282 children aged
7 years)

Wang et al. 2015b
General population (n=120 children age
5 years and 120 children aged 8 years)
PFDoDA
Wang et al. 2015b
General population (n=120 children age
5 years and 120 children aged 8 years)
FOSA
Gump et al. 2011

NS (p>0.05)
NS (p>0.05)
Inverse association (p<0.05)*

0.38 and 0.37 ng/mL
IQ score(maternal median PFDoDA
Age 5 years
for 5- and 8-year-old children) Age 8 years

NS (p>0.05)
NS (p>0.05)

0.75 ng/mL (mean FOSA)

Inverse association (p<0.05)*

General population (n=83 children aged 9–
11 years)

Performance on task
requiring behavioral
inhibition

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 13 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

ADHD = attention deficit hyperactivity disorder; FOSA = perfluorooctane sulfonamide; MDI/PDI = mental and psychomotor development indices;
NHANES = National Health and Nutrition Examination Survey; NS = not significant; OR = odds ratio; PFDA = perfluorodecanoic acid;
PFDoDA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid

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Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa
Reference and study populationb
PFOA
Lopez-Espinosa et al. 2011

Serum perfluoroalkyl level Outcome evaluated
26 and 20 ng/mL (median
PFOA in boys and girls)

Community (C8) (n=3,076 boys and 2,931 girls
aged 8–18 years)
Lopez-Espinosa et al. 2016

Age of puberty
Boys
Girls

34.8 and 30.1 ng/mL (median Estradiol
PFOA in boys and girls)

Community (C8) (n=1,169 boys and 1,123 girls
aged 6–9 years)

Total testosterone

Insulin-like growth factor-1

Christensen et al. 2011
General population (n=448 girls)
Itoh et al. 2016
General population (n=189 infants)

Resultc

OR 0.95 (0.84–0.07)
OR 0.54 (0.35–0.84)*, 2nd quartile
NS (interquartile difference of 4.3,
95% CI -0.4–9.1), boys
NS (4.2, 95% CI -0.7–9.4), girls
Inverse association (-4.9, 95%
CI -8.7 to -0.8)*, boys
NS (-2.5, 95% CI -6.7–1.8), girls
NS (-0.4, 95% CI -3.4–2.7), boys
Inverse association (-3.6, 95%
CI -6.6 to -0.5)*, girls
OR 1.01 (0.61–1.68)

3.7 ng/mL (maternal median
PFOA)

Earlier age of menarche

1.4 ng/mL (maternal median
PFOA)

Cord estradiol
NS (p>0.05)
Cord testosterone
NS (p>0.05)
Cord testosterone: estradiol NS (p>0.05)
ratio
Cord progesterone
NS (p>0.05)
Cord prolactin
NS (p>0.05)
Cord LH
NS (p>0.05)
Cord FSH
Cord SHBG
Cord insulin-like factor 3
Cord inhibin
Males
FemalesNS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p=0.040)*
NS (p>0.05)

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Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Kristensen et al. 2013

3.6 and 4.4–19.8 ng/mL
Age of menarche(maternal median PFOA and Menstrual cycle length
3rd PFOA tertile)
Total testosterone
SHBG
Free androgen index

Association (p=0.01)*
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

General population (n=343 females
approximately 20 years of age)

Lind et al. 2017a
General population (n=649 pregnant women)
Maisonet et al. 2015
General population (n=72 girls aged 15 years)
Vesterholm Jensen et al. 2014
General population (n=107 cases
cryptorchidism [29 from Denmark and 78 from
Finland] and 108 matched controls from
Denmark and Finland)
PFOS
Lopez-Espinosa et al. 2011
Community (C8) (n=3,076 boys and 2,931 girls
aged 8–18)

Dehydroepiandrosterone
sulphate

NS (p>0.05)

Anti-Müllerian hormone
Number of follicles/ovary
Anogenital distanceNS (p>0.05)
NS (p>0.05)
NS (p=0.71), boys
NS (p=0.71), girls>4.1 ng/mL (maternal
3rd tertile PFOA)

Testosterone
SHBG

β 0.24 (0.05–0.43)*, 3rd tertile
β 5.02 (-13.07–11.00), 3rd tertile

2.6 and 2.1 ng/mL (mediancord blood PFOA Denmarkand Finland cohorts)

Cryptorchidism

OR 0.51 (0.21–1.20), whole cohort
OR 0.35 (0.12–0.99, p=0.04 fortrend)*, Finland cohort 3rd tertile

20 and 18 ng/mL (PFOS
median in boys and girls)

Age of puberty
Boys
Girls

1.7 ng/mL (median maternal
serum PFOA)

OR 0.58 (0.37–0.90)*, 3rd quartile
OR 0.55 (0.35–0.86)*, 3rd quartilePERFLUOROALKYLS

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Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Lopez-Espinosa et al. 201622.4 and 20.9 ng/mL (PFOS
median in boys and girls)

Inverse association (interquartile
difference of -4.0, 95% CI -7.7
to -0.1)*, boys
NS (-0.3, 95% CI -4.6–4.2), girls
Inverse association (-5.8, 95%
CI -9.4 to -2.0)*, boys
Inverse association (-6.6, 95%
CI -10.1 to -2.8)*, girls
Inverse association (-5.9, 95%
CI -8.3 to -3.3)*, boys
Inverse association (-5.6, 95%
CI -8.2 to -2.9)*, girls
OR 0.68 (0.40–1.13)

Estradiol

Community (C8) (n=1,169 boys and 1,123 girls
aged 6–9 years)
Total testosterone

Insulin-like growth factor-1

Christensen et al. 201119.8 ng/mL (maternal median Earlier age of menarche
PFOS)

General population (n=448 girls)
Itoh et al. 2016
General population (n=189 infants)

5.2 ng/mL (maternal median
PFOS)

Cord estradiol
Males
Association (p=0.021)*
FemalesNS (p>0.05)
Cord testosterone
NS (p>0.05)
Cord testosterone: estradiol
ratio
Males
Inverse association (p=0.008)*
FemalesNS (p>0.05)
Cord progesterone
Males
Association (p=0.043)*
Females
Association (p=0.002)*
Cord prolactin
Males
NS (p>0.05)
Females
Association (p=0.001)*
Cord LH
NS (p>0.05)
Cord FSH
Cord SHBG

NS (p>0.05)
NS (p>0.05)

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Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa
Reference and study populationb

Kristensen et al. 2013
General population (n=343 young women
approximately 20 years of age)

Lind et al. 2017a
General population (n=649 pregnant women)
Toft et al. 2016

Serum perfluoroalkyl level Outcome evaluatedResultc

Cord insulin-like factor 3
Cord inhibin
Males
Females
21.1 ng/mL (maternal median Age of menarche
PFOS)
Menstrual cycle length
Total testosterone
SHBG
Free androgen index
Dehydroepiandrosterone
sulphate
Anti-Müllerian hormone
Number of follicles/ovary
8.1 ng/mL (median maternal Anogenital distanceserum PFOS)

NS (p>0.05)>1.4 ng/mL (amniotic fluid
3rd tertile PFOS)

Cryptorchidism

OR 1.01 (0.66–1.53), 3rd tertile

Hypospadias
Testosterone
Androstenedione
Progesterone
Cortisol
DHEAS

OR 0.69 (0.35–1.38), 3rd tertile
Association (p=0.002)*
Association (p=0.001)*
Association (p=0.001)*
Association (p<0.001)*
NS (p=0.93)

Insulin-like factor 3
Cryptorchidism

Inverse association (p<0.001)*
OR 0.83 (0.44–1.58), whole cohort

General population (270 cases cryptorchidism,
75 cases hypospadias, and 300 controls)

Vesterholm Jensen et al. 2014
General population (n=107 cases
cryptorchidism [29 from Denmark and 78 from
Finland] and 108 matched controls from
Denmark and Finland)

9.1 and 5.2 ng/mL (mediancord blood PFOS Denmarkand Finland cohorts)

Association (p<0.001)*
NS (p>0.05)
NS (p=0.28)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
β 0.5 (-1.2–2.2, p=0.55), boys
β -0.4(-3.8 to -0.7, p<0.01)*, girls

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Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa
Reference and study populationb
PFHxS
Lopez-Espinosa et al. 2016

Serum perfluoroalkyl level Outcome evaluatedResultc

8.1 and 7.0 ng/mL (PFHxS
median in boys and girls)

NS (interquartile difference of -1.3,
95% CI -5.5–3.1), boys
NS (2.1, 95% CI -2.2–6.5), girls
NS (-2.7, 95% CI -6.4–1.2), boys
NS (0.2, 95% CI -3.5–4.0), girls
NS (-2.5, 95% CI -5.2–0.3), boys
NS (-2.1, 95% CI -4.8–0.7), girls
OR 0.89 (0.65–1.22)

Community (C8) (n=1,169 boys and 1,123 girls
aged 6–9 years)

Estradiol

Total testosterone
Insulin-like growth factor-1

Christensen et al. 2011

1.6 ng/mL (maternal median
PFHxS)

Earlier age of menarche

0.3 ng/mL (median maternal
serum PFHxS)

Anogenital distanceNS (p=0.56), boys
NS (p=0.10), girls>1.9 ng/mL (maternal
3rd tertile PFHxS)

Testosterone

β 0.18 (0.00–0.35), 3rd tertile

SHBG

β 5.31 (-21.61–11.00), 3rd tertile

1.7 and 1.7 ng/mL (PFNA
median in boys and girls)

Estradiol

NS (interquartile difference of -2.5,
95% CI -6.2–1.4), boys
NS (-2.4, 95% CI -6.3–1.7), girls
NS (-2.1, 95% CI -5.5–1.3), boys
NS (-1.9, 95% CI -5.5–1.9), girls
Inverse association (-3.5, 95%
CI -6.0 to -1.0)*, boys
Inverse association (-3.8, 95%
CI -6.4 to -1.2)*, girls
β -0.5 (-2.1–1.1, p=0.63), boys
β -1.8 (-3.5 to -0.1, p=0.05)*, girls

General population (n=448 girls)
Lind et al. 2017a
General population (n=649 pregnant women)
Maisonet et al. 2015
General population (n=72 girls aged 15 years)
PFNA
Lopez-Espinosa et al. 2016
Community (C8) (n=1,169 boys and 1,123 girls
aged 6–9 years)

Total testosterone
Insulin-like growth factor-1

Lind et al. 2017a
General population (n=649 pregnant women)

0.7 ng/mL (median maternal
serum PFNA)

Anogenital distancePERFLUOROALKYLS

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Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa
Reference and study populationb

Serum perfluoroalkyl level Outcome evaluatedResultc

Maisonet et al. 2015

>0.6 ng/mL (maternal
3rd tertile PFNA)

Testosterone
SHBG

β 0.05 (-0.14–0.24), 3rd tertile
β 7.91 (-8.69–24.52), 3rd tertile

0.3 ng/mL (median maternal
serum PFDA)

Anogenital distance

β -0.6 (-2.0–0.9, p=0.97), boys
β -1.3 (-2.8–0.2, p=0.04)*, girls

0.2 ng/mL (maternal median
FOSA)

Earlier age of menarche

OR 0.91 (0.67–1.24)

General population (n=72 girls aged 15 years)
PFDA
Lind et al. 2017a
General population (n=649 pregnant women)
FOSA
Christensen et al. 2011
General population (n=448 girls)

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 13 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

CI = confidence interval; DHEAS = dihydroepiandrosterone sulfate; FOSA = perfluorooctane sulfonamide; FSH = follicle stimulating hormone; LH = luteinizing
hormone; NS = not significant; OR = odds ratio; PFDA = perfluorodecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; SHBG = sex hormone binding globulin

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alterations in birth weight were found for other perfluoroalkyls (PFHxS, PFNA, PFDA, PFUnA,
PFDoDA). Overall, no associations were found between serum PFOA, PFOS, PFHxS, PFNA, or PFUnA
and increases in the risk of low birth weight or small for gestational age infants. The small number ofstudies (2 or less) examining potential developmental effects of PFHpA, PFBA, and FOSA do not allow
for assessing possible associations with pregnancy outcomes or birth outcomes.

No consistent results for risks of birth defects have been found; these potential endpoints were only
examined for a few perfluoroalkyls. The available epidemiological data do not suggest associations
between perfluoroalkyls and IQ or scholastic achievement for PFOA, PFOS, PFHxS, PFNA, PFDA,PFUnA, or PFDoDA. Similarly, no associations were found between PFOA, PFOS, PFHxS, PFNA, or
PFDA and increased risk of ADHD; several studies found decreased risk of ADHD. Inconsistent results
have been found between PFOA and PFOS and delays in puberty or age of puberty, especially in girls.

Summaries of laboratory animal studies are presented in Tables 2-1, 2-3, 2-4, and 2-5 and the NOAEL
and LOAEL values are presented in Figures 2-6, 2-8, 2-9, and 2-10; no data were available for PFHpA or
FOSA. Laboratory animal studies provide strong evidence of the developmental toxicity of a number ofperfluoroalkyls. Prenatal losses and decreases in pup survival were observed following exposure to
PFOA, PFOS, PFNA, PFDA, PFDoDA and PFHxA; no deaths were observed in a single study of PFBS.
Decreases in fetal weights, birth weight, and pup weight were observed in studies of PFOA, PFOS,
PFNA, PFDA, PFUnA, PFBS, and PFHxA; no effects on weight were observed in studies on PFHxS or
PFDoDA. In PFOA studies, delays in mammary gland development were observed at fairly low doses.
Several studies have demonstrated biphasic alterations in motor activity in rodents exposed to PFOA,PFOS, and PFHxS; no effects on locomotor activity were observed in a study of PFDA. Studies inlaboratory animals have examined a number of developmental endpoints, including pup survival,
malformations, birth weight, mammary gland development, and neurodevelopment.
PFOA

Epidemiological Studies—Pregnancy Outcomes. The results of available epidemiological studies ofwomen living near a PFOA facility and the general population do not suggest an association between
serum PFOA levels and adverse pregnancy outcomes. No increases in risk of miscarriage (Darrow et al.
2014; Jensen et al. 2015; Savitz et al. 2012b; Stein et al. 2009), stillbirths (Savitz et al. 2012b), pregnancy
loss (Buck Louis et al. 2016), or pre-term birth (Chen et al. 2012a; Darrow et al. 2013; Hamm et al. 2010;
Manzano-Salgado et al. 2017a; Sagiv et al. 2018; Stein et al. 2009; Whitworth et al. 2012a) were found.

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The Whitworth et al. (2012a) general population study reported a decrease in the risk of preterm births
among women with serum PFOA levels in the 4th quartile. Most studies did not find an association
between maternal PFOA levels and gestational age (Apelberg et al. 2007b; Chen et al. 2012a; Lauritzen etal. 2017; Li et al. 2017; Manzano-Salgado et al. 2017a) or gestational length (Lind et al. 2017; Sagiv et al.
2018). The exception is a study by Wu et al. (2012) of pregnant women with higher serum PFOA levels
which found an inverse association between maternal serum PFOA levels and gestational age.

Epidemiological Studies—Birth Outcomes. Community and general population exposure studies haveevaluated a number of birth outcomes including birth weight; risk of low birth weight; risk of small for
gestational age; birth length; head, chest, and abdominal circumferences; ponderal index; sex ratio; andbirth defects. In highly exposed populations, no association between maternal serum PFOA levels andbirth weight were found (Darrow et al. 2013; Nolan et al. 2009; Savitz et al. 2012b). Several general
population studies have found associations between maternal serum PFOA and birth weight. Fei et al.
(2007, 2008a), Lauritzen et al. (2017), Lenters et al. (2016a), Maisonet et al. (2012), Minatoya et al.
(2017), Starling et al. (2017), and Wu et al. (2012) found inverse associations between maternal serum
PFOA and birth weight. However, 23 other general population studies did not find associations(Alkhalawi et al. 2016; Ashley-Martin et al. 2017; Bach et al. 2016; Callan et al. 2016; Cao et al. 2018;
Chen et al. 2012a; Govarts et al. 2016; Hamm et al. 2010; Kim et al. 2011; Kobayashi et al. 2017;
Lauritzen et al. 2017; Lee et al. 2013, 2016; Li et al. 2017; Lind et al. 2017; Manzano-Salgado et al.
2017a; Monroy et al. 2008; Robledo et al. 2015a; Sagiv et al. 2018; Shi et al. 2017; Wang et al. 2016;
Washino et al. 2009; Whitworth et al. 2012a). As illustrated in Figure 2-35, most studies found noassociation between maternal serum PFOA levels and the risk of low birth weight infants (typicallydefined as <2,500 g) (Chen et al. 2012a; Darrow et al. 2013; Fei et al. 2007, 2008a; Manzano-Salgado etal. 2017a; Savitz et al. 2012b; Stein et al. 2009) or found a decreased risk of low birth weight infants(Nolan et al. 2009; Savitz et al. 2012a). Similarly, most studies found no increases in the risk for small
for gestational age (Chen et al. 2012a; Fei et al. 2007, 2008a; Hamm et al. 2010; Lauritzen et al. 2017;
Manzano-Salgado et al. 2017a; Savitz et al. 2012b; Wang et al. 2016; Whitworth et al. 2012a); these data
are presented in Figure 2-36. One study (Savitz et al. 2012b) of C8 participants did find an increase in therisk of small for gestational age; however, when the maternal serum PFOA levels were categorized into
percentiles, the risk was not increased in infants whose maternal serum PFOA levels were ≥80th percentile(21.0–717.6 ng/mL). A general population study (Lauritzen et al. 2017) also found an increased risk of
small for gestational age (Lauritzen et al. 2017). Using data compiled from four European birth cohort
studies in which cord serum PFOA was measured or estimated from breast milk levels, Govarts et al.
(2018) did not find an association between cord PFOA and the risk of small for gestational age.

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Figure 2-35. Risk of Low Birth Weight Infant Relative to PFOA Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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2. HEALTH EFFECTS

Figure 2-36. Risk of Small for Gestational Age Infant Relative to PFOA Levels (Presented as Adjusted Odds
Ratios)PERFLUOROALKYLS

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However, among women who smoked during pregnancy, cord serum PFOA was associated with anincreased risk of small for gestational age infants (OR 2.177, 95% CI 1.022–4.643); no association was
found among nonsmoking women (OR 0.511, 95% CI 0.869–2.632). Six general population studies
found inverse associations between maternal serum PFOA levels and birth length, abdominal
circumference, and/or ponderal index (ratio of birth weight to birth length) (Alkhalawi et al. 2016;
Apelberg et al. 2007b; Cao et al. 2018; Fei et al. 2007, 2008a; Lauritzen et al. 2017; Wu et al. 2012).
However, most studies did not find associations between maternal serum PFOA levels and birth length;
head, chest, or abdominal circumference; or ponderal index (Alkhalawi et al. 2016; Bach et al. 2016;
Callan et al. 2016; Cao et al. 2018; Chen et al. 2012a; Kobayashi et al. 2017; Lauritzen et al. 2017; Lee etal. 2013; Maisonet et al. 2012; Manzano-Salgado et al. 2017a; Minatoya et al. 2017; Robledo et al. 2015a;
Shi et al. 2017; Wang et al. 2016). Studies examining newborn leptin and adiponectin levels (AshleyMartin et al. 2017; Minatoya et al. 2017) and adiposity (Starling et al. 2017) have not found associations
with maternal PFOA levels.

In a systematic review of 19 epidemiological studies discussed above, Johnson et al. (2014) evaluated thepossible association between PFOA exposure and fetal growth and concluded that there was sufficientevidence that PFOA reduces fetal growth based on a moderate rating of the human evidence. A metaanalysis of the Apelberg et al. (2007b), Chen et al. (2012a), Fei et al. (2007, 2008a), Fromme et al.
(2010), Hamm et al. (2009), Kim et al. (2011), Maisonet et al. (2012), Washino et al. (2009), andWhitworth et al. (2012) studies showed an association between PFOA and birth weight; a 1 ng/mL
increase in serum or plasma PFOA was associated with a -18.9 g (95% CI -29.8 to -7.9) change in birthweight. The results of this meta-analysis are also reported in Lam et al. (2014). Johnson et al. (2014) and
Lam et al. (2014) discuss whether glomerular filtration rate was a possible confounder in evaluating theassociation between serum PFOA and birth weight. They concluded that there was insufficient evidenceof an association between glomerular filtration rate and birth weight.

A second meta-analysis (Verner et al. 2015) of the Apelberg et al. (2007b), Chen et al. (2012a), Fei et al.
(2007), Hamm et al. (2010), Maisonet et al. (2012), Washino et al. (2009), and Whitworth et al. (2012a)
studies found a similar result, a 1 ng/mL increase in PFOA levels was associated with a 14.72 g(95% CI -21.66 to -7.78) decrease in birth weight. Verner et al. (2015) also utilized a PBPK model tosimulate maternal PFOA levels at delivery and evaluate the influence of glomerular filtration rate on theassociation between maternal PFOA and birth weight. In contrast to the conclusions of Johnson et al.
(2014) and Lam et al. (2014), Verner et al. (2015) found that a 1 ng/mL increase in PFOA was associatedPERFLUOROALKYLS

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2. HEALTH EFFECTS

with a 7.13 g (95% CI -8.46 to -5.80) decrease in birth weight; suggesting that glomerular filtration rate
may be a confounding factor.

A third meta-analysis conducted by Negri et al. (2017) of the Apelberg et al. (2007b), Bach et al. (2016),
Chen et al. (2012a), Darrow et al. (2013), Fei et al. (2007), Fromme et al. (2010), Hamm et al. 2009), Kim
et al. (2011), Maisonet et al. (2012), Monroy et al. (2008), Washino et al. (2009), and Whitworth et al.
(2012a) studies reported a -12.80 g (95% CI -23.21 to -2.38) change in birth weight associated with a
1 ng/mL increase in serum PFOA.

A fourth meta-analysis conducted by Steenland et al. (2018) included 24 studies; 11 of the 12 studies
included by Negri et al. (2017) (the Monroy et al. 2008 study was excluded) plus studies by Wu et al.
(2012), Robledo et al. (2015a), Callan et al. (2016), Lee et al. (2016), Wang et al. (2016), Lenters et al.
(2016a); Minatoya et al. (2017), Shi et al. (2017), Li et al. (2017), Manzano-Selgado et al. (2017);
Starling et al. (2017), and Sagiv et al. (2018). The study found a that a 1 ng/mL increase in serum PFOA
was associated with a -10.5 g (95% CI -16.7 to -4.4) change in birth weight. In sensitivity analysis,
inclusion of the Savitz et al. (2012b) study, which used predicted maternal serum concentrations based on
estimated environmental exposure, resulted in a birth weight change of -1.0 g (95% CI -2.4–0.4) per
1 ng/mL increase in serum PFOA. Categorizing studies based on when maternal serum PFOA levels
were sampled resulted in differences in birth weight change; -3.3 g (95% CI -9.6–3.0) when sampled
early in pregnancy or shortly after conception and -17.8 g (-25.0 to -10.6) when sampled late inpregnancy. The investigators suggested that this may be indicative of reverse causality or confounding.

A small number of studies have examined the potential associations between PFOA exposure and risks ofbirth defects. In a study of C8 Health Study participants, no increases in the risk of brain, gastrointestinal,
kidney, craniofacial, eye, limb, genitourinary, or heart defects were found (Stein et al. 2014c).

Epidemiological Studies—Neurodevelopmental Outcomes. A number of epidemiological studies haveevaluated neurodevelopment at various ages using maternal serum PFOA or cord blood PFOA as abiometric of exposure. Fei et al. (2008b) did not find an increased risk of Apgar scores of <10 innewborns. Another study found an inverse association between maternal serum PFOA and the 5-minute
Apgar score (Wu et al. 2012). Utilizing the Neonatal Intensive Care Unit Network Neurobehavioral Scale(NNNS) in 5-week-old infants, Donauer et al. (2015) found an increased risk of reduced muscle tone
(hypotonia), which was associated with maternal serum PFOA levels, but found no associations on testsof social/easy going or high arousal/difficult. Goudarzi et al. (2016b) reported lower scores on tests of

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mental and psychomotor development in female 6-month-old infants; no association was found whenmale and female infants were grouped together. When the infants were tested at 18 months of age, noassociation between maternal PFOA levels and mental and psychomotor indices were found. Fei et al.
(2008b) did not find associations between maternal PFOA levels and the risk of delays in motor,
cognitive, or language development in 6- and 18-month-old infants. It is noted that in the Fei et al.
(2008b) study, the mothers were asked to recall at what age the infants reached a developmental
milestone, whereas standardized tests of development were used in the other two studies. Although the
Donauer et al. (2015) and Goudarzi et al. (2016b) studies suggest some delays in neurodevelopment inyoung infants, more research is needed before establishing a possible relationship with PFOA.

Studies in children have examined possible associations between PFOA and IQ, motor skills, behavior,
and ADHD. An association between estimated in utero PFOA levels and IQ was found in 6–12-year-old
children participating in the C8 Health Studies (Stein et al. 2013); higher IQ scores were found in children
with the highest estimated PFOA exposure levels. The study did not find an association with reading ormath skills. A general population study (Wang et al. 2015b) did not find an association between maternal
serum PFOA levels and IQ scores in children 5 or 8 years of age. Jeddy et al. (2017) did not find an
association between maternal PFOA levels and early communication development in 15-month-olds;
among 38-month-olds, an inverse association was found for intelligibility scores, but there were no
associations with other scores of communication development. In a prospective study, maternal PFOA
levels were not associated with reading scores in 5- or 8-year-old children (Zhang et al. 2018). Readingscores at age 5 years were associated with serum PFOA levels when the children were 3 years of age andserum PFOA levels in 5-year-olds were not associated with reading scores at 8 years of age (Zhang et al.
2018). In a study of adults (20 years of age), Strøm et al. (2014) did not find an association between
maternal PFOA levels and scholastic achievement. A community study of children and adolescents did
not find an association between serum PFOA levels and learning problems in 12–15- or 5–18-year-olds(Stein and Savitz 2011). Two studies (Fei and Olsen 2011; Høyer et al. 2015a) did not find associations
between maternal PFOA levels and motor coordination in 7-year-old children or motor skills in 5–9-yearold children.

Several studies have examined possible associations between maternal or child PFOA levels and scoreson tests/surveys that assess behavioral problems. No associations were found between maternal PFOA
levels and behavioral problems in 7-year-old children (Fei and Olsen 2011) or behavioral regulation
problems in 5- or 8-year-old children (Vuong et al. 2016) or 7-year-old children (Oulhote et al. 2016).
Similarly, no associations between serum PFOA levels and scores on behavioral tests were observed in 7-

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year-old children (Oulhote et al. 2016) or 9–11-year-old children (Gump et al. 2011). No associations
between breast milk PFOA levels and behavioral development in 6- and 24-month-old infants wereobserved (Forns et al. 2015). In contrast, Høyer et al. (2015a) found an association between maternal
PFOA levels and behavioral problems in 5–9-year-old children; the risk was increased in children withmaternal PFOA levels in the 3rd tertile. Stein et al. (2014a) found an association between the children’s
serum PFOA levels and survey results on behavioral problems and emotional disturbances in girls aged
6–12 years of age; this association was not found in boys or in boys and girls combined. Additionally, theassociation was only found when the survey was completed by mothers, but not when completed by thechild’s teacher. Oulhote et al. (2016) found associations between serum PFOA in 5-year-old children andbehavioral survey scores, particularly for internalizing problems, peer relationships, and autism screening
scores. In a study of 8-year-old children, Vuong et al. (2018) found an association between PFOA and at
risk metacognition scores, but no associations with at risk behavior regulation or global executive scores.

Ten studies have looked for a possible association between PFOA and ADHD in children. Two studies ofparticipants of the C8 Health Study found lower scores on tests for ADHD (Stein et al. 2013) or lower
risks of ADHD (Stein and Savitz 2011) associated with estimated in utero PFOA or child PFOA levels,
respectively. In a third community study in which parents and teachers completed surveys regarding
ADHD-like behaviors (Stein et al. 2014a), no association between the child’s serum PFOA (measured 3–
4 years before the surveys were completed) and ADHD-like behaviors were found when the mothers
completed the survey and an inverse association was found when the teachers completed the survey.
Segregating the children by sex resulted in an association in girls (mother-completed survey only) and noassociations in boys. Two general population studies have found associations between the risk of ADHD
or increases in ADHD behavior in children. An increase in the risk of parent-reported ADHD diagnosis
was observed in a study of 12–15-year-old NHANES participants (Hoffman et al. 2010). The second
study (Høyer et al. 2015a) found increases in hyperactivity among 5–9-year-old children with maternal
serum PFOA levels in the 3rd tertile. When this multinational cohort was segregated by country, theassociation was only found in the group of children from Greenland, but not in the Ukrainian cohort.
Median serum PFOA levels were slightly higher in the Greenland cohort; it is also noted that the medianmaternal PFOS levels were 4 times higher in the Greenland cohort than in the Ukraine cohort. Other
general population studies have not found associations. Two case-control studies of children did not findincreased risks of being diagnosed with ADHD associated with maternal PFOA levels (Liew et al. 2015)
or cord blood PFOA levels (Ode et al. 2014). Two studies did not find associations between cord blood
PFOA levels and performance on tests evaluating for ADHD symptoms in 7-year-old children (Lien et al.
2016) or 18-month-old infants (Quaak et al. 2016). A third study found no association between maternalPERFLUOROALKYLS

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2. HEALTH EFFECTSPFOA levels and ADHD in 20-year-olds (Strøm et al. 2014). In addition to looking at possible
relationships between PFOA and ADHD, two studies did not find associations between maternal PFOA
levels and autism behaviors (Braun et al. 2014) or the risk of autism diagnosis (Liew et al. 2015).

Epidemiological Studies—Development of the Reproductive System. Studies exploring possible
associations between PFOA and alterations in the development of the reproductive system have examinedseveral outcomes including hormone levels in cord blood, hormone levels in children and adolescents,
anogenital distance, congenital malformations of reproductive organs, and age of puberty in boys andgirls.

A multinational case-control general population study (Vesterholm Jensen et al. 2014) found a decrease in
the risk of cryptorchidism in the Finnish cohort, but not in the Danish cohort or in the combined cohort.
With the exception of inhibin levels, no associations between maternal serum PFOA levels and cord
blood levels of reproductive hormones were found (Itoh et al. 2016). Cord inhibin was associated withmaternal serum PFOA levels in male infants, but not in female infants (Itoh et al. 2016). Some alterations
in reproductive hormone levels were found in 6–9-year-old boys and girls participating in the C8 HealthStudy (Lopez-Espinosa et al. 2016). In boys, an inverse association between serum PFOA levels and total
testosterone levels were observed; no associations were found for estradiol levels or insulin-like growth
factor 1. In girls, an inverse association was found for insulin-like growth factor 1 levels and noassociations were found for estradiol or testosterone levels. In adolescent girls, an association between
maternal PFOA levels and testosterone levels was found (Maisonet et al. 2015a). This association was
not found in young adult females (Kristensen et al. 2013). Other reproductive hormones were not shown
to be associated with maternal PFOA levels (Kristensen et al. 2013; Maisonet et al. 2015a). Lind et al.
(2017a) found no association between maternal PFOA levels and anogenital distance in boys or girls.

In a community exposure study (Lopez-Espinosa et al. 2011), increasing levels of serum PFOA wereassociated with delays in menarche in girls aged 8–18 years. Serum PFOA levels in the 2nd, 3rd, and4th quartiles were associated with 142-, 163-, and 130-day delays in the onset of menarche, respectively.
Using PBPK modeling, Wu et al. (2015) examined whether the association between serum PFOA anddelays in the onset of menarche observed in the Lopez-Espinosa et al. (2011) study were due to reverse
causality using a Monte Carlo PBPK model. They found that rapid growth around the time of
menstruation onset may contribute to the apparent association between PFOA and delay of menarche. In
the PBPK simulated study, the delay in the onset of menarche was 48 days for the 4th quartile (OR 0.82,
95% CI 0.76–0.88). A delay in menarche was also observed in a general population study; a 162-day

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delay was estimated in the daughters of women with maternal serum PFOA levels in the 3rd tertile(Kristensen et al. 2013). A second general population study did not find an association between maternal
serum PFOA levels and an earlier age of menarche (Christensen et al. 2011).

The only study available on age of puberty in males (Lopez-Espinosa et al. 2011) did not find an
association with serum PFOA levels.
Laboratory Animal Exposure Studies. Exposure of pregnant Sprague-Dawley rats to 25 mg/m3 APFO
on GDs 6–15 resulted in a statistically significant reduction (10.3%) in neonatal body weight on PND 1,
but the difference over controls was no longer significant on PND 4 (Staples et al. 1984). Exposure
concentrations ≤10 mg/m3 did not affect neonatal body weight. The incidence of malformations andvariations among the exposed groups and controls was comparable.

In utero exposure to PFOA resulted in prenatal losses and decreases in pup survival. An increase inresorbed embryos were observed in mice administered 10 mg/kg on GD 13 (Chen et al. 2017b). An
increase in resorptions was observed in mice administered ≥5 mg/kg/day throughout gestation (Lau et al.
2006) or 2 mg/kg/day on GDs 11–16 (Suh et al. 2011). Prenatal losses were also observed in PFOA
mouse studies administering ≥6 mg/kg/day (Abbott et al. 2007), 5 mg/kg/day (White et al. 2011), or
20 mg/kg/day (Lau et al. 2006) throughout gestation; an increase in the percentage of dams with total
litter loss was also observed at 5 mg/kg/day (Wolf et al. 2007). Administration of 20 mg/kg/day PFOA
on GDs 7–17 or 10–17 did not result in litter loss (Wolf et al. 2007); no effect on litter size was observed
as a result of administration of 5 mg/kg/day on GDs 8–17 (White et al. 2009). Gestational exposure(GDs 1–17) to PFOA also resulted in perinatal losses in mice administered 3 mg/kg/day PFOA (Ngo et al.
2014) and decreases in pup survival in mice exposed to ≥0.6 mg/kg/day (Abbott et al. 2007), 3 mg/kg/day(Albrecht et al. 2013), or 5 mg/kg/day (Lau et al. 2006; Yahia et al. 2010; White et al. 2011, Wolf et al.
2007); 100% pup mortality was observed in the offspring of mice exposed to 10 mg/kg/day throughout
gestation (Yahia et al. 2010). Decreased pup survival was also observed in mice exposed to 5 mg/kg/day
PFOA on GDs 15–17 (Wolf et al. 2007). No alterations in fetuses/litter or survival were observed at 1
mg/kg/day PFOA (Lau et al. 2006; White et al. 2011). Butenhoff et al. (2004b) also reported increases inpup mortality on PNDs 6–8 in the offspring of rats administered 30 mg/kg/day PFOA throughout
gestation and during lactation.

Decreases in birth weight have not been consistently found in mouse studies with PFOA. No significant
alterations in birth weight were observed in mice exposed to 3 mg/kg/day (Albrecht et al. 2013), 5 or

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10 mg/kg/day (Lau et al. 2006), or 20 mg/kg/day (Abbott et al. 2007); decreases in birth or fetal weight
were observed at 5 mg/kg/day (Hines et al. 2009; Yahia et al. 2010), 10 mg/kg/day (Suh et al. 2011), and20 mg/kg/day (Lau et al. 2006). A decrease in mean litter weight on PNDs 2–14 was observed in miceadministered ≥0.5 mg/kg/day PFOA on GDs 6–17 (Hu et al. 2010) and a decrease in pup body weight on
PND 20 was observed in mice exposed to 5 mg/kg/day on GDs 8–17 or 12–17 (White et al. 2007). In
utero exposure of mice to PFOA throughout gestation resulted in decreases in pup body weight in mice
exposed to 1 mg/kg/day (Abbott et al. 2007; Hines et al. 2009), ≥3 mg/kg/day (Lau et al. 2006; Wolf et al.
2007), and 5 mg/kg/day (Yahia et al. 2010; White et al. 2007, 2011). In a cross-fostering study, lactationonly exposure (maternal dose of 5 mg/kg/day PFOA) resulted in decreased body weight in female pups onsome PNDs (2, 3, 4, and 22, but not on PNDs 7, 10, 15, or 17) (Wolf et al. 2007). Hines et al. (2009)
monitored body weights from birth to 18 months of age in female mice exposed in utero to PFOA on
GDs 1–17. At weaning, decreases in body weight were observed at 1 and 5 mg/kg/day; by 10 weeks ofage, there were no differences in body weight between the controls and mice exposed to ≥1 mg/kg/day.
Significant increases in body weight were observed in mice exposed to 0.1 and 0.3 mg/kg/day, and by
20–29 weeks of age, the increases in body weight were observed in mice exposed to 0.01, 0.1, or
0.3 mg/kg/day. The largest increase in body weight gain (9.6%) was observed at 0.1 mg/kg/day; because
the weight increase was less than 10%, the 0.1 mg/kg/day was considered a NOAEL. At 40 weeks of age,the increased body weight was observed in the 0.1 and 0.3 mg/kg/day groups. At termination (18 monthsof age), there were no differences in body weight between the controls and mice exposed to 0.01–
3 mg/kg/day; a decrease in body weight was observed at 5 mg/kg/day. During the period of increased
body weight in the lower-dose animals, there were no changes in serum glucose levels or the response toa glucose challenge, but there were significant increases in insulin and leptin levels at 0.01 and
0.1 mg/kg/day. Although there were no changes in the percentage of body fat to body weightmeasurements in mice at 42 weeks of age, at 18 months of age, significant decreases in abdominal body
fat and increases in intrascapular brown fat was observed at ≥1 mg/kg/day PFOA (Hines et al. 2009).
Based on systematic review of pup body weight data from the Abbott et al. (2007), Hines et al. (2009),
Lau et al. (2006), White et al. (2007, 2009, 2011), and Wolf et al. (2007) mouse studies, Koustas et al.
(2014) concluded that there was sufficient evidence that exposure to PFOA adversely affected fetal
growth in animals. A meta-analysis estimate was a decrease of 0.023 g pup body weight per 1 mg/kg/day
increase in PFOA dose.

A few studies have examined the potential of PFOA to induce malformations/variations. Lau et al. (2006)
reported reductions in ossification of the proximal phalanges at ≥1 mg/kg/day and supraoccipital at 10 or
20 mg/kg/day. This study also reported enlarged fontanels in pups exposed to ≥1 mg/kg/day and tail andPERFLUOROALKYLS

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limb defects at ≥5 mg/kg/day; however, there was no clear dose-response for these effects. Koskela et al.
(2016) found altered femur and tibial bone morphology and decreased tibial mineral density in theoffspring of mice exposed to 0.3 mg/kg/day in the diet on GDs 1–21. An increased percentage of litterswith microcardia was also observed in the offspring of mice exposed to 10 or 20 mg/kg/day (Lau et al.
2006). No increases in the occurrence of malformations/variations were observed in the offspring of rats
administered 100 mg/kg/day on GDs 6–15 (Staples et al. 1984) or in a 2-generation study at doses as highas 30 mg/kg/day (Butenhoff et al. 2004b).
Delayed eye opening was observed in the offspring of mice administered ≥1 mg/kg/day PFOA on GDs 1–
17 (Abbott et al. 2007) and in mice administered 5 mg/kg/day throughout gestation (Lau et al. 2006; Wolfet al. 2007). Neither Albrecht et al. (2013) nor Lau et al. (2006) found alterations in eye opening in mice
exposed to 3 mg/kg/day PFOA on GDs 1–17. Lau et al. (2006) also reported advanced (earlier thancontrols) preputial separation at ≥1 mg/kg/day and delayed vaginal opening at 20 mg/kg/day. The effectin the male offspring is in contrast to the Butenhoff et al. (2004b) study, which found delays in preputial
separation in rats exposed to 30 mg/kg/day PFOA; a delay in vaginal patency was also observed at thisdose.

A series of studies conducted by White and associates found significant delays in mammary glanddevelopment in the offspring of mice administered 1 mg/kg/day PFOA via gavage on GDs 8–17 (White etal. 2011) or 5 mg/kg/day PFOA on GDs 1–17, 8–17, 12–17, 10–17, 13–17, or 15–17 (White et al. 2007,2009, 2011). The delay was characterized as reduced ductal elongation and branching and delays intiming and density of terminal end buds and was observed at all observational periods (PNDs 10, 20, 22,
and 42, and 63 and 18 months of age). Decreases in mammary epithelial growth, as assessed bydevelopmental scoring, were observed in the offspring of mice exposed to 0.01 mg/kg/day on GDs 1–17
(Tucker et al. 2015), 0.3 mg/kg/day on GDs 1–17 (Macon et al. 2011), or 0.01 mg/kg/day on GDs 10–17(Macon et al. 2011). Tucker et al. (2015) noted that the delays in mammary gland development began at
puberty and continued during young adulthood. Albrecht et al. (2013) did not find any alterations inmammary gland development on PND 20 in mouse offspring following in utero exposure to PFOA on
GDs 1–17. Delayed mammary gland development was also observed in offspring only exposed via
lactation (maternal dose of 3 mg/kg/day PFOA on GDs 1–17); the effects were observed on PNDs 42 and63, but not on PND 22 (White et al. 2009). In a multigeneration study conducted by White et al. (2011),
delays in mammary gland development were not consistently observed in the F2 offspring of F1 females
that were exposed in utero to 1 or 5 mg/kg/day PFOA. However, delays in mammary gland development
were observed in the F1 and F2 offspring exposed to 0.001 mg/kg/day in utero (GDs 7–17) andPERFLUOROALKYLS

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postnatally. The investigators (White et al. 2011) noted that the delay in mammary gland development
did not appear to affect lactational support based on normal survival and growth of the F2 pups. Tucker
et al. (2015) noted dose-related strain differences on the effect of PFOA on mammary gland differences;
effects were observed in CD-1 mice at ≥0.01 mg/kg/day and in C57BL/6 mice at ≥0.3 mg/kg/day (thehighest NOAEL for this strain was 0.1 mg/kg/day); it is noted that the serum PFOA concentrations at agiven dose were lower in the C57Bl/6 mice than in the CD-1 mice. Yang et al. (2009) reported strain
differences in mammary gland effects in peripubertal mice administered PFOA for 4 weeks beginning on
PND 21. In BALB/c mice, reductions in ductal length and decreased numbers of terminal end buds andstimulated terminal ducts were observed at 5 and 10 mg/kg. In contrast, 5 mg/kg resulted in mammary
gland growth stimulation in C57BL/6 mice, as evidenced by increased number of terminal end buds withno alterations in ductal length. Mammary gland inhibition was observed in the C57BL/6 miceadministered 10 mg/kg. Stimulation of mammary gland growth was also observed in PPARα knockout
mice similarly administered 5 mg/kg (Zhao et al. 2010). In a series of experiments to evaluate themechanism of PFOA-induced alterations in mammary gland development, Zhao et al. (2010) found thatPFOA did not result in alterations in ovariectomized C57BL/6 mice administered 5 mg/kg 5 days/week
for 4 weeks. In ovary-intact mice, PFOA enhanced mammary gland responses to exogenous estradiol andprogesterone. Increased levels of epidermal growth factor receptor, hepatocyte growth factor, cyclin D1,
and proliferating cell nuclear antigen levels were also found in PFOA-exposed C57BL/6 and PPARαknockout mice (Zhao et al. 2010).

A consistent finding in the five mouse studies evaluating the neurodevelopmental toxicity of PFOA is anincrease in motor activity. Increases in horizontal and ambulatory locomotor activity (tested on PND 60)
were observed in the offspring of mice exposed to 0.1 mg/kg/day in the diet on GD 7 through PND 21(Sobolewski et al. 2014); a decrease in resting time was also observed in the males. Increased ambulatory
activity was observed on PND 18 in the offspring of mice administered 1 mg/kg/day on GDs 1–17
(Goulding et al. 2017). Significant increases in open field activity were observed at PND 36 in theoffspring of mice exposed to 1.6 mg/kg/day throughout gestation and lactation (Cheng et al. 2013).
Johansson et al. (2008) and Onishchenko et al. (2011) demonstrated a biphasic alteration in motor
activity: an initial period of decreased activity followed by increased activity. Johansson et al. (2008)
administered a single dose of 8.7 mg/kg/day PFOA to mice on PND 10 and monitored spontaneous
activity for a 1-hour period when the mice were 2 or 4 months of age. In the first 20-minute period, there
was a decrease in spontaneous activity, followed by a 20-minute period with an activity level similar tocontrols, and a 20-minute period with significantly increased spontaneous activity. Similarly,
Onishchenko et al. (2011) reported an increase in activity in a 48-hour period in the adult offspring of

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mice exposed to 0.3 mg/kg/day PFOA throughout gestation; however, there was a decrease in activity
during the initial 3 hours of testing. Johansson et al. (2008) also found an increased susceptibility of thecholinergic system in mice exposed to 0.58 or 8.7 mg/kg/day PFOA on PND 10. In control mice, an
injection of nicotine resulted in increases in activity; mice exposed to 0.58 mg/kg/day also responded withan increase in activity, although the increase was less than that observed in the controls. In contrast,
nicotine resulted in a decrease in activity in mice exposed to 8.7 mg/kg/day. Exposure to PFOA did notalter learning or memory, as evidenced by the lack of effect on maze tests (Cheng et al. 2013; Johansson
et al. 2008). Tests of neurobehavioral development found altered motor coordination and impaired
negative geotaxis reflex, but no effect on righting reflex or cliff avoidance, in the offspring of mice
exposed to 1.6 mg/kg/day throughout gestation and lactation (Cheng et al. 2013). Decreases in initialnovel object exploratory behavior were also observed at 0.1 mg/kg/day, but there were no alterations inrecognition time for novel objects (Sobolewski et al. 2014).

Support for the heart effects observed in the mouse study conducted by Lau et al. (2006) comes from aseries of studies in chicken embryos and hatchlings that demonstrate the developmental cardiotoxicity of
PFOA (Jiang et al. 2012, 2013, 2016). The avian model was selected due to the similarity between avian
and mammalian cardiovascular development and the lack of direct maternal influence (Jiang et al. 2012).
The effects following in ovo exposure include thinning of the right ventricular wall in chick embryos andalterations in left ventricular posterior wall dimension, volume, heart rate, stroke volume, and ejection
fraction in the hatchlings (Jiang et al. 2012). Tests with WY 14,643, a PPARα agonist, and PFOA
provide evidence that the cardiotoxicity involves both PPARα and bone morphorgenic protein 2 (BMP2)
pathways (Jiang et al. 2013). Comparisons of results following in ovo exposure and in vitro exposuresuggest that the cardiotoxicity was not likely due to cytotoxicity, but rather an alteration in early cardio
morphology and function processes (Jiang et al. 2016).

Summary. Epidemiological studies have examined a number of potential developmental outcomes incommunities living near a PFOA facility and in general populations. Although not consistently reported,
the available general population studies suggest an inverse association between maternal serum PFOA
levels and birth weight; a number of studies have not found this association. Several systematic reviewsof these data have concluded that there was sufficient evidence that maternal PFOA levels are associatedwith reductions in fetal growth. After correcting for glomerular filtration rate, a small decrease in birthweight was associated with increases in maternal serum PFOA. Two of the three studies evaluating
possible effects of sexual maturation found small delays in the start of menarche associated with maternal
serum PFOA levels. Overall, the data do not suggest associations between serum PFOA levels andPERFLUOROALKYLS

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adverse pregnancy outcomes such as miscarriages or stillbirths, most birth outcomes (e.g., risk of lowbirth weight, risk of small for gestational age, birth length, ponderal index, sex ratio, or birth defects), or
neurodevelopmental outcomes (IQ or scholastic achievement, motor skills, and risk of ADHD). Animalstudies provide strong evidence that developmental toxicity is a sensitive target of PFOA toxicity.
Observed effects include prenatal losses and decreases in pup survival, decreases in birth weight,
developmental delays such as delayed eye opening, delays in mammary gland development, andincreased motor activity.
PFOS

Epidemiological Studies—Pregnancy Outcomes. No associations between maternal PFOS levels andthe risk of miscarriages were observed in several studies (Darrow et al. 2014; Jensen et al. 2015; Stein etal. 2009). Three studies reported increases in the risk of preterm birth associated with maternal serum
PFOS levels in the >90th percentile (>23.2 ng/mL) (Stein et al. 2009), maternal serum levels in the 2nd, 3rd,or 4th quartiles (≥18.9 ng/mL) (Sagiv et al. 2018), or cord blood PFOS levels in the 3rd and 4th quartiles(≥5.68 ng/mL) (Chen et al. 2012a), and one study reported a decrease risk in preterm birth (Whitworth etal. 2012a). Three other studies did not find associations for preterm birth (Fei et al. 2007, 2008a; Hamm
et al. 2010; Manzano-Salgado et al. 2017a), one study found no association between serum PFOS andpregnancy loss (Buck Louis et al. 2016), and five studies found no associations between maternal PFOS
levels and gestational age or length (Lauritzen et al. 2017; Li et al. 2017; Lind et al. 2017a; ManzanoSalgado et al. 2017a).

Epidemiological Studies—Birth Outcomes. Occupational, community, and general population exposurestudies have examined the possible associations between maternal PFOS levels and a number of birthoutcomes including birth weight; risk of low birth weight; risk of small for gestational age; birth length;
head, chest, and abdominal circumferences; ponderal index; sex ratio; and birth defects. Most studies did
not find associations between maternal serum PFOS levels and birth weight (Alkhalawi et al. 2016;
Apelberg et al. 2007b; Ashley-Martin et al. 2016, 2017; Callan et al. 2016; Cao et al. 2018; Darrow et al.
2013; Bach et al. 2016; Fei et al. 2007, 2008a; Govarts et al. 2016; Hamm et al. 2010; Kim et al. 2011;
Kobayashi et al. 2017; Lauritzen et al. 2017; Lee et al. 2013, 2016; Lenters et al. 2016a; Lind et al. 2017a;
Maisonet et al. 2012; Manzano-Salgado et al. 2017a; Minatoya et al. 2017; Monroy et al. 2008; Robledo
et al. 2015a; Sagiv et al. 2018; Shi et al. 2017; Starling et al. 2017; Whitworth et al. 2012a), including an
occupational exposure study (Grice et al. 2007) in which female workers were exposed to very high levels
of PFOS (serum levels ranged from 1,300 to 1,970 ng/mL). Five studies did find inverse associations

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between birth weight and maternal serum PFOS levels. In the Washino et al. (2009) study, an inverse
association was found between maternal serum PFOS levels and birth weight; segregating by sex resulted
in an inverse association in girls, but not in boys. The magnitude of the change was small, 148.8 g
decrease in birth weight per log unit increase in maternal PFOS for combined. Maisonet et al. (2012) also
reported small decreases in birth weight (140.1 g) in infants whose mother’s serum PFOS levels were in
the 3rd tertile. Lauritzen et al. (2017) also reported an inverse association between birth weight andmaternal serum PFOS levels (292 g per ln unit increase in PFOS). Similarly, Chen et al. (2012a) reported
an inverse association between cord blood PFOS and birth weight, but the magnitude was small (110.2 g
decrease per ln unit increase in cord PFOS levels). Li et al. (2017) also reported a small decrease in birthweight associated with cord PFOS levels (95 g decrease per ln increase in cord PFOS levels); wheninfants were categorized by sex, the association was only found among boys. Although these studies
found decreases in birth weight associated with PFOS levels, no studies found increases in the risk of lowbirth weight infants (Chen et al. 2012a; Darrow et al. 2013; Fei et al. 2007, 2008a; Manzano-Salgado etal. 2017a; Stein et al. 2009) or small for gestational age infants (Chen et al. 2012a; Fei et al. 2007, 2008a;
Hamm et al. 2010; Lauritzen et al. 2017; Manzano-Salgado et al. 2017a; Whitworth et al. 2012a). The
ORs for low birth weight and small for gestational age risks are presented in Figures 2-37 and 2-38.
Analysis of data compiled from four European birth cohort studies found an inverse association between
cord PFOS levels (measured levels and levels estimated from breast milk PFOS levels) and small for
gestational age (OR 0.823, 95% CI 0.741–0.913) (Govarts et al. 2018). When subjects were segregatedbased on whether they smoked during pregnancy, a positive association was found among smokers (OR1.627, 95% CI 1.024–2.588) and an inverse association was found among nonsmokers (OR 0.661, 95%
CI 0.644–0.717). Three studies have evaluated leptin and adiponectin hormone levels or adiposity innewborns. Maternal PFOS levels were not associated with alterations in leptin levels (Ashley-Martin etal. 2017; Minatoya et al. 2017). Mixed results were found for adiponectin levels with one study finding
no alterations (Ashley-Martin et al. 2017) and another finding an association (Minatoya et al. 2017). No
association was found between maternal PFOS levels and adiposity at birth (Starling et al. 2017).

Verner et al. (2015) conducted a meta-analysis of the Apelberg et al. (2007b), Chen et al. (2012a), Fei etal. (2007), Hamm et al. (2010), Maisonet et al. (2012), Washino et al. (2009), and Whitworth et al.
(2012a) studies and found that a 1 ng/mL increase in maternal PFOS levels was associated with a 5.00 g(95% CI -8.92 to -1.09) decrease in birth weight. When the data were re-analyzed utilizing a PBPK
model to account for glomerular filtration rate, the magnitude of the effect of PFOS on birth weightdecreased (Verner et al. 2015). A 1 ng/mL increase in PFOS was associated with a 2.72 g (95%
CI -3.40 to -2.04) decrease in birth weight. A second meta-analysis conducted by Negir et al. (2017)

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Figure 2-37. Risk of Low Birth Weight Infant Relative to PFOS Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

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Figure 2-38. Risk of Small for Gestational Age Infant Relative to PFOS Levels (Presented as Adjusted Odds
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utilized data from the Fei et al. (2007), Monroy et al. (2008), Washino et al. (2009), Hamm et al. (2010),
Chen et al. (2012a), Maisonet et al. (2012), Whitworth et al. (2012a), and Bach et al. (2016) studies. The
investigators found a -0.92 g (95% CI -3.43–1.60) change in birth weight per 1 ng/mL increase in serum
PFOS.

Maternal PFOS was not associated with birth length (Alkhalawi et al. 2016; Apelberg et al. 2007b; Bachet al. 2016; Callan et al. 2016; Cao et al. 2018; Chen et al. 2012a; Kobayashi et al. 2017; Laurizten et al.
2017; Lee et al. 2013; Manzano-Salgado et al. 2017a; Robledo et al. 2015a; Shi et al. 2017; Washino et al.
2009) with the exception of the finding of small decreases in birth length (≤1.2 cm) that was associatedwith serum PFOS levels (Fei et al. 2007, 2008a; Lauritzen et al. 2017). Four studies reported inverse
associations between ponderal index and cord blood PFOS levels (Apelberg et al. 2007b) or maternal
serum PFOS levels (Alkhalawi et al. 2016; Lee et al. 2013; Minatoya et al. 2017); other studies did not
find this effect (Callan et al. 2016; Cao et al. 2018; Chen et al. 2012a; Maisonet et al. 2012; Robledo et al.
2015a; Shi et al. 2017). Two studies reported small decreases in head circumference, which wereassociated with maternal serum PFOS levels (Apelberg et al. 2007b) and cord blood PFOS (Chen et al.
2012a); other studies have not found associations (Bach et al. 2016; Callan et al. 2016; de Cock et al.
2014; Fei et al. 2007, 2008a; Lauritzen et al. 2017; Lee et al. 2013; Manzano-Salgado et al. 2017a;
Robledo et al. 2015a; Washino et al. 2009).

One study reported no increases in the risk of birth defects associated with maternal serum PFOS levels(Stein et al. 2009); a second study found an increased risk of congenital cerebral palsy in girls, but not inboys (Liew et al. 2014). Bae et al. (2015) did not find associations between the odds of having a boy andpaternal or maternal serum PFOS levels.

Epidemiological Studies—Neurodevelopmental Outcomes. Epidemiological studies examined several
aspects of neurodevelopment, including age of reaching neurobehavioral milestones, IQ, motor
development, behavior, ADHD, and autism. Fei et al. (2008b) did not find associations between maternal
PFOS levels and the risk of having an Apgar score of <10 or in motor and mental development at
6 months. However, the study did find that some neurobehavioral milestones (delay in sitting, early useof word-like sounds, and delays in using two-word sentences) were associated with maternal PFOS
levels. Goudarzi et al. (2016b) did not find alterations on mental and psychomotor development in 6- and18-month-old infants that were associated with maternal serum PFOS levels. A third study of infants did
not find alterations in neurobehavioral or muscle coordination tests (Donauer et al. 2015).

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In the only study evaluating IQ, Wang et al. (2015b) did not find associations between maternal PFOS
levels and IQ score in children 5 or 8 years of age. Zhang et al. (2018) did not find associations between
maternal PFOS levels and reading scores in 5- or 8-year-old children. However, associations were foundbetween the child’s serum PFOS levels at age 3 years and reading scores at 5 years of age and serum
PFOS levels at 5 years of age and reading scores at 8 years of age. Strøm et al. (2014) found noassociations between scholastic achievement in 20-year-olds and maternal PFOS levels. In a study ofchildren living in a community with high PFOA contamination, Stein and Savitz (2011) found decreases
in the risk of learning problems in children 5–18 or 12–15 years of age. In contrast, Vuong et al. (2016)
found increased risks of global executive functioning and metacognition problems that were associatedwith maternal PFOS levels. Another study found an association between maternal PFOS levels andverbal comprehension in 15-month-olds, but an inverse association with intelligibility scores in
38-month-olds (Jeddy et al. 2017). A subsequent study by Vuong et al. (2018) did not find associations
between serum PFOS levels in 8-year-old children and metacognition or global executive functioning
scores. Four studies have not found associations between maternal PFOS levels and behavioral healthand motor coordination/skills in children (Fei and Olsen 2011; Høyer et al. 2015a; Oulhote et al. 2016),
between breast milk PFOS levels and behavioral development in 6- and 24-month-old infants (Forns et al.
2015), or between serum PFOS levels age 5 or 7 years and behavioral development in 7-year-old children(Oulhote et al. 2016). A fifth study (Vuong et al. 2016) found an increased risk for problems withbehavioral regulation. The available data do not suggest an association between maternal PFOS levels or
cord blood PFOS levels and the risk of ADHD or ADHD behaviors (Hoffman et al. 2010; Liew et al.
2015; Ode et al. 2014; Quaak et al. 2016; Stein and Savitz 2011; Strøm et al. 2014), although Liew et al.
(2015) found a decreased risk of ADHD diagnosis in children whose mothers had serum PFOS levels in
the 4th quartile. Similarly, Høyer et al. (2015a) did not find increases in the risk of hyperactivity inchildren and Gump et al. (2011) found a decrease in impulsivity. Braun et al. (2014) and Liew et al.
(2015) did not find associations between maternal PFOS and autism risk.

Epidemiological Studies—Development of Reproductive System. Several epidemiological studies haveexamined the possible associations between PFOS and the development of the reproductive system,
including the risk of congenital defects to reproductive organs, alterations in reproductive hormone levels,and age of puberty; the results of these studies are summarized in Table 2-25. No alterations in the risk ofcryptorchidism (Toft et al. 2016; Vesterholm Jensen et al. 2014) or hypospadias (Toft et al. 2016) were
found in two studies. No association between maternal PFOS levels and anogenital distance was found inboys and an inverse association was found in girls (Lind et al. 2017a). Itoh et al. (2016) reported
associations between maternal PFOS levels and alterations in cord blood hormone levels, in particularPERFLUOROALKYLS

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estradiol in males, testosterone:estradiol ratio in males (inverse association), progesterone levels in males
and females, prolactin levels in females, and inhibin levels in males. Similarly, Toft et al. (2016) foundassociations between amniotic fluid PFOS levels and levels of testosterone, androstenedione,
progesterone, and insulin-like factor 3 (inverse association) in amniotic fluid. Lopez-Espinosa et al.
(2016) also found a number of alterations in reproductive hormone levels in 6–9-year-old boys and girls.
In the boys, inverse associations between serum PFOS levels and estradiol, total testosterone, and insulinlike growth factor 1 were observed. Inverse associations between total testosterone and insulin-likegrowth factor 1 and serum PFOS levels were also observed in the girls. A study of young adult womenfound no associations between reproductive hormone levels and maternal PFOS levels (Kristensen et al.
2013).

A study of 8–18-year-old children found delays in the age of puberty in boys and girls (Lopez-Espinosa et
al. 2011) that were associated with serum PFOS levels. In the children with serum PFOS levels in the
3rd and 4th quartiles, the respectively delays were 131 and 190 days in boys and 141 and 138 days in girls.
In contrast, two other studies have not found alterations in either the age of menarche or an earlier age ofmenarche that were associated with maternal PFOS levels (Christensen et al. 2011; Kristensen et al.
2013). The differences in the biomarker of exposure and the potential exposure to high levels of PFOA in
the Lopez-Espinosa et al. (2011) community study make it difficult to compare the results of these threestudies. As discussed in the PFOA section, Wu et al. (2009) reanalyzed the Lopez-Espinosa et al. (2011)
data using a Monte Carlo PBPK model, which accounted for rapid growth occurring around puberty, andfound much shorter delays in the age of menarche than found in the Lopez-Espinosa et al. (2011) study.
In the girls with simulated serum PPFOS levels in the 4th quartile, the delay was 72 days (OR 0.75, 95%
CI 0.70–0.81).

Laboratory Animal Exposure Studies. Increases in fetal mortality and decreases in pup survival havealso been observed in rats and mice exposed to PFOS in utero (Abbott et al. 2009; Chen et al. 2012b;
Fuentes et al. 2006; Grasty et al. 2003, 2005; Lau et al. 2003; Lee et al. 2015a; Luebker et al. 2005a,
2005b; Ngo et al. 2014; Thibodeaux et al. 2003; Xia et al. 2011; Yahia et al. 2008). Increases in thenumber of resorptions and dead fetuses were observed in mice administered ≥0.5 mg/kg/day (Lee et al.
2015a); increases in abortions between GD 22 and 28 were observed in rabbits treated with
3.75 mg/kg/day PFOS by gavage on GDs 6–20 (Case et al. 2001). Decreases in the number of live
fetuses were observed in mice exposed to ≥2.0 mg/kg/day on GDs 11–16 and 20 mg/kg/day on GDs 1–17
(Thibodeaux et al. 2003) or GDs 0–17 (Yahia et al. 2008). Increases in perinatal losses were observed in
the litters of mice administered ≥0.1 mg/kg/day PFOS on GDs 1–17 (Ngo et al. 2014). Pup survival isPERFLUOROALKYLS

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affected at lower maternal doses. Significant decreases in pup survival were observed in rats at
1.6 mg/kg/day (dams were exposed for 6 weeks prior to mating and during gestation through lactation
days 4 or 21) (Luebker et al. 2005a, 2005b) and in mice exposed to 4.5 mg/kg/day on GDs 15–18 (Abbott
et al. 2009); no alterations in pup survival were observed in rats or mice exposed to 1 mg/kg/day (Luebker
et al. 2005b; Yahia et al. 2008). A series of studies by Grasty et al. (2003) in rats that were exposed for
4 days during different gestational periods showed that the pup was more susceptible if exposure occurred
later in gestation. On PND 4, pup survival was 70, 50, 60, 20, or 5% for exposures on GDs 2–5, 6–9, 10–
13, 14–17, or 17–20, respectively. Grasty et al. (2003) and others (Abbott et al. 2009; Chen et al. 2012b;
Lau et al. 2003) also noted that most deaths occurred within the first 4 PNDs, with the highest rates
occurring on PND 1. Lau et al. (2003) and Luebker et al. (2005a) found that cross fostering did not
significantly improve pup survival; deaths were observed in the in utero only exposure group. However,
Luebker et al. (2005a) showed that rats exposed in utero and during lactation had the highest pup
mortality, as compared to other cross-fostered groups. The mechanism involved in the early pup
mortality has not been identified, but there is some indication that pulmonary deficits may be acontributing factor. At high doses (50 mg/kg/day administered on GDs 19–20), pups demonstrated
difficulty breathing within minutes of birth (Grasty et al. 2003). Histological examination of the lungs ofpups exposed to 25 or 50 mg/kg/day on GDs 19–20 showed evidence of delayed lung maturation (Grasty
et al. 2003, 2005), specifically, an increase in the proportion of solid lung tissue and a decrease in the
proportion of small airway tissue. A comparison of the lungs of PFOS-exposed neonates to control
fetuses (GD 21) showed that 17 and 50% of the lung tissue in the neonates exposed to 25 or
50 mg/kg/day, respectively, on GDs 19–20 was not histologically different from the control fetuses(Grasty et al. 2005). Administration of therapeutic agents known to enhance terminal lung maturation
and accelerate surfactant production did not improve pup survival (Grasty et al. 2005). Histologicaldamage has also been reported in pups exposed to lower PFOS levels. Lung atelectasis was observed inpups exposed to 10 mg/kg/day on GDs 0–18 (Yahia et al. 2008). No lung effects were observed in pups
exposed to 1 mg/kg/day or in fetuses exposed to 20 mg/kg/day on GDs 0–17 (Yahia et al. 2008).
Alveolar hemorrhage, thickened epithelial walls of the pulmonary alveolus, focal lung consolidation, andfocal infiltration of inflammation cells were observed in pups exposed to 2 mg/kg/day on GDs 0–21; nolung effects were observed at 0.1 mg/kg/day (Chen et al. 2012b).

Decreases in fetal body weight, birth weight, and pup body weight have been observed in rats, mice, andrabbits exposed to PFOS (Case et al. 2001; Chen et al. 2012b; Era et al. 2009; Fuentes et al. 2006, 2007b;
Grasty et al. 2003; Lau et al. 2003; Lee et al. 2015a; Li et al. 2016; Luebker et al. 2005a, 2005b; Rogers etal. 2014; Xia et al. 2011; Yahia et al. 2008). In rats, the lowest-adverse-effect level for decrease in fetal

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body weight was 10 mg/kg/day following administration on GDs 2–20 (Thibodeaux et al. 2003) and thehighest no-effect level was 5 mg/kg/day, also identified in the Thibodeaux et al. (2003) study. Decreases
in rat pup birth weight and body weight on PND 4 were observed in the offspring of rats exposed to
0.4 mg/kg/day for 42 days prior to mating and gestation through lactation day 4 (Luebker et al. 2005b).
Mice appear to be less sensitive to the effect of PFOS on pup body weight than rats (Lau et al. 2003).
Exposure of rats to 2 mg/kg/day PFOS on GDs 2–21 resulted in significant decreases in birth weight andpup body weight on PNDs 1–3; exposure to 5 mg/kg/day resulted in decreases in pup body weight
through PND 19. In contrast, no alterations in birth weight or pup body weight were observed in mice
exposed to doses as high as 5 mg/kg/day on GDs 1–18. Fuentes et al. (2007b) reported the lowest
LOAEL of 6 mg/kg/day for decreases in pup weight in mice exposed on GDs 12–18. Decreases in fetal
body weight were observed in mice exposed to 10 mg/kg/day on GDs 0–17 (Yahia et al. 2008). Fuentes
et al. (2006) did not find decreases in fetal body weight following exposure to 6 mg/kg/day on GDs 6–18.
In rabbits, a decrease in fetal body weight was observed following exposure to 2.5 mg/kg/day on GDs 6–
20, but not at 1 mg/kg/day (Case et al. 2001).

Several studies also reported delays in developmental milestones. Delays in eye opening were observedin rats exposed to 2 mg/kg/day on GDs 2–21 (Lau et al. 2003) or 0.4 mg/kg/day for 42 days prior tomating and throughout the gestation and lactation periods (Luebker et al. 2005a) and in mice exposed to
8.5 mg/kg/day on GDs 15–18 (Abbott et al. 2009). Fuentes et al. (2007b) did not find a delay in eye
opening in mouse pups exposed to 6 mg/kg/day on GDs 12–18, but did find a delay in pinna detachment
at this dose level. A decrease in neuromuscular development, as evidenced by a delay in tail pull reflex,
climbing ability, and forelimb grip strength, was observed in mice exposed to 6 mg/kg/day on GDs 12–18(Fuentes et al. 2007b).

Prenatal exposure to PFOS has resulted in malformations/anomalies/variations in rats, mice, and rabbits(Case et al. 2001; Era et al. 2009; Thibodeaux et al. 2003; Yahia et al. 2008). An increased incidence ofcleft palate was observed in rats exposed to 10 mg/kg/day on GDs 2–20 (Thibodeaux et al. 2003) and inmice exposed to 10 mg/kg/day on GDs 0–17 (Yahia et al. 2008), 15 mg/kg/day on GDs 1–17
(Thibodeaux et al. 2003), 20 mg/kg/day on GDs 1–17 (Era et al. 2009), and 50 mg/kg/day on GDs 11–15(Era et al. 2009). Other skeletal and external alterations included sternal defects in rats exposed to
10 mg/kg/day on GDs 2–20 (Thibodeaux et al. 2003) and mice exposed to 1 mg/kg/day on GDs 0–17
(Yahia et al. 2008), delayed skeletal ossification in rabbits exposed to 2.5 mg/kg/day on GDs 6–20 (Caseet al. 2001), wavy ribs and spina bifida occulta in mice exposed to 10 mg/kg/day on GDs 1–17 (Yahia etal. 2008), and tail abnormalities and delayed ossification of phalanges at 20 mg/kg/day (Yahia et al.

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2008). Visceral abnormalities, consisting of enlarged right atrium at 10 mg/kg/day, and ventricular septal
defects at 20 mg/kg/day were observed in mice exposed on GDs 1–17 (Thibodeaux et al. 2003). No
malformations/anomalies/variations were found by Thibodeaux et al. (2003) in mice exposed to
1 mg/kg/day on GDs 1–17 or by Fuentes et al. (2006) in mice exposed to 6 mg/kg/day on GDs 6–18. In
addition to the previously discussed histological alterations observed in the pups exposed to lethal doses,
mild to severe intracranial dilatation of blood vessels was observed in fetuses exposed to 20 mg/kg/day on
GDs 0–17 and in pups exposed to 10 mg/kg/day on GDs 0–18 (Yahia et al. 2008). No histologicalalterations were observed in the heart of rat pups exposed to 2 mg/kg/day on GDs 2–21 (Xia et al. 2011);
the study also found no alterations in heart rate or blood pressure. Lee et al. (2015b) found increases incholesterol levels in fetal livers of mice exposed to PFOA on GDs 1–17 and Wan et al. (2014b) foundincreases in relative liver weights in pups on PND 21.
A study with wild-type mice (129S1/Svlm) and PPARα-null mice evaluated the influence of PPARα on
developmental toxicity of PFOS (Abbott et al. 2009). Decreases in pup survival and delays in eye
opening were observed in both strains, although lower LOAELs were identified in the wild-type mice.
The investigators concluded that neonatal lethality and delayed eye opening was not dependent on
PPARα activation.
Neurodevelopmental studies have shown that prenatal and/or postnatal exposure to PFOS can affectmotor activity, but does not appear to affect learning or memory. A significant decrease in locomotion
was observed in male mice aged 5–8 weeks exposed to 0.3 mg/kg/day on GDs 1–17 when they wereplaced in a novel environment (Onishchenko et al. 2011). Hallgren et al. (2015) reported biphasic
alterations in spontaneous activity in 2-month-old mice administered a single dose of 11.3 mg/kg on
PND 10; locomotor activity was reduced during the first 20-minute period, was unchanged in the second
period, and increased during the third period. Decreases in circadian activity were noted in males andincreases in the number of inactive periods were noted in males and females when they were observed
over a 48-hour period. The study also found increased inactivity in an elevated plus maze test. In an
open field test of 70-day-old mice exposed to 6 mg/kg/day on GDs 12–18, an increase in the amount oftime spent in the center of the field was found; no changes in vertical movement were found (Ribes et al.
2010). In 3-month-old mice exposed to 6 mg/kg/day on GDs 12–18, a decrease in the distance traveled
was observed after 20–25 minutes in an open field apparatus; activity was not affected during the first
5 minutes of the test (Fuentes et al. 2007a). In a 15-minute open field test, prenatal exposure to
6 mg/kg/day PFOS on GDs 12–18 did not alter motor activity in 3-month-old mice (Fuentes et al. 2007b).
In contrast, Butenhoff et al. (2009b) found a significant increase in locomotion in male rats exposed toPERFLUOROALKYLS

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0.3 or 1.0 mg/kg/day PFOS throughout gestation and lactation. However, this effect was only observed inmale rats on PND 17; no significant alterations were observed on PNDs 13, 21, or 61. An increase inlocomotion was observed in female rats on PND 21 exposed to 1.0 mg/kg/day, but not at other time
points. To evaluate the biological relevance of the increased activity, activity was analyzed by 1-minutesequential time periods. The investigators concluded that the increased activity observed in the
0.3 mg/kg/day males at PND 17 and 1.0 mg/kg/day females at PND 21 was not treatment-related due tothe lack of significant changes in total or ambulatory activity and the similarity in habituation pattern
between the treated groups and controls. In the 1.0 mg/kg/day PND 17 males, the pattern of habituationdiffered from controls and there was an increase in ambulatory activity; this increase in locomotor activity
was considered to be related to PFOS exposure. The increased activity was observed in the last three time
periods. Postnatal exposure (PND 10) to 11.3 mg/kg/day resulted in an initial decrease in motor activity
followed by an increase in activity in 2- and 4-month-old mice (Johansson et al. 2008). In 2-month-old
mice exposed to 0.75 mg/kg/day, there was a decrease in total activity during the first 20 minutes oftesting, but not during the remaining 40 minutes of the test; no changes in activity were observed in the
4-month-old mice exposed to 0.75 mg/kg/day. Johansson et al. (2009) also found an altered response tonicotine exposure. Exposure to 11.3 mg/kg/day PFOS resulted in a decrease in motor activity in response
to nicotine exposure, as compared to the increased activity observed in controls; no significant alteration
was observed at 0.75 mg/kg/day. Two studies testing muscle coordination did not find alterations in theoffspring of rats exposed to 3.2 mg/kg/day for 6 weeks prior to mating and throughout gestation andlactation (Luebker et al. 2005a) or mice exposed to 6 mg/kg/day on GDs 12–18 (Fuentes et al. 2007b). A
decrease in muscle coordination was observed in mice exposed to 0.3 mg/kg/day on GDs 1–17
(Onishchenko et al. 2011). Perinatal exposure to PFOS did not significantly alter learning or memory inrats exposed to 2 mg/kg/day on GDs 2–21 and tested on PND 21 (Lau et al. 2003), the offspring of rats
exposed to 3.2 mg/kg/day for 6 weeks prior to mating and throughout gestation and lactation and tested
on PNDs 21 and 70 (Luebker et al. 2005a), or mice exposed to 6 mg/kg/day on GDs 12–18 and tested at
3 months of age (Fuentes et al. 2007a). In contrast, decreases in spatial learning ability were observed in
the offspring of mice exposed to 0.8 mg/kg/day on GD 1 through PND 1 or on PNDs 1–7 (Wang et al.
2015b).

The effect of pre- and/or postnatal exposure to PFOS on serum lipid levels, thyroid function, and immune
function has also been evaluated by a small number of studies. In the offspring of rats exposed to
1.6 mg/kg/day for 6 weeks prior to mating through GD 20, a significant decrease in fetal serum
cholesterol levels and an increase in LDL cholesterol levels were observed (Luebker et al. 2005b). In rats
exposed through PND 4, there was a decrease in serum triglyceride levels in the pups exposed toPERFLUOROALKYLS

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1 mg/kg/day (Luebker et al. 2005b). No alterations in thyroid histology or follicular morphology wereobserved in rats exposed to 1 mg/kg/day on GD 0–PND 20 (Chang et al. 2009), and no alterations in TSHlevels were observed in the Chang et al. (2009) study or in rats exposed to 2 mg/kg/day on GDs 2–21
(Lau et al. 2003). Decreases in total and free T4 levels were observed in rats exposed to 1 mg/kg/day on
GDs 2–21 (Lau et al. 2003); free T4 levels remained low through PND 35. Similarly, a cross-fostering
study found decreases in T4 levels in rats exposed to 3.2 mg/kg/day in utero, during lactation only, andthroughout gestation and lactation (Yu et al. 2009b). Altered immune function was observed in mice
exposed to PFOS on GDs 1–17 (Keil et al. 2008). At 5 mg/kg/day, an altered IgM antibody response tosRBCs was observed in 8-week-old males; decreases in CD3+ and CD4+ lymphocytes were also
observed. At 1 mg/kg/kg/day, there was decreased in NK cell activity in males; no effects were observed
at 0.1 mg/kg/day.

Summary. A number of epidemiological studies have evaluated developmental outcomes in
occupational, community (living near a PFOA facility), and general exposure populations. Overall, thesestudies have not found associations between serum PFOS and adverse pregnancy outcomes (miscarriage,
preterm birth), most birth outcomes (risks of low birth weight or small for gestational age, birth length,
head, chest or abdominal circumferences, ponderal index, sex ratio, or birth defects), or
neurodevelopmental outcomes (IQ, motor development, behavior, ADHD, or autism). It is noted thatsome studies have found associations for these effects and for some effects, only a couple of studies
examined the endpoint. Although most studies did not find associations between maternal PFOS andbirth weight, a meta-analysis did find a small decrease in birth weight was associated with increasingmaternal PFOS levels, after adjustment for glomerular filtration rate. There is also some suggestive
evidence that PFOS levels may be associated with small delays in the age of puberty in boys and girls.
Studies in laboratory animals clearly indicate that developmental toxicity is a sensitive outcome of PFOS
exposure. Oral exposure studies have reported increases in fetal mortality and decreases in pup survival;
decreases in fetal body weight, birth weight, and pup body weight; delays in developmental milestones
such as eye opening; increases in skeletal malformations/anomalies/variations such as cleft palate anddelayed skeletal ossification; and decreases in offspring motor activity.
PFHxS

Epidemiological Studies—Pregnancy Outcomes. Six studies, summarized in Table 2-22 have evaluatedpossible associations between pregnancy outcomes and maternal PFHxS levels. Jensen et al. (2015) did
not find an association between maternal PFHxS levels and the risk of miscarriage. Hamm et al. (2010)

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found a decreased risk of preterm births among women with serum PFHxS levels in the 3rd tertile andManzano-Salgado et al. (2017a) and Sagiv et al. (2018) found no associations with risk of preterm birth.
Other studies have found no associations with gestational age (Li et al. 2017; Manzano-Salgado et al.
2017a) or length (Lind et al. 2017a; Sagiv et al. 2018).

Epidemiological Studies—Birth Outcomes. General population studies have evaluated possible
associations between maternal PFHxS levels and birth outcomes including birth weight, length, small for
gestation age, and birth defects; studies are summarized in Table 2-23. Bach et al. (2016) and Maisonet etal. (2012) reported inverse associations between maternal PFHxS levels and birth weight; however, otherstudies have not found associations (Alkhalawi et al. 2016; Ashley-Martin et al. 2017; Callan et al. 2016;
Cao et al. 2018; Hamm et al. 2010; Kim et al. 2011; Li et al. 2017; Lee et al. 2013, 2016; Lenters et al.
2016a; Lind et al. 2017a; Manzano-Salgado et al. 2017a; Monroy et al. 2008; Sagiv et al. 2018; Shi et al.
2017; Starling et al. 2017). Manzano-Salgado et al. (2017a) did not find an association between maternal
PFHxS levels and the risk of low birth weight infants. Hamm et al. (2010) and Manzano-Salgado et al.
(2017a) did not find an association between maternal PFHxS level and the relative risk of small for
gestational age. Ashley-Martin et al. (2017) did not find an association between maternal PFHxS levels
and infant leptin or adiponectin levels, but Starling et al. (2017) found an inverse association between
maternal PFHxS levels and adiposity at birth. Several studies did not find associations between maternal
PFHxS levels and birth length, head circumference, or ponderal index (Alkhalawi et al. 2016; Bach et al.
2016; Callan et al. 2016; Cao et al. 2018; Lee et al. 2013; Manzano-Salgado et al. 2017a; Shi et al. 2017).
Maisonet et al. (2012) found an inverse association for birth length, but no association for ponderal index.
Cao et al. (2018) found an association between head circumference and cord PFHxS levels. Only one
study examined possible birth defects; Liew et al. (2014) did not find an association between maternal
PFHxS levels and the risk of congenital cerebral palsy in a case-control study.

Epidemiological Studies—Neurodevelopmental Outcomes. Epidemiological studies, summarized inTable 2-24, have examined PFHxS-related alterations in risks of ADHD, autism, intelligence, andbehavior. Wang et al. (2015b) did not find associations between maternal PFHxS levels and IQ in 5- or
8-year-old children and Jeddy et al. (2017) did not find associations between maternal PFHxS levels andverbal comprehension or vocabulary comprehension production in 15-month-old infants or intelligibility,
language, or communication scores in 38-month-old children. Zhang et al. (2018) did not findassociations between reading scores at 5 or 8 years of age and maternal PFHxS levels or PFHxS levels atage 3 or 5 years. Vuong et al. (2016) found a higher risk of performing poorly on tests of global
executive function with increasing maternal PFHxS levels. However, no association was found between

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serum PFHxS levels and metacognition or global executive function in 8-year-old children (Vuong et al.
2018). No association between serum PFHxS levels and the risk of learning problems was found inchildren living in a community with high PFOA levels (Stein and Savitz 2011). Gump et al. (2011) foundan inverse association between serum PFHxS levels and performance on tasks requiring behavioral
inhibition; Vuong et al. (2016, 2018) did not find alterations in behavioral regulation associated withmaternal PFHxS levels or 8-year-old’s PFHxS levels and Oulhote et al. (2016) did not find associations
between behavioral development scores in 7-year-old children and maternal PFHxS levels or PFHxSlevels at 5 or 7 years of age. Two studies evaluated the risk of ADHD and reported conflicting findings.
Stein and Savitz (2011) reported increases in risk of ADHD in 5–18- and 12–15-year-olds with serum
PFHxS levels in the 2nd, 3rd, or 4th quartile, whereas Liew et al. (2015) reported an inverse association
between maternal PFHxS levels and risk of ADHD. This study also did not find an increase in the risk ofautism; Braun et al. (2014) also found no association between maternal PFHxS levels and performance on
tests assessing autism.

Epidemiological Studies—Development of the Reproductive System. No associations between
reproductive hormone levels and serum PFHxS levels (Lopez-Espinosa et al. 2016) or maternal serum
PFHxS levels (Maisonet et al. 2015a) were found in boys and girls 6–9 years of age or in girls 15 years ofage. Lind et al. (2017a) did not find an association between maternal PFHxS levels and anogenital
distance in boys or girls. Christensen et al. (2011) did not find an association between maternal PFHxSlevels and risk of an earlier menarche. Summaries of these epidemiological studies are presented inTable 2-25.

Laboratory Animal Studies. Administration of 9.2 mg/kg/day PFHxS on PND 10 resulted in a decreasein spontaneous motor activity during the first 20 minutes of the test and an increase in activity in the last
20 minutes of the test (Viberg et al. 2013). The study also assessed the influence of PFHxS on nicotineinduced behavior. In the 9.2 mg/kg/day PFHxS group, exposure to nicotine did not significantly affectspontaneous motor activity, which was in contrast to the nicotine-induced increases in spontaneous motor
activity observed in the controls and lower PFHxS groups. Studies evaluating the developmental toxicityof PFHxS did not find alterations in litter size, pup survival, or pup body weight in rats exposed to
10 mg/kg/day PFHxS or mice exposed to 3 mg/kg/day for 14 days prior to mating and throughout
gestation and lactation (Butenhoff et al. 2009a; Chang et al. 2018). Although the rat study did not findalterations in litter size (Butenhoff et al. 2009a), the mouse study found a decrease in the number of pups
per litter, without a change in the pup to implantation site ratio at ≥1 mg/kg/day (Chang et al. 2018).
Similarly, no alterations in litter size, perinatal loss, or sex ratio were observed in the offspring of rats

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administered up to 25 mg/kg/day PFHxS on GDs 7–22 (Ramhøj et al. 2018). The study did finddecreases in male birth weights (3.5%) at ≥5 mg/kg/day and 30 and 45% decreases in pup serum
thyroxine levels at 5 and 25 mg/kg/day (Ramhøj et al. 2018).
PFNA

Epidemiological Studies—Pregnancy Outcomes. Seven studies (summarized in Table 2-22) haveexamined pregnancy outcomes. Jensen et al. (2015) found an increase in the risk of having a miscarriage
before gestation week 12, which was associated with maternal serum PFNA levels. Another study foundno alteration in the risk of pregnancy loss (Buck Louis et al. 2016). No alterations in the risk of preterm
birth was found in studies conducted by Chen et al. (2012a), Manzano-Salgado et al. (2017a), and Sagiv
et al. (2018). Other studies found no association between PFNA and gestational age (Li et al. 2017;
Manzano-Salgado et al. 2017a) or length (Lind et al. 2017a; Sagiv et al. 2018)

Epidemiological Studies—Birth Outcomes. Several studies have examined the possible associations
between birth outcomes and maternal PFNA levels, these studies are summarized in Table 2-23. Most
studies did not find an association between birth weight and maternal PFNA levels (Bach et al. 2016;
Callan et al. 2016; Cao et al. 2018; Chen et al. 2012a; Lee et al. 2016; Lenters et al. 2016a; Li et al. 2017;
Lind et al. 2017a; Manzano-Saldago et al. 2017a; Monroy et al. 2008; Robledo et al. 2015a; Shi et al.
2017). No alterations in the risk of low birth weight or small for gestational age were found in studies
conducted by Chen et al. (2012a) and Manzano-Salgado et al. (2017a). Wang et al. (2016) did find an
inverse association between maternal PFNA levels and birth weight in girls only and Starling et al. (2017)
and Sagiv et al. (2018) found inverse associations in boys and girls combined; Starling et al. (2017) also
found an inverse association between maternal PFNA levels and adiposity. Chen et al. (2012a) found an
association between maternal PFNA levels and birth length, but other studies have not found alterations(Bach et al. 2016; Callan et al. 2016; Cao et al. 2018; Manzano-Salgado et al. 2017a; Robledo et al.
2015a; Shi et al. 2017; Wang et al. 2016). Most studies did not find alterations in ponderal index or headcircumference (Bach et al. 2016; Callan et al. 2016; Cao et al. 2018; Chen et al. 2012a; Manzano-Salgado
et al. 2017a; Robledo et al. 2015a; Shi et al. 2017; Wang et al. 2016); Chen et al. (2012a) reported aninverse association between cord PFNA levels on ponderal index. No associations between maternal
PFNA or paternal PFNA levels and the odds of a male birth were observed in a general population study(Bae et al. 2015). Liew et al. (2014) did not find alterations in the risk of congenital cerebral palsy thatwere associated with maternal PFNA levels.

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Epidemiological Studies—Neurodevelopmental Outcomes. Several potential neurodevelopmental
outcomes have been examined in epidemiological studies; these studies are summarized in Table 2-24.
No association between maternal PFNA levels and full-scale IQ scores were observed in 8-year-old
children (Wang et al. 2015b); however, an association was found for visual IQ. Maternal PFNA levels
were not associated with IQ scores in 5-year-old children (Wang et al. 2015b). Stein and Savitz (2011)
found a decrease in the risk of learning problems in 5–18- or 12–15-year-olds with serum PFNA levels in
the two highest quartiles or in the 4th quartile, respectively. No associations were found between maternal
PFNA levels and verbal and vocabulary comprehension in 15-month-olds or language skills andintelligence scores in 38-month-olds (Jeddy et al. 2017). Vuong et al. (2016) did not find an association
between maternal PFNA levels and metacognition or global executive functioning in 5- or 8-year-old
children. In a subsequent study (Vuong et al. 2018), associations were found between serum PFNA levels
at age 8 years and metacognition and global executive function scores, which were indicative of poorer
performance; When the children were categorized by sex, the associations were only found in boys. The
study also found associations between PFNA levels and at risk metacognition and global executivefunctioning scores. Reading scores in 5-year-old children were associated with serum PFNA levels when
the children were 3 years of age but were not associated with maternal PFNA levels (Zhang et al. 2018),
and reading levels at 8 years of age were not associated with maternal, 3-year-old, or 5-year-old serum
PFNA levels (Zhang et al. 2018).

Mixed results have been found in studies on behavior. Gump et al. (2011) found a decrease in behavioral
response inhibition that was associated with serum PFNA levels in children aged 9–11 years, and Lien etal. (2016) reported inverse associations between cord blood PFNA levels in inattention and hyperactivity/
inattention in 7-year-old children, but no effect on hyperactivity/impulsivity. Vuong et al. (2016) did not
find an association between maternal PFNA levels and behavior regulation, but serum PFNA levels in
8-year-old children were associated with higher at risk behavioral regulation scores (Vuong et al. 2018).
Three studies have not found associations between PFNA levels and ADHD risk (Hoffman et al. 2010;
Liew et al. 2015; Stein and Savitz 2011). Similarly, maternal PFNA levels do not appear to be associatedwith autism (Braun et al. 2014; Liew et al. 2015).

Epidemiological Studies—Development of the Reproductive System. An inverse association between
PFNA levels and insulin-like growth factor 1 was found in boys and girls aged 6–9 years (LopezEspinosa et al. 2016). No associations were found between PFNA and estradiol or total testosterone in 6–
9 years olds (Lopez-Espinosa et al. 2016) or between maternal PFNA and testosterone or sex hormone
binding globulin levels in 15-year-old girls (Maisonet et al. 2015a). Additionally, no association between

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maternal serum PFHxS levels and risk of earlier age of menarche were observed in girls (Christensen etal. 2011). Summaries of these three studies are presented in Table 2-25.

Laboratory Animal Studies. Three studies were identified that examined the developmental toxicity of
PFNA in laboratory animals. Full litter resorptions were observed in mice administered 10 mg/kg/day on
GDs 1–17; maternal weight loss was also observed at this dose level (Das et al. 2015). At≤1.5 mg/kg/day, decreases in postnatal survival were observed (Das et al. 2015; Wolf et al. 2010).
Decreases in birth weight were observed in female offspring of rats administered 5 mg/kg/day PFNA on
GDs 1–20 (Rogers et al. 2014). Postnatal growth was decreased on PNDs 1–24 in the offspring of miceadministered ≥3 mg/kg/day PFNA on GDs 1–17 (Das et al. 2015); the decreases in body weight persisted
in the males through PND 287 and in the females through PND 50. No skeletal or visceral abnormalities
were observed in mouse pups (Das et al. 2015). Reductions in nephron endowment (number offunctioning nephrons at birth) were observed in male rat pups on PND 22 (Rogers et al. 2014). This
study also found increases in systolic blood pressure in pups at 10 weeks of age; no alterations wereobserved at 26 or 52 weeks of age. Delays in eye opening and decreased in pup body weight gain wereobserved in offspring of mice administered 2.0 mg/kg/day on GDs 1–18 (Wolf et al. 2010). Studies in
PPARα knockout mice did not find alterations in pup survival, birth weight, pup body weight gain, or dayof eye opening at maternal doses as high as 2.0 mg/kg/day (Wolf et al. 2010). Comparison between the
results in tests using wild-type mice and knockout mice suggests that PPARα plays a role in PFNA
developmental toxicity (Wolf et al. 2010).
PFDA

Epidemiological Studies—Pregnancy Outcomes. Four epidemiological studies examined pregnancy
outcomes. Jensen et al. (2015) found an increased risk of miscarriage that was associated with maternal
PFDA levels. The remaining studies found no associations between maternal PFDA levels and pregnancy
loss (Buck Louis et al. 2016), gestational age (Li et al. 2017), or gestational length (Lind et al. 2017a).

Epidemiological Studies—Birth Outcomes. A small number of epidemiological studies examined risksof adverse birth outcomes associated with maternal PFDA exposure; these studies are summarized inTable 2-23. Wang et al. (2016) found an inverse association between maternal PFDA levels and birthweight in female infants only. This study also found an increased risk for small for gestational age amongfemale infants. Other studies have not found associations (Bach et al. 2016; Callan et al. 2016; Cao et al.
2018; Lee et al. 2016; Lenters et al. 2016a; Li et al. 2017; Lind et al. 2017a; Robledo et al. 2015a; Shi etPERFLUOROALKYLS

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al. 2017; Starling et al. 2017). Starling et al. (2017) also found no association with adiposity at birth.
Epidemiological studies have not found associations between birth length, ponderal index, and/or headcircumference and maternal PFDA levels (Bach et al. 2016; Callan et al. 2016; Cao et al. 2018; Robledo
et al. 2015a; Shi et al. 2017; Wang et al. 2016). Liew et al. (2014) did not find alterations in the risk ofcongenital cerebral palsy in boys or girls and Bae et al. (2015) did not find alterations in odds of a malebirth associated with maternal or paternal PFDA levels. Additionally, Kim et al. (2016b) did not findassociations between serum PFDA levels and thyroid parameters.

Epidemiological Studies—Neurodevelopmental Outcomes. Several studies have evaluated the potentialof PFDA to adversely affect neurodevelopment; see Table 2-24 for a summary of the studies. Wang et al.
(2015b) did not find associations between maternal PFDA levels and IQ in 5- and 8-year-old children.
Similarly, Vuong et al. (2016) did not find alterations in scores on tests of global executive functioning
and metacognition in 5- or 8-year-old children. This study also found no alteration in behavioral
regulation. In contrast, Gump et al. (2011) found increases in impulsivity. Oulhote et al. (2016) found an
association between serum PFDA levels in 5-year-old children and total behavioral development scoreand higher externalizing and hyperactivity/inattention scores in 7-year-old children; the study did not findassociations between behavioral development at age 7 years and maternal PFDA levels or 7-year-old
PFDA levels. Liew et al. (2015) found decreases in the risk of ADHD and autism in children.

Epidemiological Studies—Developmental of the Reproductive System. In the only study examining
reproductive outcomes, Lind et al. (2017a) found an inverse association between maternal PFDA levels
and anogenital distance in girls, but not in boys.

Laboratory Animal Studies. An increase in fetal mortality was observed in mice exposed to12.8 mg/kg/day PFDA on GDs 6–15 (Harris and Birnbaum 1989); this dose level was also associatedwith a marked decrease in fetal weight/litter (50% lower than controls), 100% incidence of variations in
ossification of the braincase, decreases in maternal body weight, and maternal mortality. Decreases infetal body weight/litter were observed at ≥1 mg/kg/day. The study did not find alterations in theoccurrence of cleft palate, soft tissue malformations, or skeletal malformations. In mice exposed to10.8 mg/kg/day PFDA on PND 10, there was no effect on spontaneous activity, habituation, performanceon an elevated maze test, or response to a nicotine injection (Johansson et al. 2008). These results differ
from the Johansson et al. (2008) findings when mice were exposed to PFOA or PFOS and the findings ofViberg et al. (2013) in mice exposed to PFHxS.

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PFUnA

Epidemiological Studies—Pregnancy Outcomes. A limited number of epidemiological studies evaluatedpregnancy outcomes. Jensen et al. (2015) did not find an alteration in the risk of miscarriage before
gestation week 12. No association between gestational age and maternal PFUnA levels were found in astudy conducted by Li et al. (2017).

Epidemiological Studies—Birth Outcomes. The results from a study conducted by Wang et al. (2016)
found an inverse association between maternal PFUnA levels and birth weight and an increased risk of
small for gestation age among female infants. Callan et al. (2016) reported an association between
maternal PFUnA levels and optimal body weight but did not find an association with birth weight. The
remaining epidemiological studies have not found alterations in infant size (birth weight, birth length,
ponderal index, head circumference) (Bach et al. 2016; Callan et al. 2016; Cao et al. 2018; Chen et al.
2012a; Lee et al. 2016; Lenters et al. 2016a; Li et al. 2017; Shi et al. 2017) or the risks of low birth weight(Chen et al. 2012a) or small for gestational age (Chen et al. 2012a). No association between serum
PFUnA levels and thyroid parameters were observed in infants (Kim et al. 2016a). The results of theepidemiological studies examining associations between birth outcome and PFUnA are presented inTable 2-23.

Epidemiological Studies—Neurodevelopmental Outcomes. The results of two studies examining
possible associations between neurodevelopmental outcome and PFUnA are summarized in Table 2-24.
Wang et al. (2015b) found no association between maternal PFUnA levels and IQ score in 5- and 8-yearold children; the study did find an inverse association with scores on tests assessing performance IQ.
Lien et al. (2016) found no associations between cord blood PFUnA levels and performance on
behavioral tests.

Laboratory Animal Studies. One study was identified that examined the potential developmental toxicityof PFUnA (Takahashi et al. 2014); the study found decreases in pup body weight at birth and on PND 4 inthe offspring of rats administered via gavage 1.0 mg/kg/day PFUnA.

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PFHpA

Epidemiological Studies. In the only epidemiological study evaluating developmental outcomes, Li et al.
(2017) found no association between cord PFHpA levels and gestational age. The study did find an
inverse association for birth weight in boys only, but not in girls and in boys and girls combined.

PFBS

Laboratory Animal Studies. No alterations in pup survival, body weight, or development were observedat doses as high as 1,000 mg/kg/day in a 2-generation rat study of potassium PFBS (Lieder et al. 2009b).
In contrast to these findings, Feng et al. (2017) reported decreases in pup body weight, delays in eye
opening, vaginal opening, and first estrous in the offspring of mice administered PFBS on GDs 1–20.
York (2002) reported decreases in fetal body weight at 1,000 mg/kg/day in a rat study; however, asubsequent study (York 2003a) found decreases in body weights in the fetuses of rats administered
2,000 mg/kg/day, but not 1,000 mg/kg/day.

Reproductive and endocrine effects were also observed in the offspring at 200 and 500 mg/kg/day; theseeffects consisted of decreases in number of ovarian follicles and corpora lutea at diestrus, decreases inuterine weight and endometrial and myometrial thickness; increases in the average number of days in
estrous stage; decreases in estrogen and progesterone levels; increases in luteinizing hormone levels;
decreases in total T4, free T4, and total T3; and increases in TSH levels (Feng et al. 2017).
PFBA

Epidemiological Studies. Li et al. (2017) did not find an association between cord PFBA levels andgestational age or birth weight. In a study conducted by Kim et al. (2016a), no associations were foundbetween serum PFBA levels and thyroid parameters in infants.

Laboratory Animal Studies. A delay (approximately 1 day) in eye opening was observed in the offspringof mice administered via gavage 35 mg/kg/day PFBA on GDs 1–17 (Das et al. 2008).

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PFDoDA

Epidemiological Studies—Pregnancy Outcomes. In the only study examining pregnancy outcome(Table 2-22), Li et al. (2017) found no association between cord serum PFDoDA levels and gestationalage.

Epidemiological Studies—Birth Outcomes. General population studies conducted by Cao et al. (2018),
Lee et al. (2016), and Lenters et al. (2016a) did not find associations between cord blood PFDoDA ormaternal PFDoDA levels and birth weight, birth length, and/or ponderal index. Wang et al. (2016) foundan inverse association between maternal PFDoDA levels and birth weight and head circumference infemale infants; no alteration in the risk of small for gestation age was found. Li et al. (2017) also foundan association between cord PFDoDA levels and birth weight in girls only; no association was found inboys or in boys and girls combined. The results of these three studies are summarized in Table 2-23.

Epidemiological Studies—Neurodevelopmental Outcomes. As summarized in Table 2-24, only one
study examined neurodevelopmental outcomes. In this study, maternal PFDoDA levels were notassociated with IQ scores in 5- or 8-year-old children (Wang et al. 2015b).

Laboratory Animal Studies. One study evaluated the developmental toxicity of PFDoDA; no alterationsin the number of live pups born, birth weight, growth, or the prevalence of external, visceral, or skeletal
anomalies were observed at 0.1 or 0.5 mg/kg/day (Kato et al. 2015). At the next highest dose
(2.5 mg/kg/day), only 1 of the 12 dams delivered live pups; 2 of these pups died on PND 0 and decreases
in body weight gain were observed in the remaining pups.

PFHxA

Laboratory Animal Studies. Administration of 500 mg/kg/day NaPFHx on GDs 1–20 resulted in 10%
decreases in fetal weight in rats (Loveless et al. 2009). Similarly, decreases in pup body weight (17–18%
during the lactation period) were observed in the offspring of rats administered 500 mg/kg/day NaPFHx
for 70 days prior to mating, during mating, and throughout gestation and lactation (Loveless et al. 2009).
This study also found no alterations in pup clinical signs, survival, or developmental landmarks. No
alterations in litter size, pup survival, or pup body weight, or occurrence of internal malformations wereobserved in the offspring of rats administered 315 mg/kg/day PFHxA (TWA dose) prior to mating
through lactation day 4 (Kirkpatrick 2005).

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FOSA

Epidemiological Studies. Robledo et al. (2015a) found an inverse association between maternal FOSA
levels and birth weight in boys, but not in girls; paternal FOSA levels were not associated with birthweight. The study did not find alterations in birth length, head circumference, or ponderal index (seeTable 2-23). Bae et al. (2015) did not find alterations in the odds of a male birth that was associated withmaternal or paternal FOSA levels. As summarized in Table 2-24, only one study evaluated possible
associations between FOSA and neurodevelopmental outcomes. Gump et al. (2011) reported an inverse
association between serum FOSA levels and performance on tasks requiring behavioral inhibition. In the
only study examining development of the reproductive system, Christensen et al. (2011) did not find an
association between maternal serum FOSA levels and the risk of an earlier age of menarche in girls (seeTable 2-25).

2.18 OTHER NONCANCER
Overview. A number of epidemiological studies have examined the possible associations between
perfluoroalkyls and outcomes related to diabetes; the results of these studies are summarized inTable 2-26, with additional study details presented in the Supporting Document for EpidemiologicalStudies for Perfluoroalkyls, Table 14. Overall, the epidemiological studies do not provide support for an
association between serum perfluoroalkyl levels and increases in the risk of diabetes or related outcomes(e.g., increases in blood glucose, glucose tolerance) for PFOA, PFOS, PFHxS, PFNA, PFDA, PFUnA,
PFHpA, or FOSA. Additionally, results of studies on PFOA, PFOS, and PFHxS do not suggest an
association between perfluoroalkyls and gestational diabetes. No epidemiological studies examining
other noncancer endpoints were identified for PFBS, PFBA, PFDoDA, or PFHxA. Only four laboratory
animal studies examined other noncancer endpoints reporting inflammation of the salivary glands in rats
exposed to PFOA, pancreatic acinar cell hyperplasia in rats exposed to PFOA, and an increase in serum
glucose levels in rats administered PFNA (Table 2-5). The fourth study did not find increases in serum
glucose in rats exposed to PFOS (Table 2-4).

PFOA

Epidemiological Studies. A cohort mortality study conducted by Leonard et al. (2008; Leonard 2006) ofworkers at the Washington Works facility found a significant increase in deaths from diabetes, asPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

PFOA
Leonard 2006

>250–≤750 ng/mL PFOA

Diabetes deaths

SMR 183 (112–283)* (males only)

Occupational (n=6,027)
Leonard et al. 2008

NR

Diabetes deaths

SMR 197 (123–298)*

Lundin et al. 2009

Probable exposure

Diabetes deaths

SMR 2.0 (1.2–3.2)*

Occupational (n=3,992)
Raleigh et al. 2014

NR

Diabetes deaths

SMR 0.76 (0.50–1.11)

Occupational (n=9,027)
Steenland et al. 2015

Estimated cumulative

Risk of diabetes

RR 1.10 (0.77–1.57) no lag
RR1.12 (0.76–1.66) 10-year lag

Occupational (n=3,713)
Steenland and Woskie 2012

580 ng/mL (median PFOA)

Diabetes deaths

Occupational (n=1,088)
Anderson-Mahoney et al. 2008

NR

Self-reported diabetes

SMR 1.90 (1.35–2.61)* no lag
SMR 1.90 (0.98–3.33) 10-year lag
SMR 1.73 (0.83–3.18) 20-year lag
SPR 1.54 (1.16–2.05)*

68.4 ng/mL, 92.8 ng/mL, 86.5
ng/mL, 82.3 ng/mL (mean andserum PFOA in type 1
diabetics, type 2 diabetics,
uncategorized diabetics, andno diabetes groups)

Type 1 diabetes (all)OR 0.69 (0.65–0.74)*
Adults (>20 years)
OR 0.74 (0.70–0.79)*
Youth (≤20 years)
OR 0.72 (0.54–0.97)*
Type 2 diabetes
OR 0.87 (0.89–0.91)*
Adults (>20 years)
OR 0.91 (0.89–0.94)*
Youth (≤20 years)
OR 0.92 (0.88–0.96)*
Uncategorized diabetes OR 0.92 (0.88–0.97)*
Adults (>20 years)
OR 1.13 (0.82–1.56)
Youth (≤20 years)
OR 1.18 (0.90–1.55)

Occupational (n=6,027)

Community (n=566)
Conway et al. 2016
Community (n=820 with type 1 diabetes,
4,291 with type 2 diabetes, 1,349 withuncategorized, and 60,439 without diabetes)

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Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Karnes et al. 2014

Estimated cumulative

Self-reported diabetes

Fasting blood glucose

HR 1.00 (0.99–1.00, p=0.60),
retrospective analysis
HR 1.00 (1.00–1.01, p=0.31),
prospective analysis
NS (p>0.05)

122.7 ng/mL (mean PFOA)

Validated diabetes

OR 0.72 (0.52–1.00) (10th decile)

4.82 ng/mL (geometric mean
serum PFOA)Type 2 diabetes

HR 1.06 (0.89–1.28, p=0.50)

Fasting blood glucose
Fasting insulin
HOMA-IR
HOMA-βHbA1c
GlucoseAt age 15
At age 21
InsulinAt age 15
At age 21
HOMA-IRAt age 15
At age 21
HOMA-βAt age 15
At age 21

Association (p<0.05)*
Association (p<0.05)*
Association (p<0.05)*
Association (p<0.05)*
Association (p<0.05)*

Community (n=32,254 C8 participants)

MacNeil et al. 2009
Community (n=13,922 C8 participants)
Cardenas et al. 2017
General population (n=957 adults at high risk ofdeveloping type 2 diabetes)

Domazet et al. 2016
General population (n=501children assessedat ages 9, 15, and 21 years)

9.7 and 9.0 ng/mL (medianserum PFOA in males andfemales at age 9 years)

β 1.87 (-1.19–4.93)
β -1.01 (-14.62–30.07)
β -12.99 (-25.95–2.23)
β -13.98 (-36.23–16.00)
β -12.54 (-25.59–2.77)
β -14.16 (-36.60–16.28)
β -11.10 (-20.28 to -1.01)*
β -7.82 (-22.44–9.66)

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Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Domazet et al. 2016

3.7 and 3.4 ng/mL (medianserum PFOA in males andfemales at age 15 years)

Glucose at age 21
Insulin at age 21
HOMA-IR at age 21
HOMA-β at age 21
Insulin

β 5.83 (-3.70–16.92)
β -0.59 (-44.76–79.43)
β 0.93 (-44.45–83.55)
β -11.70 (-37.16–24.67)
NS (p=0.12)

Blood glucose
HOMA-IR
HOMA-IR

NS (p=0.17)
NS (p=0.10)
β -0.7 (-9.8–9.4)

4.2 ng/mL (geometric mean
PFOA in child)

HOMA-IR

β -10.1 (-17.3 to -2.3)*

2.1–3.34, 3.34–5.1, and>5.1 ng/mL (serum PFOA for
2nd, 3rd, and 4th quartiles)

Diabetes

1.67 ng/mL (maternal medianserum PFOA)

Fasting glucose
Fasting insulin
2-hour glucose in oral
glucose tolerance test
HOMA-IR
HOMA-βFasting blood glucose

OR 2.13 (1.30–3.46)*, 2nd quartilemales
OR 1.47 (0.87–2.48), 4th quartile,
femalesβ-1.3 (3.0–0.5),
β -4.0 (-12.2–5.0)
β-2.6 (-6.9–1.8)

General population (n=501children assessedat ages 9, 15, and 21 years)
Fisher et al. 20132.46 ng/mL (geometric mean
PFOA)

General population (n=2,700)
Fleisch et al. 2017

5.3 ng/mL (geometric meanmaternal PFOA)

General population (n=665 children
7.7 (median) years of age)
Fleisch et al. 2017
General population (n=665 children
7.7 (median) years of age)He et al. 2018
General population (NHANES)(n=7,904 adults)
Jensen et al. 2018
General population (n=158 pregnant womenwith high risk of gestational diabetes mellitus)

Kang et al. 2018
General population (n=150 children, ages 3–
18 years)

1.88 ng/mL (median serum
PFOA)

β -5.2 (-14.2–4.7)
β -0.4 (-8.0–8.0)
β 1.262 (-1.108–3.633, p=0.294)

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Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Koshy et al. 20171.81 and 1.39 ng/mL (median HOMA-IR
serum PFOA in WTCHR groupand comparison group)

β -0.05 (-0.21–0.12, p=0.58)

1.51 ng/mL (mean log PFOA)

InsulinNS (p>0.05)

β-cell function
Fasting blood glucose
HOMA-IR
Insulinβ-cell function
Fasting blood glucose

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)
Association (p<0.05)
NS (p>0.05)

HOMA-IR
Diabetes
HOMA-IR

NS (p>0.05)
OR 0.97 (0.61–1.53, p=0.88)
NS (p=0.20)

Fasting glucose

NS (p>0.05)

Insulin
2-hour glucose inglucose tolerance test
HOMA-IR
HbA1C
β cell function
Self-reported diabetes

NS (p>0.05)
NS (p>0.05)

HOMA (adolescent)
HOMA (adult)

NS (p=0.16) (M), NS (p=0.11) (F)NS (p>0.05)

General population (n=180 children enrolled in
the WTCHR)
Lin et al. 2009
General population (NHANES)(n=474 adolescents)

General population (NHANES) (n=969 adults)

Lind et al. 2014
General population (n=1,016)
Liu et al. 2018b

1.48 ng/mL (mean log PFOA)

3.3 ng/mL (median PFOA)

1.86 ng/mL (geometric mean
serum PFOA)

General population (NHANES) (n=1,871 adults)

Melzer et al. 2010
General population (NHANES) (n=3,966)

10.39 ng/mL (M)9.47 ng/mL (F)(4th PFOA quartile)

Nelson et al. 2010

4.6 ng/mL (mean PFOA)

General population (NHANES)(n=306 adolescent and 524 adults)

Outcome evaluatedResultc

NS (p>0.05)
Association (p<0.05)*
Association (p<0.05)*
OR 0.69 (0.41–1.16, p=0.158)

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Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedShapiro et al. 20161.68 ng/mL (geometric mean
PFOA)

Gestational diabetes
NS (p=0.86 for trend)
Impaired glucose
NS (p=0.36 for trend)
tolerance
Maternal glucose levels β -0.025 (-0.046 to -0.004)*, 3rd
quartile

General population (1,274 pregnant women)
Starling et al. 2017

1.4–17.0 ng/mL (3rd quartilematernal serum PFOA)

General population (n=604 mother-infant pairs)
Su et al. 2016
5.8–8.0 ng/mL(2nd PFOA quartile)
General population (n=571)

Diabetes

5.48–112 ng/mL (3rd tertile
serum PFOA)Type 2 diabetes

OR 0.39 (0.16–0.96)* (inverse
association)
Inverse association (p<0.01 fortrend)*
Inverse association (p<0.01 fortrend)*
Inverse association (p=0.04 fortrend)*
OR 1.54 (1.04–2.28)*, 3rd tertile

7.3 ng/mL (median maternal
serum PFOA); ≥10.1 ng/mL(3rd tertile serum PFOA)

Fasting blood glucose
Fasting insulin

β -0.005 (-0.018–0.008, p=0.465)
β 0.069 (-0.005–0.143, p=0.068)

HOMA-IR
Blood glucose in oral
glucose tolerance test
Gestational diabetes
mellitus
Fasting blood glucose

β 0.074 (-0.011–0.158, p=0.087)
β 0.014 (-0.013–0.041, p=0.305)

Fasting blood glucose
Glucose tolerance
Glycated hemoglobin

Sun et al. 2018
General population (n=793 female cases and
793 female controls)
Wang et al. 2018
General population (n=385 pregnant women)

Yang et al. 2018
General population (n=148 men, 81 diagnosed
with metabolic syndrome)

Resultc

1.90 ng/mL (median serum
PFOA)

HR 2.11 (0.76–5.86, p=0.151), 3rd
tertileβ 0.545 (-1.8–2.887)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Zhang et al. 2015a3.07 and 3.94 ng/mL(geometric mean PFOA in
women with or without
gestational diabetes)

Gestational diabetes

OR 1.86 (1.14–3.02)*

21.8, 25.2, 25.1, 23.1 ng/mL(mean and serum PFOS in
type 1 diabetics, type 2
diabetics, uncategorized
diabetics, and no diabetes
groups)4.82 ng/mL (geometric mean
serum PFOS)

Type 1 diabetes (all)OR 0.65 (0.61–0.70)*
Type 2 diabetes
OR 0.86 (0.82–0.90)*
Uncategorized diabetes OR 0.93 (0.86–1.03)

General population (n=258)
PFOS
Conway et al. 2016
Community (n=820 with type 1 diabetes,
4,291 with type 2 diabetes, 1,349 withuncategorized, and 60,439 with no diabetes)
Cardenas et al. 2017
General population (n=957 adults at high risk ofdeveloping type 2 diabetes)

Domazet et al. 201644.5 and 39.9 ng/mL (medianserum PFOS in males andGeneral population (n=501 children assessed at females at age 9 years)
ages 9, 15, and 21 years)

Type 2 diabetes
Fasting blood glucose
Fasting insulin
HOMA-IR

HR 0.87 (0.74–1.02, p=0.08)
Association (p<0.05)*
Association (p<0.05)*
Association (p<0.05)*

HOMA-βHbA1c
GlucoseAt age 15
At age 21

Association (p<0.05)*
Association (p<0.05)*

InsulinAt age 15
At age 21
HOMA-IRAt age 15
At age 21
HOMA-βAt age 15
At age 21

β 0.88 (0.07–1.60)*
β 0.64 (-0.55–1.84)
β -0.29 (-4.26–3.67)
β -1.01 (-8.00–6.62)
β -12.54 (-25.59–2.77)
β -0.83 (-7.91–6.71)
β -0.29 (-4.17–3.76)
β -1.66 (-5.70–2.67)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Domazet et al. 201622.3 and 20.8 ng/mL (medianserum PFOS in males andGeneral population (n=501children assessed at females at age 15 years)
ages 9, 15, and 21 years)
Fisher et al. 20138.04 ng/mL(geometric mean PFOS)

General population (n=2,700)
Fleisch et al. 201724.4 ng/mL (geometric meanmaternal PFOS)

Outcome evaluatedResultc

Glucose at age 21
Insulin at age 21
HOMA-IR at age 21
HOMA-β at age 21
Insulin

β 0.81 (-1.27–2.72)
β 4.78 (-6.82–17.77)
β 4.74 (-6.69–17.91)
β 1.81 (-4.77–9.09)
NS (p=0.88)

Blood glucose
HOMA-IR
HOMA-IR

NS (p=0.96)
NS (p=0.25
β -0.6 (-8.2–7.6)

HOMA-IR

β -10.1 (-16.4 to -3.3)*

General population (n=665 children
7.7 (median) years of age)
Fleisch et al. 2017
General population (n=665 children
7.7 (median) years of age)He et al. 2018

6.2 ng/mL (geometric mean
PFOS in child)>25.5 ng/mL (4th quartile serum Diabetes
PFOS)

General population (NHANES) (n=7,904 adults)
Jensen et al. 20188.37 ng/mL (maternal medianserum PFOS)
General population (n=158 pregnant womenwith high risk of gestational diabetes mellitus)

Kang et al. 2018
General population (n=150 children, ages 3–
18 years)

5.68 ng/mL (median serum
PFOS)

Fasting glucose
Fasting insulin
2-hour glucose in oral
glucose tolerance test
HOMA-IR
HOMA-βFasting blood glucose

OR 1.75 (1.00–3.04), 4th quartile males
OR1.41 (0.82–2.41), 4th quartile,
females
β -0.1 (-2.3–2.2)
β 2.7 (-8.5–15.2)
β 2.9 (-2.8–8.9)
β -2.9 (-7.1–14.1)
β -2.6 (-9.7–16.6)
β 0.707 (-1.921–3.336, p=0.595)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Koshy et al. 20173.72 and 2.78 ng/mL (median HOMA-IR
serum PFOS in WTCHR groupand comparison group)

β -0.06 (-0.18–0.06, p=0.31)

3.11 ng/mL (log mean PFOS)

InsulinNS (p>0.05)

HOMA-IRβ-cell function
Blood glucose
Insulin
HOMA-IRβ-cell function

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
Association (p<0.05)*
Association (p<0.05)*
Association (p<0.05)*

Blood glucose
Diabetes
HOMA

NS (p>0.05)
OR 1.43 (0.94–22.16, p=0.09)
NS (p=0.51)

Fasting glucose

Inverse association (p<0.05)*

Insulin
2-hour glucose inglucose tolerance test
HOMA-IR
HbA1C
β cell function
Self-reported diabetes

NS (p>0.05)
NS (p>0.05)

HOMA (adolescent)
HOMA (adult)

NS (p=0.18) (M), NS (p=0.22) (F)NS (p>0.05)

General population (n=180 children enrolled in
the WTCHR)
Lin et al. 2009
General population (NHANES)(n=474 adolescents)
General population (NHANES) (969 adults)

Lind et al. 2014
General population (n=1,016)
Liu et al. 2018b

3.19 ng/mL (log mean PFOS)

13.2 ng/mL (median PFOS)

5.28 ng/mL (geometric mean
serum PFOS)

General population (NHANES) (n=1,871 adults)

Melzer et al. 2010
General population (NHANES) (n=3,966)
Nelson et al. 2010
General population (NHANES)(n=306 adolescent and 524 adults)

57.73 ng/mL (M)50.96 ng/mL (F)(4th quartile mean PFOS)
25.3 ng/mL (mean PFOS)

Outcome evaluatedResultc

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
OR 0.87 (0.57–1.31, p=0.491)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedShapiro et al. 2016

4.58 ng/mL (geometric mean
PFOS)

Gestational diabetes
NS (p=0.70 for trend)
Impaired glucose
NS (p=0.74 for trend)
tolerance
Maternal glucose levels β -0.009 (-0.020–0.003)

General population (1,274 pregnant women)
Starling et al. 2017

2.4 ng/mL (maternal medianserum PFOS)

General population (n=604 mother-infant pairs)
Su et al. 2016
>4.8 ng/mL(4th PFOS quartile)
General population (n=571)

Sun et al. 2018
General population (n=793 female cases and
793 female controls)
Wang et al. 2018
General population (n=385 pregnant women)

Yang et al. 2018
General population (n=148 men, 81 diagnosed
with metabolic syndrome)
Zhang et al. 2015a
General population (n=258)

26.3–41.4 ng/mL (2nd tertile
serum PFOS)

5.4 ng/mL (median maternal
serum PFOS); ≥7.3 ng/mL(3rd tertile serum PFOS)

3.00 ng/mL (median serum
PFOS)

13.10 and 12.04 ng/mL(geometric mean PFOS inwomen with or without
gestational diabetes)

Resultc

Diabetes
Fasting blood glucose
Glucose tolerance test
Glycated hemoglobin
Type 2 diabetes

OR 3.37 (1.18–9.65)*
Association (p<0.01 for trend)*
Association (p≤0.01 for trend)*
Association (p=0.04 for trend)*
OR 1.63 (1.25–2.12)*, 2nd tertile

Fasting blood glucose
Fasting insulin
HOMA-IR
Blood glucose in oral
glucose tolerance test
Gestational diabetes
mellitus
Fasting blood glucose

β -0.009 (-0.019–0.002, p=0.108)
β 0.013 (-0.048–0.074, p=0.672)
β 0.074 (-0.011–0.158, p=0.087)
β 0.006 (-0.015–0.028, p=0.562)

Gestational diabetes

OR 1.13 (0.75–1.72)

HR 0.71 (0.29–0.75, p=0.453),
3rd tertile
β -1.237 (-2.63–1.59)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

3.4, 3.8, 4.2, and 5.2 ng/mL(mean and serum PFHxS in
type 1 diabetics, type 2
diabetics, uncategorized
diabetics, and no diabetes
groups)4.82 ng/mL (geometric mean
serum PFOA)Type 1 diabetes (all)Type 2 diabetes
Uncategorized
diabetes)

OR 0.59 (0.54–0.64)*
OR 0.74 (0.71–0.77)*
OR 0.84 (0.78–0.90)*

Type 2 diabetes
Fasting blood glucose

HR 0.99 (0.87–1.12, p=0.82)
Association (p<0.05)*

Fasting insulin
HOMA-IR
HOMA-βHbA1c
InsulinBlood glucose
HOMA-IR

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p=0.89)
NS (p=0.98)
NS (p=0.20)

2.5 ng/mL (geometric meanmaternal PFHxS)

HOMA-IR

β -2.07 (-5.9–2.0)

2.2 ng/mL (geometric mean
PFHxS in child)

HOMA-IR

β -1.7 (-3.8–0.5)

0.9–1.64, 1.64–2.9, and>2.9 (2nd, 3rd, and 4th quartile
General population (NHANES) (n=7,904 adults) serum PFHxS)

Diabetes

OR 1.99 (1.19–3.33)*, 2nd quartilemales
OR 1.22 (0.71–2.11), 4th quartile,
females

PFHxS
Conway et al. 2016
Community (n=820 with type 1 diabetes,
4,291 with type 2 diabetes, 1,349 withuncategorized, and 60,439 with no diabetes)
Cardenas et al. 2017
General population (n=957 adults at high risk ofdeveloping type 2 diabetes)

Fisher et al. 20132.18 ng/mL (geometric mean
PFHxS)

General population (n=2,700)
Fleisch et al. 2017
General population (n=665 children
7.7 (median) years of age)
Fleisch et al. 2017
General population (n=665 children
7.7 (median) years of age)He et al. 2018

PERFLUOROALKYLS

510
2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Jensen et al. 20180.31 ng/mL (maternal medianserum PFHxS)

Fasting glucose
Fasting insulin
2-hour glucose in oral
glucose tolerance test
HOMA-IR
HOMA-βFasting blood glucose

β 1.7 (0.2–3.2)*
β 7.7 (0.1–15.9)*
β 2.9 (-0.8–6.8)

HOMA-IR

β -0.09 (-0.18–0.003, p=0.04)

General population (n=158 pregnant womenwith high risk of gestational diabetes mellitus)

Kang et al. 2018
General population (n=150 children, ages 3–
18 years)
Koshy et al. 2017
General population (n=180 children enrolled in
the WTCHR)
Lin et al. 2009
General population (NHANES)(n=474 adolescents);

General population (NHANES) (n=969 adults)

0.793 ng/mL (median serum
PFHxS)

0.67 and 0.53 ng/mL (medianserum PFHxS in WTCHR
group and comparison group)
0.95 ng/mL (log mean)

Insulin
HOMA-IRβ-cell function
Blood glucose
0.60 ng/mL (log mean PFHxS) Insulin
HOMA-IR

Lind et al. 2014

2.1 ng/mL (median PFHxS)

General population (n=1,016)
Nelson et al. 2010

2.6 ng/mL (mean PFHxS)

General population (NHANES)(n=306 adolescent and 524 adults)

β 9.5 (1.0–18.8)*
β 2.3 (-4.3–9.4)
β 0.925 (-1.779–2.164, p=0.500)

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

Β-cell function
Blood glucose
Diabetes
HOMA

NS (p>0.05)
NS (p>0.05)
OR 1.00 (0.74–1.35, p=0.98)
NS (p=0.29)

HOMA (adolescent)NS (p=0.20) (M),Inverse association (p=0.001)* (F)NS (p>0.05)

HOMA (adult)

PERFLUOROALKYLS

511
2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedShapiro et al. 20161.02 ng/mL(geometric mean PFHxS)

Gestational diabetes
NS (p=0.73 for trend)
Impaired glucose
NS (p=0.44 for trend)
tolerance
Maternal glucose levels β -0.023 (-0.044 to -0.002)*, 3rd
quartile

General population (n=1,274 pregnant women)
Starling et al. 2017

1.1–10.9 ng/mL (3rd quartilematernal serum PFHxS)

General population (n=604 mother-infant pairs)
Sun et al. 20182.15 and 2.01 ng/mL (serum
Type 2 diabetes
PFHxS in cases and controls,
General population (n=793 female cases andrespectively)
793 female controls)
Yang et al. 20183.80 ng/mL (median serum
Fasting blood glucose
PFHxS)
General population (n=148 men, 81 diagnosed
with metabolic syndrome)
PFNA
Conway et al. 2016
1.4, 1.5, 1.5, and 1.6 ng/mL
Type 1 diabetes (all)(mean and serum PFNA in type Type 2 diabetes
Community (n=820 with type 1 diabetes,
1 diabetics, type 2 diabetics,
Uncategorized
4,291 with type 2 diabetes, 1,349 withuncategorized diabetics, anddiabetes)
uncategorized, and 60,439 with no diabetes)
no diabetes groups)
Cardenas et al. 2017

General population (n=665 children
7.7 (median) years of age)

OR 1.26 (0.86–1.86), 3rd tertile

β -0.29 (-1.9–1.32)

OR 0.65 (0.57–0.74)*
OR 0.94 (0.88–1.00)*
OR 0.95 (0.85–1.06)

0.53 ng/mL (geometric mean
serum PFNA)

Type 2 diabetes
Fasting blood glucose
Fasting insulin
HOMA-IR
HOMA-βHbA1c

HR 0.99 (0.87–1.12, p=0.82)
Association (p<0.05)*
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

0.6 ng/mL (geometric meanmaternal PFNA)

HOMA-IR

β 1.4 (-8–11.7)

General population (n=957 adults at high risk ofdeveloping type 2 diabetes)

Fleisch et al. 2017

ResultcPERFLUOROALKYLS

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Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Fleisch et al. 2017

1.7 ng/mL (geometric mean
PFNA in child)

HOMA-IR

β -0.6 (-3.2–2.6)>1.64 (4th quartile serum
PFNA)

Diabetes

OR 1.19 (0.73–1.95), 4th quartile males
OR 1.01 (0.62–1.65), 4th quartile,
females
β 0.03 (-2.1–2.2)
β 12.1 (0.7–24.8)*

General population (n=665 children
7.7 (median) years of age)He et al. 2018

General population (NHANES) (n=7,904 adults)
Jensen et al. 20180.65 ng/mL (maternal medianserum PFNA)
General population (n=158 pregnant womenwith high risk of gestational diabetes mellitus)

Kang et al. 2018
General population (n=150 children, ages 3–
18 years)
Koshy et al. 2017
General population (n=180 children enrolled in
the WTCHR)
Lin et al. 2009

0.938 ng/mL (median serum
PFNA)

2-hour glucose in oral
glucose tolerance test

β 1.3 (-6.5–4.2)

HOMA-IR
HOMA-βFasting blood glucose

β 12.2 (-0.5–26.4)
β 12.4 (0.2–23.7)*
β 0.428 (-1.785–2.641, p=0.703)

0.61 and 0.49 ng/mL (median HOMA-IR
serum PFNA in WTCHR groupand comparison group)

β 0.01 (-0.13–0.14, p=0.89)

0.35 ng/mL (log mean PFNA)

Insulin
HOMA-IRβ-cell function

Inverse association (p<0.05)*
NS (p>0.05)
Inverse association (p<0.05)*

Blood glucose
Insulin
HOMA-IRβ-cell function
Blood glucose

NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)
NS (p>0.05)

General population (NHANES)(n=474 adolescents)
General population (NHANES) (n=969 adults)

Fasting glucose
Fasting insulin

0.21 ng/mL (log mean PFNA)PERFLUOROALKYLS

513
2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Lind et al. 2014

0.7 ng/mL (median PFNA)

Diabetes
HOMA

OR 1.30 (0.85–1.97, p=0.22)
NS (p=0.90)

1.3 ng/mL (mean PFNA)

HOMA (adolescent)
HOMA (adult)

NS (p=0.83) (M), (p=0.20) (F)NS (p>0.05)

0.5–6.0 ng/mL (2nd halfmaternal serum PFNA)

Maternal glucose levels β -0.025 (-0.042 to -0.009)*, 2nd half

General population (n=1,016)
Nelson et al. 2010
General population (NHANES)(n=306 adolescents and 524 adults)
Starling et al. 2017

General population (n=604 mother-infant pairs)
Su et al. 2016>5.1 ng/mL(4th PFNA quartile)
General population (n=571)

Sun et al. 2018
General population (n=793 female cases and
793 female controls)
Yang et al. 2018

Glycated hemoglobin
Type 2 diabetes

OR 0.31 (0.11–0.88)* 4th quartile(inverse association)
NS (p=0.10 for trend)
Inverse association (p<0.01 fortrend)*NS (p=0.11 for trend)
OR 0.99 (0.67–1.48), 3rd tertile

0.50 ng/mL (median serum
PFNA)

Fasting blood glucose

β -0.627 (-2.54–1.29)

1.23 and 1.20 ng/mL(geometric mean PFNA inwomen with or without
gestational diabetes)

Gestational diabetes

OR 1.06 (0.70–1.60)

0.3 ng/mL (geometric mean
PFDA in child)

HOMA-IR

β -14.7 (-22.1 to -6.5)*

0.60 and 0.61 ng/mL (serum
PFNA in cases and controls,
respectively)

Diabetes
Fasting blood glucose
Glucose tolerance test

General population (n=148 men, 81 diagnosed
with metabolic syndrome)
Zhang et al. 2015a
General population (n=258)
PFDA
Fleisch et al. 2017
General population (n=665 children
7.7 (median) years of age)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Jensen et al. 20180.26 ng/mL (maternal medianserum PFDA)

Fasting glucose
Fasting insulin
2-hour glucose in oral
glucose tolerance test
HOMA-IR
HOMA-βFasting blood glucose

β 1.3 (-3.6–1.0)
β -0.2 (-11.2–12.1)
β -3.3 (-8.7–2.5)

General population (n=158 pregnant womenwith high risk of gestational diabetes mellitus)

Kang et al. 2018
General population (n=150 children, ages 3–
18 years)
Koshy et al. 2017
General population (n=180 children enrolled in
the WTCHR)
Starling et al. 20170.0592 ng/mL (median serum
PFDA)

0.14 and 0.11 ng/mL (median HOMA-IR
serum PFDA in WTCHR groupand comparison group)
0.2–3.5 ng/mL (2nd halfmaternal serum PFDA)

General population (n=604 mother-infant pairs)
Sun et al. 20180.13 and 0.16 ng/mL (serum
PFDA in cases and controls,
General population (n=793 female cases andrespectively)
793 female controls)
Yang et al. 20180.40 ng/mL (median serum
PFDA)
General population (n=148 men, 81 diagnosed
with metabolic syndrome)

β -1.5 (-13.5–12.1)
β 3.9 (-6.4–15.2)
β -0.201 (-1.280–0.878, p=0.713)

β -0.04 (-0.11–0.03, p=0.26)

Maternal glucose levels β -0.024 g (-0.041 to -0.007)*, 2nd half

Type 2 diabetes

OR 0.71 (0.48–1.05), 3rd tertile

Fasting blood glucose

β -2.543 (-4.65 to -0.44)

PERFLUOROALKYLS

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Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Zhang et al. 2015a0.41 and 0.40 ng/mL ng/mL(geometric mean PFDA inwomen with or without
gestational diabetes)

Gestational diabetes

OR 1.04 (0.70–1.53)

0.652 ng/mL (median serum
PFUnA)

Fasting blood glucose

β 1.350 (-0.020–2.721, p=0.053)

0.12 and 0.04 ng/mL (medianserum PFUnA in WTCHR
group and comparison group)

HOMA-IR

β -0.04 (-0.10–0.02, p=0.21)

0.3 ng/mL (median PFUnA)

Diabetes
HOMA

OR 0.95 (0.59–1.52; p=0.81)
NS (p=0.32)

6.4–9.2 ng/mL(3rd PFUnA quartile)

Diabetes

OR 0.24 (0.08–0.78)* 3rd quartile(inverse association)

Fasting blood glucose

Inverse association (p<0.01 fortrend)*

Glucose tolerance test

Inverse association (p<0.01 fortrend)*

Glycated hemoglobin
Fasting blood glucose

NS (p=0.17 for trend)
β -1.821 (-3.45 to -0.189)*

General population (n=258)
PFUnA
Kang et al. 2018
General population (n=150 children, ages 3–
18 years)
Koshy et al. 2017
General population (n=180 children enrolled in
the WTCHR)
Lind et al. 2014
General population (n=1,016)
Su et al. 2016
General population (n=571)

Yang et al. 2018
General population (n=148 men, 81 diagnosed
with metabolic syndrome)

0.30 ng/mL (median serum
PFUnA)PERFLUOROALKYLS

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Table 2-26. Summary of Outcomes Related to Diabetes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

PFHpA
Lind et al. 20140.05 ng/mL (median PFHpA)

Diabetes
HOMA

OR 1.02 (0.77–1.34, p=0.90)
NS (p=0.56)

0.20 ng/mL (median serum
PFHpA)

Fasting blood glucose

β -1.101 (-5.54–3.34)

0.11 ng/mL (median FOSA)

Diabetes
HOMA

OR 1.07 (0.75–1.53, p=0.71)
NS (p=0.070)

General population (n=571)
Yang et al. 2018
General population (n=148 men, 81 diagnosed
with metabolic syndrome)
FOSA
Lind et al. 2014
General population (n=571)

aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 14 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

(F) = females; FOSA = perfluorooctane sulfonamide; HOMA = homeostatic model assessment; HR = hazard ratio; IR = insulin resistance; (M) = males;
NHANES = National Health and Nutrition Examination Survey; NR = not reported; NS = not significant; OR = odds ratio; PFDA = perfluorodecanoic acid;
PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid; SMR = standardized mortality ratio; SPR = standardized prevalence ratio;
WTCHR = World Trade Center Health RegistryPERFLUOROALKYLS

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2. HEALTH EFFECTS

compared to workers at other DuPont facilities in the region. In an update of the Leonard et al. (2008)
study, Steenland and Woskie (2012) found an increased risk of diabetes deaths when compared to otherregional DuPont employees, but not when compared to the U.S. population. However, when the workers
were categorized by estimated cumulative exposure levels, the exposure-response trend was notstatistically significant. Lundin et al. (2009) also found an increase in deaths from diabetes in workers
exposed to APFO at the 3M Cottage Grove facility in Minnesota, as compared to Minnesota death rates.
The increase was only found in workers with probable exposure to APFO, but not with definite exposure;no deaths from diabetes were observed in the workers with definite exposure to APFO. As noted by
Steenland and Woskie (2012), diabetes mortality may not be a good surrogate for the underlying diabetes
incidence data. Raleigh et al. (2014) did not find an increase in diabetes deaths at the Cottage Grove
facility and Steenland et al. (2015) did not find an increased risk of diabetes associated with estimatedcumulative PFOA exposure at the Washington Works facility.

In community exposure studies, Anderson-Mahoney et al. (2008) found an increased prevalence of selfreported diabetes in residents living near the Washington Works facility, as compared to expected rates
taken from NHANES. Conway et al. (2016) found increases in the prevalence of type 1 diabetes, type 2
diabetes, and uncategorized diabetes in C8 Health Study participants. When the participants werecategorized by age, the increases in type 1 diabetes and type 2 diabetes prevalences were found in adults
and children; uncategorized diabetes was not increased in either group. In contrast, Karnes et al. (2014)
did not find an increased risk of self-reported diabetes associated with estimated cumulative PFOA levels
and MacNeil et al. (2009) did not find an increased risk of validated diabetes in C8 Health Study
participants.

General population studies found either an inverse association between serum PFOA and risk of diabetes(Su et al. 2016), an association (He et al. 2018; Sun et al. 2018), or no association (Cardenas et al. 2017;
Lind et al. 2014; Melzer et al. 2010). Additionally, most general population studies have not foundassociations between serum PFOA levels and insulin (Fisher et al. 2013; Lin et al. 2009; Liu et al. 2018b),
blood glucose levels (Fisher et al. 2013; Lin et al. 2009; Liu et al. 2018b; Su et al. 2016; Yang et al.
2018), homeostatic model assessment for insulin resistance (HOMA-IR) (Fisher et al. 2013; Lin et al.
2009; Lind et al. 2014; Liu et al. 2018b; Nelson et al. 2010), or glucose tolerance (Liu et al. 2018b; Su etal. 2016). Cardenas et al. (2017) did find associations between serum PFOA and glycemic parameters incross-sectional analyses; however, in longitudinal analyses, no associations were found between serum
PFOA and fasting blood glucose, fasting insulin, HOMA-IR, HOMA-β, or HbA1c. Studies in children

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2. HEALTH EFFECTS

have not found associations between serum PFOA and blood glucose, blood insulin, HOMA-IR, and/or
HOMA-β (Domazet et al. 2016; Fleisch et al. 2017; Kang et al. 2017; Koshy et al. 2017).
Three studies evaluated the risk of gestational diabetes and found mixed results. In a case-control study,
Zhang et al. (2015a) found an increased risk of gestational diabetes associated with serum PFOA, whereas
Shapiro et al. (2016) and Wang et al. (2018) did not find associations between serum PFOA andgestational diabetes or impaired glucose tolerance. Additionally, Starling et al. (2017) found an inverse
association between blood glucose levels and serum PFOA in pregnant women. In contrast, Jensen et al.
(2018) did not find associations between serum PFOA and fasting glucose, fasting insulin, HOMA-IR,
HOMA-β, or blood glucose levels in a glucose tolerance test in pregnant women. The ORs for the risk of
diabetes and gestational diabetes are graphically presented in Figure 2-39.

Laboratory Animal Studies. Two chronic-duration oral studies examined other noncancer endpoints.
Inflammation of the salivary gland was observed in rats exposed to 1.5 mg/kg/day (3M 1983; Butenhoff
et al. 2012c) and an increased incidence of acinar cell hyperplasia was observed in rats exposed to13.6 mg/kg/day (Biegel et al. 2001).
PFOS

Epidemiological Studies. Inverse associations between serum PFOS and the prevalence of type 1
diabetes and type 2 diabetes were observed among participants of the C8 Health Study (Conway et al.
2016). In a general population study conducted by Su et al. (2016), an increased risk of diabetes wasnoted, as well as associations between serum PFOS levels and fasting blood glucose, response to glucose
tolerance test, and glycated hemoglobin levels. Cardenas et al. (2017) also found associations between
serum PFOS and fasting blood glucose, fasting insulin, HOMA-IR, and HOMA-β; however, theseassociations were not found in longitudinal analyses over a 3-year period. In a prospective case-control
study, Sun et al. (2018) reported an association between serum PFOS and type 2 diabetes. Four othergeneral population studies did not find increased risks of diabetes (Cardenas et al. 2017; He et al. 2019;
Lind et al. 2014; Melzer et al. 2010). Several studies have not found associations between serum PFOS
levels and insulin, blood glucose, or HOMA-IR levels (Fisher et al. 2013; Lin et al. 2009; Lind et al.
2014; Liu et al. 2018b; Nelson et al. 2010; Yang et al. 2018). In NHANES adult participants, Lin et al.
(2009) found associations between serum PFOS and insulin and HOMA-IR and Liu et al. (2018b) foundan inverse association with fasting glucose levels. No associations were found in adolescent participants

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Figure 2-39. Diabetes Risk Relative to Serum PFOA Levels (Presented as Adjusted Ratios)PERFLUOROALKYLS

520
2. HEALTH EFFECTS(Lin et al. 2009). Studies in children have not found associations between serum PFOS and fasting blood
glucose, fasting blood insulin, HOMA-IR, and/or HOMA-β (Domazet et al. 2016; Fleisch et al. 2017;
Kang et al. 2018; Koshy et al. 2017).

No alterations in the risk of gestational diabetes were observed in three general population studies(Shapiro et al. 2016; Wang et al. 2018’ Zhang et al. 2015a). Shapiro et al. (2016), Starling et al. (2017),
and Wang et al. (2018) studies also found no association between serum PFOS and blood glucose levels,
glucose tolerance or other glycemic measurements in pregnant women. The ORs for the risk of diabetes
and gestational diabetes are graphically presented in Figure 2-40.

Laboratory Animal Studies. Perinatal exposure to 3 mg/kg/day PFOS did not result in alterations inserum insulin or glucose levels in the offspring on PND 63 (Wan et al. 2014b). However, when theoffspring were fed a high fat diet, increases in fasting glucose levels were observed at 0.3 and3 mg/kg/day and fasting serum insulin levels were increased at 3 mg/kg/day.

PFHxS

Epidemiological Studies. A study of C8 Health Project participants found inverse associations between
serum PFHxS levels and the prevalence of type 1 diabetes, type 2 diabetes, and uncategorized diabetes(Conway et al. 2016). General population studies have examined diabetes-related outcomes and have notfound associations between serum PFHxS levels and diabetes risk (Cardenas et al. 2017; He et al. 2018;
Lind et al. 2014; Sun et al. 2018), gestational diabetes (Shapiro et al. 2016) or insulin, blood glucose, or
HOMA-IR levels (Cardenas et al. 2017; Fisher et al. 2013; Jensen et al. 2018; Lin et al. 2009; Lind et al.
2014; Nelson et al. 2010; Yang et al. 2018). An inverse association between serum PFHxS levels andblood glucose levels was found in pregnant women (Starling et al. 2017). No associations between serum
PFHxS and glycemic parameters were found in children (Fleisch et al. 2017; Kang et al. 2018; Koshy etal. 2017).
PFNA

Epidemiological Studies. An inverse association between serum PFNA levels and the risk of diabetes
was observed in a general population study (Su et al. 2016) and for type 1 diabetes and type 2 diabetes in
C8 Health Study participants (Conway et al. 2016). Four other studies did not find associations fordiabetes (He et al. 2018; Lind et al. 2014; Sun et al. 2018) or gestational diabetes (Zhang et al. 2015a).

PERFLUOROALKYLS

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Figure 2-40. Diabetes Risk Relative to Serum PFOS Levels (Presented as Adjusted Odds Ratios)PERFLUOROALKYLS

522
2. HEALTH EFFECTSThe Su et al. (2016) study also reported an inverse association between PFNA levels and response on a
glucose tolerance test. A study by Starling et al. (2017) also found an inverse association between PFNA
levels and blood glucose levels in pregnant women. A study of adolescent NHANES participants founddecreasing levels of insulin with increasing serum PFNA levels (Lin et al. 2009); this association was notfound in adult NHANES participants (Lin et al. 2009). Several studies did not find associations between
serum PFNA levels and fasting blood glucose, glucose tolerance, HOMA-IR, and/or HOMA-β (Cardenaset al. 2017; Fleisch et al. 2017; Jensen et al. 2018; Kang et al. 2018; Koshy et al. 2017; Lin et al. 2009;
Lind et al. 2014; Nelson et al. 2010; Yang et al. 2018).

Laboratory Animal Studies. An increase in serum glucose levels was observed in rats administered via
gavage 1 mg/kg/day PFNA for 14 days (Fang et al. 2012a).
PFDA

Epidemiological Studies. Two studies evaluated the potential association between PFDA and diabetes
risk. Sun et al. (2018) did not find an association for type 2 diabetes risk and Zhang et al. (2015a) did not
find an association between serum PFDA levels and the risk of gestational diabetes. Other studies haveexamined possible associations between serum PFDA and glycemic measurements. Fleisch et al. (2017)
found an inverse association with HOMA-IR in children. Other studies in children (Kang et al. 2018;
Koshy et al. 2017), adults (Yang et al. 2018), and pregnant women (Jensen et al. 2018) did not findassociations for fasting blood glucose, fasting insulin, glucose tolerance, HOMA-IR, and/or HOMA-β.
PFUnAEpidemiological Studies. Six epidemiological studies evaluating associations between PFUnA anddiabetes-related outcomes have found conflicting results. Su et al. (2016) found inverse associations
between serum PFUnA levels and diabetes risk, fasting blood glucose levels, and glucose tolerance test
results, Yang et al. (2018) found an inverse association with fasting blood glucose levels, and Starling etal. (2017) found an inverse association with blood glucose levels in pregnant women. Whereas Lind et al.
(2014) found no alterations in the risk of diabetes or HOMA, and Kang et al. (2018) and Koshy et al.
(2017) found no associations between serum PFUnA levels and fasting blood glucose and HOMA-IR,
respectively, in studies in children.

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PFHpA

Epidemiological Studies. Lind et al. (2014) did not find associations between serum PFHpA levels andthe risk of diabetes or HOMA alterations and Yang et al. (2018) did not find an association with fastingblood glucose levels.

FOSA

Epidemiological Studies. In the one epidemiological study identified, no associations between serum
FOSA levels and the risk of diabetes or HOMA were found (Lind et al. 2014).
2.19 CANCER
Overview. A number of occupational exposure, community, and general population studies haveexamined possible associations between perfluoroalkyls and cancer risk; these studies are summarized inTable 2-27 and the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 15.
Occupational and community exposure studies have found increases in the risk of testicular and kidneycancer associated with PFOA. No consistent epidemiologic evidence for other cancer types were foundfor PFOA. For PFOS, one occupational exposure study reported an increase in bladder cancer, but thiswas not supported by subsequent occupational studies. General population studies have not consistently
reported increases in malignant tumors for PFOS. A small number of epidemiology studies examinedpossible associations between other perfluoroalkyls and cancer risk. No consistent associations wereobserved for breast cancer risk for PFHxS, PFNA, PFHpA, or PFDoDA; increased breast cancer risks
were observed for PFDA and FOSA, but this was based on a single study. No associations between
PFOA, PFOS, PFHxS, PFNA, PFDA, or PFUnA and prostate cancer risk were found. However, among
men with a first-degree relative with prostate cancer, associations were found for PFOA, PFOS, PFHxS,PFDA, and PFUnA, but not for PFNA. Epidemiological studies examining potential cancer effects were
not identified for PFBS, PFBA, or PFHxA.

Laboratory animal studies have evaluated the carcinogenicity of PFOA and PFOS; the results of thesestudies are summarized in Tables 2-3 and 2-4. In laboratory animals, there is some evidence for increases
in Leydig cell adenomas, pancreatic acinar cell adenomas, and hepatocellular adenomas in male rats
exposed to PFOA in the diet. An increase in hepatocellular adenomas was observed in male rats exposed
to dietary PFOS for 2 years; thyroid follicular cell adenomas were observed in rats exposed to PFOS forPERFLUOROALKYLS

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Table 2-27. Summary of Cancer Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

PFOA
Gilliland 1992; Gilliland and Mandel 1993

NR

All cancer deaths

SMR 0.86 (0.72–1.01), males
SMR 0.75 (0.56–0.99), females
SMR 2.03 (0.55–4.59)
RR 1.13 (1.01–1.27) for a 1-yearincrease in employment length
RR 3.3 (1.02–10.6)* for a 10-year
employment length
SMR 100 (88–114), males
SMR 149 (77–260), females
SMR 185 (95–323), males

Occupational (n=389 deaths)
Reference population: Minnesota general
population

Leonard 2006; Leonard et al. 2008
Occupational (n=6,027)
Reference population: DuPont workers atother regional facilities

Prostate cancer

5–9,550 ng/mL (estimatedrange of PFOA)All cancer deaths
Kidney cancer deaths
Biliary passages andliver cancer deaths

SMR 133 (53–274)

Pancreatic cancer
deathsSMR 100 (50–180)

Bladder or other urinary SMR 131 (53–269)
organ cancer deaths
Prostate cancer deaths SMR 65 (34–114)
Bronchus, trachea, lung SMR 81 (63–104)
cancer deaths
Lundin et al. 2009
Occupational (n=3,993)
Reference population: Minnesota general
population; for HR analysis comparisons withworkers with low exposure or <1 year of
exposure

2,600–5,200 and 300–
All cancer deaths
SMR 0.9 (0.5–1.4), definite exposure
1,500 ng/mL (range of PFOA in
SMR 0.9 (0.8–1.1), probable exposure
subset of current workers with Pancreas cancer
SMR 0.9 (0.0–4.7), definite exposure
definite exposure jobs anddeathsSMR 1.0 (0.4–2.1), probable exposure
probable exposure jobs)
Trachea, bronchus, and SMR 1.2 (0.5–2.3), definite exposurelung cancer deaths
SMR 1.0 (0.7–1.4), probable exposure
Prostate cancer deaths SMR 2.1 (0.4–6.1), definite exposure
SMR 0.9 (0.4–1.8), probable exposure
HR 6.6 (1.1–37.7), high exposure≥6 months
HR 3.7 (1.3–10.4), definite exposurefor ≥5 years

PERFLUOROALKYLS

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Table 2-27. Summary of Cancer Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Raleigh et al. 2014

>7.9x10-4 μg/m3 (cumulative
exposure, 4th PFOA quartile)

All cancer deaths

SMR 0.87 (0.78–0.97)

Pancreatic cancer
deaths
Prostate cancer deaths
Kidney cancer deaths
Liver cancer deaths
Breast cancer deaths
Bladder cancer deaths

SMR 0.85 (0.50–1.34)

Occupational (n=9,207)
Reference population: Minnesota general
population

Raleigh et al. 2014
Occupational (n=9,207)
Reference population: non-APFO exposed
workers at a St. Paul facility

Steenland et al. 2015
Occupational (n=3,713)≤7.9x10-4 and >7.9x10-4 μg/m3 Pancreatic cancer(cumulative exposure,3rd and deaths
4th PFOA quartile)
Pancreatic cancer

SMR 0.83 (0.53–1.23)
SMR 0.53 (0.20–1.16)
SMR 0.81 (0.35–1.59)
SMR 0.82 (0.41–1.47)
SMR 0.89 (0.38–1.76)
HR 1.23 (0.50–3.00), 3rd and 4thquartiles combined
HR 1.36 (0.59–3.11), 3rd and 4thquartiles combined

Prostate cancer deaths HR 1.32 (0.61–2.84), 4th quartile
Prostate cancer
HR 1.11 (0.82–1.49), 4th quartile
Kidney cancer deaths HR 0.39 (0.11–1.32), 3rd and 4thquartiles combined
Kidney cancer
HR 0.73 (0.21–2.48), 4th quartile
Liver cancer deaths
HR 0.67 (0.14–3.27), 3rd and 4thquartiles combined
Breast cancer deaths
HR 0.54 (0.15–1.94), 3rd and 4thquartiles combined
Breast cancer
HR 1.27 (0.70–2.31), 4th quartile
Bladder cancer deaths HR 1.96 (0.63–6.15), 3rd and 4thquartiles combined
Bladder cancer
HR 1.66 (0.86–3.18), 4th quartile
Estimated cumulative exposure Bladder cancer
Inverse association (p=0.04 or
p=0.06 for trend) with no lag or
10-year lag
RR 0.23 (0.05–0.93), 4th quartile withno lagPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-27. Summary of Cancer Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Colorectal cancer

NS (p=0.91 and 0.86 for trend), with nolag or 10-year lag
NS (p=0.83 and 0.91 for trend), no lag
or 10-year lag
NS (p=0.16 and 0.55 for trend), no lag
or 10-year lag
SMR 0.94 (0.76–1.16), 4th quartile
SMR 0.92 (0.30–2.16), 4th quartile

Prostate cancer
Melanoma
Steenland and Woskie 2012
Occupational (n=1,084 deceased workers)
Reference population: DuPont workers at otherregional facilities≥2,700,000 ng/mL-years(estimated cumulative 4th
PFOA quartile)

All cancer deaths
Pancreatic cancer
deathsLung cancer deaths
Prostate cancer deaths
Bladder cancer deaths
Kidney cancer deaths

Barry et al. 2013

Estimated cumulative exposure Testicular cancer

Community and occupational (n=32,254)

24.2 and 112.7 ng/mL (median
PFOA)
Kidney cancer

Breast cancer

Colorectal cancer

SMR 0.75 (0.48–1.11), 4th quartile
SMR 0.57 (0.16–1.46), 4th quartile
SMR 0.36 (0.10–2.01), 4th quartile
SMR 2.66 (1.15–5.24)*, 4th quartile
SMR 2.82 (1.13–5.81)*, 10-year lag
SMR 3.67 (1.48–7.57)*, 20-year lag
HR 1.34 (1.00–1.79, p=0.05)* no lag
HR 1.28 (0.95–1.73, p=0.10) 10-yearlag
HR 3.17 (0.75–13.45, p=0.04 fortrend)*, 4th quartile
HR 1.10 (0.98–1.24, p=0.10), no lag(continuous)
HR 1.58 (0.88–2.84, p=0.18 for trend),
4th quartile
HR 0.94 (0.89–1.00, p=0.05)*, no lag
HR 0.93 (0.88–0.99, p=0.03)*, 10-yearlag
HR 0.99 (0.92–1.07, p=0.84), no lag

PERFLUOROALKYLS

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Table 2-27. Summary of Cancer Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Ducatman et al. 2015a, 2015b86.6 ng/mL (mean PFOA)

Prostate specificantigenNS (p<0.05)

13.5–27.8 ng/mL (2nd PFOA
quartile)

Colorectal cancer

OR 0.47 (0.31–0.74)*, 2nd quartile

Community (C8) (n=25,412 men)Innes et al. 2014
Community (n=208 cases of colorectal cancerand 47,359 cancer-free adults)
Vieira et al. 2013
Community (n=25,107)

30.8–109 and 110–655 ng/mL Kidney cancer(estimated PFOA in high andvery high exposure groups)

2.5 and 1.6 ng/mL (median
PFOA in cases and controls)

Breast cancer

AOR 2.0 (1.3–3.2)*, high exposuregroup
AOR 2.0 (1.0–3.9), very high exposuregroup
AOR 2.8 (0.8–9.2), very high exposure
group
AOR 1.5 (0.9–2.5), very high exposure
group
AOR 1.4 0.9–2.3) very high exposuregroup, females only
AOR 1.20 (0.77–1.88, p=0.43)

5.2 ng/mL (mean PFOA)

Breast cancer

RR 1.00 (0.90–1.11).

Prostate cancer
Bladder cancer
Pancreas cancer

IRR 1.18 (0.84–1.65)
IRR 0.81 (0.53–1.24)
IRR 1.55 (0.85–2.80)

Liver cancer

IRR 0.60 (0.26–1.37)

Testes cancer
Prostate cancer
Breast cancer
Bonefeld-Jorgensen et al. 2011
General population (n=31 breast cancer cases
and115 matched controls)
Bonefeld-Jorgensen et al. 2014

General population (n=250 breast cancer casesand 233 matched controls)
Eriksen et al. 2009
6.8 and 6.0 ng/mL (median
PFOA in male and female
General population (n=713 for prostate cancer, cancer patients)
n=332 for bladder cancer, n=128 for pancreatic 6.9 and 5.4 ng/mL (median
PFOA in male and female
cancer, n=67 for liver cancer, and
n=772 controls)
controls)

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-27. Summary of Cancer Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Hardell et al. 2014

2.3 and 1.9 ng/mL (mean
PFOA in cases and controls)

Prostate cancer

2.08 and 1.48 ng/mL (medianserum PFOA in cases andcontrols, respectively)

Breast cancer

OR 1.1 (0.7–1.7)
OR 2.6 (1.2–6.0)*, among subjects
with a heredity risk and serum
PFOA above the median
OR 1.26 (1.01–1.58, p=0.039)*,
continuous
OR 2.64 (1.17–5.97, p=0.019)*,
3rd tertileNR

All cancer deaths

General population (n=201 cases and186 controls)
Wielsøe et al. 2017
General population (n=77 cases and84 controls)
PFOS
Alexander et al. 2003
Occupational (n=2,083; 145 deaths)
Reference population: Alabama general
population
Alexander and Olsen 2007
Occupational (n=1,895; 1,488 deaths)
Reference population: NIOSH SEER referent
data
Grice et al. 2007
Occupational (n=1,400 current, retired, orformer workers)
Olsen et al. 2004a

Bladder and otherurinary organs cancer

NR

Bladder cancer

1,300–1,970 ng/mL (PFOSlevels in high potential
exposure group)

Colon cancer
Melanoma

OR 1.69 (0.68–4.17)
OR 1.01 (0.25–4.11)

Prostate cancer

OR 1.08 (0.44–2.69)

NR

Malignant melanoma of RREpC 12 (1.0–>100)
the skin
RREpC 10 (0.7–>100), >10 years
employment
Malignant neoplasm of RREpC 5.4 (0.5–>100)
the colon
RREpC 12 (0.8–>100), >10 years
employment

22.18 ng/mL (mean PFOS)

Prostate specificantigenOccupational (current and retired workers)

Ducatman et al. 2015a, 2015b
Community (C8) (n=25,412 men)

SMR 0.84 (0.50–1.32), high potential
exposure group
SMR 12.77 (2.63–37.35)*, highpotential exposure group
SMR 16.12 (3.32–47.14)*, highexposure group ≥1 year exposure
SIR 1.74 (0.64–3.79), high potential
exposure group
SIR 1.43 (0.16–5.15) ≥10-year
exposure group

NS (p<0.05)

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2. HEALTH EFFECTS

Table 2-27. Summary of Cancer Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Innes et al. 2014

13.6–20.1 ng/mL (2nd PFOS
quartile)

Colorectal cancer

OR 0.35 (0.24–0.53)*

45.6 and 21.9 ng/mL (median
PFOS in cases and controls)

Breast cancer

OR 1.03 (1.001–1.07, p=0.05)*

30.6 ng/mL (mean PFOS)

Breast cancer

RR 0.99 (0.98–1.01)

Prostate cancer
Bladder cancer
Pancreas cancer
Liver cancer

IRR 1.05 (0.97–1.14)
IRR 0.93 (0.83–1.03)
IRR 0.99 (0.86–1.14)
IRR 0.59 (0.27–1.27)

Prostate cancer

OR 1.0 (0.6–1.5)
OR 2.7 (1.04–6.8)*, among subjects
with a heredity risk and serum
PFOS above the medianCommunity (n=208 cases of colorectal cancerand 47,359 cancer-free adults)
Bonefeld-Jorgensen et al. 2011
General population (n=31 breast cancer cases
and 115 matched controls)
Bonefeld-Jorgensen et al. 2014

General population (n=250 breast cancer cases
and 115 matched controls)
Eriksen et al. 200935.1 and 32.1 ng/mL and
35.0 and 29.3 ng/mL (median
General population (n=713 for prostate cancer, PFOS in male and female
n=332 for bladder cancer, n=128 for pancreatic cancer patients and males andcancer, n=67 for liver cancer, andfemales in the comparison
n=772 controls)
group)
Hardell et al. 2014
11 and 10 ng/mL (mean PFOS
in cases and controls)
General population (n=201 cases of prostatecancer and 186 controls)
Wielsøe et al. 2017
General population (n=77 cases and84 controls)
PFHxS
Ducatman et al. 2015a, 2015b
Community (C8) (n=25,412 men)
Bonefeld-Jorgensen et al. 2014
General population (n=250 breast cancer cases
and 115 matched controls)

35.50 and 18.2 ng/mL (median Breast cancer
serum PFOS in cases andcontrols, respectively)

OR 1.02 (1.01–1.03, p=0.005)*,
continuous
OR 3.13 (1.20–8.15, p=0.020)*,
2nd tertile

3.58 ng/mL (mean PFHxS)

Prostate specificantigenNS (p<0.05)

1.2 ng/mL (mean PFHxS)

Breast cancer

RR 0.66 (0.47–0.94)*

PERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-27. Summary of Cancer Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

Hardell et al. 2014

1.1 and 0.940 ng/mL (meanPFHxS in cases and controls)

Prostate cancer

2.52 and 1.14 ng/mL (medianserum PFHxS in cases andcontrols, respectively)

Breast cancer

OR 1.3 (0.8–1.9)
OR 4.4 (1.7–12)*, among subjects
with a heredity risk and serum
PFHxS above the median
OR 1.16 (1.02–1.32, p=0.029)*,
continuous
OR 2.69 (1.23–5.88, p=0.013)*,
3rd tertile

1.47 ng/mL (mean PFNA)

Prostate specificantigenNS (p<0.05)

0.5 ng/mL (mean PFNA)

Breast cancer

RR 0.76 (0.30–1.94)

General population (n=201 cases of prostatecancer and 186 controls)
Wielsøe et al. 2017
General population (n=77 cases and84 controls)
PFNA
Ducatman et al. 2015a, 2015b
Community (C8) (n=25,412 men)
Bonefeld-Jorgensen et al. 2014

General population (n=250 breast cancer cases
and 115 matched controls)
Hardell et al. 2014
0.679 and 0.631 ng/mL (mean Prostate cancer
PFNA in cases and controls)
General population (n=201 cases of prostatecancer and 186 controls)
Wielsøe et al. 20173.28 and 1.83 ng/mL (median Breast cancer
serum PFNA in cases andGeneral population (n=77 cases andcontrols, respectively)
84 controls)

PFDA
Hardell et al. 2014
General population (n=201 cases of prostatecancer and 186 controls)

0.338 and 0.291 ng/mL (mean Prostate cancer
PFDA in cases and controls)

OR 1.2 (0.8–1.8)
OR 2.1 (0.9–4.8), among subjects witha heredity risk and serum PFNA above
the median
OR 1.07 (0.98–1.17, p=0.116),
continuous
OR 2.43 (1.07–5.51, p=0.034)*, 2nd
tertileOR 2.07 (0.90–4.76, p=0.056), 3rd
tertileOR 1.4 (0.9–2.1)
OR 2.6 (1.1–6.1)*, among subjects
with a heredity risk and serum
PFDA above the medianPERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-27. Summary of Cancer Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Wielsøe et al. 20171.30 n and 1.01 ng/mL (median Breast cancer
serum PFDA in cases andcontrols, respectively)

OR 1.17 (0.97–1.40, p=0.094),
continuous
OR 2.36 (1.04–5.36, p=0.041)*,
3rd tertile

0.308 and 0.285 ng/mL (mean Prostate cancer
PFUnA in cases and controls)

OR 1.2 (0.8–1.9)
OR 2.6 (1.1–5.9)*, among subjects
with a heredity risk and serum
PFUnA above the median
OR 1.06 (0.97–1.15, p=0.207),
continuous
OR 2.00 (0.88–4.53, p=0.019)*,
3rd tertile

General population (n=77 cases and84 controls)
PFUnA
Hardell et al. 2014
General population (n=201 cases of prostatecancer and 186 controls)
Wielsøe et al. 2017
General population (n=77 cases and84 controls)
PFHpA
Wielsøe et al. 2017
General population (n=77 cases and84 controls)
PFDoDA
Wielsøe et al. 2017
General population (n=77 cases and84 controls)

Outcome evaluatedResultc

2.23 and 2.02 ng/mL (medianserum PFUnA in cases andcontrols, respectively)

Breast cancer

0.11 and 0.08 ng/mL (medianserum PFHpA in cases andcontrols, respectively)

Breast cancer

OR 6.98 (0.61–80.0, p=0.119),continuous
OR 1.52 (0.54–4.24, p=0.425),
3rd tertile

0.40 and 0.21 ng/mL (medianserum PFDoDA in cases andcontrols, respectively)

Breast cancer

OR 1.03 (1.01–1.06, p=0.447),
continuous
OR 0.93 (0.45–1.91, p=0.839),
3rd tertilePERFLUOROALKYLS

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2. HEALTH EFFECTS

Table 2-27. Summary of Cancer Outcomes in Humansa
Reference and study populationb

Serum perfluoroalkyl level

Outcome evaluatedResultc

FOSA
Bonefeld-Jorgensen et al. 2014

3.5 ng/mL (mean FOSA)

Breast cancer

RR 1.89 (1.01–3.54)*, among womenwith serum FOSA >5.75 ng/mL

General population (n=250 breast cancer cases
and 115 matched controls)aSee the Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 15 for more detailed descriptions of studies.
bParticipants in occupational exposure may have also lived near the site and received residential exposure; community exposure studies involved subjects living

near PFOA facilities with known exposure to high levels of PFOA.
cAsterisk indicates association with perfluoroalkyl; unless otherwise specified, values in parenthesis are 95% confidence intervals.

AOR = adjusted odds ratio; CI = confidence interval; FOSA = perfluorooctane sulfonamide; HR = hazard ratio; IRR = incidence rate ratio; NIOSH = National
Institute for Occupational Safety and Health; NR = not reported; NS = not significant; OR = odds ratio; PFDA = perfluorodecanoic acid; PFHxS = perfluorohexane
sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid;
RR = relative risk; RREpC = risk ratio episodes of care; SEER = Surveillance Epidemiology and End Results; SIR = standardized incidence ratio;
SMR = standardized mortality ratioPERFLUOROALKYLS

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2. HEALTH EFFECTS

1 year and allowed to recover for an additional year. A discussion of the relevance of the rodent
carcinogenicity data to humans is included in Section 2.20.6.

EPA (2016e, 2016f) has concluded that there is suggestive evidence of the carcinogenic potential of
PFOA and PFOS in humans. IARC (2017) concluded that PFOA is possibly carcinogenic to humans(Group 2B).
PFOA

Epidemiological Studies. Several studies have examined the possible association between occupational
exposure to PFOA and increased cancer risk in workers at two U.S. facilities—3M facility in Cottage
Grove, Minnesota (Gilliland and Mandel 1993; Lundin et al. 2009; Raleigh et al. 2014) and DuPont
Washington Works facility in West Virginia (Leonard 2006; Leonard et al. 2008; Steenland and Woskie
2012; Steenland et al. 2015). In addition, the potential carcinogenicity of PFOA has been assessed in thecommunity near the Washington Works facility (Barry et al. 2013; Innes et al. 2014; Vieira et al. 2013)
and in the general population (Bonefeld-Jorgensen 2011, 2014; Eriksen et al. 2009; Hardell et al. 2014).

Occupational exposure studies have not found increases in the risk of all cancer deaths (Gilliland andMandel 1993; Leonard 2006; Leonard et al. 2008; Lundin et al. 2009; Raleigh et al. 2014; Steenland andWoskie 2012). The occupational exposure studies have consistently found no increases in the risk ofpancreatic, liver, or respiratory tract cancers or deaths from these cancers (Leonard 2006; Leonard et al.
2008; Lundin et al. 2009; Raleigh et al. 2014; Steenland and Woskie 2012); a general population casecontrol study also found no associations between serum PFOA and pancreas or liver cancer (Eriksen et al.
2009). Additionally, two case-control studies did not find associations between serum PFOA levels andrisk of breast cancer (Bonefeld-Jorgensen et al. 2011, 2014); a third case-control study found an
association between serum PFOA and breast cancer (Wielsøe et al. 2017). Steenland et al. (2015) foundan inverse association between estimated cumulative PFOA exposure and bladder cancer in workers;other studies have not found associations (Eriksen et al. 2009; Gilliland and Mandel 1993; Leonard 2006;
Leonard et al. 2008; Raleigh et al. 2014; Steenland and Woskie 2012).

Some associations between PFOA and cancer effects have been observed, including prostate, kidney, andtesticular cancers. Ten years of employment in the Chemical Division of the 3M Cottage Grove facility
was associated with a 3.3-fold increase in the relative risk of prostate cancer mortality, as compared to no
employment in PFOA production areas (Gilliland and Mandel 1993; data also reported in Gilliland 1992);

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2. HEALTH EFFECTS

no increase in prostate cancer risk was observed when all workers in the Chemical Division wereanalyzed. The investigators noted that the prostate cancer findings are based on a small number of casesand could have resulted from chance or unrecognized confounding from exposure to other factors. An
update of this study conducted by Lundin et al. (2009) did not find an increase in prostate cancer deaths inworkers with definite PFOA exposure. When the cohort was divided into the three exposure categories
and duration of definite exposure, increased risks for prostate cancer were found in the high-exposure
category and in workers with definite exposure for at least 5 years, as compared with workers in the lowexposure category and with the shortest cumulative exposure duration, respectively. Interpretation of the
Gilliland and Mandel (1993) and Lundin et al. (2009) studies is limited by the qualitative assessment ofpotential exposure and the fact that workers in the low exposure categories were likely research-anddevelopment professionals rather than production workers (Raleigh et al. 2014). In the most recent
evaluation of the Cottage Grove facility, which involved extensive exposure assessment, Raleigh et al.
(2014) did not find increases in prostate cancer deaths when compared to the general population or toworkers at another facility and did not find an increase in the incidence of prostate cancer when theworkers were categorized by cumulative exposure levels. Studies of the Washington Works facility
workers did not find increases in prostate cancer deaths (Leonard et al. 2008; Steenland and Woskie2012) or incidence (Steenland et al. 2015). A case-control general population study by Hardell et al.
(2014) did find an increase in prostate risk only among subjects with a heredity risk (first-degree relativewith prostate cancer) and serum PFOA levels above the median. In a study of community members,
Ducatman et al. (2015b) did not find an association between prostate-specific antigen (PSA) levels andserum PFOA levels in men 20–49 or 50–69 years of age.

In the earliest cancer assessment of workers at the Washington Works facility (Leonard 2006; Leonard etal. 2008), an increase in the number of deaths from kidney cancer relative to workers at other regional
DuPont facilities was observed; however, the CI included unity. In a follow-up study that used serum
PFOA levels collected in current workers to assess job title exposure (Steenland and Woskie 2012), an
increase in kidney cancer deaths was observed in workers with the highest exposures when analyzed withno lag, a 10-year lag, or a 20-year lag. Steenland and Woskie (2012) also found an increase in deaths
from mesothelioma; the investigators noted that this was likely due to asbestos exposure. Steenland andWoskie (2012) noted that tetrafluoroethylene, a rodent kidney carcinogen, is used in the manufacture of avariety of fluoropolymers and noted that the tetrafluoroethylene is well controlled due to its volatile andexplosive properties. It is noted that in a multisite study of tetrafluoroethylene workers, which included
workers at the Washington Works facility (Consonni et al. 2013), an increased risk of renal cancer (SMR
1.44, 95% CI 0.69–2.65) was found, although the CI included unity. Consonni et al. (2013) noted that

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2. HEALTH EFFECTS

88% of the workers were also exposed to PFOA. When PFOA exposure was used as an exposure
variable, the findings were the similar as when tetrafluoroethylene was used as the exposure variable, andthus, it was difficult for the investigators to evaluate separate associations for each compound. It is notedthat increases in kidney deaths were not observed in the Cottage Grove facility (Raleigh et al. 2014),
which did not use tetrafluoroethylene (Chang et al. 2014).

Three studies have examined the community living near the Washington Works facilities; some of thesestudies also included workers at the facility. Barry et al. (2013) reported an increased risk of testicularcancer that was associated with estimated cumulative PFOA exposure. Vieira et al. (2013) also reported
an increase in testicular cancer, but the CIs of the adjusted odds ratio (AOR) included unity. When theparticipants were grouped by water district, an increased risk of testicular cancer (AOR 5.1, 95% CI 1.6–
15.6) was observed in the Little Hocking water district, which had the highest PFOA levels in the water.
The Vieira et al. (2013) study also found increased risks of kidney cancer among participants with high orvery high exposure to PFOA; Barry et al. (2013) also concluded that there was an association between
estimated cumulative PFOA exposure and kidney cancer, although the CIs for the hazard ratio included
unity. The third study of the Washington Works community found an inverse association between serum
PFOA and risk of colorectal cancer (Innes et al. 2014).

In their review of the available epidemiological data, IARC (2017) concluded that the evidence fortesticular cancer was “considered credible and unlikely to be explained by bias and confounding,however, the estimate was based on small numbers.” Similarly, IARC (2017) concluded that the evidence
for kidney cancer was also credible but noted that chance, bias, and confounding could not be ruled out
with reasonable confidence. They considered that there was limited evidence in humans for the
carcinogenicity of PFOA.

Laboratory Animal Exposure Studies. Two studies have examined the carcinogenic potential of PFOA
in rats. In the first study of male and female Sprague-Dawley rats exposed to PFOA in the diet for 2 years(3M 1983; Butenhoff et al. 2012c), significant increases in the incidence of fibroadenoma of the
mammary gland in females and Leydig cell adenoma were found in males exposed to 15 mg/kg/day. A
high incidence of pituitary adenoma occurred among all groups, including controls. The incidence ofhepatocellular carcinoma was not significantly increased. The investigators noted that the incidence offibroadenoma in the mammary gland in the 15 mg/kg/day group was similar to the incidence found in
untreated aging rats and that the incidence of Leydig cell adenoma was similar to the spontaneous
incidence of this tumor in aged rats. The mammary gland pathology slides from this study (3M 1983;

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2. HEALTH EFFECTS

Butenhoff et al. 2012c) study were re-examined in 2005 by a Pathology Working Group (PWG) using
current diagnostic criteria (Hardisty et al. 2010). The incidences of fibroadenoma found by the PWG
were 36, 44, and 46% in the 0, 1, and 15 mg/kg/day groups, respectively; there were no statisticallysignificant differences between the groups (Hardisty et al. 2010). Additionally, there were no significant
differences in the incidence of adenocarcinoma, total benign neoplasms, or total malignant neoplasms
between the groups. In the second study of male Sprague-Dawley rats exposed to PFOA in the diet for
2 years (Biegel et al. 2001), an increase in the incidence of hepatocellular adenomas was found, but there
were no hepatocellular carcinomas in the treated group. PFOA also increased the incidence of Leydig
cell adenomas. In addition, PFOA increased the incidence of pancreatic acinar cell adenomas; apancreatic carcinoma was observed in one treated rat. Hepatic peroxisome proliferation was increased
significantly at all interim evaluation time points (1, 3, 6, 9, 12, 15, 18, and 21 months), but there was noincrease in cell proliferation. In Leydig cells, neither peroxisome proliferation nor cell proliferation wereincreased.

PFOA was a positive modulator of hepatocarcinogenesis in male Wistar rats in a biphasic (initiation with
diethylnitrosamine followed by oral treatment with PFOA) or triphasic (initiation with diethylnitrosamine[DEN] followed by dosing with 2-acetylaminofluorene and then PFOA) promotion protocol (Abdellatif etal. 1991, 2004). PFOA induced a marked increase in acylCoA oxidase activity and only a slight increasein catalase activity (Abdellatif et al. 2004). Since PFOA did not significantly increase 8-hydroxydeoxyguanosine (a marker of oxidative DNA damage in vivo) in isolated liver DNA, it appeared thatPFOA did not require extensive DNA damage for its promoting activity (Abdellatif et al. 2004). PFOA
was also found to act as a promoter in male Wistar rats in an initiation-selection-promotion protocol(Nilsson et al. 1991).

IARC (2017) concluded that there was limited evidence in experimental animals for the carcinogenicityof PFOA.
PFOS

Epidemiological Studies. Four studies have evaluated the carcinogenic potential in workers at a Decatur,
Alabama perfluorooctanesulphonyl fluoride (PFOSF) based fluorochemical production facility. In theearliest study, no increase in all cancer deaths was found, as compared to the Alabama general population(Alexander et al. 2003). An increased risk of bladder cancer was observed in workers with high potential
exposure and in workers with a high potential exposure for ≥1 year; the mortality ratio was based on threePERFLUOROALKYLS

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2. HEALTH EFFECTS

cases in the high exposure group. In a reanalysis of workers at this facility conducted by Alexander andOlsen (2007), 11 cases of bladder cancer were identified from worker surveys (n=6) and death certificates(n=5). Only two of the six self-reported bladder cancer diagnosis were confirmed via medical records;
the other four subjects declined to give consent for medical verification. When compared to incidence
data from the National Institute for Occupational Safety and Health (NIOSH) Surveillance Epidemiology
and End Results (SEER) referent data, the standardized incidence ratios for the high potential exposuregroup were elevated, but the CIs included unity. When compared with workers with <1 year of highexposure, workers with 5–<10 and ≥10 years of high exposure had relative risks of 1.92 (95% CI 0.30–
12.06) or 1.52 (95% CI 0.21–10.99). Although the study did not adjust for smoking, the investigators
noted that 83% of the living bladder cancer cases (five of the six subjects) reported cigarette use, ascompared to 56% reported in the noncases. An additional limitation of the study is inclusion of four casesof bladder cancer that were not verified by medical records. The results of this study do not appear to
confirm the findings of increased bladder cancer in the mortality study (Alexander et al. 2003). In a
subsequent study of this facility, treatment for bladder cancer was not reported among current workers(Olsen et al. 2004a). The study did find increases in the number of episodes of care for malignant
neoplasm of the prostate or malignant neoplasms of the colon, as compared to long-term workers inanother division, but the CIs included unity. No increases in the risk ratio episodes of care were found forliver, rectum, or respiratory tract (Olsen et al. 2004a). A fourth study of this facility (Grice et al. 2007)
examined possible associations between colon cancer, melanoma, and prostate cancer and PFOS
exposure. The risks of these cancers were not associated with any of the PFOS-exposure categories foranalyses that included all self-reported or only validated cancers.

General population case-control studies have evaluated several cancer types. Innes et al. (2014) reported
an inverse association between PFOS and colorectal cancer. A small-scale study of 31 cases byBonefeld-Jorgensen et al. (2011) found a slight increase in breast cancer risk, a finding not replicated inanother larger study of a different population (Bonefeld-Jorgensen et al. 2014). A third case-control study
found associations between serum PFOS and breast cancer in subjects with serum PFOS levels in thesecond tertile and higher (Wielsøe et al. 2017). Eriksen et al. (2009) and Hardell et al. (2014) did not findincreases in the risk of prostate cancer associated with serum PFOS. However, an increased risk of
prostate cancer was found among subjects with a first-degree relative with prostate cancer and PFOS
levels above the median level (Hardell et al. 2014). Eriksen et al. (2009) also found no associations
between serum PFOS and the risk of bladder cancer, pancreatic cancer, or liver cancer. Ducatman et al.
(2015b) did not find an association between serum PFOS levels and PSA levels in men participating in
the C8 studies.

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2. HEALTH EFFECTS

Laboratory Animal Studies. In a 2-year PFOS dietary exposure study bioassay in male and female
Sprague-Dawley rats (Butenhoff et al. 2012b; unpublished study by Thomford 2002b), a significant
positive trend of hepatocellular adenoma was observed in males; the incidence was significantly higher
than controls at 1.04 mg/kg/day. No hepatocellular adenomas were seen in a group of rats exposed to1.17 mg/kg/day for 1 year and allowed to recover for the second year. High-dose males from therecovery group showed a significant increase in thyroid follicular cell adenoma relative to controls. No
significant increase in this type of tumor was observed in rats exposed for 2 years. In females, there was asignificant positive trend for incidences of hepatocellular adenoma, which was associated with asignificant increase in the 1.04 mg/kg/day group. In females, there were also significant negative trends
for mammary adenoma and fibroadenoma carcinoma combined.
PFHxS

Epidemiological Studies. Three case-control studies have examined the possible association between
serum PFHxS and cancer. Bonefeld-Jorgensen et al. (2014) found in inverse association between PFHxSlevels and breast cancer risk. In contrast, Wielsøe et al. (2017) found a positive association between
serum PFHxS levels and breast cancer risk. No association between PFHxS and prostate cancer wasobserved (Hardell et al. 2014), with the exception of increased risk in men with a first-degree relativewith prostate cancer and above-median serum PFHxS levels. No associations between serum PFHxS and
PSA levels were observed in a cross-sectional study of men 20–49 or 50–69 years of age participating in
the C8 Health Studies (Ducatman et al. 2015b).

PFNA

Epidemiological Studies. The carcinogenic potential of PFNA has been examined in three case-control
studies. No consistent associations between serum PFNA levels and breast cancer (Bonefeld-Jorgensen etal. 2014; Wielsøe et al. 2017) or prostate cancer (Hardell et al. 2014) were found. Serum PSA levels were
not associated with serum PFNA levels in men participating in the C8 Health Study (Ducatman et al.
2015b).

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2. HEALTH EFFECTS

PFDA

Epidemiological Studies. Hardell et al. (2014) examined the possible association between the serum
PFDA level and risk of prostate cancer and only found an association in men with a heredity risk factor
and PFDA levels above the median. In a case-control study of breast cancer, Wielsøe et al. (2017) foundan association among women with serum PFDA levels in the third quartile.
PFUnA

Epidemiological Studies. An increased risk of prostate cancer was found in men with first-degree
relatives with prostate cancer and serum PFUnA levels above the median (Hardell et al. 2014). An
increased breast cancer risk was found in women with serum PFUnA levels in the third quartile (Wielsøe
et al. 2017).

PFHpA

Epidemiological Studies. One study evaluated possible associations between serum PFHpA and cancer
risk and found no association for breast cancer (Wielsøe et al. 2017).
PFDoDA

Epidemiological Studies. In the only cancer study for PFDoDA, Wielsøe et al. (2017) did not find anincreased risk of breast cancer in women associated with serum PFDoDA levels.

FOSA

Epidemiological Studies. Bonefeld-Jorgensen et al. (2014) reported an increased risk of breast cancer
among women with serum FOSA levels >5.75 ng/mL.
2.20 MECHANISM OF TOXICITY
The primary effects observed in rodents exposed to perfluoroalkyls are liver toxicity, developmental
toxicity, and immune toxicity. The cellular mechanisms by which hepatic effects are induced have been
extensively studied, while more limited data are available on mechanisms for other effects. The available

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2. HEALTH EFFECTS

data indicate that perfluoroalkyls produce a number of adverse effects through activation of the PPARα, amember of the nuclear receptor superfamily that mediates a broad range of biological responses(Issemann and Green 1990). However, some adverse effects of perfluoroalkyls occur through PPARαindependent mechanisms, which may include activation of other nuclear receptors, increased oxidative
stress, dysregulation of mitochondrial function, and inhibition of gap junction intercellularcommunication (GJIC). In the sections below, cellular mechanisms of action that are mediated by
PPARα and independent of PPARα are discussed, followed by discussions of mechanisms specific to thehepatic, developmental, immunotoxic, and hormone effects of perfluoroalkyls.
2.20.1 Cellular Mechanisms of Toxicity
PPARα-Dependent Mechanisms
Activation of the PPARα receptor in rodents initiates a characteristic sequence of morphological andbiochemical events, principally, but not exclusively, in the liver. These events include marked
hepatocellular hypertrophy due to an increase in number and size of peroxisomes, a large increase inperoxisomal fatty acid β oxidation, increased cytochrome 450-mediated ω hydroxylation of lauric acid,and alterations in lipid metabolism. Although there is uncertainty regarding the exact and possibly,
multiple mechanisms for liver effects of perfluoroalkyls, peroxisome proliferation mediated by PPARα is
a contributing mechanism. Proliferation of peroxisomes in laboratory animals exposed to perfluoroalkyls
is discussed in Section 2.9 (Hepatic); as discussed in that section, hepatic peroxisome proliferation has
been shown in rats exposed to PFOA and in mice exposed to PFDA.

Many, but not all, of the adverse effects induced by perfluoroalkyls in rodents are mediated throughactivation of the PPARα. Ligands, including perfluoroalkyls, bind to and activate PPARα, causing a
conformational change in the receptor that leads to dissociation of co-repressors and enables
heterodimerization with the retinoid X receptor (Corton et al. 2014). The activated receptor complex
binds to a DNA direct repeat motif (the peroxisome proliferator response element or PPRE) located in the
promoters of peroxisome proliferator responsive genes. The binding of the receptor complex leads torecruitment of co-activators, which acetylate histones and remodel chromatin, enabling RNA polymerase
to transcribe the target gene(s). PPARα regulates lipid homeostasis by modulating the expression ofgenes involved in fatty acid uptake, activation, and oxidation. Activation of nuclear receptors including
PPARα is a complex, dynamic process that depends on levels of expression of the receptors in different

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2. HEALTH EFFECTS

tissues, competition among receptors for endogenous and exogenous ligands and for binding sites onchromatin, and availability and abundance of co-activators and/or co-repressors (Corton et al. 2014).
PPARα Receptor Activation. Many perfluoroalkyls, including PFOA, PFOS, PFUnA, PFHpA, andPFDoDA have been shown to activate PPARα in mammalian cells in vitro (Bjork and Wallace 2009;
Bjork et al. 2011; Shipley et al. 2004; Takacs and Abbott 2007; Vanden Heuvel et al. 2006; Wolf et al.
2008b, 2012). Cell systems used in these studies include COS-1 cells expressing mouse, rat, or human
PPARα, and cultured rat, mouse, and human hepatocytes. In these studies, perfluoroalkyl sulfonate
compounds were less potent than perfluoroalkyl carboxylate compounds in activating PPARα-induced
gene expression, and the potency of stimulation within each class increased with carbon chain length(Bjork and Wallace 2009; Wolf et al. 2008b, 2012). In comparison with naturally occurring long-chain
fatty acids such as linoleic and α linoleic acids, PFOA and PFOS are relatively weak ligands for PPARα(Vanden Heuvel et al. 2006)
PPARα-Dependent Gene Expression Changes. Perfluoroalkyls have been shown to induce changes inthe expression of genes under the regulation of PPARα. The expression of PPARα target genes in theliver involved in fatty acid metabolism, cell cycle control, peroxisome biogenesis, and proteasome
structure and organization were upregulated, while inflammatory response genes in the liver were
downregulated in wild-type mice exposed orally to PFOA or the PPARα agonist WY-14,643 (Rosen et al.
2008a). Furthermore, PFOA and PFDA have been shown to downregulate, via PPARα activation, genes
involved in bile transport in the livers of wild-type mice exposed by intraperitoneal administration (Cheng
and Klaassen 2008a). Both compounds decreased expression of organic anion transporting polypeptides[OATP1a1, 1a4, and 1b2], and PFDA also downregulated sodium-taurocholate cotransporting
polypeptide [Nctp], via activation of PPARα. Many of these expression changes may play roles in thehepatic effects of perfluoroalkyls.

Gene expression changes induced by perfluoroalkyls have been extensively studied in experiments aimed
at determining the extent to which the adverse effects of these compounds are dependent on activation of
PPARα or interaction with other nuclear receptors (Foreman et al. 2009; Rosen et al. 2008a, 2008b, 2010,2017). These studies, comparing gene expression changes in wild-type and PPARα-null mice exposed toperfluoroalkyls, demonstrate the following:•

A majority of the gene expression changes induced in rodents by perfluoroalkyls tested to date,especially PFOA and PFNA, are dependent on activation of PPARα.

PERFLUOROALKYLS

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2. HEALTH EFFECTS•

Perfluoroalkyls also induce gene expression changes that are independent of PPARα.

•The extent to which gene expression changes induced by perfluoroalkyls are dependent on
activation of PPARα varies by compound.

Species Differences in PPARα Activation. Species differences in response to PPARα activators havebeen reviewed by Corton et al. (2014). Studies of PPARα activation by structurally diverse ligands invarious species have shown that rats and mice are the most sensitive species to PPARα agonists, whereas
guinea pigs, hamsters, nonhuman primates, and humans are less responsive (Corton et al. 2014).
However, the differences do not appear to result from differences in the PPARα gene itself: PPARαcDNA from humans is indistinguishable from the rodent PPARα. Species differences in response toexogenous PPARα activators may stem from any or all of the following: (1) differences in the expressionof PPARα in a given tissue; (2) differences in the gene product structure; and (3) differences in theligand-mediated transactivation of PPARα. Experiments quantifying mRNA and/or protein levels of
PPARα show ~10-fold higher expression of PPARα in the livers of mice and rats compared with humans
and guinea pigs, but available data are limited and require further study to validate these differences(Corton et al. 2014). In humans, variants of PPARα that may affect its transactivation potential have been
identified. For example, humans produce higher levels of a truncated PPARα (that lacks a ligand binding
domain) compared with mice and rats (Corton et al. 2014). The truncated form appears to inhibit theactivity of the full-length receptor, possibly via sequestering critical co-activators. Other, non-truncatedvariants of PPARα have been identified in humans, but the sensitivity of these variants to PPARα
activators does not differ markedly from that of the wild-type receptor.
Species and compound-related differences in PPARα transactivation by perfluoroalkyls have been
demonstrated in vitro (Shipley et al. 2004; Takacs and Abbott 2007; Vanden Heuvel et al. 2006; Wolf et
al. 2008b, 2012). In a comparison of human and mouse PPARα transactivation by different
perfluoroalkyls in transfected COS-1 cells, Wolf et al. (2008b, 2012; see Table 2-28) found that someperfluoroalkyls exhibited marked species differences in transactivation potency (for example, PFUnA,PFDA, PFDoDA), while other compounds showed similar transactivation potency for both human andmouse PPARα (for example, PFNA, PFOA, perfluoropentanoic acid [PFPeA]).

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Table 2-28. Transactivation of Human and Mouse PPARα in Transfected Cos-1
Cells Exposed to Perfluoroalkyls (In Order of Decreasing C20max in the Mouse)

Carbonnumber

NOEC
(µM)

PFNA

9

1

PFOAb

8

5, 0.5

PFUnA

11

50

PFHpA

7

<0.5

Perfluoroalkyl

Mouse
NOEC
LOEC
LOEC (µM) (µM)(µM)

C20max (µM)a

Human

5

Human

Mouse

1

5

11

5

0.5, 1

1, 3

7

6

75

5

10

86

8

0.5

3

5

15

11

<5

5

–

20

10,1

PFDA

10

100

>100c

PFDoDA

12

75

90

3

5

NA

33

PFPeA

5

0.5

1

1

5

52

45

PFHxA

6

5

10

10

20

86

45

PFBA

4

30

40

30

40

75

51

PFHxS

6

5

10

10

20

81

76

PFOS

9

20

30

60

90

262

94

PFBS

4

20

30

120

150

206

317

aPerfluoroalkyl concentration yielding 20% of maximum response given by the most active compound (PFNA).
bResults from two separate experiments.

cSlope for human PPARα dose-response line was not significant.

– = not active; LOEC = lowest-observed-effect concentration; NA = not available; NOEC = no-observed-effectconcentration; PFBA = perfluorobutanoic acid; PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoicacid; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid;
PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFPeA = perfluoropentanoic acid;PFUnA = perfluoroundecanoic acid; PPAR = peroxisome proliferator activated receptor
Source: Wolf et al. 2008b, 2012

In addition to differences in transactivation of PPARα, Corton et al. (2014) noted that there are species
differences in the transcripts controlled by PPARα. While PPARα activation leads to hypolipidemicchanges in both humans and laboratory rodents, the gene sets responsible for these changes may differ. In
a comparison between human and mouse hepatocytes exposed to the prototypical PPARα ligand
WY-14,643, some genes (ACOX1, ECH1, PEX11A, and ACAA1) were induced in both species, whilesome (Ehhadh, Pxmp4, Acot4, and Peci) were induced only in mouse hepatocytes (Corton et al. 2014).
Importantly, PPARα activators induce large increases in the expression of fatty acyl-CoA oxidase (ACO,
which is believed to play a role in oxidative stress-induced liver cancer) in rodent hepatocytes, but
relatively weak increases in human hepatocytes (Corton et al. 2014). Other hypothesized explanations forthe species difference in response to exogenous PPARα ligands include variations in the structure of thePERFLUOROALKYLS

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PPRE that alter the response of the human genes compared with rodents; differences between humans androdents in the functions of genes under the regulation of PPARα; and differences in the ability of ligandbound human and mouse PPARα receptor complex to recruit or interact with co-activators (Corton et al.
2014).

PPARα-Independent or Associative Mechanisms
Experiments using PPARα-null mice have demonstrated that perfluoroalkyls exert some adverse effects,
including developmental and hepatic effects, through mechanisms other than activation of PPARα. Thesemay include activation of other nuclear receptors, increased oxidative stress, dysregulation of
mitochondrial function, and inhibition of GJIC. While some of these effects have been seen after
exposure to PPARα activators (Corton et al. 2014), these mechanisms may also occur independent of
PPARα activation.
Activation of Other Nuclear Receptors. Examination of gene expression changes, as well as studies
using other knock-out mice, have shown that some of the PPARα-independent effects induced byperfluoroalkyls may be mediated by activation of other nuclear receptors, especially PPARγ, CAR, andERα. In a series of experiments, Rosen et al. (2008b, 2010, 2017) compared the gene expression changes
induced by perfluoroalkyls in wild-type and PPARα -null mice with gene expression changes induced by
known agonists of PPARγ, CAR, and ERα. Using these data, the study authors estimated the percentage
of gene expression changes that were independent of activation of PPARα, and identified other nuclear
receptors potentially involved in the changes induced by the perfluoroalkyls. The results, summarized inTable 2-29, show that between 10 and 24% of gene expression changes induced by perfluoroalkyls are
independent of PPARα. All four compounds tested (PFOA, PFOS, PFNA, and PFHxS) were shown toalter the expression of PPARγ- and CAR-regulated genes in PPARα-null mice, and PFNA and PFHxS
also altered the expression of ERα-regulated genes in the knock-out mice. In contrast, none of thecompounds altered the expression of genes commonly affected by an agonist of LXR in either wild-type
or null mice.

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Table 2-29. Gene Expression Changes Induced by Perfluoroalkyls
Gene expression changes similar to those induced byprototypical agonist% PPARαPPARγ
CAR
ERα
LXR
Dose
independent(mg/kg/day gene
PPARαPPARαPPARαPPARαfor 7 days) changes
WT null
WT null
WT null
WT null
PFOA
PFOS
PFNA
PFHxS
WY14,643a

3
10

~14
~16

+
+

+
+

+
+

+
+

+
+

–
–

–
–

–
–

1
~10
3
~17
3
24
10
22
0.1% in diet
2

+
+
+
+
+

+/–
+
–
+
–

+
+
+
+
–

–
+
–
+
–

+
+
+
+
+

–
+
+
+
–

–
–
–
–
–

–
–
–
–
–

aWY-14,643 is a PPARα agonist.

+ = significant (p<0.0001) similarity to gene expression changes induced by prototypical receptor agonist as
assessed by running Fisher test; +/– = equivocal evidence; CAR = constitutive androstane receptor; ER = estrogen
receptor; LXR = liver X receptor; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PPAR = peroxisome proliferator activatedreceptor; WT = wild-type
Sources: Rosen et al. 2017, 2008b, 2013; Wolf et al. 2008b

Gene expression changes typical of CAR and PXR activators (phenobarbital and pregnenolone
16 α-carbonitrile [PCN]) were also observed in rat liver after oral exposure to PFOA and PFOS (Ren et al.
2009). In addition, PFDA was shown to activate CAR-dependent genes in a study comparing wild-type
and CAR-null mice exposed by intraperitoneal injection (Cheng and Klaassen 2008b).

These data suggest that perfluoroalkyls may induce gene expression changes through activation of othernuclear receptors including PPARγ, CAR, and ERα. Support for these findings are available from in vitro
studies demonstrating binding and/or transactivation of PPARγ, CAR, and ERα by perfluoroalkyls. BothPFOA and PFOS activated PPARγ in cultured human, mouse, and rat hepatocytes, albeit with much
lower potency than the known agonist rosiglitazone; neither LXRβ nor RXRα was activated in thissystem (Vanden Heuvel et al. 2006). Zhang et al. (2014) observed binding of PFOA and PFOS to human
PPARγ in transfected Escherichia coli. However, in experiments conducted by Takacs and Abbott(2007), neither PFOA nor PFOS activated the mouse or human PPARγ.

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Oxidative Stress. Perfluoroalkyls increase oxidative stress in the liver, kidney, and brain. Increases inoxidative stress may be mediated in part via PPARα activation, but may also result from activation of theNrf2 receptor (Xu et al. 2016).

Oxidative stress may contribute to oxidative DNA damage, tumor promotion, perturbation of lipid
homeostasis, and stimulation of inflammation, among other changes; thus, increases in oxidative stresscan have diverse physiological effects. Evidence that perfluoroalkyls increase oxidative stress is available
from in vivo and in vitro studies. For example, oxidative DNA damage (measured as 8-OH-dG levels)
was significantly increased in the liver, but not the kidneys, of male rats exposed to PFOA via feed for
2 weeks (Takagi et al. 1991). In HepG2 cells cultured with PFOA or PFOS, significant increases inreactive oxygen species (ROS) (measured as 2’7’-dichlorofluorescein diacetate fluorescence) wereobserved, but there was no evidence of DNA damage measured with the comet assay (Eriksen et al.
2010). In this system, PFNA, PFBS, and PFHxA did not induce ROS production, but a significant
increase in DNA damage was seen in cells exposed to PFNA (Eriksen et al. 2010).

In male, but not female, KM mouse pups administered a single subcutaneous injection of PFOS at 1, 2, 3,
4, or 5 weeks of age, brain total antioxidant capacity (T-AOC) was lower than controls at most time
points, and significantly decreased after treatment on PND 21 (Liu et al. 2009). In the liver, T-AOC wasdecreased in male pups treated on PNDs 7 and 14, and in females treated on PND 21. Significant
decreases in superoxide dismutase (SOD) activity were noted in the brain of males treated on PNDs 7 and21, and in the liver of females treated on PND 14.
Increases in oxidative stress can lead to NFκB activation (Corton et al. 2014). NFκB activation plays arole in tumorigenesis, and NFκB transcription factors coordinate immune responses. Few studies haveexamined NFκB activation after exposure to perfluoroalkyls. An increase in NFκB mRNA level was seenin the hippocampus of neonatal rats exposed to PFOS in utero (Zeng et al. 2011). In addition, NFκB
nuclear translocation was accelerated, and NFκB was activated, in breast cancer cells exposed to PFOA
(Zhang et al. 2014). The activation of NFκB was associated with increased invasiveness of the breast
cancer cells, as coexposure to an inhibitor of NFκB reduced the invasiveness induced by PFOA.
Gap Junction Intercellular Communication (GJIC) Inhibition. Perfluoroalkyls also have been shownto inhibit GJIC both in vivo and in vitro in rats (Corton et al. 2014). GJIC plays an important role inmaintenance of tissue homeostasis, intercellular transmission of regulatory signals, and metaboliccooperation. Disruption of GJIC is thought to be involved in neurological, reproductive, and endocrinePERFLUOROALKYLS

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abnormalities, as well as in carcinogenesis (Corton et al. 2014; EPA 2016h). There are limited data
examining the effects of perfluoroalkyls on GJIC. The available studies showed that both PFOA andPFOS inhibited GJIC in the livers of rats exposed via diet for 1 week or 3 or 21 days, respectively (Hu etal. 2002; Upham et al. 1998, 2009). In vitro studies in WB-344 rat liver epithelial cells also showed
inhibition of GJIC after exposure to PFOS (Hu et al. 2002) and to perfluorinated fatty acids with 7–
10 carbons (Upham et al. 1998, 2009). In this system, PFOA activated extracellular receptor kinase,which may play a role in the inhibition of GJIC. In addition, inhibition of phosphatidylcholine-specificphospholipase C partially mitigated the GJIC inhibition, suggesting that PFOA-induced activation of thisenzyme may also be involved in GJIC inhibition (Upham et al. 1998, 2009).

PFOS was also shown to inhibit GJIC in dolphin kidney epithelial cells and rat Sertoli cells in vitro (Hu etal. 2002; Wan et al. 2014a). In Sertoli cells, GJIC plays an important role in maintenance of theblood:testes barrier and in intercellular communication during spermatogenesis (EPA 2016i).

Impaired Mitochondrial Function. Mitochondrial function, including cellular respiration as well as
mitochondrial membrane potential, has been shown to be perturbed by perfluoroalkyls. Available datasuggest that PFOA and PFOS are relatively weak mitochondrial toxicants (EPA 2016h, 2016i).
Mitochondrial proliferation was observed in rats exposed orally to PFOA for 28 days and in mice exposed
to PFOA during gestation and lactation (Quist et al. 2015a, 2015b; Waters et al. 2009). In isolated rat
liver mitochondria, higher concentrations of either PFOA or PFOS were noted to slightly increase resting
respiration rate and decrease membrane potential, possibly due to these compounds’ effects on membrane
fluidity (Starkov and Wallace 2002). Testing of other perfluoroalkyls for effects on mitochondrial
respiration rate and oxidative phosphorylation showed a wide range of inhibitory activities, with PFOS
demonstrating the highest potency (3-fold higher than PFOA and 20–30-fold higher than PFBS andPFHxA) (Wallace et al. 2013).
2.20.2 Hepatic Toxicity Mechanisms
Hepatic effects of perfluoroalkyls in rodents likely result from a combination of PPARα-dependent andindependent changes; see Table 2-30. For example, increased liver weight has been observed in bothwild-type and PPARα-null mice orally exposed to PFOA or APFO (Nakagawa et al. 2012; Rosen et al.
2008a), PFOS (Qazi et al. 2009b; Rosen et al. 2010), PFNA (Das et al. 2017; Rosen et al. 2017), or
PFHxS (Das et al. 2017; Rosen et al. 2017), but not in null mice exposed to PFBA by intraperitoneal
injection (Foreman et al. 2009). Similarly, both wild-type and PPARα-null mice exposed to APFOPERFLUOROALKYLS

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exhibited increased hepatocyte vacuolation and proliferation, while exposure to WY-14,643 did not
induce such changes in the null mice (Wolf et al. 2008b). Das et al. (2017) showed that PFOA, PFNA,
and PFHxS also increased hepatocyte cell size, percent lipid, and hepatic triglyceride levels, anddecreased hepatic DNA content, in both wild-type and PPARα-null mice, while WY-14,643 did not,indicating that these effects were not dependent on PPARα activation. Similarly, Nakagawa et al. (2012)
showed that at a lower APFO dose (1.0 mg/kg/day for 6 weeks), increases in hepatic triglyceride levels
were observed in wild-type, PPARα-null, and humanized PPAR (hPPAR) mouse strains; however, at ahigher dose (5 mg/kg/day), hepatic triglyceride levels were still increased in PPARα-null and hPPAR
mice, but decreased in wild-type mice.

Table 2-30. Hepatic Effects of Perfluoroalkyls in Wild-Type and PPARα-Null Mice
Exposed Orally↑ Relative liver ↑ % Lipid by↑ Hepatic↑ Hepatocyte ↓ Hepatic DNA
weightcell area
triglycerides
cell size
content
Dose
PPARαPPARαPPARαPPARαPPARα(mg/kg/day) WT
null
WT
null
WT null
WT null
WT null
PFOA
3+++ ++++++ +++ +++ +++
+
+
PFOS
10
++
++
ND
1
++
+
ND
PFNA
3
+++ ++
10+++ ++++++ ++++++ ++++++ ++
+
+
3
+
+
ND
PFHxS
10
+++ ++++++ ++++++ –+++ +++++
WY-14,643a 50
+++ –
+++ –
–
–
+++ –
+
–
aWY-14,643 is a PPARα agonist.

+ = statistically significant change from control (the number of plus signs indicates degree of change from controls);– = not statistically significantly different from control; DNA = deoxyribonucleic acid; ND = no data;
PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid; PPAR = peroxisome proliferator activated receptor; WT = wild type
Sources: Das et al. 2017; Rosen et al. 2008a, 2010, 2017

Lipid homeostasis is maintained through a balance between fatty acid synthesis or accumulation and fatty
acid oxidation. Available data indicate that perfluoroalkyls affect both sides of this balance, but agrowing body of evidence indicates that fatty acid accumulation induced by perfluoroalkyls tips thebalance in favor of hepatic steatosis (Das et al. 2017). As discussed above, perfluoroalkyls alter lipid
homeostasis via PPARα activation, which upregulates genes involved in fatty acid oxidation and reduces
lipid levels. However, as noted above, Das et al. (2017) indicate that perfluoroalkyls also perturb lipid
homeostasis via PPARα-independent mechanisms. In addition to the effects noted in Table 2-30,
increased incidences of hepatic steatosis were seen in PPARα-null mice exposed to perfluoroalkyls (DasPERFLUOROALKYLS

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2. HEALTH EFFECTS

et al. 2017; Minata et al. 2010; Nakagawa et al. 2012), but not in those exposed to the PPARα agonist
WY-14,643 (Das et al. 2017). Additionally, microvesicular steatosis was observed in hPPAR mice
(Nakagawa et al. 2012). The findings are consistent with earlier studies showing triglyceride
accumulation in rodent livers after exposure to perfluoroalkyls (Kudo and Kawashima 1997, 2003; Kudo
et al. 1999); hepatic steatosis and glucose intolerance in adult rats exposed to PFOS during the prenatal
and postnatal periods (Lv et al. 2013); and inhibited hepatic secretion of VLDL, resulting in steatosis, in
APOE3-Leiden mice (a rodent model with lipoprotein metabolism similar to humans) exposed to PFOS
or PFHxS (Bijland et al. 2011).

Das et al. (2017) investigated whether the steatosis induced by PFOA, PFNA, and PFHxS was mediatedby increased fatty acid or triglyceride synthesis or by inhibition of mitochondrial fatty acid transport or
β-oxidation. Microarray analysis of mouse liver after exposure to these compounds showed upregulationof genes involved in fatty acid and triglyceride synthesis in both wild-type and PPARα-null mice. In
contrast, in vitro experiments demonstrated that these perfluoroalkyls did not affect mitochondrial fatty
acid oxidation in isolated rat liver mitochondria, and neither PFOA nor PFOS altered fatty acid oxidationin HepG2/C3A human liver cells. The authors suggested that perfluoroalkyls induce hepatic steatosis byperturbing lipid homeostasis in favor of the accumulation of fatty acids and triglycerides in the liver.

Data are also available to suggest that proinflammatory cytokines may also contribute to thehepatotoxicity of perfluoroalkyls. Studies in rodents have shown that in vivo exposure to PFOA (Qazi e
al. 2013; Yang et al. 2014) or PFNA (Fang et al. 2012b, 2012c) have resulted in increases in IL-6, IL-1β,tumor necrosis factor-α (TNFα), C-reactive protein, and COX-2 at higher perfluoroalkyl doses (Fang etal. 2012b, 2012c; Yang et al. 2014) and decreases in TNFα, interferon-γ (IFN-γ), IL-4, and IL-6 levels at
lower doses (Fang et al. 2012b; Qazi et al. 2013). Exposure to PFNA also resulted in increased
expression of TNFα, IL-1β, and IL-6 mRNA (Fang et al. 2012b). Nakagawa et al. (2012) found increases
in TNFα-mRNA in wild-type (2.9-fold), PPARα-null (1.9-fold), and humanized PPARα (1.9-fold) mousestrains exposed to 5 mg/kg/day doses of PFOA. Fang et al. (2012c) suggested that PFNA exposure
stimulated liver Kupffer cells to release large amounts of TNFα and IL-1β and that the release of thesecytokines activated the NFκB p65 pathway causing suppression of PPARα promoter activity and resulting
in increases in liver triglyceride levels and steatosis.

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2.20.3 Developmental Toxicity Mechanisms
Developmental effects observed in laboratory rodents exposed to perfluoroalkyls include prenatal loss,
reduced neonate weight and viability, neurodevelopment toxicity, and delays in mammary glanddifferentiation, eye opening, vaginal opening, and first estrus (see Section 2.17 Developmental). During
development, PPARα, PPARβ, and PPARγ mRNA and protein are expressed in the embryo of rodents
and humans (Abbott 2009; Abbott et al. 2010). In humans, the fetal expression levels are equivalent tolevels in adult tissues (Abbott et al. 2010). PPARα activation also appears to be involved in some, but notall, of the developmental effects of perfluoroalkyls in mice, and the role of PPARα in mediating
developmental toxicity differs among the various compounds. For example, a gestational exposure studyof PFOA resulted in decreases in postnatal survival in wild-type mice, but not in PPARα-null mice, while
the occurrence of full-litter resorptions was similar between the two genotypes (Abbott 2009; Abbott et al.
2007). In contrast, gestational exposure to PFOS resulted in decreased pup survival in both wild-type andPPARα-null mice (Abbot et al. 2009). The developmental effects of PFNA, including reduced pup
survival and body weight and delayed eye opening, were seen only in wild-type, and not in PPARα-null
mice; however, maternal pregnancy rate was affected only in the null mice (Wolf et al. 2010). No
alterations in postnatal survival or growth were observed in wild-type mice exposed to PFBA in utero(Das et al. (2008). The investigators suggested that the contrast of these findings to that of PFOA may be
due to the shorter half-life of PFBA (daily administration did not result in reaching steady-state) and that
PFBA is a less potent agonist of PPARα than PFOA.
Abbott et al. (2012) showed that PFOA altered expression of genes that are involved in homeostatic
control of lipids and glucose, and postulated that decreased neonatal survival and body weights may be, inpart, due to metabolic disruption. It has been suggested that PFOS interacts with pulmonary surfactants,
and that this effect is responsible for neonatal mortality seen in rats. Grasty et al. (2003, 2005) showedthat neonatal mortality in PFOS-exposed rats was highest when exposure occurred during the gestational
period of lung maturation (GDs 17–20), and that the morphometry of the lungs in exposed neonates wasconsistent with immaturity. However, treatment of neonates with rescue agents that hasten lungmaturation did not prevent neonatal mortality induced by PFOS, and examination of the pulmonary
surfactant profile in exposed animals showed no difference from controls, leading Grasty et al. (2005) toconclude that neonatal mortality in neonatal rats exposed to PFOS was not due to immaturity. Other
hypotheses pertaining to the mechanisms of developmental toxicity of perfluoroalkyls were not located.
However, other molecular- and cellular-level effects of perfluoroalkyls, including increased oxidative

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stress, dysregulation of mitochondrial function, and receptor-mediated events, may be involved in theobserved developmental effects of these compounds.
2.20.4 Immunotoxicity Mechanisms
NTP (2016b) conducted a systematic review of the human, animal, and in vitro data examining
immunotoxic effects of PFOA and PFOS. The conclusion of the systematic review was that both PFOA
and PFOS are “presumed to be immune hazards to humans.” Evidence was considered strong that bothcompounds were associated with suppression of the antibody response, while there was weaker evidence
for PFOA-induced impairment of infectious disease resistance, increased hypersensitivity-related
outcomes, and increased autoimmune disease incidence, and for PFOS-induced suppression of naturalkiller cell activity. A recent study comparing the T-cell dependent antibody response (TDAR) in female
wild-type and PPARα knock-out mice after exposure to PFOA with or without antigen exposure showedthat PFOA suppressed TDAR in both wild-type and knock-out mice, indicating that the mechanism for
antibody response suppression is independent of PPARα activation (DeWitt et al. 2016). These
investigators observed no treatment-related changes in splenic lymphocyte subpopulations in exposed
mice of either genotype, suggesting that PFOA suppressed TDAR via impairment of B-cell/plasma cellfunction rather than by altering lymphocyte numbers. DeWitt et al. (2012) and Corsini et al. (2014)
reviewed mechanistic data for perfluoroalkyl-induced suppression of antibody response, and postulated
that perfluoroalkyls may modulate cell-signaling responses critical to antibody production, includingc-Jun, NF-κB, and IL-6.
2.20.5 Endocrine Mechanisms
Perfluoroalkyls have been shown to induce alterations in thyroid hormone levels in rats, and associations
between serum perfluoroalkyl concentrations and thyroid hormone levels have been reported in humanepidemiological studies (see Section 2.13). Few data examining mechanisms of thyroid hormone
disruption are available, but suggest that effects of perfluoroalkyls on thyroid function may be mediatedby binding to the thyroid hormone receptor, and/or by altering expression of genes involved in thyroid
function or thyroid hormone regulation. Several perfluoroalkyls were shown to bind to the human thyroid
hormone receptor in cultured GH2 cancer cells and in molecular docking experiments (Ren et al. 2015).
In the in vitro tests, all 16 of the tested compounds exhibited lower affinity for the receptor than T3 (Renet al. 2015). Among the tested compounds, PFOS exhibited the strongest agonist activity (Ren et al.
2015). Alterations in the mRNA or protein levels of thyroid-regulating genes have been observed after
oral exposure of male Sprague-Dawley rats to PFOS. PFOS exposure for 5 or 90 days resulted inPERFLUOROALKYLS

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decreased hepatic levels of mRNA type 1 deiodinase (DIO1, which bioactivates T3 by deiodination ofT4) (Martin et al. 2007; Yu et al. 2009a); after 5 days of exposure, hepatic mRNA for type 3 deiodinase(DIO3, which inactivates T3) was increased relative to controls (Martin et al. 2007). After 90 days,
hepatic levels of uridine diphosphoglucuronosyl transferase 1A1 (UGT1A1, which plays a role in T4
turnover) mRNA and thyroid levels of DOI1 protein were increased, while there were no changes inthyroid levels of the sodium iodide symporter, thyrotropin (THS) receptor, or activity of thyroid
peroxidase (Yu et al. 2009a).

Limited data from in vitro studies suggest the possibility that perfluoroalkyls may interact with the
estrogen and androgen receptors. PFOA, PFOS, PFHxS, PFNA, and PFDA were all shown to beantagonists of the androgen receptor, while PFOA, PFOS, and PFHxS induced transactivation of the
estrogen receptor (Kjeldsen and Bonefeld-Jorgensen 2013). Recently, analysis of gene expression datafrom the livers of wild-type and PPARα-null mice exposed to PFOA, PFOS, PFHxS, and PFNA bygavage for 7 days indicated similarities to gene expression changes induced by known ERα agonists(Rosen et al. 2017), providing indirect evidence for perfluoroalkyl changes in the liver mediated via ER
activation. However, at oral doses up to 1 mg/kg, PFOA failed to induce treatment-related alterations inuterine weight, ER-dependent gene expression, or morphology of reproductive organs in uterotrophic
assays using immature CD-1 mice (Dixon et al. 2012; Yao et al. 2014), suggesting that PFOA is either
inactive in vivo or of very low estrogenic potency.
2.20.6 Cancer Mechanisms
PFOA induced hepatocellular adenomas, Leydig cell adenomas, and pancreatic acinar cell adenomas inrats (Biegel et al. 2001). Liver tumors induced by PFOA are believed to be mediated largely throughPPARα activation, and considered to be of limited or no relevance to humans (EPA 2016h), based on
species differences in response to PPARα (see details above under PPARα activation). An expert panel
convened by EPA’s Science Advisory Board in 2006 to review issues related to the toxicity of PFOA
agreed that the weight of evidence supports the hypothesis that induction of liver tumors in rats by PFOA
is mediated by a PPARα agonism mode of action (EPA 2006); this conclusion is also reflected in the EPA
Health Effects Support Document for PFOA (EPA 2016h). A recent review by a panel of experts fromacademia, government, industry, and consulting groups updated the Klaunig et al. (2003) assessment of
PPARα agonism as a liver cancer mode of action, and drew the same conclusion: while the PPARα modeof action for liver tumors is biologically plausible, species differences in response to PPARα activation
indicate that liver tumors are unlikely to be induced by PPARα induction in humans (Corton et al. 2014).

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Studies conducted in rainbow trout, an animal model that is similar to humans in terms of insensitivity toperoxisome proliferators, suggest that some perfluoroalkyls may induce liver cancer by alternate
mechanisms (Benninghoff et al. 2011, 2012). The investigators (Benninghoff et al. 2011) found that
PFOA, PFNA, PFDA, and PFUnA were potent inducers of vitellogenin, an estrogen-responsive
biomarker protein at fairly high doses. Neither PFOA nor PFDA exposure resulted in vitellogenin
expression at serum levels corresponding to general population serum levels of 2–7 ng/L. In vitro, PFOA,PFOS, PFHpA, PFNA, PFUnA, and PFDA also had weak to very weak affinities for estrogen receptors(ERα) for several species including humans, mice, and rats (Benninghoff et al. 2011). In vivo studies
demonstrated that PFOA, PFOS, PFNA, and PFDA enhanced liver carcinogenesis in AFB1 initiated fish
via a mechanism that likely involves interactions with hepatic estrogen receptors (Benninghoff et al.
2012).

Although Leydig cell tumors are commonly induced by peroxisome proliferating agents such as
perfluoroalkyls, the mode of action by which these tumors are induced, and thus their relevance tohumans, is much less clear (Corton et al. 2014; EPA 2016h; Klaunig et al. 2003). One mode of action
proposed for the induction of Leydig cell tumors involves PFOA-induced inhibition of testosterone
biosynthesis, leading to increased production of gonadotropin releasing hormone and circulating LH,
which promotes Leydig cell proliferation. Activation of PPARα may be involved in the decreased serum
testosterone levels; PPARα-null mice did not exhibit the reduction in testosterone concentration seen inwild-type mice exposed to PFOA (Li et al. 2011). Evidence of decreased serum testosterone andincreased serum estradiol was seen in studies of male rats exposed orally to PFOA for 14 days (Biegel etal. 1995; Cook et al. 1992; Liu et al. 1996). Reduced testosterone levels may occur through theconversion of testosterone to estradiol via the enzyme aromatase. Hepatic aromatase activity was shown
to be markedly increased in male rats exposed to APFO by gavage for 14 days, and aromatase activity
was positively correlated with serum estradiol levels in these animals (Liu et al. 1996). The relevance ofLeydig cell tumors induced by PFOA to human risk assessment is uncertain. For example, anintermediate-duration study in Cynomolgus monkeys exposed to PFOA did not find treatment-related
alterations in serum estradiol, estrone, estriol, or testosterone (Butenhoff et al. 2002). Studies of humans
occupationally exposed to PFOA have not consistently reported alterations in estradiol or testosterone
levels (Klaunig et al. 2012). In addition, humans are less sensitive than rats to LH stimulation, and theaverage number of LH receptors per Leydig cell is 13-fold higher in rats than humans (Klaunig et al.
2012). In summary, the induction of Leydig cell tumors by PFOA may be mediated by effects onaromatase activity or testosterone biosynthesis, both of which may be related to PPARα activation (EPAPERFLUOROALKYLS

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2016h). While the relevance of the PPARα mode of action to humans is uncertain, the data supporting
this mode of action for Leydig cell tumors is not sufficient to rule out human relevance (EPA 2016h).

The mechanism of PFOA-induced pancreatic acinar cell tumors in rodents has not been elucidated, andrelevant data are limited. A proposed mode of action involves stimulation of PPARα leading to reduced
bile flow and/or changes in bile acid composition with subsequent increase in cholecystokinin (CCK),
which stimulates pancreatic cell proliferation and tumor formation (EPA 2016h). Effects on bile acidcomposition induced by PFOA may be mediated by effects on bile acid transporters. PFOA exposure has
been shown to decrease expression of OATPs and increase expression of MRP3 and MRP4 (Cheng andKlassen 2008a; Maher et al. 2008). In a study using wild-type and PPARα-null mice, increased biliary
excretion of PFOA was seen in wild-type mice compared with null mice, and biliary excretion of bile
acids was highest in the null mice (Minata et al. 2010). These observations suggest the possibility that
increased excretion of PFOA could diminish the excretion of bile acids that require the same transporters.
However, given the limitations in available data, information is insufficient to fully characterize the modeof action for PFOA-induced pancreatic tumors (EPA 2016e).

Mechanisms of carcinogenicity of PFOA are unknown. Liver and Leydig cell tumors produced by PFOS
may be associated with PPARα activation or may involve other mechanisms. PFOS activates PPARβ/δ,γ, and CAR and PXR (Ren et al. 2009).
2.21 GENOTOXICITY
The genotoxicity of perfluoroalkyls has not been extensively studied, with the most information available
for PFOA and PFOS. To supplement the information reported in the published literature, results of
unpublished studies taken from publicly available reviews have been included in the following
discussions. No studies of genotoxicity in humans exposed to perfluoroalkyls were located.
PFOA

The genotoxicity of PFOA has been examined in bacterial and mammalian in vitro systems and in
mammalian in vivo assays. In general, results show that PFOA can produce DNA damage, but is not
mutagenic at noncytotoxic concentrations.

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Results of in vitro studies in bacteria show that PFOA induces DNA damage but is not mutagenic. DNA
damage was observed in Paramecium caudatum following exposure to 100 µM for 12 and 24 hours(Kawamoto et al. 2010). Intracellular ROS was significantly increased but DNA damage was notreversed by the application of glutathione, a ROS inhibitor, indicating that intracellular ROS may not be
the cause of PFOA-induced DNA damage. PFOA was not mutagenic in Salmonella typhimurium
TA1535/pSK1002 (hisG46, rfa, uvrB) with or without metabolic activation using the umu test (Oda et al.
2007) or in S. typhimurium TA98, TA100, TA102, and TA104 strains with or without metabolic
activation using an Ames assay (Fernández Freire et al. 2008). Butenhoff et al. (2014) and Kennedy et al.
(2004) summarized the results of various unpublished mutagenicity studies with PFOA showing negative
results in reverse mutation assays using S. typhimurium (strains TA98, TA100, TA1535, TA1537, andTA1538), Saccharomyces cerevisiae, and Escherichia coli (WP2uvrA strain) with or without metabolic
activation.

In vitro genotoxicity assays in mammalian cells show that PFOA induced DNA damage, although
conflicting results have been reported for mutagenicity and increased micronuclei formation. Incubationof human hepatoma HepG2 cells with 50–400 µM PFOA caused DNA strand breaks and 100–400 µM
increased the incidence of micronuclei, in a dose-related manner in both cases (Yao and Zhong 2005).
These effects were accompanied by a significant increase in ROS, which the investigators suggested
caused the DNA damage. Bjork and Wallace (2009) measured mRNA expression for DNA damage
inducible Ddit3 to assess DNA damage in primary rat and human hepatocyte cultures and in HepG2/C3ahepatoma cells. Significant increases in mRNA transcription for Ddit3 were found in primary rat
hepatocytes at 100 µM PFOA and in primary human hepatocytes and HepG2/C3a hepatoma cells at
200 µM PFOA. Although both studies provide evidence of DNA damage, the tested concentrations werevery high as compared to what could be expected to occur in the environment. A significant increase in
mutation frequencies was observed in hamster-human hybrid cells exposed to 200 µM PFOA for 1–
16 days; a 79% decrease in cell viability was also observed at this concentration (Zhao et al. 2011).
Concurrent treatment with a ROS inhibitor significantly decreased mutations, indicating that ROS may
play an important role in mediating the genotoxic effects of PFOA. In contrast, Butenhoff et al. (2014)
and Kennedy et al. (2004) summarized the results of various unpublished mutagenicity studies with
PFOA. In mammalian cells, PFOA was negative for forward mutations using Chinese hamster ovary
cells, for chromosomal aberrations in Chinese hamster ovary cells and human lymphocytes, and for celltransformation in C3H 10T1/2 cells.

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Results of in vivo exposure of laboratory animals show that PFOA induced DNA damage, but not
micronuclei formation. Administration of a single intraperitoneal injection of 100 mg/kg PFOA to maleFischer-344 rats resulted in a significant increase in the levels of 8-hydroxydeoxyguanosine (a marker ofoxidative DNA damage) in liver DNA, but not in kidney DNA (Takagi et al. 1991). Oral administrationof approximately 20 mg/kg/day PFOA in the diet for 2 weeks to male Fischer-344 rats induced
hepatomegaly and increased the levels of 8-hydroxydeoxyguanosine in liver DNA but not in kidney DNA(Takagi et al. 1991). Unpublished studies summarized by Butenhoff et al. (2014) and Kennedy et al.
(2004) did not find increased micronuclei formation in mice orally exposed to PFOA.
PFOSThe genotoxicity of PFOS has been examined in bacterial and mammalian in vitro systems and in
mammalian in vivo assays. However, compared to PFOA, less information is available. Results do notprovide evidence for genotoxicity of PFOS, except for one in vitro study showing cell transformation and
one report of increased micronuclei formation following in vivo exposure.

Results of in vitro studies in bacteria and mammalian cells show that PFOS did not induce DNA damage,
mutagenicity or chromosome damage. In bacterial cell assays, as reviewed by OECD (2002), PFOS did
not induce reverse mutations in S. typhimurium or E. coli with or without metabolic activation. A study
published after this review also found that PFOS was not mutagenic in S. typhimurium TA1535/pSK1002(hisG46, rfa, uvrB) with or without metabolic activation using the umu test (Oda et al. 2007).

In vitro genotoxicity assays of PFOS in mammalian cells were negative for DNA damage, mutagenicity,
micronuclei formation, and chromosome damage, although one in vitro study reported celltransformation. PFOS did not result in DNA damage in Syrian hamster embryo cells at concentrations up
to 50 µg/mL but did induce cell transformation at noncytotoxic concentrations (0.2 and 2 µg/mL)
following 5 and 24 hours of exposure (Jacquet et al. 2012). Similarly, PFOS did not induce DNA damage
or increased micronuclei formation in human hepatoma HepG2 cells following a 24-hour exposure to
PFOS concentrations as high as 600 µM; cytotoxicity was observed at ≥300 µM (Florentin et al. 2011).
Another study of with HepG2 cells did not find evidence of DNA damage at concentrations of 100 and
400 µM PFOS (Eriksen et al. 2010). As summarized by OECD (2002), PFOS did not induce
chromosomal aberrations in human lymphocytes with or without metabolic activation and did not induce
unscheduled DNA synthesis in primary cultures of rat hepatocytes.

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Conflicting results have been reported on micronuclei formation following in vivo exposure to PFOS.
Micronuclei frequency was increased and the ratio of polychromatic erythrocytes to normochromaticerythrocytes was decreased in bone marrow of rats following oral exposure to 0.6–2.5 mg/kg PFOS for
30 days (Celik et al. 2013; Eke and Celik 2016). As summarized by OECD (2002), PFOS did not induce
micronuclei in the bone marrow of CD-1 mice in an in vivo assay.

Other Perfluoroalkyls

Little information is available on the genotoxicity of other perfluoroalkyl compounds, with available
studies focused on DNA damage. No DNA damage was found in HepG2 cells incubated with 100 or
400 µM PFHxS or PFBS for 24 hours, although a “modest” increase in DNA damage was observed at
400 µM PFNA, a cytotoxic concentration (Eriksen et al. 2010). Oral administration of approximately
10 mg/kg/day PFDA in the diet for 2 weeks to male Fischer-344 rats induced hepatomegaly and also
increased the levels of 8-hydroxydeoxyguanosine in liver DNA but not in kidney DNA (Takagi et al.
1991). In contrast, no DNA damage in liver or kidney was observed following administration of a single
intraperitoneal injection of 100 mg/kg PFBA to male Fischer-344 rats (Takagi et al. 1991).

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3.1

TOXICOKINETICS

Toxicokinetic data on perfluoroalkyls examined in this profile are available from studies in humans andanimals. Most studies in animals administered perfluoroalkyls by the oral route. These data are briefly
summarized below.
•

Absorption-

Perfluoroalkyls are absorbed following oral, inhalation, and dermal exposure.

-

Quantitative estimates of the fractional absorption of orally administered perfluoroalkyls inanimals range from >50% for PFHxS to >95% for PFOA, PFBA, PFNA, PFDA, PFUnA, andPFDoDA.

-No quantitative estimates of the fractional absorption of perfluoroalkyls following inhalation
or dermal exposure were identified.

•Distribution-

Perfluoroalkyls are widely distributed in the body, with the highest concentrations in theliver, kidneys, and blood.

•-

In the blood, perfluoroalkyls bind to albumin and other proteins.

-

Perfluoroalkyls can be transferred to the fetus during pregnancy and to nursing infants.

Metabolism-

Results of available oral and in vitro studies suggest that perfluoroalkyls are not metabolized
and do not undergo chemical reactions in the body.

-

Although no studies examining metabolism of perfluoroalkyls following inhalation or dermal
exposure were identified, metabolism by these exposure routes is not expected.

•

Excretion-

Studies of elimination rates (i.e., half-lives) of perfluoroalkyls show that elimination t1/2
values are similar following intravenous, intraperitoneal, and oral exposures. Findings
suggest that the route of absorption has no substantial effect on rates of elimination ofabsorbed perfluoroalkyls.

-

Perfluoroalkyls are primarily eliminated in the urine, with smaller amounts eliminated infeces and breast milk.

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS-Perfluoroalkyls undergo biliary excretion, but substantial reabsorption occurs; therefore,
biliary excretion is not a major elimination pathway.

-

Rates of elimination of perfluoroalkyls vary substantially across chemical species and animal
species, and show sex differences and age-dependencies within certain species.

-

In general, perfluoroalkyl sulfonates are eliminated more slowly than perfluoroalkyl
carboxylates; elimination rate decreases with increasing chain length, and increases withincreased branching.

-In humans, estimates for elimination t1/2 range from hours (PFBA: 72–81 hours) to several
years (PFOA: 2.1–8.5 years; PFOS: 3.1–7.4 years; PFHxS: 4.7–15.5 years).

-

Evidence for sex differences in elimination of perfluoroalkyls in humans is not as strong as inrats. Menstruation may contribute to faster elimination of PFOS in younger women(≤50 years) when compared to men and older women.

3.1.1

Absorption

Inhalation Exposure. Studies of the absorption of perfluoroalkyls in humans following inhalation
exposure were not located; elevated serum concentrations of perfluoroalkyls in workers in fluorochemical
production industry have been reported (see Table 5-22), indicating that perfluoroalkyls are absorbed
following inhalation exposure. Occupational exposures in these workers are likely to have included
inhalation of aerosols of perfluoroalkyls complexed with airborne dusts. Higher serum levels in workers
compared to the general population (see Table 5-20) probably reflect a predominant contribution frominhaled perfluoroalkyls.

Studies conducted in rodents provide direct evidence for absorption of inhaled perfluoroalkyls. PFOA
was detected in plasma of rats within 30 minutes of initiating nose-only exposures to aerosols (massmedian aerodynamic diameter [MMAD]=1.9–2.1 µm) of 1–25 mg ammonium PFOA/m3. Plasma
concentrations increased during the 6-hour exposure, with the highest concentrations observed at 9 hours(3 hours after cessation of exposure) in male rats and at 7 hours (1 hour after cessation of exposure) infemales (Hinderliter et al. 2006a). Assuming an elimination t1/2 of absorbed PFOA of approximately
160 hours in male rats, a peak plasma concentration at 9 hours would correspond to an absorption t1/2 ofapproximately 1.3 hours (see discussion below, Equations 3-1 and 3-2). The earlier time of highest
plasma concentration observed in female rats appears to be associated with faster elimination of absorbed
PFOA in female rats, compared to male rats (see Section 3.1.4).

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Nose-only exposure of male rats to dusts of ammonium perfluorononanoate induced significant increases
in absolute and relative liver weight, assessed 5 and 12 days after exposure, providing indirect evidence ofabsorption of this compound through the respiratory airways (Kinney et al. 1989).

Oral Exposure. Studies of absorption of perfluoroalkyls through the gastrointestinal tract in humans are
not available. A study of the general population of Europe and North America estimated that the greatest
portion of the chronic exposure to PFOS and PFOA results from the intake of contaminated food,including drinking water (Trudel et al. 2008). Direct evidence of oral absorption of perfluoroalkyls wasprovided in studies that found associations between environmental levels (e.g., drinking water) andperfluoroalkyl concentrations in human serum (Emmett et al. 2006a; Hoffman et al. 2011; Hölzer et al.
2008; Seals et al. 2011; Wilhelm et al. 2008) and by reductions in serum levels after exposures from water
were eliminated or reduced (Bartell et al. 2010; Emmett et al. 2009).

Animal data provide quantitative estimates of the fractional absorption of orally administered PFOA,PFOS, PFBA, PFHxA, PFHxS, PFHpA, PFNA, PFDA, PFUnA, and PFDoDA, with estimates ranging
from >50% for PFHxS to >95% for PFOA, PFBA, PFNA, PFDA, PFUnA, and PFDoDA. Greater than
95% of an oral dose of ammonium [14C]PFOA was absorbed in rats that received single gavage doses
ranging from 0.1 to 25 mg/kg (Kemper 2003). In male and female mice, comparison of the 24-hour area
under the curve (AUC) for oral and intravenous administration showed that 90–100% of the oral dose wasabsorbed for PFOA (females), PFNA (males and female), PFDA (males and females), PFUnA (males andfemales), and PFDoDA (males and female); however, absorption of PFOA in males was 80%, compared
to 100% in females (Fujii et al. 2015a, 2015b). Gannon et al. (2011) estimated an absorption fraction of
99% based on 168-hour urinary excretion of 14C in male and female rats and mice following single oral
doses of 2 or 100 mg/kg 14C-PFHxA. Based on comparison of the AUC for oral and intravenous
administration, the estimated oral absorption fractions were 50% in female rats administered a single
10 mg/kg dose of potassium [18O3- ]PFHxS (Sundström et al. 2012) and 79 and 55% in male and female
rats administered a single dose of 4 mg/kg sodium [18O3- ]PFHxS (Kim et al. 2016b). Sundström et al.
(2012) stated that this estimate may not be reliable due to the short (24 hours) observation period. Basedon 72-hour urinary excretion of 14C, the estimated fractional absorption of a single dose (50 mg/kg) of
14

C-PFHxA was approximately 74% in male rats, 90% in female rats, and 80% in male and female mice

(Iwai et al. 2011). A comparison of 14C disposition in rats, mice, hamsters, and rabbits following an oral
dose of 10 mg ammonium [14C]PFOA/kg showed that similar fractions of the dose were absorbed(Hundley et al. 2006). The estimated absorbed fractions (i.e., 14C in tissues, urine, and exhaled air
measured 120–168 hours after the dose) in males were 89% in rats, 82% in mice, 92% in hamsters, andPERFLUOROALKYLS

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88% in rabbits. Corresponding values for females were 76% in rats, 61%, in mice, 75% in hamsters, and
88% in rabbits. These estimates exclude 14C excreted in feces, which may have been absorbed andsecreted in bile before excretion (see Section 3.1.4). Fasting appears to increase absorption of PFOA.
Plasma PFOA concentrations in rats, 24 hours following a gavage dose of 10 mg ammonium PFOA/kg,
were 2–3 times higher when administered to fasted rats, compared to fed rats (Hinderliter et al. 2006b).
The estimated absorption fractions of ingested ammonium [14C]PFOA or potassium [14C]PFOS(administered as a 4.2 mg/kg oral dose) were >93 and >95% in rats, respectively (Johnson and Ober 1979,
1999a). Based on combined urinary excretion and retention in the carcass (excluding the gastrointestinal
tract and its contents), the estimated oral absorption fraction of [14C]PFOS (administered as a single
4.2 mg/kg dose of potassium [14C]PFOS) in male rats was >95% (Chang et al. 2012). The estimatedabsorption fraction of PFBA (administered as 30 mg/kg oral dose of PFBA) was >95% in rats (Chang etal. 2008a). Cumulative excretion of PFBA 24 hours after an oral dose (administered as 10, 30, or
100 mg/kg ammonium PFBA) was approximately 35% in urine and 4–11% in feces in male mice; and65–69% in urine, and 5–7% in feces in female mice (Chang et al. 2008a).

Studies examining the rate of absorption of PFOA, PFHxA, PFBA, and PFBS show rapid absorption fromthe gastrointestinal tract, with values for absorption t1/2 of <2 hours. For PFOA, the highest observed
concentrations of 14C in plasma occurred in male rats at approximately 10 hours (range 7.5–15 hours)
following single oral doses ranging from 0.1 to 25 mg ammonium PFOA/kg (Kemper 2003). The
elimination t1/2 of 14C in plasma estimated in these same animals was approximately 170 hours (range
138–202 hours), corresponding to an elimination rate constant (ke) of 0.0044 hour-1 (range 0.004–
0.005 hour-1). The corresponding absorption t1/2 of approximately 1.5 hours (ka=0.45 hour-1) can becalculated from these observations (Equations 3-1 and 3-2):

t max = ln
t1 / 2 =ka
1⋅k e (k a − k e )

ln(2)
ke

Eq. (3-1)

Eq. (3-2)

Where tmax = time of maximum concentration of 14C; ke = elimination rate constant; and ka = absorption
constant. The absorption rate of PFOA appears to be greater in female rats compared to male rats. The
time to peak concentrations of 14C in plasma occurred at approximately 1.1 hour (range 0.6–1.5 hours) infemale rats and 10 hours (range 7–15 hours) in male rats following single oral doses ranging from 0.1 to25 mg ammonium PFOA/kg (Kemper 2003). The elimination t1/2 of 14C in plasma estimated in thesesame animals varied with dose and ranged from 3.2 hours at the lowest dose (ke=0.23 hour-1) to
16.2 hours at the highest dose (ke=0.059 hour-1). The estimated absorption t1/2 from the observations

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made at all doses (0.1, 1, 5, and 25 mg/kg), based on Equations 3-1 and 3-2, was approximately
0.25 hours (range 0.12–0.38 hours). The absorption t1/2 of PFBA in male and female rats following
administration of a single oral dose (30 mg/kg ammonium PFBA) was 0.23 hours (3.04 hour-1) in males
and 0.17 hours (4.15 hour-1) in females (Chang et al. 2008a). In male and female mice administered 10–30 mg/kg ammonium PFBA, the absorption t1/2 was <1 hour, although the absorption rate may be dosedependent in males, with higher absorption t1/2 at doses >30 mg/kg (Chang et al. 2008a). Estimated tmax
values following administration of single doses (2 or 100 mg/kg) of 14C-PFHxA to rats and mice ranged
from 0.3 to 0.8 hours (Gannon et al. 2011). Similar results for were reported by Olsen et al. (2009) basedon estimated compartmental pharmacokinetic parameters for PFBS in serum of male and female rats
following a single intravenous or gavage dose of 30 mg potassium PFBS. Plasma concentration-time
profiles were fit to a two-compartment elimination model. The absorption t1/2 can be approximated fromthese data using Equation 3-1, with the elimination rate constant represented by the fast-phase elimination
rate constant estimated for either the oral or intravenous dose. Using the oral or intravenous parameters
yielded similar values for the absorption t1/2 (0.12–0.16 hours). The estimated tmax values following thegavage dose were 0.42 hours in males and 0.33 hours in females. The fast-phase elimination rate
constants following the gavage dose were 0.892 hours-1 (t1/2=0.79 hours) in males and 1.308 hours-1(t1/2=0.53 hours) in females. The corresponding values for absorption t1/2 were 0.14 hours (ka=5.0 hours-1)
in males and 0.12 hours (ka=5.8 hours-1) in females. Use of the fast-phase elimination rate constants
estimated following intravenous administration (male: 1.143 hours-1; female: 1.956 hours-1) yieldedvalues for the absorption t1/2 of 0.16 hours in males (ka=4.30 hours-1) and females (ka=4.45 hours-1).

Mechanisms of oral absorption of perfluoroalkyls have not been elucidated.

Dermal Exposure. Dermal exposures of rats to ammonium PFOA have been shown to produce systemic(e.g., liver, immunotoxicity) toxicity in animals (see Chapter 2). Estimates of the amount or rates ofdermal absorption in humans or animals have not been reported. PFOA was detected in serum of micefollowing dermal application of PFOA dissolved in acetone (Franko et al. 2012). The investigators noted
PFOA ingestion may have occurred during grooming and may have contributed to the body burden.
Dermal absorption of PFOS was assessed following application of single doses of potassium PFOS (doses
up to 0.30 mg/kg) and the diethanolamine salt of PFOS (doses up to 20 µg/kg) to clipped, intact skin of
rabbits (Johnson 1995a, 1995b). Analysis of the liver 28 days after application showed no increase incontent of total organic fluoride compared to controls, indicating that dermal absorption was notdetectable at low dose levels using this methodology. Dermal penetration of PFOA has been studied in
preparations of isolated rat, mouse, and human epidermis (Fasano et al. 2005; Franko et al. 2012). ThesePERFLUOROALKYLS

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studies indicate that the rat and mouse skin may be more permeable to PFOA than human skin.
Approximately 24% of a dermal dose of PFOA (0.5 mg in 1% acetone) was absorbed across isolated fullthickness human skin in 24 hours and 45% of the dose was retained in skin (Franko et al. 2012); it isnoted that the acetone, as well as the glycerol used to pretreat the skin may have enhanced PFOA
absorption. Permeability was sensitive to pH and was higher when the skin was buffered at pH 2.5(5.5x10-2 cm/hour) compared to pH 5.5 (4.4x10-5 cm/hour), well above the pKa for the terminal
carboxylic acid of PFOA (Franko et al. 2012). This suggests that permeability of the unionized acid isgreater than that of the dissociated anion. Lower permeability of ionized PFOA is also suggested byrelatively low permeability of the ammonium salt of PFOA in isolated preparations of rat and human skin.
Following application of the ammonium salt of PFOA to isolated human or rat epidermis (150 µL/cm2 of
a 20% aqueous solution of ammonium PFOA; approximately 30 mg ammonium PFOA/cm2),
approximately 0.048% of the dose was absorbed across human epidermis and 1.44% was absorbed acrossrat epidermis in 40 hours. The estimated dermal penetration coefficients were 9.49x10-7 cm/hour in theisolated human epidermis and 3.25x10-5 cm/hour in the isolated rat epidermis.

The available data suggest that absorption of PFOA and PFOS through the skin is limited and is ofminimal concern as an exposure route. No dermal absorption data were located for other perfluoroalkyls.
3.1.2

Distribution

Available information on the distribution of perfluoroalkyls is obtained from oral exposure studies inlaboratory animals and occupational exposure studies in which exposure is predominantly by inhalation.
Studies specifically examining the distribution of perfluoroalkyls by inhalation or dermal exposure were
not identified. As discussed in Section 3.1.3 (Metabolism), perfluoroalkyls do not undergo metabolism.
Therefore, distribution is expected to be the same regardless of the route of administration.

Distribution in Blood. In a study of 60 healthy Chinese participants from the general population, whole
blood:plasma ratios for PFOS, PFOA, PFHxA, and PFHxS were 0.65, 0.83, 3.0, and 0.57 (Jin et al. 2016).
These results indicate that PFHxA, but not PFOA, PFOS, or PFHxS, enters cellular components of blood.
In a study of perfluoroalkyl workers, serum:plasma ratios for PFHxS, PFOS, and PFOA were 1:1, andthis ratio was independent of the concentrations measured (Ehresman et al. 2007). The ratio of whole
blood:plasma (or serum) was approximately one-half, which corresponded to volume displacement by red
blood cells, suggesting that these perfluoroalkyls do not enter cellular components of blood. In studies
conducted in animals, most of the PFOA in blood is in the plasma fraction. In rats, 24 or 48 hours

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following an oral dose of 11.4 mg ammonium [14C]PFOA/kg, the red blood cell:plasma PFOA
concentration ratio ranged from 0.2 to 0.3, suggesting that there was no selective retention of PFOA by
red blood cells (Johnson and Ober 1999a). Blood:plasma (or serum) ratios of approximately 0.5 have also
been observed in rats following intravenous injection of PFOA (Kudo et al. 2007).

Perfluoroalkyls in plasma bind to serum albumin. The dissociation constant for binding of PFOA toserum albumin is approximately 0.4 mM (0.38 mM, ±0.04 standard deviation [SD] for human serum
albumin; 0.36 mM, ±0.08 SD for rat serum albumin) and involves 6–9 binding sites (Han et al. 2003).
Given a dissociation constant (KD) of 0.4 mM and an albumin concentration of approximately 0.6 mM,>90% of PFOA in serum would be expected to be bound to albumin when the serum concentration of
PFOA is <1 mM (<440 mg/L). This is consistent with observations of the bound fraction of
perfluoroalkyls in plasma of rats that received a gavage dose of 25 mg PFOA/kg (Han et al. 2003, 2005;
Ylinen and Auriola 1990), and in human, rat, and monkey plasma incubated in vitro with perfluoroalkyls(e.g., PFHxA, PFOA, PFOS, PFNA, PFDA) (Kerstner-Wood et al. 2003; Ohmori et al. 2003).
Comparison of dissociation constants for binding of PFOA and PFOS to human serum albumin indicatesthat PFOS (KD: 8x10-8) has a higher binding affinity than PFOA (KD: 1x10-4) for albumin, consistent withthe longer t1/2 of PFOS versus PFOA in humans (Beesoon and Martin 2015; see Section 3.1.4 foradditional information). PFOS has also been shown to bind to human hemoglobin in vitro (Wang et al.
2016). PFBS was found to bind only to albumin, whereas PFOS, PFOA, and PFHxS were found to havethe potential to bind to other human serum binding proteins, including plasma gamma-globulin, alphaglobulin, alpha-2-macroglobulin, transferrin, and beta-lipoproteins (Kerstner-Wood et al. 2003).

Distribution to Extravascular Tissues. Absorbed perfluoroalkyls distribute from plasma to soft tissues,
with the highest extravascular concentrations achieved in liver. An analysis of samples from humancadavers attempted to quantify PFOA, PFOS, FOSA, and PFHxA concentrations in serum and liver(Olsen et al. 2003c). The route of exposure was unknown. Mean serum PFOS concentration was
17.7 ng/mL (95% CI 13.0–22.5, range of <6.9 [limit of quantification] to 57 ng/mL, n=24) and was notdifferent in males (18.2 ng/mL, n=13) and females (17.2 ng/mL, n=11). The mean liver concentration
was 18.8 ng/g (95% CI 14.1–23.5; range <7.3–53.8 ng/g, n=30). The mean liver:serum concentration
ratio was 1.3 (95% CI 0.9–1.7, n=23) and was not different in males (1.3, n=13) and females (1.3, n=10).
Most liver and serum concentrations for PFOA, FOSA, and PFHxA were below the limit ofquantification; these limits were <17.9–<35.9 ng/mL for PFOA, <7.5–<19.6 ng/g for FOSA, and <3.4–<18.5 ng/mL for PFHxA.

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONSStudies conducted in nonhuman primates and rodents have provided additional information on the
distribution of absorbed perfluoroalkyls to extravascular tissues. Distribution, as assessed from tissue
perfluoroalkyl concentrations and tissue:serum ratios, exhibits profound species and sex differences aswell as dose-dependencies (e.g., tissue levels that change disproportionately with dose). These
differences have been attributed, in part, to species and sex differences in elimination kinetics of absorbed
perfluoroalkyls and dose-dependence of elimination kinetics (see Section 3.1.4). In general, a consistentfinding across species is that the liver receives a relatively high fraction of the absorbed dose and may
also experience relatively high tissue concentrations compared with other tissues, with blood(i.e., plasma) and kidney also showing relatively high concentrations. The most extensive investigationsof tissue distribution have been conducted in rodents.
Bogdanska et al. (2011) examined distribution of 35S following dietary exposure to adult male C57/BL6
mice to low (environmentally relevant; 0.031 mg/kg/day) and high (experimentally relevant;
23 mg/kg/day) doses of [35S]PFOS for 1–5 days. For both low and high doses after 1, 3, and 5 days of
exposure, 35S was distributed to the following tissues: blood, liver, lung, kidney, skin, whole bone,
pancreas, spleen, thymus, heart, testes, epididymal fat, fat pads, brain, and muscle; 35S was also detected
in tissues throughout the gastrointestinal tract. Similar tissue:blood ratios were observed in both dosegroups. In low-dose animals after 5 days of treatment, the highest tissue concentrations (excluding thegastrointestinal tract) were liver (tissue:blood=5.8), followed by lung (tissue:blood=1.4), whole bone,
including marrow (tissue:blood=1.1), blood, and kidney (tissue:blood=0.94). In high-dose animals, thehighest tissue concentrations were liver (tissue:blood=3.6), followed by lung (tissue:blood=1.6), blood,
kidney (tissue:blood=0.81), and whole bone, including marrow (tissue:blood=0.72). A similar pattern of
distribution was observed following intravenous administration of [14C]potassium PFOS (4.2 mg/kg) tomale rats (Johnson and Ober 1980). For both dose groups, the tissue:blood ratios for all other tissues
were <1. In male and female CD-1 mice administered a single oral dose (4.2 mg/kg) of [14C]PFOS, thehighest concentrations of 14C was observed in the liver, followed by serum, and then kidney, with similar
tissue levels observed in males and females (Chang et al. 2012). In male and female rats fed diets
containing 0, 2, 20, 50, or 100 mg/kg [13C]sodium PFOS (equivalent to 0, 0.14, 1.33, 3.21, and 6.34 and0, 0.15, 1.43, 3.73, and 7.58 mg/kg/day in males and females, respectively) for 28 days, PFOS levels werehighest in liver, followed by spleen, heart, and serum. Liver:serum ratios for the 2, 20, 50, and100 mg/kg/day diets were approximately 52, 42, 41, and 35, respectively, in males and 30, 47, 20, and 23,
respectively, in females (Curran et al. 2008). Except for rats fed diets containing 20 mg/kg, theliver:serum ratio in males was higher than in females. No additional data were reported to determine if
PFOS distribution differed between male and female rats.

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Kemper (2003) determined the distribution of 14C in male and female rats at the approximate time of
maximum plasma concentration in both sexes, following single gavage doses of [14C]PFOA (asammonium PFOA, 0.1–25 mg/kg). This design allows a more direct comparison of patterns of tissue
distribution in male and female rats at similar plasma concentrations, even though the elimination kinetics
in the female rat are substantially faster than in male rats (see Section 3.1.4). The highest concentrationsof 14C were observed in blood, liver, and kidney (Figure 3-1). Liver, blood, and kidney accounted forapproximately 22, 22, and 2% of the administered dose of 1 mg/kg in male rats; and 6, 7, and, 3% infemale rats (the sex difference reflected more rapid excretory elimination in females). Although blood,
liver, and kidney concentrations appeared to increase proportionately with increasing dose in male rats, infemale rats, a disproportionately higher concentration in kidney was observed following the 25 mg/kg dose
(Figure 3-1). Concentrations in other tissues ranged from 0.1 to 0.25 of that in liver or kidney;concentrations in bone and fat were <0.1 of that in liver or kidney. Profound sex differences and dosedependencies in tissue concentrations of PFOA were also observed in rats that received oral doses of
PFOA for 28 days at doses of 3, 10, or 30 mg PFOA/kg/day (Ylinen et al. 1990; Figure 3-2). Mean serum,
kidney, or liver concentrations did not increase proportionally with dose in either sex. Kidney
concentrations exhibited a disproportionate increase as the dose increased from 3 to 10 mg/kg/day, withlittle further increase at the 30 mg/kg/day dose. Sex differences in tissue distribution of PFOA in rats are
not explained by sex differences in bioavailability since the differences persist in animals that received
parenteral doses of PFOA (Johnson and Ober 1999b; Vanden Heuvel et al. 1991b, 1991c). The differences
have been attributed to more rapid elimination of PFOA in female rats, compared to male rats (seeSection 3.1.4).
A comparison of PFOA disposition in rats, mice, hamsters, and rabbits showed pronounced species andsex differences (Hundley et al. 2006; Table 3-1). In this study, rats, mice, hamsters, or rabbits received anoral dose of 10 mg ammonium [14C]PFOA/kg and 14C in tissues was measured at 120 or 168 hours(rabbits) hours post-dosing. In male rats, the highest concentrations of 14C occurred in blood, liver andkidney, and all tissues combined accounted for approximately 60% of the dose. However, in female rats,
concentrations of 14C in all tissues were below limits of quantification. In mice, liver concentrations weresimilar in males and females, and liver showed the highest concentrations; 14C levels in all tissues
combined were lower in females compared to males. The opposite pattern was evident in hamsters andrabbits, with males having lower tissue levels than females, although, in common with rats and mice,PERFLUOROALKYLS

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Figure 3-1. Tissue Concentrations of 14C in Male and Female Rats Following aSingle Gavage Dose of [14C]PFOA at 1, 5, or 25 mg/kg*

180
Blood, M

Tissue (ug/g)

160

Liver, M

140

Kidney, M

120

Blood, F

100

Liver, F

80

Kidney, F

60
40
20
0
0

5

10

15

20

Dose (mg/kg)*Tissue levels are measured at time of maximum concentration in each tissue.
Source: Kemper 2003

25

30

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Figure 3-2. Tissue Concentrations of 14C in Male (Upper Panel) and Female(Lower Panel) Rats Following Oral Doses of PFOA for 28 Days
at Doses of 3, 10, or 30 mg/kg/day

100

Male rat

Tissue (ug/g)

90
80

Serum
Liver

70
60

Kidney

50
40
30
20
10
0
0

5

10

15

20

25

30

35

Dose (mg/kg/day)

16

Female rat

14

Tissue (ug/g)

12
10
8
6
Serum

4

Liver

2

Kidney

0
0

5

10

15

20

Dose (mg/kg/day)
Source: Ylinen et al. 1990

25

30

35

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Table 3-1. Tissue Distribution and Excretion of 14C-Radioactivity from Both
Sexes of Rats, Mice, Hamsters, and Rabbits Dosed with 14C-Labeled APFOa
μg Equivalent per g (mL) wet weightb
Rat
Mouse
Hamster
SampleBlood
Liver
Kidneys
Lungs
Heart
Skin
TestesMuscle
Fat
Brain

Male
23.5
40.0
24.0
8.7
6.4
4.8
3.2
1.9
1.7
0.6

Female
<0.1
<0.1
<0.1
<0.1
<0.1
<0.01
–
<0.1
<0.1
<0.1

Tissues
Urine
Feces
Expiration
Cage wash
Percent recovered

59.6
25.6
9.2
3.6
0.6
98.5

0.6
73.9
27.8
1.5
0.8
104.6

Male
Female
13.8
10.1
43.2
45.3
c
2.9
2.2c
1.4c
1.3c
1.2c
0.6c
3.5
0.2
0.9c
–
1.1
0.5
1.6
1.3
0.2c
0.8c
Percent of dose
73.6
3.4
8.3
5.2
4.9
95.4

50.0
6.7
5.4
4.4
4.9
71.4

Rabbit

Male
0.1
0.3
0.2
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1

Female
8.8
7.3
7.1
3.8
2.9
3.4
–
0.9
1.5
0.3

Male
<0.1
0.1
0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1

Female
0.1
1.5
0.4
0.1
<0.1
<0.1
–
<0.1
<0.1
<0.1

0.7
90.3
8.2
1.3
0.6
101.1

26.5
45.3
9.3
2.9
2.1
86.1

<0.1
76.8
4.2
No data
0.5
81.6

0.3
87.9
4.6
No data
4.8
97.6

aThe rabbits were sacrificed 168 hours after dosing; all other animals were sacrificed 120 hours after dosing.

bThe μg equivalent calculations were based on the specific activity of 14C-labeled APFO, which was
1.1x106 DPM/mg. The μg equivalent per g wet weight could not accurately be determined below 0.1 μg/g.
cRepresents the μg equivalents for the entire organ.

APFO = ammonium perfluorooctanoate
Source: Hundley et al. 2006

blood, liver and kidney had the highest concentrations. Male rats that received a single oral dose of 5 mg
FOSA/kg had liver FOSA concentrations that were 3–5 times higher than serum concentrations 1 day
post-dosing (Seacat and Luebker 2000).

Sex differences in elimination that give rise to sex differences in tissue levels following oral exposure toperfluoroalkyls in rats are not evident in studies conducted with nonhuman primates. Rhesus monkeys
that received 3 or 10 mg ammonium PFOA/kg/day for 90 days had liver concentrations of 48 µg/g (onemale) or 50 µg/g (one female) at the low dose and 45 µg/g (one male) and 72 µg/g (one female) at thehigher dose, with corresponding serum concentrations of 3 and 7 µg/mL, and 9 and 10 µg/mL,
respectively (Griffith and Long 1980). Although limited to only one animal per sex, these results suggest

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that liver levels did not increase proportionately with increasing dose. A similar observation was made ina study of male Cynomolgus monkeys (Butenhoff et al. 2004c). In male monkeys that received daily oral
doses of 3 or 10 mg ammonium PFOA kg/day for 27 weeks, liver PFOA concentrations ranged from11 to 18 µg/g at the low dose and from 6 to 22 µg/g at the higher dose. Mean serum concentrations
measured after 6 weeks of exposure (which may have represented steady-state concentrations) were
77,000 ng/mL in the low-dose group and 86,000 ng/mL in the higher dose group. In this same study, ananalysis of serum PFOA kinetics following an intravenous dose of PFOA revealed similar elimination
kinetics in males and females (Butenhoff et al. 2004c; see Section 3.1.4). In Cynomolgus monkeys thatreceived daily oral doses of PFOS (0, 0.03, 0.15, or 0.75 mg PFOS/kg/day) for 26 weeks, liverconcentrations of PFOS and serum concentration were similar in males and females (liver:serum ratios
ranged from 1 to 2) and increased in approximate proportion to the administered dose (Seacat et al. 2002).
Bogdanska et al. (2014) examined distribution of 35S in 20 tissues following dietary exposure of adultmale C57/BL6 mice to PFBS (16 mg/kg/day) for 1–5 days. 35S was detected in all tissues andconcentrations reached plateau levels after 3 days of exposure. After 5 days, tissue:blood ratios(excluding stomach and small intestine) were >1 for liver (tissue:blood=1.6), kidney (tissue:blood=1.3),
whole bone (tissue:blood=1.1), and cartilage (tissue:blood=1.1). At all-time points, approximately 90%of the ingested 35S was recovered in combined blood, liver, bone, skin, and muscle.

Iwabuchi et al. (2017) compared tissue distribution following single doses or 3-month dosing of PFOS
(100 µg/kg), PFOA (100 µg/kg), PFHxA (100 µg/kg), and PFNA (50 µg/kg). Following administrationof single doses, the tissue:serum (and/or whole blood) ratio was >1 for the liver for PFOS, PFOA, and
PFNA, with tissue:serum ratios <1 for kidney, spleen, heart, and brain. For PFNA, the only tissue with atissue:serum ratio >1 was kidney. After 3 months of exposure, tissue:serum ratios >1 were observed forthe liver for PFOA and PFNA, and the liver and kidney for PFOS. For PFHxA, all tissue:serum ratios
were <1. Similar to the single dose study, the lowest serum:tissue ratio for all compounds was observed
for brain.

Subcellular Distribution. The subcellular distribution of perfluoroalkyls has been examined in rats (Hanet al. 2004, 2005; Kudo et al. 2007; Vanden Heuvel et al. 1992b). Two hours following an oral dose of
25 mg ammonium [14C]PFOA/kg, sex differences were noted in the subcellular distribution of 14C inliver; females had approximately 50% of total 14C in the cytosolic fraction compared to 26% in males(Han et al. 2005). The distributions to other cell fractions were: nuclear/cell debris fraction, 30%
females, 40% males; lysosomes, 12% females, 14% males; mitochondria, 8% females, 16% males; andPERFLUOROALKYLS

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ribosomes, <3% males and females. In kidney, 80 and 70% of the 14C was associated with the cytosolic
fraction in males and females, respectively, 16–22% in the nuclear/cell debris fraction, and the remainder
in lysosome/mitochondria/ribosome fractions. In liver, approximately 55% of cytosolic 14C was bound toproteins (>6,000 Da) in both males and females, whereas in kidney, 42% of the cytosolic fraction wasbound to protein in males and 17% in females. The subcellular distribution of PFOA is dose-dependent.
In rats, 2 hours following an intravenous dose of 0.041 mg [14C]PFOA/kg, approximately 5% 14C in theliver was associated with the cytosolic fraction, whereas approximately 45% was in the cytosolic fraction
following a dose of 16.6 mg/kg (Kudo et al. 2007). A small component of tissue-associated PFOA andPFDA appeared to be bound covalently to protein. Following an intraperitoneal dose of 9.4 µmol/kg[14C]PFDA or [14C]PFOA (4.2 mg/kg), approximately 0.1–0.5% of liver 14C was bound covalently(i.e., was not removed by repeated extraction with a methanol/ether and ethyl acetate; Vanden Heuvel etal. 1992b). Covalent binding was detected when cytosolic or microsomal fractions of rat liver wereincubated in vitro with [14C]PFDA (Vanden Heuvel et al. 1992b).
PFOA binds to rat kidney and urine α2u-globulin; dissociation constants were estimated to beapproximately 1.5 and >2 mM (for a single binding site) for the proteins isolated from rat kidney andurine, respectively. These values suggest relatively low affinity for the protein, compared to other ligandsthat are known to induce hyaline droplet nephropathy (10-4–10-7 M; Han et al. 2004).

Maternal-fetal Transfer. Perfluoroalkyls can be transferred to the fetus during pregnancy (Cariou et al.
2015; Chen et al. 2017a; Fei et al. 2007; Fisher et al. 2016; Fromme et al. 2010; Glynn et al. 2012;
Gützkow et al. 2012; Hanssen et al. 2010, 2013; Inoue et al. 2004; Kato et al. 2014; Kim et al. 2011, Leeet al. 2013; Lien et al. 2013; Liu et al. 2011; Manzano-Salgado et al. 2015; Midasch et al. 2007; Monroy
et al. 2008; Needham et al. 2011; Ode et al. 2013; Porpora et al. 2013; Yang et al. 2016a, 2016b). Studies
that measured perfluoroalkyls in maternal and fetal cord blood of matched mother-infant pairs foundrelatively strong correlations (r>0.8) between maternal and fetal serum (or plasma); however,fetal/maternal serum ratios vary depending on the structure of the perfluoroalkyl (Table 3-2). With some
exceptions, longer fluoroalkyl chain length and a terminal sulfonate group are associated with lower
fetal/maternal ratios (Glynn et al. 2012; Gützkow et al. 2012; Hanssen et al. 2013; Kim et al. 2011; Liu etal. 2011; Needham et al. 2011). PFOS was detected in amniotic fluid obtained from amniocentesis(Jensen et al. 2012). The median concentration in amniotic fluid samples from 300 pregnancies (from theDanish amniotic fluid pregnancy-screening biobank) was 1.1 ng/mL.

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Table 3-2. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant
Pairs

Study
Glynn et al. 2012

Cariou et al. 2015

Chen et al. 2017a

Fisher et al. 2016

Fromme et al. 2010

Gützkow et al. 2012

Hanssen et al. 2013

Han et al. 2018

Perfluoro- Perfluoroalkyl
alkyl
chain length
N

Maternal(ng/mL)Cord(ng/mL)

Ratioa r

PFOA
PFOS
PFNA
PFHxS
PFOA
PFOS
PFNA
PFHxS
PFOA
PFOS

7
8
8
6
7
8
8
6
7
8

413
413
413
59
89
94
22
32
32
32

4
29
0.6
0.62
1.05
3.07
0.43
0.53
8.67
1.56

1
5
0.1
0.34
0.86
1.11
0.27
0.33
3.67
1.24

NR
NR
NR
0.56
0.78
0.38
0.51
0.62
0.42
0.79

0.89
0.86
0.53
0.99
0.83
0.88
0.92
ND
ND
ND

PFHxS
PFOA
PFOS
PFHxS
PFOA
PFOS
PFNA
PFHxS
PFOA
PFOS
PFNA
PFDA
PFUnA
PFHxS
PFOA
PFOS
PFNA
FOSA
PFUnA
PFBS
PFHxS
PFHpA
PFOA
PFOS
FOSA
PFNA
PFDA
PFUnA
PFDoDA

6
7
8
6
7
8
8
6
7
8
8
9
10
6
7
8
8
8
10
4
6
6
7
8
8
8
9
10
11

315
865
648
53
53
53
53
123
123
123
123
123
123
7
7
7
7
7
7
369
369
369
369
369
369
369
369
369
369

NR
NR
NR
0.60
2.60
3.50
0.60
0.34
1.25
5.37
0.40
0.10
0.19
0.26
1.50
10.70
0.89
0.41
0.33
0.19
0.32
0.06
42.83
4.55
0.13
0.81
0.55
0.47
0.17

NR
NR
NR
0.30
1.70
1.10
<0.4
0.23
1.03
1.78
0.16
0.04
0.06
0.17
1.26
3.93
0.50
0.45
0.16
0.19
0.31
0.09
34.67
1.39
0.13
0.44
0.21
0.17
0.14

0.23
0.28
0.14
0.50
0.65
0.31
ND
0.68
0.82
0.33
0.40
ND
0.32
0.65
0.84
0.37
0.56
1.10
0.48
1.00
1.03
1.50
0.81
0.31
1.00
0.54
0.38
0.36
0.82

NR
NR
NR
0.89
0.94
0.89
ND
0.70
0.82
0.74
0.64
ND
0.67
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND

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Table 3-2. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant
Pairs

Study

Perfluoro- Perfluoroalkyl
alkyl
chain length
N

Inoue et al. 2004

PFOA

7

15

Kim et al. 2011

PFHxS
PFOA
PFOS
PFNA
PFDA
PFUnA

6
7
8
8
9
10

20
20
20
20
20
20

Kato et al. 2014

PFHxS
PFOA
PFOS
PFNA
PFDA
PFHS
PFOA
PFOS
PFHxS
PFOA
PFOS
PFNA
PFDA
PFUnA
PFDoDA
PFHxS
PFOA
PFOS
PFNA
PFOA
PFOS
PFHxS
PFOA
PFOS
PFNA
PFHxS
PFOA
PFOS
PFNA
PFDA

6
7
8
8
9
6
7
8
6
7
8
8
9
10
11
6
7
8
8
7
8
6
7
8
8
6
7
8
8
9

78
78
78
78
78
70
70
70
50
50
50
50
50
50
50
66
66
66
66
11
11
101
101
101
101
12
12
12
12
12

Lee et al. 2013

Liu et al. 2011

Manzano-Salgado etal. 2015

Midasch et al. 2007
Monroy et al. 2008

Needham et al. 2011Maternal(ng/mL)Cord(ng/mL)

Ratioa r

8.90

2.90

0.32

0.94

0.89
1.60
5.60
0.79
0.36
1.60

0.58
1.10
2.00
0.37
0.01
0.46

0.65
0.69
0.36
0.47
0.03
0.29

ND
ND
ND
ND
ND
ND

1.20
3.30
8.50
0.66
0.20
1.35
2.73
10.77
0.08
1.66
3.18
0.55
0.58
0.56
0.08
0.84
2.97
6.99
0.85
2.70
12.10
4.05
2.24
16.19
0.80
12.30
4.20
19.70
0.76
0.34

0.60
3.10
3.50
0.41
ND
0.67
2.09
3.44
0.06
1.50
1.69
0.33
0.24
0.30
ND
0.40
1.90
1.86
0.32
3.40
7.20
5.05
1.94
7.19
0.94
9.10
3.10
6.60
0.37
0.10

0.50
0.89
0.31
0.62
ND
0.57
0.84
0.35
0.79
0.91
0.53
0.61
0.41
0.53
ND
0.446
0.746
0.299
0.4
1.30
0.60
1.25
0.87
0.44
1.18
0.74
0.72
0.34
0.50
0.29

0.89
0.88
0.82
0.79
ND
ND
ND
ND
0.59
0.91
0.75
0.82
0.82
0.70
ND
NR
NR
NR
NR
0.42
0.72
ND
0.94
0.91
ND
0.05
0.91
0.82
0.84
0.91

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Table 3-2. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant
Pairs

Study
Ode et al. 2013

Porpora et al. 2013
Yang et al. 2016a

Yang et al. 2016b

Perfluoro- Perfluoroalkyl
alkyl
chain length
N

Maternal(ng/mL)Cord(ng/mL)

Ratioa r

PFOA
PFOS
PFNA
PFOA
PFOS

7
8
8
7
8

263
263
263
38
38

2.30
17.00
0.31
2.90
3.20

2.80
7.40
0.26
1.60
1.40

1.30
0.45
0.93
0.55
0.44

0.74
0.76
0.51
0.70
0.72

PFHxS
PFOA
PFOS
PFNA
PFDA
PFUnA
PFDoDA
PFHxS
PFOA
PFOS
PFNA
PFDA
PFUnA
PFDoDA

6
7
8
8
9
10
11
6
7
8
8
9
10
11

50
50
50
50
50
50
50
157
157
157
157
157
157
157

0.064
1.24
2.98
0.55
0.56
0.55
0.085
0.53
1.74
4.23
0.46
0.37
0.38
0.040

0.033
1.03
1.23
0.35
0.22
0.23
0.058
0.26
1.32
1.52
0.23
0.13
0.14
0.026

0.52
0.83
0.41
0.64
0.39
0.42
0.68
0.43
0.71
0.36
0.49
0.35
0.36
0.61

0.80
0.93
0.88
0.89
0.92
0.88
0.76
0.68
0.81
0.63
0.70
0.65
0.63
0.52

aRatio of cord:maternal perfluoroalkyl level.

FOSA = perfluorooctane sulfonamide; ND = no data (detected but below limit of quantification); NR = not reported;
PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid;
PFHxS = perfluorohexane sulfonic acid; PFHpA = Perfluoroheptanoic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFTrDA = perfluorotridecanoic acid;PFUnA = perfluoroundecanoic acid

Studies in rats and mice provide further support for maternal-fetal transfer of perfluoroalkyls. Following
gavage administration of 0.1–10 mg/kg/day PFOS to rats during gestation, PFOS was distributed to fetal
serum, liver, and brain, with fetal concentrations increasing with maternal dose (Chang et al. 2009; Lau etal. 2003; Luebker et al. 2005a, 2005b; Thibodeaux et al. 2003). Levels in fetal serum and liver generally
were similar and higher than in brain. Studies did not report on concentrations of PFOS in other fetal
tissues. Paired fetal-maternal levels of PFOS were examined in rats following exposure (gavage) topotassium PFOS at doses of 0.1, 0.4, 1.6, or 3.2 mg/kg/day on GDs 0–20 (Luebker et al. 2005b). On
GD 21, fetal:maternal serum ratios were 2.1, 1.7, 1.6, and 1.1 at doses of 0.1, 0.4, 1.6, and 3.2 mg/kg/day,
respectively; these results suggest that fetal:maternal serum ratios varied inversely with dose.
Fetal:maternal liver ratios (0.37–0.44) were similar across the dose range. In mice administered a single

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gavage dose of 12.5 mg/kg [35S]PFOS on GD 16, fetal organ:maternal blood ratios of 35S on GD 18 were
2.8 for kidneys, 2.6 for liver, 2.3 for blood, 2.1 for lungs, and 1.2 for brain (Borg et al. 2010).

Maternal-fetal transfer of PFOA has also been studied in rats and mice (Das et al. 2008; Hinderliter et al.
2005). In rats, PFOA concentrations in amniotic fluid, placenta, and fetus (measured on days 10, 15, or
21 of gestation) increased with increasing maternal oral dose (3, 10, or 30 mg/kg/day, administered daily
beginning on GD 4) (Hinderliter et al. 2005). Fetal plasma concentrations of PFOA measured on GD 21
were approximately 40% of maternal plasma concentration. Following gavage administration of 0.01, 1,
or 5 mg/kg ammonium PFOA on GD 17 in mice, PFOA was detected in amniotic fluid and pup serum,with dose-dependent increases (Fenton et al. 2009). On PND 1, pup serum PFOA concentrations wereapproximately 1.7–2.0-fold greater than levels in maternal serum.

Following administration of ammonium PFBA (35, 175, or 350 mg/kg) to pregnant mice on GDs 0–17,
fetal serum and liver levels of PFBA were determined on PND 1 (Das et al. 2008). The fetal:maternal
serum ratio of PFBA was approximately 0.15 and did not vary with maternal dose. Fetal liver:serum
ratios were 0.44, 0.75, and 0.78 at maternal doses of 35, 175, and 350 mg/kg, respectively. PFHxS wasdetected in fetal blood and in the liver of neonates following exposure of dams to potassium PFHxS (0.3,
1, 3, and 10 mg/kg) throughout gestation (Butenhoff et al. 2009a); concentrations in serum and liver
increased with dose.

Maternal-infant Transfer. Perfluoroalkyls can be transferred to nursing infants (Barbarossa et al. 2013;
Cariou et al. 2015; Fromme et al. 2010; Kärrman et al. 2007; Kim et al. 2011; Kuklenyik et al. 2004; Liuet al. 2011; Tao et al. 2008a, 2008b). Studies that measured perfluoroalkyls in maternal serum (orplasma) and breast milk in matched mother-infant pairs found highly variable correlations (Table 3-3).
Relatively high correlations have been reported for PFOA (Kärrman et al. 2007; Liu et al. 2011).
Transfer to breast milk appears to be a significant route of elimination of perfluoroalkyls during
breastfeeding. Comparisons of serum concentrations of women who did or did not breastfeed theirinfants showed that breastfeeding significantly decreases maternal serum concentrations of PFOA, PFOS,
PFHxS, and PFNA (Bjermo et al. 2013; Brantsaeter et al. 2013; Mondal et al. 2012, 2014; von Ehrenstein
et al. 2009). The decrease was estimated to be 2–3% decrease per month of breastfeeding (Brantsaeter et
al. 2013; Mondal et al. 2012, 2014). Concentrations of perfluoroalkyls in breast milk also decrease withbreastfeeding duration (Tao et al. 2008b; Thomsen et al. 2010). Numerous perfluoroalkyls (including
PFOS, PFOA, PFBS, PFHxS, PFNA, PFDA, PFDoDA, PFUnA, and FOSA) have been detected in breast
milk samples in women in China, Korea, Japan, Malaysia, Cambodia, India, Korea, Vietnam, Indonesia,

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Norway, Philippines, Sweden, and the United States (Forns et al. 2015; Fujii et al. 2012; Kang et al. 2016;
Kärrman et al. 2007; Kim et al. 2011; Liu et al. 2010, 2011; Mondal et al. 2014; So et al. 2006b; Tao et al.
2008a). The mean concentrations for perfluoroalkyls in breast milk collected from 45 women in
Massachusetts were 0.131 ng/mL (range of <0.032.0–617 ng/mL) for PFOS, 0.043.8 ng/mL (<0.0301–
0.161 ng/mL) for PFOA, and 0.0145 ng/mL (<0.0120–0.0638 ng/mL) for PFHxS (Tao et al. 2008b).
PFHpA, PFDA, PFUnA, PFDoDA, and PFBS were also detected in the breast milk; however, ≤4 samples
had levels that exceeded the limit of quantitation. Serum concentrations in breastfed infants can be higher
than maternal levels. Although cord:maternal serum ratios of PFOA, PFOS, and PFNA at birth are
typically lower than 1 (see Table 3-2), infant serum levels increase several-fold during the first 6 months
after birth (Fromme et al. 2010; Mondal et al. 2014; Post et al. 2012; Verner 2016a, 2016b). This increaseis likely because breast milk concentrations of perfluoroalkyls and fluid intake per infant body weight are
highest during this time period. Fromme et al. (2010) also showed increases in serum levels of PFNA in
infants fed formula made with contaminated drinking water. Mogensen et al. (2015b) reported that
following weaning, significant (<0.0001) decreases were observed in infant serum concentrations of
PFOS, PFOA, and PFHxS.

Table 3-3. Matched Serum (or Plasma) and Breast Milk Concentrations in
HumansStudy

Perfluoroalkyl
Perfluoroalkyl chain length
N

Cariou et al. 2015

PFHxS

6

9

2.28

0.026

0.011

0.36

PFOA

7

10

1.22

0.041

0.034

0.72

PFOS

8

19

3.62

0.040

0.011

0.85

Kärrman et al. 2007a PFHxS

6

12

4.7

0.085

0.020

PFOA

7

12

3.8

0.49

0.120

PFOS

8

12

20.7

0.20

0.010

FOSA

8

12

0.24

0.013

0.070

ND

PFNA

8

12

0.80

0.017

0.010

ND

PFHxS

6

20

0.89

0.007

0.008

NS

PFOA

7

20

1.60

0.041

0.026

NS

PFOS

8

20

5.60

0.061

0.011

PFNA

8

20

0.79

<0.0088

ND

ND

PFDA

9

20

0.36

<0.018

ND

ND

PFUnA

10

20

1.60

<0.024ND

ND

Kim et al. 2011

Serum Milk
(ng/mL) (ng/mL) Ratioa

r

ND
0.88
0.83

0.60

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Table 3-3. Matched Serum (or Plasma) and Breast Milk Concentrations in
HumansStudy

Perfluoroalkyl
Perfluoroalkyl chain length
N

Serum Milk
(ng/mL) (ng/mL) Ratioa

Liu et al. 2011

PFHxS

6

50

0.08

PFOA

7

50

1.66

0.181

0.109

0.77

PFOS

8

50

3.18

0.056

0.018

0.57

PFNA

8

50

0.55

0.026

0.048

0.62

PFDA

9

50

0.58

0.02

0.034

0.54

PFUnA

10

50

0.56

0.026

0.046

0.44

PFDoDA

11

50

0.08

ND

ND

ND

PFTrDA

12

50

0.08

ND

ND

ND

ND

r

ND

ND

aMilk to serum ratio.

FOSA = perfluorooctane sulfonamide; ND = no data (detected but below limit of quantification); NS = not significantly
correlated; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonicacid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid;
PFTrDA = perfluorotridecanoic acid; PFUnA = perfluoroundecanoic acid

Studies conducted in rats and mice provide further support for maternal-infant transfer of perfluoroalkyls
through breast milk (Fenton et al. 2009; Hinderliter et al. 2005; Lau et al. 2003; Luebker et al. 2005a; Yu
et al. 2009b). PFOA concentrations in breast milk of nursing rats increased with increasing maternal oral
dose (3, 10, or 30 mg/kg/day, administered daily beginning on GD 4) (Hinderliter et al. 2005). Milk
concentrations of PFOA measured on postpartum days 3, 7, 14, or 21 in rats were approximately 0.1 ofmaternal plasma concentration. In dams exposed to 0.1, 1, or 5 mg/kg PFOA by gavage on GD 17, adose-dependent increase in PFOA concentrations in breast milk was observed on PND 2, with breast
milk:serum ratios of approximately 0.15, 0.38, and 0.25 at 0.1, 1, and 5 mg/kg doses, respectively;
milk/serum concentration ratios for PFOA ranged from 0.15 to 0.56 (Fenton et al. 2009). Following
lactational exposure of control rat pups to PFOS in breast milk of dams treated with dietary PFOS
(3.2 mg/kg diet; approximately equivalent to 0.33 mg/kg/day), pup serum and liver concentrations
increased throughout the 35-day lactation period (Yu et al. 2009b). At PND 35, the pup liver:serum
PFOS ratios were 2.55 and 2.43 in male and female pups, respectively. Results of a cross-foster study
show that pups are exposed to PFOS through breast milk (Luebker et al. 2005a). Postnatal toxicity
observed in cross-fostered pups that nursed from exposed dams provides additional evidence of maternalinfant transfer of PFOS in rats and mice (see Section 2.17).

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Mechanisms of Distribution. Perfluoroalkyls in plasma bind to serum albumin and various other plasma
proteins including gamma-globulin, alpha-globulin, alpha-2-macroglobulin, transferrin, and betalipoproteins (Bischel et al. 2011; Butenhoff et al. 2012d; Chen and Guo 2009; Han et al. 2003, 2005;
Kerstner-Wood et al. 2003; Luo et al. 2012; Ohmori et al. 2003; Salvalaglio et al. 2010; Vanden Heuvel etal. 1992b; Wu et al. 2009; Ylinen and Auriola 1990; Zhang et al. 2009). The dissociation constant foralbumin-bound PFOA in serum is approximately 0.4 mM (0.38 mM, ±0.04 SD for human serum albumin;
0.36 nM, ±0.08 SD for rat serum albumin) and involves 6–9 biding sites (Han et al. 2003). Noncovalentbinding appears to be at the same sites as fatty acids (Chen and Guo 2009). Interactions between PFOS
and human serum albumin include interaction of PFOS polar sulfonyl groups with albumin hydrophilic
sites and interaction of perfluorinated groups with albumin hydrophobic sites (Luo et al. 2012).
Absorbed perfluoroalkyls distribute from plasma to soft tissues, with the highest extravascularconcentrations achieved in liver. Mechanisms by which perfluoroalkyls enter the liver have not been
elucidated and may involve interactions with organic anion transporters that function in the distribution of
fatty acids or other organic anions (Andersen et al. 2008). PFOA appears to be a substrate for organic
anion transporters in the luminal and basolateral membranes of renal tubular epithelial cells, whichfacilitates entry of PFOA into renal tubular cells (Kudo et al. 2002; Nakagawa et al. 2008; Vanden Heuvel
et al. 1992b; Weaver et al. 2010). The subcellular distribution of PFOA is sex- and dose-dependent inrats (Han et al. 2005; Kudo et al. 2007) and the association with the membrane fraction of liver cells
decreases with increasing dose (Kudo et al. 2007), consistent with limited capacity of membrane proteinsthat bind PFOA (e.g., membrane transport proteins). Intracellular PFOA binds to proteins; protein
complexes formed have not been fully characterized. PFOA exhibits a low affinity for binding to rat
kidney and urine alpha-2µ-globulin (dissociation constants 1.5 and >2 mM, respectively) (Han et al.
2004).
3.1.3

Metabolism

Results of available intraperitoneal and in vitro studies suggest that the perfluoroalkyls discussed in thisprofile are not metabolized and do not undergo chemical reactions in the body. The absence of significant
metabolism is attributed to the high stability and low reactivity of carbon-fluorine bonds inperfluoroalkyls. Studies conducted in male and female rats did not detect fluorine metabolites in theurine, plasma, or liver following a single injection of 4–150 mg/kg PFOA or 5–50 mg/kg PFDA (Goecke
et al. 1992; Vanden Heuvel et al. 1991b, 1991c; Ylinen and Auriola 1990). Following a single
intraperitoneal dose of approximately 4 mg/kg of 14C-PFOA, only parent compound was excreted in thePERFLUOROALKYLS

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urine and bile (Vanden Heuvel et al. 1991c). PFOA was not metabolized when incubated withmicrosomal fractions of human or rat intestine, kidney, or liver homogenates (Kemper and Nabb 2005).
Although no studies examining metabolism of other perfluoroalkyls, including PFOS, following
inhalation, oral, or dermal exposure were identified, metabolism by these exposure routes is not
anticipated.

3.1.4

Excretion

As noted in Section 3.1.3 (Metabolism), there is presently no evidence that perfluoroalkyls undergo
metabolism. The absence of significant metabolism is attributed to the high stability and low reactivity ofcarbon-fluorine bonds in perfluoroalkyls. Therefore, route-specific differences in excretion patterns are
not expected. Selected studies in which elimination half-lives rates (i.e., t1/2) of perfluoroalkyls have been
determined (see summaries in Table 3-5) show that, in general, elimination t1/2 values are similar
following intravenous, intraperitoneal, and oral exposures. Findings suggest that the route of absorption
has no substantial effect of rates of elimination of absorbed perfluoroalkyls (Butenhoff et al. 2004c;
Chang et al. 2008a; Kemper 2003; Kudo et al. 2002; Ohmori et al. 2003; Vanden Heuvel et al. 1991b;
Ylinen et al. 1990). As discussed in this section, perfluoroalkyls are primarily eliminated in the urine,with smaller amounts eliminated in the feces, breast milk (see Section 3.1.2; Distribution, Maternal-fetal
Transfer), and menstrual fluid. Perfluoroalkyls undergo biliary excretion, but substantial reabsorption
occurs; therefore, biliary excretion does not represent a major elimination pathway. Perfluoroalkyls do
not appear to be eliminated in sweat, as induction of perspiration by exercise or sauna does not alter
clearance of PFOA, PFOA, PFHxA, or PFNA (Genuis et al. 2013). The elimination of perfluoroalkyls in
menstrual fluid appears to contribute to sex differences in serum elimination rates (Wong et al. 2014,2015; Zhang et al. 2013). Only free (unbound) perfluoroalkyls are available for redistribution, excretion,and renal reabsorption; the interaction of perfluoroalkyls with proteins plays a critical role inbioaccumulation, and the tissue environment highly favors protein bonding.

In humans, absorbed perfluoroalkyls are excreted in urine. Estimates of renal clearance of PFOA andPFOS from serum in humans ranged from 0.8 to 3.3 mL/day for PFOA (serum concentration range: 5–
16 ng/mL) and 0.1–1.5 mL/day for PFOS (serum concentration range 9–49 ng/mL). These clearance
values were <0.001% of glomerular filtration rate (Harada et al. 2005a). Assuming that 99% of the serum
PFOA and PFOS was bound to albumin (see Section 3.1.2), <0.1% of filtered perfluoroalkyls wereexcreted in urine, suggesting extensive reabsorption of filtered PFOA and PFOS in the renal tubule.
Renal clearance was not different in males and females. Mean renal clearances for PFOA werePERFLUOROALKYLS

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2.12 mL/day (±0.80 SD, n=5) in males and 1.15 (±0.33 SD, n=5) in five females (mean age 22 and23 years, respectively). Mean renal clearances for PFOS were 0.66 mL/day (±0.48 SD, n=5) in males and0.91 (±0.56 SD, n=5) for females. Fujii et al. (2015a) reported renal clearances (mL/day/kg; mean±SD)
for several perfluoroalkyls in humans (three males and five females), including PFOA (0.044±0.01),
PFNA (0.038±0.01), PFDA (0.015±0.01), PFUnA (0.005±0.00), and PFDoDA (0.005±0.00). Zhang et al.
(2013) reported renal clearances for several perfluoroalkyls (mL/day/kg) and found that clearance of
PFOS was similar in younger females (≤50 years, 0.050 mL/day/kg, 95% CI 0.037–0.064) and a
combined group of males and older females (grouped together since there were no significant differences
in serum concentrations) (0.037 mL/day/kg, 95% CI 0.026–0.049). However, there appeared to bedifferences in renal clearance for PFOA; clearance rates were 0.30 mL/day/kg (95% CI 0.11–0.49) inyoung females and 0.77 mL/day/kg (95% CI 0.47–1.1) in the combined older women and all males group.
Urinary excretion of perfluoroalkyls may show sex and age differences (Zhang et al. 2015b). Urinary
excretion of PFOA as a fraction of estimated intake in male adults (n=29) was 31% (p=0.002) higher thanin nonpregnant female adults (n=25). In addition, urinary excretion of PFOS was inversely correlatedwith age (r=0.334; p=0.015).

Absorbed PFOA and PFOS are also secreted into bile in humans, but the biliary pathway is not a major
excretory pathway because PFOA and PFOS are reabsorbed after biliary secretion. Estimates of total
body clearance, serum-to-urine clearance, and serum-to-bile clearance of PFOA and PFOS in humans arepresented in Table 3-4 (Harada et al. 2007). Biliary clearances of PFOA and PFOS were 1.06 and2.98 mL/kg body weight/day, respectively, and greatly exceeded total body clearance (0.150 and
0.106 mL/kg/day) and urinary clearance (0.030 and 0.015 mL/kg/day). Based on these estimates,
approximately 89% of the PFOA secreted into bile and 97% of secreted PFOS was estimated to have beenreabsorbed from the gastrointestinal tract. Fujii et al. (2015a) also reported that biliary clearances ofseveral perfluoroalkyls (PFOA, PFNA, PFDA, PFUnA, PFDoDA) were much higher than total bodyclearance in humans, further supporting that perfluoroalkyls excreted in bile undergo extensive
reabsorption.

Table 3-4. Excretory Clearance of PFOA and PFOS in Humans
Parameter

Units

PFOA

PFOS

Serum t1/2aday
mL/kg/daymL/kg/day

1,387
0.150
0.030

1,971
0.106
0.150

Total clearanceb
Urinary clearancec

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Table 3-4. Excretory Clearance of PFOA and PFOS in Humans
Parameter

Units

Biliary clearanced

mL/kg/day%Reabsorbed from bilee

PFOA

PFOS

1.06
89

2.98
97

aEstimates from Olsen et al. (2005).
bln(t1/2)xVd, where Vd is the volume of distribution (300 mL/kg).
cEstimates from Harada et al. (2005a).
dEstimates from Harada et al. (2007).
e1-(Total-Urinary)/Biliary.

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid
Source: Harada et al. (2007)

Studies conducted in nonhuman primates and rodents provide further evidence that urine is the majorroute of excretion of perfluoroalkyls, accounting for >93% of absorbed PFOA and PFOS (Benskin et al.
2009; Butenhoff et al. 2004c; Chang et al. 2008a, 2012; Chengelis et al. 2009a; Hanhijarvi et al. 1982,
1987; Hundley et al. 2006; Johnson and Ober 1979, 1980, 1999a, 1999b; Kemper 2003; Kudo et al. 2001;
Olsen et al. 2009; Sundström et al. 2012; Vanden Heuvel et al. 1991b, 1991c). Studies conducted in rats
have shown that PFDA, PFNA, PFOA, and PFHxA are secreted in bile and undergo extensive
reabsorption from the gastrointestinal tract (Kudo et al. 2001; Vanden Heuvel et al. 1991b, 1991c).
PFOS, PFHxS, and PFBS are excreted in feces following intravenous dosing of rats, suggesting that theseperfluoroalkyls may also be secreted into bile (Chang et al. 2012; Johnson et al. 1984; Olsen et al. 2009;
Sundström et al. 2012). The percentage of the dose excreted in the feces appears to vary with compound,
8–13% for PFOS, <0.5% for PFHxS, and 0.13–0.36% for PFBS. Renal clearances of PFOA from plasma
in rats were approximately 0.032 mL/minute/kg body weight in male rats and 0.73 mL/minute/kg infemale rats; plasma concentrations of PFOA during these measurements ranged from approximately
0.8 to 80 µg/mL (Kudo et al. 2002). In the latter study, approximately >95% of plasma PFOA was boundto high molecular weight protein and the glomerular filtration rate was approximately 10 mL/minute/kg;
therefore, urinary excretion of PFOA was approximately 6% of the rate of glomerular filtration of PFOA
in males and 146% in females. These estimates indicate that net renal tubular reabsorption of filtered
PFOA occurred in male rats, whereas net renal tubular secretion of PFOA occurred in female rats (i.e.,
clearance of free PFOA in plasma > glomerular filtration rate). The pronounced sex difference in renal
clearance of PFOA has been attributed to modulation of renal excretory transport of PFOA by
testosterone and estradiol (Kudo et al. 2002; Vanden Heuvel et al. 1992a; see Section 3.1.5).

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Rates of elimination of perfluoroalkyls vary substantially across chemical species and animal species, andshow sex differences and age-dependencies within certain species. Table 3-5 summarizes estimates of theelimination t1/2 for perfluoroalkyls in humans and experimental animals. In compiling the estimatespresented in Table 3-5, preference was given to the terminal t1/2 when multiple t1/2 values were reported.
The significance of the terminal t1/2 is that it determines the time required for complete elimination of theperfluoroalkyl as well as the exposure duration required to achieve a steady state. Most of the t1/2 values
in Table 3-5 were estimated from analyses of data on declining serum concentrations of perfluoroalkyls
after a single dose or following cessation of a period of repeated dosing. Estimates of the terminal t1/2
based on serum concentrations can vary with the length of the observation period following the last dose
and with the modeling approach used to estimate the t1/2. Longer observation times are required toestimate the slowest phases of elimination. As a result, estimates of t1/2 based on observation periods of
1–2 days can be much shorter than estimates for the same perfluoroalkyl based on observation periods ofseveral weeks. Direct comparisons of t1/2 values should be made with consideration of whether or not theobservation periods were comparable. Differences in estimation methodology can also contribute todifferences in t1/2 values. Values reported in Table 3-5 are based on fitting data to single or multicompartment models, or noncompartmental modeling of the data. While the terminal t1/2 provides a
metric for comparing times required for complete elimination and steady state, it does not always provide
a measure of how rapidly the perfluoroalkyl is cleared from the body. A more useful metric for this is thesystemic clearance (ClS), typically estimated from the absorbed dose (AD) and the area under the serum
concentration curve (AUCS):

ClS =

AD
AUCS

Eq. (3-3)

Equation 3-3 will provide an accurate estimate of systemic clearance following an oral dose if the oral
dose is completely absorbed. Accurate estimation of AUCS also depends on fitness of the underlying
model used to predict serum concentrations. Estimates of systemic clearance based on pharmacokinetics
analyses of serum data from animal studies are presented in Table 3-6.

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Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls
Estimated in Humans and Experimental Animals

Species, age, and sex Route

Dose

Exposure Elimination halfdurationa lifeb
Reference

PFOA—Human
Human (n=26), adult, NA
M (n=24) F (n=2)

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

3.8 years (95%
CI 3.1–4.4,
GM 3.5)
2.8 years (95%
CI 2.4–3.4)
2.4 years (95%
CI 2.0–3.0)
2.6 years(SE 0.4, GM 1.2)
2.1 years(SE 0.3, GM 1.5)
3.9 years

Human (n=5), 22±0.9, NA
M
Human (n=5), 68±5, NA
M
Human (n=5), 23±3, NAF
Human (n=5), 69±5, NAF
Human (n=200)
Oral
54±15, M, F
Human (n=643),
Oral
adult, M, F

NA

NA

2.3 yearsNANA

2.6 yearsNANA

3.5 yearsNANA

2.9 years

NA

NA

NA

NA

Human (n=1,029),
adult, M, F

NA

NA

Humans (n=17), adult, Oral
NA
M, F
Humans (n=6) adults, Inhalation NA
F
PFOS—Human
Human (n=26), adult, NANA
M (24) F (2)NA

2.3 years (95%
CI 2.1–2.4)
2.9 years
Seals et al. 2011(<4 years)(95% CI 2.3–3.8)
10.1 years(>4 years)
8.5 years
Seals et al. 2011(<9 years)(95% CI 7.1–
10.1)
5.1 years (SDCosta et al. 2009
1.7, GM 4.8)
2.5 (range 1.8– Gomis et a. 2016
3.1)

Human (n=20) 15–
50 years, M
Human (n=30) 15–
50 years, F
Human (n=66),>50 years, M, F
Human (n=20),≤50 years, F
Human (n=45), M, F

Human (n≅1,000),>12–>80 years, M

Oral

NA

NA

NA

NA

NA

5.4 years (95%
CI 3.9–6.9, GM
4.8)
4.7 years

Olsen et al.
2007a
Li et al. 2018
Li et al. 2018
Zhang et al. 2013
Zhang et al. 2013
Worley et al.
2017aHarada et al.
2005aHarada et al.
2005aHarada et al.
2005aHarada et al.
2005aBartell et al. 2010

Olsen et al.
2007aWong et al. 2014

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls
Estimated in Humans and Experimental Animals

Dose

Exposure Elimination halfdurationa lifeb
Reference

NA

NA

NA

4.3 years (95%
CI 4.1–4.5)

NA

NA

NA

NA

NA

NA

NA

NA

NA

Human (n=20) 15–NA
50 years M
Human (n=30) 15–NA
50 years, F
Human (n=5), 22±0.9, NA
M
Human (n=5), 68±5, NA
M
Human (n=5), 23±3, NAF
Human (n=5), 69±5, NAF
PFHxS—Human
Human (n=26), adult, NA
M (24), F (2)

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

27 years (SE 3.1, Zhang et al. 2013
GM 18)
6.2 years
Zhang et al. 2013
(SE 0.5, GM 5.8)
3.3 years
Worley et al.
2017a
4.6 years (95% Li et al. 2018
CI 3.7–6.1)
3.1 years (95% Li et al. 2018
CI 2.7–3.7)
4.9 years
Harada et al.
2005a
7.4 years
Harada et al.
2005a
4.5 years
Harada et al.
2005a
4.6 years
Harada et al.
2005a

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

Human (n=66),NA>50 years, M, F
PFBA—Human
Human (n=3), adult, NA
M
Human (n=9), adult, NA
M (7), F (2)
PFBS—Human
Human (n=6), adult M(5), F(1)

NA

NA

NA

NA

NA

NA

Species, age, and sex Route
Human (n≅1,000),>12–>80 years, F
Human (n=66),>50 years, M, F
Human (n=20),≤50 years, F
Human (n=45), M, F

Human (n=20),≤50 years, F
Human (n=20) 15–
50 years, M
Human (n=30) 15–
50 years F
Human (n=45), M, F

8.5 years (95%
CI 6.4–10.6,
GM 7.3)7.7 years(SE 0.6, GM 7.1)
7.4 years (95%
CI 6.0–9.7)
4.7 years (95%
CI 3.9–5.9)
15.5 years

Wong et al. 2015

Olsen et al.
2007aZhang et al. 2013
Li et al. 2018
Li et al. 2018

Worley et al.
2017a
35 years (SE 3.9, Zhang et al. 2013
GM 25)
81 hours (SD 41) Chang et al.
2008b
72 hours (SD 38) Chang et al.
2008b
665 hours(SD 266)

Olsen et al. 2009

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Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls
Estimated in Humans and Experimental Animals

Dose

Exposure Elimination halfdurationa lifeb
Reference

NA

NA

NA

NA

NA

NA

Human (n=66),>50 years, M, F
Human (n=20),≤50 years, F
PFUnA—Human

NA

NA

NA

NA

NA

NA

Human (n=66),>50 years, M, F
Human (n=20),≤50 years, F
PFHpA—Human

NA

NA

NA

NA

NA

NA

Human (n=66),>50 years, M, F

NA

NA

NA

Human (n=20),NA≤50 years, F
PFOA—Nonhuman primate
Cynomolgus monkey, Oral
adult, M
Cynomolgus monkey, IV
adult, M
Cynomolgus monkey, IV
adult, FNA

NA

10 mg/kg/day

6 months 20.1 days

10 mg/kg

1 day

10 mg/kg

1 day

0.15 mg/kg/day

6 months 170 days

Species, age, and sex Route
PFNA—Human
Human (n=66),>50 years, M, F
Human (n=20),≤50 years, F

4.3 years
Zhang et al. 2013
(SE 0.5, GM 3.2)
2.5 years
Zhang et al. 2013
(SE 0.6, GM 1.7)

PFDA—Human

PFOS—Nonhuman primate
Cynomolgus monkey, Oral
adult, M
Cynomolgus monkey, Oral
adult, M
Cynomolgus monkey, Oral
adult, F
Cynomolgus monkey, Oral
adult, F
Cynomolgus monkey, IV
adult, M
Cynomolgus monkey, IV
adult, F

0.75 mg/kg/day
0.15 mg/kg/day
0.75 mg/kg/day
2 mg/kg
2 mg/kg

12 years (SE 1.5, Zhang et al. 2013
GM 7.1)
4.5 years
Zhang et al. 2013
(SE 0.4, GM 4.0)
12 years (SE 2.0, Zhang et al. 2013
GM 7.4)4.5 years
Zhang et al. 2013
(SE 0.5, GM 4.0)
1.2 years
Zhang et al. 2013
(SE 0.2,
GM 0.82)
1.5 years
Zhang et al. 2013
(SE 0.3, GM 1.0)

20.9 days(SD 12.5)
32.6 days(SD 8.0)

Butenhoff et al.
2004cButenhoff et al.
2004cButenhoff et al.
2004c

Seacat et al.
2002
6 months 170 days
Seacat et al.
2002
6 months 170 days
Seacat et al.
2002
6 months 170 days
Seacat et al.
2002
1 day
132 days (SE 7) Chang et al.
2012
1 day
110 days (SE 15) Chang et al.
2012

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls
Estimated in Humans and Experimental Animals

Dose

Exposure Elimination halfdurationa lifeb
Reference

10 mg/kg

1 day

10 mg/kg

1 day

10 mg/kg

1 day

10 mg/kg

1 day

10 mg/kg

1 day

10 mg/kg

1 day

10 mg/kg

1 day

10 mg/kg

1 day

10 mg/kg

1 day

10 mg/kg

1 day

11.4 mg/kg

Oral

Species, age, and sex Route
PFHxA—Nonhuman primate
Cynomolgus monkey, IV
adult, M
Cynomolgus monkey, IV
adult, FPFHxS—Nonhuman primate
Cynomolgus monkey, IV
adult, M
Cynomolgus monkey, IV
adult, F
PFBA—Nonhuman primate
Cynomolgus monkey, IV
adult, M
Cynomolgus monkey, IV
adult, F
PFBS—Nonhuman primate
Cynomolgus monkey, IV
adult, M
Cynomolgus monkey, IV
adult, F
Cynomolgus monkey, IV
adult, M
Cynomolgus monkey, IV
adult, F
PFOA—Rat
Rat (CR), adult, M
Oral
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M

5.3 days (SD 2.5) Chengelis et al.
2009a
2.4 days (SD 1.7) Chengelis et al.
2009a
141 days(SE 30.)87 days (SE 27)

Sundström et al.
2012
Sundström et al.
2012

40.3 hours(SD 2.4)
41.0 hours(SD 4.7)

Chang et al.
2008bChang et al.
2008b15.0 hours(SD 9.8)
8.0 hours(SD 2.0)
95.2 hours(SE 27.1)
83.2 hours(SE 41.9)

Chengelis et al.
2009aChengelis et al.
2009aOlsen et al. 2009

1 day

115 hours

0.1 mg/kg

1 day

Oral

1 mg/kg

1 day

Oral

1 mg/kg

1 day

202 hours(SD 38)138 hours(SD 32)44 hours

Johnson andOber 1980
Kemper 2003

Oral

5 mg/kg

1 day

Oral

25 mg/kg

1 day

IV

1 mg/kg

1 day

IV

1 mg/kg

1 day

Oral

0.4 mg/kg

1 day

Olsen et al. 2009

Kemper 2003
Kim et al. 2016b

174 hours(SD 29)157 hours(SD 38)185 hours(SD 19)39 hours

Kemper 2003

322 hours(SD 38)

Benskin et al.
2009

Kemper 2003
Kemper 2003
Kim et al. 2016b

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Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls
Estimated in Humans and Experimental Animals

Species, age, and sex RouteRat (SpragueDawley), adult, M
Rat (Wistar), adult,M
Rat (Wistar), adult,M
Rat (SpragueDawley), adult, M
Rat (Wistar), adult, M
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (Wistar), adult, F

Oral

Dose

Exposure Elimination halfdurationa lifeb
Reference
De Silva et al.
2009
Kudo et al. 2002

Oral

0.022 mg/kg/day 12 weeks 218 hours (95%
CL 127–792)
21.5 mg/kg
1 day
136 hours(SD 24)20.1 mg/kg
1 day
135 hours(SD 29)3.9 mg/kg
1 day
216 hours(SE 30.9)50 mg/kg
1 day
105 hours
0.1 mg/kg
1 day
3.2 hours(SD 0.9)
1 mg/kg
1 day
3.5 hours(SD 1.1)
1 mg/kg
1 day
3.6 hours

Oral

5 mg/kg

1 day

Kemper 2003

Oral

25 mg/kg

1 day

IV

1 mg/kg

1 day

IV

1 mg/kg

1 day

4.6 hours(SD 0.6)
16.2 hours(SD 9.9)
2.8 hours(SD 0.5)
4.6 hoursIV

21.5 mg/kg

1 day

Kudo et al. 2002

Rat (Wistar), adult, FIV

20.1 mg/kg

1 day

Rat (SpragueDawley), adult, F
Rat (Wistar), adult, F
PFOS—Rat
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M

IP

3.9 mg/kg

1 day

IP

50 mg/kg

1 day

1.9 hours(SD 0.7)
1.9 hours(SD 0.7)
2.9 hours(SE 0.2)
24 hours

Oral

4.2 mg/kg

1 day

179 hours

Oral

Johnson andOber 1979
0.27 mg/kg
1 day
809 hours
Benskin et al.
2009
0.023 mg/kg/day 12 weeks 1,968 hours (95% De Silva et al.
CL 1.584–2.568) 2009
2 mg/kg
1 day
1,495 hours
Chang et al.
(SE 50)2012
2 mg/kg
1 day
635 hours
Kim et al. 2016b

Oral

15 mg/kg

1 day

1,707 hours(SE 270)

IV
IV
IP
IP
Oral
Oral

Oral
Oral
Oral

Ohmori et al.
2003
Vanden Heuvel
et al. 1991cYlinen et al. 1990
Kemper 2003
Kemper 2003
Kim et al. 2016b

Kemper 2003
Kemper 2003
Kim et al. 2016b

Ohmori et al.
2003
Vanden Heuvel
et al. 1991cYlinen et al. 1990

Chang et al.
2012

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Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls
Estimated in Humans and Experimental Animals
Exposure Elimination halfdurationa lifeb
ReferenceSpecies, age, and sex RouteDose

Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, F
FOSA—Rat
Rat (SpragueDawley), adult, M
PFDA—Rat
Rat (SpragueDawley), adult, M
Rat (Wistar), adult, M

Oral

Oral

0.023 mg/kg/day 12 weeks 1,992 hours (95% De Silva et al.
CL 1,752–2,280) 2009
2 mg/kg
1 day
919 hours
Chang et al.
(SE 56)2012
2 mg/kg
1 day
564 hours
Kim et al. 2016b

Oral

15 mg/kg

1 day

IV

2 mg/kg

IV

Oral

1 day

989 hours(SE 48)689 hours

Chang et al.
2012
Kim et al. 2016b

2 mg/kg

1 day

595 hours

Kim et al. 2016b

Oral

5.0 mg/kg

1 day

125 hours

Seacat andLuebker 2000

IP

4.8 mg/kg

1 day

1,008 hours

IV

25 mg/kg

1 day

Rat (Wistar), adult, FIV

25 mg/kg

1 day

Rat (SpragueDawley), adult, FIP

4.8 mg/kg

1 day

958 hours(SD 207)
1,406 hours(SD 140)552 hours

Vanden Heuvel
et al. 1991b
Ohmori et al.
2003
Ohmori et al.
2003
Vanden Heuvel
et al. 1991b

Oral

0.2 mg/kg

1 day

974 hours

PFHpA—Rat
Rat (Wistar), adult, M IV

17.7 mg/kg

1 day

Rat (Wistar), adult, F

17.7 mg/kg

1 day

2.4 hours(SD 1.2)
1.2 hours(SD 0.2)

PFNA—Rat
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult M
Rat (Wistar), adult, M
Rat (SpragueDawley), adult, F
Rat (Wistar), adult, F

Oral
Oral
IV
Oral
IV

IV

Benskin et al.
2009
0.029 mg/kg/day 12 weeks 1,128 hours (95% De Silva et al.
CL 935–1,416)
2009
1, 3, or 10 mg/kg 1 day
734.4 hours
Tatum-Gibbs etal. 2011
22.6 mg/kg
1 day
710 hours
Ohmori et al.
(SD 55)2003
1, 3, or 10 mg/kg 1 day
33.6 hours
Tatum-Gibbs etal. 2011
22.6 mg/kg
1 day
58.6 hours
Ohmori et al.
(SD 9.8)
2003
Ohmori et al.
2003
Ohmori et al.
2003

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls
Estimated in Humans and Experimental Animals

Dose

Exposure Elimination halfdurationa lifeb
ReferenceIV

10 mg/kg

1 day

1.0 hourOral

50 mg/kg

1 day

2.2 hours

Oral

150 mg/kg

1 day

2.4 hours

Oral

300 mg/kg

1 day

2.5 hoursIV

10 mg/kg

1 day

0.42 hour

Oral

50 mg/kg

1 day

2.6 hours

Oral

150 mg/kg

1 day

2.2 hours

Oral

300 mg/kg

1 day

2.1 hours

Oral

2 mg/kg

1 day

Oral

10 mg/kg

1 day

Oral

2 mg/kg

1 day

Oral

10 mg/kg

1 day

Oral

50 mg/kg/day

26 days

1.7 hours(SD 0.6)
0.5 hours(SD 0.1)
1.5 hours(SD 0.2)
0.7 hours(SD 0.3)
2.0 hours

Chengelis et al.
2009aChengelis et al.
2009aChengelis et al.
2009aChengelis et al.
2009aChengelis et al.
2009aChengelis et al.
2009aChengelis et al.
2009aChengelis et al.
2009aGannon et al.
2011
Gannon et al.
2011
Gannon et al.
2011
Gannon et al.
2011
Kirkpatrick 2005

Oral

150 mg/kg/day

26 days

2.1 hours

Kirkpatrick 2005

Oral

300 mg/kg/day

26 days

2.9 hours

Kirkpatrick 2005

Oral

50 mg/kg/day

26 days

1.9 hours

Kirkpatrick 2005

Oral

150 mg/kg/day

26 days

2.2 hours

Kirkpatrick 2005

Oral

300 mg/kg/day

26 days

3.0 hours

Kirkpatrick 2005

Oral

0.030 mg/kg

1 day

382 hours

Oral

4 mg/kg

1 day

645.6 hours

Benskin et al.
2009
Kim et al. 2016b

Oral

4 mg/kg

1 day

41.28 hours

Kim et al. 2016b

Species, age, and sex Route
PFHxA—Rat
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
PFHxS—Rat
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, F

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls
Estimated in Humans and Experimental Animals

Dose

Exposure Elimination halfdurationa lifeb
ReferenceIV

4 mg/kg

1 day

496.8 hours

Kim et al. 2016b

IV

10 mg/kg

1 day

IV

4 mg/kg

1 day

688 hours(SE 14.4)
21.12 hours

Sundström et al.
2012
Kim et al. 2016b

IV

10 mg/kg

1 day

39 hours (SE 1.9) Sundström et al.
2012

Oral

30 mg/kg

1 day

IV

30 mg/kg

1 day

Oral

30 mg/kg

1 day

IV

30 mg/kg

1 day

9.22 hours(SE 0.75)
6.38 hours(SE 0.53)
1.76 hours(SE 0.26)
1.03 hours(SE 0.03)

Chang et al.
2008bChang et al.
2008bChang et al.
2008bChang et al.
2008b

IV

10 mg/kg

1 day

2.1 hoursIV

30 mg/kg

1 day

4.51 hours(SE 2,22)

Chengelis et al.
2009aOlsen et al. 2009

Oral

30 mg/kg

1 day

IV

10 mg/kg

1 day

4.68 hours(SE 0.07)
0.64 hours

IV

30 mg/kg

1 day

Oral

30 mg/kg

1 day

Oral

1 mg/kg

1 day

1,027 hours

Mouse (CD), adult, M Oral

20 mg/kg

1 day

874 hours

Mouse (CD), adult, F

Oral

1 mg/kg

1 day

907 hours

Mouse (CD), adult, F

Oral

20 mg/kg

1 day

731 hours

Species, age, and sex RouteRat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
PFBA—Rat
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
PFBS—Rat
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), Rat (SD),adult, M
Rat (SpragueDawley), adult, M
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
Rat (SpragueDawley), adult, F
PFOS—Mouse
Mouse (CD), adult, M

3.96 hours(SE 0.21)
7.42 hours(SE 0.79)

Olsen et al. 2009
Chengelis et al.
2009aOlsen et al. 2009
Olsen et al. 2009

Chang et al.
2012
Chang et al.
2012
Chang et al.
2012
Chang et al.
2012

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls
Estimated in Humans and Experimental Animals

Dose

Exposure Elimination halfdurationa lifeb
ReferenceOral

1 mg/kg

1 day

732 hours

Oral

20 mg/kg

1 day

671 hours

Oral

1 mg/kg

1 day

597 hours

Oral

20 mg/kg

1 day

643 hours

1 or 10 mg/kg

1 day

1 or 10 mg/kg

1 day

823.2–
1,653.6 hours
619.2–
1,641.6 hours

Tatum-Gibbs etal. 2011
Tatum-Gibbs etal. 2011

10 mg/kg

1 day

30 mg/kg

1 day

100 mg/kg

1 day

10 mg/kg

1 day

30 mg/kg

1 day

100 mg/kg

1 day

13.34 hours(SE 4.55)
16.3 hours(SE 7.2)
5.22 hours(SE 2.27)
2.87 hours(SE 0.30)
3.08 hours(SE 0.26)
2.79 hours(SE 0.3)

Chang et al.
2008bChang et al.
2008bChang et al.
2008bChang et al.
2008bChang et al.
2008bChang et al.
2008bSpecies, age, and sex RoutePFHxS—Mouse
Mouse (CD), adult,
M
Mouse (CD), adult,
M
Mouse (CD), adult,
F
Mouse (CD), adult,
F

PFNA—Mouse
Mouse (CD-1), adult, Oral
M
Mouse (CD-1), adult, OralF
PFBA—Mouse
Mouse (CD1), adult, Oral
M
Mouse (CD1), adult, Oral
M
Mouse (CD1), adult, Oral
M
Mouse (CD1), adult, OralF
Mouse (CD1), adult, OralF
Mouse (CD1), adult, OralF
PFOS—Rabbit
Rabbit (New Zealand), Oral
adult, F

Sundström et al.
2012
Sundström et al.
2012
Sundström et al.
2012
Sundström et al.
2012

0.085 mg/kg/day 102 days 87 days (SD 31) Tarazona et al.
2016

aExposure durations of 1 day indicate that a single dose was administered.
bReported half-lives are arithmetic means for the terminal elimination phase if multiple elimination phases wereobserved.
CI = confidence interval; CL = confidence limit; F = female; GM = geometric mean; IP = intraperitoneal;
IV = intravenous; M = male; NA = not applicable; PFBA = perfluorobutanoic acid; PFDA = perfluorodecanoicacid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoicacid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; FOSA = perfluorooctane
sulfonamide; SD = standard deviation; SE = standard errorPERFLUOROALKYLS

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Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated inExperimental Animals

Species, age, and sex

Dose Exposure Systemic clearance
Route (mg/kg) duration (mL/day/kg)a
Reference

PFOA—Nonhuman primate
Cynomolgus monkey,IVadult, M
Cynomolgus monkey,IVadult, F
PFOS—Nonhuman primate
Cynomolgus monkey,IVadult, M
Cynomolgus
IVmonkey, adult, F
PFHxA—Nonhuman primate
Cynomolgus
IVmonkey, adult, M
Cynomolgus
IVmonkey, adult, F

10

1 day

12.4 (SD 7.4)

Butenhoff et al. 2004c

10

1 day

5.3 (SD 3.3)

Butenhoff et al. 2004c

2

1 day

1.10 (SE 0.06)

Chang et al. 2012

2

1 day

1.65 (SE 0.04)

Chang et al. 2012

10

1 day

569

Chengelis et al. 2009a

10

1 day

535

Chengelis et al. 2009a

10

1 day

1.3 (SE 0.1)

Sundström et al. 2012

10

1 day

1.9 (SE 0.4)

Sundström et al. 2012

10

1 day

2,371 (SE 293)

Chang et al. 2008a

10

1 day

1,075 (SE 91)

Chang et al. 2008a

10

1 day

159

Chengelis et al. 2009a

10

1 day

238

Chengelis et al. 2009a

10

1 day

12,264 (SE 3384)

Olsen et al. 2009

10

1 day

8,832 (SE 2880)

Olsen et al. 2009

Oral

0.1

1 day

23.1 (SD 5.8)

Kemper 2003

Oral

1

1 day

20.9 (SD 3.8)

Kemper 2003

Oral

1

1 day

40.40 (SD 2.29)

Kim et al. 2016b

PFHxS—Nonhuman primate
Cynomolgus monkey,IVadult, M
Cynomolgus monkey,IVadult, F
PFBA—Nonhuman primate
Cynomolgus monkey,IVadult, M
Cynomolgus monkey,IVadult, F
PFBS—Nonhuman primate
Cynomolgus monkey,IVadult, M
Cynomolgus monkey,IVadult, F
Cynomolgus monkey,IVadult, M
Cynomolgus monkey,IVadult, F
PFOA—Rat
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M

PERFLUOROALKYLS

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Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated inExperimental Animals

Species, age, and sex

Dose Exposure Systemic clearance
Route (mg/kg) duration (mL/day/kg)a
ReferenceRat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
Rat (Wistar), adult, M

Oral

5

1 day

20.4 (SD 5.0)

Kemper 2003

Oral

25

1 day

27.1 (SD 7.4)

Kemper 2003

IV

1

1 day

21.5 (SD 2.0)

Kemper 2003

IV

1

1 day

47.39 (SD 3.40)

Kim et al. 2016b

Oral

0.1

1 day

778 (SD 144)

Kemper 2003

Oral

1

1 day

655 (SD 173)

Kemper 2003

Oral

1

1 day

645.12 (SD 43.44)

Kim et al. 2016b

Oral

5

1 day

1,164 (SD 118)

Kemper 2003

Oral

25

1 day

842 (SD 166)

Kemper 2003

IV

1

1 day

816 (SD 221)

Kemper 2003

IV

1

1 day

612.84 (SD 32.54)

Kim et al. 2016b

IV

21.5

1 day

50.4 (SD 14.4)

Kudo et al. 2002

Rat (Wistar), adult, F

IV

21.5

1 day

2,233 (SD 805)

Kudo et al. 2002

Rat (Wistar), adult, M

IV

20.1

1 day

135 (SD 29)

Ohmori et al. 2003

Rat (Wistar), adult, F

IV

20.1

1 day

2,233 (SD 805)

Ohmori et al. 2003

Oral

2

1 day

7.33 (SD 0.55)

Kim et al. 2016b

Oral

2

1 day

11.3 (SE 0.56)

Chang et al. 2012

Oral

15

1 day

4.9 (SE 0.52)

Chang et al. 2012

IV

2

1 day

9.24 (SD 0.37)

Kim et al. 2016b

Oral

2

1 day

8.52 (SD 0.37)

Kim et al. 2016b

Oral

2

1 day

22.2 (SE 0.28)

Chang et al. 2012

Oral

15

1 day

5.4 (SE 20)

Chang et al. 2012

IV

2

1 day

9.82 (SD 0.21)

Kim et al. 2016b

PFOS—Rat
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, FPERFLUOROALKYLS

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Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated inExperimental Animals

Species, age, and sex

Dose Exposure Systemic clearance
Route (mg/kg) duration (mL/day/kg)a
Reference

PFDA—Rat
Rat (Wistar), adult, M

IV

25

1 day

207 (SD 0.054)

Ohmori et al. 2003

Rat (Wistar), adult, F

IV

25

1 day

140 (SD 0.008)

Ohmori et al. 2003

PFNA—Rat
Rat (Wistar), adult, M

IV

22.6

1 day

6.9 (SD 0.6)

Ohmori et al. 2003

Rat (Wistar), adult, F

IV

22.6

1 day

106 (SD 31)

Ohmori et al. 2003

PFHpA—Rat
Rat (Wistar), adult, M

IV

17.7

1 day

1,604 (SD 558)

Ohmori et al. 2003

Rat (Wistar), adult, F

IV

17.7

1 day

3,071 (SD 781)

Ohmori et al. 2003

IV

10

1 day

2,784

Chengelis et al. 2009a

IV

10

1 day

18,600Chengelis et al. 2009a

Oral

4

1 day

7.15 (SD 0.06)

Kim et al. 2016b

IV

4

1 day

9.01 (SD 0.05)

Kim et al. 2016b

IV

10

1 day

6.7 (SE 0.06)

Sundström et al. 2012

Oral

4

1 day

124.83 (SD 3.40)

Kim et al. 2016b

IV

4

1 day

227.93 (SD 6.73)

Kim et al. 2016b

IV

10

1 day

53.4 (SE 4.38)

Sundström et al. 2012

IV

30

1 day

851 (SE 61)

Chang et al. 2008a

IV

30

1 day

2,949 (SE 59)

Chang et al. 2008a

Oral

30

1 day

494 (SE 29)

Chang et al. 2008a

Oral

30

1 day

1,527 (SE 145)

Chang et al. 2008a

IV

10

1 day

946

Chengelis et al. 2009a

IV

10

1 day

7,464

Chengelis et al. 2009a

PFHxA—Rat
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, FPFHxS—Rat
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, F
PFBA—Rat
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, F
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, F
PFBS—Rat
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, FPERFLUOROALKYLS

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Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated inExperimental Animals

Species, age, and sex
Rat (Sprague-Dawley),
adult, M
Rat (Sprague-Dawley),
adult, F
PFOA—Mouse
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, F
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, F
PFOS—Mouse
Mouse (CD), adult, M
Mouse (CD), adult, M
Mouse (CD), adult, F
Mouse (CD), adult, F
PFHxS—Mouse
Mouse (CD), adult, M
Mouse (CD), adult, M
Mouse (CD), adult, F
Mouse (CD), adult, F
PFNA—Mouse
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, F
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, F
PFDA—Mouse
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, F
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, F

Dose Exposure Systemic clearance
Route (mg/kg) duration (mL/day/kg)a
Reference
IV

30

1 day

2,856 (SE 816)

Olsen et al. 2009

IV

30

1 day

11,265 (SE 960)

Olsen et al. 2009

IV

0.13

1 day

14.2 (SD 8.4)

IV

0.13

1 day

11.8 (SD 6.1)

Oral

1.3

1 day

13.1 (SD 7.4)

Oral

1.3

1 day

9.0 (SD 1.9)

Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b

Oral
Oral
Oral
Oral

1
20
1
20

1 day
1 day
1 day
1 day

4.7
4.7
5.0
6.0

Chang et al. 2012
Chang et al. 2012
Chang et al. 2012
Chang et al. 2012

Oral
Oral
Oral
Oral

1
20
1
20

1 day
1 day
1 day
1 day

2.9
4.8
2.7
3.8

Sundström et al. 2012
Sundström et al. 2012
Sundström et al. 2012
Sundström et al. 2012

IV

0.14

1 day

3.9 (SD 1.9)

IV

0.14

1 day

5.1 (SD 2.3)

Oral

1.4

1 day

4.0 (SD 1.7)

Oral

1.4

1 day

2.4 (SD 1.0)

Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b

IV

0.16

1 day

2.2 (SD 0.9)

IV

0.16

1 day

2.8 (SD 1.2)

Oral

1.6

1 day

3.9 (SD 1.8)

Oral

1.6

1 day

2.2 (SD 1.1)

Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b

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Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated inExperimental Animals

Species, age, and sex
PFUnA—Mouse
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, F
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, FPFDoDA—Mouse
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, F
Mouse (FVB/NJcl),
adult, M
Mouse (FVB/NJcl),
adult, F
PFBA—Mouse
Mouse (CD1), adult, M

Dose Exposure Systemic clearance
Route (mg/kg) duration (mL/day/kg)a
Reference
IV

0.17

1 day

2.8 (SD 1.0)

Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b

IV

0.17

1 day

3.4 (SD 1.5)

Oral

1.7

1 day

5.7 (SD 2.6)

Oral

1.7

1 day

3.1 (SD 1.7)

IV

0.19

1 day

4.4 (SD 1.6)

IV

0.19

1 day

4.8 (SD 2.4)

Oral

1.9

1 day

9.4 (SD 4.1)

Oral

1.9

1 day

5.2 (SD 3.2)

Oral

10

1 day

280 (SE 72)

Chang et al. 2008b

Mouse (CD1), adult, M

Oral

30

1 day

296 (SE 640)

Chang et al. 2008b

Mouse (CD1), adult, M

Oral

100

1 day

784 (SE 112)

Chang et al. 2008b

Mouse (CD1), adult, F

Oral

10

1 day

564 (SE 24)

Chang et al. 2008b

Mouse (CD1), adult, F

Oral

30

1 day

696 (SE 32)

Chang et al. 2008b

Mouse (CD1), adult, F

Oral

100

1 day

1,336 (SE 64)

Chang et al. 2008b

Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b
Fujii et al. 2015a,
2015b

aAs reported in units of mL/day/kg or converted from mL/hour (x24), mL/hour (x24/body weight) or mL/minute(x60x24).
CI = confidence interval; F = female; IV = intravenous; M = male; PFBA = perfluorobutanoic acid;
PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoic acid; PFHpA = perfluoroheptanoic acid;
PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; SD = standard deviation; SE = standard error

Elimination of Perfluoroalkyls in Humans. Elimination t1/2 values for PFOA, PFOS, PFHxS, PFBA,
and PFBS have been estimated in humans (Bartell et al. 2010; Costa et al. 2009; Chang et al. 2008a;
Glynn et al. 2012; Harada et al. 2005a; Li et al. 2018; Olsen et al. 2007a, 2009; Seals et al. 2011;
Spliethoff et al. 2008; Yeung et al. 2013; Wong et al. 2014, 2015; Worley et al. 2017a; Zhang et al. 2013).
Estimates in humans are based on measurements of the decline in serum perfluoroalkyl concentrations
following cessation or an abrupt decrease in exposure, or on measurements of renal plasma clearancePERFLUOROALKYLS

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from serum in a general population sample from Japan (Harada et al. 2005a). The latter clearance
estimates were converted to t1/2 values, for display in Table 3-5 as follows (Equations 3-4 and 3-5):

ke =

Cl
V

Eq. (3-4)

ln(2)
ke

Eq. (3-5)

t1 / 2 =where ke is the elimination rate constant (e.g., day-1), Cl is the renal plasma clearance (e.g., mL
plasma/day/kg), and V is the plasma volume (L/kg), which is assumed to be 4.3% of body weight (ICRP
1981). In general, these studies show that longer chain length is associated with slower elimination rates.
For example, the elimination t1/2 for PFBA was estimated to be 70–80 hours (Chang et al. 2008a),
whereas the t1/2 values for PFHxS, PFOS, and PFOA range from 2 to 35 years (Bartell et al. 2010; Haradaet al. 2005a; Li et al. 2018; Olsen et al. 2007a; Seals et al. 2011; Worley et al. 2017a; Zhang et al. 2013).
Longer t1/2 values for PFOA have been reported with longer monitoring follow-up times, which allow thedetection of slower elimination phases of multiphasic elimination kinetics (Seals et al. 2011).
Perfluoroalkyl sulfonates are eliminated more slowly in humans than corresponding carboxylates of thesame chain length (Zhang et al. 2013). Analytical methods typically used to measure serum
perfluoroalkyls do not discriminate between linear and branched isomers and, as a result, these studies
estimate elimination rates for the isomer mixture. A study that compared elimination rates of isomers of
PFOA found that linear isomers tend to be eliminated more slowly than branched isomers (Zhang et al.
2013), consistent with results of studies conducted in rats (Benskin et al. 2009; De Silva et al. 2009).

An analysis of serum PFOS data from NHANES indicated that t1/2 in females may be shorter (4.3 years)
compared to males (4.7 years; Wong et al. 2014, 2015). The NHANES data are cross-sectional and,
therefore, the estimates of t1/2 required fitting the data to age patterns of PFOS intake. An improved fit to
the data for females was achieved when estimated losses of PFOS in menstrual fluids were considered,suggesting that menstrual loss of PFOS may account for some, but not all, of the sex difference in theelimination rate (Verner and Longnecker 2015; Wong et al. 2015). Li et al. (2018) also found apparent
sex differences in PFOS elimination in male and female residents in Sweden exposed to contaminateddrinking water. The estimated t1/2 for PFOS were 4.6 years in males and 3.1 years in females. Zhang etal. (2013) estimated serum t1/2 for various age and sex strata in a population of 86 individuals. Serum t1/2
for PFOS was lower for PFOS in younger females (≤50 years, t1/2 = 6.2 years±0.3 SE, n=66) compared tomales and older females (t1/2 =27 years±3.1 SE, n=20). Zhang et al. (2013) attributed the difference inserum t1/2 to clearance in menstrual fluids. However, the estimated serum t1/2 of 27 years is much higher
than values calculated from other studies; Zhang et al. (2013) noted that the serum t1/2 should bePERFLUOROALKYLS

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considered as an upper limit estimate. Estimated t1/2 for PFOA was not different in younger females(2.1±0.3 SE, n=20) compared to males and older females (2.6±0.4 SE, n=66). Declines in serum PFOA
concentrations were observed in populations following initiation of activated carbon filtration of public
water supplies that had been contaminated with PFOA (Bartell et al. 2010). The estimated mean serum
t1/2 for a group of 200 adults followed for 1 year after filtration was initiated was 2.3 years (95% CI 2.1–
2.4). Elimination rates were not different in males and females. Serum PFOA concentration ranged from
16 to 1,200 ng/mL. A larger follow-up study measured serum PFOA concentrations in two populationsof former residents (n=1,672) of the same water districts (Seals et al. 2011). In one population (n=643),
the serum t1/2 increased with increasing elapsed time since leaving the water district. The t1/2 values were
2.9 years (95% CI 2.3–3.8) for elapsed time of <4 years and 10.1 years for elapsed time of >4 years. In asecond population with an elapsed time since residence of <9 years, the t1/2 was 8.5 years (95% CI 7.1–
10.1). Elimination rates (based on the annual percent decrease in serum concentrations) were faster inmales (27%) compared to females (18%) for the first 4 years post-exposure; however, no difference wasevident between sexes when elapsed time from exposure was >4 years.

Bartell (2012) and Russell et al. (2015) point out that most studies examining PFOA elimination halflives fail to account for ongoing background exposure, which could result in an overestimation ofelimination half-lives. Bartell (2012) estimated that the bias from background exposure could resulted in
1–26% overestimation of calculated PFOA half-lives and that greater overestimations can occur for halflives based on longer follow-up times. Russell et al. (2015) estimated that the bias was greatest in
populations with serum PFOA levels closest to background levels. In a re-analysis of the Olsen et al.
(2007) occupational exposure data, Russell et al. (2015) estimated that overestimation was approximately
1.2% in workers with initial serum concentrations >500 ng/mL (100 times higher than NHANES general
population data) and 13% for workers with lower initial serum PFOA levels. Restricting the elimination
half-life calculation to workers with initial serum PFOA levels of >500 ng/mL would result in a half-lifeof 3.0 years (Russell et al. 2015), compared to 3.8 years calculated for the whole cohort (Olsen et al.
2007).

Analysis of kinetics of serum PFOS concentrations in retired U.S. fluorochemical production workers(24 males, 2 females) yielded a mean serum elimination t1/2 estimate of 5.4 years (95% CI 3.9–6.9;
geometric mean: 4.8 years, 95% CI 4.0–5.8) in subjects whose serum PFOS concentrations ranged from37 to 3,490 ng/mL (Olsen et al. 2007a). Estimates for the two females in the same study were 4.9 and6.8 years. Estimates based on renal clearance of PFOS from serum in subjects from the general
population of Japan ranged from 2.9 to 7.4 years; these subjects had serum PFOS concentrations that

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ranged from 4 to 49 ng/mL (Harada et al. 2005a). Estimates in males (7.4, 2.9 years) were similar tofemales (4.5, 4.6 years). This same study measured serum PFHxS concentrations in retired U.S.
fluorochemical production workers (24 males, 2 females) and yielded a mean estimate of 8.5 years (95%
CI 6.4–10.6; geometric mean: 7.3 years, 95% CI 5.8–9.2) for the serum elimination t1/2 in subjects whose
serum PFHxS concentrations ranged from 10 to 1,295 ng/mL (Olsen et al. 2007a). Estimates for the two
females in the same study were 12.2 and 13.3 years.

The elimination rate of PFBA was estimated in fluorochemical workers who may have been exposed tovarious PFBA precursors (Chang et al. 2008a). In three male workers, the estimated mean t1/2 based onserum PFBA kinetics was 81 hours (±41 SD). In a larger study of nine workers (seven males, twofemales), the mean t1/2 was 72 hours (±38 SD). Estimates for the two female subjects were 56 and118 hours. The combined mean value for the 12 estimates was 75 hours (±38 SD). Olsen et al. (2009)
estimated serum t1/2 of PFBS in six fluorochemical workers. The mean t1/2 was 27.4 days (±11.1 SD).
The group included a single female whose t1/2 was 45.7 days. Based on these observations, PFBA (chain
length 3) and PFBS (chain length 4) are eliminated substantially faster in humans than perfluoroalkyls
having longer carbon chain lengths, such as PFHxS (chain length 6), PFOA (chain length 7), and PFOS
(chain length 8).

Temporal trends in perfluoroalkyl serum concentrations have also been used to estimate population
halving times (Glynn et al. 2012; Olsen et al. 2012; Spleithoff et al. 2008; Yeung et al. 2013). Population
halving times are influenced by temporal trends in intakes and may therefore not accurately reflect
clearance. Population halving times for PFOS ranged from 4 to 5 years (Olsen et al. 2012; Spleithoff et
al. 2008; Yeung et al. 2013). Glynn et al. (2012) monitored serum perfluoroalkyls in a population ofpregnant women (n=413) in Sweden over the period 1996–2010. Halving times were 22 years (95%
CI 16–38) for PFOA and 8.2 years (95% CI 6.3–12) for PFOS.

Elimination of Perfluoroalkyls in Nonhuman Primates. Elimination t1/2 values and systemic clearancesfor PFOA, PFOS, PFHxA, PFHxS, PFBA, and PFBS have been estimated in Cynomolgus monkeys(Buttenoff et al. 2004c; Chang et al. 2012; Chengelis et al. 2009a; Olsen et al. 2009; Seacat et al. 2002;
Sundström et al. 2012). Estimated terminal t1/2 values were 20–30 days for PFOA, 100–170 days for
PFOS, 90–140 days for PFHxS, 40 hours for PFBA and 8–95 hours for PFBS. Elimination of
perfluoroalkyls in monkeys is multiphasic and, as a result, estimates of the terminal t1/2 can vary with theduration of the observation period and assumptions made in modeling elimination kinetics (Chang et al.
2012; Chengelis et al. 2009a; Olsen et al. 2009; Sundström et al. 2012). For example, the t1/2 values forPERFLUOROALKYLS

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONSPFBS were 8 and 15 hours in female and male monkeys, respectively, when monkeys were monitored for
48 hours following a single intravenous dose (Chengelis et al. 2009a), whereas the t1/2 values were 95 and83 hours in male and female monkeys, respectively, when the monitoring period was extended to 14 days
and a three-compartment model was used to estimate the terminal t1/2 (Olsen et al. 2009). Studies inmonkeys confirm general trends observed in humans that perfluoroalkyl sulfonates are more slowly
eliminated than perfluoroalkyl carboxylates and that elimination of longer-chain perfluoroalkyls occurs
more slowly than short-chain perfluoroalkyls. Systemic clearances were lower for PFOS, PFHxS, andPFBS compared to the corresponding carboxylates, PFOA, PFHxA, and PFBA (Table 3-6). Systemic
clearances were similar in male and female monkeys (Table 3-6).

Elimination of Perfluoroalkyls in Rats. Elimination t1/2 values and systemic clearances for PFOA,PFOS, FOSA, PFDA, PFNA, PFHpA, PFHxA, PFHxS, PFBA, and PFBS have been estimated in rats
(Benskin et al. 2009; Chang et al. 2008b, 2012; Chengelis et al. 2009a; De Silva et al. 2009; Johnson andOber 1979; Kemper 2003; Kim et al. 2016b; Kudo et al. 2002; Ohmori et al. 2003; Olsen et al. 2009;
Seacat and Luebker 2000; Sundström et al. 2012; Vanden Heuvel et al. 1991b, 1991c; Ylinen et al. 1990).
Consistent with observations made in humans and Cynomolgus monkeys, perfluoroalkyl sulfonates are
more slowly eliminated than perfluoroalkyl carboxylates and short-chain perfluoroalkyls (e.g., PFBA,
PFBS) are eliminated faster in rats than long-chain perfluoroalkyls (e.g., PFOA, PFOS, PFHxA, PFHxS);
Tables 3-5 and 3-6. Linear PFOA isomers tend to be eliminated more slowly than branched isomers(Benskin et al. 2009; De Silva et al. 2009).

Elimination of perfluoroalkyls exhibits pronounced sex differences in rats, with faster elimination infemales than in males (Benskin et al. 2009; Chang et al. 2008b; Chengelis et al. 2009a; Kemper 2003;
Kim et al. 2016b; Kudo et al. 2002; Ohmori et al. 2003; Sundström et al. 2012; Tatim-Gibbs et al. 2011;
Vanden Heuvel et al. 1991c; Ylinen et al. 1990). Estimates of systemic clearance for PFOA in male rats
ranged from 20 to 50 mL/day/kg, whereas estimates for female rats ranged from 600 to 2,200 mL/day/kg(Kemper 2003; Kudo et al. 2002; Ohmori et al. 2003). Systemic clearances of PFOA, PFOS, PFNA,PFHxA, PFHxS, PFBA, and PFBS are also higher in female rats compared to male rats (Table 3-6).
Pronounced sex difference in elimination rates in rats (faster elimination in females) was observed in rats
following 30-minute nose-only exposures to aerosols (MMAD=1.9–2.1 µm) of 1–25 mg ammonium
PFOA/m3 (Hinderliter et al. 2006a). Plasma PFOA concentrations were not detectable 12 hours after
exposure of female rats, and were approximately 90% of peak plasma concentrations 24 hours after the
exposure in male rats. The slower elimination of PFOA in male rats resulted in steady-state plasma
concentrations within 3 weeks of repeated exposures (6 hours/day, 5 days/week) in male rats, whereas inPERFLUOROALKYLS

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female rats, daily periodic oscillations of plasma concentrations from peak to below detection occurred oneach day of exposure. Steady-state plasma concentrations in male rats were approximately 10 times thatof daily peak concentrations in female rats.

Pronounced dose dependence appears in the t1/2 estimates for PFOA in female rats. With increasing dose,
plasma elimination kinetics in female rats converts from monophasic to biphasic. Following an oral doseof PFOA of 0.1, 1, 5, or 25 mg/kg, the terminal t1/2 values in female rats were 3.2, 3.5, 4.6, or 16.2 hours,
respectively; no apparent dose dependence was observed in male rats over the same dose range (Kemper2003). Dose-dependent elimination of PFOA has been attributed to a capacity-limited renal tubular
secretion of PFOA in female rats (see discussion below on Mechanisms of Excretion). The divergence inelimination kinetics between male and female rats appears to be age-dependent, with faster elimination
becoming evident in female rats after 30 days of age, consistent with the timing of sexual maturation andinvolvement of sex hormones in the modulation of the renal excretion of PFOA in rats (Hinderliter et al.
2006b).

Elimination of Perfluoroalkyls in Mice. Elimination t1/2 values and systemic clearances for PFOS,
PFHxS, and PFBA have been estimated in mice (Chang et al. 2008a, 2012; Sundström et al. 2012).
Consistent with studies conducted in rats and monkeys, PFBA is eliminated more rapidly in mice than
PFOS and PFHxS. Systemic clearances ranged from 5 to 6 mL/day/kg for PFOS (Chang et al. 2012),
from 3 to 5 mL/day/kg for PFHxS (Sundström et al. 2012), and from 300 to 1,300 mL/day/kg for PFBA
(Chang et al. 2008a). Sex differences in elimination in mice were observed for PFBA, but not PFOS or
PFHxS. Systemic clearances of PFBA in female mice were approximately 2 times that of males (Changet al. 2008a). Systemic clearance of PFBA in male and female mice appeared to be dependent on dose.
Systemic clearance following a single oral dose of 100 mg PFBA/kg was approximately 2 times higher
than the systemic clearance following a dose of 10 or 30 mg PFBA/kg. Possible explanations for theapparent dependence of clearance on dose are dose-dependent bioavailability or that the one-compartment
model used to estimate elimination rates and serum AUC did not adequately fit the serum kinetics
observed at the higher dose (Chang et al. 2008a). The latter could occur if renal tubular reabsorption of
PFBA or plasma protein binding of PFBA is saturable in mice. Systemic clearance rates for PFOA weresimilar in male mice (13.1 mL/kg/day) and in female mice (9.0 mL/kg/day) (Fuji et al. 2015a, 2015b).

Elimination of Perfluoroalkyls in Other Species. Sex differences in elimination of PFOA have also been
observed in hamsters; unlike the rat, male hamsters excreted absorbed PFOA more rapidly than female
hamsters. Following a single gavage dose of 10 mg/kg as ammonium [14C]PFOA, cumulative excretion

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of 14C in urine at 24 hours post-dosing was 96.4% of the dose in female rats and 8.7% in male rats; 24.6%
and 84.5% in female and male hamsters, respectively; 4.1% in male and female mice; and 90.5 and 80.2%
in female and male rabbits, respectively (Hundley et al. 2006).

Mechanisms of Excretion. Urinary excretion of perfluoroalkyls involves glomerular filtration and renal
tubular secretion and reabsorption (for PFOA, see Harada et al. 2005a; Kudo et al. 2002; Ohmori et al.
2003). Glomerular filtration of PFOA is limited by extensive binding of PFOA to albumin and other highmolecular weight proteins in plasma (Han et al. 2003, 2005; Ohmori et al. 2003; Kerstner-Wood et al.
2003; Vanden Heuvel et al. 1992a, 1992b; Ylinen and Auriola 1990). Elimination of PFOA and otherperfluoroalkyls shows pronounced sex differences in rats, with slower elimination in males for PFOA,PFOS, PFNA, PFHxA, PFHxS, PFBA, and PFBS (Chang et al. 2008a, 2012; Chengelis et al. 2009a;
Kemper 2003; Kudo et al. 2002; Ohmori et al. 2003; Sundström et al. 2012). The sex difference in PFOA
elimination in rats is dependent on testosterone (Hinderliter et al. 2006b; Kudo et al. 2002; Vanden
Heuvel et al. 1992a). The significantly slower elimination of PFOA in adult male rats compared tofemale rats has been attributed to sex hormone modulation of organic anion transporters in kidney. At
similar doses administered to male and female rats, PFOA undergoes net tubular reabsorption in male rats
(i.e., urinary excretion rate < rate of glomerular filtration of PFOA) and net tubular secretion in female
rats (i.e., urinary excretion rate > rate of glomerular filtration of PFOA) (Harada et al. 2005a; Kudo et al.
2002; Ohmori et al. 2003). In rats, several transporters have been shown to have affinity for C7–C9
perfluoroalkyl carboxylates. The transporters, OAT1 and OAT3, located on the basolateral membrane of
the renal proximal tubule, appear to participate in secretion of C7–C9 perfluoroalkyl carboxylates into thetubular fluid (Nakagawa et al. 2008; Weaver et al. 2010). The transporters, OATP1a1 (rat), OAT4
(human), and URAT1 (human), located on the apical membrane, appear to mediate reabsorption of C8–
C10 perfluoroalkyl carboxylates from the tubular fluid (Katakura et al. 2007; Nakagawa et al. 2009;
Weaver et al. 2010; Yang et al. 2009, 2010). In rats and mice, expression of OAT1, OAT3, and
OATP1a1 is controlled by male sex hormones and shows higher activities in males (Buist and Klaassen
2004; Gotoh et al. 2002; Kobayashi et al. 2002; Li et al. 2002; Lu et al. 1996; Lubojevic et al. 2004). The
slower elimination of PFOA (and other long-chain perfluoroalkyl carboxylates) in male rats has been
attributed to OATP1a1 (Weaver et al. 2010; Yang et al. 2009). Higher activity of OATP1a1 in male rats
results in higher reabsorptive transport and lower rates of urinary excretion. However, saturation of thistransporter could result in an increase in urinary elimination of perfluoroalkyls due to decreased tubular
reabsorption. This is consistent with the apparent plateau in plasma concentration with increasing dose
observed in cancer patients treated with PFOA (Convertino et al. 2018). Affinities of OATP1a1 (rat),
OAT4 (human), and URAT1 (human) are highest for C7–C10 perfluoroalkyl carboxylates (Weaver et al.

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2010; Yang et al. 2009, 2010). Affinity of rat OATP1a1 is strongly correlated with total clearance in rats
(r2=0.98; Yang et al. 2009).

Although sex differences for elimination of perfluoroalkyls have been detected in laboratory animals,
human monitoring studies have not consistently detected sex differences in elimination t1/2 ofperfluoroalkyls; this may reflect limitations in the studies, including numbers and age of subjects (Bartell
et al. 2010; Seals et al. 2011; Wong et al. 2014, 2015; Zhang et al. 2013). Menstruation may contribute tofaster elimination of PFOS in women (Wong et al. 2014, 2015; Zhang et al. 2013). The effect of
menstruation or other variables related to menstruation appear to contribute to faster elimination inyounger (≤50 years) women compared to men and older women (Zhang et al. 2013). Two studies havefound evidence for elimination of PFOS being affected by menstruation (Wong et al. 2014, 2015; Zhang
et al. 2013). The estimated t1/2 for PFOA was not different in younger females compared to males andolder females. Mechanisms by which menstruation could affect PFOS clearance are not understood.
Bulk elimination of blood would be expected to affect serum clearance of both PFOS and PFOA;
therefore, other mechanisms must contribute that discriminate between perfluoroalkyl species. A better
metric than serum t1/2 for evaluating sex differences in elimination for this would be systemic or renal
clearance of the perfluoroalkyl. Harada et al. (2005a) measured renal clearance in a small sample ofyoung adults (five males and five females, age 22–23 years) and found that renal clearance was notdifferent in males and females. Zhang et al. (2013) estimated renal clearance of PFOA and PFOS in a
population of younger females (≤50 years, n=20), older females (>50 years), younger males (≤50 years),and older males (>50 years) and did not find significant sex or age differences. Studies that measured
systemic clearance in monkeys also have not found significant sex differences in systemic clearance of
PFOA (Buttenoff et al. 2004c) or PFOS (Chang et al. 2012).

Studies conducted in rats have shown that PFDA, PFNA, PFOA, PFOS, and PFHxA are secreted in bileand undergo extensive reabsorption from the gastrointestinal tract (Johnson et al. 1984; Kudo et al. 2001;
Vanden Heuvel et al. 1991b, 1991c). Biliary secretion rates of PFOA are similar in male and female rats
when renal excretion is blocked by ligation of the kidneys (Vanden Heuvel et al. 1991a, 1991b). This
lack of sex influence on biliary secretion (compared to the sex influence on renal clearance) may reflect a
relative sex insensitivity of OAT2 (or other organic anion transporter) expression in liver, compared tokidney; the latter is approximately 7–8 times higher in adult female rats compared to male rats (Kudo etal. 2002).

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3.1.5

Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

PBPK models use mathematical descriptions of the uptake and disposition of chemical substances toquantitatively describe the relationships among critical biological processes (Krishnan et al. 1994). PBPK
models are also called biologically based tissue dosimetry models. PBPK models are increasingly used inrisk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical thatwill be delivered to any given target tissue following various combinations of route, dose level, and test
species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use
mathematical descriptions of the dose-response function to quantitatively describe the relationshipbetween target tissue dose and toxic endpoints.
Several PBPK models of PFOA and PFOS have been reported. These include a human model for PFOA
and PFOS (Fàbrega et al. 2014, 2016; Loccisano et al. 2011; Worley et al. 2017b), models for PFOA andPFOS in monkeys (Loccisano et al. 2011), models for PFOA and PFOS in rats (Harris and Barton 2008;
Loccisano et al. 2012a, 2012b; Tan et al. 2008; Worley and Fisher 2015a. 2015b), and a model for PFOA
in mice (Rodriguez et al. 2009). Models of PFOA and PFOS kinetics during gestation and lactation inrats and mice also have been reported (Loccisano et al. 2012a, 2012b; Rodriguez et al. 2009). Various
empirical and compartmental models have also been reported (Hoffman et al. 2011; Lorber and Egeghy
2011; Lou et al. 2009; Thompson et al. 2010; Verner et al. 2016; Wambaugh et al. 2013; Wu et al. 2009).
Tardiff et al. (2009) utilized a human pharmacokinetic model to estimate an average daily oral dosecorresponding to a Reference Dose for PFOA plasma concentration in humans. Cheng and Ng (2017)
developed a permeability-limited PBPK model for PFOA in male rats that could be used for in vitro toin vivo extrapolation. Kim et al. (2018) developed a PBPK model for PFHxS in rats and humans. PBPK
models were not identified for other perfluoroalkyls examined in this profile. Given the toxicokinetic
differences between compounds, the PFOA, PFOS, and PFHxS PBPK models may not be appropriate forother compounds.

3.1.5.1 Loccisano et al. (2012a, 2012b) Rat Models
Loccisano et al. (2012a) developed a model for simulating the kinetics of PFOA and PFOS in male andfemale rats. The model was based, in part, on a multi-compartmental model developed by Tan et al.
(2008; Andersen et al. 2006). The female rat model (Loccisano et al. 2012a) was subsequently extended
to include gestation and lactation (Loccisano et al. 2012b). The general structures of the models are
depicted in Figures 3-3, 3-4, and 3-5. Complete lists of parameters and parameter values and the bases

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for parameter values and evaluations of model predictions in comparison to observations are described in
Loccisano et al. (2012a, 2012b).

Figure 3-3. Structure of PBPK Model of PFOA and PFOS in the Rat

Intravenous

Oral,
diet

Gut
kabs

QLiv

PlasmaLiver
Bmax, Kb, koff

kunabskbile

storagefeces

Rest of body
QTis

Free
fraction

Kidney
QKid

QFil

Tm,Kt

Filtrate

storageurine
Bmax = liver binding capacity; kabs = first-order absorption rate constant; Kb = liver binding affinity
constant; kbile = biliary excretion rate constant; Koff = liver binding dissociation constant; Kt = affinity
constant; kunabs = rate of unabsorbed dose to appear in feces; PBPK = physiologically based
pharmacokinetic; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; QFil = clearance
from plasma to glomerular filtrate; QKid = blood flow in and out of kidney; QLiv = blood flow in and out ofliver; QTis = blood flow in and out of tissues; Tm = transporter maximum
Source: Loccisano et al. 2012a (reproduced with permission of Elsevier Inc. in the format reuse in agovernment report via Copyright Clearance Center; Reproductive Toxicology by Reproductive Toxicology
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Figure 3-4. PBPK Model Structure for Simulating PFOA and PFOS Exposure
During Gestation in the Rat (Dam, Left; Fetus, Right)
Oral dose

Gut

QFBrn
kunabs

kabs
QLiv

QKid

kbile

Liver

storage

Fetal brain
feces

Fetal
plasmaKidney

QFLiv

Fetal liver
QFTis

Tm,Kt
QFil

Filtrate

Plasmafree
fractionstorageurine

Rest of fetal
tissues/body

Fetal structure for PFOS

ktrans1
QPla

QMam

QFat

Placentaktrans2

Amniotic
fluid

Mammary
Fat

Fetal
plasmaktrans4

QFTis
QTis

ktrans3

Rest of fetal
tissues/bodyRest of bodykabs = first-order absorption rate constant; kbile = biliary excretion rate constant; Kt = affinity constant;ktrans1/ktrans 2 = transfer between placenta and fetal plasma; ktrans3/ktrans4 = transfer between
amniotic fluid and rest of the body; kunabs = rate of unabsorbed dose to appear in feces;
PBPK = physiologically based pharmacokinetic; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane
sulfonic acid; QFat = blood flow in and out of fat; QFBrn = blood flow in and out of fetal brain;
QFil = clearance from plasma to glomerular filtrate; QFLiv = blood flow in and out of fetal liver;
QFTis = blood flow in and out of fetal tissue; QKid = blood flow in and out of kidney; QLiv = blood flow inand out of liver; QMam = blood flow in and out of mammary tissue; QPla = blood flow in and out ofplacenta; QTis = blood flow in and out of tissues; Tm = transporter maximum
Source: Loccisano et al. 2012b (reproduced with permission of Elsevier Inc. in the format reuse in agovernment report via Copyright Clearance Center; Reproductive Toxicology by Reproductive Toxicology
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Figure 3-5. PBPK Model Structure for Simulating PFOA/PFOS Exposure During
Lactation in the Rat (Dam, Left; Pup, Right)

QTis

Rest of body
PAMilkQMam

QLiv

Pup gut

Pup feceskabsP

Mammary
tissue
Liver

klac

Milk
Oral dose

Pup liver
kabs

QPLiv

Gut
Pup kidney

Plasmakbile

storage

Pup urineFreefraction

QPKid

TmP,KtPPup filtrate

QFat

QKid

Fat

Pup
plasma

QPFil

feces

KidneyRest of body

QPTis

Tm,Kt
QFil

Filtrate
Transfer of PFOS to milk

Plasmastorage

QMam

Free
fraction

Milk

klac

Pup gut

urinekabs = first-order absorption rate constant; kabsP = pup first-order absorption rate constant; kbile = biliary
excretion rate constant; klac = transfer to pup through milk; Kt = affinity constant; KtP = pup affinity
constant; PAMilk = transfer from mammary tissue to liver; PBPK = physiologically based pharmacokinetic;
PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; QFat = blood flow in and out of fat;
QFil = clearance from plasma to glomerular filtrate; QKid = blood flow in and out of kidney; QLiv = bloodflow in and out of liver; QMam = blood flow in and out of mammary tissue; QPFil = clearance from pup
plasma to glomerular filtrate; QPKid = blood flow in and out of pup kidney; QPLiv = blood flow in and outof pup liver; QPTis = blood flow in and out of pup tissue; QTis = blood flow in and out of tissues;
Tm = transporter maximum; TmP = pup transporter maximum
Source: Loccisano et al. 2012b (reproduced with permission of Elsevier Inc. in the format reuse in agovernment report via Copyright Clearance Center; Reproductive Toxicology by Reproductive Toxicology
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The basic (i.e., adult nonpregnant rat) model includes compartments representing plasma (including abound and free fraction), kidney and renal glomerular filtrate, liver, and a lumped compartment
representing all other tissues. Two storage compartments are included in the model: one receives
perfluoroalkyl from the gastrointestinal tract (unabsorbed) and liver (bile) and the other receives
perfluoroalkyl from the glomerular filtrate. The storage compartments were included in the model tosimulate time delays between elimination from plasma and appearance of perfluoroalkyl in feces or urine.
Absorption from the gastrointestinal tract is simulated as the balance between first-order absorption andfecal excretion of unabsorbed chemical. Absorbed PFOA and PFOS are assumed to be delivered to theliver where saturable binding of PFOS (but not PFOA) to liver proteins occurs. Saturable binding of
PFOS in liver was included to simulate the relatively long retention times of PFOS in liver that have been
observed in rats. Exchanges between PFOA or PFOS in liver (free fraction), kidney, and other tissues
with the free pool in plasma are assumed to be flow-limited (governed by blood flow) with equilibrium
determined by the tissue:blood partition coefficient. PFOA and PFOS in plasma are simulated as
instantaneous distributions into free and bound fractions. Extensive binding of PFOA and PFOS toplasma proteins has been demonstrated in various animal species including rats (see Section 3.1.2). For
PFOA, the free fraction is assigned a constant of 4.5% in females and 0.6% in males. These values were
optimized to fit observed kinetics of PFOA in plasma and urine of rats following intravenous and oral
exposures (Loccisano et al. 2012a). Adequate fit to observed PFOS plasma kinetics following single
doses of PFOS required introducing a time-dependence in binding of PFOS to protein (Loccisano et al.
2012a; Tan et al. 2008). The free fraction for PFOS in plasma decreases from an initial value (after
dosing) of 2.2% to a minimum of 0.1% with a t1/2 for the change of approximately 14 hours in a 0.25-kg
rat (k=0.035 hours-1/kg-0.25). The relatively short t1/2 for the change limits the effects of the timedependent plasma kinetics over the first 1–2 days of dosing (including peak concentrations) and has noeffect on longer-term kinetics or steady state. Although the time-dependence of the free fraction inplasma was needed to simulate short-term plasma PFOS kinetics in rats, the physiological mechanism fora dependence of plasma binding on the time following dosing (i.e., not on concentration of PFOS in
plasma or some other dose surrogate) has not been established. Elimination of absorbed chemical occurs
by biliary excretion and urinary excretion. Transfer from liver to feces (representing excretion following
biliary transfer) is represented as a first-order process acting on the free fraction in liver. Excretion in
urine is simulated as the balance between transfer from the free fraction to the glomerular filtrate andrenal tubular reabsorption, which removes PFOA and PFOS from the glomerular filtrate and returns it tokidney tissue. Renal tubular reabsorption is simulated as a capacity-limited process with parameters Tm(µg/hour/kg body weight), representing the maximum rate of transport, and KT (µg/L), representing
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is half of maximum). This representation of renal tubular reabsorption is used to simulate observed sex
differences in elimination of PFOA from plasma, which have been attributed to higher reabsorptive
capacity in male rats (see Section 3.1.4). Values for the maximum and affinity parameters for PFOA
result in higher reabsorptive clearances from the glomerular filtrate (Tm/KT=4.1) in male rats compared tofemale rats (Tm/KT=0.045), and correspondingly lower urinary clearance of PFOA from plasma in malerats. Reabsorption parameters for PFOS are the same in both sexes and result in reabsorptive clearancesthat are approximately twice that of PFOA in female rats (Tm/KT=7.2).

The basic rat model was extended to simulate gestation with inclusion of additional compartments
representing adipose and mammary tissue in the dam, placenta, and fetus (Figure 3-4); Loccisano et al.
2012b). Transfer of PFOA and PFOS to the fetus is simulated as a flow-limited transfer to the placenta,
with first-order exchange between the placenta and the free fraction in fetal plasma. The free fraction in
fetal plasma is simulated as a constant fraction for PFOA and PFOS (i.e., no dependence on time as in theadult). Within the fetus, PFOA in the free fraction of plasma exchanges with a single lumped
compartment representing the fetal body, which exchanges with PFOA in amniotic fluid. The fetal PFOS
model subdivides fetal tissue into brain, liver, and a lumped compartment for other tissues, all of which
undergo flow-limited exchanges with the free fraction of PFOS in fetal plasma. Binding of PFOA andPFOS in fetal liver is assumed to be negligible. Differences in the structure of the fetal models for PFOA
and PFOS reflect the differences in the availability of data for estimating parameter values for the various
compartments (e.g., perfluoroalkyl concentrations in amniotic fluid, liver).

The lactation model extends the dam portion of the gestational model to include milk and pup(Figure 3-5; Loccisano et al. 2012b). Transfer of PFOA to milk occurs through the mammary gland withflow-limited exchange between plasma and mammary tissue and diffusion into milk from mammary
tissue. The model also includes transfer from the pup to the dam, which occurs during maternal
stimulation of the neonatal pup to induce elimination and during pup grooming. Data on PFOS inmammary tissue of rodents were not available to establish parameters for a mammary tissuecompartment; therefore, the mammary tissue compartment was left out of the PFOS model, and transfer
of PFOS to milk is simulated as diffusion directly from plasma. The pup model includes compartments
representing the free fraction in plasma, liver, kidney, glomerular filtrate, and a lumped compartment
representing all other pup tissues. This structure is essentially identical to the nonpregnant rat model(Loccisano et al. 2012a) with a few differences. Absorption from the gastrointestinal tract is assumed tobe complete in pups, and binding in pup liver is assumed to be negligible in pups. There are no storage
compartments for biliary or glomerular filtrate perfluoroalkyl in the pup model. Sex differences in renal

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tubular reabsorption of PFOA are assumed to develop in response to sexual maturation and, therefore, are
not present during lactation (i.e., parameter values are allometrically scaled to pup body weight from themale rat values). Reabsorptive transport parameters for PFOS are allometrically scaled from the lactatingdam. The liver/plasma partition coefficient for PFOS in the pups was set lower than that in the dam,based on observations in rats. All other parameters for PFOA and PFOS in the pup were the same orallometrically scaled from values for the dam.

Optimization of parameter values and evaluations of the rat models are described in Loccisano et al.
(2012a, 2012b). Data sets utilized in developing and evaluating the nonpregnant rat models included
single-dose intravenous and gavage studies and short-term feeding studies (Johnson and Ober 1979;
Kemper 2003; Kudo et al. 2007; Perkins et al. 2004). Data used in development and evaluation of thegestation and lactation models included data from gestational and/or lactational exposure studies in rats
(Chang et al. 2009; Hinderliter et al. 2005; Kuklenyik et al. 2004; Luebker et al. 2002, 2005a, 2005b;
Thibodeaux et al. 2003).

Applications for Dosimetry Extrapolation and Risk Assessment. The wealth of data on
pharmacokinetics of PFOA and PFOS in rats allowed an extensive evaluation of the rat models forpredicting plasma urinary and liver PFOA and PFOS following single intravenous or single and repeatedoral dosing. Inclusion of renal tubular reabsorption parameters in the model provided accurate
simulations of sex differences in elimination rates of PFOA from plasma and excretion in urine, anddifferences in rates of elimination of PFOA and PFOS. The gestation model successfully predicted fetal
plasma and liver PFOA and PFOS at the end (or near the end) of pregnancy. Consistent withobservations, the model predicts higher fetal plasma concentrations and lower fetal liver concentrations of
PFOS compared to maternal, and lower internal exposure (plasma concentrations) to PFOA in the fetus
compared to maternal (fetal liver data were not available for PFOA). The lactation model successfully
predicted PFOA and PFOS in pup plasma following dosing of the dam. Predicted plasma concentrationsof PFOA in nursing pups were approximately 10–50% lower than maternal concentrations, whereasmaternal and pup concentrations of PFOS were similar. The model could be used to estimate liver doses
and corresponding plasma profiles resulting from single or repeated dosing of adult male or female rats,
and maternal-fetal and maternal-pup transfer of PFOA and PFOS. The rat model was evaluated with datafrom a 14-week oral dosing study and has not been tested for longer exposures. Harris and Barton (2008)
developed a PBPK model for PFOS in the rat and found that time adjustments that increased renal
clearance and decreased the liver-plasma partition coefficient as a function of time and dose improved
predictions of plasma and liver PFOS in adult rats exposed for a period of 105 weeks. Although the

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suggest the possibility that clearance of PFOS may be age- and/or dose-dependent in rats. This may
reflect age- or dose-related changes in kidney function, including tubular reabsorption or secretion of
PFOS.

3.1.5.2 Loccisano et al. (2011, 2013) Monkey and Human Models
Loccisano et al. (2011) developed a model for simulating the kinetics of PFOA and PFOS in monkeys
and humans. The human model described in Loccisano et al. (2011) was subsequently extended toinclude simulations of pregnancy and lactation (Loccisano et al. 2013). The monkey model was based, inpart, on a multi-compartmental model developed by Tan et al. (2008; Andersen et al. 2006) for simulating
the kinetics of plasma and urinary PFOA in monkeys. The structures of the monkey and human models
are identical (Figure 3-6) and are very similar to the structure of the rat model (Loccisano et al. 2012a),with inclusion of compartments representing fat and skin, and absence of a storage compartment forbiliary transfer. Complete lists of parameters and parameter values and the bases for parameter values
and evaluations of model predictions in comparison to observations are reported in Loccisano et al.
(2011).

Parameters in the monkey and human models differ in several ways from the rat model. The free fractionin plasma is represented as a constant for both PFOA and PFOS; time-dependency for PFOS in the rat
model is absent in the monkey and human models. The parameters for renal tubular reabsorption of
PFOA and PFOS are the same for males and females. This is consistent with the absence of evidence fora sex difference in elimination kinetics in monkeys (Butenhoff et al. 2002, 2004a; Seacat et al. 2002).

Values for the affinity constant (KT) and maximum (Tm) for tubular reabsorption were optimized toplasma concentration kinetics in monkeys. The value for KT in monkeys was used in the human model.
The value for Tm for PFOA in humans was set to yield a plasma elimination t1/2 of 2.3 or 3.8 years. The
latter two values were derived from estimates of the serum t1/2 in populations exposed to PFOA in
drinking water (2.3 years; Bartell et al. 2010) or in retired fluorochemical workers (3.8 years; Olsen et al.
2007a). The value for Tm for PFOS in humans was set to yield a plasma elimination t1/2 of 5.4 years,
based on observations in retired fluorochemical workers (Olsen et al. 2007a). Binding of PFOA andPFOS in the liver was assumed to be negligible in monkeys and humans. Tissue-plasma partition
coefficients used in both models were derived from observations in rodents and were the same in themonkey and human models.

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Figure 3-6. Structure of PBPK Model for PFOA and PFOS in Monkeys andHumans

QGut

QLiv
QFat
Intravenous

Oral dose,
drinking water

Gut

Liver

Fat

PlasmaFree
fraction

QSkin
QR
QKid

Skin

Rest of body
KidneyTm,Kt

QFil

Filtrate
storagekurineUrine

Kt = half-saturation constant; kurine = urinary elimination rate; PBPK = physiologically based pharmacokinetic;
PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; QFat = blood flow in and out of fat;
Qfil = clearance from plasma to glomerular filtrate; QGut = blood flow in and out of gut; QKid = blood flow in and outof kidney; QLiv = blood flow in and out of liver; QR = blood flow in and out of rest of body; QSkin = blood flow in andout of skin; Tm = transport maximum
Source: Loccisano et al. 2011 (reproduced with permission of Academic Press in the format reuse in a government
report via Copyright Clearance Center; Regulatory Toxicology and Pharmacology: RTP by International Society ofRegulatory Toxicology and Pharmacology)

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Optimization of parameter values and evaluation of the monkey and human models are described in
Loccisano et al. (2011). Data sets utilized in developing and evaluating the monkey model included
single-dose intravenous and oral studies and repeated-dose oral studies conducted in Cynomolgus
monkeys (Butenhoff et al. 2004c; Noker and Gorman 2003; Seacat et al. 2002). Data used in evaluating
the human model consisted of serum measurements in people who experienced environmental exposures(Emmett et al. 2006a; Hölzer et al. 2008; Steenland et al. 2009b), adult Red Cross donors (Olsen et al.
2003b, 2008), and retired fluorochemical workers (Olsen et al. 2007a). In general, PFOA and PFOS
intakes and exposure durations were not known with certainty in these populations and, as a result, thesedata do not yield confident evaluations of the ability of the human model to predict intake-plasma level
relationships. Follow-up monitoring after a cessation or decrease in exposure can provide data that allow
evaluation of the ability of the model to accurately simulate elimination kinetics. Predicted declines inserum PFOA concentrations encompassed observed group mean declines when the Tm for renal tubular
reabsorption was set to yield an elimination t1/2 of 2.3 or 3.8 years. Group mean declines in serum PFOS
were predicted reasonably well for some populations, but not all populations, when the Tm for renal
tubular reabsorption was optimized to yield an elimination t1/2 of 5.4 years.

The human pregnancy model includes additional compartments representing the free fractions in plasma,amniotic fluid, and a lumped compartment for fetal tissue (Loccisano et al. 2013). The same conceptual
approach was used in the rat pregnancy model (Loccisano et al. 2012b, Figure 3-4). Rate constants forplacental transfer were initially those from the rat model, adjusted to yield predicated maternal/fetal
plasma ratios that agreed with observed maternal/fetal ratios in cord blood (Apelberg et al. 2007b; Fei etal. 2007; Midasch et al. 2007; Washino et al. 2009). Transfers from amniotic fluid to fetus were the sameas those used in the rat model, as there were no data on which to base estimates for humans. The lactation
model included additional compartments for mammary milk and a lumped compartment representing theinfant. Transfer of PFOA to milk is simulated as flow-limited exchange between plasma and milk,
governed by mammary tissue blood flow and a milk/plasma partition coefficient. This structure obviatedthe need to simulate mammary tissue kinetics, for which there were no data in humans. The milk/plasma
partition coefficient was calibrated to yield predictions of observed milk/plasma ratios (Fromme et al.
2010; Kärrman et al. 2007). Transfer from maternal milk to infants is the product of the milk
concentration and milk production rate (assumed to be equal to sucking rate). The pregnancy model was
evaluated by comparing predicted maternal/fetal plasma ratios for PFOA and PFOS with observations
from various human monitoring studies (Fei et al. 2007; Fromme et al. 2010; Hanssen et al. 2010; Inoueet al. 2004; Kim et al. 2011; Midasch et al. 2007; Monroy et al. 2008; Tittlemier et al. 2004). The
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with observations from various human monitoring studies (Fromme et al. 2009; Kärrman et al. 2007; Liuet al. 2011). In general, most model predictions were within plus or minus 2-fold of observations.

Applications for Dosimetry Extrapolation and Risk Assessment. The model predicts plasma
concentrations and tissue levels of PFOA and PFOS following intravenous or oral dosing. A skincompartment is included in the model, which may serve for simulating absorption and distribution
following deposition onto the skin surface; however, the dermal absorption model was not evaluated in
Loccisano et al. (2011). The human model was calibrated to predict t1/2 values estimated for humanpopulations (e.g., 2.3 or 3.8 years for PFOA, 5.4 years for PFOS). As a result, comparisons madebetween observed and predicted serum concentrations evaluate whether or not the populations actuallyexhibit the t1/2 to which the model was calibrated, and not the validity of the model to predict the internal
distribution of PFOA or PFOS. It is not currently possible to assess with confidence whether the humanmodel can accurately predict doses to liver or any other tissues. Fábrega et al. (2014) applied the humanadult model to estimate plasma concentrations and tissue levels of PFOA and PFOS in human autopsy
samples. Exposure inputs to the model were intakes of PFOA and PFOS estimated from public watersupply concentrations in the local area where the subjects had resided (Catalonia, Spain) andconcentrations in local market basket foods (Domingo et al. 2012a, 2012b). The human model predictedlevels of PFOA in plasma and liver that were approximately 10- and 5-fold higher, respectively, thanobserved. Predicted plasma levels of PFOS were approximately 2-fold higher than observed, andpredicted levels of PFOS in kidney were approximately 25% of observed. Fábrega et al. (2014) exploredalternative values for tissue/plasma partition coefficients, determined from human autopsy issues (Maestri
et al. 2006). The adjusted partition coefficients improved predictions of observed tissue PFOA and PFOS
levels. Although the model could be applied to predicting plasma concentrations of PFOA and PFOS or
intakes associated with specific plasma concentrations (e.g., oral MRLs), it is not clear what advantages
the model offers over simpler empirical or compartmental models similarly calibrated to predict the serum
t1/2. The monkey model has been more thoroughly evaluated for predicting plasma and urinary kinetics of
PFOA and PFOS. This was possible because of the availability of more extensive experimental data on
plasma and urine PFOA and PFOS following intravenous and oral (single and repeated) dosing in maleand female monkeys. Nevertheless, data on internal distribution were not available to allow evaluation of
how well the monkey model predicts doses to the liver or other tissues. Predictions of plasma PFOA andPFOS concentrations from the monkey (and human) model were highly sensitive to values assigned to the
maximum rate for tubular reabsorption (Tm) and other parameters that govern urinary elimination of
PFOA and PFOS (e.g., free fraction in plasma and glomerular filtration rate; Loccisano et al. 2011).
Optimization of the monkey models relied heavily on adjusting these same parameters and, for the humanPERFLUOROALKYLS

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model, the target plasma elimination t1/2 was achieved solely by adjusting Tm. Thus, despite thecomplexity of the models, their potential to accurately predict plasma elimination kinetics and, therefore,
steady-state plasma concentrations and associated oral intakes, depends largely on how well they predict
plasma clearance. If plasma clearance and the free-fraction in plasma can be reliably predictedempirically for the animal species of interest, then far simpler compartmental models can be used for
dosimetry extrapolation of steady-state free plasma concentrations.
3.1.5.3 Rodriguez et al. (2009) Mouse Model
Rodriguez et al. (2009) developed a model for simulating the maternal-fetal and maternal-pup kinetics of
PFOA in mice. The general structure of the model is depicted in Figure 3-7. Complete lists ofparameters and parameter values and the bases for parameter values and evaluations of model predictions
in comparison to observations are reported in Rodriguez et al. (2009). The maternal, fetal, and pup
systems are simulated as single well-mixed compartments. Absorption from the gastrointestinal tract issimulated as first-order with complete absorption of the ingested dose. Elimination of absorbed PFOA
from the maternal system is simulated as the balance between glomerular filtration and renal tubular
reabsorption. The latter is represented as a saturable process with parameters Tm and KT. Transfer to thefetus is flow-limited and governed by a fetus/maternal partition coefficient and placental blood flow.
Transfer from the maternal system to the pup by lactation is simulated as first-order governed by alactation transfer rate constant. Elimination of PFOA from the pup is first-order to urine. Data setsutilized in developing and evaluating the mouse model included oral gestational dosing studies.

Applications for Dosimetry Extrapolation and Risk Assessment. The model predicted observed
concentrations of PFOA in maternal, fetal, and pup serum following oral gestational exposures to mice
(Abbott et al. 2007; Lau et al. 2006; White et al. 2007). Residuals for predictions are presented, which
provide a quantitative measure of how well the model predicted observations (Rodriguez et al. 2009).
Similar to the rat, the mouse model predicts higher internal exposure (serum PFOA concentrations) in thematernal system compared to the fetus. It also predicts accelerated loss of PFOA from the maternal
system during lactation. The model simulates the maternal, fetal, and pup systems as single
compartments. Although this serves for simulating plasma concentrations (the main objective of themodeling effort), it does not allow for simulation of tissue levels of PFOA in the maternal system, fetus,
or pup.

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Figure 3-7. Renal Resorption Pharmacokinetic Model of Gestation and Lactation
used in the Analysis of CD-1 Mice

Gestation days 1–18

Concepti
Vcon
Qcon

Qcon
KidneyDam

Oral dose(mg/kg)
Lactation days 19–39

Ccon

Qur

kad

Cdam

Vdam

free
QGF

Filtrate

Qr-QGF

Renal
plasmaklac
Pup excreta
recirculation(from birth topostnatal day 4)

Urine

Tm; KtMilk
Qr-Qur

Cmilk

Vm
klac

Pups
Cpup

Vpup
kep

Urine
Ccon = concentration in concepti; Cdam = concentration in dam; Cmilk = concentration in milk; Cpup = concentrationin pup; kad = first-order absorption rate; kep = urinary excretion rate; klac = transfer rate via milk; Kt = half-saturation
constant; Qcon = blood flow to and from placenta; QGF = glomerular filtrate; Qr = renal plasma flow; Qur = urine flow;
Tm = transport maximum; Vcon = volume in concepti; Vdam = volume in dam; Vmilk = volume in milk; Vpup = volume
in pupSource: Rodriguez et al. 2009 (reproduced with permission of Elsevier Inc. in the format reuse in a government
report via Copyright Clearance Center; Reproductive Toxicology by Reproductive Toxicology Center; Washington,
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3.1.5.4. Wambaugh et al. 2013 (Andersen et al. 2006) Model
The Wambaugh et al. (2013) model is a three-compartment model based on the three-compartmentalmonkey model of Andersen et al. (2006). The structure of the two models are identical (Figure 3-8).
Parameter values for the Wambaugh et al. (2013) model are presented in Table 3-7. The model includes acentral compartment, a secondary distribution compartment, and a renal glomerular filtrate compartment.
The central compartment (C1), which includes plasma, receives PFOA or PFOS from oral dosing (firstorder ka, hour-1) and exchanges perfluoroalkyl with the secondary compartment (C2, which lumps allother tissues and distribution volumes into a single compartment) and with the glomerular filtrate (C3). A
fraction of the perfluoroalkyl in C1 is free (Free) and available for exchange with C2 and C3. Exchanges
between C1 and C2 are first order (k12, k21, hour-1) with k21 assigned a value equal to the RV2/V1, where
RV2/V1 is the ratio of the volumes of the two compartments (V2/V1). Transfer of perfluoroalkyl into theglomerular filtrate is first order and governed by the glomerular filtration rate (Qfilc, L/hour). Transfer for
perfluoroalkyl from the glomerular filtrate to C1 (representing renal tubular reabsorption) is capacity
limited (Tmaxc, µmol/hr; KT, µM). Perfluoroalkyl that is not reabsorbed is excreted.

Parameter values for the various species and strains were estimated from experimental pharmacokinetic
data for each species and strain using Bayesian Markov Chain Monte Carlo (MCMC) analysis. Studies
that provided data used to estimate parameter values are listed in Wambaugh et al. (2013). The parametervalues shown in Table 3-7 are the mean values and posterior distributions (95% credible interval) from
the MCMC analyses.

Applications for Dosimetry Extrapolation and Risk Assessment. Wambaugh et al. (2013) applied themodel to predicting internal doses (mean and maximum serum concentrations and plasma AUC) for
Benchmark Dose Software (BMDS) modeling and for comparing internal dosimetry from in vivo toxicity
studies to estimates of potency (AC50, maximum Efficacy) from in vitro studies. EPA applied the
Wambaugh et al. (2013) model to deriving chronic oral reference doses (RfDs) for PFOA and PFOS (EPA
2016e, 2016f). The model was used to predict internal doses (time-integrated plasma PFOA or PFOS
concentrations) achieved in toxicity studies conducted in various laboratory animal models (CD-1 mouse,
C57Bl/6 mouse, Sprague-Dawley rat, Cynomolgus monkey). Plasma concentrations were thenextrapolated to equivalent steady-state concentrations in humans using a model of first-order eliminationof PFOA and PFOS from plasma. The same approach was used to derive MRLs for PFOA and PFOS (seeAppendix A).

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Figure 3-8. Andersen et al. (2006) Pharmacokinetic Model with Oral Absorption

Agut is the amount of chemical in the gut; ka is the first-order rate constant for absorption from the gut; Qfil is the flow
through the filtrate compartment; C1, C2, and C3 are the chemical concentrations in the central, second, and filtratecompartments, respectively; Vc, Vt, and Vfil are the volumes of distribution of the central, second, and filtratecompartments; free is the free fraction of compound in the central compartment; Qd is the flow between the central
and second compartments; the saturable resorption process from the filtrate back into the central compartment ismodeled with Michaelis-Menten kinetics, with a maximum rate Tmaximum and a half-maximum concentration KT.
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Table 3-7. Estimated and Assumed Pharmacokinetic Parameters for the Modified Andersen et al. (2006) Modelfor PFOA and PFOS

ReferenceSpecies

Cardiac outputa
BW (kg) (L/hour/kg0.74) Ka (hour-1)

Vcc (L/kg)

Parameter (units)
RV2:V1Tmaxc
k12 (hour-1)(unitless)(µmole/hour) KT (µM)

Free(unitless)Qfilc (L/hour) Vfilc (L/kg)

Lou et al.
(2009)

Mouse: CD1 0.02
(F)

8.68

290 (0.6–
73,000)0.18 (0.16–
2.0)

Dewitt et al.
(unpublished)

Mouse:
0.02
C57Bl/6 (F)8.68

340 (0.53–
69,000)0.17 (0.13–
2.3)

PFOAb
0.021
(3.1x10-10 to
3.8x104)
0.35 (0.058–
52)

12.39

1.7 (1.1–3.1)

0.14 (0.11–
0.17)

0.098 (0.039– 9.2 (3.4–28)
0.27)

0.037
0.011
0.077 (0.015– 9.7x10-4(0.0057–0.17) (0.0026–
0.58)(3.34x10-9–
0.051
7.21)
2.7 (0.95–22) 0.12 (0.033– 0.034 (0.014– 0.017 (0.010– 7.6x10-5
0.24)
0.17)
0.081)(2.7x10-10–
6.4)
1.1 (0.25–9.6) 1.1 (0.27–4.5) 0.086 (0.031– 0.039 (0.014– 2.6x10-5
0.23)
0.13)
(2.9x10-10–28)

12.39

1.1 (0.83–1.3) 0.15 (0.13–
0.16)

0.028
8.4 (3.1–23)(0.0096–0.08)

190 (5.5–
50,000)0.092
0.08 (0.03–(3.4x10-4–1.6) 0.22)

19.8

230 (0.27–
73,000)0.0011(2.4x10-10 to
3.5x104)

3.9 (0.65–
9,700)

0.043(4.3x10-5–
0.29

Kemper (2003) Rat:
0.20
Sprague(0.16–
Dawley (F) 0.23)c
Kemper (2003) Rat:
0.24
Sprague(0.21–
Dawley (M) 0.28)c
Butenhoff et al. Monkey:
7 (m),(2004b)Cynomolgus 4.5 (f)(M/F)

ReferenceSpecies

Cardiac outpute
BWd (kg) (L/hour/kg0.74) Ka (hour-1)

Chang et al.
(2012)

Mouse: CD1 0.02
(F)

8.68

Chang et al.
(2012)

Mouse: CD1 0.02
(M)

8.68

Chang et al.
(2012)Rat:
0.203
SpragueDawley (F)
Rat:
0.222
SpragueDawley (M)Monkey:3.42
Cynomolgus
(M/F)

12.39

Chang et al.
(2012)
Seacat et al.
(2002) andChang et al.
(2012)
a

12.39

19.8

1.16 (0.617–
42,400)0.4 (0.29–
0.55)

Vcc (L/kg)

1.07 (0.26–
5.84)
53 (11–97)

0.98 (0.25–
3.8)

4.91 (1.75–
2.96)

Parameter (units)
Tmaxc
RV2:V1
k12 (hour-1)(unitless)(µmol/hour)

PFOS
0.264 (0.24– 0.0093
0.286)(2.63e-10–
38,900)0.292 (0.268– 2,976 (2.8e0.317
10–4.2e4)

1.01 (0.251–
4.06)

KT (µM)

0.22 (0.011–
58)

0.0082(1.3x10-8–7.6)

0.01 (0.0026– 0.15 (0.02–
0.038)
24)

0.0021(3.3x10-9–6.9)

Free(unitless)57.9 (0.671–
32,000)0.01090.00963(1.44x10-5–(0.00238–
1.45)
0.0372)433.4 (0.51–
1.29 (0.24–
1.1e4 (2.1–
381
0.012
803.8
4.09)
7.9e4)(2.6x10-5–(0.0024–2,900)
0.038)
4.65 (3.02–
0.535 (0.49– 0.0124 (3.1e- 0.957 (0.238– 1,930 (4.11– 9.49
0.00807
1,980)
0.581)
10–46 800)
3.62)
83,400)(0.00626–(0.00203–
11,100)0.0291)0.836 (0.522– 0.637 (0.593– 0.00524
1.04 (0.256– 1.34e-06
2.45
0.00193
1.51)
0.68)(2.86e-10–
4.01)(1.65e-10–44) (4.88x10-10– (0.000954–
43,200)60 300)0.00249)132 (0.225–
0.303 (0.289– 0.00292
1.03 (0.256– 15.5 (0.764– 0.00594 (2.34 0.0101-572,100)0.314)(2.59e-10–
4.05)
4,680)
x10 –0.0941) (0.00265–
34,500)0.04)

Cardiac outputs obtained from Davies and Morris (1993).
Means and posterior distributions from the Bayesian Markov Chain Monte Carlo (MCMC) analysis (95% credible interval in parentheses) are reported.
Estimated average body weight (BW) for species used except with Kemper (2003) study where individual rat weights were available and assumed to be constant.
dAverage BW for species: individual-specific BWs.
e
Cardiac outputs obtained from Davies and Morris (1993).
bc

Source: Wambaugh et al. (2013)

Qfilc (L/hour) Vfilc (L/kg)
0.439
0.00142(0.0125–307) (4.4x10-10–
6.2)
27.59 (0.012– 0.51283)
(3.5x10-10–
6.09)
0.06660.0185(0.0107–8.95) (8.2x10-7–7.34)
0.01220.000194(0.0101–(1.48x10-9–0.025)
5.51)
0.198 (0.012– 0.0534
50.5)(1.1x10-7–
8.52)

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3.1.5.5 Harris and Barton (2008) Rat Model
Harris and Barton (2008) developed a model for simulating PFOS kinetics in adult rats. The general
structure of the model is depicted in Figure 3-9. Complete lists of parameters and parameter values andthe bases for parameter values and evaluations of model predictions in comparison to observations arereported in Harris and Barton (2008). The model includes systemic compartments representing blood(including a bound and free fraction of plasma and red blood cells), liver, and a lumped compartment
representing all other tissues. The gastrointestinal tract is simulated as separate compartments representing
the upper and lower tracts. Absorption occurs from both the upper and lower tracts, with distinct firstorder rate constants assigned to each. Biliary PFOS is transferred from liver to the lower tract. Absorbed
PFOS is delivered to the liver where it enters plasma to be distributed to other tissues. Exchanges between
PFOS in plasma and all tissues are assumed to be diffusion-limited, with the free pool in plasma
participating in the exchange with red blood cells, and the total plasma pool exchanging with liver and allother tissues. Binding of PFOA to plasma albumin is assumed to be saturable, with a dissociation constant
10-7 M and a maximum capacity 4.1x 10-4 M. This is implemented by assigning bound PFOA to a
subcompartment of plasma in which PFOA enters (binds) or exits (unbinds) at rates governed by bindingon and off rates, respectively, that yield a dissociation constant of 10-7 M. Elimination of absorbed
chemical occurs by biliary excretion and urinary excretion. Transfer from liver to the lower
gastrointestinal tract (representing excretion following biliary transfer) is represented as a first-orderprocess acting on the total amount of PFOS in liver. PFOA is transferred to urine from the free fraction ofplasma at a rate governed by a urinary clearance parameter, which is assigned a value of 28% of renal
plasma flow.

In evaluating performance of the model for simulating PFOS concentrations in a chronic rat feeding
study, Harris and Barton (2008) found that the model predicted plasma and liver concentrations measured
at 4 and 16 weeks, but over-predicted both at 104 weeks. Performance of the model was improved byhaving renal clearance increase and the liver/plasma partition coefficient decrease as a function of time(i.e., study duration). These results suggest the possibility that clearance of PFOS may be dependent on
age and/or a metric of dose (e.g., cumulative internal dose). This may reflect age- or dose-related changes
in kidney function, including tubular reabsorption or secretion of PFOS.

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Figure 3-9. Conceptual Representation of a Physiologically Based
Pharmacokinetic Model for PFOS Exposure in Rats
intravenous

P + A ↔ P:A Plasma

QPlas

urine

Red blood cells
Rest of body plasma

QR

Rest of body tissue
QL

Liver plasma

Liver tissue
kau

oral

Upper
gastrointestinal ktl
tract

kal

Lower
gastrointestinal
tract

kb

feces

kal = rate of absorption from the lower gastrointestinal tract; kau = rate of absorption from the upper gastrointestinal
tract; kb = maximum rate of biliary elimination; ktl = rate of transfer from upper-lower gastrointestinal tract;
P:A = PFOS-bound albumin in plasma; PFOS = perfluorooctane sulfonic acid QL = plasma flow rate to the liver;
QPlas = plasma flow rate by the heart; QR = plasma flow rate to the rest of body
Source: Harris and Barton 2008 (reproduced with permission of Elsevier Ireland Ltd. in the format reuse in agovernment report via Copyright Clearance Center; Toxicology Letters by European Societies of Toxicology)

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONSApplications for Dosimetry Extrapolation and Risk Assessment. The model simulates kinetics of PFOS
following oral or intravenous dosing in adult rats and includes several features that are different fromother PBPK models of perfluoroalkyls. The Harris and Barton (2008) model includes a red cellcompartment that allows predictions of whole-blood concentrations. The utility of this feature remains to
be determined, since PFOS does not appreciably concentrate in red blood cells and PFOS (and otherperfluoroalkyls) is typically monitored in the central compartment with measurements of plasma or serum
concentrations. The model assumes that the total concentration of PFOS (not just the free concentration)in plasma is available for distribution to liver and other tissues, whereas other models assume that only
the free pool in plasma exchanges with tissues. The practical consequence of this difference may not besignificant in terms of the toxicokinetics of PFOS if the tissue/plasma partition coefficients in the various
models were estimated based on the relevant perfluoroalkyl pool in plasma. However, without basing
distribution kinetics on the free concentration, it is not possible for concentration-dependent free fraction
to be modeled. The model assumes time-dependence in the liver uptake and urinary excretion of PFOS,
which were needed to improve predictions of plasma and liver concentrations of PFOS during chronic
exposures. Other rat models (Loccisano et al. 2012a) have not been similarly evaluated. A mechanistic
understanding of the time-dependent changes in PFOS kinetics will be important for applications of thesemodels for dosimetry extrapolation across exposure durations.
3.1.5.6 Worley and Fisher (2015a, 2015b) Rat Model
Worley and Fisher (2015a, 2015b) expanded the Loccisano et al. (2012a) adult rat model to include
simulation of renal proximal tubule apical (tubule-lumen) and basolateral (tubule-plasma) PFOA
transport. This configuration allowed the use of data from in vitro studies of kinetics of specifictransporters thought to be involved in proximal tubular transport of PFOA in the parametrization of themodel. The kidney compartment was expanded to include compartments representing the proximal
tubule lumen (glomerular filtrate) and proximal tubule cells. In the model, transfer of PFOA to the tubule
lumen is governed by the glomerular filtration rate, represented by a clearance parameter (L/hour/kg
kidney). PFOA in the tubule lumen can undergo first-order transfer to urine or saturable transport into thetubule cell (Km, Vmax). PFOA in the tubule exchanges with PFOA in plasma by three mechanisms:
saturable transport from plasma into the cell (Km, Vmax), first-order transport from the cell to plasma(kefflux), or bidirectional diffusion between the cell and plasma (kdif). Parameter values (Km, Vmax) for
apical and basolateral transport of PFOA were derived from in vitro estimates for OATP1a1 (apical) andOAT1 and OAT3 (basolateral) (Nakagawa et al. 2008; Weaver et al. 2010; Yamada et al. 2007). Theseestimates were scaled to kidney proximal tubule cell mass (Hsu et al. 2014) and the mass-scaled estimates

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of Vmax were adjusted with relative activity factors, which were calibrated to in vivo observations ofplasma PFOA elimination kinetics in rats (Kemper 2003). Values for kefflux (proximal tubule cell tokidney plasma) and kdif (diffusion between kidney plasma and the tubule cell) were also calibrated within vivo data (Kemper 2003; Kudo et al. 2007).

Calibration of the relative activity factor for apical and basolateral membrane transport of PFOA to serum
observations made in male and female rats resulted in lower values for activity of both transporters infemales compared to males. This resulted in the model predicting lower rates of reabsorptive transfer offiltered PFOA to plasma, and higher renal and systemic (plasma) clearance in females compared to males.
Because proximal tubule transporters were assumed to be saturable, the model predicts an increase inclearance with increasing PFOA dose, with larger increases in clearance at lower doses in females
compared to males. The model simulated the observed dose-dependent increase in serum clearance(decreasing serum t1/2) and higher serum clearance of PFOA (lower t1/2) in female rats compared to males(Kemper 2003).

3.1.5.7 Worley et al. (2017b) Human Model
Worley et al. (2017b) scaled and calibrated the Worley and Fisher (2015a, 2015b) rat model to simulate
PFOA kinetics in humans exposed to PFOA in drinking water. Physiological parameters wereallometrically scaled to the human. Tissue-plasma partition coefficients were derived from human
autopsy data (kidney, liver) or studies of distribution of PFOA in rats (Fabrega et al. 2014; Kudo et al.
2007; Perez et al. 2013). Parameter values (Km, Vmax) for apical and basolateral transport of PFOA
were derived from in vitro estimates for OAT4 (apical) and OAT1 and OAT3 (basolateral) (Nakagawa et
al. 2008; Weaver et al. 2010; Yang et al. 2010; Yamada et al. 2007). These estimates were scaled tokidney proximal tubule cell mass (Hsu et al. 2014) and the mass-scaled estimates of Vmax were adjustedwith relative activity factors. Parameters that control apical and basolateral transfers of PFOA in theproximal tubule and absorption in the gastrointestinal tract were calibrated against data on serum PFOA
concentrations measured in people who drank water from a municipal water supply (Worley et al. 2017b).
Model parameter values were adjusted to achieve agreement with geometric mean serum PFOA
concentrations measured at two times separated by 6 years. The model was evaluated by comparing
predicted and observed serum PFOA concentrations in populations exposed to PFOA in drinking water(Bartell et al. 2010; Emmett et al. 2006b; Steenland et al. 2009a, 2009b). A sensitivity analysis of themodel identified that following biokinetic parameters that had standardized sensitivity coefficients >0.1:
parameters controlling proximal tubule transport and urinary excretion, plasma-liver partition coefficient,PERFLUOROALKYLS

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biliary excretion and protein binding. These parameters, along with drinking water consumption, wereassigned probability distributions to conduct a Monte Carlo analysis of predicted serum PFOA predictions
associated with exposures to PFOA in drinking water. The probabilistic model simulated interindividual
variability in serum PFOA concentrations observed in exposed populations (Bartell et al. 2010; Emmett etal. 2006b; Steenland et al. 2009a, 2009b). These results suggest that that biokinetic variability, as well as
exposure variability, may contribute to variability in serum PFOA concentrations observed in
populations.
3.1.5.8 Fàbrega et al. (2014, 2016) Human Model
Fàbrega et al. (2014, 2016) modified the Loccisano et al. (2011, 2013) human models for PFOA andPFOS with inclusion of brain and lung compartments and removal of the skin compartment. Tissueplasma partition coefficients were re-estimated using data from human cadavers (Maestri et al. 2006) inplace of estimates based on rat data (Loccisano et al. 2011). The major differences in the partition
coefficients for PFOA were lower values for liver in humans (1.03) compared to rats (2.20), higher values
for fat in humans (0.47) compared to rats (0.04), and inclusion of partition coefficients for brain (0.17)
and lung (1.27). For PFOS, the major differences in the partition coefficients were lower values for liverin humans (2.67) compared to rats (3.72) and higher values for fat in humans (0.33) compared to rats
(0.14). Values for parameters that control urinary excretion (Tm and Km for reabsorptive transport fromglomerular filtrate to kidney tissue) were recalibrated based on plasma concentration data (Ericson et al.
2007). Fàbrega et al. (2014) compared predictions to observed concentrations of PFOA and PFOS in
cadaver samples (from Tarragona County, Spain) for constant intakes of 0.11 µg/day for PFOA or
0.13µg/day for PFOS. Better agreement with observations was achieved with partition coefficients basedon cadaver data. Fàbrega et al. (2016) performed a quantitative uncertainty analysis of predictions oftissue PFOA and PFOS concentrations by assigning lognormal probability distributions to renal transportparameters, the unbound fraction in plasma, and intake. Probability distributions for PFOA and PFOS
intakes were based on data from Domingo et al. (2012a, 2012b). Distributions for biokinetic parameters
were established to achieve a coefficient of variation of 0.3 (Allen et al. 1996; Brochot et al. 2007;
Sweeney et al. 2001). Observations of tissue PFOA and PFOS were within uncertainty bounds on
predictions.

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3.1.5.9 Kim et al. (2018) Rat and Human Model
Kim et al. (2018) developed a model for simulating the kinetics of PFHxS in rats and humans. The
structures of the rat and human models are identical (Figure 3-10). Complete lists of parameters andparameter values and the bases for parameter values and evaluations of model predictions in comparison
to observations are reported in Kim et al. (2018). The model includes compartments representing plasma(including a bound and free fraction), brain, gastrointestinal tract, heart, lung, kidney and renal glomerular
filtrate, liver, and a lumped compartment representing all other tissues. A storage compartment receives
PFHxS from the glomerular filtrate and is included in the model to simulate the time delay between
elimination from plasma and appearance of PFHxS urine. Absorption from the gastrointestinal tract issimulated as the balance between first-order absorption and fecal excretion of unabsorbed PFHxS.
Absorbed PFHxS is assumed to be delivered to the liver. Exchanges between PFHxS in tissues with thefree pool in plasma are assumed to be flow-limited (governed by blood flow) with equilibrium determinedby the tissue:plasma partition coefficient. Partition coefficients were estimated from the tissue:plasma
concentration ratios measured in female and male rats 14 days after a single intravenous dose of PFHxS(0.5–10 mg/kg). Values for each sex were significantly different for brain, lung, liver, spleen,gastrointestinal tract, adipose, and skeletal muscle; in each case, male>female. The highest partition
coefficient was in male liver (approximately 0.13), with the value for female being approximately half ofthe male value. PFHxS in plasma is simulated as instantaneous distributions into free and boundfractions. The free fraction was estimated from ultrafiltration studies of rat and human plasma. The free
fraction was assigned a constant of 0.069% in female and 0.076% in male rats.

Elimination of absorbed PFHxS in the rat model occurs by fecal and urinary excretion. Fecal excretion ofabsorbed PFHxS is represented as flow-limited transfer from plasma to the gastrointestinal tract and firstorder transfer from the gastrointestinal tract to feces. Excretion in urine is simulated as the balance
between transfer from the free fraction of plasma to the glomerular filtrate and renal tubular reabsorption,
which removes PFHxS from the glomerular filtrate and returns it to kidney tissue. Renal tubular
reabsorption is simulated as a capacity-limited process with parameters Tm (µg/hour), representing the
maximum rate of transport, and KT (µg/L), representing affinity for the transporter (the concentration in
the glomerular filtrate at which reabsorptive transport rate is half of maximum). This representation ofrenal tubular reabsorption is used to simulate observed sex differences in elimination of PFHxS from

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Figure 3-10. Structure of the PBPK Model for PFHxS in Rats and Humans*
Qbr
Brain
Qhe
Heart
Input
(IV)

Qlu
Lung
Qrb
Rest of body
PlasmaQki
KidneyTm • Kt

Qfil

Kst

Filtrate

Storage

Ku

Urinary
excretion

Qli
Liver
Qgi

Menstrual
blood loss

Kabs

G.I. tract
Kf

Input
(PO)

Fecal
excretion*PFHxS can be resorbed into the kidney with transporter maximum (Tm) and transporter affinity constant(Kt). Ks indicates a rate constant; Kst, the rate constant to the storage compartment; Ku, the urinary
elimination rate constant; Kf, the transfer rate constant from the G.I. tract to fecal elimination; and Kabs, theoral absorption rate constant. Qs refers to the blood flows between plasma and tissues, except for Qfil,
which is a clearance from the plasma to the filtrate compartment. Menstrual blood loss (dotted square) is
only applicable to female humans.
G.I. = gastrointestinal; IV = intravenous; PBPK = physiologically based pharmacokinetic;
PFHxS = perfluorohexane sulfonic acid; PO = per os
Source: Reprinted by permission from Springer Nature, Kim et al. 2018

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plasma, which have been attributed to higher reabsorptive capacity in male rats (see Section 3.1.4).
Values for the maximum and affinity parameters for PFHxS result in higher reabsorptive clearances fromthe glomerular filtrate (Tm/KT=5.2) in male rats compared to female rats (Tm/KT=0.057), andcorrespondingly lower urinary clearance of PFHxS from plasma in male rats. Values for Tm and Kt in
humans were assumed to be the same as those in rats. Tissue volumes and blood flows were assigned
values based on various sources (Davies and Morris 1993; Igari et al. 1983). Glomerular filtrate volume
and flow were assigned values from Loccisano et al. (2012a).

The rat model was calibrated and evaluated against data on plasma and tissue levels of PFHxS measured
following a single intravenous (0.5–10 mg/kg) or gavage dose (1 or 4 mg/kg) of PFHxS (Kim et al. 2018).
Temporal profiles of plasma PFHxS and cumulative urinary excretion following intravenous or oral
dosing were within ±1 SD of observations. Predicted cumulative urinary excretion of PFHxS reproduced
the observed sex differences in urinary excretion with slower excretion and higher plasma levels in males
compared to females. Terminal levels of PFHxS in heart, kidney, liver, and lung predicted for 14 days
following oral dosing were within the range of observed values.

The human model was developed from the rat model with the following attributes:•

Human tissue volumes and blood flows were assigned values based on various sources (Davies
and Morris 1993; Igari et al. 1983).

•

Glomerular filtrate volume and flow were assigned values from Loccisano et al. (2011).

•

Values for the free fraction in human plasma were 0.023% in females and 0.025% in males, basedon results from ultrafiltration studies.

•Sex-specific values for renal tubular reabsorption parameters, Tm and Kt, were assumed to be thesame in rats and humans.

•

First order rate constants were scaled by 0.25 power of body weight (BW0.25).

•

Loss of PFHxS in menstrual blood was included in the human female model. This is represented
as a direct loss of loss of 42.5 mL blood (25 mL plasma) per month (Verner and Longnecker2015).

Kim et al. (2018) does not report an evaluation of the human model.

Applications for Dosimetry Extrapolation and Risk Assessment. The rat and human models wereapplied interspecies dosimetry extrapolation of a rat NOAEL for PFHxS (1 mg/kg/day). The rationale forthe rat NOAEL is described in Kim et al. (2018). The dosimetry extrapolation was applied to the rat

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model to predict a steady-state plasma concentration of PFHxS corresponding to a chronic oral dose of
1 mg/kg/day (value not reported). The equivalent human dose was predicted from the human PBPK
model as the daily dose required to achieve the same steady state concentration in the human.
3.1.6

Animal-to-Human Extrapolations

Interspecies differences in the toxicokinetics of perfluoroalkyls and possible differences in themechanisms of toxicity have been found. The elimination rate for PFOA in female rats is approximately
45 times faster than in male rat, 150 times faster than in Cynomolgus monkeys, and approximately 5,000–
9,000 times faster than in humans (Bartell et al. 2010; Butenhoff et al. 2004c; Kemper 2003; Olsen et al.
2007a). Elimination of PFOS in male rats is approximately 3 times faster than in Cynomolgus monkeys
and approximately 40 times faster than in humans (Chang et al. 2012; De Silva et al. 2009; Olsen et al.
2007a; Seacat et al. 2002). These large differences in elimination rates imply that similar external PFOA
or PFOS dosages (i.e., mg/kg/day) in rats, monkeys, or humans would be expected to result in
substantially different steady-state internal doses (i.e., body burdens, serum concentrations) of thesecompounds in each species. In addition, exposure durations required to achieve steady state would be
expected to be much longer in humans than in monkeys or rats. Assuming a terminal elimination t1/2 of
1,400 days for PFOA in humans (Olsen et al. 2007a), a constant rate of intake for 17 years would be
required to achieve 95% of steady state. Steady state (i.e., 95%) would be achieved in approximately
110 days in monkeys (t1/2=25 days, Butenhoff et al. 2004c), 30 days in male rats (t1/2=7 days; Kemper2003), and 1 day in female rats (t1/2=0.2 days; Kemper 2003). Using an internal dose metric such asserum perfluoroalkyl concentration and PBPK models that can account for these differences inelimination rates can decrease the uncertainty in extrapolating from animals to humans.

The mode of action for most health outcomes associated with perfluoroalkyl exposure has not been fully
characterized in humans or laboratory animals. Some perfluoroalkyl-induced effects observed in rats andmice appear to be mediated through the PPARα-dependent and -independent mechanisms (seeSection 2.20 for additional information). Interpretation of the relevance of the effects observed inlaboratory animals is complicated since it is generally agreed that humans and nonhuman primates are
refractory, or at least less responsive than rodents, to PPARα-mediated effects (Corton et al. 2014;
Klaunig et al. 2003; Maloney and Waxman 1999). While studies in mice have identified specific effects
that require PPARα activation, for example, postnatal viability (Abbott et al. 2007) and someimmunological effects (Yang et al. 2002b), other effects such as hepatomegaly and antigen-specificantibody response (DeWitt et al. 2016) were reported to be PPARα-independent (Yang et al.

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2002b). Therefore, further studies are needed to expand the knowledge regarding PPARα-dependent and-independent effects that would allow selection of an appropriate animal model for perfluoroalkyls
toxicity. In the absence of data to the contrary, ATSDR assumes that the health effects observed inlaboratory animals are relevant to humans. The exception is some of the hepatic effects observed inrodents; increases in liver weight and hepatocellular hypertrophy observed in rats and mice wereconsidered adaptive and not relevant to humans (see Section 2.9 for details).
3.2

CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

This section discusses potential health effects from exposures during the period from conception tomaturity at 18 years of age in humans. Potential effects on offspring resulting from exposures of parental
germ cells are considered, as well as any indirect effects on the fetus and neonate resulting from maternal
exposure during gestation and lactation. Children may be more or less susceptible than adults to healtheffects from exposure to hazardous substances and the relationship may change with developmental age.

This section also discusses unusually susceptible populations. A susceptible population may exhibit
different or enhanced responses to certain chemicals than most persons exposed to the same level of thesechemicals in the environment. Factors involved with increased susceptibility may include genetic
makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke).
These parameters can reduce detoxification or excretion or compromise organ function.

Populations at greater exposure risk to unusually high exposure levels to perfluoroalkyls are discussed in
Section 5.7, Populations with Potentially High Exposures.

The possible association between serum perfluoroalkyl levels in children and health effects has been
examined in participants of the C8 Health Project and in the general population. The studies examined anumber of health effects including alterations in serum lipid levels, adverse renal outcomes,
neurodevelopmental alterations, and reproductive development. Immunotoxicity has been examined inchildren in several general population studies. Additionally, a large number of studies have examined thepossible association of elevated serum perfluoroalkyl levels and adverse birth outcomes.

Similar to adults, associations between serum PFOA and PFOS and serum cholesterol levels wereobserved in a study of over 12,000 children (Frisbee et al. 2010); an increased risk of high cholesterol was
also observed in children with higher serum PFOA and PFOS levels. A smaller study of children (n=43)

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living in the Mid-Ohio Valley did not find associations between serum PFOA levels and hematology
parameters, total cholesterol and liver enzymes, indices of kidney function, or serum TSH levels (Emmett
et al. 2006b). Another study of highly-exposed residents did not find any associations between serum
PFOA levels in children aged 6–12 years and IQ, reading and math skills, language, memory, learning, or
attention (Stein et al. 2013). Similarly, no association between serum PFOA, PFOS, or PFNA levels inchildren 5–18 years old and the likelihood of ADHD diagnosis was observed in a study of highly-exposed
residents, although the study did find an increased risk associated with higher PFHxS levels (Stein and
Savitz 2011). A general population study that utilized the NHANES data found an association between
serum PFOA, PFOS, and PFHxS levels and the risk of ADHD diagnosis (as reported by the parent)(Hoffman et al. 2010). Another smaller-scale study found associations between serum PFOS, PFNA,
PFDA, PFHxS, and FOSA and impulsivity; no association with PFOA was found (Gump et al. 2011). A
study of children 8–18 years of age participating in the C8 studies found reduced odds of reaching
puberty at higher serum PFOA levels (Lopez-Espinosa et al. 2011); however, the biological significanceof the short delay (4–5 months) is not known.

Several studies have evaluated immunotoxicity in children and adolescents. These studies have found
impaired antibody responses associated with serum PFOA, PFOS, PFHxS, and PFDA (Grandjean et al.
2012, 2017; Granum et al. 2013; Mogensen et al. 2015a; Stein et al. 2016a). An increased asthma
diagnosis was also associated with serum PFOA levels (Dong et al. 2013; Humblet et al. 2014; Zhu et al.
2016). Marginal evidence of an association with asthma diagnosis was also found for PFOS, PFHxS,
PFNA, PFDA, PFBS, and PFDoDA (Dong et al. 2013; Zhu et al. 2016), although some studies found noassociations for these compounds (Humblet et al. 2014; Smit et al. 2015; Stein et al. 2016a).

Hines et al. (2009) showed that in utero exposure (GDs 1–17) to low levels of PFOA (0.01–
0.3 mg/kg/day) resulted in increases in body weight gain in 10–40-week-old mice; by 18 months of age,the body weights in these mice were similar to controls. Increases in serum insulin and leptin levels werealso observed in the mice exposed to 0.01 and 0.1 mg/kg/day. The study also compared body weight andbody composition of in utero exposed mice (exposed on GDs 1–17) and adult exposed mice (exposed for
17 days starting at 8 weeks of age) and found that in utero exposure to 1 mg/kg/day resulted insignificantly higher body weight, brown fat weight, and white fat weight; this was not observed in mice
exposed to 5 mg/kg/day. The results of the study suggest that gestational exposure to low doses of PFOA
may result in increased susceptibility to PFOA toxicity.

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A number of studies of highly exposed residents and the general population have examined the potential
associations between serum perfluoroalkyl levels and alterations in birth weight. Decreases in birthweight have been found to be associated with higher PFOA (Fei et al. 2007; Lee et al. 2013; Maisonet etal. 2012; Savitz et al. 2012b) or PFOS levels (Maisonet et al. 2012), but not with lower levels ofperfluoroalkyls (Fei et al. 2007; Hamm et al. 2010; Inoue et al. 2004; Kim et al. 2011; Monroy et al.
2008; Washino et al. 2009; Whitworth et al. 2012b). The decreases in birth weight were small (<20 g or
0.7 ounces per 1 ng/mL). Additionally, no increases in the risk of low birth weight infants were found in
highly exposed populations (Darrow et al. 2013; Nolan et al. 2009; Savitz et al. 2012b; Stein et al. 2009).
No apparent alterations in the risk of birth defects were found in C8 Health Studies (Darrow et al. 2013;
Savitz et al. 2012b; Stein et al. 2009) or in another study of these communities (Nolan et al. 2009).

The developmental toxicity of PFOA and PFOS has been investigated in a number of rat and mousestudies. The observed effects include PFOA- and PFOS-induced increases in prenatal losses anddecreases in pup survival, decreases in pup body weight, and neurodevelopmental toxicity (Abbott et al.
2007; Albrecht et al. 2013; Case et al. 2001; Chen et al. 2012b; Era et al. 2009; Fuentes et al. 2006,
2007a, 2007b; Grasty et al. 2003; Hu et al. 2010; Johansson et al. 2008; Lau et al. 2003, 2006; Luebker et
al. 2005a, 2005b; Onishchenko et al. 2011; Thibodeaux et al. 2003; White et al. 2007, 2009, 2011; Wolfet al. 2007; Xia et al. 2011; Yahia et al. 2008, 2010). Additionally, delays in mammary glanddevelopment were observed in mice exposed to PFOA (Macon et al. 2011; White et al. 2007, 2009,2011). A limited number of developmental endpoints have been examined in rats and mice exposed to
PFDA, PFHxS, or PFBA (Butenhoff et al. 2009a; Das et al. 2008; Harris and Birnbaum 1989; Johansson
et al. 2008; Viberg et al. 2013). A more in-depth discussion of the developmental toxicity ofperfluoroalkyls in animals is included in Section 2.17.

PFOA and PFOS, as well as other perfluoroalkyls, are valid biomarkers of exposure to these compounds
in children, as they are in adults. No relevant studies were located regarding interactions ofperfluoroalkyls with other chemicals in children or adults.

No studies examining increased susceptibility to the toxicity of perfluoroalkyls were identified. The
available epidemiological data identify several potential targets of toxicity of perfluoroalkyls, andindividuals with pre-existing conditions may be unusually susceptible. For example, it appears that
exposure to PFOA or PFOS can result in increases in serum lipid levels, particularly cholesterol levels.
Thus, an increase in serum cholesterol may result in a greater health impact in individuals with high levelsof cholesterol or with other existing cardiovascular risk factors. Associations have been found between

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONSPFOA and PFOS levels and an increased risk of hypertension/pre-eclampsia in pregnant women. The
liver has been shown to be a sensitive target in a number of animal species and there is some indicationthat it is also a target in humans. Therefore, individuals with compromised liver function may represent asusceptible population. Likewise, individuals with a compromised immune system may have an
increased risk of perfluoroalkyl-induced immunotoxicity.

3.3

BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They havebeen classified as biomarkers of exposure, biomarkers of effect, and biomarkers of susceptibility(NAS/NRC 1989).

A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction
between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartmentof an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substanceitself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. Biomarkers of
exposure to perfluoroalkyls are discussed in Section 3.3.1. The National Report on Human Exposure to
Environmental Chemicals provides an ongoing assessment of the exposure of a generalizable sample of
the U.S. population to environmental chemicals using biomonitoring (see http://www.cdc.gov/
exposurereport/). If available, biomonitoring data for perfluoroalkyls from this report are discussed in
Section 5.6, General Population Exposure.

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an
organism that (depending on magnitude) can be recognized as an established or potential healthimpairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals oftissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial
cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lungcapacity. Note that these markers are not often substance specific. They also may not be directly
adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effect causedby perfluoroalkyls are discussed in Section 3.3.2.

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability
to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic orother characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in thePERFLUOROALKYLS

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biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are
discussed in Section 3.2, Children and Other Populations that are Unusually Susceptible.
3.3.1

Biomarkers of Exposure

Measurement of serum or whole-blood perfluoroalkyl concentrations is the standard accepted biomarker
of perfluoroalkyl exposure in humans. Perfluoroalkyls have been detected in the serum of workers,
residents living near perfluoroalkyl facilities, and the general population. As part of NHANES, CDC has
been measuring serum levels of perfluoroalkyls in the U.S. general population since 1999. Of the
12 perfluoroalkyls examined in this toxicological profile, blood concentrations of 7 compounds (PFOA,PFOS, PFDA, PFHxS, PFNA, and PFUnA) were detected in enough subjects to allow for estimation of
the geometric mean. As compared to the general population, serum PFOA and PFOS levels are muchhigher in individuals with occupational exposure to these compounds (Olsen et al. 2003a; Sakr et al.
2007a) and PFOA levels are much higher in individuals living near a PFOA manufacturing facility(Emmett et al. 2006a; Steenland et al. 2009a), suggesting that serum levels are a good biomarker of
exposure. Due to the long half-life of some perfluoroalkyls, particularly PFOA and PFOS, elevatedserum levels may not be indicative of recent exposure. Although elevated serum levels are likely to be
indicative of exposure to the parent compound, their presence in blood can also indicate exposure to otherperfluoroalkyls. For example, PFOS can be derived from metabolism of FOSA (Olsen et al. 2005; Seacatand Luebker 2000). PFOA can be derived from metabolism of 8-2 fluorotelomer alcohol (Fasano et al.
2006; Henderson and Smith 2007; Kudo et al. 2005; Nabb et al. 2007). Exposure of mice to 8–2 telomer
alcohol also generated PFNA as a metabolite (Kudo et al. 2005). Most epidemiological studies measured
serum perfluoroalkyl levels as a biomarker of exposure. In general, these studies provided a one-time
serum perfluoroalkyl level, but lacked information on actual environmental exposure concentrations or
doses, route of exposure, and exposure duration. The differences in elimination half-lives between
perfluoroalkyls also confounds the interpretation of one-time measurements; the relative concentration of
the perfluoroalkyls measured in serum may not be reflective of the actual mixture to which the individual
was exposed.

Two studies have also evaluated the use of perfluoroalkyl levels in hair as a biomarker of exposure. In
rats administered PFOA, PFOS, or PFNA in the drinking water for 90 days, significant correlations
between hair perfluoroalkyl levels and serum and tissue (liver, heart, lung, kidney) levels were found,suggesting that hair perfluoroalkyl levels may be a reliable biomarker of exposure (Gao et al. 2015). A
study in humans (Alves et al. 2015) has also found detectable levels of PFBA, PFHxA, PFOA, PFBS, andPERFLUOROALKYLS

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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONSPFHxS in hair samples, but PFHpA, PFNA, and PFOS were not detected in hair samples. The study did
not evaluate the potential relationship between serum perfluoroalkyl levels and hair levels, which does notallow for an assessment of whether hair is a viable biomarker of exposure.

Urinary perfluoroalkyl levels have also been evaluated as a biomarker of exposure (Worley et al. 2017a).
A study of highly exposed residents measured urinary PFOA, PFOS, PFNA, and PFHxS levels. With the
exception of PFOA, the proportion of values below the detection limit was too high to calculate mean ormedian values. The study found a strong linear correlation between serum PFOA levels and urinary
PFOA levels in men and a nonsignificant weak correlation between serum and urinary PFOA levels inwomen.
3.3.2

Biomarkers of Effect

There are no specific biomarkers of effect caused by perfluoroalkyls.
3.4

INTERACTIONS WITH OTHER CHEMICALSThere are limited data on the interactions of perfluoroalkyls with other chemicals. Particularly absent arestudies examining toxicological and toxicokinetic interactions of a perfluoroalkyl with otherperfluoroalkyls. Olestra decreased the absorption of PFOA from the gastrointestinal tract of mice
(Jandacek et al. 2010). No additional information was located regarding interactions among chemicals of
this class or between perfluoroalkyls and other chemicals. Both PFOA and PFOS (and many otherdiverse chemicals) can activate the PPARα, as well as other PPARs to a lesser extent (Takacs and Abbott
2007; Vanden Heuvel et al. 2006). Therefore, it is not unreasonable to speculate that interactions at thereceptor level might occur; however, there are no experimental data to support or rule out thispresumption. PPARα-independent mechanism are also involved in the toxicity of perfluoroalkyls andinteractions between compounds are also likely to influence these mechanisms.

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CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION
4.1

CHEMICAL IDENTITY

Information regarding the chemical identity of perfluoroalkyls is located in Table 4-1. This information
includes synonyms, chemical formulas and structures, and identification numbers. The perfluoroalkyls
discussed in this profile exist as linear and branched isomers depending upon the method of production(see Chapter 5) and the reported values for the physical-chemical properties are typically reflective of the
mixtures rather than a single specific isomer.
4.2

PHYSICAL AND CHEMICAL PROPERTIES

Information regarding the physical and chemical properties of perfluoroalkyls is located in Table 4-2.

Perfluoroalkyls are very stable, owing to the strength of the carbon-fluorine bonds, the presence of thethree electron pairs surrounding each fluorine atom, and the shielding of the carbon atoms by the fluorine
atoms (3M 1999; Kissa 2001; Schultz et al. 2003). Perfluoroalkyl carboxylates and sulfonates areresistant to direct photolysis and reaction with acids, bases, oxidants, and reductants (3M 2000; EPA
2008a; OECD 2002, 2006a, 2007; Schultz et al. 2003).

APFO was shown to decompose starting at 196°C (Krusic and Roe 2004) and PFOA was shown todecompose rapidly in the presence of crushed borosilicate glass at 307°C (Krusic et al. 2005).
1-H perfluoroheptane and perfluoroheptene are noted degradation products.

Perfluoroalkyl carboxylates and sulfonates consist of a perfluorocarbon tail that is both hydrophobic andoleophobic and a charged end that is hydrophilic (3M 1999; de Vos et al. 2008; Kissa 2001; Schultz et al.
2003). This combination of hydrophobic and oleophobic characteristics makes these substances very
useful as surfactants. The ability of these substances to repel oil, fat, and water has resulted in their use insurface protectants (Kissa 2001). Their ability to reduce the surface tension of aqueous systems to<20 mN/m has resulted in their use as wetting agents (Kissa 2001). Neutral or uncharged perfluoroalkyls
or very long chain constituents are expected to form separate layers when mixed with hydrocarbons andwater. Conversely, charged species, salts, and ionized species at relevant pH (i.e., PFOS, PFOA, PFHpA,
PFNA) and short-chain species (i.e., PFBA, PFBS) have relatively good solubility in water and alcohol.

PERFLUOROALKYLS

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-1. Chemical Identity of Perfluoroalkyls
Characteristic
Chemical name
Synonym(s)Registered trade name(s)Chemical formula

Information
Perfluorooctanoic acid
Ammonium perfluorooctanoate
PFOA; pentadecafluoro-1-octanoic
APFO; ammonium
acid; pentadecafluoro-n-octanoic acid; pentadecafluorooctanoate; octanoic
pentadecafluorooctanoic acid;
acid, 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8perfluorocaprylic acid;pentadecafluoro-ammonium salt (1:1)
perfluorooctanoic acid;perfluoroheptanecarboxylic acid;octanoic acid,
2,2,3,3,4,4,5,5,6,6,7,7,8,8,
8-pentadecafluoroNo data
No data
C8HF15O2
C8H4F15NO2

Chemical structureF
F
CAS Registry Number

335-67-1

F
F

F
F

F
F

F
F

F
F

F

No data
C4HF7O2

O

O

F
O

F

OH
F

Perfluorobutanoic acid
PFBA; heptafluoro-1-butanoic acid;heptafluorobutanoic acid;heptafluorobutyric acid;perfluorobutyric acid;perfluoropropanecarboxylic acid;
2,2,3,3,4,4,4-heptafluorobutanoic
acid

F

F

F
F

F

F

F

F
F

F

F

F

F

F
F

3825-26-1

F

375-22-4

F
F

F

O
OH

F

F

PERFLUOROALKYLS

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-1. Chemical Identity of Perfluoroalkyls
Characteristic

Information

Chemical name
Synonym(s)Perfluorohexanoic acid
Perfluoroheptanoic acid
PFHxA; undecafluoro-1-hexanoic acid; PFHpA; perfluoro-n-heptanoic acid;hexanoic acid,tridecafluoro-1-heptanoic acid;
2,2,3,3,4,4,5,5,6,6,6-undecafluoroheptanoic acid, 2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-

Registered trade name(s)Chemical formula

No data
C6HF11O2

No data
C7HF13O2O

Chemical structure
F

OH

F
F

F
F

F
F

F
F
F

CAS Registry Number

307-24-4

FFF

375-85-9

F
F

F
F

F
F

F
F

F

Perfluorononanoic acid
PFNA; perfluoro-n-nonanoic acid;perfluorononan-1-oic acid; heptadecafluoro-nonanoic acid;nonanoic acid,
2,2,3,3,4,4,5,5,6,6,7,7,8,8,
9,9,9-heptadecafluoroNo data
C9HF17O2

O
OH

F

F
F
F

F
F

375-95-1

F
F

F
F

F
F

F
F

F
F

F

O
OH

F

F

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-1. Chemical Identity of Perfluoroalkyls
Characteristic
Chemical name
Synonym(s)Registered trade name(s)Chemical formula

Information
Perfluorodecanoic acid
PFDA; PFDeA; Ndfda;
nonadecafluoro-n-decanoic acid;nonadecafluorodecanoic acid;perfluoro-n-decanoic acid; decanoic
acid, 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,
10,10,10-nonadecafluoroNo data
C10HF19O2

Chemical structure

F

F

F

CAS Registry Number

335-76-2

F

F
F

F
F

F

F

F
F

F
F

F
F

F

Perfluoroundecanoic acid
Perfluorododecanoic acidPFUnA; perfluoro-n-undecanoic acid;
PFDoDA; tricosafluorododecanoic
henicosafluoroundecanoic acid;acid; dodecanoic acid,
2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11, 2,2,3,3,4,4,5,5,6,6,7,7,8,
11,11-heneicosafluoroundecanoic acid 8,9,9,10,10,11,11,12,12,12-tricosafluoroNo data
C11HF21O2

No data
C12HF23O2

O
OH

F

F

F
F

F
F

2058-94-8

F
F

F
F

F
F

F
F

F
F

F
F

F
F

F

O
OH

F

F

F
F

F
F

F
F

307-55-1

F
F

F
F

F
F

F
F

F
F

F
F

F
F

F

O
OH

F

F

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-1. Chemical Identity of Perfluoroalkyls
Characteristic
Chemical name
Synonym(s)Information
Perfluorohexane sulfonic acid
PFHxS; perfluorohexane-1-sulphonic acid; 1-hexanesulfonic acid, 1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluoro-;
1,1,2,2,3,3,4,4,5,5,6,6,6-tridecafluorohexane-1-sulfonicRegistered trade name(s)Perfluorooctane sulfonic acid
PFOS; 1-perfluorooctanesulfonic acid; heptadecafluoro1-octanesulfonic acid; heptadecafluorooctan-1-sulphonicacid; perfluorooctane sulfonate; perfluorooctylsulfonicacid; 1-octanesulfonic acid, 1,1,2,2,3,3,4,4,5,5,6,6,7,7,
8,8,8-heptadecafluoroNo data

Chemical formulaC8HF17O3SC6HF13O3S

Chemical structureF
F

CAS Registry Number

1763-23-1

F
F

F
F

F
F

F
F

F
F

F
F

F
F

No data

O
OH
S
O
F

F
F

355-46-4

F
F

F
F

F
F

F
F

F
F

O
OH
S
O
F

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-1. Chemical Identity of Perfluoroalkyls
Characteristic
Chemical name
Synonym(s)Information
Perfluorooctanesulfonamide
FOSA; perfluorooctylsulfonamide; perfluorooctanesulfonic acid amide; heptadecafluorooctanesulphonamide; 1-octanesulfonamide, 1,1,2,2,3,3,4,4,
5,5,6,6,7,7,8,8,8-heptadecafluoro-

Registered trade name(s)Perfluorobutane sulfonic acid
PFBS; 1-perfluorobutanesulfonic acid; nonafluoro1-butanesulfonic acid; nonafluorobutanesulfonic acid;
pentyl perfluorobutanoate; 1,1,2,2,3,3,4,4,4-nonafluoro1-butanesulfonic acid; 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonic acid; 1-butanesulfonic acid,nonafluoro- (6Cl,7Cl,8Cl)
No data

Chemical formulaC4HF9O3S

C8H2F17NO2S

Chemical structure

CAS Registry Number

No data

O
OH
F
S
F
F
O
F
F
F
F
F
F

375-73-5

CAS = Chemical Abstracts Services
Sources: Calafat et al. 2007a, 2007b; CAS 2008; ChemIDplus 2008, 2017; RTECS 2008

FF

754-91-6

F
F

F
F

F
F

F
F

F
F

F
F

F
F

O
NH2
S
O
F

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls
Property
Molecular weight

PFOA
414.069

APFO
a

431.1

Color

White to off-white

Physical state

Solide

d

a

PFBA

b

PFHxA

214.039a314.06c

No data

No data

Colorlessd

SolidbLiquidaLiquidda

Melting point

54.3°C

Decomposition starts -17.5°C
above 105°Cb

Boiling point

188°CaNo data

121°Ca168°C at 742 mm
Hgf

Density at 20°C

1.8 g/cm3g

No data

1.651 g/cm3a1.789fOdor

No data

No data

No data

No data

Odor threshold:
Water
Air

No data
No data

No data
No data

No data
No data

No data
No data

9.5x103 mg/L at
25°Ch
2.29 x103 mg/L at
24°Ci
3.3x103 mg/L at
25°Cj
4.34x103 mg/L at
24.1°Ck
No data>500 g/Lb

2.14x105 mg/L at
25°Cl

15,700 mg/Lm

No data

Soluble in ethanol
and toluene;
insoluble inpetroleum ethera

No data

Not applicablen
1.69–2.36o
2.06p

No data
KOC 49–230q

Not applicablen
Not applicableno2.17, average (n=7) 2.06, average (n=7)o

pKa

-0.5r
0.5s

No data

0.08 (estimated)t-0.16mVapor pressure

0.017 mm Hg at
0.0081 Pa at 20°Cb
20°C (extrapolated);
0.962 mm Hg at
59.25°C (measured)u0.0316 mm Hg at
25°Ci

44 mm Hg at 56°Ch

No data

Henry's law constant

0.362 Pa-m3/moll

No data

1.24Pa-m3/moll

No data

Autoignition
temperature

Not applicablev

No data

Not applicablev

Not applicablev

Flashpoint

Not applicablev

No data

Not applicablev

Not applicablev

Flammability limits

Not applicableu

Solubility:
Water

Organic solvents

Partition coefficients:
Log Kow
Log Koc

Not applicableu

No data3

No data3

Not applicableu

Conversion factors

1 ppm=16.94 mg/m ; 1 ppm=17.63 mg/m ; 1 ppm=8.75 mg/m ; 1 ppm=12.84 mg/m3;
1 mg/m3=0.059 ppmw 1 mg/m3=0.057 ppmw 1 mg/m3=0.11 ppmw 1 mg/m3=0.078 ppmw

Explosive limits

Not applicablev

Not applicablev

3

Not applicablev

Not applicablev

PERFLUOROALKYLS

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls
Property
Molecular weight
Color

PFHpA

PFNA

u

u

514.084

No data

No data

No data

364.06Beige

464.08

d
d

PFDA

PFUnA
t

564.085w

Physical state

Crystalline solid

No data

No data

No data

Melting point

24–30°Cx

No data

No data

97.9–100.3°Cx

Boiling point

175°C at 742 mm
Hgh

No data

219°C

No dataDensity at 20°C

1.792 g/cm3 y

No data

No data

No dataOdor

No data

No data

No data

No data

Odor threshold:
Water
Air

No data
No data

No data
No data

No data
No data

No data
No data

No data

No data

No dataOrganic solvents

4.37x105 mg/L at
25°Cl
No data

No data

No data

No data

Partition coefficients:
Log Kow
Log Koc

Not applicablen
Not applicableno2.04, average (n=7) 2.39p

Not applicablen
2.79p

Not applicablen
3.30p

pKa

-0.15 (estimated)t-2.29 (estimated)-0.17 (estimated)t-0.17 (estimated)t

Vapor pressure

4.6 mm Hg at 25°Ch 4.83x10-3 mm Hg at 7.62x10-4 mm Hg at
0.133 at 25°Cd
20°C (extrapolated); 20°C (extrapolated);
8.4 mm Hg at
23.5 mm Hg at
99.63°C (measured)t 129.56°C(measured)aa

3.44x10-4 mm Hg at
20°C (extrapolated);
4.62 mm Hg at
112.04°C(measured)aa

Henry's law constantat 25°C

0.573 Pa-m3/molh

No data

No data

No data

Autoignition
temperature

Not applicablev

Not applicablev

Not applicablev

Not applicablev

Flashpoint

Not applicablev

Not applicablev

Not applicablev

Not applicablev

Flammability limits

Not applicablev

Solubility:
Water-0.21 (estimated)d

Not applicablev
3

Not applicablev
3

Not applicablev

Conversion factors

1 ppm=14.89 mg/m ; 1 ppm=18.98 mg/m ; 1 ppm=21.03 mg/m ; 1 ppm=23.07 mg/m3;
1 mg/m3=0.067 ppmw 1 mg/m3=0.053 ppmw 1 mg/m3=0.048 ppmw 1 mg/m3=0.043 ppmw

Explosive limits

Not applicablev

Not applicablev

3

Not applicablev

Not applicablev

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls
Property

PFDoDA
c

PFOS

PFHxS

c

400.12c

Molecular weight614.1

500.03Color

No data

No data

No data

Physical state

No data

No data

No data

Melting point

No data≥400°C (potassium salt)z

No dataBoiling point

No data

No data

No dataDensity at 20°C

No data

No data

No dataOdor

No data

No data

No data

Odor threshold:
Water
Air

No data
No data

No data
No data

No data
No data

Solubility:
Water

No data

570 mg/L (potassium salt in No data
pure water)z
No data
No dataOrganic solvents

No data

Partition coefficients:
Log Kow
Log Koc

Not applicablej
No data

Not applicablej
3.14, average (n=7)o
2.57p

Not applicablej
2.28, average (n=7)opKa-0.17 (estimated)t

0.14 (estimated)t

0.14 (estimated)t

-60

-6

Vapor pressure

5.11x10 mm Hg at 20°C
(extrapolated)z

2.48x10 mm Hg at 20°C
(potassium salt)e

No data

Henry's law constantat 25°C

No data

No data

No data

Autoignition
temperature

Not applicablev

Not applicablev

Not applicablev

Flashpoint

Not applicablev

Not applicablev

Not applicablev

Flammability limits

Not applicablev

Not applicablev
3

Not applicablev
3

Conversion factors

1 ppm=25.12 mg/m ;1 mg/m3=0.04 ppmw

1 ppm=20.45 mg/m ;1 mg/m3=0.049 ppmw

1 ppm=16.36 mg/m3;
1 mg/m3=0.061 ppmw

Explosive limits

Not applicablev

Not applicablev

Not applicablev

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls
Property

PFBS

FOSA

c

499.15c

Molecular weight

300.1

Color

No data

No data

Physical state

No data

No data

Melting point
Boiling point
Density at 20°C
Odor
Odor threshold:
Water
Air
Solubility:
Water
Organic solvents
Partition coefficients:
Log Kow
Log Koc
pKa
Vapor pressure
Henry's law constantAutoignition
temperature
Flashpoint
Flammability limits

No data

No data

No data
No data
No data
No data

No data
No data

No data
No data

No data
No data

No data
No data

Not applicablen
2.06 avg (n=7)o

Not applicablen
No data

0.14 (estimated)t

6.24 (estimated)t

No data

No data

No data
Not applicablev

No data

Not applicablev

Not applicablevv

Not applicablev

No data
No data

Not applicableNot applicablev

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4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls
Conversion factors

1 ppm=12.27 mg/m3; 1 mg/m3=0.081 ppmu 1 ppm=20.42 mg/m3; 1 mg/m3=0.049 ppmw

Explosive limits

Not applicableu

Not applicableu

aLide 2005.

bEPA 2014.

cEPA 2008c.

dHSDB 2019.
e3M 2008c.

fSavu 1994a.

gKroschwitz and Howe-Grant 1994.
hKauck and Diesslin 1951.

iBhhatarai and Gramatica 2011.
jInoue et al. 2012.

kRahman et al. 2014.
lKwan 2001.

mZhao et al. 2014.

nThe log K
ow is not measurable since these substances are expected to form multiple layers in an octanol-water

mixture (3M 1999, 2008c; EPA 2005a).

oMcGuire et al. 2014.

pHiggins and Luthy 2006.

qPrevedouros et al. 2006.
rGoss 2008.

sVierke et al. 2013.
tSPARC 2008.

uKaiser et al. 2005.

vPerfluorocarboxylates and perfluorosulfonates are nonflammable (3M 1999, Kissa 2001, OECD 2007).

However,they readily degrade via incineration (Krusic and Roe 2004; Krusic et al. 2005; Yamada et al. 2005).
wCalculated using molecular weight and the equation ppm=(X mg/m3) x (24.45/molecular weight); mg/m3=(X.ppm) x(molecular weight/24.45).
xChemID Plus 2008.
yKunleda and Shinoda 1976.
zSiegemund et al. 2015.
aa
3M 2000.
APFO= ammonium perfluorooctanoate; FOSA = perfluorooctane sulfonamide; PFBA = perfluorobutanoic acid;
PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid;
PFHpA = perfluoroheptanoic acid; PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid;
PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid;PFUnA = perfluoroundecanoic acid

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4. CHEMICAL AND PHYSICAL INFORMATION

The formation of an emulsified layer between the octanol and water interface makes the accurate
measurement of properties such as log Kow very difficult using conventional experimental techniques likethe shake flask method or the slow stir technique (EPA 2005a, 3M 1999, 2008c). Xiang et al. (2018) usedreverse-phase high-performance liquid chromatography (HPLC) to study the partitioning between thestationary column and mobile phase as a means of simulating the octanol-water partitioning process. As
discussed in this study, acidic ionizable compounds are difficult to measure with this method since the pHof the mobile phase should be 2 log units lower than the pKa of the chemical; however, extremely low
pHs damage the stationary column. Therefore, a mobile phase over a range of pHs (1.09–5.00) was used
to estimate the log D (sum of the ionized and unionized species in octanol/sum of the ionized andunionized species in water) over this pH range for 11 perfluoroalkylcarboxylic acids, including PFOA,
and then the log D was converted to the neutral species log Kow. The estimated log Kow values of theperfluoroalkylcarboxylic acids (C4–C14) were in the range of 1.05 (PFBA) to 7.19 (perfluorotetradecanoic acid).

Both the potential to form separate layers when mixed with hydrocarbons and water and the propensity
for charged or ionized perfluoroalkyls to concentrate at interfaces make the measurement of the n-octanol
water partition coefficient impractical (3M 1999; EPA 2005a).

The pKa range (Table 4-2) indicates that perfluoroalkyls will exist in anion form when in contact withwater at environmental and physiologically relevant pHs. An estimated pKa of 6.24 indicates that FOSA
will exist as both the anion and the neutral species (SPARC 2008). Perfluoroalkyl salts, such as APFO,
will form the corresponding anions when dissolved in water. Prevedouros et al. (2006) reported a Krafft
point of 22°C and critical micelle concentration of 3.7x103 mg/L for the perfluorooctanoate anion (PFO).
At temperatures above the Krafft point, the solubility of PFO is expected to increase abruptly due to theformation of micelles.

Vapor pressures at 25°C were extrapolated for PFOA, PFNA, PFDA, PFUnA, and PFDoDA using
Antoine coefficients. Experimental vapor pressures were as follows: 0.962–724 mm Hg (59.25–
190.80°C) for PFOA; 8.40–750 mm Hg (99.63–203.12°C) for PFNA; 23.5–750 mm Hg (129.56–
218.88°C) for PFDA; 4.62–750 mm Hg (112.04–237.65°C) for PFUnA; and 6.42–750 mm Hg (127.58–
247.36°C) for PFDoDA (Kaiser et al. 2005).

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CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE
5.1

OVERVIEW

Perfluoroalkyls have been identified in at least 4 of the 1,854 hazardous waste sites that have been proposed
for inclusion on the EPA National Priorities List (NPL) (ATSDR 2017). However, the number of sites inwhich substance perfluoroalkyls have been evaluated is not known. Figure 5-1 illustrates perfluorinatedcompound (PFAS) sites with ATSDR, state health department, EPA, or Department of Defense involvement.

Figure 5-1. Perfluorinated Compound (PFAS) Sites with ATSDR, State
Health Department, U.S. Environmental Protection Agency, orDepartment of Defense Involvement

Source: ATSDR 2018•••

The general population is exposed to the perfluoroalkyls through food and water ingestion, dust
ingestion, inhalation exposure, and hand-to-mouth transfer of materials containing thesesubstances.
PFOA, PFOS, and their precursor substances are no longer produced or used in the United States
or most other industrialized nations; however, these substances are persistent in the environment
and exposure near highly contaminated sites may continue to occur.
Serum levels of PFOA and PFOS in the general population of the United States have declined
dramatically since 2000.

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5. POTENTIAL FOR HUMAN EXPOSURE

Perfluoroalkyls have been released to air, water, and soil in and around fluorochemical facilities locatedwithin the United States (3M 2007b, 2008a, 2008b; Barton et al. 2007; Davis et al. 2007; DuPont 2008;
EPA 2008a; Post et al. 2013). Since the early 2000s, eight companies in the fluorochemical industry havebeen working in concert with the EPA to phase out the production and use of long-chain perfluoroalkyls
and their precursors (3M 2008a; DuPont 2008; EPA 2007a, 2008a, 2016a). Perfluorocarboxylic acids
containing seven or more perfluorinated carbon groups and perfluoroalkyl sulfonic acids containing six ormore perfluorinated carbon units are considered long-chain substances. Perfluorinated carboxylic acids
and sulfonic acids containing less than seven and six perfluorinated carbons, respectively, are consideredshort-chain substances. PFOA, PFOA precursors, and higher homologues have been phased out by theeight corporations in the perfluorotelomer/fluorotelomer industry (Arkema, Asahi, BASF [successor toCiba], Clariant, Daikin, 3M/Dyneon, DuPont, and Solvay Solexis) as part of the EPA’s PFOA
Stewardship Program (DuPont 2008; EPA 2008a, 2016a). Industrial releases of these compounds in the
United States have declined or have been totally eliminated based on company reports submitted to EPA(EPA 2008a, 2016a). It is noted that PFOA and PFOS may still be produced domestically, imported, andused by companies not participating in the PFOA Stewardship Program. PFOA and PFOS may also bepresent in imported articles. Although the United States and most industrialized nations have stopped
producing PFOA and PFOS, China remains a major producer and user of both substances, and its
production has increased as production in the rest of the world has declined (HAES 2017; Li et al. 2015;
Lim et al. 2011).

Perfluoroalkyl carboxylic acids and sulfonic acids are expected to dissociate in the environment based on
their low pKa values (Kissa 2001; SPARC 2008), and anions will not volatilize from water or soil
surfaces (Prevedouros et al. 2006). The unique surfactant properties of these substances may prevent total
dissociation of perfluoroalkyls in water (EPA 2005a; Kissa 2001; Prevedouros et al. 2006); therefore,
some volatilization of perfluoroalkyls may occur since the neutral forms of these substances are
considered to be volatile (Barton et al. 2007; EPA 2005a; Kim and Kannan 2007). Perfluoroalkyls havebeen detected in air both in the vapor phase and as adsorbed to particulates (Kim and Kannan 2007).
Perfluoroalkyls are very stable compounds and are resistant to biodegradation, direct photolysis,
atmospheric photooxidation, and hydrolysis (3M 2000; EPA 2008a; OECD 2002, 2007; Schultz et al.
2003). Perfluoroalkyls released to the atmosphere are expected to adsorb to particles and settle to theground through wet or dry deposition (Barton et al. 2007; Hurley et al. 2004; Prevedouros et al. 2006).
The chemical stability of perfluoroalkyls and the low volatility of these substances in ionic form indicatethat perfluoroalkyls will be persistent in water and soil (3M 2000; Prevedouros et al. 2006). Soil

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5. POTENTIAL FOR HUMAN EXPOSURE

adsorption coefficient data as well as monitoring studies suggest that perfluoroalkyls such as PFOA are
mobile in soil and can leach into groundwater (Davis et al. 2007; Prevedouros et al. 2006).

Perfluoroalkyls have been detected in environmental media and biota of the Arctic region and in otherremote locations such as open ocean waters (Barber et al. 2007; Brown et al. 2018; Prevedouros et al.
2006; Wei et al. 2007a; Yamashita et al. 2005, 2008). Proposed source pathways include long-range
atmospheric transport of precursor compounds followed by photooxidation to form perfluoroalkyls, direct
long-range transport of perfluoroalkyls via oceanic currents, and transport of perfluoroalkyls in the formof marine aerosols (Armitage et al. 2006; Barber et al. 2007; Brown et al. 2018; Prevedouros et al. 2006;
Wania 2007). Direct transport of perfluoroalkyls in the atmosphere has also been proposed as a source
pathway since these substances have been detected in the vapor phase in outdoor air samples (CEMN
2008; Prevedouros et al. 2006). The actual source of perfluoroalkyls in remote locations is likely to be a
combination of these pathways.

The highest concentrations of PFOA and PFOS were in apex predators, such as polar bears, whichindicates that these substances biomagnify in food webs (de Vos et al. 2008; Houde et al. 2006b; Kannan
et al. 2005; Kelly et al. 2007; Smithwick et al. 2005a, 2005b, 2006). The bioaccumulation potential of
perfluoroalkyls is reported to increase with increasing chain length (de Vos et al. 2008; Furdui et al. 2007;
Martin et al. 2004b). In living organisms, perfluoroalkyls bind to protein albumin in blood, liver, andeggs and do not accumulate in fat tissue (de Vos et al. 2008; Kissa 2001).

The levels of PFOA and PFOS in serum samples of U.S. residents have decreased appreciably since thephase out of these substances in the United States. The geometric mean serum levels of PFOS havedeclined over 84% from NHANES survey years 1999–2000 (30.4 ng/mL) to 2013–2014 (4.72 ng/mL)
and the geometric mean serum levels of PFOA have declined 70% over the same temporal period,
decreasing from 5.2 ng/mL in years 1999–2000 to 1.56 ng/mL for 2015–2016 (CDC 2018).

Mean concentrations of PFHpA, PFNA, PFDA, PFUnA, PFDoDA, PFBS, PFBA, and FOSA are
generally <1 ng/mL (Calafat et al. 2006b, 2007a, 2007b; CDC 2015; De Silva and Mabury 2006;
Kuklenyik et al. 2004; Olsen et al. 2003a, 2003b, 2004c, 2005, 2007a). Major PFOS exposure pathways
proposed for the general population include food and water ingestion, dust ingestion, and hand-to-mouthtransfer from mill- or home-treated carpets (Trudel et al. 2008). For PFOA, the major exposure pathways
are proposed to be oral exposure resulting from general food and water ingestion, inhalation from
impregnated clothes, and dust ingestion. While migration of residual PFOA in paper packaging andPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

wrapping into food is also a potential route of exposure (Trudel et al. 2008), polyfluoroalkyl phosphoric
acids in food packaging can also be metabolized in the body to PFOA (D’eon and Mabury 2007; D’eon etal. 2009). Polyfluoroalkyl phosphoric acids are fluorinated surfactant substances used to greaseproof
food-containing paper products. Biotransformation of the 8:2 polyfluoroalkyl phosphoric acid and the
8:2 fluorotelomer alcohol into PFOA has been demonstrated (D’eon et al. 2009). Based on these
proposed exposure pathways, Trudel et al. (2008) estimated that adult uptake doses for high-exposure
scenarios were approximately 30 and 47 ng/kg body weight/day for PFOS and PFOA, respectively. The
estimated dosage for children under the age of 12 under a high-exposure scenario were estimated to be
101–219 and 65.2–128 ng/kg body weight/day for PFOS and PFOA, respectively (Trudel et al. 2008). It
is noted that the Trudel et al. (2008) study used older monitoring data and thus, may not be an accurate
reflection of current intakes. Estimated daily doses for the general population were also estimated by
Vestergren et al. (2008) to range from 3.9 to 520 ng/kg body weight/day for PFOS and from 0.3 to
150 ng/kg body weight/day for PFOA. Infants and toddlers had the highest estimated dosages due togreater hand-to-mouth contact with treated carpeting, mouthing activities of clothes, and greater dust
ingestion. While conversion of precursor compounds to PFOA and PFOS was generally considered as aminor contribution to the total exposure, under certain scenarios, it was estimated that up to 80% of theintake could be attributable to exposure to precursor substances followed by subsequent metabolism to
PFOS or PFOA (Vestergren et al. 2008).

Perfluoroalkyls have been detected in human breast milk and umbilical cord blood. The reported
maximum concentrations of PFOS and PFOA measured in human breast milk samples were 0.360–
0.685 and 0.210–0.609 ng/mL, respectively (Kärrman et al. 2007; Llorca et al. 2010; So et al. 2006b;
Völkel et al. 2008). Maximum concentrations of other perfluoroalkyls were <0.18 ng/mL (Kärrman et al.
2007). PFOS and PFOA have been detected in most umbilical cord blood samples with reported
concentrations of 4.9–11.0 and 1.6–3.7 ng/mL, respectively (Apelberg et al. 2007a, 2007b; Fei et al.
2007; Inoue et al. 2004; Midasch et al. 2007). Other perfluoroalkyls have been detected less frequently,
with maximum concentrations of <2.6 ng/mL.

Individuals who perform jobs that require frequent contact with perfluoroalkyl-containing products, suchas individuals who install and treat carpets or firefighters, are expected to have occupational exposure tothese substances. Individuals who work at fluorochemical facilities generally have had higher
perfluoroalkyl serum levels than the general population based on exposures in the work environment (3M
2007b, 2008b, 2008c; Barton et al. 2006; Davis et al. 2007). Studies of individuals living nearfluorochemical facilities indicate that drinking water is the major exposure pathway (Emmett et al. 2006a;

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5. POTENTIAL FOR HUMAN EXPOSURE

Hölzer et al. 2008; Wilhelm et al. 2009). 3M conducted an exposure assessment to estimate thecumulative exposure to PFOA due to activities at the Decatur, Alabama facility. On-site exposure to
groundskeepers, maintenance workers, construction workers, and on-site trespassers were considered.
Off-site exposures to anglers, boaters, and residential individuals were also estimated. Various plausible
exposure scenarios were considered, and the highest PFOA exposure doses by receptor and pathway
occurred for local residents from groundwater followed by residents consuming drinking water from theWest Morgan/East Lawrence (WM/EL) public drinking water supply (3M 2008c).
5.2
5.2.1

PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL
Production

Perfluoroalkyls have been manufactured industrially by electrochemical fluorination (ECF), fluorotelomer
iodide oxidation, fluorotelomer olefin oxidation, and fluorotelomer iodide carboxylation (Prevedouros etal. 2006; Schultz et al. 2003). During the ECF process, an organic acyl or sulfonyl fluoride backbone
structure is dissolved in a solution of aqueous hydrogen fluoride (Savu 1994b; Siegemund et al. 2005). A
direct electrical current is then passed through the solution, which replaces all of the hydrogens on themolecule with fluorines. Perfluoroacyl fluorides produced by ECF are hydrolyzed to form theperfluorocarboxylic acid, which is then separated via distillation. This method was used extensively by
3M in the production of perfluoroalkylsulfonates such as PFOS (3M 1999; Hekster et al. 2003; Schultz etal. 2003).
RhCOF + HF 
→ RfCOF + H2 + byproducts

→ RfCOOH + HF
RfCOF + H2O 
Perfluoroalkanesulfonyl fluorides produced by ECF are hydrolyzed under alkaline conditions to form thecorresponding salt (Savu 1994b; Siegemund et al. 2005). Acidification followed by distillation yields theanhydrous perfluoroalkanesulfonic acid.
RhSO2F + HF 
→ RfSO2F + H2
RfSO2F + KOH 
→ RfSO3K + HF

→ RfSO3H + KHSO4
RfSO3K + H2SO4 
Perfluorosulfonamide compounds, such as FOSA, can be formed by reacting the perfluoroalkanesulfonyl
fluoride with a primary or secondary amine (3M 1999; Hekster et al. 2003; Siegemund et al. 2005).

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5. POTENTIAL FOR HUMAN EXPOSURE

The fluorotelomer iodide oxidation process was developed by DuPont and has served as the basis for theirfluoropolymer production chemistry (Buck et al. 2011; Hekster et al. 2003; Savu 1994a; Siegemund et al.
2005). It begins with the preparation of pentafluoroiodoethane from tetrafluoroethene. Tetrafluoroetheneis then added to this product at a molar ratio that gives a product of desired chain length. Finally, theproduct is oxidized to form the carboxylic acid. The process produces linear perfluorocarboxylic acids ofeven carbon numbers as illustrated below.
5C2F4 + IF5 + 2I2 catalyst
→ 5C2F5I
C2F5I + nC2F4 
→ C2F5(C2F4)nI
C2F5(C2F4)nI SO
C2F5(C2F4)n-1CF2COOH
→3Fluorotelomer alcohols are created similarly, but the perfluoroalkyl iodide (telomer A) is reacted with
ethylene to create F(CF2)nCH2CH2I (telomer B), which is converted to the alcohol. The ECF process
resulted in a mixture of linear and branched isomers, whereas the telomerization processes yielded
predominantly linear products. It has been reported that the 3M ECF process resulted in approximately
70% linear and 30% branched isomers for PFOS and 78% linear and 22% branched isomers for PFOA
(Benskin et al. 2009).

No information is available in the TRI database on facilities that manufacture, process, or otherwise use
perfluoroalkyls because this class of substances is not required to be reported under Section 313 of theEmergency Planning and Community Right-to-Know Act (Title III of the Superfund Amendments andReauthorization Act of 1986) (EPA 2005a, 2016g). The Chemical Data Reporting (CDR) rule, under the
Toxic Substances Control Act (TSCA), requires manufacturers (including importers) to provide EPA withinformation on the production and use of chemicals in commerce in large quantities. Information on
perfluoroalkyls can be found at (https://www.epa.gov/chemical-data-reporting/basic-informationchemical-data-reporting#what).

Perfluoroalkyls have been manufactured for their direct use in commercial products as well as for theiruse in industrial process streams. Two important chemicals that have resulted from manufacturing
involving perfluoroalkyls, namely PFOS and PFOA, are of worldwide interest given their detection in
multiple media in the environment. However, these substances and related long-chain perfluoroalkyls
have been essentially phased out as a joint effort by EPA and industry (Lindstrom et al. 2011). The
timeline for history of perfluorinated compound production, use, and phase out is presented in Figure 5-2.

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5. POTENTIAL FOR HUMAN EXPOSURE

Figure 5-2. Timeline of Important Events in the History of Polyfluorinated Compounds

EPA = U.S. Environmental Protection Agency; PFC = perfluorinated compound; PFOA = perfluorooctanoic acid; PTFE = polytetrafluoroethylene;
SNUR = significant new use rule; WV = West Virginia
Source: Reprinted (adapted) with permission from Lindstrom et al. 2011 (Environ Sci Technol 45:7954-7961). Copyright 2011 American Chemical
Society.

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5. POTENTIAL FOR HUMAN EXPOSURE

Given their unique properties, certain narrow exceptions exist for specific applications. Additionally,
many of the substances that were used in the production of stain resistant or anti-sticking products that
could break down into PFOA and PFOS have also been replaced.

The 3M Company was the principal worldwide manufacturer of PFOS and related chemicals. As a resultof its phase-out decision in May 2000, 3M no longer manufactures perfluorooctanyl compounds (PFOA
and PFOS). The company ceased manufacturing and using the vast majority of these compounds withinapproximately 2 years of the phase-out announcement, and ceased all manufacturing and the lastsignificant use of this chemistry by the end of 2008 (3M 2008a; EPA 2007a). In 2000, EPA finalized the
SNUR for 88 perfluoroalkyl sulfonate compounds, which requires manufacturers to notify EPA 90 days
prior to commencing manufacture or import of these substances for a significant new use to allow timefor evaluation (EPA 2002, 2007a, 2008a). The purpose of this rule was to limit future manufacturing andimportation of these substances. According to EPA, the rule allowed for the continuation of a few
limited, highly technical uses for which no alternatives are available, and which are characterized by very
low volume, low exposure, and low releases. The SNUR was amended in 2007 to include 183 additional
perfluoroalkyl sulfonate compounds (EPA 2007a, 2008a).

Included on the current list are PFOS, PFHxS, and FOSA. EPA believed that the perfluoroalkyl sulfonate
compounds listed under the SNUR were no longer manufactured in the United States; however, during
the comment period of the 2007 amendment, EPA learned of the ongoing use of tetraethylammonium
perfluorooctanesulfonate as a fume/mist suppressant in metal finishing and plating baths (EPA 2007a).
EPA has since excluded this from the list of significant uses. This rule has been amended again by the
EPA to designate the processing, use, or importation of long-chain perfluoroalkyls as a significant newuse if there are no current ongoing uses, or for uses that were scheduled to end December 31, 2015 (EPA2015). As part of this amendment, EPA proposed to amend a SNUR for perfluoroalkyl sulfonate
chemical substances that would make the exemption inapplicable for persons who import perfluoroalkyl
sulfonate chemical substances as part of carpets or any articles that contain long-chain perfluoroalkyls.

In 2006, the eight major companies of the perfluoropolymer/fluorotelomer industry agreed to participate
in EPA's PFOA Stewardship Program (EPA 2008a). All public documents and reports from the PFOA
Stewardship Program may be reviewed at the EPA docket (EPA-HQ-OPPT-2006-0621). This program
included voluntary commitments from these companies to reduce facility emissions and product content
of PFOA and related chemicals on a global basis by 95% no later than 2010, and to work towardelimination of these substances in products by 2015. Progress reports have been submitted annuallyPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

beginning in 2007 and are available from the EPA PFOA Stewardship Program website. Data from thesereports that list the content and percent reduction of PFOA, PFOA precursors, and higher PFOA
homologues in products are listed in Table 5-1. Nonconfidential emission reports from 2014 and 2015
obtained from the EPA docket indicate that the companies have met the goals of the program. According
to its 2015 emission report to EPA, Solvay Specialty Polymers (formerly Solvay Solexis) ceased using
PFOA and related higher homologs in 2010 and ceased importation of products containing PFOA
residuals in December 2015 (Jones 2016). DuPont does not use PFOA any longer in the emulsion
polymerization of polytetrafluoroethylene (PTFE), replacing it with a processing aid consisting of theammonium salt of 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, also known as GenX or
hexafluoropropylene oxide dimer acid (HFPO-DA) (Wang et al. 2013b). (In 2013, DuPont separated its
performance chemicals, titanium technologies, fluoroproducts division, and chemical solutions into aseparate company named Chemours). Similarly, 3M and other manufacturers are using various poly- andperfluoroether acid salts in fluoropolymer manufacturing and have reformulated surface treatment
products to employ short-chain substances that are not as bioaccumulative as the long-chain
perfluoroalkyls. Wang et al. (2013b) provide a comprehensive review of the newer substances that
manufacturers are using as replacements for legacy perfluoroalkyls in fluoropolymer manufacturing,
metal plating, firefighting foams, and other miscellaneous uses such as food packaging materials.
Although expected to be less, bioaccumulative modeling studies have suggested that short-chain
homologues and other replacements are likely to be persistent and mobile in the environment (Gomis etal. 2015)

Table 5-1. Content (ppm) and Percent Reduction of PFOA, PFOA Homologues, or
PFOA Precursors in Products from 2006 and 2013 U.S. Operations of
Fluoropolymer/Fluorotelomer Companies

Company

Chemicals

Dispersions
Other fluoropolymers
Telomers
Percent
Percent
Percent
Content reductiona Content reductiona Content reductiona
2006 (EPA 2008a)

Arkema, Inc. PFOA and higher >500–0%>70–150 30
homologues
1,000
Precursors
Not
Not
Not
Not
applicable applicable applicable applicableNot
applicableNot
applicableNot
applicableNot
applicablePERFLUOROALKYLS

656
5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-1. Content (ppm) and Percent Reduction of PFOA, PFOA Homologues, or
PFOA Precursors in Products from 2006 and 2013 U.S. Operations of
Fluoropolymer/Fluorotelomer Companies

Company

Chemicals

Dispersions
Other fluoropolymers
Telomers
Percent
Percent
Percent
Content reductiona Content reductiona Content reductiona

Asahi Glass PFOA, PFOA
500–1,570 12%
Company
salts, and higher
homologues
Precursors
Not
Not
applicable applicable
Ciba
PFOA
0.05 kg>99%
Specialty
Higher
0.05 kg>99%
Chemicals
homologues
Corporation
Precursors
0>99%
Clariant
Not applicable
Not
Not
International
applicable applicable
Ltd.
Daikin
PFOA
280
34%
America, Inc. Precursors and Not
Not
higherapplicable applicablehomologues
E.I. DuPont PFOA, PFOA
547
44%
de Nemours salts
andDirect precursors Not
Not
Company
applicable applicable
3M/Dyneon PFOA
0
100%

0.12

Not
Not
Not
applicable applicable applicableNot
applicable
0.05 kg
0.05 kg

Not
applicable
>99%
>99%

Not
applicable
0.05 kg
0.05 kg

Not
applicable
>99%
>99%

0
>99%
0
>99%
Not
Not
Not
Not
applicable applicable applicable applicable
2; 300
0%
0.28
Not
Not
2,500
applicable applicable

72%
78%

69

80%

246 kg50%

Not
applicableNot
reported
Not
applicable
170–200

Not
applicableNot
reported
Not
applicable
0%

57 kg

14%

Not
applicable
SolvayPFOA and PFOA 600–700
59%
Not
Solexissalts
applicable
HigherNot
Not
Not
homologues
applicable applicableapplicable
Precursors
0
Not
Not
Not
Not
applicable applicable applicable applicable2013 (EPA 2016a)
Arkema, Inc. PFOA and higher Not
100%>25–7596%
Nothomologues
applicableapplicable
Precursors
Not
Not
Not
Not
Not
applicable applicable applicable applicable applicableNot
applicableNot
applicableNot
applicableNot
applicableAsahi Glass PFOA, PFOA
0
100%
18
100%
Negligible
Company
salts, and higher
homologues
Precursors
Not
Not
Not
Not
Not
applicable applicable applicable applicable applicableNot
applicableNot
applicableNot
applicableNot
applicablePERFLUOROALKYLS

657
5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-1. Content (ppm) and Percent Reduction of PFOA, PFOA Homologues, or
PFOA Precursors in Products from 2006 and 2013 U.S. Operations of
Fluoropolymer/Fluorotelomer Companies

Company

Chemicals

Dispersions
Other fluoropolymers
Telomers
Percent
Percent
Percent
Content reductiona Content reductiona Content reductiona

BASF (Ciba PFOA and higher Not
Specialty
homologues
applicableChemicals
Corporation)
Precursors
Notapplicable
Clariant
PFOA, PFOA
None
International salts, and higher reported
Ltd.
homologues
Precursors
Nonereported
DaikinPFOA
NoneAmerica, Inc.
reported
Precursors and Nonehigherreportedhomologues

100%

Not
100%
applicable

Not
100%
applicable

Not
None
applicable reported
100%
None
reported
Not
None
applicable reported

Not
<7 kg
applicable
100%
None
reported
Not
None
applicable reported

Not
applicable
100%

E.I. DuPont PFOA and PFOA 1
de Nemours salts
andCompany
Higher1
homologues
Precursors
Nonereported
3M/Dyneon PFOA, PFOA
0salts, and higher
homologues
Precursors
Noprecursor
production

99%

0

99%

9 kg

>99%

99%

0

99%

99%

None
reported100%

Nonereported0

Nonereported
Not
applicableNonereportedNonereported
0

100%

Not
100%
Not
100%
applicableapplicable
Not
None
Not
<1 kg
Not
applicable reported
applicableapplicable

>99%

98%

No
telomereproduction
No
No
No
No
No
precursor precursor precursor precursor precursor
production production production production production

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-1. Content (ppm) and Percent Reduction of PFOA, PFOA Homologues, or
PFOA Precursors in Products from 2006 and 2013 U.S. Operations of
Fluoropolymer/Fluorotelomer Companies
Dispersions
Other fluoropolymers
Telomers
Percent
Percent
Percent
Content reductiona Content reductiona Content reductiona

Company

ChemicalsSolvaySolexisPFOA, PFOA
Not
>99.999% Not>99.999%
salts, and higher applicableapplicablehomologues
Precursors
Not
Not
Not
Not
applicable applicable applicable applicableaPercent reduction in product content of these compounds from baseline year levels.

Not>99.999%
applicableNot
Not
applicable applicable

The baseline year is the year

nearest to the year 2000 for which company data are available.
PFOA precursors include: octane, 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7, 8,8-heptadecafluoro-8-iodo- (CAS 507-63-1);
1-decanol, 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-(CAS 678-39-7); 1-decene,
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro- (CAS 21652-58-4); 2-propenoic acid,
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl ester (CAS 27905-45-9); 2-propenoic acid, 2-methy 1-,
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl ester (CAS 1996-88-9); 2-decenoic acid,
3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro- (CAS 70887-84-2); and decanoic acid, 3,3,4,4,5,5,6,6,7,
7,8,8,9,9,10,10,10-heptadecafluoro- (CAS 27854-31-5).
Higher homologues include: dodecane, 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12-pentacosafluoro12-iodo (CAS 307-60-8); decane, 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10-heneicosafluoro-10-iodo(CAS 423-62-1); nonanoic acid, heptadecafluoro- (CAS 375-95-1); decanoic acid, nonadecafluoro- (CAS 335-76-2);
1-Decanol, 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro- (CAS 678-39-7); decane,
1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-10-iodo- (CAS 2043-53-0); dodecane,
1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10-heneicosafluoro-12-iodo- (CAS 2043-54-1); 2-propenoic acid,
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl ester (CAS 4980-53-4); and 2-propenoic acid, 2-methyl-,
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heneicosafluorododecyl ester (CAS 17741-60-5).
CAS = Chemical Abstracts Service; PFOA = perfluorooctanoic acid

China is one of the few remaining producers and consumers of PFOA and its salts, with a total of
480 metric tons produced from 2004 to 2012 (Li et al. 2015). China also continues to be a producer of
PFOS. Growth in production volumes in China have coincided with decreases in production in the west.
For example, China produced approximately 30 metric tons of PFOS in 2001; however, as 3M ceased
production, China’s production of PFOS increased to 91, 165, and 247 metric tons in 2004, 2005, and2006, respectively (Lim et al. 2011). PFOA production in China was approximately 30 metric tons in
2004, but increased to approximately 90 metric tons in 2012 (Li et al. 2015). According to a report fromthe Hubei Academy of Environmental Sciences (HAES), China is planning to gradually phase out the
production of some PFOS uses before 2019 and conduct a best available technology (BAT)/bestenvironmental practice (BEP) analysis with the ultimate goal of completely phasing out the production
and use of PFOS and potential precursors (HAES 2017).

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Historical U.S. production volume data for PFOA, PFBA, and PFOS reported by manufacturers under the
EPA Inventory Update Rule (IUR) are provided in Table 5-2. Production volume ranges for theammonium salt of PFOA, APFO, are also listed. During the reporting year 2002, manufacturers reported
that the production volumes were within the range of 10,000–500,000 pounds (6–227 metric tons) for
PFOS and PFOA and within the range of 500,000–1,000,000 pounds (227–454 metric tons) for APFO(EPA 2008b). PFBA was reported as having a production volume within the range of 10,000–
500,000 pounds (6–227 metric tons) during 1986; however, PFBA production volumes were not reported
for subsequent years (EPA 2008b). None of the other perfluoroalkyls were listed in EPA’s IUR database.
Current U.S. production volume data for perfluoroalkyls are limited. The IUR database has beensuperseded by the Chemical Data Reporting (CDR) database. Data for 2012 indicated that PFOA was notimported into the United States, but any use or production volume data were reported as confidential
business information. No data were located in the CDR for the other substances listed in Table 5-2.
Nonconfidential emission reports from 2015 obtained from the EPA docket indicate that there is no
current production of PFOA or PFOS in the United States.

Table 5-2. U.S. Production Volume Ranges for Perfluoroalkyls (1986–2002)
Reported under the EPA Inventory Update Rule
Reporting year production volume range (pounds)
1990
1994
1998
2002

Perfluoroalkyl

1986

PFOA

10,000–500,000 Not reported

APFO
PFBA
PFOS

10,000–500,000 10,000–500,000 10,000–500,000 10,000–500,000 500,000–1,000,000
10,000–500,000 Not reported
Not reported
Not reported
Not reported
Not reported
Not reported
10,000–500,000 Not reported
10,000–500,000

10,000–500,000 10,000–500,000 10,000–500,000

APFO = ammonium perfluorooctanoate; EPA = Environmental Protection Agency; PFBA = perfluorobutanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid
Source: EPA 2008b

5.2.2

Import/Export

The SNURs cited in Section 5.2.1 severely limits the production, import, or export of the long-chain
perfluoroalkyls. There were no reported imports of chemicals listed in Table 4-1 in 2012 from the CDR
database. Production volumes and import volumes of the 8:2 fluorotelomer alcohol were listed asconfidential business information by DuPont. Shaw Industries Group reported that they imported
37,478 pounds of 6:2 fluorotelomer alcohol into the United States in 2012, but DuPont declared bothproduction volume and import volumes as confidential business information (EPA 2016d).

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5.2.3

Use

Applications of perfluoroalkyls have made use of their unique surfactant properties (Schultz et al. 2003).
The alkyl tails of perfluoroalkyls make these substances both hydrophobic (water-repelling) andoleophobic (oil-repelling) (3M 1999; Kissa 2001; Schultz et al. 2003). Because of these properties,
perfluoroalkyls have been used extensively in surface coating and protectant formulations (Kissa 2001).
Major applications have included protectants for paper and cardboard packaging products, carpets, leather
products, and textiles that enhance water, grease, and soil repellency (Hekster et al. 2003; Schultz et al.
2003). These compounds have been widely used in industrial surfactants, emulsifiers, wetting agents,
additives, and coatings as well (3M 1999; Schultz et al. 2003). Perfluoroalkyls have been used in firefighting foams since they are effective in extinguishing hydrocarbon fueled fires (Schultz et al. 2003).
Perfluoroalkyls have also been used as processing aids in the manufacture of fluoropolymers such as
nonstick coatings on cookware, membranes for clothing that are both waterproof and breathable, personalcare products (such as dental floss, cosmetics, sunscreens), electrical wire casing, fire and chemical
resistant tubing, and plumbing thread seal tape (DuPont 2008; EPA 2008a).
5.2.4

Disposal

Information concerning disposal of individual perfluoroalkyl products may be found on Material Safety
Data Sheets (MSDS) or Safety Data Sheets (SDS) from the manufacturers of the chemicals. Two
methods are generally recommended for the disposal of fluoropolymer dispersions. The first method
involves precipitation, decanting, or filtering to separate solids from liquid waste. The dry solids are thendisposed of in an approved industrial solid waste landfill or incinerated, while the liquid waste isdischarged to a waste water treatment facility (Plastics Europe 2012). The second method involves
incineration at temperatures >800°C using a scrubber to remove hydrogen fluoride (Plastics Europe2012). According to perfluorochemical facility assessment reports, historical disposal of perfluoroalkyl
containing waste has been through on- and off-site landfills, through sludge incorporation (subsurface
injection), and through incineration (3M 2007b, 2008a; ATSDR 2005). Pilot scale studies in whichcarpet samples were incinerated using a rotary kiln incinerator indicated that most perfluoroalkyls wereeffectively destroyed in combustors (Lemieux et al. 2007). Similar conclusions were reached by Yamada
et al. (2005) when studying the incineration of textiles and paper treated with fluorotelomer-based acrylic
polymers. Incineration at conventional temperatures is a proven technology for treating wastes containing
perfluoroalkyls.

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5.3

RELEASES TO THE ENVIRONMENT

There is no information listed in EPA’s Toxic Release Inventory (TRI) on releases of perfluoroalkyls tothe environment from facilities manufacturing, processing, or otherwise using perfluoroalkyls because
these releases are not required to be reported within this program (EPA 2005b, 2016g).

Perfluoroalkyls are man-made compounds that are not naturally occurring in the environment.
Perfluoroalkyls such as PFOS and PFOA have been widely used in the manufacturing of many consumer
products (Hekster et al. 2003; Schultz et al. 2003). These substances are still detected in both
environmental and biological media around the world as well as in serum samples collected from thegeneral population (Calafat et al. 2006b, 2007a, 2007b; CDC 2018, 2019; De Silva and Mabury 2006;
Kuklenyik et al. 2004; Olsen et al. 2003b, 2003c, 2004b, 2004c, 2005, 2007a; Prevedouros et al. 2006).

In 2006, the eight major companies of the perfluoropolymer/perfluorotelomer industry agreed toparticipate in EPA's PFOA Stewardship Program (EPA 2008a). This included voluntary commitmentsfrom these companies to reduce facility emissions and product content of PFOA and related chemicals on
a global basis by 95% no later than 2010, and to work toward elimination of these substances by 2015
(EPA 2008a). Data from 2007 and 2013 progress reports regarding releases of PFOA, PFOA precursors,and higher PFOA homologues to all media as well as percent reduction in releases are listed in Table 5-3.

Table 5-3. Reported Emissions of PFOA, PFOA Homologues, or PFOA
Precursors in Products from the 2006 and 2013 U.S. Operations of
Fluoropolymer/Fluorotelomer Companies

Company
Arkema, Inc.

Asahi Glass
Company

BASF (CibaSpecialty
Chemicals
Corporation)

Chemicals

Releases to all media from fluorotelomer and telomer manufacturing
kg of release/100 kg of Percent reductionkg
product producedin emissionsa2006 Data (EPA 2008a)
PFOA and higher>1,000–10,000 For fluorotelomer
homologues
production: >0.1–1
Precursors
Not applicableNot applicable
PFOA, PFOA salts, 4,922
For fluorotelomer
and higher
production: <1homologues
Precursors
Not applicableNot applicable
b
PFOA
0.05
Higher homologues 0.05b
Precursors
0b

22%
Not applicable6%

Not applicable
>99%
>99%
>99%

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Table 5-3. Reported Emissions of PFOA, PFOA Homologues, or PFOA
Precursors in Products from the 2006 and 2013 U.S. Operations of
Fluoropolymer/Fluorotelomer Companies

Company

Chemicals

Clariant
Not applicable
International Ltd.
Daikin America, PFOA
Inc.

Releases to all media from fluorotelomer and telomer manufacturing
kg of release/100 kg of Percent reductionkg
product producedin emissionsa
Not applicableNot applicableNot applicable

Confidential
business
information

For fluorotelomer
production: 8.0x10-3; fortelomer production:
6.4x10-7
For production: 6.4x10-7

94% for FP
production; 92% fortelomer production

Not reported
Not reported

098%
Confidential
business
information
100%

Not applicableNot applicable

Precursors andConfidential
higher homologues businessinformation
E.I. DuPont deNemours andCompany

PFOA, PFOA salts
Direct precursors

3M/Dyneon

PFOA

Solvay Solexis

PFOA and PFOA
Not applicablesalts
Higher homologues >1,000–10,000
Precursors

Arkema, Inc.

Asahi Glass
Company

BASF (CibaSpecialty
Chemicals
Corporation)

PFOA and higher
homologues
Precursors
PFOA, PFOA salts,
and higher
homologues
Precursors
PFOA

Precursors
Clariant
PFOA, PFOA salts
International Ltd.
Precursors
Daikin America, PFOA
Inc.

1,100
Confidential
business
information
022% for telomer
production

For fluorotelomer
production: 0.161
Not applicableNot applicable2013 data (EPA 2016a)>500–2,000>0.001–0.005

28%

Not applicable0

Not applicableNot applicableNot applicable100%

Not applicableNot applicableNot applicableNot applicableNot applicable100%

Not applicableNot applicableNot applicableNot applicable100%
Not applicableNot applicable0

Not applicable0

Not applicable100%

Not applicable91%

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Table 5-3. Reported Emissions of PFOA, PFOA Homologues, or PFOA
Precursors in Products from the 2006 and 2013 U.S. Operations of
Fluoropolymer/Fluorotelomer Companies
Releases to all media from fluorotelomer and telomer manufacturing
kg of release/100 kg of Percent reductionkg
product producedin emissionsa

Company

Chemicals

E.I. DuPont deNemours andCompany

Precursors and0higher homologues

0

100%

PFOA, PFOA salts 90
Higher homologues None reported
Precursors
Confidential
business
information
PFOA, PFOA salts, 0
and higher
homologues
Precursors
0None reported
None reported
None reported

0

99.8%
None reported
Confidential
business
information
100%0

Not applicable

PFOA, PFOA salts, 0
and higher
homologues
Precursors
00>99.999%0

Not applicable

3M/Dyneon

Solvay Solexis

aPercent reduction in product content of these compounds from baseline year levels.

The baseline year is the year

nearest to the year 2000 for which company data are available.
bTotal for emissions and product content
PFOA = perfluorooctanoic acid

While the United States and most industrialized countries around the world have ceased production of
PFOS and PFOA, China is still a major producer of both substances (Li et al. 2015; Lim et al. 2011).
Over the period from 2004 to 2012, it was estimated that 250 metric tons of PFOA were released to theenvironment from production in China (Li et al. 2015). Fluoropolymer manufacturing and processing
was considered the dominant source of environmental releases, accounting for >80% of the total, while
PFOA releases related to end use consumer products accounted for 6% of the total. Brazil produced
379 metric tons of N-EtFOSA for use in the pesticide, Sulfuramid, from 2004 and 2015, which contributeto PFOS releases to the environment (Wang et al. 2017).

Prevedouros et al. (2006) estimated the total global historical emissions of perfluoroalkyl carboxylates
into the environment from both direct and indirect sources from the time period of 1951–2004. These
data are provided in Table 5-4. Based on these estimations, direct emissions (3,200–6,900 metric tons)
have far exceeded indirect emissions (30–350 metric tons). The largest direct emissions identified are

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from industrial processes such as the manufacture of perfluoroalkyl carboxylates (470–900 metric tons),
fluoropolymer manufacture (2,400–5,400 metric tons), and fluoropolymer processing (210–320 metrictons). Direct release of perfluoroalkyl carboxylates from use of aqueous firefighting foams and consumer
and industrial products were estimated to be 50–100 and 40–200 metric tons, respectively. The largest
indirect emissions identified were from perfluoroalkyl carboxylate residual impurities in perfluorooctylsulfonyl fluoride products (20–130 metric tons) and fluorotelomer-based precursor degradation (6–130 metric tons). Wang et al. (2014) expanded upon the work of Prevedouros et al. (2006) by considering
additional emission sources of these substances and estimating emissions from 2003 to 2015 andprojecting future emissions. These authors estimated emissions of 820–7,180 metric tons for 2003–2015
and projected between 20 and 6,420 metric tons for years 2016–2030. The estimates by Prevedouros etal. (2006) and Wang et al. (2014) contain a great degree of uncertainty as demonstrated by the wide rangeof values presented in the data. Wang et al. (2014) stated that uncertainty analysis using Monte Carlo
methods is not possible because there is insufficient information available with respect to the range or
distribution of the emissions. Instead, they introduced a scoring system to provide a qualitativedescription of the accuracy of the estimates that ranged from 0–1 (low uncertainty) to 2–3 (highuncertainty where estimates were based on crude assumptions or extrapolations).

Table 5-4. Global Historical PFCA Production and Emissions Estimates from1951 to 2004aEnvironmental input source
Direct PFCA sources
PFCA manufacture
PFO/APFOPFN/APFN
Total manufactured
Industrial and consumer uses
Fluoropolymer manufacture (APFO)
Fluoropolymer dispersion processing (APFO)
Fluoropolymer manufacture (APFN)
Fluoropolymer processing (APFN)
Aqueous firefighting foams (AFFF)
Consumer and industrial products

Historical time
period (years)

Estimated total global
historical PFCA emissions(tonnes)

1951–2004
1975–2004

400–700
70–200470–900

1951–2004
1951–2004
1975–2004
1975–2004
1965–1974
1960–2000

2,000–4,000
200–300
400–1,400
10–20
50–10040–200PERFLUOROALKYLS

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Table 5-4. Global Historical PFCA Production and Emissions Estimates from1951 to 2004aEnvironmental input source
Total direct
Indirect PFCA sources
POSF-based products
PFCA residual impuritiesb
POSF-based precursor degradation
POSF-based AFFF
Fluorotelomer-based products
PFCA residual impuritiesb
Fluorotelomer-based precursor degradation
Fluorotelomer-based AFFF
Total indirect
Total source emissions (direct and indirect)

Historical time
period (years)

Estimated total global
historical PFCA emissions(tonnes)
3,200–6,900

1960–2002
1960–2002
1970–2002

20–130
1–30
3–30

1974–2004
1974–2004
1975–2004

0.3–30
6–130<1
30–3503,200–7,300

aLow and high estimated values as well as the period of use/production for each source are based upon publicly

available information cited in the text.
bSome authors classify residual impurities as a direct emission source rather than indirect emission source (Buck et

al. 2011).
AFFF = aqueous firefighting foams; APFN = ammonium perfluorononanoate; APFO = ammonium perfluorooctanoate; PFCA = perfluorinated carboxylic acid; PFN = perfluorononanoate; PFO = perfluorooctanoate;
POSF = perfluorooctanesulfonyl fluoride
Source: Prevedouros et al. 2006

Wang et al. (2017) estimated the global emissions in 1958–2015 as 1,228–4,930 tonnes of PFOS and
1,230–8,738 tonnes of PFOS precursors, with most emissions occurring from 1958 to 2002. It wasestimated that PFOS emissions from 2016 to 2030 will be 8–153 tonnes.
5.3.1

Air

There is no information listed in the TRI on releases of perfluoroalkyls to the atmosphere from facilities
manufacturing, processing, or otherwise using perfluoroalkyls because these releases are not required tobe reported (EPA 2005b, 2016g).

According to 3M, low levels of PFOA were released to air during manufacturing processes at the Decatur,
Alabama facility until use of this substance ceased in 2004 (3M 2008b). This company states that there
are currently no process-related air emissions of PFOA at this facility (3M 2008b). PFOA concentrations
as high as 75,000–900,000 pg/m3 were measured at the fence line of the DuPont Washington WorksPERFLUOROALKYLS

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facility near Parkersburg, West Virginia in 2004 (Barton et al. 2006; Davis et al. 2007; Prevedouros et al.
2006). High volume air samples collected at several monitoring stations near the Washington Works
facility during nine events between August and October of 2005 contained PFOA at reported
concentrations ranging from 10 to 75,900 pg/m3 (EPA 2007b). The mean and median of these reported
concentrations are 5,500 and 240 pg/m3, respectively.

The presence of perfluoroalkyls in indoor air and dust indicates that perfluoroalkyl-containing consumer
products such as treated carpets and textiles may be sources of release to air (Barber et al. 2007; Jahnke etal. 2007b; Kubwabo et al. 2005; Moriwaki et al. 2003; Prevedouros et al. 2006; Shoeib et al. 2004;
Strynar and Lindstrom 2008). Perfluoroalkyls have also been identified on both indoor and outdoor
window films (Gewurtz et al. 2009). Disposal of perfluoroalkyl-containing consumer products is also
expected to be a source of release to air (Prevedouros et al. 2006). Harada et al. (2005a, 2006) proposedthat automobiles may be a source of PFOA in urban air based on elevated levels measured near heavy
traffic areas and the widespread use of this substance in automobile materials.

Perfluoroalkyl carboxylic acids and perfluoroalkyl sulfonic acids are formed by the atmosphericphotooxidation of precursor compounds such as fluorotelomer alcohols and perfluoroalkyl sulfonamides(D'eon et al. 2006; Ellis et al. 2004; Martin et al. 2006; Wallington et al. 2006; Wania 2007).
Perfluoroalkyl carboxylic acids including PFOA, PFNA, PFHpA, and PFBA were observed as products
during a laboratory study involving the photooxidation of 4:2, 6:2, and 8:2 fluorotelomer alcohols (Ellis etal. 2003, 2004). D'eon et al. (2006) observed both perfluoroalkyl carboxylic acids and perfluorobutane
sulfonate among products of the photooxidation of N-methyl perfluorobutane sulfonamidoethanol.

5.3.2

Water

There is no information listed in the TRI on releases of perfluoroalkyls to water from facilities
manufacturing, processing, or otherwise using perfluoroalkyls because these releases are not required tobe reported (EPA 2005b, 2016g).

There are a number of sources of perfluoroalkyl release to surface water and groundwater, including
release from manufacturing sites, industrial use, use and disposal of perfluoroalkyl-containing consumer
products, fire/crash training areas, waste water treatment facilities, and from the use of contaminatedbiosolids (3M 2008b; Clara et al. 2009; Davis et al. 2007; Eggen et al. 2010; EPA 2009a; Kelly andPERFLUOROALKYLS

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Solem 2009; Moody and Field 1999; Moody et al. 2003; Sinclair and Kannan 2006; Prevedouros et al.
2006).

Waste water discharge was identified as a release pathway for APFO from the DuPont Washington
Works facility in West Virginia (Davis et al. 2007). The average monthly concentrations of APFO
measured in surface water from three outlets at the facility during 2007 and early 2008 ranged from3.65 to 377 µg/L (EPA 2008d). Reported concentrations of APFO and PFOA measured in surface waterfrom four separate outlets at this facility during the same period were 3–64 and 2.3–61 µg/L, respectively.
During perfluorochemical operations at the 3M Cottage Grove facility in Minnesota, waste water
treatment plant effluent containing perfluoroalkyls was discharged to the Mississippi River. Discharge
into Bakers Creek from the waste water treatment plant at the 3M Decatur facility was a principal sourceof PFOA release from this facility (3M 2008b).

Elevated levels of perfluoroalkyls, such as PFOA, PFOS, and PFHxS, measured in groundwater near firetraining areas are attributed to the use of these substances in aqueous firefighting foams (Moody and Field
1999; Moody et al. 2003). The concentrations of these three perfluoroalkyls in groundwater near amilitary fire-training site in Michigan were 8–105, 4.0–110, and 9–120 µg/L, respectively (Moody et al.
2003). A study of landfill leachates showed that perfluoroalkyls were primarily distributed to the waterphase of leachates, which could eventually contaminate ground water (Eggen et al. 2010). Lang et al.
(2017) estimated that between 563 and 638 kg of perfluoroalkyl substances were released from landfill
leachate in the United States in 2013.

Waste water treatment plants have been shown to be significant contributors to perfluoroalkyls
contamination of surface and ground water (Clara et al. 2009; EPA 2009a; Kelly and Solem 2009;
Loganathan et al. 2007; Sinclair and Kannan 2006; Yu et al. 2009c). Influent, effluent, and sludge
samples from 28 public and private waste water treatment plants in Minnesota were analyzed for
13 perfluoroalkyls; detectable concentrations of perfluoroalkyls were found in several facilities, primarily
urban treatment plants (Kelly and Solem 2009). Elevated levels of PFOS at one facility (1.51 µg/L in
effluent) were attributed to a chrome plating facility using a surfactant containing fluorosulfonate tocontrol hexavalent chromium emissions. Another study of chromium electroplating facilities in Chicago,
Illinois and Cleveland, Ohio also found them to be significant sources of PFOS and other perfluoroalkyls
in the environment (EPA 2009a). It was determined that perfluoroalkyls were being discharged from all
11 facilities at quantifiable levels and that PFOS was detected in waste water from 10 out of 11 facilities
at levels of 0.0314–39 µg/L. PFOA and PFOS were detected in effluents of six waste water treatment

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5. POTENTIAL FOR HUMAN EXPOSURE

plants located in New York at levels of 0.058–1.05 and 0.003–0.068 µg/L, respectively (Sinclair andKannan 2006). PFOS and PFOA were detected in effluents of two waste water treatment plants located in
Singapore at levels of 0.0053–0.5609 and 0.0112–1.057 µg/L, respectively (Yu et al. 2009c). PFOA,PFOS, and several other perfluoroalkyls were detected in effluent samples of 21 waste water treatment
plants and 9 industrial point sources; PFOA and PFOS were reportedly identified in the effluents of all of
the facilities monitored at an average level of 0.060 µg/L for both substances (Clara et al. 2009).

Studies comparing perfluoroalkyl levels in influent and effluent from municipal waste water treatment
facilities have found higher levels of some perfluoroalkyls, such as PFNA, PFOA, PFOS, and FOSA, inthe effluent, as compared to the influent (Loganathan et al. 2007; Schultz et al. 2006b). For others, suchas PFHxS and PFDA, waste water treatment resulted in lower concentrations or no change in theconcentrations. Increases in perfluoroalkyl concentrations are likely due to the breakdown ofperfluoroalkyl precursors such as polyfluoroalkyl phosphoric acids or fluorotelomer alcohols (D’eon et al.
2009; Gauthier and Mabury 2005; Wang et al. 2005a, 2005b).

A study of eight waste water treatment plants that discharge effluent to the San Francisco Bay foundincreases in PFBA and PFHxA levels between 2009 and 2014 and declines in longer-chain legacy
substances (Houtz et al. 2016). Average concentrations of PFBA were 7.4±4.7 ng/L in 2009 and
16±5.8 ng/L in 2014 and the average concentration of PFHxA rose from 17±4.0 ng/L in 2009 to
25±5.1 ng/L in 2014. The average PFOA concentration decreased from 32±30 ng/L in 2009 to
21±13 ng/L in 2014 and the average PFOS concentration decreased from 24±32 ng/L in 2009 to
13±4.4 ng/L in 2014.

Land application of biosolids (treated sewage sludge) can also result in the release of perfluoroalkyls tosurface and groundwater (Clark and Smith 2011; Lindstrom et al. 2011; Sepulvado et al. 2011). Thereappears to be some differences in the distribution of PFOA and PFOS in waste water effluent andbiosolids, with higher levels of PFOA in waste water and higher PFOS levels in biosolids (Guo et al.
2010).
5.3.3

Soil

There is no information listed in the TRI on releases of perfluoroalkyls to soil from facilities
manufacturing, processing, or otherwise using perfluoroalkyls because these releases are not required tobe reported (EPA 2005b, 2016g).

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Perfluoroalkyls can be inadvertently released to soils through the use of biosolids applied as fertilizer tohelp maintain productive agricultural soils and stimulate plant growth. PFOA and PFOS were detected inboth biosolids and biosolid-amended soils (Sepulvado et al. 2011). Six samples of biosolids obtained
from the Metropolitan Water Reclamation District of Greater Chicago had levels of PFOS and PFOA of
80–219 and 8–68 ng/g, respectively (Sepulvado et al. 2011). The mean sum (±SD) of all perfluoroalkyls
in the biosolids was 433±121 ng/g, with PFOS being most prominent. Perfluoroalkyls can also be
released into soil due to atmospheric transport and wet/dry deposition (Rankin et al. 2016; Strynar et al.
2012).

Liu et al. (2007) measured PFOA as a product of the biodegradation of 8:2 fluorotelomer alcohol in soil.
This result, along with similar findings in activated sludge tests, indicates that biodegradation offluorotelomer alcohols may result in the formation of perfluoroalkyl carboxylic acids in soil (Liu et al.
2007; Rankin et al. 2014; Wang et al. 2005a, 2005b).

5.4
5.4.1
Air.

ENVIRONMENTAL FATE
Transport and Partitioning
Barton et al. (2007) investigated the atmospheric partitioning of PFOA during rain events near an

industrial facility and concluded that this substance will be primarily adsorbed to particles in the air since
PFOA was not detected in the vapor phase (detection limit of 0.2 ng/m3). Concentrations of PFOA inraindrops and as particulates were 11.3–1,660 ng/L and 0.09–12.40 ng/m3, respectively. The authors
proposed that PFOA or APFO released into air from industrial facilities will be scavenged by atmosphericparticles (including aqueous aerosols and raindrops) and dissociate to form the perfluorooctanoate anion.
Although Barton et al. (2007) did not detect PFOA in the vapor phase during rain events, lowconcentrations (<0.12–3.16 pg/m3) of vapor-phase perfluoroalkyls measured by Kim and Kannan (2007)
in urban air provide evidence of a partitioning equilibrium. Wet and dry deposition are expected to be theprincipal removal mechanisms for perfluoroalkyl carboxylic acids and sulfonic acids in particulate form
from the atmosphere. Residence times with respect to these processes are expected to be days to weeks(Barton et al. 2007; Hurley et al. 2004; Kim and Kannan 2007).

Long-range atmospheric transport of precursor compounds such as fluorotelomer alcohols andperfluoroalkyl sulfonamides followed by the atmospheric photooxidation of these substances to form
perfluoroalkyl carboxylic acids and perfluoroalkyl sulfonic acids resulted in PFOA and PFOSPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

contamination in remote locations with no direct point sources for these compounds (Barber et al. 2007;
D'eon et al. 2006; Dinglasan-Panlilio and Mabury 2006; Ellis et al. 2004; Martin et al. 2006; Simcik
2005; Small 2009; Wallington et al. 2006; Wania 2007). Fluorotelomer alcohols and perfluoroalkyl
sulfonamides are volatile and possess long enough atmospheric residence times for long-range transport
to occur (Barber et al. 2007; Yarwood et al. 2007). The presence of fluorotelomer alcohols andperfluoroalkyl sulfonamides in urban and Arctic air offers evidence of long-range atmospheric transport(Loewen et al. 2005; Shoeib et al. 2006; Stock et al. 2004). Photooxidation studies have demonstrated theconversion of these substances to perfluoroalkyl carboxylic acids and sulfonates. According to Young etal. (2007), the presence of perfluorodecanoic acid and perfluoroundecanoic acid in an Arctic ice cap
indicates atmospheric oxidation of precursors as a source. Yeung et al. (2017) collected samples of snow
and water from the Central Arctic region in 2012 and observed that perfluorinated alkyl substances were
only detectable in ocean waters above a depth of 150 m. Atmospheric deposition from precursors wasestimated to account for approximately 34–59% of the PFOA input to the ocean. Gawor et al. (2014)
studied the distribution of fluorotelomer alcohols, fluorinated sulfonamides, and fluorinatedsulfonamidoethanols in polar, remote, and urban regions of the world during four sampling campaigns
covering the years 2005–2011. They observed higher levels of fluorotelomer alcohols as compared to thefluorinated sulfonamides and sulfonamidoethanols, with the 8:2 fluorotelomer alcohol being thepredominant species in most samples.
Water.

The pKa range of perfluoroalkyls indicates that these substances will exist primarily as thedissociated conjugate base (anion) when in contact with water at environmental pH (pH 5–9).
Volatilization will not be an important environmental fate process when the substances exist as anions;however, under acidic conditions, undissociated perfluoroalkyls may volatilize into the atmosphere(Martin et al. 2006). Perfluoroalkyls may be transported to remote areas by direct oceanic advection ofthese substances (Armitage et al. 2006; Barber et al. 2007; Simcik 2005; Wania 2007; Yamashita et al.
2005, 2008). Perfluoroalkyls may also be transported over long distances in the form of marine aerosols(Barber et al. 2007; CEMN 2008; Prevedouros et al. 2006). This transport mechanism may be especiallyrelevant since surfactants have been shown to accumulate in upper sea layers and at water surfaces(Prevedouros et al. 2006).

Perfluoroalkyls have been measured in invertebrates, fish, amphibians, reptiles, birds, bird eggs, andmammals located around the world (Brown et al. 2018; Dai et al. 2006; Giesy and Kannan 2001; Houdeet al. 2005, 2006a, 2006b; Keller et al. 2005; Kannan et al. 2001a, 2001b, 2002a, 2002b, 2002c, 2002d,
2005, 2006; Sinclair et al. 2006; So et al. 2006a; Wang et al. 2008). The highest concentrations of PFOAPERFLUOROALKYLS

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and PFOS in animals are measured in apex predators, such as polar bears, which indicates that thesesubstances biomagnify in food webs (de Vos et al. 2008; Houde et al. 2006b; Kannan et al. 2005; Kelly et
al. 2007). Loi et al. (2011) also provided evidence of the biomagnification potential of several
perfluoroalkyl substances in tropical food webs. Evidence for biomagnification of chlorinatedpolyfluoroalkyl ether sulfonic acids, which have been used in the plating industry, has recently beenreported (Liu et al. 2017; Shi et al. 2015). Table 5-5 shows levels of PFOA and PFOS measured in Arcticorganisms. The bioaccumulation potential of perfluoroalkyls increases with increasing chain length from4 to 8 carbon units and then declines with further increases in chain length (Conder et al. 2008; de Vos etal. 2008; Furdui et al. 2007; Martin et al. 2004b). In living organisms, perfluoroalkyls bind to protein
albumin in blood, liver, and eggs and do not accumulate in fat tissue, which may explain why
bioconcentration factors (BCFs) are lower than expected in aquatic organisms (de Vos et al. 2008; Kissa
2001). The Arctic Monitoring and Assessment Programme December 2017 report contains a large
summary of environmental monitoring data for perfluoroalkyl substances in the Arctic (AMAP 2017).
Temporal trends indicated declining residues of PFOA in the liver of ringed seals at several Arctic
monitoring sites; however, PFNA and PFDA showed increasing levels at some locations and declining
levels at others (AMPA 2017). Declining levels of PFOA and PFOS were observed for polar bears in
Canadian Arctic and Greenland; however, total perfluoroalkyl levels remained relatively constant asprecursor substances appear to continue to be transported and degraded in the Arctic food web.
Moreover, newer perfluorinated substances such as perfluoroethylcyclohexane sulfonate (used inhydraulic fluids) and perfluorobutane sulfonamide (a PFBS precursor) have been detected in someenvironmental media.

Table 5-5. Biological Monitoring of PFOA and PFOS in the Arctic

Location and organism

Concentration (ng/g)
PFOA
PFOS

Northeastern Canada, 1996–2002; wet weighta
Zooplankton (n=5)
Clams (n=5)
Shrimp (n=7)
Arctic cod (n=6)
Redfish (n=7)
Walrus (n=5)
Narwhal (n=5)
Beluga (n=5)
Black-legged kittiwake (n=4)
Glaucous gulls (n=5)

2.6
ND
0.17
0.16
1.2
0.34
0.9
1.6
ND
0.14

Reference
Tomy et al. 2004

1.8
0.28
0.35
1.3
1.4
2.4
10.9
12.6
10.0
20.2

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-5. Biological Monitoring of PFOA and PFOS in the Arctic

Location and organism

Concentration (ng/g)
PFOA
PFOS

Northern Canada, 1992–2002a
Polar bear (n=7)
Arctic fox (n=10)
Ringed seal (n=9)
Mink (n=10)
Common loon (n=5)
Northern fulmar (n=5)
Black guillemot (n=5)
White sucker (n=3)
Brook trout (n=2)
Lake whitefish (n=2)
Lake trout (n=1)
Northern pike (n=1)
Arctic sculpin (n=1)
Northwestern Canada, 2004
Zooplankton (n=3)
Arctic cod (n=5)
Ringed seal (n=5)
Bearded seal (n=1)
Northern Norway; ng/g wet weighta
Herring gull eggs
Glaucous gulls
Eggs (n=10)
Plasma (n=20)
Nanavut, Canada
Thick-billed murresNorthern fulmars
Ringed seals

Reference
Martin et al. 2004a

8.6
<2
<2
<2
<2
<2
<2
<2
<2
<2
<2
<2
<2

3,100
250
16
8.7
20
1.3
ND
7.6
39
12
31
5.7
12
Powley et al. 2008

ND
ND
ND

ND–0.2
0.3–0.7
2.5–8.6
1.3
Verreault et al. 2005, 2007

<0.091–0.652

21.4–42.2<0.70<0.70–0.74

104
134
Butt et al. 2007a, 2007b<MDLb–0.16<MDLb–0.09<0.85–6.2

Northern Canada, 2002–2005
Ringed seal livers (n=110)<0.7–13.9
Greenland
Ringed seals<1.2
North American and European Arctic, 1999–2002
Polar bears (n>72)<2.3–57.1
Greenland, 1999–2001
Polar bears (n=29)a10
Greenland, 1972–2002
Polar bears
1.6–4.4
Arviat, 2010–2012
Ringed seal liver (n=28)
0.62±0.6<0.40–0.76<0.40–0.60
2–20
Butt et al. 2008
0.89–189
Bossi et al. 2005
12.5–95.6
Smithwick et al. 2005a
263–6,340
Smithwick et al. 2005b
2,470
Smithwick et al. 2006
120–1,400
AMAP 2017
No dataPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-5. Biological Monitoring of PFOA and PFOS in the Arctic

Location and organism
Pangnirtung, 2009–2011
Ringed seal liver (n=7)
Resolute, 2010–2013
Ringed seal liver (n=46)
Sachs Harbor, 2011–2013
Ringed seal liver (n=29)
Ulukhaktok, 2010–2013
Ringed seal liver (n=9)

Concentration (ng/g)
PFOA
PFOS

Reference
AMAP 20170.22±0.15

No data
AMAP 20170.23±0.16

No data
AMAP 2017

0.54±0.36

No data1.4±0.11

No data

AMAP 2017

aReported as mean values
bMinimum detection limits for study analytes ranged from 0.03 to 2.3 ng/g.

To calculate means, concentrations lessthan the MDL were replaced with a random value that was less than half the MDL.

MDL = minimum detection limit; ND = not detected; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonicacid

Sediment and Soil.

Koc values of 17–230 measured for PFOA in soils of various organic carbon

content indicate that PFOA will be mobile in soil and will not adsorb to suspended solids and sediment in
the water column (Davis et al. 2007; Prevedouros et al. 2006); rather, it tends to remain in solution andmigrate with groundwater (Davis et al. 2007). This is supported by the presence of PFOA in groundwaterat the Decatur, Cottage Grove, and Washington Works fluorochemical industrial facilities (3M 2007b,
2008b; Davis et al. 2007). Other sources of perfluoroalkyls in soil include air emissions followed byatmospheric deposition to soils and subsequent leaching (Davis et al. 2007). Low volatility, high watersolubility (9,500 mg/L at 25°C), and low sorption to solids indicate that the perfluorooctanoate anion willaccumulate in surface waters, especially oceans (Armitage et al. 2006; Kauck and Diesslin 1951;
Prevedouros et al. 2006; Wania 2007). McGuire et al. (2014) reported field-based Koc values for several
perfluoroalkyl substances (see Table 4-2).

Perfluoroalkyls can be taken up by plants in contaminated soils. Laboratory studies have suggested thatshort-chain perfluoroalkyls such as PFBA are more concentrated in edible portions of plants whencompared to longer carbon chain substances such as PFOA or PFOS (Blaine et al. 2013, 2014a, 2014b;
MDH 2014). Yoo et al. (2011) studied the accumulation of perfluoroalkyl carboxylic acids,
perfluorosulfonic acids, and fluorotelomer alcohols in grass samples collected near Decatur, Alabama andcalculated the grass-soil accumulation factor (GSAF), which is the concentration of perfluoroalkyl ingrass divided by the concentration of perfluoroalkyl in soil. The shortest chain compounds had the largest
GSAFs, and accumulation factors decreased rapidly with chain length. The mean (±SD) GSAF values

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5. POTENTIAL FOR HUMAN EXPOSURE

were 3.4±2.6, 0.90±0.66, 0.25±0.23, 0.12±0.08, 0.10±0.08, 0.11±0.09, and 0.10±0.09 for PFHxA,
PFHpA, PFOA, PFNA, PFDA, PFUnA, and PFDoDA, respectively. The GSAF for PFOS was
0.07±0.04. Increasing salinity and temperature was shown to increase uptake and transport from the roots
into the shoots by the wheat plants grown in hydroponic systems spiked with perfluorocarboxylic acids(Zhao et al. 2016). Transport into the shoots also increased with decreasing carbon chain length.
Concentrations in the shoots of the wheat plants increased in the following order: PFBA > PFHpA> PFOA > PFDoDA. Stahl et al. (2009) demonstrated that both PFOA and PFOS were taken up from soil
by five cultivated plants (spring wheat, oats, potatoes, maize, and perennial ryegrass) and the amount of
uptake was generally linearly dependent upon the concentration of PFOA or PFOS spiked to the soil.
Lysimeter studies suggested that PFOA and short-chain perfluoroalkyls such as PFBA pass through thesoil and get taken up by plants more quickly as compared to PFOS (Stahl et al. 2013).

Krippner et al. (2014) analyzed the uptake of perfluoroalkyl substances with chain length of C4–C10 overa pH range of 5–7. They observed that short-chain perfluoroalkyls partition predominantly and at higher
concentrations to the shoot. Longer-chain substances such as PFOA, PFNA, and PFDA, as well as
PFHxS and PFOS, accumulated at higher concentrations in the roots of maize plants. Maize grown in soil
pots containing perfluoroalkyls only accumulated compounds with a chain length ≤C8 in the kernels(Krippner et al. 2015).
Other Media.

Data are not available regarding the transport and partitioning of perfluoroalkyls in othermedia.
5.4.2

Transformation and Degradation

Perfluoroalkyls are considered to be environmentally persistent chemicals (EPA 2008a; OECD 2002,
2007; Schultz et al. 2003). The carbon atoms of the perfluoroalkyl chain are protected from attack by theshielding effect of the fluorine atoms; furthermore, environmental degradation processes generally do notpossess the energy needed to break apart the strong fluorine-carbon bonds (3M 2000; Hekster et al. 2003;
Schultz et al. 2003). Perfluoroalkyls are resistant to biodegradation, direct photolysis, atmosphericphotooxidation, and hydrolysis (OECD 2002, 2007; Prevedouros et al. 2006).
Air. Although transport and partitioning information indicates that air will not be a sink forperfluoroalkyls in the environment, low concentrations of perfluoroalkyl carboxylic acids, sulfonic acids,
and sulfonamides have been measured in air both in the vapor phase and as bound to particulates (Barton

PERFLUOROALKYLS

675
5. POTENTIAL FOR HUMAN EXPOSUREet al. 2007; Kim and Kannan 2007). Available information indicates that photodegradation will notcompete with wet deposition as an atmospheric removal process for perfluoroalkyls (Barton et al. 2007;
Hurley et al. 2004; Prevedouros et al. 2006). However, photooxidation may be an important degradation
mechanism for perfluoroalkyl sulfonamides (D'eon et al. 2006; Martin et al. 2006).

PFOA does not absorb UV light at environmentally relevant wavelengths (>290 nm); Hori et al. (2004a)
reported a weak absorption band for PFOA that ranged from 220 to 270 nm. Based on the measured
absorption wavelength of PFOA, perfluoroalkyl carboxylic acids are not expected to undergo direct
photolysis. Following irradiation of the potassium salt of PFOS with light of wavelength 290–800 nm for
67–167 hours, it was concluded that there was no evidence of direct photolysis of PFOS under any of thetest conditions (OECD 2002). Based on these test results for PFOS, perfluoroalkyl sulfonic acids are notexpected to undergo direct photolysis in the atmosphere.

A measured photooxidation rate constant is not available for PFOA. Hurley et al. (2004) measured thereaction of short-chain (C1–C4) perfluoroalkyl carboxylic acids with photochemically generated hydroxyl
radicals. The proposed mechanism begins with abstraction of the carboxyl hydrogen, which is followedby the removal of the carboxyl group and generation of a perfluoroalkyl radical. Finally, theperfluoroalkyl chain is broken down one carbon atom at a time through an unzipping sequence. The samerate constant, 1.69x10-13 cm3/molecule-second, was measured for the photooxidation of the C2, C3, andC4 molecules, indicating that the chain length may have little effect on the reactivity of perfluoroalkyls
with hydroxyl radical. According to the authors, this rate constant corresponds to a half-life of 130 days.
Based on the data for the short-chain structures, the authors concluded that atmospheric photooxidation of
perfluoroalkyl carboxylic acids is not expected to compete with wet and dry deposition, which ispredicted to occur on a time scale of the order of 10 days.

Atmospheric photooxidation data are not available for perfluoroalkyl sulfonic acids. Atmosphericphotooxidation studies involving n-methyl perfluorobutane sulfonamidoethanol (Me-FBSE) and n-ethyl
perfluorobutanesulfonamide (Et-FBSA) indicate possible mechanisms for the reaction of these substanceswith atmospheric hydroxyl radicals (D'eon et al. 2006; Martin et al. 2006). Products observed from thephotooxidation of these compounds indicate the following pathways: removal of an alkyl from the amide(cleavage of the N-C bond); removal of the amido group (cleavage of the S-N bond); and removal of thesulfonamido group (cleavage of the S-C bond) (D'eon et al. 2006; Martin et al. 2006). The last two
pathways indicate that FOSA may be photooxidized through removal of the amido or sulfonamido group.
The third pathway, cleavage of the S-C bond, also indicates a photooxidation mechanism forPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

perfluoroalkyl sulfonic acids. Martin et al. (2006) proposes an unzipping sequence for the perfluoroalkyl
chain following removal of the sulfonyl group.

Measured rate constants for the reaction of Me-FBSE and Et-FBSA with atmospheric hydroxyl radicals
are 5.8x10-12 and 3.74x10-13 cm3/molecule-second, respectively (D'eon et al. 2006; Martin et al. 2006).
Atmospheric half-lives calculated using these rate constants were 2 days for Me-FBSE and 20–50 daysfor Et-FBSA.
Water.

PFOS and PFOA are expected to be stable to hydrolysis in the environment based on half-livesof 41 and 92 years, respectively, calculated from experimental hydrolysis data that were measured at pH
5, 7, and 9 (OECD 2002, 2006b). Based on the data for PFOS and PFOA, hydrolysis is not expected to
be an important degradation process for perfluorinated carboxylates and sulfonates in the environment.
Hydrolysis data were not located for perfluoroalkyl sulfonamides.

Available information indicates that perfluoroalkyls are resistant to aerobic biodegradation. PFOA and
PFNA were not biodegraded using an Organisation for Economic Co-operation and Development(OECD) guideline (301F) manometric respirometry screening test for ready biodegradability; 0% of thetheoretical oxygen demand was reached after 28 days (Stasinakis et al. 2008). Meesters and Schröder(2004) reported that PFOA and PFOS were not degraded from an initial concentration of 5 mg/L in
aerobic sewage sludge in a laboratory scale reactor.

Substances such as fluorotelomer alcohols and perfluoroalkyl sulfonamides are degraded to othersubstances such as PFOA and PFOS in water and can be considered a source of these substances in theenvironment (Liu et al. 2007).
Sediment and Soil.

Data are not available regarding the transformation and degradation of

perfluoroalkyls in sediment and soil. Based on the chemical stability of these substances and theirresistance to biodegradation in screening tests, environmental degradation processes are not expected to
be important removal mechanisms for perfluoroalkyls in sediment and soil (3M 2000; EPA 2008a;
Hekster et al. 2003; OECD 2002, 2007; Prevedouros et al. 2006; Schultz et al. 2003).

Substances such as fluorotelomer alcohols and perfluoroalkyl sulfonamides are degraded to othersubstances such as PFOA and PFOS in soil and sediment and can be considered a source of thesesubstances in the environment (Liu et al. 2007; Washington and Jenkins 2015; Washington et al. 2015).

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Other Media.

Data are not available regarding the transformation and degradation of perfluoroalkyls

in other media.
5.5

LEVELS IN THE ENVIRONMENT

Reliable evaluation of the potential for human exposure to perfluoroalkyls depends, in part, on thereliability of supporting analytical data from environmental samples and biological specimens.
Concentrations of perfluoroalkyls in unpolluted atmospheres and in pristine surface waters are often so
low as to be near the limits of current analytical methods. In reviewing data on perfluoroalkyls levels
monitored or estimated in the environment, it should also be noted that the amount of chemical identified
analytically is not necessarily equivalent to the amount that is bioavailable.

Table 5-6 shows the limits of detection typically achieved by analytical analysis in environmental media.
An overview summary of the range of concentrations detected in environmental media is presented inTable 5-7.

Detections of perfluoroalkyls in air, water, and soil at NPL sites are summarized in Table 5-8.

Table 5-6. Lowest Limit of Detection Based on Standardsa
Media

Detection limit

Reference

Air
Drinking water
Surface water andgroundwater
Soil
Sediment
Whole blood
Serum

0.1 pg/m3
0.5–6.5 ng/L
0.2 ng/L

Harada et al. 2006
EPA 2009c (Method 537)
Nakayama et al. 2007

0.11–0.75 µg/kg (median reporting limits)
0.21–1.2 µg/kg (median reporting limits)
0.1–2 ng/mL
0.082–0.2 ng/mL

Anderson et al. 2016
Anderson et al. 2016
Kärrman et al. 2005
CDC 2015

aDetection limits based on using appropriate preparation and analytics.

situations.

These limits may not be possible in all

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-7. Summary of Environmental Levels of Perfluoroalkylsa
Media

Low

Highb

1.22
0.46

900,000
9.8

For more information

Outdoor air (pg/m3)
PFOA
PFOS
Indoor air (pg/m3)
PFOA
PFOS
Dust (ng/g)
PFOA
PFOS
Surface water (ppb)
PFOA
PFOS
Groundwater (ppb)
PFOA
PFOS
Drinking water (ppb)
PFOA
Ocean water (pg/L)
PFOA
PFOS
Food (ppb)
PFOA
PFOS
Soil (ppb)
PFOA
PFOS

Table 5-9

Table 5-10
4.4 (mean)<47.4 (mean)
Table 5-11
<2.29
<4.56

9,818
18,0710.00051<0.00008

598
8,970

0.083
0.0404619
4,300<0.0023~100

Tables 5-12, 5-14, 5-17

Tables 5-14, 5-17

EPA 2010
Table 5-1588
8

192,000
57,700
Fromme et al. 2007b

0.025
0.025

118.291.03<0.00017
0.0002140
9700

Tables 5-16, 5-17

aFor PFOA or PFOS only.
bHigh levels are representative of monitoring data at localized contaminated sites and are not reflective of

background environmental levels.

Table 5-8. Perfluoroalkyls Levels in Water, Soil, and Air of National Priorities List
(NPL) Sites

MediumPFOA
Water (ppb)
Soil (ppb)Mediana

Geometricmeana

Geometric
standard
deviationa

Number ofquantitative
measurements NPL sites

0.35
18,0500.25
18,050

6,064
1,000

5
2

4
2

Air (ppbv)

No data

PFOS
Water (ppb)

0.91

0.35

9,089

4

3

Soil (ppb)
Air (ppbv)

108,000

108,000

1,000
No data2

2

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-8. Perfluoroalkyls Levels in Water, Soil, and Air of National Priorities List
(NPL) Sites
Geometric
standard
deviationa

Number ofquantitative
measurements NPL sites

Mediana

Geometric
meana

2.15
1,600

1.03
1,600

28,1921,000
No data

3
2

3
2

0.05
224

0.02
224

6,770
1,000
No data

2
2

2
2

0.07
1,275

0.04
1,275

3,169
1,000
No data

3
2

2
2

0.25
1,175

0.10
1,175

8,444
1,000
No data2222Water (ppb)

0.26

1.12

52,4964

3

Soil (ppb)
Air (ppbv)

5,585

5,585

1,000
No data

2

2

27.2

27.2

No data
1,000
No data22Water (ppb)

0.18

0.11

3,465

3

3

Soil (ppb)
Air (ppbv)

178

178

1,000
No data2

2MediumPFBA
Water (ppb)
Soil (ppb)
Air (ppbv)

PFBS
Water (ppb)
Soil (ppb)
Air (ppbv)

PFHpA
Water (ppb)
Soil (ppb)
Air (ppbv)

PFHxA
Water (ppb)
Soil (ppb)
Air (ppbv)

PFHxS

PFNA
Water (ppb)
Soil (ppb)
Air (ppbv)

PFPeA

aConcentrations found in ATSDR site documents from 1981 to 2017 for 1,854 NPL sites (ATSDR 2017).

Maximum
concentrations were abstracted for types of environmental media for which exposure is likely. Pathways do notnecessarily involve exposure or levels of concern.

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

5.5.1

Air

Perfluoroalkyl levels have been measured in outdoor air at locations in the United States, Europe, Japan,
and over the Atlantic Ocean (Barber et al. 2007; Barton et al. 2006; Harada et al. 2005a, 2006; Kim andKannan 2007). Concentrations reported in these studies are provided in Table 5-9.
Mean PFOA levels ranged from 1.54 to 15.2 pg/m3 in air samples collected in the urban locations in
Albany, New York; Fukuchiyama, Japan; and Morioka, Japan and in the rural locations in Kjeller,
Norway and Mace Head, Ireland. Higher mean concentrations (101–552 pg/m3) were measured at theurban locations in Oyamazaki, Japan and Manchester, United Kingdom, and semirural locations inHazelrigg, United Kingdom. Maximum reported concentrations at Oyamazaki and Hazelrigg were
919 and 828 pg/m3, respectively. The authors attributed the elevated concentrations at the Hazelrigg
location to emissions from a fluoropolymer production plant located 20 km upwind of this semiruralcommunity.

Elevated levels of PFOA were observed in air samples collected along the fence line of the DuPont
Washington Works fluoropolymer manufacturing facility, which is located near Parkersburg, West
Virginia, in the Ohio River valley (Barton et al. 2006).

Table 5-9. Concentrations of Perfluoroalkyl in Outdoor Air

Location

Mean (range) concentration (pg/m3)
PFOA
PFHpA
PFNA

Reference

Urban
Albany, New YorkGas phase (n=8)

3.16 (1.89–6.53)

Particulate phase (n=8)

2.03 (0.76–4.19)

Oyamazaki, Japan (n=12)262.7 (72–919);
3,412.8 ng/g indust
15.2; 314 ng/g indust
2.0 (1.59–2.58)

Fukuchiyama, Japan
Morioka, Japan (n=8)
Manchester, United
Kingdom (n=2,1)a341, 15.7

0.26 (0.13–0.42)

0.21 (0.16–0.31)

Kim and
Kannan 2007
0.37 (<0.12–0.81) 0.13 (<0.12–0.40) Kim andKannan 2007——
Harada et al.
2005b
—

—

—

—

8.2, 0.2<26.6, 0.8

Harada et al.
2006
Harada et al.
2005b
Barber et al.
2007

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-9. Concentrations of Perfluoroalkyl in Outdoor Air
Rural
Kjeller, Norway (n=2)
Mace Head, Ireland (n=4)

1.54

0.87

0.12

8.9

<0.001<3.3

Hazelrigg, United Kingdom 101, 552b,c
1.6, 14.4b(semi-rural) (n=10)
Marine air
Near Europe (northwest)
1.22 (0.5–2.0)<0.6 (ND–<0.6)(n=3)
Near Africa (east coast)<0.5 (ND–0.7)
ND(n=5)
Source dominated
DuPont Washington Works 430,000 (75,000– —Facility; Parkersburg, West 900,000)d
Virginia (n=28)
DuPont Washington Works 5,500 (10–75,900) —Facility; Parkersburg, West
Virginia (n=90)

0.9

0.3 (ND–0.5)<0.2 (ND–0.3)

Barton et al.
2006—

EPA 2007b

Location
Urban
Albany, New YorkGas phase (n=8)

0.63 (0.24–1.56)<0.12 (ND–0.16)

Particulate phase (n=8)

0.27 (0.13–0.49)

ND

Oyamazaki, Japan (n=12)——

Fukuchiyama, Japan——

Morioka, Japan (n=8)——

5.4, <0.8<0.01, <0.4

<0.15

<0.12

<0.12

<2.8

<0.002<0.0030.7<0.01

Mace Head, Ireland (n=4)

Hazelrigg, United Kingdom 1.0, 8.3b
(semi-rural) (n=10)

Jahnke et al.
2007aJahnke et al.
2007a

—

Mean (range) concentration (pg/m3)
PFDA
PFUnA
PFDoDA

Manchester, United
Kingdom (n=2,1)aRural
Kjeller, Norway (n=2)

Barber et al.
2007
Barber et al.
2007
Barber et al.
2007

Reference

0.27 (0.14–0.43)

Kim and
Kannan 2007
0.12 (<0.12–0.38) Kim andKannan 2007—
Harada et al.
2005b—Harada et al.
2006—
Harada et al.
2005b<0.01, <0.01
Barber et al.
2007
Barber et al.
2007
Barber et al.
2007
Barber et al.
2007

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-9. Concentrations of Perfluoroalkyl in Outdoor Air
Marine air
Near Europe (northwest)<0.6 (ND–0.6)(n=3)
Near Africa (east coast)
ND(n=5)
Source dominated
DuPont Washington Works —Facility; Parkersburg, West
Virginia (n=28)
DuPont Washington Works —Facility; Parkersburg, West
Virginia (n=90)ND<0.14 (ND–0.17)

0.03 (ND–0.2)

ND

—

—

Barton et al.
2006

—

—

EPA 2007b

Location

Mean (range) concentration (pg/m3)
PFOS
PFBS
PFHxS
FOSA

Urban
Albany, New YorkGas phase (n=8)

1.70 (0.94–3.0)—

Particulate phase (n=8)

0.64 (0.35–1.16) —Oyamazaki, Japan (n=12)

5.2 (2.51–-9.80); —72.2 ng/g in dust
2.2; 46.0 ng/g in —dust
0.7 (0.46–1.19) —Fukuchiyama, Japan
Morioka, Japan (n=8)
Manchester, United
Kingdom (n=2,1)aRural
Kjeller, Norway (n=2)

0.31 (0.13– 0.67 (0.22–
0.44)
2.26)
<0.12
0.29 (<0.12–
0.79)
—
—
—

—

—

—

46, 7.1

2.2, <1.6

1.0, 0.1<1.6, <0.2

1.0

<0.09

0.05

0.78

<1.8

<1.0

0.07

<0.56

Hazelrigg, United Kingdom 1.6
2.6(semi-rural) (n=10)
Marine air
Near Europe (north west) 1.36 (0.4–2.5)
ND(n=3)
Near Africa (east coast)
0.544 (0.05–1.9) ND
(n=5)

0.04

0.2

Mace Head, Ireland (n=4)

0.12 (0.02– ND
0.3)
0.013 (ND– ND
0.05)

Jahnke et al.
2007aJahnke et al.
2007aReference

Kim and
Kannan 2007
Kim and
Kannan 2007
Harada et al.
2005bHarada et al.
2006
Harada et al.
2005b
Barber et al.
2007
Barber et al.
2007
Barber et al.
2007
Barber et al.
2007
Jahnke et al.
2007aJahnke et al.
2007a

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-9. Concentrations of Perfluoroalkyl in Outdoor Air
Source dominated
DuPont Washington Works —Facility; Parkersburg, West
Virginia (n=28)
DuPont Washington Works —Facility; Parkersburg, West
Virginia (n=90)

—

—

—

Barton et al.
2006

—

—

—

EPA 2007b

aMean values were reported for separate sampling sessions.
bThe second concentration reported was measured during an earlier sampling session (n=2).
cA maximum PFOA concentration of 828 pg/m3 was measured in air at Hazelrigg, United Kingdom.
dAverage and range of concentrations in 6 out of 28 samples that contained PFOA.

“—“ indicates no available data; FOSA = perfluorooctane sulfonamide; ND = not detected; PFBS = perfluorobutane
sulfonic acid; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoicacid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid

The reported concentrations in these samples ranged from 75,000 to 900,000 pg/m3. The highest
concentrations were measured at locations downwind of the facility. High volume air samples collected
at several monitoring stations near the Washington Works facility contained PFOA at reported
concentrations ranging from 10 to 75,900 pg/m3 (EPA 2007b). The mean and median of these reported
concentrations are 5,500 and 240 pg/m3, respectively.

PFOS was detected above quantitation limits in most of the studies, but concentrations were generally
below 5 pg/m3. A concentration of 46 pg/m3 was reported in samples from Manchester, United Kingdom.
Reported concentrations of other perfluoroalkyls (PFHpA, PFNA, PFDA, PFUnA, PFDoDA, PFBS,PFHxS, and FOSA) were generally <1 pg/m3 in these studies. PFHpA was detected at slightly higher
concentrations (8.2 and 14.4 pg/m3) at Manchester and Hazelrigg, United Kingdom, respectively.

Jahnke et al. (2007a) collected eight marine air samples during a cruise between Germany and South
Africa (53°N to 33°S). Perfluoroalkyl concentrations steadily declined as the sampling moved further
from Europe and toward less industrialized regions. Only PFOS was detected in the two samples
collected over the Atlantic Ocean east of southern Africa.

Measurements of perfluoroalkyls in snow samples collected from Canadian Arctic ice caps suggest thatvolatile precursors, such as fluorinated telomer alcohols, may oxidize in the atmosphere at these locations(Young et al. 2007). Reported concentrations in these snow samples were 2.6–86 pg/L for PFOS, 12–
147 pg/L for PFOA, 5.0–246 pg/L for PFNA, <8–22 pg/L for PFDA, and <6–27 pg/L for PFUnA.

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5. POTENTIAL FOR HUMAN EXPOSURE

The concentration of PFOS measured in rainwater collected during a rain event in Winnipeg, Manitoba
was 0.59 ng/L (Loewen et al. 2005). PFOA, PFNA, PFDA, PFUnA, and PFDoDA were not detected in
the rainwater. Reported method detection limits for these compounds were 7.2, 3.7, 1.7, 1.2, and
1.1 ng/L, respectively.

Studies of perfluoroalkyl concentrations in indoor environments are available. The reported mean
concentrations of perfluoroalkyls measured in four indoor air samples collected from Tromso, Norway(Barber et al. 2007) are presented in Table 5-10.

Table 5-10. Concentrations of Perfluoroalkyl in Indoor Aira
Mean concentration (pg/m3)
PFOA
PFHpA
PFNA
PFDA
PFUnA
PFDoDA
PFOS
PFBS
PFHxS
FOSA

4.4
0.8
2.7
3.4
<1.3
1.2
<47.4
<0.5
<4.1
2.8

aSamples (n=4) collected in Tromso, Norway in May–June 2005.

FOSA = perfluorooctane sulfonamide; PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoic acid;
PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid;
PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid;PFUnA = perfluoroundecanoic acid
Source: Barber et al. 2007

Several studies have measured perfluoroalkyl levels in indoor dust samples (Table 5-11). Kubwabo et al.
(2005) measured the concentrations of selected perfluoroalkyls in dust samples from 67 Canadian homes.
PFOA, PFOS, and PFHxS were each detected in 37, 33, and 15% of these samples, respectively(detection limits of 2.29, 4.56, and 4.56 ng/g, respectively). FOSA was only detected above 0.99 ng/g in
10% of the samples and PFBS was not detected in any of the samples. Moriwaki et al. (2003) measured
PFOS and PFOA concentrations in vacuum cleaner dust samples collected from 16 Japanese homes.
PFOS and PFOA were detected in every sample with reported concentrations of 11–140 and 69–380 ng/g,
respectively, in 15 of the 16 samples. One of the samples contained 2,500 ng/g PFOS and 3,700 ng/g
PFOA. The geometric means of PFOA and PFOS in pooled indoor air sample meta data analysis werePERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

reported as 37.34 and 38.91 ng/g, respectively (Mitro et al. 2016). Precursor substances present in dust
can be biotransformed to perfluoroalkyl substances and may be a further source of human exposure.
Fluorotelomer alcohols were detected in hotel dust in China at levels ranging from 24.8 to 678 ng/g (Yaoet al. 2018). Makey et al. (2017) reported precursor substances such as dipolyfluoroalkyl phosphates(diPAPs), fluorotelomer alcohols, perfluorooctyl sulfonamides, and sulfonamidoethanols in airborne anddust samples.

Table 5-11. Concentrations of Perfluoroalkyls in Indoor Dust
Location

Concentration (ng/g): mean (range); median
PFOA
PFHpA
PFNA

Ottawa, Canada (n=67)

106.00 (<2.29– —
1,234); 19.72a
Japan (n=16)
380 (70–3,700); —165
North Carolina and Ohio
296 (<10.2–
109 (<12.5–1,150);(n=112)
1,960); 142b
50.2b
United Kingdom, Australia, 96.5 (9,818)
97.3 (5,195)
German, and UnitedStates (n=39)c
Stockholm, Swedend—
Houses (n=10)
54 (15–98)
Apartments (n=38)
93 (17–850)
Daycare centers (n=10) 41 (31–110)
Offices (n=10)70 (14–510)
Cars (n=5)
33 (12–96)——

Kubwabo et al.
2005
Moriwaki et al. 2003

22.1 (<11.3–
263); 7.99b<LOQ (832)

Strynar andLindstrom 2008
Kato et al. 2009a—

Björklund et al.
2009

Location

Concentration (ng/g): mean (range) median
PFDA
PFUnA
PFDoDA

Ottawa, Canada (n=67)—

Japan (n=16)—
North Carolina and Ohio
15.5 (<9.40–(n=112)267); 6.65b
United Kingdom, Australia, <LOQ (1,965)
German, and UnitedStates (n=39)c
Stockholm, Swedend—

Reference———
30.4 (<10.7–588);
7.57b<LOQ (732)—18.0 (<11.0–
520); 7.78b<LOQ (1,048)——

Reference
Kubwabo et al.
2005
Moriwaki et al. 2003
Strynar andLindstrom 2008
Kato et al. 2009aConcentration (ng/g): mean (range); median
PFOS
PFBS
PFHxS
FOSA

Reference

Ottawa, Canada (n=67)

443.68 (<4.56– NDa
5,065); 37.8a<0.99aKubwabo et al.
2005

Japan (n=16)

200 (11–2,500); 24.5
761 (<8.93–
12,100); 201b—

Moriwaki et al. 2003

Location

North Carolina and Ohio(n=112)—391.96(<4.56–4,305); 23.1a—

41.7 (<12.5– 874 (<12.9– —
1,150); 9.11b 35,700); 45.5b

Strynar andLindstrom 2008

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Table 5-11. Concentrations of Perfluoroalkyls in Indoor Dust
United Kingdom, Australia, 479.6 (18,071) 359.0 (7,718) 185.5
German, and United(43,765)
States (n=39)c
Stockholm, Swedend——
Houses (n=10)
39 (15–120)
Apartments (n=38)
85 (8–1,100)
Daycare centers (n=10) 31 (23–65)
Offices (n=10)110 (29–490)
Cars (n=5)
12 (8–33)<LOQ(18.4)

Kato et al. 2009a—

Björklund et al.
2009

aMethod detection limits (MDL) and percent below MDL are as follows: PFOA (2.29 ng/g, 37%), PFOS (4.56 ng/g,33%), PFBS (1.38 ng/g, 100%), PFHxS (4.56, 15%), and FOSA (0.99 ng/g, 90%).
PFHpA (12.5 ng/g, 74.1%), PFOA (10.2 ng/g, 96.4%), PFNA
(11.3 ng/g, 42.9%), PFDA (9.40 ng/g, 30.4%), PFUnA (10.7 ng/g, 36.6%), PFDoDA (11.0 ng/g, 18.7%), PFOS
(8.93 ng/g, 94.6%), PFHxS (12.9 ng/g, 77.7%), PFBS (12.5 ng/g, 33.0%). Values below the LOQ were assigned avalue of LOQ/1.412 when calculating the median and mean.
cReported values are the 50th percentile and (maximum) values; all minimum values were <LOQ.
dReported values are the median and range.
bLOQ and percent above LOQ are as follows:“—“ indicates no available data; FOSA = perfluorooctane sulfonamide; LOQ = limit of quantification; ND = notdetected; PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoicacid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluorundecanoic acid

Strynar and Lindstrom (2008) measured perfluoroalkyl levels in 112 indoor dust samples collected fromhomes and daycare centers in North Carolina and Ohio. These authors detected PFHpA, PFOA, PFNA,
PFDA, PFUnA, PFDoDA, PFOS, PFHxS, and PFBS. PFOS and PFOA were detected in 94.6 and 96.4%
of the samples, respectively. Maximum detections in the samples were as high as 12,100 ng/g for PFOS
and 35,700 ng/g for PFHxS. Household dust samples collected from the United Kingdom, Australia,
Germany, and the United States showed the presence of perfluoroalkyls (Kato et al. 2009a). PFOS,
PFBS, and PFHxS were detected in 74.4, 92.3, and 79.5% of the samples, respectively, whereas PFOA,PFNA, and PFDA were detected in 64.1, 25.6, and 38.5% of the samples, respectively. Björklund et al.
(2009) measured PFOA and PFOS in dust samples collected in houses, apartments, daycare centers,
offices, and cars in Sweden. PFOA and PFOS were detected in 100 and 79% of the apartment samples
and in 100 and 60% of the car samples. The authors concluded that while dietary intake was the major
PFOA/PFOS exposure pathway for adults and toddlers in the general population, dust ingestion could
become an important pathway under a worst-case scenario (e.g., high dust ingestion and maximum dustlevels).

Perfluoroalkyls in indoor and outdoor environments in urban, suburban, and rural locations near Toronto,
Ontario, Canada were assessed using window films for passive sampling. The sum of perfluoroalkyls
concentrations on outdoor window films ranged from 0.04 to 0.75 pg/cm2 in winter and from 0.04 toPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

0.92 pg/cm2 in summer, with higher values found in urban and suburban locations than in rural locations.
Indoors, concentrations on window film ranged from less than the detection limit (which ranged from
0.033 to 0.06 pg/cm2) to 2.1 pg/cm2 in winter and from 0.08 to 4.3 pg/cm2 in summer, although there were
no distinct trends between urban and rural for indoor concentrations (Gewurtz et al. 2009).

5.5.2

Water

PFOS and PFOA have been widely detected in surface water samples collected from various rivers, lakes,
and streams in the United States (Boulanger et al. 2004; DRBC 2013; Kannan et al. 2005; Kim andKannan 2007; Nakayama et al. 2007; Simcik and Dorweiler 2005; Sinclair et al. 2004, 2006). Levels ofthese substances in surface water appear to be declining since the phase out of these two substances.
Zhang et al. (2016) measured surface water levels of perfluoroalkyls in 2014 at 37 sites across thenortheastern United States. Detectable levels of PFOA and PFNA were found at all sites, and PFHxS,PFOS, and PFDA were detectable at >90% of the sites. The respective maximum concentrations of
PFOA, PFOS, PFHxS, and PFNA were 56 ng/L measured in the Passaic River, New Jersey, 27.5 ng/L
measured in the Woonasquatucket River, Rhode Island, 43 ng/L measured at Mill Cove, Rhode Island,and 14 ng/L measured at Mill Cove, Rhode Island (Zhang et al. 2016).

Less data are available regarding the concentrations of other perfluoroalkyls in surface water. PFHpA
and PFHxS were commonly detected in the few studies that analyzed surface water for these compounds(DRBC 2013; Kim and Kannan 2007; Nakayama et al. 2007; Simcik and Dorweiler 2005).
Concentrations of PFOA and PFOS measured in surface water are presented in Table 5-12 and otherperfluoroalkyls are summarized in Table 5-13. Maximum concentrations of PFOS, PFOA, PFHpA,
PFNA, PFDA, PFUnA, PFDoDA, PFBS, and PFHxS measured in surface water collected from the Cape
Fear Basin, North Carolina were 287, 132, 329, 194, 120, 52.1, 4.46, 9.41, and 35.1 ng/L, respectively(Nakayama et al. 2007). Much higher concentrations of PFOS (198–1,090 ng/L) have been measured in
Onondaga Lake in Syracuse, New York (Sinclair et al. 2006). Onondaga Lake is a Superfund site that has
become contaminated through industrial activity along its banks.

Table 5-12. Concentrations of PFOA and PFOS in Surface Water (ng/L)

Location

PFOA

Concentration
PFOS

Great Lakes
Lake Ontario (n=8)

Reference
Boulanger et al. 2004

15–70

6–121

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-12. Concentrations of PFOA and PFOS in Surface Water (ng/L)

Location

PFOA

Lake Erie (n=8)
New York State waters
Lake Ontario (n=13)
Niagara River (n=3)
Lake Erie (n=3)
Finger Lakes (n=13)
Onondaga Lake (n=3)

21–47

Oneida Lake (n=1)
Erie Canal (n=3)
Hudson River (n=8)
Lake Champlain (n=4)
Albany, New York
Lake water (n=11)
Surface water runoff (n=14)

Reference

11–39
Sinclair et al. 2006

18–34
18–22
13–27
11–20
39–64
19
25–59
22–173(median=35)
10–46

2.9–30
3.3–6.7
2.8–5.5
1.3–2.6
198–1,090(median=756)
3.5
5.7–13
1.5–3.4
0.8–7.7
Kim and Kannan 2007

3.27–15.8(median=7.20)
0.51–29.3(median=3.80)
56 (maximum)
3.5 (median)

New York/New Jersey/Rhode Island
metropolitan region
Michigan water regions
Detroit (n=10)<8–16.14
Flint (n=4)<8–23.01
Saginaw Bay (n=5)<8–24.08
Northeastern Michigan (n=2)<8Upper Peninsula (n=7)<8–13.77
Northwestern Michigan (n=2)
11.96Western Michigan (n=6)<8–15.17
Southwestern Michigan (n=5)
8.74–35.86
Lansing (n=3)<8–13.37
Minnesota Waters and Lake Michigan
Remote (n=4)
LoitenLittle Trout
Nipisiquit
Tettegouche
Urban (n=4)
CalhounLake Harriet
Lake of the Isles

Concentration
PFOS

ND–9.30(median=2.88)<0.25–14.6(median=0.81)
27.5 (maximum)
0.96 (median)

Zhang et al. 2016
Sinclair et al. 2004

<0.08–6.13
1.50–12.31
3.10–12.69
0.87–6.34<0.8–3.09<0.8–4.48<0.8–5.32
7.22–29.26
1.04–4.96
Simcik and Dorweiler
2005

0.7
0.3
0.1
0.5

ND
1.2
ND
0.2

20
3.5
0.5

47
21
2.4

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-12. Concentrations of PFOA and PFOS in Surface Water (ng/L)
Concentration
PFOS

Location

PFOA

Minnesota River
Lake Michigan (n=4)
Cape Fear Basin, North Carolina
80 Sites (n=100)
MeanMedianMinimum
Maximum
Percent not detecteda
Raisin and St. Clair Rivers, Michigan
Raisin River
St. Clair River (n=3)

1.2<0.6–0.5

14.7
4.0–5.0

3.5
1.9–3.9

Conasauga River, Georgia

253–1,150

192–318

Konwick et al. 2008

Dalton, Georgia

49.9–299

15.8–120

Konwick et al. 2008

Tidal Delaware River (six locations)
2007
2008
2009
Several rivers in Japan
Lake Victoria Gulf, Kenya

Nakayama et al. 2007
43.4
12.6
ND
287
7.6

31.2
28.9
<1
132
0
Kannan et al. 2005

DRBC 2013
3.54–75.40
3.99–48
3.29–27.7
0.1–67,000
0.4–96.4 (rivers)
0.4–11.6 (lakes)
1–1,270

River Po, Italy

Reference

9
1–3.2

2.70–8.42
3.53–11.7
2.86–7.97
0.3–59Harada and Koizumi
2009<0.4–13.23 (rivers); Orata et al. 2009
<0.4–2.53 (lakes)
1–25
Loos et al. 2008

aDetection limit is 0.05 ng/L

ND = not detected; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

Table 5-13. Concentrations of Other Perfluoroalkyls in Surface Water
Location(reference)a

PFHpA

PFNA

PFDA

Great Lakes (Boulanger et al. 2004)
Lake Ontario —
—
—
(n=8)
Lake Erie
—
—
—
(n=8)
New York State waters (Sinclair et al. 2006)
Onondaga———
Lake (n=3)

Concentration (ng/L)
PFUnA PFDoDA PFBS

PFHxS

FOSA

—

—

—

—

—

—

—

—

—

—

—

—

—

4.2–8.5—

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-13. Concentrations of Other Perfluoroalkyls in Surface Water
Location(reference)a

PFHpA

PFNA

PFDA

Concentration (ng/L)
PFUnA PFDoDA PFBS

PFHxSErie Canal
—
—
—
—
—
—
2.5–5.6(n=3)
Other lakes —
—
—
—
—
—
0.5–2.8
and rivers
Albany, New York (Kim and Kannan 2007)
Lake water 1.15–12.7 ND–3.51 0.25–3.58 ND–1.45 ND–<0.25 —<0.25–(n=11)
4.05
Surface<0.25–<0.25–
ND–8.39 ND–1.99 ND–1.60 —ND–13.5
water runoff 6.44
5.90
(n=14)New York/New Jersey/Rhode Island metropolitan region (Zhang et al. 2016)
48.2
14 (max); 5.8 (max); 1.9 (max); 2.6 (max); 6.2 (max); 43 (max);(max); 0.9 0.4
0.2
0.1
0.0
0.4
0.7
(median) (median) (median) (median) (median) (median) (median)Minnesota waters and Lake Michigan (Simcik and Dorweiler 2005)
Remote(n=4)
Loiten
10
ND
ND
—
—
—
—
Little Trout 4.8
ND
ND
—
—
—
—
Nipisiquit
0.9
<0.3
ND
—
—
—
—
Tettegouche 3.1
ND
ND
—
—
—
—
Urban (n=4)———
Calhoun
11
0.6
0.5
—
—
—
—
Lake Harriet 2.6
ND
ND
—
—
—
—
Lake of the 0.4
ND
ND
—
—
—
—
Isles
Minnesota 0.7
1.9
ND
—
—
—
—
River
Lake
<0.6–4.1 <0.6–3.1 ND————
Michigan(n=4)
Cape Fear Basin, North Carolina (Nakayama et al. 2007)
80 Sites(n=100)
Mean
38.7
33.6
22.1
10.4
2.17
2.58
7.29
Median
14.8
5.70
13.2
5.67
1.95
2.46
5.66
Maximum
329
194
120
52.1
4.46
9.41
35.1
Percent not 32.9
10.1
15.2
17.7
53.2
38.0
45.6
detectedb
Raisin and St. Clair Rivers, Michigan (Kannan et al. 2005)
Raisin River —
—
—
—
—
—
<1
St. Clair
—
—
—
—
—
—
<1
River (n=3)

FOSA
—
—

ND–0.47
ND–2.14

—

—
—
—
—
—
—
—
—
—
—

—
—
—
—

<10
<10

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-13. Concentrations of Other Perfluoroalkyls in Surface Water
Location(reference)a

PFHpA

PFNA

PFDA

Concentration (ng/L)
PFUnA PFDoDA PFBS

PFHxS

FOSA

Delaware River (6 locations) (DRBC 2013)
2007

ND–24.30 1.71–976 ND-9.97

ND-26

ND

—

ND-4.48ND

2008

2.03–16.3 3.24–650 ND-5.25

ND-11.8

ND—

BD-3.55

ND

2009

1.14–47.4 1.65–546 ND-1.75

ND-8.3ND—

ND-3.62

ND

aSee Table 5-12 for numbers of samples collected at these locations.
bDetection limit = 0.05 ng/L.

“—“ indicates no available data; ND = not detected; FOSA = perfluorooctane sulfonamide; PFBS = perfluorobutane
sulfonic acid; PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoicacid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFUnA = perfluoroundecanoic acid

Higher levels of perfluoroalkyls are expected in surface water and groundwater surrounding
perfluorochemical industrial facilities. Paustenbach et al. (2007) estimated PFOA concentrations inenvironmental media for communities located near the DuPont Washington Works chemical
manufacturing facility. From this analysis, the authors concluded that much of the PFOA detected ingroundwater near the facility was attributed to deposition to soil surfaces following atmosphericemissions from the plant followed by subsequent leaching into groundwater. DuPont entered into anagreement with the EPA to collect monitoring data for PFOA in the Ohio River around the DuPont
Washington Works facility. In its final phase III assessment, it was reported that levels of PFOA
downstream from the facility in 2011 were about an order of magnitude lower than when monitoring
began in 2002, while levels upstream essentially remained unchanged (URS 2012). The maximum
concentration measured in 2011 was 200 ng/L and was obtained from a monitoring location adjacent tothe site.

PFOA, PFOS, PFBA, PFHxS, and PFBS have been detected in the municipal drinking water ofcommunities located near the 3M Cottage Grove fluorochemical facility (ATSDR 2008). Xiao et al.
(2015) summarized soil and groundwater monitoring data of select perfluoroalkyls near this facility.
Groundwater samples for PFBA, PFHxA, PFOA, PFHxS, and PFOS in wells surrounding the site
obtained from 2009 to 2013 showed little or no change in concentration over this time period, eventhough 3M had stopped producing perfluoroalkyls at this facility in 2002. Levels in groundwater wereshown to decrease exponentially with distance from the source. A measured PFOA concentration of
approximately 20,000 ng/L was observed from a well near the historical unlined disposal site of thisPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

facility, but levels decreased to <100 ng/L measured at a distance of 1.4 km away. Some other examples
are provided in Table 5-14.

Table 5-14. Concentrations of Perfluoroalkyls in Surface Water and Groundwaterat Fluorochemical Industrial Facilities

Location

Percent detection and concentration (µg/L)
PFOA
PFBA PFOS
PFHxS PFBS

DuPont Washington Works Facility, West Virginia
Groundwater
Borings (n=18)
Percent detected
89%a
—
—
a
Minimum
0.0912——
Maximum
78a——
Wells (n=14)
Percent detected
100%aMinimum
0.081aMaximum
37.1a
Wells (n=3)
Percent detected
100%
Minimum
2.8
Maximum
100
Surface water
Outlets (n=4)
Percent detected
100%
Minimum
2.3
Maximum
61
3M Cottage Grove Facility, Minnesota
Groundwater
Wells (n=1–7)
Percent detected
100%
Minimum
24.6
Maximum
619
Surface water
East and West Cove (n=3–9)
Percent detected
100%
Minimum
0.172
Maximum
2.79
Mississippi River Shoreline (n=52–80)
Percent detected
60%
Maximum
0.760

Davis et al. 2007
—
—
—

—
—
—

—
—
—

—
—
—
—
—
—
—
—

—
—
—
—
—
—
—
—

—
—
—
—
—
—
—
—

—
—
—

—
—
—

—
—
—

—
—
—

100%
23.3
318

100%
26.0
26.0

100%
6.47
40.0

100%
2.11
26.1

—
—
—

Reference

Davis et al. 2007

EPA 2008d

EPA 2008d

3M 2007b

3M 2007b
100%
0.803
1.01

100%
0.227
3.12

100%
0.0936
4.58

78%
0.304
9.69

52%
6.92

43%
0.539

28%
1.04

56%
3.05

3M 2007b

PERFLUOROALKYLS

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Table 5-14. Concentrations of Perfluoroalkyls in Surface Water and Groundwaterat Fluorochemical Industrial Facilities

Location

Percent detection and concentration (µg/L)
PFOA
PFBA PFOS
PFHxS PFBS

Mississippi River Transect (n=34–44)
Percent detected
14%
12%
Maximum
0.0501
0.05303M Decatur Facility, Alabama
Groundwater
Off-site groundwater (n=18)
Percent detected
94%
—
Mean
1.87
—
Range
0.083–19.8 —Off-site groundwater
Range
Groundwater range (n=51)

Reference
3M 2007b

0%
ND

0%
ND

0%
ND

3M 2008c
—
—
—

—
—
—

—
—
—
3M 20100.0404–2.41

0.0396–0.622

0.0615–0.480

0.149–6.41 0.0104– 0.012–
1.26
0.151

0.0127–0.08750.0101–0.0766

Lindstrom et al.
2011

Surface water
On-site surface water (n=7)
Percent detected
100%—Median2.66—
Range
0.32–127 —Off-site surface water (n=60)
Percent detected
98%
—
Range
0.026–27.7 —Tennessee River
Upstream of facility (n=19)
Percent detected
0%
—
Range
<25
—
Downstream of facility (n=21)
Percent detected
0%—Median355—
Range<25–598—

3M 2008c
—
—
—

—
—
—

—
—
—
3M 2008c

—
—

—
—

—
—
Hansen et al.
2002

100%
—
16.8–52.6 —
—
100%
—
107
—
30.3–144 —

—
—
—
—
—
—

aAnalyte was reported as APFO.

“—“ indicates no available data; APFO = ammonium perfluorooctanoate; ND = not detected; PFBA = perfluorobutanoicacid; PFBS = perfluorobutane sulfonic acid; PFHxS = perfluorohexane sulfonic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acidGroundwater sampling of PFOA and PFOS was conducted at 401 military installations (DoD 2018). The
PFOS/PFOA levels exceeded EPA’s lifetime health advisories of 70 ppt at 22% of the installations (9/64
Army, 40/127 Navy/U.S. Marine Corp, 39/203 Air Force, and 2/7 Defense Logistics Agency

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

installations). The PFOS/PFOA levels exceeded the EPA lifetime health advisories in 1,621 of the2,668 groundwater wells sampled (61%).

Yamashita et al. (2005) measured PFOA, PFOS, PFNA, and PFHxS concentrations in ocean watercollected from locations in the Atlantic Ocean, Pacific Ocean, and areas near China, Korea, and Japan.
These concentrations are listed in Table 5-15. Wei et al. (2007a) measured perfluoroalkyl concentrations
in surface seawaters from the western Pacific Ocean, Indian Ocean, and near-Antarctic region. PFOS andPFOA were detected in 60 and 40% of the samples, respectively, with maximum concentrations of
71.7 and 441.6 pg/L, respectively. Concentrations of other perfluoroalkyls (PFHxS, PFBS, PFDoDA,
PFDA, PFNA, PFHpA) were generally below detection in most samples, with the exceptions being insamples collected near Shanghai, the Philippines, and Indonesia. Maximum concentrations of theseperfluoroalkyls ranged from 3.1 to 70.2 pg/L near Shanghai. PFOA, PFOS, and other perfluoroalkyl
species were monitored in waste water effluents and 20 rivers located in Japan (Murakami et al. 2008).
Perfluoroalkyls were ubiquitous in the river water samples, with concentrations of PFOA as large as
0.054–0.192 µg/L in seven of the river samples with low waste water effluent sources.

Table 5-15. Concentrations of PFOA and PFOS in Ocean Watera

Location

PFOA

Concentration (pg/L)
PFOS
PFNA

North Atlantic (n=9)
Mid Atlantic (n=7)
Central to Eastern Pacific (n=14)
Western Pacific (n=2)
Tokyo Bay (n=8)

160–338
100–439
15–62
136–1421,800–192,000

8.6–3637–73
1.1–20
54–78
338–57,700

15–36—
1.0–16—
163–71,000

4.1–6.1
2.6–12
0.1–1.6
2.2–a2.8
17–5,600

Offshore Japan (n=4)
Coastal Hong Kong (n=12)
Coastal China (n=14)
Coastal Korea (n=10)
Sulu Sea (n=5)
South China Sea (n=2)

137–1,060
673–5,450
243–15,300
239–11,350
88–510
160–420

40–75
70–2,600
23–9,680
39–2,530<17–109
8–113—
22–207
2.0–692
15–518——

3.0–6.1<5–311<5–1,360<5–1,390
<0.2
<0.2

PFHxS

aIncludes samples of coastal and open ocean water.

“—“ indicates no available data; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid
Source: Yamashita et al. 2005

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The presence of PFOA and PFOS in surface water in the United States indicates that drinking water takenfrom these sources may contain detectable levels of these substances. The most vulnerable drinking water
systems are those in close proximity to sites that are contaminated with perfluoroalkyls. PFOA wasdetected in 12 out of 13 samples collected from four municipal drinking water treatment plants that draw
water from the Tennessee River and are located downstream from the 3M Decatur Facility in Alabama.
Reported concentrations ranged from 0.025 to 0.16 μg/L (3M 2008c). PFOA was not detected in any
samples collected from a fifth plant located upstream of the 3M Decatur facility (3M 2008c). Sampling
conducted in October 2015 continued to show a presence of perfluoroalkyls in water samples collected atnine sites along the Tennessee River near Decatur, with maximum PFOS, PFBS, and PFOA levels
reported as 0.220, 0.160, and 0.120 μg/L, respectively (Newton et al. 2017). Waterways adjacent to areas
where aqueous film forming foams (AFFFs) used to fight fires have been shown to have high levels ofperfluoroalkyls. For example, a PFOS concentration of 2,210 μg/L was detected in the Etobicoke Creek,
Canada following the use of AFFF at the Toronto Pearson Airport (D’agostino and Mabury 2017). The
vertical distribution of 15 perfluoroalkyl substances was studied in concrete samples obtained from alocation in which AFFFs were used in firefighter training (Baduel et al. 2015). At the surface of theconcrete pad, PFOS was observed to be the dominant substance measured; however, shorter-chain
compounds were observed to a depth of 12 cm from the surface, suggesting vertical transport of theshorter-chain compounds and the potential for movement into groundwater.

Hu et al. (2016) presented geospatial monitoring data for six perfluoroalkyls (PFBS, PFHxS, PFHpA,
PFOA, PFOS, and PFNA) in U.S. drinking water from information contained in the EPA third
Unregulated Contaminant Monitoring Rule (UCMR 3) program. Frequency of detection andconcentrations in drinking water was correlated with proximity to industrial facilities using
perfluoroalkyls, military fire training areas, and the number of waste water treatment plants. Note that
UCMR 3 required all large water systems (4,120 PWSs, serving >10,000 people) and a representative
sample of 800 small water systems (serving ≤10,000 people) to monitor for PFOA and PFOS from 2013
through 2015.

It was reported that 66 public drinking water systems that serve 6 million U.S. residents had at least one
sample that exceeded the current EPA health advisory level of 0.07 μg/L for PFOA and PFOS (Hu et al.
2016). The dataset used by Hu et al. (2016) has since been updated by the EPA (EPA 2017). The mostrecent report dated January 2017 showed that PFOS, PFOA, PFNA, PFHxS, PFHpA, and PFBS weredetected above their respective minimal reporting level in 95, 117, 14, 55, 86, and 8 out of 4,920 public
water systems (EPA 2017). PFOA and PFOS were identified above the health advisory level ofPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

0.07 μg/L in 13 and 46 out of the 4,920 public water supplies, respectively (EPA 2017). It is possible thatcombined concentrations of PFOA and PFOS may exceed the advisory level while individual
concentrations may still be below 0.07 μg/L.
Based on a memorandum of understanding with the EPA, DuPont began collecting water monitoring dataof both public and private wells near the Washington Works chemical plant. The quarterly reports andmonitoring data affiliated with these reports may be obtained from the regulations.gov portal(http://www.regulations.gov). In samples of water collected at 17 public water facilities from 2002 to2009 in West Virginia and Ohio, PFOA levels ranged from below the detection limit (0.0023 μg/L) tonearly 100 μg/L in a few test wells in Little Hocking, Ohio (EPA 2010). In the final phase III summary
report, PFOA concentrations were reported to range from below the detection limit to 0.79 μg/L in
34 wells located approximately 3 miles upstream and 82 miles downstream from the facility (URS 2012).

Rumsby et al. (2009) reviewed the presence of PFOS and PFOA in drinking waters worldwide anddiscussed treatment methods for removing these substances from public water supplies. Conventional
waste water treatment does not always efficiently remove perfluoroalkyls, and effluent may containhigher levels of some perfluoroalkyls than influent due to degradation of precursor substances during thetreatment process (Schultz et al. 2006a, 2006b). While granulated activated carbon and reverse osmosis
followed by nanofiltration have been shown to be effective methods of removing perfluoroalkyls,
conventional methods such as chlorination, ozonolysis, and slow sand filtration may not be as effective.
As a consequence, public drinking water systems impacted by effluent from waste water treatment plants
often contain higher levels of perfluoroalkyls than systems that are not impacted by waste water treatment
plant effluent. Quinones and Snyder (2009) analyzed raw and finished water at seven different public
water systems in the United States for the presence of perfluoroalkyls. Water systems that were heavily
impacted by waste water treatment plant effluents had greater frequency and higher levels ofperfluoroalkyls when compared to water systems that were not highly impacted by waste water treatment
plants. For example, no perfluoroalkyls were detected in either influent or finished water from a public
water system in Aurora, Colorado with no impact from waste water treatment plant effluent; however,
PFHxA, PFOA, PFNA, PFDA PFUnA, PFHxS, and PFOS were detected in all samples of a Los Angeles,
California public water system that was highly impacted by waste water effluent. Perfluoroalkyls werecommonly detected in the influent and effluent of 10 waste water treatment plants across the UnitedStates (Schultz et al. 2006a). PFBS was detected in 100% of both influent and effluent samples of the
10 plants, while other perfluoroalkyls like PFOA, PFOS, PFNA, PFHxA, PFHpA, and PFHxS weredetected in 80% of the influent and effluent samples at the 10 plants. In a national study ofPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

10 perfluoroalkyls in raw and treated drinking water of France, Boiteux et al. (2012) observed that several
perfluoroalkyl carboxylic acids had greater concentrations in treated water than the raw water. In eight
drinking water treatment plants, PFBA, PFHxA, and PFHpA were not detected in raw water, but weredetected in treated water, indicating that these substances were released from saturated activated carbon
used to treat raw waters or were formed by the degradation of precursor substances. Perfluoroalkyl
sulfonates appeared to be removed more efficiently than the carboxylates. PFHxS, PFBS, and PFOS
were detected less frequently in treated water as compared to raw water influent. These three compounds
comprised 53% of the total concentration of perfluoroalkyls in the raw water samples, but only 37% of
the total concentration of the perfluoroalkyls in the treated water. The summed concentration of
10 perfluoroalkyls was analyzed in the raw water and treated water of two drinking water treatment plants
downstream from a fluoropolymer manufacturing facility located in France (Dauchy et al. 2012). The
total concentration of perfluoroalkyls in the raw water at four sampling locations of the first plant ranged
from 0.140 to 0.287 μg/L, while the summed concentration in the treated water was 0.179 μg/L. The total
concentration of the 10 perfluoroalkyls in raw water at the second plant was 0.132 μg/L, while the total
concentration in the treated water was 0.130 μg/L. Levels of PFHxA were greater in the treated water
than the raw water at three of the four raw water sampling points, and levels of PFNA were greater intreated water than raw water at all sampling points of the first plant, but were slightly lower in the treatedwater of the second drinking water plant even though both systems used simple chlorination to treat thewater.

PFOA was detected in 65% of the public drinking water systems tested in New Jersey in 2006 at
concentrations ranging from 0.005 to 0.039 μg/L (Post et al. 2009). In a follow-up study conducted in
2009, PFOA was detected in 57% of raw water samples from 29 additional public drinking water systems
in New Jersey at a maximum concentration of 0.100 μg/L (Post et al. 2013). Nine other perfluoroalkyls
were also tested for, with PFOS and PFNA being the most frequently detected compounds (30% detection
frequency each) after PFOA. PFOA and PFOS were detected in tap water from 21 cities located in China
at concentrations of <0.0001–0.0459 and <0.0001–0.0148 μg/L, respectively (Jin et al. 2009). Mak et al.
(2009) published a study comparing detections of perfluoroalkyls including PFOA and PFOS in tap watercollected in China, Japan, India, Canada, and the United States. PFOA and PFOS were the predominant
species measured, accounting for 40–50% of the total perfluoroalkyls present in water, with the exceptionof certain location of India where PFOS or PFOA may not have been present or were present at low
levels.

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Gellrich et al. (2013) analyzed 119 samples of mineral water, 26 samples of tap water, 18 spring water
samples, and 14 raw water samples from Germany for the presence of perfluoroalkyls. Perfluoroalkyls
were detected in 58% of all of the samples tested, with the greatest summed total concentration observedin tap water at 0.0427 μg/L. The maximum concentration of individual perfluoroalkyls occurring inbottled water, spring water, untreated water, and tap water were observed for PFBS (0.0133 μg/L), PFOA
(0.0074 μg/L), PFBS (0.010 μg/L), and PFHxS (0.0121 μg/L), respectively. Perfluoroalkyls were widely
detected in drinking water samples collected in 2008 at 40 different locations of Catalonia, Spain (Ericson
et al. 2009). Median concentrations ranged from 0.00002 μg/L (FOSA) to 0.00098 μg/L (PFOA). The
most frequently detected compounds were PFOS and PFHxS, which were detected in 35 and 31 samples,
respectively. PFOS, PFOA, and PFHxS were detected in all samples collected in a study of drinking
water contamination of perfluoroalkyls in Rio de Janeiro, Brazil (Quinete et al. 2009). Concentration
ranges were 0.00058–0.00670 μg/L (PFOS), 0.00035–0.00282 μg/L (PFOA), and 0.00015–0.001 μg/L
(PFHxS) respectively.

Perfluoropolyethers (PFPEs) such as perfluoroether carboxylic and sulfonic acids containing one or more
ether oxygens in the carbon backbone are expected to be less persistent than the legacy substances.
However, hexafluoropropylene oxide trimer and dimer acid (HFPO-TA and HFPO-DA) were detected indownstream water samples near a fluoropolymer facility in China at levels of 5.2–68.5 μg/L (Pan et al.
2017). Pan et al. (2018) also provided data of HFPO-DA and HFPO-TA in surface waters in China,
United Kingdom, United States, Sweden, Germany, Netherlands, and South Korea. The substances were
frequently detected in surface waters in all countries with median levels of 0.00095 µg/L (HFPO-DA) and
0.00021 μg/L (HFPO-TA). Gebbink et al. (2017) also reported that the GenX (HFPO-DA) was detected
in all sampling sites downstream from a fluoropolymer facility in the Netherlands and at three out of four
drinking water facilities located near the facility. Short-chain perfluoroalkyl compounds and legacy
perfluoroalkyls were analyzed for in 97 drinking water samples from Canada and other nations in 2015–2016 (Kabore et al. 2018). PFOA and PFOS levels did not exceed 0.005 μg/L in any of the 97 samples;
however, high detection frequencies ranging from 64 to 92% were observed in tap water for some shortchain perfluoroalkyls.
5.5.3

Sediment and Soil

Concentrations of perfluoroalkyls in soils are expected to be greater in the vicinity of fluorochemicalplants that produced or used these substances as processing aids in the manufacture of fluoropolymers
than in the environment at large. Levels of some perfluoroalkyls measured in soil and sedimentPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

surrounding perfluorochemical industrial facilities are listed in Table 5-16. PFOA was detected in mostsoil and sediment samples collected on- and off-site at the 3M Decatur facility in Alabama in monitoringstudies conducted between October 2004 and December 2006. Maximum soil concentrations were ashigh as 14,750 ng/g on-site and 7.85 ng/g off-site, and maximum sediment concentrations were as high as
347 ng/g on-site and 2,385 ng/g off-site (3M 2008c). The highest levels of PFOA were measured in soil
from on-site fields formerly amended with PFOA-containing sludge. In its final project report for thislocation, six on-site soil samples were analyzed in December 2012 for the presence of PFOA, PFOS,
PFBS, and PFHxS. Average levels were 3.86–3,890 ng/g (PFOS), 3.56–270 ng/g (PFHxS), 0.423–
64.8 ng/g (PFBS), and 17.0–1,410 ng/g (PFOA) (3M 2012).

Table 5-16. Concentrations of Perfluoroalkyls in Soil and Sediment at
Fluorochemical Industrial Facilities

Location

Percent detection and concentration (ng/g)
PFOA
PFBA
PFOS
PFHxS PFBS

DuPont Washington Works Facility, West Virginia
Soil
Boring samples (n=22)
Percent detected
36%aMinimum<0.17aMaximum
170a
3M Cottage Grove Facility, Minnesota
Soil
Boring samples (n=50–108)
Percent detected
100%
Maximum
21,800Fire training area (n=8–11)
Percent detected
91%
Maximum
262
Sediment
East and West Cove (n=21–28)
Percent detected
100%
Minimum
0.764
Maximum
1,845
Mississippi River shoreline (n=84–92)
Percent detected
70%
Maximum
341
Mississippi River transect (n=38–40)
Percent detected
18%
Maximum
1.09

Reference

Davis et al.
2007

—
—
—

—
—
—

—
—
—

—
—
—

—
—

95%
104,000

90%
3,470

60%
139

82%
11.5

100%
2,948

100%
62.2

73%
24.6

3M 2007b

3M 2007b

3M 2007b
93%
ND
94.6

100%
40.0
65,450

96%
ND
126

65%
ND
9.14

44%
124

80%
79.0

28%
11.5

29%
29.4

0%
ND

82%
3.16

0%
ND

0%
ND

3M 2007b

3M 2007b

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-16. Concentrations of Perfluoroalkyls in Soil and Sediment at
Fluorochemical Industrial Facilities

Location

Percent detection and concentration (ng/g)
PFOA
PFBA
PFOS
PFHxS PFBS

3M Decatur Facility, Alabama
Soil
On-site former sludge incorporation area (n=357)
Percent detected
99%
—
Mean
885–929Range
2.91–14,750 —On-site background (n=18)
Percent detected
100%
—
Mean
3.53–4.1
Range
1.61–6.03—
Off-site soil (n=23)
Percent detected
Mean
Range

Reference

3M 2008c
—

—

—

—

—

—
3M 2008c

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

3M 2008c
100%
3.68–4.6
0.72–7.85

Sediment
On-site sediment (n=8)
Percent detected
88%—Median16.8
Range
1.64–347—
Off-site sediment (n=30)
Percent detected
93%
—
Range
0.39–2,385 —3M Decatur Facility, Alabama December 2012
On-site former sludge
incorporation area (n=6)
Percent detected
100%
—
Mean
17.0–1,410 —3M Cottage Grove Facility, Minnesota
Surface soil along U.S.
Highway 10 near facility
Percent detected
100%Median8.0
Range
5.5–125.7

3M 2008c

3M 2008c
—
—

—
—

—
—
3M 2012

100%
3.86–
3,890

86%
3.56–
270

86%
0.423–
64.8
Xiao et al. 2015

—

100%
—
12.2
0.2–28.2—

aAnalyte was reported as APFO.

“—“ indicates no available data; APFO = ammonium perfluorooctanoate; ND = not detected; PFBA = perfluorobutanoicacid; PFBS = perfluorobutane sulfonic acid; PFHxS = perfluorohexane sulfonic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid

PERFLUOROALKYLS

701
5. POTENTIAL FOR HUMAN EXPOSUREPFOA, PFOS, and PFHxS were detected in 90–100% of soil samples collected from a former tar
neutralization area, a former sludge disposal area, a former solids burn pit area, a former waste water
treatment plant area, and a former fire training area at the 3M Cottage Grove facility in Minnesota (3M2007b). PFBS was detected in 60–73% of these samples. Maximum concentrations for these substanceswere 21,800, 104,000, 3,470, and 139 ng/g, respectively. Levels of PFBA were only reported for soil in
the fire training area; it was detected in 9 out of 11 samples from this location at 0.306–11.5 ng/g. The
percent detection of these compounds in sediment from the East and West Cove sites was similar to thatin soil. Maximum concentrations of PFOA and PFOS were 1,845 and 65,450 ng/g, respectively. These
perfluoroalkyls were also analyzed in Mississippi River sediment near the Cottage Grove Facility. Levelsof these compounds were much greater along the facility shoreline compared to levels in transect samples
collected at points crossing the river. Maximum shoreline concentrations for PFOA, PFBA, PFOS,
PFHxS, and PFBS were 341, 124, 79.0, 11.5, and 29.4 ng/g, respectively. PFHxS, PFBS, and PFBA were
not detected in any of the transect samples, and PFOA was found in only 18%. Although the maximum
concentration of PFOS was 3.16 ng/g, it was still detected in 82% of the transect samples.

PFOA and PFOS were detected in all surface soils (top 10 cm) samples collected at 28 sites in September
and October of 2012 along U.S. Highway 10 running from Cottage Grove, Minnesota (where the former
3M perfluoroalkyl manufacturing facility was located) to Big Lake, Minnesota (Xiao et al. 2015).
Measured levels of PFOS and PFOA ranged from 0.2 to 28.2 and from 5.5 to 125.7 ng/g, respectively.
Subsurface soils up to a depth of 65 cm were collected at four sites as well. Levels of PFOA and PFOS
generally increased with increasing depth at each of the locations, suggesting a downward movement of
the contaminants and the potential to contaminate groundwater.

The use of aqueous firefighting foams at fire training areas of military installations has resulted inwidespread contamination of perfluoroalkyls in the soil and groundwater at these facilities. Monitoringdata obtained from 40 sites at 10 U.S. military installations in the continental United States and Alaska
were collected for several perfluoroalkyls (Anderson et al. 2016). These data are summarized inTable 5-17.

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-17. Summary of Perfluoroalkyls Detected in Soil, Sediment, Surface
Water, and Groundwater at 10 Military Installationsa

Compound Parameter
PFBA

PFBS

PFHxA

PFHxS

PFHpA

PFOA

FOSA

PFOS

PFNA

PFDA

PFUnA

Surface soil Subsurface(µg/kg)soil (µg/kg)

Sediment(µg/kg)

Surface water Groundwater(µg/L)(µg/L)DFMedianMaximum
DF
MedianMaximum
DF
MedianMaximum
DF
MedianMaximum
DF
MedianMaximum
DF
MedianMaximum

38.46
1.00
31.0
35.16
0.775
52.0
70.33
1.75
51.0
76.92
5.70
1,300
59.34
0.705
11.4
79.12
1.45
58.0

29.81
0.960
14.0
34.62
1.30
79.0
65.38
1.04
140
59.62
4.40
520
45.19
0.660
17.0
48.08
1.55
140

24.24
1.70
140
39.39
0.710
340
63.64
1.70
710
72.73
9.10
2,700
48.48
1.07
130
66.67
2.45
950

84.00
0.076
110
80.00
0.106
317
96.00
0.320
292
88.00
0.710
815
84.00
0.099
57.0
88.00
0.382
210

85.51
0.180
64.0
78.26
0.200
110
94.20
0.820
120
94.93
0.870
290
85.51
0.235
75.0
89.86
0.405
250

DF
MedianMaximum
DF
MedianMaximum
DF
MedianMaximum
DF
MedianMaximum
DF
MedianMaximum

64.84
1.20
620
98.90
52.5
9,700
71.43
1.30
23.0
67.03
0.980
15.0
45.05
0.798
10.0

29.81
0.470
160
78.85
11.5
1,700
14.42
1.50
6.49
12.50
1.40
9.40
9.62
1.15
2.00

75.76
1.30
380
93.94
31.0
190,000
12.12
1.10
59.0
48.48
1.90
59.0
24.24
160
14.0

52.00
0.014
15.0
96.00
2.17
8,970
36.00
0.096
10.0
52.00
0.067
3.20
20.00
0.021
0.210

48.55
0.032
12.0
84.06
4.22
4,300
46.38
0.105
3.00
34.78
0.023
1.80
8.70
0.025
0.086

PERFLUOROALKYLS

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Table 5-17. Summary of Perfluoroalkyls Detected in Soil, Sediment, Surface
Water, and Groundwater at 10 Military Installationsa

Compound Parameter
PFDoDA

Surface soil Subsurface(µg/kg)soil (µg/kg)

DF
MedianMaximum

21.98
1.95
18.0

Sediment(µg/kg)

6.73
2.40
5.10

45.45
2.80
84.0

Surface water Groundwater(µg/L)(µg/L)
20.00
0.058
0.071

4.35
0.022
0.062

aWater concentrations are ppb (µg/L); soil and sediment levels are ppb (µg/kg).

DF = detection frequency as a percentage; FOSA = perfluorooctane sulfonamide; PFBA = perfluorobutanoic acid;
PFBS = perfluorobutane sulfonic acid; PFDoDA = perfluorododecanoic acid; PFDA = perfluoro-n-decanoic acid;
PFHpA = perfluoroheptanoic acid; PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid;
PFNA = perfluorononanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid
Source: Anderson et al. (2016)

Perfluoroalkyls have been detected in soils that were amended with biosolids (Sepulvado et al. 2011).
Several perfluoroalkyls were detected in biosolid-amended soils, with PFOS being the predominantcompound with levels ranging from 5.5 to 483 ng/g, depending upon the loading rate.
5.5.4

Other MediaIn a study conducted by the Food and Drug Administration (FDA) of 91 food samples collected during
the 2017 Total Diet Study, PFOS was detected in 10 meat/seafood samples; the levels ranged from
0.134 ng/g in a boiled frankfurter to 0.865 ng/g in baked tilapia (FDA 2019). PFBA was detected in one
sample of raw/frozen pineapple (0.068 ng/g). PFOA, PFHxS, PFNA, PFDA, PFBS, and PFHxA levels
were below the lower limit of quantitation. It is important to note that FDA states that the sample size islimited and cannot be used to draw definitive conclusions. Levels of PFOS, PFOA, PFBS, PFHxS,
PFHxA, PFHpA, PFDA, PFNA, and PFDoDA were analyzed in 31 food items collected from 5 grocery
stores located in Texas in 2009 (Schecter et al. 2010). PFOA was the most frequently detected item
(detected in 17 of 31 of the food samples), with levels ranging from 0.07 ng/g in potatoes to 1.80 ng/g inolive oil. PFOS, PFHxA, PFHpA, PFNA, PFDA, and PFDoDA were not detected in any samples. PFBS
and PFHxS were detected in cod at 0.12 and 0.07 ng/g, respectively. The data for PFOA are summarizedin Table 5-18. Several studies have evaluated the levels of perfluoroalkyls in fish from lakes and rivers in
the United States; these data are summarized in Table 5-19.

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Table 5-18. Detections of PFOA in 31 U.S. Food Items
Food

PFOA concentration in ng/g (LOD for non-detects)

Hamburger
Bacon
Sliced turkey
Sausage

0.15
0.24
ND (0.02)
0.09

Ham
Sliced chicken breast
Roast beef
Canned chili
SalmonCanned tuna

0.02
0.02
ND (0.02)
0.02
0.23
ND (0.05)

Fresh catfish fillet
Tilapia
Cod
Canned sardines
Frozen fish sticks
ButterAmerican cheese

0.30
0.10
0.10
0.19
0.21
1.07
ND (0.04)

Other cheese
Whole milk
Ice cream
Frozen yogurt
Whole milk yogurt
Cream cheese

ND (0.04)
ND (0.02)
ND (0.03)
ND (0.02)
ND (0.02)
ND (0.03)

Eggs
Olive oil
Canola oil
Margarine
Cereals
ApplesND (0.04)
1.80
ND (0.05)
0.19
ND (0.04)
ND (0.02)

Potatoes
Peanut butter

0.07
0.10

LOD = limit of detection; ND = not detected; PFOA = perfluorooctanoic acid
Source: Schecter et al. 2010

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Table 5-19. Detections of Perfluoroalkyls in Fish from U.S. Lakes and Rivers
Type of seafood(location)
PFOA
Lake trout (Lake 1.1
Superior)
Lake trout (Lake <0.42
Superior)
Lake trout (Lake 4.4
Michigan)
Lake trout (Lake 1.6
Huron)
Lake trout (Lake <0.42
Huron)
Lake trout (Lake 1.6
Erie)
Lake trout<0.42(Eastern Lake
Erie)
Walleye (Western 0.50
Lake Erie)
Lake trout (Lake 1.5
Ontario)
Lake trout (Lake 0.88
Ontario)
Mixture of whole <1.00
fish (Missouri
River)
Mixture of whole <0.20
fish (Mississippi
River)
Mixture of whole <1.00
fish (Ohio River)
Smallmouth bass <2(Raisin River)

Perfluoroalkyl concentration in ng/g
PFOS
4.8

PFHxS
<0.01–
0.43
<0.10

PFNA
1.0

PFDA
0.72

PFUnA
0.90

0.70

0.39

1.1

<0.01–
0.87<0.01–
6.2
<0.10

0.57

0.76

0.74

2.8

2.2

2.7

1.4

1.3

1.8

2.9

4.9

3.5

96

<0.01–
1.2
1.4

2.6

6.1

1.1

<0.10

1.2

46

0.65

2.5

2.3

PFHpA
<0.02–0.87

PFBS

PFDoDA FOSA
0.37
0.25

Reference

0.97

Furdui et al. 2007

<0.02–
0.97<0.02–
1.43
NE

0.41

0.99

DeSilva et al.
2011
Furdui et al. 2007

0.88

1.6

Furdui et al. 2007

0.97

2.1

5.7

<0.02–
0.71
NE

DeSilva et al.
2011
Furdui et al. 2007

2.0

DeSilva et al.
2011

3.6

3.1

NE

1.1

1.1

1.8

1.6

0.70

0.70

0.90

1.4

2.

<0.02–
1.39
0.64

DeSilva et al.
2011
Furdui et al. 2007

84.7

1.89

0.43

0.25

<1.00

1.53

<0.40

0.49

DeSilva et al.
2011
Ye et al. 2008

83.1

0.42

0.78

1.24

3.38

0.27

<0.20

<0.40

Ye et al. 2008

147

0.52

1.03

3.88

6.57

<4.00

<0.40

1.72

Ye et al. 2008

16
39
17
121

2.0–41.3 <1

0.74

0.82

0.32

<1–4.1

Kannan e al.
2005

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Table 5-19. Detections of Perfluoroalkyls in Fish from U.S. Lakes and Rivers
Type of seafood(location)
PFOA
Smallmouth bass <2(St Clair River)
Smallmouth bass <2(Calumet River)Carpa (Saginaw<36
Bay)
Carpa (Saginaw
Bay)
Lake whitefisha(Michigan waters)
Chinook salmona(Michigan waters)
Brown trouta(Michigan waters)
Bluegill (St Croix
River, Minnesota)
Bluegill (Lake
Calhoun,Minnesota)
Bluegill (HawRiver, North
Carolina)
Mixture of fish
fillet (Zumbrol
Lake, Minnesota)
Mixture of fish
fillet (McCarrons
Lake, Minnesota)

Perfluoroalkyl concentration in ng/g
PFOS
<2–2.7

PFHxS
<1

PFNA

PFDA

PFUnA

PFHpA

PFBS

PFDoDA FOSA
1.1–6.3

2.5–7.6

<1

<1

124

<34

<19

120
130
110
<6–46

Reference
Kannan e al.
2005
Kannan e al.
2005
Kannan e al.
2005
Giesy and
Kannan 2001
Giesy and
Kannan 2001
Giesy and
Kannan 2001
Giesy and
Kannan 2001
Delinsky et al.
2009
Delinsky et al.
2009

2.87

<LOQ

<LOQ

<LOQ

272

5.82

4.18

4.72

29.8

10.3

26.9

7.25

52.4

3.24

Delinsky et al.
2010

47.3

1.97

Delinsky et al.
2010

Delinsky et al.
2009

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Table 5-19. Detections of Perfluoroalkyls in Fish from U.S. Lakes and Rivers
Type of seafood(location)
PFOA
Mixture of fish
fillet (Pickerel
Lake, Minnesota)
Mixture of fish
fillet (Carlos Lake,
Minnesota)
Mixture of fish
fillet (other
Minnesota lakes)
Mixture of fish
fillet (Mississippi
River sites,
Minnesota)

Perfluoroalkyl concentration in ng/g
PFOS
10.0

PFHxS

PFNA

PFDA
1.23

PFUnA

PFHpA

PFBS

PFDoDA FOSA

Reference
Delinsky et al.
2010

12.3

Delinsky et al.
2010

1.08–
5.13

Delinsky et al.
2010

3.06–
20.00

0.47

2.94–15.0

2.13–
6.72

3.74–
4.42

Delinsky et al.
2010

aPerfluoroalkyl levels measured in muscle.

Grayed cells indicate that study did not evaluate compound; FOSA = perfluorooctane sulfonamide; LOQ = limit of quantification; NE = not evaluated;
PFBS = perfluorobutane sulfonic acid; PFDoDA = perfluorododecanoic acid; PFDA = perfluorodecanoic acid; PFHpA = perfluoroheptanoic acid;
PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOS = perfluorooctane sulfonic acid; PFUnA = perfluoroundecanoic acid

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Concentrations of perfluoroalkyls have been reported in foods sampled in Canada, the United Kingdom,
and Germany (Food Standards Agency 2006; Fromme et al. 2007b; Tittlemier et al. 2007).
Perfluoroalkyls were detected in only 9 out of 54 food composites collected during Canadian Total Diet
studies from 1992 to 2004 (Tittlemier et al. 2007). PFOS was detected in beef steak, ground beef,luncheon meats, marine fish, freshwater fish, and microwave popcorn at concentrations ranging from
0.98 to 2.7 ng/g, wet weight. PFOA was detected in roast beef, pizza, and microwave popcorn at 0.74–
3.6 ng/g, wet weight. PFHpA was detected in pizza and microwave popcorn at 1.5–2.0 ng/g, wet weight.
PFNA was detected only in beef steak at 4.5 ng/g, wet weight. PFDA, PFUnA, and PFDoDA wereanalyzed for but not detected in any of the food composites. During the U.K. Food Standards Agency
Total Diet Study, PFOS was detected in eggs, sugars and preserves, potatoes, and canned vegetables at 1,
1, 10, and 2 μg/kg, respectively (Food Standards Agency 2006). PFOA was detected only in potatoes at
1 μg/kg. Neither substance was detected in the bread, miscellaneous cereals, carcass meats, offal, meatproducts, poultry, fish, oils and fats, green vegetables, other vegetables, fresh fruit, fruit products,
beverages, milk, dairy products, or nuts categories. Fromme et al. (2007b) detected PFOS, PFOA, andPFHxS in 33, 45, and 3%, respectively, of 214 daily duplicate food portions for 31 adults in the city of
Munich, Germany. Concentrations were 0.025–1.03 ng/g fresh weight for PFOS, 0.025–118.29 ng/g
fresh weight for PFOA, and 0.05–3.03 ng/g fresh weight for PFHxS. Reported 90th percentile values were0.11 and 0.21 ng/g fresh weight for PFOS and PFOA, respectively (Fromme et al. 2007b).

The temporal trend of perfluoroalkyl residues in eggs, milk, and farmed rainbow trout from Sweden werestudied from 1999 to 2010 (Johansson et al. 2014). Over this period, the mean annual decreases in levels
of PFOS were 18 and 31% in rainbow trout and eggs, respectively. The mean annual decreases of PFOA
and PFHxS were 12 and 11%, respectively, in eggs. The detection frequency of PFOA and PFHxS was
too low in milk samples to assess changes in levels over the time period, and decreases in the levels of
PFOS were found to be not statistically significant over the temporal period. The mean annual decreasein levels of PFHxS in rainbow trout was 4.3% annually.

Elevated levels of PFOS were measured in water and fish samples obtained from 2009 and 2012 at six
sampling locations along the Welland River and Lake Niapenco in Ontario, Canada (Gewurtz et al. 2014).
These locations were downstream from the Hamilton International airport where PFOS containing AFFF
was used until the mid-1990s at a firefighting training facility at the airport. PFOS concentrations weregenerally highest in benthic feeding fish collected at the sampling locations nearest to the airport. The
maximum level of PFOS was observed in common carp collected at a site near the airport at aconcentration of 2,300 ng/g. Maximum levels of PFOS in smallmouth bass, largemouth bass, andPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

channel catfish were 640, 450, and 430 ng/g, respectively. Freshwater fish and seafood obtained from
China had detectable levels of nine perfluoroalkyls, with PFOS being detected in 62% of the samples at aconcentration range of <0.10–26.2 ng/g and PFOA detected in 70% of the samples at levels of <0.10–
1.99 ng/g (Zhang et al. 2011).
PFOA was detected in the packaging paper of two microwave popcorn bags at 0.3–4.7 ng/cm2 uncooked
and 0.5–4.3 ng/cm2 cooked (Sinclair et al. 2007). The mean mass of PFOA in the gas phase of popcorn
vapors following popping was 16–17 ng/cm2. PFHpA, PFNA, PFDA, PFUnA, and PFDoDA weredetected in one of the bags at 0.4–3.2 ng/cm2 uncooked and 0.5–4.3 ng/cm2 cooked; however, theseperfluoroalkyls were not detected (<0.2 ng/cm2) in the second bag. Begley et al. (2005) measured PFOA
concentrations of 6–290 μg/kg in microwave popcorn bags. These authors also tested a hamburger
wrapper, sandwich wrapper, French fry box, and soak-proof paper plates and did not find PFOA above
the detection limit in these products. The concentration of PFOA measured in undiluted perfluoro paper
coating formulations ranged from 88,000 to 160,000 μg/kg (Begley et al. 2005).
A study of perfluorinated and polyfluorinated substances in food packaging from U.S. fast foodrestaurants found perfluoroalkyl carboxylates (such as PFOA and PFHxA), perfluoroalkyl sulfonates(such as PFBS), fluorotelomer sulfonates, and unknown polyfluorinated compounds (Schaider et al.
2017). PFOA was detected in 6 of the 20 samples collected in 2014–2015. Fluorotelomer alcohols thatcan degrade or metabolize to perfluoroalkyl carboxylic acids such as PFOA continue to be detected infood packaging materials. Yuan et al. (2016) analyzed 69 food contact materials (paper tableware, paper
cups, cupcake cups, paper boxes, paper bags, and microwave popcorn bags) produced in China and25 materials (paper tableware, microwave popcorn bags, and paper cups) produced in the United States.
The median concentration of total fluorotelomer alcohols in food contact materials produced in China(sum of 6:2, 8:2, 10:2, 12:2, 14:2, 16:2, and 18:2 fluorotelomer alcohol) ranged from 2 to 18,200 ng/g,with the highest levels observed in microwave popcorn bags. The detection frequencies of 6:2, 8:2, 10:2,
12:2, 14:2, 16:2, and 18:2 fluorotelomer alcohol in all food contact materials were reported as 38, 65, 77,
70, 58, 35, and 30%, respectively. The only fluorotelomer detected in paper tableware produced in the
United States was 6:2 fluorotelomer alcohol, with a detection frequency of 11%; however, allfluorotelomer alcohols, with the exception of 18:2 fluorotelomer alcohol, were detected in microwave
popcorn bags from the United States, although the levels were much lower than those produced in China.
Table 5-20 shows the median concentration of the fluorotelomer alcohols in microwave popcorn bags
produced in the United States versus those produced in China. In contrast to the products produced in
China, the predominant fluorotelomer alcohol currently detected in food contact materials produced in thePERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

United States appears to be 6:2 fluorotelomer alcohol. The authors concluded that the results of the
PFOA Stewardship Program had effectively reduced the usage of long-chain fluorotelomer alcohols in the
United States; however, they were still widely present in products produced in China.

Table 5-20. Fluorotelomer Alcohols Detected in Microwaveable Popcorn Bags
Produced in China and the United States

Fluorotelomer
alcohol

Median concentration of FTOH in
microwave popcorn bag produced in
China (ng/g)

Median concentration of FTOH in
microwave popcorn bag produced in
the United States (ng/g)

6:2 FTOH
8:2 FTOH
10:2 FTOH
12:2 FTOH
14:2 FTOH
16:2 FTOH

80
4,810
6,700
5,650
384
61

485
1.36
0.73
0.55
0.12
<MQL

18:2 FTOH

7.5

Not detected

FTOH = fluorotelomer alcohol; MQL = method quantitation limit
Source: Yuan et al. 2016

Washburn et al. (2005) measured the concentration of the perfluorooctanoate anion in fluorotelomertreated consumer articles as well as the fluorotelomer formulations used for the treatments. PFOA wasdetected in mill-treated carpeting (0.2–0.6 mg/kg), carpet-care solution-treated carpeting (0.2–2 mg/kg),
treated apparel (<0.02–1.4 mg/kg), treated home textiles (<0.02–1.4 mg/kg), industrial floor waxes andwax removers (0.0005–0.06 mg/kg), latex paint (0.02–0.08 mg/kg), and home and office cleaners (0.005–
0.05 mg/kg). The concentrations of PFOA measured in the formulations used for these applications were
30–80, 1–50, <1–40, <1–40, 5–120, 50–150, and 50–150 mg/L, respectively. PFOA was not detected intreated upholstery (<0.034 mg/kg), treated technical textiles (<0.034 mg/kg), treated nonwoven medical
garments (<0.034 mg/kg), or stone, tile, and wood sealants (<0.1 mg/kg).

Liu et al. (2014) measured levels of perfluoroalkyls in 35 consumer products that are typically usedindoors, such as treated home textiles, food contact paper, carpet care products, and floor waxes. All
products were obtained from retail stores in the United States between March 2007 and September 2011.
The general trend was that these products contained decreasing quantities of perfluorocarboxylic acids,
including PFOA, over the temporal period studied; however, there was an increase in use of PFBS,
presumably as a replacement of PFOS in consumer products. Levels of perfluoroalkyls were analyzed in
115 random samples of consumer products obtained in Germany in 2010, including textiles, carpets,

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5. POTENTIAL FOR HUMAN EXPOSURE

cleaning and impregnating agents, leathers, food contact materials, baking and sandwich paper, and ski
waxes (Kotthoff et al. 2015). Cleaning agents and some baking and sandwich papers had nondetectableor negligible amounts of perfluoroalkyls; however, PFOA and PFOS were frequently detected in outdoor
textiles, ski wax, leather products, gloves, awning cloths, nanosprays, impregnation sprays, and foodcontact materials. Cleaning agents, nanosprays, and impregnation sprays tended to have the highest levelof fluorotelomer alcohols. EPA (2009b) analyzed 116 articles of commerce obtained from retail outlets in
the United States from March 2007 and May 2008 for the presence of perfluorocarboxylic acids ranging
in carbon number from C5 (perfluoropentanoic acid) to C12 (perfluorododecanoic acid). Total C5–C12
perfluorocarboxylic acid levels ranged from below the detection limit (1.5 ng/g) to 47,100 ng/g, withlevels of PFOA ranging from below the detection limit to 6,750 ng/g.

PTFE is a fluoropolymer used in applications such as nonstick cookware coatings and plumbing sealanttape. In the past, PFOA had been used as a processing aid in the emulsion polymerization of PTFE
(DuPont 2008). PFOA was largely removed from the fluoropolymer material during the baking andcuring step of nonstick cookware coatings in a high temperature oven; however, residual PFOA could befound in the final coatings (DuPont 2008). Begley et al. (2005) measured PFOA concentrations of 4–
75 μg/kg in PTFE cookware, 3 μg/kg in PTFE-based dental floss, 4 μg/kg in PTFE-based dental tape, and1,800 μg/kg in PTFE film/sealant tape. PFOA was not detected in tubing made of a fluoro-ethylenepropene copolymer (Begley et al. 2005).

Studies have been conducted that investigated the release of PFOA from PTFE cookware when heated.
Sinclair et al. (2007) reported PFOA release concentrations ranging from 19 to 287 pg/cm2 measured
using four new nonstick frying pans. These concentrations were measured at normal cooking
temperatures within the range of 180–229°C. PFOA was detected in water (7 and 75 ng) boiled for
10 minutes in two out of five non-stick pans (Sinclair et al. 2007). PFOA was not found above thedetection limit (0.1 ng/cm2) during 40 extraction tests on PTFE cookware using an ethanol/water mixture(Washburn et al. 2005). Likewise, Powley et al. (2005) conducted extraction texts on commercial
fluoropolymer-treated cookware using water and water/ethanol mixtures at 100 and 125°C. Under
simulated cooking conditions, PFOA was not identified above the detection limit of 100 pg/cm2. Begley
et al. (2005) reported that additional PFOA was not generated in the PTFE coating of three empty pans
heated to 320°C (DuPont 2008). According to DuPont, the non-stick coating on a pan may begin to
deteriorate if the pan is accidentally heated above 348°C, which is well above the maximum
recommended cooking temperature of 260°C (DuPont 2008). Although it is possible for an unattended

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5. POTENTIAL FOR HUMAN EXPOSURE

empty pan to reach these high temperatures, overheating non-stick cookware is expected to be prevented
in most cases because food oils begin to generate smoke around 190°C (Begley et al. 2005).

A comprehensive study that examined 116 articles of commerce (AOC) found perfluorocarboxylic acids,
including PFOA, in many commercially available substances, such as carpet care products and waxes(EPA 2009b). Levels of PFOA ranged from nondetectable to 6,750 ng/g, and levels of total
perfluorocarboxylic acids (the sum of C5–C12 acids) ranged from nondetectable to 47,100 ng/g.
Perfluoroalkyls, including PFOA, have been detected at low levels in personal care products such as
cosmetics and sunscreens (Fujii et al. 2013).
5.6

GENERAL POPULATION EXPOSURE

Levels of perfluoroalkyls have been measured in indoor air, outdoor air, dust, food, surface water, andvarious consumer products. Possible exposure pathways have been proposed; however, the relative
importance of these pathways, including their association with the accumulation of perfluoroalkyls inblood, remains unclear (Apelberg et al. 2007b; Begley et al. 2005; Calafat et al. 2006b; Trudel et al. 2008;
Washburn et al. 2005). For populations that have elevated levels of perfluoroalkyls in water supplies, theprimary route of exposure is expected to be ingestion of contaminated drinking water.

Trudel et al. (2008) provides a thorough analysis of general population exposure to PFOS and PFOA
based on the available information and proposes the following possible exposure pathways: food andwater consumption, ingestion of house dust, hand-to-mouth transfer from treated carpets, migration into
food from PFOA-containing paper or cardboard, inhalation of indoor and ambient air, and inhalation ofimpregnation spray aerosols. Other pathways proposed to be less significant included oral exposure fromhand-to-mouth contact with clothes and upholstery, migration into food prepared with PTFE-coatedcookware, dermal exposure from wearing treated clothes, deposition of spray droplets on skin while using
impregnation sprays, skin contact with treated carpet and upholstery, and deposition of dust onto skin
(Trudel et al. 2008). The strong correlation between PFOA and PFOS concentrations in human serum
samples indicates that common exposure pathways for these two substances are possible (Calafat et al.
2007a).

In order to estimate human uptake and the major pathways for human exposure to PFOS and PFOA,
reported levels of these compounds in various environmental media, including food and consumer
products, were analyzed with respect to product use patterns, personal activity patterns, and personalPERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

intake rates (Trudel et al. 2008). For PFOS, the major exposure pathways in a high-exposure scenario
were proposed to be food and water ingestion, dust ingestion, and hand-to-mouth transfer frommill-treated carpets. Relative contributions of these pathways to the total uptake of PFOS in adults were
estimated to be approximately 80, 15, and 5%, respectively (Trudel et al. 2008). For PFOA, the major
exposure pathways in a high-exposure scenario were proposed to be oral exposure resulting from
migration from paper packaging and wrapping into food, general food and water ingestion, inhalationfrom impregnated clothes, and dust ingestion. Relative contributions of these pathways to the total uptakeof PFOA in adults were estimated to be approximately 60, 15, 15, and 10%, respectively (Trudel et al.
2008). Major exposure pathways for the intermediate and low exposure scenarios were proposed to bethrough food and drinking water (PFOA and PFOS) and ingestion of house dust (PFOA only). Based onthese proposed exposure pathways, adult uptake doses estimated for low, medium, and high exposure
scenarios were approximately 7, 15, and 30 ng/kg body weight/day, respectively, for PFOS andapproximately 0.4, 2.5, and 41–47 ng/kg body weight/day, respectively, for PFOA (Trudel et al. 2008).
The estimated uptake values were similar for men and women. Trudel et al. (2008) used older monitoringdata and the estimated intakes may not be reflective of current exposure since there has been a downward
trend in PFOA and PFOS exposure.

Fromme et al. (2009) assessed human exposure to perfluoroalkyls for adults in the general population ofwestern countries. Based on measurements of indoor and outdoor air, house dust, drinking water, anddietary PFOS and PFOA levels, the investigators estimated average daily exposure levels of 1.6 ng/kg
body weight/day for PFOS and 2.9 ng/kg body weight/day for PFOA. Upper daily exposure levels were
determined to be 8.8 ng/kg body weight/day for PFOS and 12.6 ng/kg body weight/day for PFOA. The
investigators concluded that the oral route, especially diet, was the primary route of exposure toperfluoroalkyls (Fromme et al. 2007a, 2007b, 2009).

As a group of compounds, perfluoroalkyls appear to be ubiquitous in human blood based on thewidespread detection of these substances in human serum samples (Byrne et al. 2017; Calafat et al.
2006b, 2007a, 2007b; De Silva and Mabury 2006; Kuklenyik et al. 2004; Olsen et al. 2003b, 2003c,
2004b, 2004c, 2005, 2007a). Tables 5-21 and 5-22 list concentrations of perfluoroalkyls measured inserum samples collected from a representative sample of the general population in the United States.
Most studies have reported that PFOA and PFOS levels have been detected in over 90% of subjects(Calafat et al. 2006b, 2007a, 2007b; Olsen et al. 2003b, 2007b, 2004c, 2005, 2008). PFHxS, PFNA, andPFDA are also typically detected in over 90% of the subjects (Calafat et al. 2006b, 2007a, 2017a, 2007b;
Kuklenyik et al. 2004; Olsen et al. 2017a, 2017b).

PERFLUOROALKYLS

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Table 5-21. Concentrations of PFOA and PFOS in Human Serum Collected in the
United States

Location

Detection and concentration (ng/mL [ppb])a
PFOA
PFOS
Reference

U.S. Residents—NHANES
1999–2000 (n=1,562)
Percent >LOD
LOD
Geometric mean
95th percentile

100%
0.1
5.2
11.9

100%
0.2
30.4
75.6

2003–2004 (n=2,094)
Percent >LOD
LOD
Geometric mean
95th percentile

99.7%
0.1
3.95
9.80

99.9%
0.4
20.7
54.6

NR
0.1
3.92
11.3

NR
0.2
17.1
47.5

2005–2006 (n=2,120)
Percent >LOD
LOD
Geometric mean
95th percentile
2007–2008 (n=2,100)
Percent >LOD
LOD
Geometric mean
95th percentile
2009–2010 (n=2,233)
Percent >LOD
LOD
Geometric mean
95th percentile
2011–2012 (n=1,904)
Percent >LOD
LOD
Geometric mean
95th percentile
2013–2014 (n=2,165)
Percent >LOD
LOD
Geometric mean
95th percentile

Calafat et al. 2007a

Calafat et al. 2007b

CDC 2018

CDC 2018
NR
0.1
4.12
9.60

NR
0.2
13.2
40.5
CDC 2018

NR
0.1
3.07
7.50

NR
0.2
9.32
32.0
CDC 2018

NR
0.1
2.08
5.68

NR
0.2
6.31
21.7
CDC 2018

NR
0.1
1.94
5.57

NR
0.2
4.99
18.5

PERFLUOROALKYLS

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Table 5-21. Concentrations of PFOA and PFOS in Human Serum Collected in the
United States

Location
2015–2016 (n=1,993)
Percent >LOD
LOD
Geometric mean
95th percentile
U.S. blood donors
2000–2001 (n=645)
Percent >LLOQb
Geometric mean
95th percentilec
Maximum
2006 (n=600)
Geometric mean
95th percentile

Detection and concentration (ng/mL [ppb])a
PFOA
PFOS
Reference
CDC 2019
NR
0.1
1.56
4.17

Olsen et al. 2003b
92%
4.6
12.1
52.3

99.8%
34.9
88.5
1,656.0
Olsen et al. 2008, 2017b

3.44
7.9

2010 (n=600)
Geometric mean
2.44
95th percentile
5.6
2015 (n=616)
Geometric mean
1.09
95th percentile
3.2
U.S. Regional
Minneapolis-St. Paul blood donors (plasma)2005 (n=40)
Percent >LLOQ
95%
LLOQ
NR
Geometric mean
2.2
75th percentile
3.5
Maximum
4.7
Atlanta, Georgia
2003 (n=20)
Percent >LOD
LOD
Mean
Minimum
Maximum

NR
0.2
4.72
18.3

14.5
31.5
Olsen et al. 2017b
8.3
21.8
Olsen et al. 2017b
4.3
8.6

Olsen et al. 2007b
100%
3.4
15.1
20.2
36.9
Kuklenyik et al. 2004

100%
0.1
4.9
0.2
10.4

100%
0.4
55.8
3.6
164.0

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Table 5-21. Concentrations of PFOA and PFOS in Human Serum Collected in the
United States

Location

Detection and concentration (ng/mL [ppb])a
PFOA
PFOS
Reference

Seattle, Washington elderly individuals
No date reported (n=238)
Percent >LLOQb
99.2%
Geometric mean
4.2b95th percentile
9.7
Maximum
16.7
Washington County, Maryland
1974 (n=178)
Percent >LLOQ
71%
LLOQ
1.9
Geometric mean
2.1
75th percentile
3.0
1989 (n=178)
Percent >LLOQ
99%o
Geometric mean
5.5
LLOQ
1.9
75th percentile
6.7
Pease Tradeport, Portsmouth, New Hampshire
2015–2016 (n=1,578)
Percent >LLOQ
99.2
LOD
0.1
Geometric mean
8.59
th
95 percentile
8.28–8.91
St. Lawrence Island, Alaska
2013–2014 (n=85)
Percent >LOD
92th
50 percentile
1.01
95th percentile
2.14

Olsen et al. 2004c
99.5%
31.0
84.1
175.0
Olsen et al. 2005
100%
3.9
30.1
40.2
Olsen et al. 2005
100%p
33.3
3.9
44.0
NH HHS 2016
99.8
0.1
3.09
2.99–3.19
Byrne et al. 2017
99
4.55
12.32

a"Less than" values indicate that the concentration was reported as below the LOD or LLOQ.

For cases where
samples had concentrations below the limit of detection or lower limit of quantification, a value between zero and theLOD or LLOQ was assigned when calculating the mean concentration.
bExperimental LLOQs not determined.
cReported as bias-corrected estimates.
dLLOQ, LOQ, or LOD not reported.
CI = confidence interval; LLOQ = lower limit of quantification; LOD = limit of detection; LOQ = limit of quantification;
NR = not reported; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

PERFLUOROALKYLS

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Table 5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collectedin the United States
Detection and concentration (ng/mL [ppb])a
PFDA
PFUnA
PDoDA PFBS
PFHxSSample population PFHpA
PFNA
U.S. Residents NHANES
1999–2000 (n=1,562) (Calafat et al. 2007a)
Percent >LOD 10%
95%
25%
LOD
0.4
0.1
0.2
Geometric
<0.4
0.5
<0.2
mean
95th percentile NR
1.7
0.5
2003–2004 (n=2,094) (Calafat et al. 2007b)
Percent >LOD 6.2%
98.8%
31.3%
LOD
0.3
0.1
0.3
Geometric
<0.3
1.0
<0.3
mean
95th percentile 0.4
3.2
0.8
2005–2006 (n=2,120) (CDC 2018)
Percent >LOD NR
NR
NR
LOD
0.4
0.1
0.2
Geometric
—
1.09
0.355
mean
95th percentile 0.700
3.60
1.50
2007–2008 (n=2,100) (CDC 2018)
Percent >LOD NR
NR
NR
LOD
0.4
0.082
0.2
Geometric
—
1.22
0.286
mean
95th percentile 0.500
3.28
0.900
2009–2010 (n=2,233) (CDC 2018)
Percent >LOD NR
NR
NR
LOD
0.1
0.082
0.1
Geometric
—
1.26
0.279
mean
95th percentile 0.200
3.77
0.900
2011–2012 (n=1,904) (CDC 2018)
Percent >LOD NR
NR
NR
LOD
0.1
0.1
0.1
Geometric
—
0.881
0.199
mean
95th percentile 0.220
2.54
0.690

FOSA

12%
0.2
<0.2

<1%
0.2
<0.2

100%
0.1
2.1

100%
0.05
0.4

NR

NR

8.7

1.4

9.7%
0.3
<0.3

<0.1%
1.0
<1.0

<0.4%
0.4
<0.4

98.3%
0.3
1.9

22.2%
0.2
<0.2

0.6

<1.0

<0.4

8.3

0.2

NR
0.2
—

NR
0.2
—

NR
0.1
—

NR
0.1
1.67

NR
0.1
—

0.700

<LOD

0.1

8.30

0.300

NR
0.2
—

NR
0.2
—

NR
0.1
—

NR
0.1
1.95

NR
0.1
—

0.600

<LOD

<LOD

9.80

<LOD

NR
0.1
0.172

NR
0.1
—

NR
0.1
—

NR
0.1
1.66

NR
0.1
—

0.900

<LOD

<LOD

6.90

<LOD

NR
0.1
—

NR
0.1
—

NR
0.1
—

NR
0.1
1.28

NR
0.1
—

0.620

0.140

<LOD

5.44

<LOD

PERFLUOROALKYLS

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Table 5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collectedin the United States
Detection and concentration (ng/mL [ppb])a
PFDA
PFUnA
PDoDA PFBS
PFHxS

FOSA

NR
0.1
—

NR
0.1
—

NR
0.1
1.35

NR
0.1
NR

0.200

<LOD

5.60

NR

Sample population PFHpA
PFNA
2013–2014(n=2,168) (CDC 2018)
Percent >LOD NR
NR
NR
NR
LOD
0.1
0.1
0.1
0.1
Geometric
—
0.675
0.185
—
mean
95th percentile 0.200
2.00
0.700
0.500
2015–2016(n=1,993) (CDC 2019)
Percent >LOD
NR
NR
NR
LOD
0.1
0.1
0.1
Geometric
0.577
0.154
—
mean
95th percentile
1.90
0.700
0.400
U.S. blood donors
2000–2001 (n=645) (Olsen et al. 2003b, 2017a, 2017b)
Percent
62%
100%
97.7%
93.8%
>LLOQcGeometric
0.13
0.57
0.16
0.10
mean
95th percentileb 0.5
1.4
0.4
0.3
2006 (n=600) (Olsen et al. 2008, 2017a, 2017b)
Percent>LLOQ 62%
100%
99.8%
d
LLOQ
<0.5
NR
<0.05
Geometric
0.09
0.97
0.34
mean
95th percentile 0.4
2.2
0.8

NR
0.1
1.18

<LOD

4.90

22.6%

52%

2%

NR

1.9

NR

0.04

9.5

NR

99.8%
<0.05
0.18

68%
<0.05
0.04

1.2%
<0.5
LLOQ

95.7%
<0.5
1.52

0.5

0.07

LLOQ

5.7

2010 (n=600) (Olsen et al. 2017a, 2017b)
Percent>LLOQ 79.7%
100%
100%
99.8%
d
LLOQ
<0.05
NR
NR
<0.025
Geometric
0.05
0.83
0.27
0.14
mean
95th percentile 0.2
2.3
0.8
0.5 0.06
2015 (n=616) (Olsen et al. 2017a, 2017b)
Percent>LLOQ 3.3%
100%
96.9%
d
LLOQ
<0.09
<0.093<0.093
Geometric
NR
0.43
0.15
mean
95th percentile 0.16
1.1
0.49

NR
0.1
—

46.2% 22.5%<0.025 <1.0
0.03
LLOQ
0.3

95.5%
<0.05
1.34

5.3

47.9%
<0.466
NR

0.6%
8.4%
<0.932 <0.047
NR
LLOQ

99.7%
<0.04
0.87

0%
<0.093
LLOQ

0.25

LLOQ

3.5

LLOQ

0.02

PERFLUOROALKYLS

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Table 5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collectedin the United States
Detection and concentration (ng/mL [ppb])a
PFDA
PFUnA
PDoDA PFBS
PFHxSSample population PFHpA
PFNA
U.S. Regional
Midwestern United States (De Silva and Mabury 2006)
2004–2005 (n=16)
Percent
100%
100%
13%
detectede
Mean
0.77
0.17
NR
Maximum
1.2
0.25
0.067
Atlanta, Georgia (Kuklenyik et al. 2004)
2003 (n=20)
Percent >LOD 10%
100%
75%
85%
LOD
0.3
0.1
0.3
0.3
b
Mean
<0.3
2.6
0.7
0.8
Maximum
8.5
3.9
1.2
1.4
Seattle, Washington; elderly population (Olsen et al. 2004c)
No date reported (n=238)
Percent>LLOQcGeometricmean
95th percentileb
Maximum
Washington County, Maryland (Olsen et al. 2005)
1974 (n=178)
Percent >LLOQ
LLOQ
Geometricmean
75th percentile
1989 (n=178)
Percent >LLOQ
LLOQ
Geometricmean
75th percentile

FOSA

0%
NA
NA

10%
1
<1
1.6

100%
0.3
3.9
11.2

75%
0.2
0.34
0.7

76%

"Few"

2.2

NR

8.3
40.3

NR
NR

63%
1.5
2.5
82%
1.4
2.5
1.6

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Table 5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collectedin the United States
Detection and concentration (ng/mL [ppb])a
Sample population PFHpA
PFNA
PFDA
PFUnA
PDoDA PFBS
PFHxS
FOSA
Pease Tradeport, Portsmouth, New Hampshire (NH HHS 2016)
2015–2016 (n=1,578)
Percent >LOD 0.9
85.2
42.1
30.0
4.7
20.0
94.2
2.0
LOD
NA
0.1
0.1
0.1
NA
NA
0.1
0.1
Geometric
0.07
0.73
0.22
0.19
0.08
0.04
4.12
0.13
mean
95th percentile 0.07
0.70–
0.21–
0.18–0.19 0.08
0.04
3.92–4.33 0.12–0.14
0.75
0.23
St. Lawrence Island, Alaska (Byrne et al. 2017)
2013–2014 (n=85)
Percent >LOD
99
39
72
32
th
50 percentile
2.21
<LOD
0.72
<LOD
th
95 percentile
7.35
1.06
1.72
2.74
a"Less than" values indicate that the concentration was reported as below the LOD or LLOQ.

For cases where
samples had concentrations below the LOD or LLOQ, a value between zero and the LOD or LLOQ was assigned
when calculating the mean concentration.
bReported as bias-corrected estimates.
cExperimental LLOQs not determined.
dHighest LLOQ listed.
eLOD not reported.
Grayed cells indicate that study did not evaluate compound; “—“ indicates no available data;
FOSA = perfluorooctane sulfonamide; LLOQ = lower limit of quantification; LOD = limit of detection; NA = notapplicable; NR = not reported; PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoic acid;
PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid;
PFNA = perfluorononanoic acid; PFUnA = perfluoroundecanoic acid

As illustrated in Figure 5-3, there has been a clear trend in decreasing serum levels of both PFOS andPFOA in the general population of the United States since 2000 as these substances were phased out;
from 1999–2000 to 2015–2015 (CDC 2018, 2019), the geometric mean serum PFOS and PFOA levels in
the general population have declined approximately 84 and 70%, respectively. Serum concentrations for
PFHxS and PFDA (Figure 5-3) have also been declining over time, whereas serum PFNA concentrations
increased from 1999–2000 to 2009–2010 and then started to decrease (Figure 5-3).

PERFLUOROALKYLS

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Figure 5-3. Geometric Mean Concentrations of PFOA, PFOS, PFHxS, PFNA, andPFDA in U.S. Residents from 1999 to 2016

NHANES = National Health and Nutrition Examination Survey; PFDA = perfluorodecanoic acid;
PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid
Source: CDC 2018

Serial studies of American Red Cross blood donors also allow for temporal evaluations of serum
perfluoroalkyl levels. Olsen et al. (2008) reported a nearly 60% decline in PFOS blood levels whencomparing data from 2001 to 2006; from 2006 to 2015, the serum PFOS levels dropped another 70%(Olsen et al. 2017b). From 2000 to 2015, the PFOS levels dropped 88%. Serum PFOA levels among theblood donors decreased 76% from 2000 to 2015 (Olsen et al. 2003b, 2017b). Geometric mean serum
PFHxS levels went from 1.9 ng/mL in 2000 to 0.87 ng/mL in 2015, a 54% decrease (Olsen et al. 2003b,
2017a, 2017b). From 2006 to 2015, both serum PFNA and PFDA levels decreased by 56% (Olsen et al.
2017a, 2017b).

Several studies have evaluated sex- and age-related differences in serum perfluoroalkyl levels in thegeneral population. In an analysis of NHANES data from 1999 to 2008, Kato et al. (2011) found thatmales had significantly higher levels of PFOA, PFOS, and PFNA than females and that PFOS levels
increased with age, especially in females. Fu et al. (2014b) analyzed the effects of sex and age on levelsof perfluoroalkyls in a study of 133 (79 male, 54 female) participants. In general, higher levels of PFOA,PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

PFOS, PFNA, and PFDA were observed in male subjects; however, differences were only statisticallysignificant for PFOA and PFDA. Sex differences in other perfluoroalkyls were not observed. For bothmale and female subjects, increasing levels of PFOA, PFNA, and PFOS were positively correlated withincreasing age. Age- and sex-specific differences have been incorporated into a regression model
developed by Jain (2015), which uses measured serum PFOA and PFOS levels to predict total serum
perfluoroalkyl levels.

A small number of studies have measured serum perfluoroalkyl levels in U.S. children (Tables 5-23 and5-24). NHANES has included adolescents (ages 12–19 years) in the 1999–2000 through 2013–2014
surveys (Calafat et al. 2007a, 2007b; CDC 2018). Analysis of NHANES data from younger children
were conducted for the 2001–2002 survey (ages 6–11 years) (Kato et al. 2009b) and 2013–2014 survey(ages 3–5 and 6–11 years) (CDC 2018). Pinney et al. (2014) measured serum PFOA, PFOS, PFHxS,
PFNA, and PFDA levels in girls (ages 6–8 years) living in Cincinnati, Ohio and San Francisco,California; and Olsen et al. (2004b) measured PFOA, PFOS, PFHxS, and FOSA in the serum of children
ages 2–12 years from various locations in the United States who were diagnosed with group A
streptococcal infections. Serum levels of several perfluoroalkyls were examined in children exposed to
the World Trade Center (WTC) disaster (n=123) and a sociodemographically-matched comparison group(n=185) (Trasande et al. 2017). Children exposed during the WTC disaster were identified from theWTC Health Registry (WTCHR). All participants were ≤8 years of age on September 11, 2001. Blood
serum levels of PFOA, PFOS, PFHxS, PFNA, PFDA, and PFUnA were collected during 2014–2016. For
all perfluoroalkyls, serum levels in WTCHR children were significantly (p<0.01) higher than in matched
controls, with percentage increases above control as follows: PFOA 29%; PFOS 34%; PFHxS 26%;
PFNA 24%; PFDA 27%; and 200% PFUnA.

Geometric mean serum perfluoroalkyl levels in adolescents (ages 12–19 years) included in NHANES are
similar to geometric mean concentrations reported for adults (Calafat et al. 2007a, 2007b; CDC 2018).
For example, geometric mean concentrations of PFOA and PFOS measured during the 1999–2000 and
2003–2004 NHANES surveys were 3.9–5.5 and 19.3–29.1 ng/mL, respectively, in adolescent serum and3.9–5.2 and 20.7–30.4 ng/mL, respectively, in serum of the total population. The most recent NHANES
survey (2013–2014) also included serum levels for children aged 3–5 and 6–11 years; the geometric mean
concentrations in the younger children were similar to those in adolescents and the total population.

Olsen et al. (2004b) also found that the geometric mean serum PFOA, PFOS, PFHxS, and PFNA levels inolder children (12–19 years of age) were similar to those measured in adults (Olsen et al. 2003b).

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However, estimated 95th percentile values of PFHxS measured in children were noted to be higher thanvalues estimated for adults. Olsen et al. (2004b) reported bias-corrected 95th percentile estimates of
65 ng/mL for PFHxS in the serum of children ages 2–12 years. This value is higher than bias-corrected
95th percentile estimates of 9.5 and 8.3 ng/mL based on PFHxS measurements in the serum of adult blood
donors (Olsen et al. 2003b) and elderly individuals (Olsen et al. 2004c), respectively (see Table 5-22).
The difference is less extreme in the NHANES data, with PFHxS 95th percentile values of 12.9–
13.1 ng/mL reported for children compared to values of 8.3–8.7 ng/mL reported for the total population.
Reasons for the observed differences of PFHxS levels in childhood serum samples compared to adultsamples have not been determined. Olsen et al. (2004b) stated that different exposure and activity
patterns between children and adults should be considered. For example, children may have a higher
exposure than adults to PFHxS, a substance that has been used in carpet treatment applications, since they
are lower to the ground and have increased contact with carpeted floors (Calafat et al. 2007a; Olsen et al.
2004b).

Table 5-23. Percent Detection and Levels of PFOA and PFOS in Children’s Serum

Location

Detection and concentration (ng/mL[ppb])aPFOA
PFOS

U.S. Adolescents—NHANES (ages 12–19)
1999–2000 (n=543)
Percent >LOD
100%
LOD
0.1
Geometric mean
5.5
95th percentile
11.2
2003–2004 (n=640)
Percent >LOD
99.7%bLOD
0.1
Geometric mean
3.9
95th percentile
8.6
2005–2006 (n=640)
Percent >LOD
NR
LOD
0.1
Geometric mean
3.59
95th percentile
8.40
2007–2009 (n=357)
Percent >LOD
NR
LOD
0.1
Geometric mean
3.91
95th percentile
7.30

Reference
Calafat et al. 2007a

100%
0.2
29.1
56.8
Calafat et al. 2007b
99.9%b
0.4
19.3
42.2
CDC 2018
NR
0.2
15.0
38.5
CDC 2018
NR
0.2
11.3
28.0

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-23. Percent Detection and Levels of PFOA and PFOS in Children’s Serum

Location
2009–2010 (n=364)
Percent >LOD
LOD
Geometric mean
95th percentile
2011–2012 (n=344)
Percent >LOD
LOD
Geometric mean
95th percentile

Detection and concentration (ng/mL[ppb])aPFOA
PFOS

Reference
CDC 2013

NR
0.1
2.74
5.00

NR
0.2
6.84
18.1

NR
0.1
1.80
3.59

NR
0.2
4.16
10.8

CDC 2018

2013–2014 (n=401)
Percent >LOD
NR
LOD
0.1
Geometric mean
1.66
95th percentile
3.47
2015–2016 (n=353)
Percent >LOD
NR
LOD
0.1
Geometric mean
1.25
95th percentile
2.47
U.S. Children—NHANES
2001–2002; ages 6–11 (n=936)
Least square mean
6.1–7.6
2013–2014; ages 3–5 (n=181)
Percent >LOD
100%
LOD
0.1
Geometric mean
2.00
95th percentile
5.58
2013–2014; ages 6–11 (n=458)
Percent >LOD
100%
LOD
0.1
Geometric mean
1.89
95th percentile
3.84
U.S. Regional
Girls ages 6–8; Cincinnati, Ohio (n=353)
Percent >LODc
99.7%
Geometric mean
7.8Median7.3

CDC 2018
NR
0.2
3.54
9.30
CDC 2019
NR
0.2
2.94
6.60
Kato et al. 2009b30.45–42.45
100%
0.1
3.38
8.82

Ye et al. 2018a; CDC
2018

100%
0.1
4.15
12.4

Ye et al. 2018a; CDC
2018

Pinney et al. 2014
99.7%
13.2
13.6

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-23. Percent Detection and Levels of PFOA and PFOS in Children’s Serum

Location

Detection and concentration (ng/mL[ppb])aPFOA
PFOS

Girls ages 6–8; San Francisco, California (n=351)
Percent >LODc
100%
100%
Geometric mean
5.7
13.2
Median5.8
12.5
Children ages 6–10; Project Viva, Boston Massachusetts
2007–2010 (n=653)
Percent >LOD
99.5%
99.5%
Geometric mean
4.2
6.2
th
90 percentile
7.9
13.7
Children ages 2–12; 23 states and District of Columbia
1994–1995 (n=598)
Percent >LLOQc
96%
100%
Geometric mean
4.9
37.5
95th percentiled
1089Children ages 1–19; West Virginia and Ohio
2005–2006 (n=4,943)
Geometric mean
31.2
19.2
90th percentile
201
36.8
Children (DOB: 9/11/1993–9/10/2001); New York City, WTCHR
2014–2016 (n=123)
Percent >LOD
100%
100%
Median
1.81
3.72
Children (DOB: 9/11/1993–9/10/2001); New York City, not eligible for WTCHR
2014–2016 (n=185)
Percent >LOD
100%
100%
Median1.39
2.78

Reference
Pinney et al. 2014

Harris et al. 2017

Olsen et al. 2004b

Mondal et al. 2012

Trasande et al. 2017

Trasande et al. 2017a"Less than" values indicate that the concentration was reported as below the LOD or LLOQ.

For cases where
samples had concentrations below the LOD or LLOQ, a value between zero and the LOD or LLOQ was assigned
when calculating the mean concentration.
bPercent detection for the adolescent age group was not specified for the 2003–2004 NHANES samples.
Percentages listed here are for the total sample population.
cLOD or LLOQ not reported.
“—“ indicates no available data; DOB = date of birth; LLOQ = lower limit of quantification; LOD = limit of detection;
LOQ = limit of quantification; NR = not reported; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonicacid; WTCHR = World Trade Center Health RegistryPERFLUOROALKYLS

726
5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-24. Percent Detection and Levels of Other Perfluoroalkyls in Children’s
Serum
Samplepopulation

PFHpA

PFNA

Detection and concentration (ng/mL [ppb])a
PFDA
PFUnA
PFDoDA PFBS
PFHxS

FOSA

U.S. Adolescents NHANES (ages 12–19)
1999–2000 (n=543) (Calafat et al. 2007a)
Percent >LOD
10%b96%
Geometric mean —0.5
95th percentile —1.1
2003–2004 (n=640) (Calafat et al. 2007b)
Percent >LOD
6.2%b98.8%bGeometric mean <0.3
0.9
95th percentile 0.5
2.7
2005–2006 (n=640) (CDC 2018)
Percent >LOD
NR
NR
Geometric mean —0.929
95th percentile 1.10
2.70
2007–2008 (n=357) (CDC 2018)
Percent >LOD
NR
NR
Geometric mean —1.16
95th percentile 0.600
2.54
2009–2010 (n=364) (CDC 2018)
Percent >LOD
NR
NR
Geometric mean —1.10
95th percentile 0.400
2.62
2011–2012 (n=344) (CDC 2018)
Percent >LOD
NR
NR
Geometric mean —0.741
95th percentile 0.190
2.06

15%
<0.2
0.5

12%b
—
—

<1%b
—
—

31.3%b
<0.3
0.7

9.7%b
<0.3
<0.3

<0.1%b
<1.0
<1.0

NR
0.295
0.800

NR
—
0.500

NR
0.231
0.800

100%
2.7
12.9

100%
0.4
1.5

<0.4%b<0.4<0.4

98.3%a2.4
13.1

22.2%b
<0.2
0.3

NR
—
<LOD

NR
—
0.100

NR
2.09
14.1

NR
—
0.300

NR
—
0.300

NR
—
<LOD

NR
—
<LOD

NR
2.40
15.9

NR
—
0.300

NR
0.220
0.600

NR
—
0.400

NR
—
<LOD

NR
—
<LOD

NR
2.03
12.3

NR
—
<LOD

NR
0.146
0.360

NR
—
0.250

NR
—
<LOD

NR
—
<LOD

NR
1.28
6.45

NR
—
<LOD

2013–2014 (n=402) (CDC 2018)
Percent >LOD
NR
NR
Geometric mean —0.599
95th percentile 0.200
2.00

NR
0.136
0.400

NR
—
0.200

NR
—
0.200

NR
—
<LOD

NR
1.27
6.30

NR
—
<LOD

2015–2016 (n=353) (CDC 2019)
Percent >LOD
NR
Geometric mean
0.481
95th percentile
1.20

NR
—
0.300

NR
—
0.200

NR
—
<LOD

NR
0.918
3.10

U.S. Children NHANES
2001–2002; ages 6–11 (n=936) (Kato et al. 2009b)
0.7-1.2
Least squaremean
2013–2014; ages 3–5 (n=181) (Ye et al. 2018a, 2018b; CDC 2018)
Percent >LOD
27%
100%
50%
27%
0%
LOD
0.1
0.1
0.1
0.1
0.1
Geometric mean <LOD
0.764
<LOD
<LOD
<LOD
95th percentile 0.310
3.49
0.370
0.370
<LOD

1%
0.1
<LOD
<LOD

100%
0.1
0.715
1.62

7%
0.1
<LOD
0.110

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-24. Percent Detection and Levels of Other Perfluoroalkyls in Children’s
Serum
Samplepopulation

PFHpA

PFNA

Detection and concentration (ng/mL [ppb])a
PFDA
PFUnA
PFDoDA PFBS
PFHxS

2013–2014; ages 6–11 (n=458) (Ye et al. 2018a, 2018b; CDC 2018)
Percent >LOD
15%
100%
46%
28%
0%
LOD
0.1
0.1
0.1
0.1
0.1
Geometric mean <LOD
0.809
<LOD
<LOD
<LOD
95th percentile 0.170
3.19
0.350
0.250
<LOD

7%
0.1
<LOD
0.130

FOSA

100%
0.1
0.913
4.14

2%
0.1
<LOD
<LOD

Girls ages 6–8; Cincinnati, Ohio (n=353) (Pinney et al. 2014)
Percent >LODc
99.9
75.8
Geometric mean
1.4
0.3
Median
1.4
0.3

99.7
5.1
5.2

19
<LOD
<LOD

Girls ages 6–8; San Francisco, California (n=351) (Pinney et al. 2014)
Percent >LODc
100
78.7
Geometric mean
1.7
0.3Median
1.6
0.3

100
3.0
2.3

10
<LOD
<LOD

Children ages 6–10; Project Viva, Boston Massachusetts
2007–2010 (n=653) (Harris et al. 2017)
Percent >LODc
99.5%
88.2%
Geometric mean
1.7
0.3
th
90 percentile
3.8
0.6

99.5%
2.2
7.0

0.9%
<LOD
<LOD

Children ages 2–12; 23 states and District of Columbia
1994–1995 (n=598) (Olsen et al. 2004b)
Percent >LLOQ
LLOQ
Geometric mean
95th percentileb

78%
NR
4.5
65

14%
1.0
<2.0
<2.0

U.S. Regional

Children (DOB: 9/11/1993–9/10/2001); New York City, WTCHR
2014–2016 (n=123) (Trasande et al. 2017)
Percent >LOD
99.7d
75d
53d
Median
0.61
0.14
0.12

100
0.67

Children (DOB: 9/11/1993–9/10/2001); New York City, not eligible for WTCHR
2014-2015 (n=185) (Trasande et al. 2017)
Percent >LOD
99.7d
75d
53d
Median
0.49
0.11
0.04

100
0.53

a"Less than" values indicate that the concentration was reported as below the LOD or LLOQ.

For cases where
samples had concentrations below the LOD or LLOQ, a value between zero and the LOD or LLOQ was assigned
when calculating the mean concentration.
bPercent detection for the adolescent age group was not specified for these samples. Percentages listed here arefor the total sample population.
cLOD or LLOQ not reported.
d%>LOD reported for combined WTCHR and non-WTCHR groups.
Gray cells indicate that chemical was not evaluated; “—“ indicates no available data; DOB = date of birth;
FOSA = perfluorooctane sulfonamide; LLOQ = lower limit of quantification; LOD = limit of detection; LOQ = limit ofquantification; NC = not calculated; ND = no data; NR = not reported; PFBS = perfluorobutane sulfonic acid;
PFDA = perfluorodecanoic acid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid;
PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFUnA = perfluoroundecanoic acid

PERFLUOROALKYLS

728
5. POTENTIAL FOR HUMAN EXPOSURE

When estimating PFOS and PFOA uptake doses for children, Trudel et al. (2008) assumed the same
exposure pathways for children as were proposed for adults, but considered exposure from hand-to-mouthtransfer from treated carpets to be much larger in children. This pathway was estimated to contribute 40–
60% of the total uptake of both PFOS and PFOA in infants (0–1 years), toddlers (1–4 years), and children(5–11 years) in the high-exposure scenario. Exposure via human breast milk was included in the foodconsumption pathway for infants. Exposure via mouthing of clothes, carpet, and upholstery was also
considered for children <12 years old; however, this was considered to be a minor pathway of exposure.
PFOS uptake doses estimated for the low-, medium-, and high-exposure scenarios were 18.1–219 ng/kg
body weight/day for infants, 14.8–201 ng/kg body weight/day for toddlers, and 9.7–101 ng/kg bodyweight/day for children. PFOA uptake doses estimated for the low-, medium-, and high-exposure
scenarios were 2.2–121 ng/kg body weight/day for infants, 1.2–128 ng/kg body weight/day for toddlers,and 0.8–65.2 ng/kg body weight/day for children. In contrast to the estimates for children under age 12,
relative exposure pathways and uptake doses estimated for teenagers (12–20 years old) wereapproximately the same as for adults.

Perfluoroalkyls have been measured human breast milk and umbilical cord blood; reported concentrations
are listed in Tables 5-25 and 5-26. Measurements of perfluoroalkyls in amniotic fluid, meconium,
neonatal blood, or other tissues have not been located.

Table 5-25. Percent Detection and Levels of PFOA and PFOS in Umbilical Cord
Blood and Breast Milk

Location

Detection and concentration (ng/mL[ppb])aPFOA
PFOS

Umbilical cord blood
San Francisco, California
Percent >LODc
Geometric mean
95th percentile

Reference
Morello-Frosch et al.
2016

56%
–
1.68

100%
2.27
4.35

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-25. Percent Detection and Levels of PFOA and PFOS in Umbilical Cord
Blood and Breast Milk

Location

Detection and concentration (ng/mL[ppb])aPFOA
PFOS

Baltimore THREE Study
Cord serum (n=299)
Percent >LOD
LOD
Geometric mean
Minimum
Maximum
Maternal serum (n=293)
MedianGermany
Cord plasma (n=11)
Percent detected
LOQMedianMaternal plasma (n=11)
Percent detected
LOQMedianSpain
Cord serum (n=66)
Percent >LOD
Minimum
Maximum
Maternal serum (n=53)
Percent >LOD
Minimum
Maximum
Danish National Birth Cohort
Cord blood (n=50)
Percent >LLOQ
LLOQ
Mean
Maternal blood (n=200)
Percent >LLOQ
LLOQ
Mean

Reference
Apelberg et al.
2007a, 2007b100%
0.1–0.2
1.6
0.3
7.1
1.4–1.6

99%
0.2
4.9
<0.2
34.8
4.1–5.0
Midasch et al. 2007

100%
0.5
3.4

100%
0.5
7.3

100%
0.5
2.6

100%
0.5
13.0
Manzano-Salgado etal. 2015

100%
0.60
10.56

100%
0.53
4.71

100%
0.86
14.54

100%
1.17
23.14
Fei et al. 2007

98%
1.0
3.7

100%
1.0
11.0

98%
1.0
4.5

100%
1.0
29.9

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-25. Percent Detection and Levels of PFOA and PFOS in Umbilical Cord
Blood and Breast Milk

LocationJapan
Cord serum (n=15)
Percent >LOD
LOD
Range
Maternal serum (n=15)
Percent >LOD
LOD
Range
Breast milk
Massachusetts (n=45)
Milk
Percent >LOQb
Mean
Minimum
Maximum
Sweden (n=12)
Milk
Percent >LOD
LOD
Mean
Range
Maternal serum
Percent >LOD
LOD
Mean
Range
Sweden (n=20)
Milk
LOD
1997 Mean2007 Mean
Norway (n=9)
Milk
LODMedianRange

Detection and concentration (ng/mL[ppb])aPFOA
PFOS

Reference
Inoue et al. 2004

0%
0.5

100%
0.5
1.6–5.3

20%
0.5
0.5–2.3

100%
0.5
4.9–17.6
Tao et al. 2008b89%
0.0438<0.0301
0.161

96%
0.131
<0.032
0.617
Kärrman et al. 2007

8%c
0.01
–
<0.209–0.492

100%
0.005
0.201
0.060–0.470

100%
0.01
3.8
2.4–5.3

100%
0.005
20.7
8.2–48.0
Sundstrom et al.
2011

0.005
0.138
0.086

0.005
0.237
0.122
Thomsen et al. 2010

0.008
0.05
0.016–0.19

0.003
0.11
0.028–0.36

PERFLUOROALKYLS

731
5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-25. Percent Detection and Levels of PFOA and PFOS in Umbilical Cord
Blood and Breast Milk

Location

Detection and concentration (ng/mL[ppb])aPFOA
PFOS

China (n=19)
Percent >LOD
100%
LOD
0.021–0.027
Range
0.047–0.210
Middle East, including Jordan (n=19)
Percent >LOQ
100%
LOQ
0.01
Mean
0.14
Range
0.024–1.22
France (n=48)
Percent >LOD
LOD
Mean
Range
France (n=61)
Percent >LOD
LOD
Mean
Range
Belgium
Percent >LOD
LOD
Mean
Italy (n=49)
Percent >LOD
LOD
Mean
Italy
Primiparous (n=21)
Percent >LOQ
LOQ
Mean
Range
Multiparous (n=16)
Percent >LOQ
LOQ
Mean
Range

Reference
So et al. 2006b100%
0.001–0.0036
0.045–0.360
Al-sheyab et al. 2015
94%
0.01
0.035
0.006–0.18
Antignac et al. 2013

90%
0.05
0.082
<LOD-0.22

98%
0.05
0.092
<LOD-0.33

77%
0.05
0.041
<LOD-0.31

82%
0.04
0.04
<LOD-0.376

Cariou et al. 2015

Croes et al. 2012
100%
0.01
0.08

100%
0.01
0.13
Guerranti et al. 2013

2% (1 sample)
0.5e
8.04 e

27%
0.5d
0.85e
Barbarossa et al.
2013

81%
0.024
0.076
<LOQ–-0.24

90%
0.015
0.057
<LOQ–0.29

69%
0.024
0.043
<LOQ–0.1

62%
0.015
0.036
<LOQ–0.12

PERFLUOROALKYLS

732
5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-25. Percent Detection and Levels of PFOA and PFOS in Umbilical Cord
Blood and Breast Milk
Detection and concentration (ng/mL[ppb])aPFOA
PFOS

Location
Korea
Percent >LODLODMedianCzech Republic (n=50)
Percent >LOQ
LOQ
Mean
Range

98%
0.019
0.072

98%
0.007
0.05

100%
0.006
0.05
0.012–0.13

100%
0.005
0.033
0.007–0.11

Germany/Hungary (n=70)
Percent >LOQ
Minimum
Maximum

16%<0.200
0.460

100%
0.028
0.639

Reference
Kang et al. 2016

Lankova et al. 2013

Völkel et al. 2008a"Less than" values indicate that the concentration was reported as below the LOD or LLOQ. For cases where
samples had concentrations below the LOD or LLOQ, a value between zero and the LOD or LLOQ was assigned
when calculating the mean concentration.
bLOD or LLOQ not reported.
cReported as bias-corrected estimates.
dng/g wet weight.

“—“ indicates no available data; DOB = date of birth; LLOQ = lower limit of quantification; LOD = limit of detection;
LOQ = limit of quantification; NR = not reported; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonicacid; WTCHR = World Trade Center Health Registry

Table 5-26. Percent Detection and Levels of Other Perfluoroalkyls in Children’s
Umbilical Cord Blood and Breast Milk
Samplepopulation

PFHpA

PFNA

Detection and concentration (ng/mL [ppb])a
PFDA
PFUnA
PFDoDA PFBS
PFHxS

FOSA

Umbilical cord blood
San Francisco, California (Morello-Frosch et al. 2016) (n=65)
Percent >LODc
56%
97%
9%
84%
Geometric mean —
0.29
—
0.03
95th percentile
0.23
0.93
0.49
0.16

0%
—
—

25%
—
0.03

91%
0.02
0.10

Baltimore THREE Study (Apelberg et al. 2007a, 2007b)
Cord serum (n=299)
Percent >LOD
2%
24%
34%
LOD
0.4
0.2
0.2
Minimum
<0.4
<0.2
<0.2
Maximum
2.6
1.1
1.9

5%
0.2
<0.2
1.7

3%
0.1
<0.1
0.2

26%
0.05
<0.05
0.8

PERFLUOROALKYLS

733
5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-26. Percent Detection and Levels of Other Perfluoroalkyls in Children’s
Umbilical Cord Blood and Breast Milk
Samplepopulation

PFHpA

PFNA

Detection and concentration (ng/mL [ppb])a
PFDA
PFUnA
PFDoDA PFBSPFHxSJapan (Inoue et al. 2004)
Cord serum (n=15)
Percent >LOD
LOD
Maternal serum(n=15)
Percent >LOD
LOD

0%
1.0

0%
1.0

Spain (Manzano-Salgado et al. 2015)
Cord blood (n=66)
Percent >LOD
100%
Minimum
0.13
Maximum
2.24
Maternal serum (n=53)
Percent >LOD
100%
Minimum
0.20
Maximum
5.37

88%
0.05
1.93
96%
0.05
2.53

Breast milk
Massachusetts (n=45) (Tao et al. 2008b)
Milk
Percent >LOQb <1%
64%
Mean
NR
0.01726
Minimum<0.010<0.0052
Maximum
0.02340.0184
France (n=49) (Antignac et al. 2013)
Percent >LOD
2%
2%
LOD
0.05
0.05
Mean
—
—
Minimum<LOD<LOD
Maximum
0.074
0.064
France (n=61) (Cariou et al. 2015)
Percent >LOD
0%
LOD
0.05
Mean
0.014
Minimum<LOD
Maximum<LOD
Belgium (n=40) (Croes et al. 2012)
Percent >LOD
42%
LOD
0.01
Mean
—

FOSA

<1%
NR
<0.00772
0.0111<1%
NR<0.00499
0.00884<1%
NR<0.00440
0.00974<1%NR<0.0100
0.019851%
0.0145<0.0120
63.8
100%
NR
0.049
0.040
0.066
15%
0.03
0.026
<LOD
0.217
20%
0.01
—

PERFLUOROALKYLS

734
5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-26. Percent Detection and Levels of Other Perfluoroalkyls in Children’s
Umbilical Cord Blood and Breast Milk
Samplepopulation

PFHpA

PFNA

Sweden (n=12) (Kärrman et al. 2007a)
Milk
Percent >LOD
17%
LOD
0.005
Mean
0.017
Range
<0.005–0.020
Maternal serum
Percent >LOD
100%
LOD
0.005
Mean
0.80
Range
0.43–2.5
China (n=19) (So et al. 2006b)
Percent >LOD
37%
LOD
0.005–
0.010
Range<0.005–0.0067100%
0.001–
0.010
0.01–
0.062

Detection and concentration (ng/mL [ppb])a
PFDA
PFUnA
PFDoDA PFBS
PFHxS

FOSA

0%
0.008
—
—

0%
0.005
—
—

100%
0.01
0.085
0.031–
0.172

67%
0.007
0.013
<0.007–
0.030

100%
0.008
0.53
0.27–1.8

100%
0.005
0.40
0.20–1.5

100%
0.01
4.7
1.8–11.8

75%
0.007
0.24
0.16–0.19100%
0.0011–0.00250.0038–0.011

100%
0.0022–0.00500.0091–0.056

11%0.001–
0.005<0.001–0.0025100%
0.001–
0.010
0.004–
0.10

a"Less than" values indicate that the concentration was reported as below the LOD or LLOQ.

For cases where
samples had concentrations below the LOD or LLOQ, a value between zero and the LOD or LLOQ was assigned
when calculating the mean concentration.
bLOD or LLOQ not reported.
Gray cells indicate that chemical was not evaluated; “—“ indicates no available data; DOB = date of birth;
FOSA = perfluorooctane sulfonamide; LLOQ = lower limit of quantification; LOD = limit of detection; LOQ = limit ofquantification; ND = no data; NR = not reported; PFBS = perfluorobutane sulfonic acid; PFDA = perfluorodecanoicacid; PFDoDA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonicacid; PFNA = perfluorononanoic acid; PFUnA = perfluoroundecanoic acidTao et al. (2008b) measured perfluoroalkyl concentrations in 45 human breast milk samples collectedfrom Massachusetts. PFOS, PFOA, PFHxS, and PFNA were each detected in 96, 89, 51, and 64% of thesamples, respectively, with median concentrations of 106, 36.1, 12.1, and 6.97 pg/mL, respectively.
PFHpA, PFDA, PFUnA, PFDoDA, and PFBS were each detected in <1% of the samples. Perfluoroalkyls
have also been measured in the human breast milk of individuals from Sweden, China, and Germany/
Hungary (Kärrman et al. 2007; So et al. 2006b; Völkel et al. 2008). PFOS was detected in all samples,while detection of PFOA ranged from 8 to 100% in these studies. The reported maximum concentrationsof PFOS and PFOA measured in human breast milk samples collected during these studies were 0.360–
0.639 and 0.210–0.490 ng/mL, respectively (Kärrman et al. 2007; So et al. 2006b; Völkel et al. 2008).
Other perfluoroalkyls detected in human breast milk included PFHpA, PFNA, PFDA, PFUnA, PFBS,PERFLUOROALKYLS

735
5. POTENTIAL FOR HUMAN EXPOSURE

PFHxS, and FOSA. Maximum concentrations of these compounds were reported to be <0.18 ng/mL(Kärrman et al. 2007).

The presence of perfluoroalkyls in umbilical cord blood indicates that these substances can cross theplacental barrier resulting in the exposure of babies in utero (Apelberg et al. 2007a, 2007b; Fei et al.
2007; Inoue et al. 2004; Midasch et al. 2007). In most studies, PFOS and PFOA have been detected inmost umbilical cord blood samples with reported maximum (or 95th percentile) concentrations of 5.3–
34.8 and 1.68–7.1 ng/mL, respectively (Apelberg et al. 2007a, 2007b; Fei et al. 2007; Inoue et al. 2004;
Midasch et al. 2007; Morello-Frosch et al. 2016). Inoue et al. (2004) did not detect PFOA in 15 cord
blood samples from Japan; however, this compound was only detected in the maternal serum of threemothers. Apelberg et al. (2007a) also reported concentrations of other perfluoroalkyls measured in 299
cord serum samples collected during the Baltimore THREE Study. Of these compounds, PFDA, PFUnA,
and FOSA were detected most frequently (24, 34, and 26%, respectively). Maximum concentrations inthese samples ranged from 1.1 to 1.9 ng/mL. PFHpA, PFDoDA, and PFBS were each detected in <6% of
the samples, with maximum concentrations ranging from 0.2 to 2.6 ng/mL. Manzano-Salgado et al.
(2015) studied the potential transfer of perfluoroalkyls from mothers to their children during pregnancy.
Maternal blood and cord serum were collected from 66 mother-child pairs and analyzed for the presenceof perfluoroalkyls. A positive correlation was found between maternal plasma and maternal serum withcord serum levels, and the authors concluded that either maternal plasma or maternal serum could be used
as a method to estimate fetal exposure to perfluoroalkyls. Median concentrations of PFOS and PFOA
were 6.18 and 2.85 ng/mL, respectively, in maternal plasma and 6.99 and 2.97 ng/mL, respectively, inmaternal serum. PFOS and PFOA levels in cord serum were 1.86 and 1.90 ng/mL, respectively. A
biomonitoring survey of 1,533 pregnant females in Denmark from 2008 to 2013 showed decreasing levelsof most perfluoroalkyls in the females’ blood during this time period (Bjerregaard-Olesen et al. 2016).
The results of this study showed that serum levels of PFHxS, PFOS, PFOA, PFNA, and PFDA decreased
at a rate of 7.0, 9.3, 9.1, 6.2, and 6.3 per year, respectively. Morello-Frosch et al. (2016) measured thelevels of perfluoroalkyls in 77 maternal and 65 paired umbilical cord blood samples from pregnant
females and newborn children in San Francisco, California. Perfluoroalkyls, including PFOA and PFOS,
were widely detected; however, concentrations in cord blood or serum were typically equal to or lower
than maternal blood levels.

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

5.7

POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Potentially high exposures to perfluoroalkyls can occur in the following population categories:
perfluoroalkyl production and manufacturing workers, communities located near fluorochemical
facilities, and individuals with prolonged use of perfluoroalkyl-containing products. Workers at
perfluoroalkyl production and manufacturing facilities and community members living near thesefacilities may have higher exposure to perfluoroalkyls than the general population based on elevatedconcentrations of these substances measured in air, soil, sediment, surface water, groundwater, andvegetation surrounding these facilities (3M 2007b, 2008b, 2008c; Barton et al. 2006; Davis et al. 2007;
Olsen 2015). Additionally, children may be at risk for higher potential exposure due to hand-to-mouthtransfer of chemicals from dust and the ingestion of dirt (Shoeib et al. 2004; Trudel et al. 2008). Levelsof perfluoroalkyls measured in the blood of production and manufacturing workers at several facilities arelisted in Table 5-27. The serum PFOA, PFOS, and PFHxS levels in workers were frequently 100–
1,000 times higher than in the general population. 3M estimated PFOA doses for various on-site
exposure scenarios based on monitoring information collected at the Decatur Facility in Alabama (3M2008c). Occupational exposure scenarios included groundskeeper/maintenance worker andconstruction/utility worker exposed to on-site soils, surface water, and sediment. According to 3M,
estimated on-site exposure to PFOA ranged from 3.2x10-6 to 2.4 ng/kg/day, with the highest estimatedexposure corresponding to construction/utility workers engaged in projects involving contact with soil
from an on-site field. Chang et al. (2008a) measured concentrations of PFBA in the serum of 127 former
employees and 50 current employees of the 3M Cottage Grove Facility in Minnesota. PFBA serum
concentrations were below the detection limit in 73.2% of the former employees and 68.0% of the current
employees. Only 4% of the serum samples contained PFBA above 2 ng/mL, with maximum
concentrations of 6.2 ng/mL for the former employees and 2.2 ng/mL for the current employees.

Table 5-27. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for
Occupationally Exposed Individuals

Location

Mean concentration (ng/mL [ppb])
PFOA
PFOS
PFHxS

Reference

3M Decatur, Alabama
1993 (n=111)
1995 (n=80)

0.00–80,000 (range)
0.00–114,100 (range)

Olsen et al. 1998b
Olsen et al. 1998b

1995 (n=90)
1997 (n=84)
1998 (n=126)
2000 (n=215)

1,536
11,900

2,440
1,960
1,505
1,400

345

Olsen et al. 1999
Olsen et al. 1999
Olsen 2015
Olsen et al. 2003a

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-27. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for
Occupationally Exposed Individuals

Location
2000 (n=263)
1999–2004 (n=26 retired
workers)
InitialFinal
3M Cottage Grove, Minnesota
1993 (n=111)
1995 (n=80)
1997 (n=74)
2000 (n=122)

Mean concentration (ng/mL [ppb])
PFOA
PFOS
PFHxS
1,780

1,320

250

691
262

799
403

290
182

5,000 (1,100
geometric mean)
6,800 (1,200
geometric mean)
6,400 (1,300
geometric mean)
4,630 (810 geometric 860
mean)

Olsen 2015
Olsen et al. 2007a

Olsen et al. 2000;
Olsen 2015
Olsen et al. 2000;
Olsen 2015
Olsen et al. 2000;
Olsen 2015
Olsen and Zobel
2007; Olsen 2015

DuPont Washington Works, Ohio
1979-2004
All workers (n=1308 workers,
2125 samples)

Reference

Woskie et al. 2012
2,050

Direct PFOA exposure (n=170 5,470
workers; 541 samples)
Direct PFOA exposure (n=96
workers; 208 samples)
2004–2005
Substantial occupational
exposure (n=18)
2004
Current occupational exposure(n=259)Intermittent current
occupational exposure (n=160)
Past occupational exposure(n=264)
3M Antwerp, Belgium
1995 (n=88)
1997 (n=65)
2000 (n=206)
2000 (n=258)

2,530
Emmett et al. 2006a
824
Sakr et al. 2007b494 (median)
176 (median)
195 (median)

1,030

1,930
1,480
960

840

800

Olsen et al. 1999
Olsen et al. 1999
Olsen et al. 2003a170

Olsen 2015

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-27. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for
Occupationally Exposed Individuals

Location
Miteni, Trissino, Italy
2007
Current occupational exposure(n=39)
Former occupational exposure(n=11)
2000 (n=25)
2001 (n=42)
2002 (n=46)
2003 (n=41)
2004 (n=34)
2006 (n=49)
2007 (n=50)

Mean concentration (ng/mL [ppb])
PFOA
PFOS
PFHxS

Reference

5,710c (200–47,040)

Costa et al. 2009

4,430c (530–18,660)

Costa et al. 2009

18,80019,70019,30013,700

Costa et al. 2009
Costa et al. 2009
Costa et al. 2009
Costa et al. 2009

11,40010,80011,600

Costa et al. 2009
Costa et al. 2009
Costa et al. 2009

aData include results from three retirees from the 3M plant in Cottage Grove, Minnesota.

Gray cells indicate that chemical was not evaluated; PFHxS = perfluorohexane sulfonic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acidIndividuals who performed jobs that require frequent and/or prolonged contact with perfluoroalkyl
containing products, such as firefighters, waste handlers, individuals who install and treat carpets, orindividuals with prolonged use of ski wax may also have higher occupational exposure to perfluoroalkyls.
Some firefighting foams contain perfluoroalkyls, and firefighters who use these products have beenshown to have greater exposures as compared to the general population. Dobraca et al. (2015) compared
perfluoroalkyl serum levels of a group of firefighters in California to an adult population from the
NHANES survey. Levels of PFOA and PFOS were only slightly higher in the firefighter group(geometric means 3.75 and 12.50 ng/mL, respectively) when compared to adult males in the 2009–2010
NHANES general population survey (3.61 and 12.13 ng/mL, respectively); however, PFDA serum
concentrations of firefighters were up to 3 times greater than the NHANES comparison group for the
25th–95th percentiles (50th percentile in firefighters; 0.72 ng/mL compared to 0.30 ng/mL) and thegeometric mean (0.90 ng/mL compared to 0.30 ng/mL). In a small-scale study of 37 firefightersparticipating in the C8 Health Project, significantly (adjusted for age, water district, household income,and smoking) higher levels of PFOA and PFHxS were found in the firefighters compared to 5,373 maleparticipants with other jobs (Jin et al. 2011). Geometric mean PFOA and PFHxS levels were 37.59 and4.77 ng/mL, respectively, in the firefighters and 31.59 and 3.62 ng/mL, respectively, in the otherPERFLUOROALKYLS

739
5. POTENTIAL FOR HUMAN EXPOSURE

participants. No significant differences in PFOS or PFNA levels were found between the groups. A
biomonitoring study of 149 firefighters in Australia showed that 100% of serum samples collected had
detectable levels of PFOA, PFOS, PFHxS, and PFNA (Rotander et al. 2015). Serum levels of PFHxS
were found to be approximately 10–15 times higher than levels found in the general population ofAustralia and Canada, while PFOS levels in the firefighters were approximately 6–10 times greater than
the general population of these nations.

Elevated serum levels of PFOA, PFNA, PFHxA, PFHpA, PFDA, and PFUnA have been found in
professional ski waxes containing fluorotelomers; the perfluoroalkyls were likely formed via
fluorotelomer metabolism (Olsen 2015). Christensen et al. (2016) conducted a biomonitoring study ofperfluoroalkyls on male fishermen from Wisconsin ≥50 years old with a history of sport fishconsumption. Increasing age and lower BMI were generally associated with higher levels of theperfluoroalkyls; however, there were only weak correlations observed between amounts of fishconsumption and perfluoroalkyl levels, with the exception of PFDA. Levels of PFOA, PFNA, andPFHxS in the blood of the male anglers were similar to the levels for a subset of the NHANES 2011–2012 survey (non-Hispanic white males ≥50 years old); however, levels of PFOS and PFDA wereapproximately 2 times greater in the anglers as compared to the NHANES survey subgroup. The medianand 95th percentile concentrations of PFOS in the anglers were 19.00 and 54.00 ng/mL, respectively, as
compared to 10.33 and 25.83 ng/mL, respectively, in the NHANES study group. The median and 95th
percentile concentrations of PFDA in the anglers were 0.52 and 1.90 ng/mL, respectively, as compared to
0.23 and 0.53 ng/mL in the NHANES study group. Family members of occupationally exposed workers
have been shown to have higher exposure to perfluoroalkyls via dust transfer as compared to family
members of nonoccupationally exposed workers (Fu et al. 2015).

PFOA, PFOS, PFBA, PFBS, PFNA, and PFHxS have been detected in the municipal drinking water andprivate wells of some communities located near fluorochemical facilities (3M 2008c; ATSDR 2008;
Emmett et al. 2006a; Hoffman et al. 2011; Hölzer et al. 2008; Post et al. 2013; Steenland et al. 2009a;
Wilhelm et al. 2009). Emmett et al. (2006a) compared PFOA serum levels to various types of exposurefor individuals living in the Little Hocking community (near DuPont's Washington Works facility) andconcluded that residential water source was the primary determinant of serum PFOA at this location.
These authors reported that the mean human serum PFOA level was 105 times higher than the residential
drinking water level. Median serum PFOA levels were 371 ng/mL in residents for whom this was the
only residential water source and 71 ng/mL in those who used bottled, cistern, or spring water. Increased
serum PFOA was associated with increasing number of drinks of tap water daily and also with increasing

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

use of water for making soups and stews and in-home canning of fruits and vegetables. Use of a carbon
water filter reduced PFOA levels by about 25%. In a follow-up study, 231 study participants in the Little
Hocking Water District were evaluated 15 months later with 88% using bottled water exclusively; 8% had
made other changes to their ingestion of residential water including use of activated carbon water filters.
PFOA levels had decreased an average of 26% from the initial levels (Emmett et al. 2009). Similarly,
Bartell et al. (2010) found that serum levels of PFOA declined significantly following the implementationof GAC filtration of the public water supply. The average decrease in serum PFOA levels for Lubeck,
West Virginia residents primarily consuming public water at home (n=130) was 26% 1 year after
treatment began. Similar trends were reported for residents of Little Hocking, Ohio. The average
decrease in PFOA serum levels for residents primarily consuming public water (n=39) was about 11%
6 months after treatment began.

Median PFOA serum levels for residents currently residing in six water districts located in the mid-Ohio
Valley near the Washington Works facility ranged from 12.1 to 224.1 ng/mL, while the medianconcentration ranged from 10.5 to 33.7 ng/mL for residents who previously worked or resided in these
districts (Steenland et al. 2009a). Former employees at the chemical plant had much higher levels(median=75 ng/mL) than people who had not worked at the plant (median=24 ng/mL), but lower levels
than those who continued to be employed at the plant during the monitoring period (median=148 ng/mL).
Another study of this community reported a median serum PFOA concentration of 24.3 ng/mL for
45,276 non-occupationally exposed individuals in 2005–2006 (Shin et al. 2011a). This was about 8 times
greater than the median concentration (3.20 ng/mL) of 2,120 residents of the general population takenfrom the NHANES data for 2005–2006 (CDC 2018).

A study of residents consuming drinking water from the Ohio River and the Ohio River Aquifer reported
elevated median PFOA levels of 13.8 ng/mL in blood samples collected in 1991–1993 from 139 residents(Herrick et al. 2017). In samples collected in 2011–2013 (n=133), the serum PFOA levels dropped to
4.3 ng/mL. The serum PFOS levels in samples collected in 1994–1996 (median of 32.2 ng/mL, n=189)
were similar to levels in the general population (Herrick et al. 2017); similar to the decline observed in thegeneral population, median serum PFOS levels were 6.3 ng/mL in 2011–2013.

The Minnesota Department of Health conducted a biomonitoring study of 196 residents living inWashington county, east of the Minneapolis-St. Paul metropolitan area; private and municipal drinking
water wells were shown to be contaminated with perfluoroalkyls (MDH 2009). In 2008–2009, geometricmean serum PFOA, PFOS, and PFHxS levels were 15.4, 35.9, and 8.4 ng/mL, respectively; these values

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

were higher than levels reported in NHANES (Landsteiner et al. 2014; MDH 2009). The investigators
noted that the geometric mean serum concentrations of these three substances were greater in residents
obtaining drinking water from municipal water supplies as compared to residents with private wells(Landsteiner et al. 2014). Monitoring efforts also conducted in Washington County, Minnesota near the
3M Cottage Grove Facility revealed widespread contamination of PFBA in the groundwater in 2006
(ATSDR 2008). PFBA was detected in 28% of the community members’ serum samples; the75th percentile serum concentration for PFBA was 0.135 ng/mL and the maximum concentration was
8.5 ng/mL (MDH 2000).

ATSDR performed an exposure investigation for residents of Decatur, Alabama following an accidental
release of perfluoroalkyls into the Decatur waste water treatment plant (ATSDR 2013). A group of
155 residents had their blood tested for levels of eight perfluoroalkyls. Serum levels for PFNA, PFDA,
and FOSA were lower or similar to levels of the general population when compared to the NHANES
results. Elevated serum PFOA, PFOS, and PFHxS levels were observed; geometric mean values were
16.3, 39.8, and 6.4 ng/mL, respectively. Residents who used the West Morgan/East Lawrence public
water supply had significantly higher geometric mean serum levels of PFOA (17.59 ng/mL) and PFHxS(6.68 ng/mL) as compared to the geometric mean for a similar demographic group from the NHANES
survey. Serum perfluoroalkyl levels in the residents were shown to be much lower than levels found in
occupationally exposed individuals who regularly worked with these substances (ATSDR 2013).

Additional blood serum levels of PFOA and PFOS for residents in selected areas of Ohio, West Virginia,
New Jersey, and Minnesota whose residential source of drinking water may have been contaminated areavailable from the EPA docket on PFOA and related perfluoroalkyls (EPA-HQ-OPPT-2003-0012) (Bilott
2004, 2005a, 2005b, 2007).

The Emmett et al. (2006a) and Steenland et al. (2009a) studies of the community near the Washington
Works facility and the 3M (2008c) study of the Decatur Facility in Alabama found age-related differences
in serum PFOA levels. In a comparison of serum PFOA levels in various age groups of residents serviced
by the Little Hocking Water Association district, Emmett et al. (2006a) found that 2–5-year-old children
had a higher serum PFOA (median 600 ng/mL) compared with residents in all other age groups (median
321 ng/mL) except for the group aged >60 years, whose levels were similar to those in young children.
Several factors may have contributed to the observed high levels in children: infants and young children
proportionally drink more water per kg of body weight than adults; children (and also the elderly) tend to
spend more time at home with exclusive use of residential water than other age groups; and trans-

PERFLUOROALKYLS

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5. POTENTIAL FOR HUMAN EXPOSURE

placental and breast milk exposures could also contribute to levels in children. In the Steenland et al.
(2009a) study, PFOA serum levels tended to be highest for children aged 0–9 years and persons >50 years
old. The serum levels of the 69,030 residents participating in this study categorized by age are provided
in Table 5-28. 3M (2008c) estimated doses for various off-site exposure scenarios based on monitoring
information collected at the Decatur Facility. Exposure scenarios include local children and adultresidents exposed to PFOA in off-site soils, groundwater, municipal water, fish from the Tennessee River,and surface water and sediments in the Tennessee River. According to 3M, estimated off-site exposure of
local residents to PFOA ranged from 0.011 to 260 ng/kg/day, with the highest estimated exposure
corresponding to children whose source of drinking water was groundwater adjacent to the southern sideof the facility.

Table 5-28. Blood Serum Levels for 69,030 Current and Former Residents of Six
Water Districts in the Mid-Ohio Valley (2005–2006)
Age (years)

Number (percentage of total)

Median perfluorooctanoic acid(PFOA) level (ng/mL)

0–9
10–19

4,915 (7.1)
9,658 (14.0)

32.8
26.6

20–29
30–39
40–49
50–59
60–69
≥70

10,073 (14.6)
10,547 (15.3)
12,113 (17.6)
10,515 (15.2)
6,881 (10)4,328 (6.3)

21.0
22.7
28.0
33.6
42.9
40.1

Source: Steenland et al. 2009a

PERFLUOROALKYLS

743

CHAPTER 6. ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
adequate information on the health effects of perfluoroalkyls is available. Where adequate information is
not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program ofresearch designed to determine the adverse health effects (and techniques for developing methods todetermine such health effects) of perfluoroalkyls.

Data needs are defined as substance-specific informational needs that, if met, would reduce theuncertainties of human health risk assessment. This definition should not be interpreted to mean that alldata needs discussed in this section must be filled. In the future, the identified data needs will be
evaluated and prioritized, and a substance-specific research agenda will be proposed.
6.1

Existing Information on Health Effects

Studies evaluating the health effects of inhalation, oral, and dermal exposure of humans and animals to
PFOA, PFOS, and other perfluoroalkyls that are discussed in Chapter 2 are summarized in Figures 6-1,
6-2, and 6-3, respectively. The purpose of these figures is to illustrate the information concerning thehealth effects of perfluoroalkyls. The number of human and animal studies examining each endpoint isindicated regardless of whether an effect was found and the quality of the study or studies.

As illustrated in Figures 6-1, 6-2, and 6-3, most of the data on the toxicity of PFOA, PFOS, and otherperfluoroalkyls come from epidemiological studies in humans; oral exposure is the assumed route of
exposure for the epidemiological studies. The epidemiology database consists of health evaluations ofsubjects exposed in occupational settings (primarily PFOA and PFOS), highly exposed residents living
near a PFOA facility, and studies of the general population. The most commonly examined endpoints inthe epidemiological studies were developmental, hepatic, reproductive, and immunological effects.

PERFLUOROALKYLS

744
6. ADEQUACY OF THE DATABASE

Figure 6-1. Summary of Existing Health Effects Studies on PFOA by Route andEndpoint*
Potential body weight, hepatic, and developmental effects were the most studied
endpoints
The majority of the studies examined oral exposure in humans (versus animals)*Oral exposure was the presumed route of exposure for human studies involving environmental exposure. Human andanimal studies may have examined more than one endpoint. A “—“ indicates that no studies are available.

PERFLUOROALKYLS

745
6. ADEQUACY OF THE DATABASE

Figure 6-2. Summary of Existing Health Effects Studies on PFOS by Route andEndpoint*
Potential developmental, hepatic, and reproductive effects were the most studied
endpoints
The studies examined oral exposure in humans (versus animals)*Oral exposure was the presumed route of exposure for human studies involving environmental exposure. Human andanimal studies may have examined more than one endpoint. A “—“ indicates that no studies are available.

PERFLUOROALKYLS

746
6. ADEQUACY OF THE DATABASE

Figure 6-3. Summary of Existing Health Effects Studies on Other Perfluoroalkyls
by Route and Endpoint*
Potential hepatic, immunological, and developmental effects were the most studied
endpoints
The majority of the studies examined oral exposure in humans (versus animals)*Oral exposure is the presumed route of exposure for human studies involving environmental exposure. Most humanstudies examined multiple perfluoroalkyls. Human and animal studies may have examined more than one endpoint.
A “—“ indicates that no studies are available. Includes data for PFBA, PFHxA, PFHpA, PFNA, PFDA, PFUnA, PFBS,PFHxS, PFDoDA, and FOSA.

PERFLUOROALKYLS

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6. ADEQUACY OF THE DATABASE

Most of the information regarding the effects of perfluoroalkyls in animals has been derived from oral
studies; considerably less information is available from inhalation and dermal exposure studies. PFOA
and PFOS have been the most extensively studied members of this class of chemicals, and oral
administration has been the preferred route of exposure in animal studies. Information regarding otherperfluoroalkyls covered in this profile is limited to acute-duration oral studies with PFHxS, PFNA,
PFDA, PFBA, PFDoDA, PFHxA, and FOSA; intermediate-duration oral studies with PFHxS, PFNA,
PFDA, PFUnA, PFBS, PFBA, PFDoDA, and PFHxA; and a chronic-duration oral study with PFHxA.
An acute-duration-inhalation study with PFNA is also available. The most commonly examined
endpoints were hepatic, body weight, developmental, reproductive, and immunological effects.
6.2

Identification of Data Needs

Missing information in Figures 6-1, 6-2, and 6-3 should not be interpreted as a “data need.” A data need,
as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to
Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct
comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any
substance-specific information missing from the scientific literature.
Acute-Duration MRLs. The available acute inhalation database for PFOA was considered inadequate
for derivation of an MRL due to lack of measured serum PFOA levels in the available animal studies andthe lack of PBPK model parameters that could be used to predict serum levels. The inhalation databasefor PFNA was not considered adequate due to the limited endpoints examined and the short exposure
duration of the only available study. No inhalation data were available for PFOS or the otherperfluoroalkyls. A number of studies have evaluated the acute toxicity of PFOA and PFOS following oral
exposure and have identified several sensitive targets of toxicity. Smaller numbers of studies evaluatedpotential sensitive targets of acute toxicity for PFNA and PFDA. However, toxicokinetic differences
between humans and laboratory animals, particularly the relative short half-life in rodents compared tohumans, preclude derivation of an acute MRL for these compounds. For other perfluoroalkyls (PFHxS,PFBA, PFDoDA, FOSA), the available studies were not considered adequate for identification of criticaltargets; did not examine sensitive targets that were identified for other perfluoroalkyls, such as
developmental and immunological endpoints; or involved a single exposure. No acute oral data wereidentified for PFUnA, PFHpA, or PFBS. Research is needed to develop a PBPK model that would allow
for extrapolation from rodents to humans. Additionally, toxicity studies are needed for mostperfluoroalkyls to identify critical targets of toxicity and/or establish dose-response relationships. ThesePERFLUOROALKYLS

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6. ADEQUACY OF THE DATABASE

studies should examine developmental and reproductive endpoints that have been established as the mostsensitive targets of toxicity for PFOA and PFOS.
Intermediate-Duration MRLs. No intermediate-duration inhalation studies were identified for
perfluoroalkyls. Oral studies suggest that developmental and immune effects are the most sensitive
targets of toxicity; similar effects are likely to occur following inhalation exposure because
perfluoroalkyls are not metabolized. Inhalation studies are needed to establish dose-response
relationships and to establish whether the respiratory tract is a sensitive target of toxicity. Theintermediate-duration oral databases were considered adequate for derivation of MRLs for PFOA andPFOS. The MRL for PFOA is based on altered bone development measured in mature mice exposed inutero. The principal study only tested one PFOA dose level and only examined long bones; additional
studies utilizing several dose levels, examining other types of bone, and testing a second species would
provide support for the MRL. A modifying factor was used for PFOS due to the lack of PBPK modelingparameters; additional studies are needed that would allow for predicting steady-state serum PFOS levels
for immunotoxicity studies in laboratory animals. An important decision made in the derivation ofintermediate oral MRLs was to use the time-weighted average serum concentrations (CTWA) of PFOA orPFOS as the basis for extrapolations of the dose-response PODs from animal studies to human equivalentdoses (HEDs). However, the available data on the toxicity of PFOA and PFOS do not provide convincing
evidence that toxicity outcomes are more likely to be determined by CTWA rather than Cmax. Since the
PBPK model used for dosimetry modeling of the animal studies predicted that CTWA is lower than Cmax inthe principal studies for the MRLs, selection of CTWA as the internal dose metric results in lower values
for MRLs. Therefore, use of CTWA, rather than Cmax is a health-protective decision that might be more
adequately evaluated with additional studies that evaluate associations between Cmax, CTWA, and toxicity
outcome responses.

Intermediate-duration MRLs were also derived for PFHxS and PFNA; however, these were based on
marginal databases and additional dose-response studies are needed to support the basis of the MRL. The
databases were not considered adequate for PFUnA, PFBS, PFBA, or PFDoDA due to the lack of studies
examining potential sensitive targets (developmental and/or immune effects). No intermediate-duration
oral studies are available for PFDA, PFHpA, or FOSA. Intermediate-duration oral studies are needed forthese seven perfluoroalkyls to provide information on sensitive targets and establish dose-response
relationships. These studies should include measurement of serum perfluoroalkyl levels, which would
allow for estimating HEDs.

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6. ADEQUACY OF THE DATABASE

An additional uncertainty in the MRLs was the confidence in the elimination half-lives for perfluoroalkyls
used in the empirical model for calculating HEDs. Estimated half-lives for PFOA and PFOS vary andcontributors to this variability have not been completely characterized. The empirical model used to
calculate HEDs is linear; therefore, the change in the HED is approximately proportional to the change inthe half-life. A halving of the half-life would result in a doubling of the HED. Studies that can improve
confidence in the half-life estimates would increase confidence in MRLs.
Chronic-Duration MRLs. The lack of chronic-duration inhalation studies for perfluoroalkyls
precluded derivation of chronic MRLs. Chronic toxicity studies examining a wide range of endpoints areneeded to identify the most sensitive target and establish concentration-response relationships. A small
number of chronic duration oral studies have been identified in laboratory animals. Four studies
examined the chronic toxicity of PFOA, PFOS, or PFHxA. These studies were not considered suitablefor derivation of MRLs because they did not evaluate immunotoxicity which was a sensitive target
following shorter term exposures. Studies examining this potentially sensitive endpoint are needed to
identify the most sensitive target following chronic exposure.
Health Effects. Over 600 studies have evaluated the toxicity of perfluoroalkyls; epidemiologicalstudies account for over 400 of the toxicity studies. Evidence from epidemiological studies suggest
associations between perfluoroalkyl exposure and several health outcomes including liver damage,increases in serum lipids, thyroid disease, immune effects, reproductive toxicity, and developmental
toxicity. The primary health effects observed in laboratory animals are liver, developmental, and immune
toxicity. Although a large number of studies evaluating health effects are available, there is a need for
additional studies to address data gaps. Future laboratory animal studies should include measurement ofserum perfluoroalkyl levels, as this would provide valuable information for comparing effects observed inlaboratory animals to effects observed in humans.

Hepatic Effects. Evidence from acute, intermediate, and/or chronic oral studies in rats, mice, andmonkeys indicates that the liver is a sensitive target of PFOA, PFOS, PFHxS, PFNA, PFDA, PFUnA,PFBA, PFBS, PFDoDA, and PFHpA toxicity. The effects observed in rodents differ from thoseobserved in humans. In humans, exposure to PFOA, PFOS, PFNA, and PFDA appear to result inincreases in serum lipid levels, particularly total cholesterol levels. However, animal studies havefound decreases in serum lipid levels associated with exposure to most perfluoroalkyls. It is notknown if the species differences are due to different mechanisms of toxicity or differences inPERFLUOROALKYLS

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6. ADEQUACY OF THE DATABASE

exposure levels (serum levels observed in animal studies are orders of magnitude higher than those in
human studies).
Immune Effects: Epidemiological data suggest an association between PFOA, PFOS, PFHxS, andPFDA and decreased antibody response to vaccines. This is supported by acute- and intermediateduration studies of PFOA and PFOS in laboratory animals. There is also evidence of immunotoxicity
following a single injection of PFNA; some of the immune effects persisted 4 weeks post-exposure.
Shorter-term studies are needed for other perfluoroalkyls. In addition, chronic-duration studies
evaluating immune endpoints, particularly immunosuppression, for all perfluoroalkyls would allow
for identification of the critical targets of toxicity.

Reproductive Effects. Decreases in mammary gland development have been demonstrated inseveral PFOA mouse studies. The effect levels observed in these studies are very low, although there
is some indication that at lower doses, the changes in mammary gland development do not affectlactation. Additional studies are needed to evaluate the adversity of these alterations. This endpoint
has not been evaluated for other perfluoroalkyls and studies are needed to determine whether it is alsoa sensitive effect for these compounds.
Developmental Effects. Based on the results of laboratory animal studies, developmental
endpoints are targets of PFOA, PFOS, PFHxS, PFNA, PFDA, PFUnA, and PFBA toxicity following
acute- and/or intermediate-duration oral exposure. Studies are needed to evaluate potential
developmental effects for PFHxS following intermediate-duration oral exposure. Additionally, crossfostering studies would provide information that could be used to evaluate the health impact of
lactational exposure to perfluoroalkyls. Epidemiological studies in children suggest altered responses
to vaccination; two animal studies have evaluated immune effects following perinatal exposure to
PFOA and PFOS, but data are lacking for other perfluoroalkyls.
Potential Interactions between Perfluoroalkyls. A common limitation of the epidemiological
data is co-exposure to multiple perfluoroalkyls. There are limited data on possible interactions
between perfluoroalkyls and possible effects on toxicity and toxicokinetics. Animal studies
examining the possible interactions between perfluoroalkyls would be useful for interpreting theepidemiological study results; this is especially important since humans are typically exposed tomultiple perfluoroalkyls and many of them are likely to have similar mechanisms of action.

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6. ADEQUACY OF THE DATABASE

Mechanisms of Toxicity. Many of the effects observed in rodents, particularly liver anddevelopmental effects, involve the activation of PPARα; humans and nonhuman primates are lessresponsive to PPARα agonists than rats and mice. However, the results of studies in PPARα-nullmice suggest that PPARα-independent mechanisms also play a role in the liver, immunological, anddevelopmental toxicity. Additional studies are needed on the mechanisms of toxicity to assess
whether the effects observed in laboratory animals are relevant to humans. Mechanistic studies
would also provide support for the critical effects used to derive the MRLs for PFOA, PFOS, PFHxS,and PFNA.
Epidemiology and Human Dosimetry Studies. As previously mentioned, information is available
regarding the effects of exposure to perfluoroalkyls in humans derived from health evaluations of subjects
exposed in occupational settings, residents living near a PFOA manufacturing facility with high levels of
PFOA in the drinking water, and the general population. Although many studies found statisticallysignificant associations between serum perfluoroalkyl levels and the occurrence of an adverse healtheffect, the findings were not consistent across studies. Interpretation of the human data is limited by thereliance of cross-sectional studies, which do not establish causality, and the lack of exposure data.
Studies on serum lipids suggest that the dose-response curve is steeper at lower concentrations andflattens out at higher serum perfluoroalkyl concentrations (Steenland et al. 2010a); additional studies that
could be used to establish dose-response relationships would be valuable. Mechanistic studies examining
the association between perfluoroalkyl exposure and serum lipid levels would also provide valuable
insight. Clarification of the significance and dose-response relationships for other observed effects is alsoneeded. Longitudinal studies examining a wide range of endpoints would be useful for identifying criticaltargets of toxicity in humans exposed to perfluoroalkyls. The available human studies have identified
some potential targets of toxicity; however, cause-and-effect relationships have not been established forany of the effects, and the effects have not been consistently found in all studies. Mechanistic studies
would be useful for establishing causality. When possible, health assessments should include subjects ofdifferent race/ethnicity and age to determine potential race/ethnicity- and age-based susceptibilities.
Another limitation of the epidemiological studies is co-exposure to other perfluoroalkyls; studies thatstatistically controlled for co-exposure to other pollutants would decrease this uncertainty. As noted
previously, there is a need for studies evaluating potential interactions between perfluoroalkyls.
Biomarkers of Exposure and Effect. Data are available regarding levels of perfluoroalkyls in serumfrom the general population, highly exposed residents, and perfluoroalkyl workers. Information is needed
regarding the toxicokinetics (see also below) of perfluoroalkyls in humans to be able to relate levels of

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6. ADEQUACY OF THE DATABASE

these compounds in serum to exposure to specific perfluoroalkyls; data on matched serum and urine
samples would be valuable. Also needed is further information on the relationship between serum andliver concentrations of perfluoroalkyls in humans.
Absorption, Distribution, Metabolism, and Excretion. Several epidemiological studies haveexamined the kinetics of serum perfluoroalkyl concentrations following a change in environmental or
occupational exposure, from which estimates of terminal elimination half-lives in adults are available for
PFOA, PFOS, PFHxS, PFBA, and PFBS. Other studies provide data on the renal clearances of PFOA
and PFOS, binding of PFOA, PFOS, and PFHxS to human plasma protein, tissue levels (primarily blood,maternal and fetal cord serum, and breast milk). Data on other aspects of the toxicokinetics ofperfluoroalkyls in humans are not available and could serve to improve predictions of internal dosimetry
associated with exposures to perfluoroalkyls (bioavailability, kinetics of tissue distribution andelimination, binding in tissues, external-internal dose relationships, all aspects of toxicokinetics inchildren and aging populations).

Toxicokinetics of perfluoroalkyls have been studied much more extensively in rodents (rats and mice) andless extensively in Cynomolgus monkeys; however, a number of data gaps have been identified:•Absorption studies; oral absorption data are available for PFOA, PFOS, and PFBA, but are more
limited for other perfluoroalkyls and for other exposure routes. Studies elucidating themechanisms of pulmonary and gastrointestinal absorption are also needed.

•

Studies have shown that elimination kinetics, and therefore, internal dose-external dose
relationships, are dependent on structure, including the terminal acid group (carboxylate or
sulfonate), carbon chain length, and carbon chain branching. These structural features affectplasma and tissue protein binding, renal and biliary clearances, tissue levels, maternal-fetaltransfer, and lactational transfer of perfluoroalkyls. Studies examining differences between
perfluoroalkyls would be useful for extrapolating health effects and toxicokinetic data acrosscompounds.

•

Toxicokinetic studies have found sex- and dose-dependent subcellular distribution of PFOA in
rats. Further studies on the mechanisms for dose-dependency, characterization of subcellularbinding proteins, and mechanistic linkages between subcellular distribution and toxicity ofperfluoroalkyls are needed.

•

The distribution and elimination of PFOA and PFOS are greatly influenced by binding
interactions with albumin and other high molecular weight plasma proteins; available datasuggest that binding to plasma proteins, as well as the volume of distribution, may be sex- andspecies-specific. Interactions with albumin have been partially characterized to the extent thatbinding capacity and affinity constants have been estimated, but the rates of association anddissociation have not been reported.

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6. ADEQUACY OF THE DATABASE•

Liver uptake and renal clearance of PFOS also appeared to be time-dependent in a PBPK model
used to predict plasma and liver in concentrations of PFOS in a chronic rat study (Harris andBarton et al. 2008). Mechanisms underlying these time dependencies have not been elucidated.

Comparative Toxicokinetics. Toxicokinetic studies conducted in various rodent species (mice, rats,
hamsters, rabbits) and in Cynomolgus monkeys have revealed profound species and sex differences aswell as dose dependencies in the tissue distribution and elimination kinetics of PFOA and PFOS. Studies
conducted in rats have revealed contributing mechanisms for sex differences in elimination of PFOA;
slower elimination of PFOA in male rats compared to female rats has been attributed to sex hormonemodulated renal tubular transport of PFOA that results in markedly lower renal clearance of PFOA in thesexually mature male rat (see Section 3.5.1, Excretion). Sex differences in elimination of PFOA havealso been observed in hamsters; unlike the rat, male hamsters excreted absorbed PFOA more rapidly thanfemale hamsters. Sex differences in elimination of PFOA have not been observed in other rodent species,in Cynomolgus monkeys, or in limited observations made in humans. Sex differences in elimination rates
of perfluoroalkyls in humans have not been demonstrated in population studies of serum elimination
kinetics or renal clearance. Although the few studies that estimated elimination half-lives or renal
clearances in male and female humans have not found significant sex differences, these outcomes may
reflect the relatively low serum concentrations in these subjects compared with studies that wereconducted in nonhuman primates and rodents (i.e., sex differences in elimination may vary with dose
and/or plasma concentration). Additionally, the failure to account for the influence of reduced estrogenlevels (in postmenopausal women) and reduced testosterone levels (in older males) in occupational and/orsite-related epidemiological studies may also account for the lack of findings of sex-related differences.
Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, anddevelopmental effects expressed either prenatally or during childhood, are discussed in the Health Effects
subsection above. It is not known whether children are more or less susceptible than adults to the effects
of exposure to perfluoroalkyls because there are no studies that specifically addressed this question.
Several studies have examined the possible associations between perfluoroalkyl exposure and healthoutcomes in children living in an area with high PFOA contamination and in the general population.
Although some studies have found statistically significant associations, they are not adequate forestablishing causality. Follow-up studies of the C8 population could allow for a longitudinal assessmentof health effects in children and would be useful in determining whether the observed effects are due toperfluoroalkyl exposure. Toxicokinetics information in children is needed. Half-life studies have been
conducted in adults; there is the need to understand if these are applicable to children. There are no

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6. ADEQUACY OF THE DATABASE

studies that have examined whether young animals are more or less susceptible than adults toperfluoroalkyls toxicity. Additional information on this issue would be useful.
Physical and Chemical Properties.

Perfluoroalkyls have unique and complex physical andchemical properties (Kissa 2001; Schultz et al. 2003). Sources are available that provide helpful insights
into the structural aspects and surfactant nature of these substances; however, many of the properties arestill not well understood (CEMN 2008; Kissa 2001; Schultz et al. 2003). In general, specific properties
such as physical state, melting point, boiling point, density, solubility, vapor pressure, micelle formation,
and acid dissociation in water have not been determined or are not well described for these compounds.
Measurements of these endpoints are needed. Information regarding the potential association of these
species in water would be useful. Where determination of a particular endpoint is not possible, athorough description of the physical and chemical properties as they relate to that endpoint would be
helpful. Perfluoroalkyls discussed in this profile exist as a mixture of linear and branched isomers.
Isomer-specific data would also be useful for the various physical-chemical properties. Wang et al.
(2013b) identified several of the fluorinated compounds that are currently being used by major
manufacturers as alternatives to PFOA and PFOS. These compounds are being used as processing aids inthe emulsion polymerization of PTFE and other polymers as well as surface treatment uses, metal plating
uses, firefighting foams, and other miscellaneous uses such as food contact materials. A data need exists
to determine the physical and chemical properties of these replacement substances.

The production, use, import, and export of perfluoroalkyls have changed dramatically since 2000. Most
nations no longer produce or use PFOS or PFOA (China is a notable exception). Major fluoropolymer
manufacturers in the United States have altered their chemical processes to use alternative fluorinatedsubstances in their production processes. Information regarding the production, import, and export
volumes of these substances is needed.

Recommended methods for the disposal of perfluoroalkyls have not been located. In the past,
perfluoroalkyl-containing waste has been disposed of in on- and off-site landfills, through sludge
incorporation, and through incineration (3M 2007b, 2008b; ATSDR 2005). New disposal methods thatavoid release of these substances into the open environment and prevent contamination of nearby soil,
sediment, and groundwater should be developed. The eventual breakdown of fluorotelomer-based
polymers with the eventual release of substances such as PFOA is not well understood. Early researchers
have concluded that the half-life for this process is >1,000 years; however, more recent data suggest much
shorter time scale of 1–2 decades (Rankin et al. 2014; Washington and Jenkins 2015; Washington et al.

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6. ADEQUACY OF THE DATABASE

2009, 2014, 2015). Additional studies on the potential release of perfluoroalkyls from the eventual
degradation of fluoropolymers in landfills would be useful.
Environmental Fate.

Perfluoroalkyls are very stable compounds and are resistant to biodegradation,

direct photolysis, atmospheric photooxidation, and hydrolysis (3M 2000; EPA 2008a; OECD 2002, 2007;
Schultz et al. 2003). The chemical stability of perfluoroalkyls and the low volatility of these substances
in ionic form indicate that perfluoroalkyls will be persistent in water and soil (3M 2000; Prevedouros etal. 2006). Koc values ranging from 17 to 230 indicate that PFOA will be mobile in soil and can leach into
groundwater (Davis et al. 2007; Prevedouros et al. 2006). Environmental fate and potential pathways of
PFOA exposure at and near the DuPont Washington Works site have been discussed (Small 2009). Wanget al. (2013b) identified several of the fluorinated compounds that are currently being used by major
manufacturers as alternatives to PFOA and PFOS. Environmental fate and toxicity research of newer
replacement substances is ongoing (De Silva et al. 2016; Gomis et al. 2018; Kabore et al. 2018).
Bioavailability from Environmental Media.

Perfluoroalkyls are widely detected in humans andanimals, indicating that several of these substances are bioavailable. The bioaccumulation potential of
perfluoroalkyls is reported to increase with increasing chain length (de Vos et al. 2008; Furdui et al. 2007;
Martin et al. 2004b). In living organisms, perfluoroalkyls bind to protein albumin in blood, liver, andeggs and do not accumulate in fat tissue (de Vos et al. 2008; Kissa 2001). The mechanism ofperfluoroalkyl uptake in animals is not fully understood; additional studies would be helpful (de Vos et al.
2008). Perfluoroalkyls discussed in this profile exist as a mixture of linear and branched isomers. Data
regarding the bioavailability of branched versus linear substances would be useful. A data need exists todetermine the bioavailability of the replacement substances identified in Wang et al. (2013b) used in placeof PFOA and PFOS.

Food Chain Bioaccumulation.

High levels of certain perfluoroalkyls in animals have beenmeasured in apex predators, such as polar bears, which indicates that some perfluoroalkyls possess theability to bioaccumulate (de Vos et al. 2008; Houde et al. 2006a; Kannan et al. 2005; Smithwick et al.
2005a, 2005b, 2006). Perfluoroalkyl sulfonates with carbon chain length lower than 8 tend tobioaccumulate less than PFOS. Ongoing monitoring of perfluoroalkyl levels in animals may help todetermine whether efforts to phase out these substances will have had an effect on their biomagnification.
A data need exists to determine the bioaccumulation potential of the new replacement substances used inplace of PFOA and PFOS.

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Exposure Levels in Environmental Media.

Reliable monitoring data for the levels ofperfluoroalkyls in contaminated media at hazardous waste sites are needed so that the information
obtained on levels of perfluoroalkyls in the environment can be used in combination with the known bodyburden of perfluoroalkyls to assess the potential risk of adverse health effects in populations living in thevicinity of hazardous waste sites.

Concentrations of perfluoroalkyls have been measured in surface water from several locations across theUnited States (Boulanger et al. 2004; Kannan et al. 2005; Kim and Kannan 2007; Nakayama et al. 2007;
Simcik and Dorweiler 2005; Sinclair et al. 2004, 2006). Continued monitoring for perfluoroalkyls insurface water would be useful. Data are available regarding levels of perfluoroalkyls in outdoor air,indoor air, indoor dust, food, food packaging, and consumer products (3M 2001; Barber et al. 2007;
Begley et al. 2005; Food Standards Agency 2006; Fromme et al. 2007b; Harada et al. 2005b, 2006;
Jogsten et al. 2009; Kim and Kannan 2007; Kubwabo et al. 2005; Moriwaki et al. 2003; Tittlemier et al.
2007; Washburn et al. 2005). Comprehensive studies monitoring for perfluoroalkyls in these matrices
within the United States are needed. Elevated concentrations of perfluoroalkyls have been measured inair, water, soil, and sediment near fluorochemical industrial facilities (3M 2007b, 2008b, 2008c; Barton etal. 2006; Davis et al. 2007; Hansen et al. 2002). Additional research is needed to evaluate how soil
physical and chemical properties influence the bioavailability of perfluoroalkyls. Continued monitoringfor perfluoroalkyls in these matrices are needed to assess exposure of individuals working at theselocations and individuals who live near these facilities. A data need also exists to perform environmental
monitoring of the replacement substances identified in Wang et al. (2013b) used in place of PFOA andPFOS, particularly near manufacturing locations.
Exposure Levels in Humans.

Trudel et al. (2008) provided a thorough assessment of the exposureof the general population to PFOS and PFOA. 3M (2008b) provided an assessment of exposure ofindividuals to PFOA on-site at a fluoropolymer facility. Uptake values and exposure pathways
determined in these studies should be examined further. Conclusions made in these assessments are
expected to be adjusted as future monitoring data are made available. Large-scale monitoring of
perfluoroalkyls in human serum in the United States is ongoing (Calafat et al. 2006a). Future results ofhuman monitoring studies would be useful for assessing human exposure to these substances over time.
The results of these studies can be examined for correlations between human perfluoroalkyl levels and thephasing out of perfluoroalkyls by companies of the fluorochemical industry. Levels of perfluoroalkyls inhuman urine have been reported (Jurado-Sanchez et al. 2014). Higher exposure levels for individuals
who reside in areas where substances such as PFOA contaminated both public and private water supplies

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have been documented (Emmett et al. 2006a, 2009). Continued biomonitoring of legacy compounds suchas PFOA and PFOS as well as other perfluoroalkyls is needed.

This information is necessary for assessing the need to conduct health studies on these populations.

Exposures of Children. Trudel et al. (2008) provided a thorough assessment of the exposure ofchildren to PFOS and PFOA. These conclusions should be reexamined with respect to future
biomonitoring data when they become available. Data are available regarding the levels ofperfluoroalkyls in young children (Kato et al. 2009b; Olsen et al. 2004b; Toms et al. 2009). NHANES
monitoring data for 2013–2014 for children of ages 3–11 years have recently been released (CDC 2018;
Ye et al. 2018a). Data provided from these efforts will be useful in assessing the exposure of young
children to perfluoroalkyls.

Concentrations of perfluoroalkyls have been measured in human breast milk and cord blood (Apelberg etal. 2007a, 2007b; Fei et al. 2007; Inoue et al. 2004; Kärrman et al. 2007; Midasch et al. 2007; So et al.
2006b; Völkel et al. 2008). Additional monitoring for perfluoroalkyls in these media would be useful.
Continued biomonitoring of legacy compounds such as PFOA and PFOS as well as replacement
substances is needed.

6.3

Ongoing Studies

A number of federal agencies are sponsoring ongoing studies; a list of these studies are available athttps://www.atsdr.cdc.gov/pfas/PFAS-health-effects.html.

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CHAPTER 7. REGULATIONS AND GUIDELINES
Pertinent international and national regulations, advisories, and guidelines regarding perfluoroalkyls in
air, water, and other media are summarized in Table 7-1. This table is not an exhaustive list, and current
regulations should be verified by the appropriate regulatory agency. A list of some select state drinking
water regulations/guidelines or health-based values are summarized in Table 7-2.

ATSDR develops MRLs, which are substance-specific guidelines intended to serve as screening levels by
ATSDR health assessors and other responders to identify contaminants and potential health effects that
may be of concern at hazardous waste sites. See Section 1.3 and Appendix A for detailed information on
the MRLs for perfluoroalkyls.

Table 7-1. Regulations and Guidelines Applicable to Perfluoroalkyls
AgencyDescription

EPA
WHO

RfC
Air quality guidelines

Information

Reference

No data
No data

IRIS 2018
WHO 2010

Air

EPA

WHO
FDA

Water & Food
Drinking water standards and health advisories
DWEL
PFOA
0.00037 mg/L
PFOS
0.00037 mg/L
Lifetime Health Advisory
PFOA
0.07 μg/L
PFOS
0.07 μg/L
National primary drinking water regulations No data
RfD
No data
PFOA
2x10-5 mg/kg/day
PFOS
2x10-5 mg/kg/day
Drinking water quality guidelines
Substances added to foodEPA 2018
EPA 2016e
EPA 2016f
EPA 2016e
EPA 2016f
EPA 2009d
IRIS 2018
EPA 2016e
EPA 2016f

No data
No dataa

WHO 2017
FDA 2018

A3b
No data
No data

ACGIH 2001
NTP 2016a
IRIS 2018

Suggestive evidence
for carcinogenic
potential

EPA 2016e

Cancer
ACGIH
HHS
EPA

Carcinogenicity classification
APFO
Carcinogenicity classification
Carcinogenicity classification
PFOA

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Table 7-1. Regulations and Guidelines Applicable to Perfluoroalkyls
AgencyIARC

Description
PFOS

Information
Suggestive evidence
for carcinogenic
potential

Reference

10-6 Cancer risk
PFOA

0.5 μg/L

EPA 2016e

Carcinogenicity classification
PFOAGroup 2Bc

EPA 2016f

IARC 2017
Occupational

ACGIH
OSHA

TLV-TWAAPFO
PEL (8-hour TWA) for general industry,
shipyards and construction
PEL (8-hour TWA) for shipyards andconstruction
PEL (8-hour TWA) for construction

NIOSH

REL (up to 10-hour TWA)

EPA
DOE

AEGLs-air
PACs-air
PFOA
PAC-1c
PAC-2c
PAC-3cPFBA
PAC-1c
PAC-2c
PAC-3c0.01 mg/m3 d
No data
No data
No data

No data
Emergency Criteria
No data

ACGIH 2001
OSHA 2018b 29 CFR
1910.1000, Table Z-1
OSHA 2018a 29 CFR
1915.1000, Table Z
OSHA 2018c 29 CFR
1926.55, Appendix A
NIOSH 2016
EPA 2016b
DOE 2018b

1.1 mg/m3
12 mg/m3
75 mg/m3
0.5 mg/m3
5.5 mg/m3
33 mg/m3

aThe Substances Added to Food inventory replaces EAFUS and contains the following types of ingredients: food andcolor additives listed in FDA regulations, flavoring substances evaluated by FEMA or JECFA, GRAS substances
listed in FDA regulations, substances approved for specific uses in food prior to September 6, 1958, substances thatare listed in FDA regulations as prohibited in food, delisted color additives, and some substances "no longer FEMA
GRAS".
bA3: confirmed animal carcinogen with unknown relevance to humans.
cGroup 2B: possibly carcinogenic to humans.
dSkin notation.
eDefinitions of PAC terminology are available from DOE (2018a).
ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline level;
AIHA = American Industrial Hygiene Association; APFO = ammonium perfluorooctanoate; CFR = Code of Federal
Regulations; DOE = Department of Energy; DWEL = Drinking Water Equivalent Level; EAFUS = Everything Added
to Food in the United States; EPA = Environmental Protection Agency; FAO = Food and Agriculture Organization of
the United Nations; FDA = Food and Drug Administration; FEMA = Federal Emergency Management Agency;
GRAS = generally recognized as safe; HHS = Department of Health and Human Services; IARC = International
Agency for Research on Cancer; IRIS = Integrated Risk Information System; JEFCA = Joint FAO/WHO Expert
Committee on Food Additives; NIOSH = National Institute for Occupational Safety and Health; NTP = NationalPERFLUOROALKYLS

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7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to Perfluoroalkyls
AgencyDescription

Information

Reference

Toxicology Program; OSHA = Occupational Safety and Health Administration; PAC = Protective Action
Criteria; PEL = permissible exposure limit; PFBA = perfluorobutanoic acid; PFOA = perfluorooctanoic acid;
PFOS = perfluorooctane sulfonic acid; REL = recommended exposure limit; RfC = inhalation reference
concentration; RfD = oral reference dose; TLV = threshold limit values; TWA = time-weighted average;
WHO = World Health Organization

Table 7-2. Select State Drinking Water Guidelines for Perfluoroalkylsa
Value (ppb or µg/L)
PFOS
PFBS PFBAPFNA PFHxS Reference

0.07b

ND

ND

0.07b

0.07c

0.07c

ND

ND

0.07b

0.07ba

ND

ND

0.07d

0.07d

ND

ND

0.42

0.011

ND

ND

Value type
PFOA
Connecticut
Drinking water action level 0.07b
Maine
Maximum exposure
guideline for drinking
water
Massachusetts
Drinking water guidelines
Michigan
Residential andnonresidential drinking
water criteria
Human noncancer
drinking water value
Minnesota
Health risk limite
Short-term
Subchronic
Chronic
Health-based valuee
Short-term
Subchronic
Chronic
NevadaBasic comparison level
New Jersey
Health-based chronic
maximum contaminant
level

0.07b

Connecticut
DPH 2016

ND

MECDC
2016

0.07b

MassDEP
2018

ND

ND

Michigan
DEQ 2018a

ND

ND

Michigan
DEQ 2016

ND

0.07b

MDH 2019
0.035
0.035
0.035

ND
ND
0.3

ND
9
7

7
7
7

ND
ND
ND

ND
ND
ND

ND
ND
ND

0.015
0.015
0.015

3
3
2

ND
ND
ND

ND
ND
ND

0.047
0.047
0.047

0.667

0.667

667

ND

ND

ND

0.014
0.013
ND
(recommend- (recommendation)
ation)

ND

0.013 ND

NDEP 2017
DWQI
2018a,
2017,2018b,
2015

PERFLUOROALKYLS

761
7. REGULATIONS AND GUIDELINES

Table 7-2. Select State Drinking Water Guidelines for Perfluoroalkylsa

Value type

PFOA

Value (ppb or µg/L)
PFOS
PFBS PFBA

North Carolina
Interim maximum
allowable concentration in
groundwater

2

ND

ND

ND

Vermont
Drinking water healthadvisory

0.02b

0.02b

ND

ND

PFNA PFHxS Reference
ND

0.02b

ND

NC DEQ
2013,
NCDENR2012

0.02b

Vermont
DOH 2018

aCurrent as of September 2018.
bValue applies to the sum of PFOA, PFOS, PFHxS, PFHpA, and PFNA concentrations.
cMECDC notes that according to the EPA lifetime health advisory for PFOA and PFOS, when both PFOS and PFOA

are present in drinking water, the combined levels are not to exceed 0.07 ppb.

dValue applies to the sum of PFOA and PFOS groundwater concentrations (Michigan DEQ 2018b).
eHealth risk limits are rule values and health-based values are guidance values. Guidance is developed in-between
rulemaking and may update an older rule. As a result, both rules and guidance values may be available for acontaminant (dual guidance) and the two values may be different (MDH 2014).

DEQ = Department of Environmental Quality; DOH = Department of Health; DPH = Department of Public Health;DWQI = Drinking Water Quality Institute; MassDEP = Massachusetts Department of Environmental Protection;
MECDC = Maine Center for Disease Control and Prevention; MDH = Minnesota Department of Health;
NCDENR = North Carolina Department of Environment and Natural Resources; ND = no data; NDEP = Nevada
Division of Environmental Protection; PFBA = perfluorobutanoic acid; PFBS = perfluorobutane sulfonic acid;
PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid;PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

PERFLUOROALKYLS

762

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APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETSMRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or themost sensitive health effect(s) for a specific duration for a given route of exposure. An MRL is an
estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable riskof adverse noncancer health effects over a specified route and duration of exposure. MRLs are based on
noncancer health effects only; cancer effects are not considered. These substance-specific estimates,
which are intended to serve as screening levels, are used by ATSDR health assessors to identify
contaminants and potential health effects that may be of concern at hazardous waste sites. It is important
to note that MRLs are not intended to define clean-up or action levels.

ATSDR uses the POD/uncertainty factor approach to derive MRLs. Potential PODs are NOAELs,
LOAELs, or the BMDL. They are below levels that might cause adverse health effects in the people mostsensitive to such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and chronic (≥365 days) durations and for the oral and inhalation routes of exposure.
Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified
a method suitable for this route of exposure. MRLs are generally based on the most sensitive substanceinduced endpoint considered to be of relevance to humans. Serious health effects (such as irreparable
damage to the liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure
to a level above the MRL does not mean that adverse health effects will occur.

MRLs are intended only to serve as a screening tool to help public health professionals decide where tolook more closely. They may also be viewed as a mechanism to identify those hazardous waste sites thatare not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of
the lack of precise toxicological information on the people who might be most sensitive (e.g., infants,
elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR
uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public healthprinciple of prevention. Although human data are preferred, MRLs often must be based on animal studies
because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes
that humans are more sensitive to the effects of hazardous substance than animals and that certain persons
may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels thathave been shown to be nontoxic in laboratory animals. ATSDR utilizes uncertainty factors to account for
uncertainties associated with extrapolating from: (1) a LOAEL to a NOAEL; (2) extrapolating fromanimals to humans; and (3) to account for human variability (Chou et al. 1998; Pohl and Abadin 1995).

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APPENDIX A

Default values of 10 are used for each of these categories of uncertainty factors; a value of 1 can be used
if complete certainty exists for a particular uncertainty factor category. A partial uncertainty factor of 3
can be used when chemical-specific data decreases the uncertainty. On a case-by-case basis, ATSDR alsoutilizes modifying factors to account for MRL-specific database deficiencies.

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the
Division of Toxicology and Human Health Sciences, expert panel peer reviews, and agency-wide MRL
Workgroup reviews, with participation from other federal agencies and comments from the public. They
are subject to change as new information becomes available concomitant with updating the toxicological
profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published MRLs.
For additional information regarding MRLs, please contact the Division of Toxicology and Human
Health Sciences, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, Mailstop
S102-1, Atlanta, Georgia 30329-4027.

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APPENDIX ATABLE OF CONTENTS
Introduction ............................................................................................................................................... A-5
PFOA Acute Inhalation MRL Worksheet ............................................................................................... A-14
PFOA Intermediate Inhalation MRL Worksheet .................................................................................... A-15
PFOA Chronic Inhalation MRL Worksheet ........................................................................................... A-16
PFOA Acute Oral MRL Worksheet ........................................................................................................ A-17
PFOA Intermediate Oral MRL Worksheet ............................................................................................. A-19
PFOA Chronic Oral MRL Worksheet .................................................................................................... A-34
PFOS Acute Inhalation MRL Worksheet ............................................................................................... A-35
PFOS Intermediate Inhalation MRL Worksheet ..................................................................................... A-36
PFOS Chronic Inhalation MRL Worksheet ............................................................................................ A-37
PFOS Acute Oral MRL Worksheet ........................................................................................................ A-38
PFOS Intermediate Oral MRL Worksheet .............................................................................................. A-40
PFOS Chronic Oral MRL Worksheet ..................................................................................................... A-49
PFHxS Acute Inhalation MRL Worksheet ............................................................................................. A-50
PFHxS Intermediate Inhalation MRL Worksheet ................................................................................... A-51
PFHxS Chronic Inhalation MRL Worksheet .......................................................................................... A-52
PFHxS Acute Oral MRL Worksheet ...................................................................................................... A-53
PFHxS Intermediate Oral MRL Worksheet ............................................................................................ A-54
PFHxS Chronic Oral MRL Worksheet ................................................................................................... A-58
PFNA Acute Inhalation MRL Worksheet ............................................................................................... A-59
PFNA Intermediate Inhalation MRL Worksheet .................................................................................... A-60
PFNA Chronic Inhalation MRL Worksheet ........................................................................................... A-61
PFNA Acute Oral MRL Worksheet ........................................................................................................ A-62
PFNA Intermediate Oral MRL Worksheet ............................................................................................. A-63
PFNA Chronic Oral MRL Worksheet .................................................................................................... A-68
PFDA Acute Inhalation MRL Worksheet ............................................................................................... A-69
PFDA Intermediate Inhalation MRL Worksheet .................................................................................... A-70
PFDA Chronic Inhalation MRL Worksheet ........................................................................................... A-71
PFDA Acute Oral MRL Worksheet ........................................................................................................ A-72
PFDA Intermediate Oral MRL Worksheet ............................................................................................. A-73
PFDA Chronic Oral MRL Worksheet .................................................................................................... A-74
PFUnA Acute Inhalation MRL Worksheet ............................................................................................. A-75
PFUnA Intermediate Inhalation MRL Worksheet .................................................................................. A-76
PFUnA Chronic Inhalation MRL Worksheet ......................................................................................... A-77
PFUnA Acute Oral MRL Worksheet ...................................................................................................... A-78
PFUnA Intermediate Oral MRL Worksheet ........................................................................................... A-79
PFUnA Chronic Oral MRL Worksheet .................................................................................................. A-80
PFHpA Acute Inhalation MRL Worksheet ............................................................................................. A-81
PFHpA Intermediate Inhalation MRL Worksheet .................................................................................. A-82
PFHpA Chronic Inhalation MRL Worksheet ......................................................................................... A-83
PFHpA Acute Oral MRL Worksheet ...................................................................................................... A-84
PFHpA Intermediate Oral MRL Worksheet ........................................................................................... A-85
PFHpA Chronic Oral MRL Worksheet .................................................................................................. A-86

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APPENDIX APFBS Acute Inhalation MRL Worksheet................................................................................................ A-87
PFBS Intermediate Inhalation MRL Worksheet ..................................................................................... A-88
PFBS Chronic Inhalation MRL Worksheet ............................................................................................ A-89
PFBS Acute Oral MRL Worksheet......................................................................................................... A-90
PFBS Intermediate Oral MRL Worksheet .............................................................................................. A-91
PFBS Chronic Oral MRL Worksheet ..................................................................................................... A-92
PFBA Acute Inhalation MRL Worksheet ............................................................................................... A-93
PFBA Intermediate Inhalation MRL Worksheet .................................................................................... A-94
PFBA Chronic Inhalation MRL Worksheet............................................................................................ A-95
PFBA Acute Oral MRL Worksheet ........................................................................................................ A-96
PFBA Intermediate Oral MRL Worksheet ............................................................................................. A-97
PFBA Chronic Oral MRL Worksheet..................................................................................................... A-98
PFDoDA Acute Inhalation MRL Worksheet .......................................................................................... A-99
PFDoDA Intermediate Inhalation MRL Worksheet ............................................................................. A-100
PFDoDA Chronic Inhalation MRL Worksheet..................................................................................... A-101
PFDoDA Acute Oral MRL Worksheet ................................................................................................. A-102
PFDoDA Intermediate Oral MRL Worksheet ...................................................................................... A-103
PFDoDA Chronic Oral MRL Worksheet.............................................................................................. A-104
FOSA Acute Inhalation MRL Worksheet ............................................................................................. A-105
FOSA Intermediate Inhalation MRL Worksheet .................................................................................. A-106
FOSA Chronic Inhalation MRL Worksheet ......................................................................................... A-107
FOSA Acute Oral MRL Worksheet ...................................................................................................... A-108
FOSA Intermediate Oral MRL Worksheet ........................................................................................... A-109
FOSA Chronic Oral MRL Worksheet .................................................................................................. A-110
PFHxA Acute Inhalation MRL Worksheet ........................................................................................... A-111
PFHxA Intermediate Inhalation MRL Worksheet ................................................................................ A-112
PFHxA Chronic Inhalation MRL Worksheet ....................................................................................... A-113
PFHxA Acute Oral MRL Worksheet .................................................................................................... A-114
PFHxA Intermediate Oral MRL Worksheet ......................................................................................... A-115
PFHxA Chronic Oral MRL Worksheet ................................................................................................ A-117

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APPENDIX AINTRODUCTION
Overview of Epidemiological Studies
A large number of epidemiological studies have evaluated a wide range of potential health outcomes
resulting from exposure to perfluoroalkyls, particularly PFOA and PFOS. The epidemiological studies
fall into three broad categories: occupational exposure primarily to airborne PFOA and PFOS, exposure
to PFOA-contaminated drinking water by residents living near a PFOA production facility, and general
population exposure to background levels of perfluoroalkyls. Most of the occupational exposure studies
were conducted in workers at four facilities in Minnesota, Alabama, West Virginia, and the Netherlands.
Studies of the highly-exposed residents primarily come from several large-scale studies (C8 Health
Project, C8 Health Study) of Mid-Ohio Valley residents living near the Washington Works facility inWest Virginia who were exposed to high levels of PFOA in the drinking water. General population
studies primarily utilized data collected in NHANES in the United States and several large-scale healthstudies conducted in Europe.
Most of the epidemiological studies lack environmental monitoring data and there is a potential for
multiple sources of exposure (inhalation and oral). However, the majority of the epidemiological studies
used serum perfluoroalkyl levels as a biomarker of exposure. One limitation of the C8 Health Studies isthat they used blood samples collected in 2005–2006. However, the facility started using PFOA in the
1950s and peak usage was in the 1990s and by 2003, there was an 87% decline in PFOA emissions, ascompared to 1999 levels (Emmett et al. 2006a). Therefore, serum PFOA levels measured in 2005–2006
likely do not represent earlier higher exposures, which may have contributed to observed healthoutcomes. As an alternative to using older serum PFOA levels, several C8 Health Studies estimatedserum levels based on data on the release of PFOA from the facility and pharmacokinetic modeling. Of
the three categories of subjects examined in the epidemiological studies, workers have the highest
potential exposure to perfluoroalkyls, followed by the highly-exposed residents in the Mid-Ohio Valley(referred to as community exposure), and then the general population. In one study of workers at the
Washington Works facility in West Virginia, the average serum PFOA level in 2001–2004 was
1,000 ng/mL (Sakr et al. 2007a); the mean PFOA level in community residents (without occupational
exposure) near this facility was 423 ng/mL in 2004–2005 (Emmett et al. 2006a). By comparison, thegeometric mean concentration of PFOA in the U.S. population was 3.92 ng/mL in 2005–2006 (CDC2013).
Identification of Adverse Health Effects Based on Epidemiological Studies. Although alarge number of epidemiological studies have examined the potential of perfluoroalkyls to induce adverse
health effects, most of the studies were cross-sectional in design and do not establish causality.
Epidemiological studies have found statistically significant associations between serum perfluoroalkyl
levels and several health effects, although the results were not consistent across studies. Many of thestudies reported dose-related trends, but these trends were not as apparent when comparing across studies;some effects were observed in populations with background PFOA levels but not in populations with highserum PFOA levels. Given the inconsistencies, ATSDR evaluated whether the preponderance of the data
supported an association between perfluoroalkyl exposure and a particular health effect, taking into
consideration the consistency of the findings across studies, the quality of the studies, dose-response, andplausibility. It should be noted that although the data may provide strong evidence for an association, it
does not imply that the observed effect is biologically relevant because the magnitude of the change iswithin the normal limits or not indicative of an adverse health outcome. Plausibility depends primarily on
experimental toxicology studies that establish a biological mechanism for the observed effects.

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APPENDIX A

Using this approach, the available epidemiological data identify several potential health hazards of PFOA,PFOS, PFHxS, PFNA, and PFDA in humans as listed below.
PFOA• Pregnancy-induced hypertension/pre-eclampsia• Increases in serum hepatic enzymes, particularly alanine aminotransferase, and decreases inserum bilirubin levels• Increases in serum lipids, particularly total cholesterol and LDL cholesterol• Decreased antibody response to vaccines• Small (<20 g or 0.7 ounces per 1 ng/mL increase in blood perfluoroalkyl level) decreases in birthweightPFOS• Pregnancy-induced hypertension/pre-eclampsia• Liver damage, as evidenced by increases in serum enzymes and decreases in serum bilirubinlevels• Increases in serum lipids, particularly total cholesterol and LDL cholesterol• Decreased antibody response to vaccines• Small (<20 g or 0.7 ounces per 1 ng/mL increase in blood perfluoroalkyl level) decreases in birthweightPFHxS• Liver damage, as evidenced by increases in serum enzymes and decreases in serum bilirubinlevels• Decreased antibody response to vaccines
PFNA• Increases in serum lipids, particularly total cholesterol and LDL cholesterol• Decreased antibody response to vaccines (based on limited evidence)
PFDA• Increases in serum lipids, particularly total cholesterol and LDL cholesterol• Decreased antibody response to vaccines
Limitations of Epidemiological Data. There are sufficient epidemiological data to identify possible
sensitive targets for many of the perfluoroalkyls; however, there are two major limitations to establishingdose-response relationships for these effects and using the epidemiological studies to derive MRLs:
accurate identification of environmental exposure levels producing increased risk for adverse effects(exposure estimates and routes of exposure) and likely co-exposure to mixtures of perfluoroalkyls. Other
limitations include the cross-sectional design of the majority of epidemiological studies and the potentialthat reverse causality contributes to the observed associations.
Uncertainty in Exposure Estimates. In general, epidemiological studies provide a one-time serum
perfluoroalkyl concentration, but lack information on actual environmental exposure concentration ordoses, routes of exposure, and exposure duration. Although serum perfluoroalkyl levels provide reliable
information on recent exposure (weeks to years, depending on the elimination t1/2 for the perfluoroalkyl),
they likely do not reflect historical exposure levels or exposure levels at the onset of the effect. This isespecially true for occupational exposure cohorts where past exposure levels were higher before industrial
hygiene improved and in the C8 community studies since peak PFOA levels in drinking water occurred atleast 10 years prior to the onset of the studies. Additionally, data from NHANES suggest that somePERFLUOROALKYLS

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APPENDIX A

perfluoroalkyl (PFOA, PFOS, PFHxS, and PFDA) levels are declining in the general population; forexample, the geometric mean serum levels of PFOA and PFOS declined from 5.2 and 30.4 ng/mL,
respectively, in 1999–2000 to 1.56 and 4.72 ng/mL in 2015–2016. In contrast, levels of PFNA haveincreased during that time frame; the geometric mean went from 0.5 ng/mL in 1999–2000 to 1.26 ng/mL
in 2009–2010 and then decreased to 0.675 ng/mL in 2015–2016. Most studies do not provide adequate
information to determine whether perfluoroalkyl levels reflect a steady state and relatively constant
exposure, since most designs only include a single measurement. An added uncertainty occurs in studies
that used maternal serum levels as the biomarker of exposure for effects in children or for effects on
fertility.
It is assumed that workers were primarily exposed via inhalation; however, oral exposure may have also
contributed to the total perfluoroalkyl body burden, particularly since workers frequently lived incommunities with elevated levels of PFOA in the drinking water. It has been determined that drinking
water was the primary source of perfluoroalkyls in residents living near a PFOA facility (Emmett et al.
2006a); however, it is likely that airborne PFOA contributed to overall body burden. Drinking water isthe likely primary route of exposure for the general population.
Uncertainty due to Co-Exposure to Other Perfluoroalkyls. Based on NHANES data, the U.S. general
population is exposed to a variety of perfluoroalkyls. A number of studies reported a high degree ofcorrelation between different perfluoroalkyls; however, most studies did not control for exposure to otherperfluoroalkyls. Given that many of the perfluoroalkyls have similar targets of toxicity and possible
mechanisms of action, it is likely that several perfluoroalkyls contributed to the observed effects. The
potential interactions between different perfluoroalkyls have not been fully elucidated.
In summary, the epidemiological databases for several perfluoroalkyls provide valuable information on
hazard identification; however, uncertainties regarding doses associated with adverse effects and possible
interactions between compounds preclude use of these data to derive MRLs.
Overview of Laboratory Animal Studies
Laboratory animal studies are available for 11 perfluoroalkyls (no data were located for PFHpA);
however, more than 70% of the studies examined PFOA and/or PFOS. The laboratory animal studies
primarily involved oral exposure and examined a wide range of potential health outcomes. The primary
health effects observed in laboratory animals were liver toxicity, developmental toxicity, and immune
toxicity. Other effects typically observed at higher doses included weight loss, histological alterations in
reproductive tissues, and histological alterations in the thyroid gland. The sensitive targets of toxicity
identified in the laboratory animals are similar to those observed in epidemiological studies.
Limitations of Laboratory Animal Studies for Derivation of MRLs. Use of controlled animalstudies eliminates the uncertainties regarding effective doses and co-exposure to other perfluoroalkyls.
However, there are uncertainties associated with derivation of MRLs based on animal studies, in part,
because of large interspecies differences in the toxicokinetics of perfluoroalkyls for which mechanisms
are not completely understood. Available information on the toxicokinetics of perfluoroalkyls in humans,
nonhuman primates, and various rodent species indicate that elimination rates (and very likely elimination
mechanisms and hormonal regulation of these mechanisms) vary substantially across chemical species(i.e., carbon chain length) and animal species (i.e., slower in humans compared to nonhuman primates androdents), and show pronounced sex differences within certain species (e.g., faster elimination in femalerats). As a result, there is some uncertainty associated with extrapolation of external dose-response
relationships from animals to humans. Several PBPK models of PFOA and PFOS have been reported thatsimulate the substantial differences in pharmacokinetics of these compounds between humans andnonhuman primates or between humans and rats. These include human models for PFOA and PFOS (seePERFLUOROALKYLS

A-8
APPENDIX A

Section 3.1.5). An additional uncertainty in the animal data is the relevance of effects associated withactivation of PPARα. Many of the effects observed in rodents, particularly liver and developmental
effects, involve the activation of PPARα; humans and nonhuman primates are less responsive to PPARαagonists than rats and mice. However, studies in PPARα-null mice suggest that PPARα-independent
mechanisms also play a role in the liver, immunological, and developmental toxicity.
MRL Approach
The following approach was used for derivation of MRLs:• Identify sensitive endpoints from epidemiological studies• Identify laboratory animal studies that have evaluated dose-response relationships for toxicity
targets identified in epidemiological studies• Estimate a POD using animal serum perfluoroalkyl levels for sensitive endpoints• Calculate HEDs using the assumption that a serum concentration resulting in an effect in alaboratory animal would also result in an effect in humans. An empirical pharmacokinetic model
was used to estimate a human dose associated with this serum concentration for PFOA and PFOS.
Measured serum concentrations in laboratory animal studies were used to calculate the HEDs for
PFHxS and PFNA.
• Apply appropriate uncertainty factors informed by comparison of the POD to serum
perfluoroalkyl levels reported in epidemiological studies
Rationale for Internal Dose Metric Used in Dosimetry Extrapolation. The time-weighted
average serum concentration (CTWA) was selected as the internal dose metric for dose-response modelingand dosimetry extrapolation. The CTWA was used rather than the maximum concentration (Cmax) for thefollowing reasons:•

CTWA provides a better representation of the history of exposure in the principal studies selected
for the MRLs for PFOA (Koskela et al. 2016) and PFOS (Luebker et al. 2005a). The relatively
slow elimination of PFOA and PFOS predicted in mice and rats results in a build-up of serum
concentrations during the exposure duration. As a result, the Cmax is predicted to occur soon after
the last dose in these studies (based on the Wambaugh et al. 2013 model).

•The assumption that must be accepted to justify using the Cmax is that only the last dose of PFOA
or PFOS, which results in the Cmax, determines the toxicity outcome, and the earlier exposure
history contributes only by building up the levels to the Cmax.

•

The available data on the toxicity of PFOA and PFOS do not provide convincing evidence that
toxicity outcomes are more likely to be determined by Cmax rather than the exposure history,
represented by CTWA.

•

Given that Cmax is predicted to exceed CTWA in the principal studies (based on the Wambaugh et
al. 2013 model), the resulting HED that achieves a steady-state serum concentration equal to theCmax would be larger than the corresponding HED based on CTWA. In the absence of strong
evidence for Cmax being a more appropriate dose metric than CTWA, use of CTWA for dosimetry
extrapolation is an appropriate health-protective assumption in the derivation of the MRL.

Predicting Mean Serum PFOA and PFOS Concentrations in Laboratory Animals. TWA
serum concentrations corresponding to external doses (mg/kg/day) and exposure durations (days) werepredicted with a pharmacokinetic (PK) model for the animal species, strain, and sex used in the studies(Wambaugh et al. 2013). The Wambaugh et al. (2013) model was selected over other available

PERFLUOROALKYLS

A-9
APPENDIX A

pharmacokinetic models for the following reasons: (1) it provided a single model structure (parameters)
for simulating kinetics of PFOA and PFOS; (2) Wambaugh et al. (2013) derived parameter values for sexspecific species and strains used in the candidate principal studies for the oral MRLs (female and maleCD1 mouse, C57BL/6 mouse, Sprague-Dawley rat, cynomolgus monkey); and (3) models were calibratedusing Bayesian parameter estimation based on multiple PFOA (n=6) and PFOS (n=2) pharmacokinetics
studies for specific species, strains, and sexes; and were then evaluated by comparing predicted andobserved serum concentrations from toxicology studies performed on the same species, strains, and sex.
Predicted and observed terminal serum concentrations for PFOA and PFOS agreed within a factor of 2,
showed strong linear correlation, and distributed symmetrically along the line of identity, suggesting
minimal bias in predictions across species, strains, and sexes.
The TWA serum concentration was calculated as follows (Equation A-1):

CTWA =C AUC
ED

Eq. (A-1)

where CTWA is the predicted TWA serum concentration (mg/L), CAUC is the predicted area under the curve(AUC) of the serum concentration-time profile for the exposure (mg hour/L), and ED is the exposure
duration (hour). Gavage studies were simulated as a single dose (e.g., gavage) given once every 24 hours.
Daily drinking water exposures were simulated as a 12-hour period of dosing followed by 12 hours withno dosing. This assumes that the animals consumed water during a 12-hour active period and received
the total daily dose during this 12-hour period. The dosing interval was 0.1 hour.
The Wambaugh et al. (2013) model was originally implemented in R (v2.10.0) and was migrated to
MATLAB (vR2016) for calculations of MRLs. Wambaugh et al. (2013) reported mean and confidence
limits for parameter values estimated from a Bayesian Markov Chain Monte Carlo (MCMC) analysis.
The posterior means were used as point estimates for parameters in the MATLAB version. Function of
the point estimate implementation in MATLAB was verified by comparing predictions of CAUC obtained
from the MATLAB version with predictions from the MCMC analysis reported in EPA (2016e, 2016f).
This comparison for PFOA included a total of 18 predictions of CAUC for female CD-1 mice (Lau et al.
2006; Wolf et al. 2007), female C57Bl6 mice (DeWitt et al. 2008), and male Sprague-Dawley rats
(Butenhoff et al. 2004b). The r2 for MATLAB vs R predictions of CAUC was 0.99 and the average relative
percent difference (MATLAB-R) was 2.8% (range: -6.6–13.5). The comparison for PFOS included a
total of 28 predictions of CAUC for female CD-1 mice (Lau et al. 2003), female Sprague-Dawley rats
(Butenhoff et al. 2009b; Lau et al. 2003; Luebker et al. 2005a, 2005b), and male and female Cynomolgus
monkeys (Seacat et al. 2002). The r2 for MATLAB vs R predictions of CAUC was 1.00 and the averagerelative percent difference (MATLAB-R) was 4.6% (range: -11–20).
Estimating TWA Serum PFHxS and PFNA Concentrations in Laboratory Animals. Because
a PK model for predicting the TWA serum concentrations was not identified for PFHxS and PFNA, a
TWA serum concentration was estimated from measured serum concentrations. ATSDR estimated the
TWA values from the areas under the curve calculated using the trapezoid rule. Since most studies did
not report pre-exposure levels, serum concentrations in the control group were used as the baseline
concentration.
Estimating HEDs for Perfluoroalkyls. The serum concentration PODs identified from thelaboratory animal data were converted to an equivalent dose in humans, which is defined as thecontinuous ingestion dose (mg/kg/day) that would result in steady-state serum concentrations ofperfluoroalkyl equal to the serum concentration (µg/mL) selected as the POD. Although human PBPK
models for PFOA and PFOS have been reported, the simpler empirical model was selected for deriving

PERFLUOROALKYLS

A-10
APPENDIX A

HEDs for the following reasons. Human PBPK models have not been validated with observations madein humans for which individual exposures were known with sufficient certainty to evaluate confidence inpredicting dose-serum concentration relationships. Calibration and validation of human PBPK models
have relied on comparing predicted and observed declines in serum concentrations following declines or
cessation of exposure (Fàbrega et al. 2014, 2016; Loccisano et al. 2011; Worley et al. 2017b). Thisapproach validates the ability of the models to predict serum concentration half-lives, which can be
estimated directly from the observation data and represented in the empirical model. However, it does not
validate the ability of the models to predict serum concentration in association with known exposures.
Worley et al. (2017b) reported good agreement between the distribution of observed and predicted serum
concentrations of PFOA within a study population, when assumptions about variability in exposure andbiokinetics were incorporated into the simulations.
The relationship between perfluoroalkyl external dosage (mg/kg/day) and steady-state serum
concentration (Css, mg/L) in humans was estimated assuming a single-compartment first-order model inwhich elimination kinetics are adequately represented by observed serum elimination t1/2 values for the
specific perfluoroalkyl, an assumed apparent volume of distribution (Vd, L/kg) and gastrointestinal
absorption fraction. In the first-order single-compartment model, continuous exposure will result in a
steady-state body burden (BBSS, mg/kg) for PFOA or PFOS, which will be distributed in a single volumeof distribution to yield a steady-state serum concentration (Equation A-2):

C SS =BBSS
Vd

Eq. (A-2)

At steady state, the rate of first-order elimination rate (a constant fraction of the body burden, ke per day)will equal the absorbed dosage (Dss, mg/kg/day) adjusted for gastrointestinal absorption (AF)
(Equation A-3):

DSS ⋅ AF = BBSS ⋅ ke

Eq. (A-3)

Rearrangement of Equation A-3 allows calculation of the steady-state body burden corresponding to agiven external dosage (Equation A-4):

BBSS =DSS ⋅ AFke

Eq. (A-4)

The relationship between the elimination rate constant (ke, day-1) and the elimination half-life (t1/2, day), is
given in Equation A-5:

ke =

ln(2)
t1 / 2

Eq. (A-5)

Combining Equations A-2 and A-3 yields an expression relating the external steady-state dosage andsteady-state serum concentration (Equation A-6):

DSS =CSS ⋅ ke ⋅ Vd
AF

Eq. (A-6)

PERFLUOROALKYLS

A-11
APPENDIX A

The above estimates of CSS/DSS are sensitive to the input parameters, t1/2, AF, and Vd. The empiricalmodel used to calculate HEDs is linear; therefore, the change in the HED is approximately proportional tothe change in the half-life. A halving of the half-life would result in a doubling of the HED.
PFOA and PFOS. Several studies have estimated PFOA and PFOS half-lives (t1/2) in workers (Costa etal. 2009; Olsen et al. 2007a) or highly exposed residents (Bartell et al. 2010). Estimates of the half-lives
based on Olsen et al. (2007a) were derived from longitudinal measurements of serum concentrations of
PFOA and PFOS in a group of fluorochemical production workers (24 males, 2 females); the estimatedhalf-lives were 3.8 years (95% confidence limit [CL] 3.1–4.4) and 5.4 years (95% CL 3.9–6.9),
respectively. Costa et al. (2009) reported a half-life for PFOA of 5.1 years (SD 1.7) for a group of
workers (n=16) following their cessation of PFOA production work. A longitudinal study by Bartell et al.
(2010) followed serum PFOA concentrations in 200 subjects recruited from the Lubeck Public Service
District and Little Hocking Water Association and followed for a period of 6–12 months after mitigationof exposures from drinking water. The estimated half-life for PFOA was 2.3 years (95% CL 2.1–2.4). A
fourth study estimated half-lives in a cross-sectional study of residents served by the Lubeck PublicService District and Little Hocking Water Association (Seals et al. 2011). The estimated half-lives
ranged from 2.9 to 10.1 years (1,059–3,687 days) for PFOA. Results from the longitudinal studies areshown in Table A-1. For the MRL calculations, the PFOA half-life estimated by Olsen et al. (2007a) was
selected over the half-life estimated by Bartell et al. (2010) because the Olsen et al. (2007a) study had alonger follow-up time (>5 years compared to 6–12 months) and estimates of the terminal half-life appear
to increase with longer follow-ups because slower kinetics make a larger contribution to the terminal halflife (Seals et al. 2011). This may reflect a larger contribution of slower kinetics or ongoing exposure to
the terminal half-life observable with longer follow-ups (Worley et al. 2017a) or other factors such as
differences in the age-distribution of the populations studied. The decision to use the longer half-life
from Olsen et al. (2007a) is also health protective in that a longer half-life would result in higher
predicted serum concentrations for a given intake and, therefore, lower HEDs for a given serum
concentration POD. Estimates of the half-life for PFOA and PFOS are most applicable to serum
concentrations within the above ranges and would be less certain if applied to serum concentrations
substantially below or above these ranges. Serum concentrations during the 5-year observation period in
the Olsen et al. (2007a) study are provided in Table A-2.

Table A-1. Half-Life PFOA and PFOS Levels in Humans
PFOA t1/2 (days)
1,378
1,862
840

PFOS t1/2 (days)
1,976
NA
NA

Exposure typeOccupational
Occupational
Environmental

Number26
16
200

SourceOlsen et al. (2007a)
Costa et al. (2009)
Bartell et al. (2010)

NA = not available; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

PERFLUOROALKYLS

A-12
APPENDIX A

Table A-2. Serum PFOA and PFOS Concentrations Measured in Fluorochemical
Production Workers

InitialPFOA (ppb)408 (72, 5,100)

PFOS (ppb)626 (145, 3,490)

Final

148 (17, 2,435)

295 (37, 1,740)

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid
Source: Olsen et al. 2007a

Estimates of volume of distribution (Vd) are based on non-compartmental modeling of serum
concentration kinetics in monkeys and are assumed to be applicable to humans at the above serum
concentrations (Table A-3).

Table A-3. Apparent Volume of Distribution for PFOA and PFOSPFOA Vd (L/kg)
0.18 (male)
0.20 (female)
NA
NA
0.3

PFOS Vd (L/kg)
NANA
0.20 (male)
0.27 (female)
0.3

SourceButenhoff et al. (2004c)
Chang et al. (2012)
Harada et al. (2005a)

NA = not applicable; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

Numerous studies conducted in various animal models provide evidence for approximately complete
absorption of oral doses of PFOA and PFOS (i.e., AF≈1, see Section 3.1.1).
PFHxS. For PFHxS, the estimate of the elimination t½ was derived from longitudinal measurements ofserum concentrations of PFHxS in a group of retired fluorochemical production workers (24 males and2 females) observed for a 5-year period; the estimated half-life was 8.5 years (3,109 days) (Olsen et al.
2007a). The range of initial serum concentrations was 16–1,295 ng/mL (mean of 290 ng/mL), and thefinal concentrations ranged from 10 to 791 ng/mL (mean of 182 ng/mL). Estimates of the t½ for PFHxS
are most applicable to serum concentrations within the above ranges and would be less certain if applied
to serum concentrations substantially below or above these ranges.
Estimates of volume of distribution (𝑉𝑉𝑑𝑑 ) are based on non-compartmental modeling of serum
concentration kinetics in monkeys and are assumed to be applicable to humans at the above serum
concentrations. Sundström et al. (2012) estimated the apparent Vd for PFHxS at 0.287 L/kg for male
Cynomolgus monkeys and at 0.213 L/kg for female Cynomolgus monkeys.
Few studies have been conducted in animals that provide estimates for a gastrointestinal absorption factorof oral doses of PFHxS. Sundström et al. (2012), based on comparison of the AUC for oral andintravenous administration, estimated an oral absorption fraction for PFHxS (administered as a single
10 mg/kg dose) of 50% in female rats. However, as the authors point out, this estimate may not be
reliable due to the short (24 hours) observation period (Sundström et al. 2012) and that “female Cmax
values did not differ significantly between the oral and IV doses, and Tmax after oral dosing was estimatedto be at approximately 30 min.” These latter observations suggest approximately completebioavailability. The AUC for male rats following oral exposure was not available, and the AUC afterPERFLUOROALKYLS

A-13
APPENDIX A

intravenous administration was done in only one male rat (Sundström et al. 2012). A study conducted byKim et al. (2016) in rats estimated an approximately 100% oral bioavailability based on the Cmax valueand AUC comparison between oral and intravenous doses. Therefore, an absorption fraction (AF) of
1 was used for PFHxS.
PFNA. For PFNA, the elimination half-life estimates were derived by paired blood and urine samples(n=86) from Chinese adults in a study that measured the concentrations of a number of perfluoroalkyls,
including PFNA (Zhang et al. 2013). The participants were first divided into four groups; young females(age ≤50 years, n=20), older females (>50 years, n=19), young males (≤50 years, n=32), and older males(>50 years, n=15). The group of young females had significantly lower levels of perfluoroalkyls than theother groups; therefore, the three other groups were combined. The lower perfluoroalkyl levels werelikely due to the elimination via menstrual bleeding, pregnancy, and lactation. The estimated arithmetic
mean elimination half-lives for the young female group and the combined male and older female groupfor PFNA were 2.5 and 4.3 years (913 and 1,570 days), respectively.
Toxicokinetics parameters for perfluorocarboxylic acids, among them PFOA and PFNA analogs, were
investigated in rats by Ohmori et al. (2003). The authors estimated that the 𝑉𝑉𝑑𝑑 values in steady state were
not much different between the perfluorocarboxylic acids and between the sexes. Based on this, theestimated volume of distribution for PFNA in humans will be assumed to be the same for PFOA,
0.2 L/kg.
There are no studies on absorption of PFNA in humans. In rodents, oral absorption occurs rapidly as
indicated by its presence in the serum of rodents soon after oral administration (Tatum-Gibbs et al. 2011).
Therefore, based on animal studies of PFNA and other perfluorocarboxylic acid analogs, as well as
sufficient findings of PFNA and other perfluorocarboxylic acids in human blood, it can be assumed that
PFNA is well absorbed after oral exposure; therefore, an AF of 1 was used.
Model Input Parameters. The first-order one-compartment model input parameters (t1/2, Vd, and AF) areprovided in Table A-4.

Table A-4. First Order One-Compartment Model Parameters
Parameter

PFOA

PFOS

PFHxS

PFNA

Serum elimination half-lifea; t1/2 (day)1,400a2,000a3,100a900b

Serum elimination rate constantc, ke (day-1)

4.95x10-4

3.47x10-4

2.23x10-4

7.59x10-4

Gastrointestinal absorption fractiond, AF

1

1

1

1

Apparent volume of distribution, Vd (L/kg)

0.2e

0.2e

0.287f0.2e

aEstimates from Olsen et al. (2007a).
bEstimates from Zhang et al. (2013) for young females.
cCalculated using Equation 5.
dBased on studies in rodents and nonhuman primates.
eEstimates based on studies in nonhuman primates (Butenhoff et al. 2004c; Chang et al. 2012; Harada et al. 2005a).
fEstimates based on studies in nonhuman male primates (Sundström et al. 2012).

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFHxS = perfluorohexane sulfonic acid;
PFNA = perfluorononanoic acid

PERFLUOROALKYLS

A-14
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanoic acid (PFOA)
335-67-1
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFOA.
Rationale for Not Deriving an MRL: Derivation of an inhalation MRL was precluded because
inhalation-specific PBPK/pharmacokinetic model parameters are not available for PFOA and none of thestudies reported serum PFOA concentrations.
Four studies have examined the acute toxicity of airborne PFOA in laboratory animals (Griffith and Long
1980; Kennedy et al. 1986; Staples et al. 1984). The observed effects included excessive salivation andeye and nose irritation in rats exposed to 18,600 mg/m3 for 1 hour (Griffith and Long 1980), weight loss
and pulmonary edema in rats exposed to 380 mg/m3 for 4 hours (Kennedy et al. 1986), weight loss in rats
exposed nose-only to 84 mg/m3 6 hours/day, 5 days/week for 2 weeks (Kennedy et al. 1986), anddecreases in maternal weight gain at 10 mg/m3 and maternal deaths and decreases in neonatal bodyweight at 25 mg/m3 in rats exposed 6 hours/day on GDs 6–15 (Staples et al. 1984). The 2-week study
also reported increases in liver weight and hepatocellular hypertrophy in rats exposed to 7.6 mg/m3.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-15
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanoic acid (PFOA)
335-67-1
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFOA.
Rationale for Not Deriving an MRL: No intermediate-duration inhalation studies in laboratory animals
were identified for PFOA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-16
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanoic acid (PFOA)
335-67-1
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFOA.
Rationale for Not Deriving an MRL: No chronic-duration inhalation studies in laboratory animals wereidentified for PFOA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-17
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanoic acid (PFOA)
335-67-1
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFOA.
Rationale for Not Deriving an MRL: An acute-duration oral MRL cannot be derived for PFOA because
the modeling approach used for estimating HEDs cannot be used to estimate acute human exposure where
the exposure duration of 14 days is 1% of the elimination half-life in humans.
Acute-duration oral studies are available in rats and mice and provide information on body weight,
hepatic, immunological, reproductive, and developmental effects. The liver effects consisted of increases
in liver weight, hepatocellular hypertrophy, and/or decreases in serum cholesterol and triglycerides in rats
and mice exposed to ≥1 mg/kg/day (Cook et al. 1992; Elcombe et al. 2010; Haughom and Spydevold
1992; Ikeda et al. 1985; Kawashima et al. 1995; Kennedy 1987; Liu et al. 1996; Pastoor et al. 1987; Iwai
and Yamashita 2006; Permadi et al. 1992, 1993; Vetvicka and Vetvickova 2013; White et al. 2009; Wolfet al. 2007; Xie et al. 2003; Yang et al. 2000, 2001, 2002b). Consistent with the Hall et al. (2012) criteria(see Section 2.9 for a discussion of the criteria), the liver weight increases and hypertrophy observed inrats and mice were not considered relevant to human risk assessment. Although there is uncertainty
regarding the exact, and possibly multiple, mechanism(s) for these liver effects, peroxisome proliferation
is a likely contributor, a mechanism that cannot be reliably extrapolated to humans (Hall et al. 2012).
Therefore, increases in liver weight and hepatocellular hypertrophy, and alterations in serum lipid levels
observed in rats and mice, in the absence of other degenerative lesions, were not considered appropriate
endpoints for deriving MRLs.
The immunological effects consisted of impaired responses to T-dependent antigens, such as sRBCs,
altered antibody response, and decreases in spleen and thymus weights at 11.5 mg/kg/day and higher(DeWitt et al. 2009; Vetvicka and Vetvickova 2013; Yang et al. 2001, 2002a). Information on thepotential reproductive toxicity of PFOA is limited to three studies that reported increases in serum
estradiol levels in rats exposed to ≥2 mg/kg/day for 14 days (Biegel et al. 1995; Cook et al. 1992; Liu etal. 1996). A number of studies have evaluated the developmental toxicity of PFOA. In the only acuteduration developmental toxicity study in rats, no alterations in fetal body weight or malformations wereobserved at 100 mg/kg/day (Staples et al. 1984). Mice appear to be more sensitive to PFOA’s
developmental toxicity; observed effects include decreases in litter weight (Hu et al. 2010), decreases inpup body weight (White et al. 2007, 2009; Wolf et al. 2007), alterations in spontaneous activity(Johansson et al. 2008), increases in resorbed embryos (Chen et al. 2017b), and delays in mammary glanddevelopment (White et al. 2007, 2009; Wolf et al. 2007). The lowest LOAEL for developmental effects
in mice was 0.5 mg/kg/day for decreased litter weight. A list of the NOAEL and LOAEL values for the
immunological, reproductive, and developmental effects is presented in Table A-5.

PERFLUOROALKYLS

A-18
APPENDIX A

Table A-5. Summary of the Adverse Effects Observed in Laboratory Animals
Following Acute-Duration Oral Exposure
Species andexposure
duration
ImmunologicalMouse
10 daysMouse
10 daysMouse
7 daysMouse
7 daysReproductive
Rat
14 daysMouse
GDs 1–7Rat
14 daysRat
14 days
Developmental
Mouse
GDs 6–17
Mouse
PND 10NOAELLOAELa(mg/kg/day) (mg/kg/day) Effect
11.5
7.5

15
20
24

0.2

2
2.5

1

10
25

Reference

Decreased spleen and thymus
weights
Altered response to sRBC

Yang et al. 2001

Altered response to sRBC,
decreased antibody formation
Decreased response to horse red
blood cells

Vetvicka andVetvickova 2013
Yang et al. 2002a

DeWitt et al. 2009

2-Fold increase in serum estradiol Liu et al. 1996
levelsDecrease in the number of corpora Chen et al. 2017blutea
63% increase in serum estradiol
Cook et al. 1992
levels
184% increase in serum estradiol Biegel et al. 1995
levels0.5

Decreased litter weight on PND 2

0.58

Decreased spontaneous behavior Johansson et al.
and altered response to cholinergic 2008
stimulant
Altered mammary gland
White et al. 2007
development, decreased pup bodyweight on PND 20
Delayed mammary gland
White et al. 2007
development, decreased pup bodyweight on PND 20
Delayed mammary gland
White et al. 2009
development; decreased pup body Wolf et al. 2007
weight at weaning

Mouse
GDs 8–17 or 12–
17
Mouse
GDs 8–17

5

Mouse
Various GDs5

5

Hu et al. 2010

aLOAELs are for less serious effects.

GD = gestation day; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level;
PND = postnatal day; sRBC = sheep red blood cell

The lowest LOAEL values were identified for developmental effects; Hu et al. (2010) identified a
LOAEL of 0.5 mg/kg/day for decreases in litter weight on PND 2 and Johansson et al. (2008) identified a
LOAEL of 0.58 mg/kg for decreases in spontaneous behavior (locomotion and total activity) anddecreased response to a cholinergic stimulant in adult mice exposed to PFOA on PND 10. Neither study
identified NOAEL values.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-19
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:
MRL:
Critical Effect:
Reference:
Point of Departure:
Uncertainty Factor:
LSE Graph Key:Species:

Perfluorooctanoic acid (PFOA)
335-67-1
March 2020
Final
Oral
Intermediate
3x10-6 mg/kg/day
Skeletal alterations in adult offspring
Koskela et al. 2016
0.000821 mg/kg/day
300
63
Mouse

MRL Summary: An intermediate-duration oral MRL of 3x10-6 mg/kg/day was derived for PFOA basedon skeletal alterations at 13 and 17 months of age in the offspring of mice fed a diet containing PFOA on
GD 1 through GD 21 (Koskela et al. 2016). The MRL is based on a HED LOAEL of 0.000821
mg/kg/day and a total uncertainty factor of 300 (10 for use of a LOAEL, 3 for extrapolation from animals
to humans with dosimetric adjustments, and 10 for human variability).
Selection of the Critical Effect: Intermediate-duration oral studies of PFOA in animals indicate that theliver, immune system, reproductive system, and the developing organism are the primary targets of
toxicity because adverse outcomes were observed at lower doses than other effects and have been
consistently observed across studies. A summary of the lower LOAEL values (and associated NOAEL
values) for these tissues/systems is presented in Table A-6; given the large number of studies, this table islimited to studies that identified LOAEL values of ≤4 mg/kg/day. Although these studies identified thelowest LOAEL values, not all were considered suitable as the basis of an intermediate-duration oral
MRL.
Exposure to low levels of PFOA results in increases in liver weight, hepatocellular hypertrophy, anddecreases in serum lipids in rats, mice, and monkeys exposed to PFOA for intermediate durations. The
increases in liver weight, hepatocellular hypertrophy, and alterations in serum lipid levels observed in therodents are likely adaptive responses to peroxisome proliferation and are not considered relevant forhuman risk assessment (Hall et al. 2012). Consistent with the Hall et al. (2012) criteria, the increases inliver weight and hepatocellular hypertrophy, in the absence of other degenerative alterations, were notconsidered adverse. Although there is uncertainty regarding the exact, and possibly multiple,
mechanism(s) for these liver effects, peroxisome proliferation is a likely contributor, a mechanism thatcannot be reliably extrapolated to humans (Hall et al. 2012). Therefore, increases in liver weight,
hepatocellular hypertrophy, and alterations in serum lipid levels, in the absence of other degenerative
lesions, were not considered appropriate endpoints for deriving MRLs.
A small number of animal studies have reported degenerative lesions, lesions to specialty cells, bile duct
lesions, or inflammation; these endpoints were considered relevant for human risk assessment (Butenhoff
et al. 2004b; Cui et al. 2009; Loveless et al. 2008). The lowest LOAEL for adverse liver effects was
0.96 mg/kg/day for increased liver weight, hepatocellular hypertrophy, and focal necrosis in mice exposedfor 28 days (Loveless et al. 2008). In utero exposure has also resulted in liver effects in offspring (Filgoet al. 2015a; Quist et al. 2015a); the lowest maternal LOAEL identified in these studies wasPERFLUOROALKYLS

A-20
APPENDIX A

0.01 mg/kg/day (Quist et al. 2015a). Because the Quist et al. (2015a) study did not provide incidence data
for the reported inflammation, this study was not considered suitable for derivation of an MRL. Hepaticeffects consisting of increases in absolute liver weight at ≥3 mg/kg/day and increases in serum
triglyceride levels at 30/20 mg/kg/day have also been observed in monkeys administered capsules
containing PFOA (Butenhoff et al. 2002); no histological alterations were observed in surviving animals,
but hepatocellular degeneration and necrosis was noted in a monkey sacrificed early due to morbidity.
The small number of animals examined and early deaths at several dose levels precludes using this study
as the basis of an MRL.
Two studies examining the immunotoxicity of PFOA following intermediate-duration oral exposure
found decreases in antigen-specific antibody responses in mice exposed for 15 days (DeWitt et al. 2008,2016); the lowest LOAEL was 1.88 mg/kg/day (DeWitt et al. 2016). Reproductive and developmental
toxicity studies have identified very low LOAELs of ≥0.0024 mg/kg/day for delays in mammary glanddevelopment in dams and offspring (Macon et al. 2011; Tucker et al. 2015; White et al. 2011). However,
the mammary gland effect did not result in an adverse effect on lactational support at maternal doses ashigh as 1 mg/kg/day, based on normal growth and survival in F2 pups (White et al. 2011). Given thatmilk production was adequate to support growth, the biological significance of the delayed developmentof the mammary gland observed at very low doses is uncertain and was not considered a suitable basis for
the MRL. Other developmental effects include increases in locomotor activity (Cheng et al. 2013;
Goulding et al. 2017; Onishchenko et al. 2011; Sobolewski et al. 2014) at ≥0.1 mg/kg/day, reduced
ossification of proximal phalanges and early preputial separation and delayed vaginal opening at≥1 mg/kg/day (Lau et al. 2006; Yang et al. 2009), altered long bone morphology and decreased bonemineral density in 13- and 17-month-old mice following in utero exposure to 0.3 mg/kg/day (Koskela etal. 2016), decreases in pup survival at ≥0.6 mg/kg/day (Abbott et al. 2007; Albrecht et al. 2013),
decreases in the number of successful births at ≥3 mg/kg/day (Ngo et al. 2014), and reduced neonatal
weight gain and delayed eye opening at ≥3 mg/kg/day (Wolf et al. 2007).

Table A-6. Summary of the Adverse Effects Observed in Laboratory Animals
Following Intermediate-Duration Oral Exposure
Species andexposure
duration
Hepatic
Mouse
GDs 1–17
Mouse
28 daysMouse
GDs 1–17(examined at
18 months ofage)
Rat
70–90 days
Monkey26 weeks

NOAEL(mg/kg/day)

LOAELa(mg/kg/day)
0.01

0.29

0.96

0.3

1

1

3

3

EffectReference

Hepatocellular hypertrophy andperiportal inflammation in offspring
Moderate to severe hepatocellular
hypertrophy and focal necrosis
Increased severity of chronic
inflammation in liver

Quist et al.
2015a, 2015b
Loveless et al.
2008
Filgo et al.
2015a, 2015b

Increased liver weight,
hepatocellular hypertrophy andnecrosis
Increased absolute liver weight

Butenhoff et al.
2004b
Butenhoff et al.
2002

PERFLUOROALKYLS

A-21
APPENDIX A

Table A-6. Summary of the Adverse Effects Observed in Laboratory Animals
Following Intermediate-Duration Oral Exposure
Species andexposure
duration
ImmunologicalMouse
15 daysMouse
15 days
Reproductive
Mouse
GDs 1–17

NOAEL(mg/kg/day)

LOAELa(mg/kg/day)

0.94
1.88

Mouse
GDs 1–17

EffectReference

1.88

Reduced antibody response

3.75

Reduced sRBC response

DeWitt et al.
2016
DeWitt et al.
2008

0.0024

Delayed mammary glanddevelopment in dams (3-generation
study)
Delayed mammary glanddevelopment in dams (singlegeneration study)

1

White et al.
2011
White et al.
2011

Developmental
Mouse
GD 7–PND 22

0.0024

Impaired development of mammary White et al.
glands2011

Mouse
GDs 10–17

0.01

Impaired development of mammary Macon et al.
glands2011

Mouse
GDs 1–17

0.01

Impaired development of mammary Tucker et al.
glands2015

Mouse
GD 7–PND 21

0.1

Neurodevelopmental

Mouse
GDs 1–21

0.3

Mouse
GDs 1–21
Mouse
GDs 1–17
Mouse
GDs 1–17
Mouse
GDs 1–17

0.3

1

Altered exploratory behavior in adult Onishchenko etoffspring; increased global activity in al. 2011
males
Skeletal alterations in mature
Koskela et al.
offspring
2016
Impaired development of mammary Macon et al.
glands2011
Decreased pup survival
Abbott et al.
2007
Reduced ossification of proximal
Lau et al. 2006
phalanges and advanced preputial
separation
Delayed vaginal opening
Yang et al. 20091

Increased ambulatory activity

1.6

Neurodevelopmental

3

Decreased number of successful
births

0.3
0.3

Mouse
4 weeks starting

0.6(SLOAEL)
1

Sobolewski etal. 2014

at PND 21

Mouse
GDs 1–17
Rat
GD 1–PND 21
Mouse
GDs 1–17

0.3

0.1

Goulding et al.
2017
Cheng et al.
2013
Ngo et al. 2014

PERFLUOROALKYLS

A-22
APPENDIX A

Table A-6. Summary of the Adverse Effects Observed in Laboratory Animals
Following Intermediate-Duration Oral Exposure
Species andexposure
duration

NOAEL(mg/kg/day)

LOAELa(mg/kg/day)

EffectReference

Mouse
GDs 1–17

3

Reduced pups per litter on PND 20

Albrecht et al.
2013

Mouse
GDs 1–17

3

Reduced weight gain, delayed eye
opening

Wolf et al. 2007

aUnless otherwise noted, LOAELs are for less serious effects.

GD = gestation day; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level;
PND = postnatal day; SLOAEL = serious LOAEL; sRBC = sheep red blood cell

Selection of the Principal Study: As outlined in the MRL approach section, serum PFOA levels werepredicted for the administered doses for most of the studies listed in Table A-6. Mean serum PFOA
levels could not be predicted for four studies because pharmacokinetic model parameters were notavailable for Wistar rats (Cheng et al. 2013), male CD-1 mice (Loveless et al. 2008), or 129S1/SvlmJ
wild-type mice (Abbott et al. 2007; Albrecht et al. 2013). A summary of the predicted serum PFOA
levels is presented in Table A-7.

Table A-7. Summary of the Predicted TWA Serum PFOA levels in Laboratory
Animals Following Intermediate-Duration Oral Exposure
Species andexposure
Doseduration(mg/kg/day)
HepaticCD
Mouse
28 days
129/Sv
Mouse
GDs 1–17

SpragueDawley
Rat
70–90 days
Cynomolgus
Monkey6 months

0.29
0.96
9.6
0.01
0.1
0.3
1
5
1
3
10
30
3
10
20/30

Predicted TWA
serum PFOA(µg/mL)Not calculated
0.423
4.21
12.5
39.2
102
60.4
136
222
242
68.5
93.8
113

EffectReference

Moderate to severe
Loveless et al.
hepatocellular hypertrophy and 2008
focal necrosis at 0.96 mg/kg/day
Increased severity of chronic
Filgo et al.
inflammation in liver of offspring 2015a, 2015b
aged 18 months at 1 mg/kg/day

Increased liver weight,
hepatocellular hypertrophy andnecrosis at 10 mg/kg/day

Butenhoff et al.
2004b

Increased liver weight at
3 mg/kg/day

Butenhoff et al.
2002

PERFLUOROALKYLS

A-23
APPENDIX A

Table A-7. Summary of the Predicted TWA Serum PFOA levels in Laboratory
Animals Following Intermediate-Duration Oral Exposure
Species andexposure
Doseduration(mg/kg/day)Predicted TWA
serum PFOA(µg/mL)

EffectReference

21.4
42.5
58.4
83.5
21.4
42.5
58.4
83.5
109
149

Reduced antibody response at
1.88 mg/kg/day

DeWitt et al.
2016

Reduced sRBC response at
3.75 mg/kg/day

DeWitt et al.
2008

2.23

Neurodevelopmental effects
Sobolewski et al.
(increased horizontal and vertical 2014activity and decreased resting
activity) at 0.1 mg/kg/day
Skeletal alterations at
Koskela et al.
0.3 mg/kg/day
2016

Immunological
C58BL/6NMouse
15 days

C57BL/6NMouse
15 days

0.94
1.88
3.75
7.5
0.94
1.88
3.75
7.5
15
30

Developmental
C57BL/6
0.1
Mouse
GD 7–
PND 21C57BL/6
0.3
Mouse
GDs 1–21
C57BL/6
0.3
Mouse
GDs 1–21
129S1/SvlmJ
Mouse
GDs 1–17

CD-1
Mouse
GDs 1–17

0.1
0.3
0.6
1
3
5
10
20
1
3
5
10
20
40

8.29

8.29

Neurodevelopmental (decreased Onishchenko etnumber of inactive periods,
al. 2011
altered novelty induced activity)
at 0.3 mg/kg/day
Decreased pup survival at
Abbott et al. 2007
0.6 mg/kg/day

Not calculateda

39.2
83.6
102
125
155
205

Reduced ossification of proximal Lau et al. 2006
phalanges and advanced
preputial separation at
1 mg/kg/dayPERFLUOROALKYLS

A-24
APPENDIX A

Table A-7. Summary of the Predicted TWA Serum PFOA levels in Laboratory
Animals Following Intermediate-Duration Oral Exposure
Species andexposure
Doseduration(mg/kg/day)Mouse
4 weeks
starting at
PND 21
Mouse
GDs 1–17

Predicted TWA
serum PFOA(µg/mL)

EffectReference
Yang et al. 20091
5
10

Not calculated

Delayed vaginal opening

0.1
0.3
1
1.6

4.21
12.5
39.2
Not calculated

Increased ambulatory activity at Goulding et al.
1 mg/kg/day
2017

C57BL/6J
Mouse
GDs 1–17
SV/129Mouse
GDs 1–17

0.1
3

2.43
62.0

3

Not calculatedb

Reduced pups per litter on
PND 20 at 3 mg/kg/day

Albrecht et al.
2013

CD-1
Mouse
GDs 1–17

3
5

84.8
102

Reduced weight gain, delayed
eye opening at 3 mg/kg/day

Wolf et al. 2007

WistarRat
GD 1–PND 21

Neurodevelopmental effects
Cheng et al. 2013
(increased locomotor activity inmales and decreased activity infemales) at 1.6 mg/kg/day
Decreased number of successful Ngo et al. 2014
births at 3 mg/kg/day

aReported serum PFOA concentrations at weaning for the dams that did not have pups which survived to weaning

were 4.4, 10.4, 17.4, 26.3, 76.6, 72.4, and 68.2 µg/mL in the 0.1, 0.3, 0.5, 1, 5, 10, and 20 mg/kg/day group,
respectively.
bReported serum PFOA concentration was 17 µg/mL for dams treated with 1.6 mg/kg/day.
GD = gestation day; PFOA = perfluorooctanoic acid; PND = postnatal day; sRBC = sheep red blood cell;
TWA = time-weighted average

Selection of the Point of Departure for the MRL: The NOAEL/LOAEL and the benchmark dose
(BMD) approaches were utilized to identify potential PODs for derivation of the intermediate-duration
oral MRL for PFOA. The only datasets with predicted TWA serum PFOA levels amenable to BMD
modeling were from the DeWitt et al. (2008, 2016) immunotoxicity studies and Lau et al. (2006)
developmental toxicity study. The Sobolewski et al. (2014), Onishchenko et al. (2011), Koskela et al.
(2016), Ngo et al. (2014), and Wolf et al. (2007) studies were not considered for BMD modeling because
only one or two PFOA doses were tested. No adequate BMD models adequately fit the data from the Lau
et al. (2006) study. Adequate fit was found for the DeWitt et al. (2008, 2016) studies; the BMD modeling
results are presented at the end of this section.
HEDs were calculated for each potential PODs (NOAEL, LOAEL, or BMD value) identified inlaboratory animal studies using the first order single-compartment model previously discussed and theassumption that humans would have similar effects as the laboratory animal at a given serum
concentration. The HEDs for each POD are presented in Table A-8. The potential PODHED values weredivided by an uncertainty factor to calculate candidate MRLs; these values are also presented inTable A-8. The candidate MRLs range from 7.4x10-7 mg/kg/day for neurodevelopmental effects in micePERFLUOROALKYLS

A-25
APPENDIX A(Sobolewski et al. 2014) to 4.5x10-4 mg/kg/day for liver effects in male rats (Butenhoff et al. 2004b). The
lowest LOAEL (expressed as predicted serum concentration) was identified in the Sobolewski et al.
(2014) study, which found neurodevelopmental effects in mouse offspring at predicted serum PFOA
concentration of 2.23 µg/mL. However, this study was not considered suitable as the basis of the MRL
because the subroute and vehicle used for the controls (peanut oil with anisole administered via gavage)
were different from the PFOA group (PFOA dissolved in water and added to diet). Rather, theOnishchenko et al. (2011) and Koskela et al. (2016) studies, which identified the second lowest LOAEL(serum PFOA concentration) of 8.29 µg/mL were considered. In the Onishchenko et al. (2011) study,
circadian activity was assessed using a TrafficCage in which all animals in the group were placed in asingle cage and activity was measured. Thus, activity was only measured on a group basis and it ispossible that one animal could skew the results. Thus, this study was not considered a suitable basis for
an MRL.

Table A-8. Summary of Potential Points of Departures (PODs) and Human
Equivalent Doses (HEDs) for Intermediate-Duration Oral MRL for PFOA

Endpoint (reference)

Predicted serum
concentrations(µg/mL)NOAEL or
BMDL
LOAEL

Neurodevelopmental effects(increased horizontal and verticalactivity and decreased resting
activity) in mice (Sobolewski et al.
2014)
Neurodevelopmental effects(decreased number of inactive
periods, altered novelty induced
activity) in mice (Onishchenko et al.
2011)
Skeletal alterations in mice (Koskela
et al. 2016)
Decreased number of successful
2.43
births in mice (Ngo et al. 2014)
Reduced ossification of proximal
phalanges and advanced preputial
separation in mice (Lau et al. 2006)
Increased ambulatory activity
12.5(Goulding et al. 2017)
Reduced weight gain and delayed
eye opening (Wolf et al. 2007)
Reduced response to dinitrophenyl- 12.23
ficoll (DNP) antigen in female mice (BMDL1SD)(DeWitt et al. 2016)
Increased severity of chronic
12.5
inflammation in liver of offspring
aged 18 months (Filgo et al. 2015a,
2015b)PODHEDa(mg/kg/day)

Candidate
MRLs
Total UF (mg/kg/day)

2.23

0.000221300b

7.4x10-78.29

0.000821300b

2.7x10-68.29

0.000821300b

2.7x10-6

62.0

0.00024130c

8.0x10-6

39.2

0.00388300b

1.3x10-539.2

0.0012430c

4.1x10-5

84.8

0.00840300b

2.8x10-50.0012130c

4.0x10-50.0012430c

4.1x10-5

39.2

PERFLUOROALKYLS

A-26
APPENDIX A

Table A-8. Summary of Potential Points of Departures (PODs) and Human
Equivalent Doses (HEDs) for Intermediate-Duration Oral MRL for PFOA

Endpoint (reference)
Reduced response to sRBC infemale mice (DeWitt et al. 2008)
Increased liver weight,
hepatocellular hypertrophy, andnecrosis in male rats (Butenhoff et
al. 2004b)

Predicted serum
concentrations(µg/mL)NOAEL or
BMDL
LOAEL
33.49
(BMDL1SD)
136
222

PODHEDa(mg/kg/day)

Candidate
MRLs
Total UF (mg/kg/day)

0.0033230c

1.1x10-4

0.013530c

4.5x10-4

aHED calculated using Equation A-6 where C is the serum concentration associated with the NOAEL or BMDL or
ss
the LOAEL if there was no NOAEL or BMDL, Ke=4.95x10-4; Vd=0.2, and AF=1.
bUF of 10 for extrapolation from a LOAEL, 3 for extrapolation from animals to humans with dosimetric adjustments,
and UF of 10 for human variability.
cUF of 3 for extrapolation from animals to humans with dosimetric adjustments, and 10 for human variability.

BMDL = lower confidence limit on the BMD; HED = human equivalent dose; LOAEL = lowest-observed-adverseeffect level; MRL = Minimal Risk Level; NOAEL = no-observed-adverse-effect level; POD = point of departure;sRBC = sheep red blood cell; UF = uncertainty factor

Summary of the Principal Study:
Koskela A, Finnila MA, Korkalainen M, et al. 2016. Effects of developmental exposure toperfluorooctanoic acid (PFOA) on long bone morphology and bone cell differentiation. Toxicol Appl
Pharmacol 301:14-21.
Pregnant C57BL/6/Bk1 mice were exposed to PFOA (96% pure) in food at dose levels of 0 mg/kg/day(n=10) or 0.3 mg/kg/day (n=6) from GD 1 throughout pregnancy (presumed GD 21). PFOA was
dissolved in ethanol and applied to palatable food in volumes adjusted according to individual bodyweights to provide 0.3 mg/kg/day, followed by evaporation of ethanol; controls received food withethanol applied and then evaporated. It is noted that litter mates of these offspring were examined forneurobehavioral effects in a study conducted by Onishchenko et al. (2011). Groups of five female
offspring were sacrificed at either 13 or 17 months of age. The following parameters were used to assess
toxicity: body weight and morphometric/biochemical properties in bone (femurs and tibias) of offspring.
As reported in Onishchenko et al. (2011), no differences in dams weight gain, litter size or sex ratio, or
pup body weight or brain weight at birth were observed; significant increases in pup liver weight wasobserved in the PFOA group. Offspring body weight was significantly higher in comparison with
controls at 13 and 17 months of age (9.9 and 7.8%, respectively). In 17-month-old offspring, there was a
6.8% increase in periosteal area of the femoral cortical bone and increases in the peri- and endosteal
perimeters (3.2 and 5.2%, respectively) and the marrow area (10.0%); an increase in medullary area wasalso observed. There were no differences in femoral cortical bone area or femoral mineral density. In thetibia, the total area inside the periosteal envelope and the periosteal perimeter were increased (4.9 and
3.5%, respectively). Although the investigators noted in the text that tibial medullary areas were
“essentially the same between groups,” data in Figure 2 of the paper show a significant increase at
17 months. Significant decreases in tibial mineral density were observed at 13 and 17 months. TherePERFLUOROALKYLS

A-27
APPENDIX A

were no significant differences in the tibial medullary area or the endosteal perimeter. There was a trend
for increasing maximum force (Fmax); however, the effect was not statistically significant. There wereno significant effects on any other measured biochemical parameter in the femur or tibia (stiffness,
maximum energy, absorption). Concentrations of PFOA in the femurs and tibias of treated animals weresignificantly higher (4–5 times) than controls at 13 and 17 months. Koskela et al. (2016) suggested that
the PFOA-induced increase in body weight gain may have indirectly affected bone homeostasis, but notedthat in vitro data provide evidence of a direct effect on osteoblasts and osteoclasts.
Strengths and Weaknesses: The Koskela et al. (2016) study has a number of strengths including
examination of several measures of bone status tested at different ages, measurement of bone PFOA levels,and tests to evaluate potential mechanisms of action. To evaluate whether developmental exposure
resulted in bone damage in mature animals, the study evaluated bone morphology (periosteal, cortical, andmedullary areas and bone mineral density) and bone biomechanical properties (stiffness, maximum force,and maximum energy); all tests were conducted on femur and tibia bone. Measurement at two ages
(13 and 17 months) allowed for an evaluation of whether the effect of PFOA on bone changed as theanimals aged. The companion in vitro study of osteoclasts and osteoblasts provided mechanistic support
for the in vivo findings. Additionally, the in vitro study evaluated four PFOA concentrations and foundconcentration-related differences.
There are several study limitations that affect the interpretation of the study results; these include the small
number of animals tested, use of only one PFOA dose level, inadequate reporting of dietary PFOA levels,and lack of measured serum PFOA levels. Tests of potential alterations in bone mineral density and bonebiomechanical properties were only evaluated in 5–6 female offspring per group; however, support for thefinding comes from the consistency of the findings at 13 and 17 months of age. The use of only one PFOA
dose level does not allow for the establishment of dose-response relationships. This study limitation is
mitigated by the extensive intermediate-duration oral exposure database, which allows for an overall
assessment of dose-response. The dams were exposed to PFOA dissolved in alcohol and sprayed onto thefood pellets. The study did not measure the amount of residual alcohol or the actual amount of PFOA on
the food pellets. Koskela et al. (2016) measured PFOA levels in the tibias and femurs but did not measureserum PFOA levels. ATSDR estimated the TWA serum PFOA concentrations using the Wambaugh et al.
(2013) model. The lack of measured serum PFOA levels did not allow for validation of whether the model
accurately predicted serum levels; the model was validated using data from other intermediate-duration
PFOA studies in rats and mice.
Calculation of Internal Dosimetric: TWA serum PFOA concentrations corresponding to external doses
and exposure durations were predicted from a pharmacokinetic model (Wambaugh et al. 2013) using
animal species-, strain-, and sex-specific parameters (see MRL approach section for details).
Human Equivalent Dose: HEDs were calculated based on the assumption that humans would have
similar effects as the laboratory animal at a given serum concentration. HEDs that would result in steadystate serum concentrations of PFOA equal to the serum concentration selected as the POD were
calculated using the first-order single-compartment model (see MRL approach section for details).
Uncertainty Factor: The LOAELHED is divided by a total uncertainty factor of 300:
• 10 for the use of a LOAEL• 3 for extrapolation from animals to humans with dosimetric adjustment• 10 for human variability
MRL = LOAELHED ÷ UFs
0.000821 mg/kg/day ÷ (10 x 3 x 10) = 3x10-6 mg/kg/dayPERFLUOROALKYLS

A-28
APPENDIX A

Other Additional Studies or Pertinent Information that Lend Support to this MRL: In vitro studies
conducted by Kosela et al. (2016) found that at lower concentrations (0.1–10 µM), PFOA stimulated
osteoblast differentiation, as evidenced by increased osteocalcin mRNA expression and increased calcium
secretion. At higher PFOA levels (>100 µM), osteocalcin expression and calcium secretion weredecreased. Lower concentrations of PFOA (0.1–1.0 µM) also increased the number of osteoclasts andincreased resorption activity; as with osteoblasts, decreased activity was observed at >100 µM PFOA
concentrations.
Epidemiological studies have not evaluated the potential association between serum PFOA levels andimpaired development of bone. A small number of studies in adults have examined potential associations
with osteoarthritis risk. Innes et al. (2011) reported an elevated risk of physician diagnosed osteoarthritis
among adults under 55 years of age with serum PFOA concentrations >13.6 ng/mL; the OR (95% CI) was
1.22 (1.02–1.45) among participants with serum PFOA in the second quartile (13.6–28.0 ng/mL). In a
study of NHANES participants, Khalil et al. (2016) found an elevated risk of osteoarthritis among
women, OR of 1.84 (1.17–2.90); the mean serum PFOA concentration was 3.7 ng/mL. This study also
found in inverse association between serum PFOA and femur neck mineral density in women, but not inmen. A second study of NHANES participants also found an elevated risk of osteoarthritis in womenwith serum PFOA levels of >5.89 ng/mL, OR of 1.98 (1.24–3.19) (Uhl et al. 2013). When segregated byage, an association was found in younger women (20–49 years of age), OR of 4.95 (1.27–19.4), but notamong older women (50–84 years of age), OR of 1.33 (0.82–1.16) (Uhl et al. 2013). No association
between estimated cumulative exposure to PFOA and the risk of osteoarthritis was observed in an
occupational study in which 80% of the cohort was male (Steenland et al. 2015). A discussion of theother findings from epidemiological studies is presented in the MRL introduction section.
Benchmark Dose Modeling: BMD modeling was conducted for the DeWitt et al. (2008) and DeWitt etal. (2016) immunotoxicity studies. Using predicted TWA serum PFOA levels as the internal dosimetric,
the IgM response data (summarized in Tables A-9 and A-10) were fit to all available continuous models
in EPA’s Benchmark Dose Software (BMDS, version 2.6.0). The following procedure for fitting
continuous data was used: the simplest model (linear) was first applied to the data while assuming
constant variance; if the data were consistent with the assumption of constant variance (p≥0.1), then thefit of the linear model to the means was evaluated and the polynomial, power, and Hill models were fit to
the data while assuming constant variance. Adequate model fit was judged by three criteria: goodnessof-fit p-value (p>0.1), visual inspection of the dose-response curve, and scaled residual at the data point(except the control) closest to the predefined benchmark dose response (BMR). Among all of the models
providing adequate fit to the data, the lowest BMDL (the lower limit of a one-sided 95% CI on the BMD)
was selected as a reasonably conservative POD when differences between the BMDLs estimated fromthese models are >2–3-fold; otherwise, the BMDL from the model with the lowest Akaike's information
criterion (AIC) was chosen. If the test for constant variance was negative, the linear model was run again
while applying the power model integrated into the BMDS to account for nonhomogenous variance. If
the nonhomogenous variance model provided an adequate fit (p≥0.1) to the variance data, then the fit of
the linear model to the means was evaluated and the polynomial, power, and Hill models were fit to thedata and evaluated while the variance model was applied. Model fit and POD selection proceeded as
described earlier. For both datasets, a BMR of 1 SD change from the control was used.

PERFLUOROALKYLS

A-29
APPENDIX A

Table A-9. T-Cell Independent IgM Antibody Response in C57BL/6N Female Mice
Immunized with Sheep Red Blood Cells
Predicted TWA serum IgM antibody titersa
PFOA concentration [mean serum IgM titer(µg/mL)(log2) to reach 0.5 OD] SEa

Administered
Number ofdose
animals per group (mg/kg/day)
8
8
8
8

0
0.94
1.88
3.75

0
21.4
42.5
58.4

7.28
7.39
7.08
6.75b

0.13
0.07
0.10
0.09

8

7.5

83.5

6.61b

0.12

aData taken from Figure 3-C using GrabIt.
bStatistically different from controls (p<0.05).

PFOA = perfluorooctanoic acid; SE = standard error; TWA = time-weighted-average
Source: DeWitt et al. 2008

Table A-10. T-Cell Independent IgM Antibody Response In C57BL/6 Female Mice
Immunized with Dinitrophenyl-Ficoll
Number of Administeredanimals per dosegroup
(mg/kg/day)Predicted TWA serum T-cell independent IgM antibody
PFOA concentration responsea [mean serum titer(µg/mL)(log2) to reach 0.5 OD]
SDa

8

0

0

11.38

0.56

8
8
8
8

0.94
1.88
3.75
7.5

21.4
42.5
58.4
83.5

11.01
9.67b
9.81b
9.62b

1.11
1.34
1.46
0.97

aData taken from Figure 3b using GrabIt.
bStatistically different from controls (p<0.05).

PFOA = perfluorooctanoic acid; SE = standard error; TWA = time-weighted-average
Source: DeWitt et al. 2016

The results of the BMD analysis of the DeWitt et al. (2008) and DeWitt et al. (2016) datasets arepresented in Tables A-11 and A-12. For the DeWitt et al. (2008) data, the Hill model with constantvariance provided the best fit to the IgM response data, as judged by the model with the lowest AIC since
the range of BMDL values were sufficiently close; the fit of this model is presented in Figure A-1. For
the DeWitt et al. (2016) IgM response data, constant variance models provided adequate fit; since theestimated BMDL values were not sufficiently close, the model with the lowest BMDL (Exponential 4)
was selected; the fit of this model is presented in Figure A-2.

PERFLUOROALKYLS

A-30
APPENDIX A

Table A-11. T-Cell Independent IgM Antibody Response in C57BL/6N Female
Mice Immunized With Sheep Red Blood Cells Using Predicted TWA SerumPFOA as the Dose Metric (DeWitt et al. 2008)
c

Model

Scaled residuals
Test forsignificant
Dose Dose
difference Variance Means below above Overall
p-valuea p-valueb p-valueb BMC BMC largest AIC

BMD1SD BMDL1SD(ng/mL) (ng/mL)

Constant variance
Exponential(model 2)dExponential(model 3)dExponential(model 4)dExponential(model 5)dHilld,eLinearf
Polynomial(2-degree)f
Polynomial(3-degree)f
Polynomial(4-degree)f
Powerd<0.0001

0.46

0.08

1.73

<0.0001

0.46

0.10

<0.0001

0.46<0.00010.72 1.73-50.41 ND

ND

0.16 -1.30 1.33

-50.61 42.55

26.37

0.08

1.73

0.72 1.73-50.41 ND

ND

0.46

0.36

-0.14

0.09 0.67-52.34 44.11

33.33<0.0001<0.0001<0.0001

0.46
0.46
0.46

0.41
0.09
0.08

-0.05 0.06 0.60
1.69 0.67 1.69
0.10 -1.41 1.43

-52.47 43.57-50.66 ND-50.00 ND

33.49
ND
ND

<0.0001

0.46

0.08

0.10 -1.41 1.43

-50.00 ND

ND<0.0001

0.46

0.08

0.10 -1.41 1.43

-50.00 ND

ND<0.0001

0.46

0.10

0.16 -1.32 1.35

-50.49 42.62

26.23

aValues >0.05 fail to meet conventional goodness-of-fit criteria.
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
cScaled residuals at doses immediately below and above the benchmark dose; also the largest residual at any dose.
dPower restricted to ≥1.
eSelected model.

Constant variance model provided adequate fit to variance data. With constant variance model
applied, the only models that provided adequate fit to the means were the Exponential 3 and 5, Hill, and Powermodels. BMDLs for models providing adequate fit were considered to be sufficiently close (differed by <2–3-fold);
therefore, the model with the lowest AIC was selected (Hill).
fCoefficients restricted to be negative.
AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the exposure concentration associatedwith the selected benchmark response; BMDL = 95% lower confidence limit on the BMD (subscripts denotebenchmark response: i.e., 10 = exposure concentration associated with 10% extra risk); ND = not determined, model
did not provide adequate fit; PFOA = perfluorooctanoic acid; SD = standard deviation; TWA = time-weighted averagePERFLUOROALKYLS

A-31
APPENDIX A

Figure A-1. Predicted (Hill Model with Constant Variance, 1 Standard Deviation
Benchmark Response) and Observed IgM Response Using Predicted TWA
Serum PFOA as the Dose Metric
Hill Model, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
Hill
7.6

7.4

Mean Response

7.2

7

6.8

6.6

6.4

BMDL

BMD

6.2
0

10

20

30

40
dose

09:21 02/16 2017

50

60

70

80

PERFLUOROALKYLS

A-32
APPENDIX A

Table A-12. T-Cell Independent IgM Antibody Response In C57BL/6 Female Mice
Immunized With Dinitrophenyl-Ficoll Using Predicted TWA Serum PFOA as the
Dose Metric (DeWitt et al. 2016)

Model

Scaled residualsc
Test forsignificant
Dose Dose
difference Variance Means below above Overall
p-valuea p-valueb p-valueb BMC BMC largest AIC

BMD1SD BMDL1SD(ng/mL) (ng/mL)

0.0029

0.12

0.34

-1.47

-0.17 -1.47

54.00

45.00

29.56

0.0029

0.12

0.34

-1.47

-0.17 -1.47

54.00

45.00

29.56

0.0029

0.12

0.31

1.01

-1.06 -1.06

54.97

29.22

12.23

0.0029

0.12

0.71

0.00

-0.08

0.29

54.76

26.62

18.75

0.00290.00290.0029

0.12
0.12
0.12

0.93
0.30
0.30

0.00
-1.52
-1.52

-0.08 0.29
-0.23 -1.52-0.23 -1.52

52.76
54.27
54.27

23.66
47.96
47.96

19.11
32.63
32.63

0.0029

0.12

0.30

-1.52

-0.23 -1.52

54.27

47.96

32.63

0.0029

0.12

0.30

-1.52

-0.23 -1.52

54.27

47.96

32.63

0.0029

0.12

0.30

-1.52

-0.23 -1.52

54.27

47.96

32.63

Constant variance
Exponential(model 2)dExponential(model 3)dExponential(model 4)d,e
Exponential(model 5)dHilld
Linearf
Polynomial(2-degree)f
Polynomial(3-degree)f
Polynomial(4-degree)f
PowerdaValues >0.05 fail to meet conventional goodness-of-fit criteria.
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
cScaled residuals at doses immediately below and above the benchmark dose; also the largest residual at any dose.
dPower restricted to ≥1.
eSelected model.

Constant variance model provided adequate fit to variance data. With constant variance model
applied, all models provided adequate fit to the means. BMDLs for models providing adequate fit were notconsidered to be sufficiently close (differed by >2-fold, but <3-fold). In order to remain conservative, the model withthe lowest BMDL was selected (Exponential 4).
fCoefficients restricted to be negative.
AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the exposure concentration associatedwith the selected benchmark response; BMDL = 95% lower confidence limit on the BMD (subscripts denotebenchmark response: i.e., 10 = exposure concentration associated with 10% extra risk); NA = not applicable (BMDL
computation failed); SD = standard deviation; TWA = time-weighted averagePERFLUOROALKYLS

A-33
APPENDIX A

Figure A-2. Predicted (Exponential 4 Model with Constant Variance, 1 Standard
Deviation Benchmark Response) and Observed IgM Response Using Predicted
TWA Serum PFOA as the Dose Metric
Exponential 4 Model, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
Exponential 4
12

11.5

Mean Response

11

10.5

10

9.5

9

8.5
BMDL
0

10

BMD
20

30

40
dose

08:25 02/16 2017

Agency Contacts (Chemical Managers): Melanie Buser

50

60

70

80

PERFLUOROALKYLS

A-34
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanoic acid (PFOA)
335-67-1
March 2020
Final
Oral
Chronic

MRL Summary: ATSDR did not identify an adequate study with an exposure duration of ≥365 days.
Although adequate data are available for intermediate-duration exposure, ATSDR does not extrapolate
across exposure duration.
Rationale for Not Deriving an MRL: The chronic oral animal database for PFOA is limited to dietary
exposure studies in male and female rats (3M 1983; Butenhoff et al. 2012c) or male rats (Biegel et al.
2001). The lowest LOAEL identified in the Butenhoff et al. (2012c; 3M 1983) study was 1.5 mg/kg/day
for inflammation of salivary gland in male rats exposed to PFOA in the diet for 2 years. At
15 mg/kg/day, hepatocellular necrosis was observed after 1 year of exposure and vascular mineralization
was observed in the testes. In the Biegel et al. (2001) study, exposure to 13.6 mg/kg/day PFOA in thediet for 2 years resulted in decreases in body weight gain, increases in Leydig cell hyperplasia, andpancreatic acinar cell hyperplasia in male rats.
The chronic-duration database for PFOA was not considered adequate for MRL derivation due touncertainty in the selection of the critical effect. The Butenhoff et al. (2012c) study identified the salivary
gland as the most sensitive target, but these alterations were only observed in males and may have been
due to an antemortem viral infection. Intermediate-duration oral studies have suggested that the immune
system is a sensitive target of toxicity in mice; however, potential alterations in immune function have notbeen investigated in chronic-duration studies; the Butenhoff et al. (2012c) study did conduct histologicalexaminations of immune tissues.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-35
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctane sulfonic acid (PFOS)
1763-23-1
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFOS.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFOS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-36
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctane sulfonic acid (PFOS)
1763-23-1
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFOS.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFOS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-37
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctane sulfonic acid (PFOS)
1763-23-1
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFOS.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFOS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-38
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctane sulfonic acid (PFOS)
1763-23-1
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFOS.
Rationale for Not Deriving an MRL: An acute-duration oral MRL for PFOS cannot be derived because
the modeling approach used for estimating HEDs cannot be used to estimate acute human exposure where
the exposure duration of 14 days is <1% of the PFOS elimination half-life in humans.
A number of studies have examined the toxicity of PFOS in laboratory animals following acute-duration
exposure. The available data suggest that the liver, developing organism, and immune system aresensitive targets. The liver effects consisted of decreases in serum lipids, increases in liver weight, andhepatocellular hypertrophy (Elcombe et al. 2012a, 2012b; Era et al. 2009; Fuentes et al. 2006; Haughom
and Spydevold 1992; Vetvicka and Vetvickova 2013; Wan et al. 2011); using the Hall et al. (2012)
criteria (see Section 2.9 for a discussion of the criteria) for assessing the adversity of liver alterations forperoxisome proliferators, these effects were not considered relevant for human risk assessment. Although
there is uncertainty regarding the exact, and possibly multiple, mechanism(s) for these liver effects,
peroxisome proliferation is a likely contributor, a mechanism that cannot be reliably extrapolated tohumans (Hall et al. 2012). Therefore, increases in liver weight, hepatocellular hypertrophy, andalterations in serum lipid levels observed in rats and mice, in the absence of other degenerative lesions,were not considered appropriate endpoints for deriving MRLs. A decrease in serum HDL cholesterollevels was also observed in male and female monkeys receiving three doses of 13.3 or 14 mg/kg/day(TWA dose in males and females, respectively) over 315 days (Chang et al. 2017).
Immunological effects included altered responses to sRBC and decreased IgM antibody formation in
response to antigen exposure in mice (Vetvicka and Vetvickova 2013; Zheng et al. 2009). Developmental
effects consisted of decreases in neonatal survival (Abbott et al. 2009; Grasty et al. 2003), increases inpost-implantation losses (Lee et al. 2015a), decreases in fetal body weight (Case et al. 2001; Era et al.
2009; Fuentes et al. 2007b; Lee et al. 2015a), increases in malformations (Era et al. 2009), and alterations
in motor activity (Hallgren et al. 2015; Johansson et al. 2008). The lowest LOAEL identified was
0.5 mg/kg/day for increased post-implantation losses in mice (Lee et al. 2015a). A summary of theadverse effect levels for the immunological and developmental effects are presented in Table A-13.

PERFLUOROALKYLS

A-39
APPENDIX A

Table A-13. Summary of the Adverse Effects Observed in Laboratory Animals
Following Acute-Duration Oral Exposure to PFOS
Species andexposure
duration

NOAEL
LOAELa(mg/kg/day) (mg/kg/day) EffectImmunologicalMouse
7 daysMouse
7 daysDevelopmental
Mouse
GDs 11–16
Mouse
Once
RabbitGDs 6–20
Mouse
GDs 15–18
Mouse
GDs 12–18
Mouse
Once
Rat
GDs 19–20
Rat
GDs 2–5, 6–9,
10–13, 14–17, or
17–20
Mouse
GDs 11–15

1

Reference

5

Impaired response to T-cell
Zheng et al. 2009
mitogens; suppressed response to
sRBC

20

Inhibition of T lymphocyte
proliferation in response to sRBC;
decreased phagocytosis byperipheral blood cells and NK cell
activity; decreased IgM antibody
formation in response to OVA

0.5

Increased post-implantation losses Lee et al. 2015a

0.75

Decreased motor activity

2.5

Decreased fetal body weight

4.5

Decreased number of live pups per Abbott et al. 2009
litter on PND 15
Reduced pup body weight on
Fuentes et al.
PNDs 4 and 8
2007b
Altered spontaneous behavior inHallgren et al.
pups
2015
Decreased neonatal survival
Grasty et al. 2003

6
11.3
25
(SLOAEL)
25(SLOAEL)50

Decreased neonatal survival

Cleft palate and reduced fetal
body weight

Vetvicka andVetvickova 2013

Johansson et al.
2008
Case et al. 2001

Grasty et al. 2003

Era et al. 2009aUnless otherwise noted, the LOAEL is for a less serious effect.

GD = gestation day; LOAEL = lowest-observed-adverse-effect level; NK = natural killer; NOAEL = no-observedadverse-effect level; perfluorooctane sulfonic acid; PND = postnatal day; SLOAEL = LOAEL for a serious effect;sRBC = sheep red blood cell

Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-40
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:
MRL:
Critical Effect:
Reference:
Point of Departure:
Uncertainty Factor:
Modifying Factor:
LSE Graph Key:Species:

Perfluorooctane sulfonic acid (PFOS)
1763-23-1
March 2020
Final
Oral
Intermediate
2x10-6 mg/kg/day
Delayed eye opening and decreased pup body weight
Luebker et al. 2005a
0.000515 mg/kg/day
30
10
35
Rat

MRL Summary: An intermediate-duration oral MRL of 2x10-6 mg/kg/day was derived for PFOS basedon delayed eye opening and transient decrease in F2 body weight during lactation in the offspring of rats
administered PFOS via gavage in a 2-generation study (Luebker et al. 2005a). The MRL is based on a
HED NOAEL of 0.000515 mg/kg/day and a total uncertainty factor of 30 (3 for extrapolation fromanimals to humans with dosimetric adjustments and 10 for human variability) and a modifying factor of
10 for concern that immunotoxicity may be a more sensitive endpoint than developmental toxicity.
Selection of the Critical Effect: Intermediate-duration studies in monkeys, rats, and mice have identified
several sensitive targets of PFOS toxicity including the liver, nervous system, immune system, and thedeveloping organism; adverse outcomes occurred in these tissues at lower doses than other effects. The
lowest LOAEL and NOAEL values for these outcomes are presented in Table A-14; given the large
number of intermediate-duration studies, this table was limited to studies which identified LOAEL valuesof ≤3 mg/kg/day. The liver effects observed in monkeys, rats, and mice included increases in liver
weight, decreases in serum lipids, hepatocellular degeneration, and focal necrosis (Cui et al. 2009; Curran
et al. 2008; Elcombe et al. 2012a; Lefebvre et al. 2008; Seacat et al. 2002, 2003; Thibodeaux et al. 2003;
Wan et al. 2011; Yahia et al. 2008). In the absence of degenerative changes such as necrosis, the liver
hypertrophy observed in rodent studies was not considered relevant to human risk assessment (Hall et al.
2012). Although there is uncertainty regarding the exact, and possibly multiple, mechanism(s) for theseliver effects, peroxisome proliferation is a likely contributor, a mechanism that cannot be reliably
extrapolated to humans (Hall et al. 2012). Therefore, increases in liver weight, hepatocellular
hypertrophy, and alterations in serum lipid levels observed in rats and mice, in the absence of otherdegenerative lesions, were not considered appropriate endpoints for deriving MRLs.
Several studies have examined potential neurological endpoints and found overt signs of neurotoxicity(cachexia, lethargy, and tonic convulsions in response to stimuli) in rats exposed to 5 or 8.5 mg/kg/day(Cui et al. 2009; Kawamoto et al. 2011) and impaired spatial learning and memory in mice exposed to
2.15 mg/kg/day (Long et al. 2013). Four studies have evaluated the immune response of PFOS exposed
mice following exposure to an antigen (sRBC) or a virus (Dong et al. 2009, 2011; Guruge et al. 2009;
Peden-Adams et al. 2008). Although the studies have consistently reported adverse effects, there isconsiderable overlap in LOAEL values. Peden-Adams et al. (2008) identified the lowest LOAEL of
0.00166 mg/kg/day with a NOAEL of 0.000166 mg/kg/day for a suppressed response to sRBC in miceadministered PFOS for 28 days. Longer duration studies (Dong et al. 2009, 2011) have identified
NOAEL values (0.0083 and 0.0167 mg/kg/day) in mice exposed to PFOS for 60 days that are higher thanPERFLUOROALKYLS

A-41
APPENDIX A

the LOAELs identified in the Peden-Adams et al. (2008) study. It is noted that the studies used different
mouse strains (B6C3F1 in the Peden-Adams study and C57BL/6N in the Dong studies), which may
account for this difference. A variety of developmental effects have been observed in rats and mice; theseinclude increases in postnatal mortality (Chen et al. 2012b; Lau et al. 2003; Luebker et al. 2005a, 2005b;
Xia et al. 2011; Yahia et al. 2008), neurodevelopmental alterations (locomotor activity and impaired
learning) (Butenhoff et al. 2009b; Onishchenko et al. 2011; Wang et al. 2015c), developmental delays(Lau et al. 2003; Luebker et al. 2005a), and malformations and anomalies (sternal defects and cleft palate)(Era et al. 2009; Thibodeaux et al. 2003; Yahia et al. 2008). The Wang et al. (2015c) study showed that
decreases in spatial learning were observed in rats exposed in utero and in rat pups exposed postnatally(PND 7). Other effects that occur at similar doses include decreases in body weight (Lefebvre et al. 2008;
Luebker et al. 2005a, 2005b; Seacat et al. 2002) and alterations in thyroid hormone levels (decreases in
T3 and T4 levels and increases in TSH levels) (Curran et al. 2008; Luebker et al. 2005b; Thibodeaux et al.
2003).
The most sensitive targets of PFOS toxicity in laboratory animals are similar to those identified in longer
term epidemiological studies. These effects include liver damage and increases in serum lipids, decreased
antibody response to vaccines, and small decreases in birth weight; epidemiological studies have notconsistently found neurological effects to be associated with serum PFOS levels.

Table A-14. Summary of the Adverse Effects Observed in Laboratory Animals
Following Intermediate-Duration Oral Exposure to PFOS
Species andexposure
duration

NOAEL
LOAELa(mg/kg/day) (mg/kg/day) Effect

Reference

Hepatic
Monkey26 weeks

0.15

0.75

Increased liver weight, decreased
serum cholesterol, hepatocellular
hypertrophy, lipid vacuolation

Seacat et al.
2002

0.43

2.15

Impaired spatial learning andmemoryLong et al. 2013

Mouse
28 days

0.000160.00166 Suppressed response to sRBC

Mouse
21 days

0.005

0.025

Decreased resistance to influenza Guruge et al.
virus
2009

Mouse
60 days0.0083

0.083

Impaired response to sRBC

Dong et al. 2009

Mouse
60 days0.01670.083

Impaired response to sRBC

Dong et al. 2011

0.3

Decreased locomotion, muscle
strength, motor coordination in
adult offspring

Onishchenko et
al. 2011

0.4

Delayed eye opening

0.4

Decreased pup weight

Luebker et al.
2005a
Luebker et al.
2005b

NeurologicalMouse
3 months
Immunological

Developmental
Mouse
GDs 1–21
Rat
84 daysRat
67 days

0.1

Peden-Adams etal. 2008

PERFLUOROALKYLS

A-42
APPENDIX A

Table A-14. Summary of the Adverse Effects Observed in Laboratory Animals
Following Intermediate-Duration Oral Exposure to PFOS
Species andexposure
duration

NOAEL
LOAELa(mg/kg/day) (mg/kg/day) EffectRat
GD 1–PND 1
Rat
GD 0–PND 20

Mouse
GDs 1–17
Mouse
GDs 0–17
Rat
GDs 1–21
Rat
GDs 2–21

Reference

0.8

Decreased spatial learning

Wang et al.
2015c

1

Butenhoff et al.
2009b

1

Increased locomotor activity andconcurrent failure to habituate to
test environment in male pups on
PND 17
Delayed eye opening

1

Increased sternal defects

Yahia et al. 2008

0.1

2

Chen et al. 2012b

0.6

2

Increased postnatal mortality andsevere lung histopathology
Increased neonatal mortality

0.3

Lau et al. 2003

Xia et al. 2011

aLOAELs for less serious health effects.

GD = gestation day; LOAEL = lowest-observed-adverse-effect level; NK = natural killer; NOAEL = no-observedadverse-effect level; PFOS = perfluorooctane sulfonic acid; PND = postnatal day; sRBC = sheep red blood cell

Selection of the Principal Study: Using the Wambaugh et al. (2013) pharmacokinetic model, TWA
serum concentrations corresponding to external doses (mg/kg/day) and exposure durations (days) werepredicted for the studies listed in Table A-14. Pharmacokinetic model parameters were not available for
C57BL/6N mice, B6C3F1 mice, or Wistar rats, which precluded predicting TWA serum concentrations
for the Long et al. (2013), Dong et al. (2009, 2011), Guruge et al. (2009), Peden-Adams et al. (2008),
Wang et al. (2015c), Onishchenko et al. (2011), and Yahia et al. (2008) studies. The predicted serum
PFOS levels for each administered dose is presented in Table A-15.

Table A-15. Summary of the Predicted TWA Serum PFOS levels in Laboratory
Animals Following Intermediate-Duration Oral Exposure
Species andexposure
Doseduration(mg/kg/day)Predicted TWA
serum PFOS(µg/mL)

Hepatic
Cynomolgus 0.03 (males)
Monkey0.15 (males)
26 weeks
0.75 (males)
0.03 (females)
0.15 (females)
0.75 (females)

7.81
37.8
150
7.72
37.6
146

EffectReference

Increased liver weight,
Seacat et al.
decreased serum cholesterol,
2002
hepatocellular hypertrophy, mild
bile stasis, lipid vacuolation at
0.75 mg/kg/dayPERFLUOROALKYLS

A-43
APPENDIX A

Table A-15. Summary of the Predicted TWA Serum PFOS levels in Laboratory
Animals Following Intermediate-Duration Oral Exposure
Species andexposure
Doseduration(mg/kg/day)
Neurological
C57BL/6
Mouse
3 months
Immunological
B6C3F1Mouse
28 days

B6C3F1Mouse
21 days
C57BL/6N
Mouse
60 days

C57BL/6N
Mouse
60 days

Developmental
C57BL/6
Mouse
GDs 1–21
SpragueDawley
Rat
84 daysSpragueDawley
Rat
67 days

0.43
2.15
10.75
0.000160.00166
0.003310.0166
0.03310.005
0.025
0.00830.083
0.41667
0.83332.08330.00830.01670.083
0.41667
0.8333

Predicted TWA
serum PFOS(µg/mL)Not calculated

EffectReference

Impaired spatial learning andmemory at 2.15 mg/kg/day

Long et al. 2013

Suppressed response to sRBC
at 0.00166 mg/kg/day

Peden-Adams etal. 2008

Decreased resistance toinfluenza virus at
0.025 mg/kg/day
Impaired response to sRBC at
0.083 mg/kg/day

Guruge et al.
2009

Impaired response to sRBC at
0.083 mg/kg/day

Dong et al. 2011

Not calculateda

Not calculateda

Dong et al. 2009

Not calculateda

Not calculateda

0.3

Not calculated

0.1
0.4
1.6
3.2
0.4
0.8
1
1.2
1.6
3.2

7.43
29.7
119
238
24.1
48.1
60.1
72.2
96.2
120

Decreased locomotion, muscle Onishchenko etstrength, motor coordination inal. 2011
adult offspring at 0.3 mg/kg/day
Delayed eye opening in F1 pups Luebker et al.
and transient decrease in F2 pup 2005abody weight during lactation at
0.4 mg/kg/day
Decreased pup weight per litterat birth and on LD 5 at
0.4 mg/kg/day

Luebker et al.
2005b

PERFLUOROALKYLS

A-44
APPENDIX A

Table A-15. Summary of the Predicted TWA Serum PFOS levels in Laboratory
Animals Following Intermediate-Duration Oral Exposure
Species andexposure
Doseduration(mg/kg/day)WistarRat
GD 1–PND 1SpragueDawley
Rat
GD 0–
PND 20
CD-1
Mouse
GDs 1–17

ICR
Mouse
GDs 0–17
SpragueDawley
Rat
GDs 1–21
SpragueDawley
Rat
GDs 2–21

Predicted TWA
serum PFOS(µg/mL)

EffectReference

0.8

Not calculatedb

Decreased spatial learning at
0.8 mg/kg/day

Wang et al.
2015c

0.1
0.3
1

3.75
11.3
37.5

Increased locomotor activity and Butenhoff et al.
concurrent failure to habituate to 2009b
test environment in male pups
on PND 17 at 1 mg/kg/day

1
5
10
15
20
1

31.9
146
216
244
260
Not calculated

Delayed eye opening at
1 mg/kg/day

Lau et al. 2003

Increased sternal defects at
1 mg/kg/day

Yahia et al. 2008

0.1
2

2.01
40.1

Increased postnatal mortality
and severe lung histopathology
at 2 mg/kg/day

Chen et al. 2012b

0.1
0.6
2

1.92
11.5
38.3

Increased neonatal mortality at
2 mg/kg/day

Xia et al. 2011

aSee Table A-17 for measured serum PFOS concentrations.
bReported serum PFOS concentrations of 25.7 and 64.3 µg/mL in dams on PND 7 and 35, respectively.

GD = gestation day; LD = lactation day; PFOS = perfluorooctane sulfonic acid; PND = postnatal day; sRBC = sheep
red blood cell; TWA = time-weighted average

Selection of the Point of Departure for the MRL: None of the studies with predicted serum PFOS levels
had datasets that were amenable for BMD modeling; thus, the NOAEL/LOAEL approach was used to
identify PODs for derivation of the intermediate-duration MRL for PFOS. A summary of the PODs ispresented in Table A-16. HEDs were calculated for each potential POD (NOAEL or LOAEL) identified
in laboratory animal studies using the first-order single-compartment model previously discussed and theassumption that humans would have similar effects as the laboratory animal at a given serum
concentration. The HEDs for each POD are presented in Table A-16. The potential PODHED values weredivided by a total uncertainty factor to calculate candidate MRLs; these values are also presented inTable A-16. The lowest administered doses associated with adverse effects were found in the
immunotoxicity studies conducted by Dong et al. (2009, 2011), Guruge et al. (2009), and Peden-Adams etal. (2008). These data could not be considered as PODs because TWA serum PFOS values could not be
predicted due to the lack of pharmacokinetic model parameters for the two mouse strains tested.
Although there is considerable overlap between the LOAEL for IgM response to sRBC
(0.00166 mg/kg/day) identified in the Peden-Adams et al. (2008) 28-day study and the NOAELs for IgM

PERFLUOROALKYLS

A-45
APPENDIX A

response to sRBC (0.0083 and 0.0167 mg/kg/day) identified in the Dong et al. (2009, 2011) 60-day
studies, the data do suggest that immunotoxicity could occur at <0.3 mg/kg/day (the lowest LOAEL
identified in developmental toxicity studies).

Table A-16. Summary of Potential Points of Departures Human Equivalent Doses(PODHED) for Intermediate-Duration Oral MRL for PFOS

Endpoint (reference)

Predicted serum
concentrations(µg/mL)NOAEL LOAELPODHEDa(mg/kg/day)

Candidate
MRLs
Total UF (mg/kg/day)

40.1

0.000139300b

4.6x10-7

24.1

0.001673,000c5.6x10-7

31.9

0.002213,000c7.4x10-7

11.3

37.5

0.000780

300b

2.6x10-6

Delayed eye opening and7.43
decreased F2 rat pup body weight(Luebker et al. 2005a)
Increased neonatal mortality in rat 11.5
pups (Xia et al. 2011)
Hepatic effects in monkeys
37.8(Seacat et al. 2002)

29.7

0.000515300b

1.7x10-6

38.3

0.000797300b

2.7x10-6150

0.00262300b

8.7x10-6

Increased rat pup mortality andlung histopathology (Chen et al.
2012b)
Decreased rat pup weight at birthand on PND 4 (Luebker et al.
2005b)
Delayed eye opening in mouse
pups (Lau et al. 2003)
Neurodevelopmental effects inmale rat pups (Butenhoff et al.
2009b)

2.01

aHED calculated using Equation A-6 where C is the serum concentration associated with the NOAEL or BMDL or
ss
the LOAEL if there was no NOAEL or BMDL, Ke=3.74x10-4; Vd=0.2, and AF=1.
bUFs of 3 for extrapolation from animals to humans with dosimetric adjustments and 10 for human variability andmodifying factor (MF) of 10 for concern that immunotoxicity may be a more sensitive endpoint than developmental
toxicity.
cUF of 10 for extrapolation from a LOAEL, 3 for extrapolation from animals to humans with dosimetric adjustments,
and UF of 10 for human variability and MF of 10 for concern that immunotoxicity may be a more sensitive endpoint
than developmental toxicity.

BMDL = lower limit on the benchmark dose; LOAEL = lowest-observed-adverse-effect level; MRL = Minimal Risk
Level; NOAEL = no-observed-adverse-effect level; PFOS = perfluorooctane sulfonic acid; PND = postnatal day;
UF = uncertainty factor

The serum PFOS concentrations predicted to occur at the lowest LOAEL values were 24.1, 29.7, and31.9 µg/mL identified in the Luebker et al. (2005b), Luebker et al. (2005a), and Lau et al. (2003) studies;decreases in pup body weight and delays in eye opening were observed at these levels. Luebker et al.
(2005a) was the only study that identified a NOAEL for these effects. The predicted serum concentration
for this NOAEL dose was selected as the basis for the MRL.

PERFLUOROALKYLS

A-46
APPENDIX A

Summary of the Principal Study:
Luebker DJ, Case MT, York RG, et al. 2005a. Two-generation reproduction and cross-foster studies ofperfluorooctanesulfonate (PFOS) in rats. Toxicol 215:126-148.
Groups of Sprague-Dawley rats (P generation) (35/sex/dose level) were administered PFOS (86.9% pure)by gavage in deionized water with 2% Tween-80 at doses of 0, 0.1, 0.4, 1.6, or 3.2 mg/kg/day for 6 weeks
before mating and until sacrifice (after mating for males, GD 10 for some females, and PND 21 for theremaining females). Body weight and feed consumption were evaluated during the dosing period. Prior
to mating, 15 females per dose group were evaluated for estrous cycling. Ten females/dose group weresacrificed on GD 10 and the remaining females were allowed to give birth (F1 generation). Parental rats
sacrificed on GD 10 were examined for number of corpora lutea, implantations, and viable and non-viable
fetuses. Body weight of F1 was evaluated during lactation; also, F1 rats were assessed for developmental
landmarks during lactation. On PND 22, the F1 rats were started on the same diet as the parental rats. At
approximately PND 90, F1 were mated to produce the F2 generation. F1 males and females were killed
as the P generation. F1 females and males were evaluated for vaginal patency and preputial separation,
respectively. At age 24 days, F1 rats were administered three neurobehavioral tests (learning, memory
retention, and avoidance memory). At the age of 70 days, F1 were administered three different
neurobehavioral tests (neuromuscular coordination, swimming ability, learning, and memory). PFOS was
analyzed in liver and blood from parental females and in liver from F1on PND 21; and in liver and serumfrom parental males after mating and after 42–56 days of dosing.
There were no deaths in parental males or females and no clinical signs in parental males. High-doseparental males had significantly reduced terminal body weight (11% reduction). Absolute and relative
food consumption was reduced during treatment in males by less than 10%. Parental females at
0.4 mg/kg/day and higher had localized areas of partial alopecia. Body weight of parental females in the
3.2 mg/kg/day group was significantly lower during cohabitation and gestation (11% reduced). Absoluteand relative food consumption were significantly reduced in 3.2 mg/kg/day parental females during
premating and gestation (>15%) and in 1.6 mg/kg/day parental females during lactation. Administrationof PFOS did not affect any mating or fertility parameter. Estrous cycling was not affected. Examinationof parental females sacrificed on GD 10 showed no significant effect on numbers of corpora lutea or
implantations or viable and non-viable fetuses. Significant delivery observations for 3.2 mg/kg/day
parental females included reduced number of implantations per delivered litter, decreased gestational
length, increased number of dams with all pups dying on PNDs 1–4 (also at 1.6 mg/kg/day). Observationof F1 pups during PNDs 1–21 showed significantly reduced weight and decreased viability(≥1.6 mg/kg/day). Examination of dead F1 pups did not reveal a cause of death; no labored breathing wasnoted in pups at birth. Developmental delays were noted at 1.6 mg/kg/day (pinna unfolding, surface
righting, and air righting), and 0.4 mg/kg/day (eye opening). The investigators noted that the delay in eye
opening was not considered an adverse outcome but did not provide a rationale for this conclusion.
Follow-up observations of 0.1 and 0.4 mg/kg/day offspring showed no alterations in body weight or foodconsumption, including F1 females during gestation and lactation. Sexual maturation was not affected in
F1 males or females; no effects were noted in the neurobehavioral tests. Reproductive performance of F1
were not affected. Viability of F2 pups during PNDs 1–21 was not affected. F2 pup weight wassignificantly reduced at 0.4 mg/kg/day on PND 7 (13%) and PND 14 (9.6%). The investigators noted thatthe decrease in pup weight was not considered toxicologically relevant and may have been due tominimally larger live litter sizes, as compared to the control group, and that there were no differences on
PND 21. ATSDR notes that there were no significant differences in pup body weight between the control
group and the 0.4 mg/kg/day group on PND 4 prior to culling and after culling, and considers the delay ineye opening to be toxicologically relevant. Serum and liver PFOS increased with dose.

PERFLUOROALKYLS

A-47
APPENDIX A

Strengths and Weaknesses: The Luebker et al. (2005a) study is a well-designed 2-generation study
evaluating a number of reproductive and developmental endpoints in adequate number of animals. The
study was designed to evaluate four PFOS dose levels administered prior to mating and during mating,gestation, and lactation across two generations. The test included a number of parameters to assess
reproductive performance (mating, estrous cycling, and fertility), reproductive outcomes (gestation
length, number of implantation sites, stillbirths), and neonatal toxicity (survival and body weight). The
experiment also included a cross-foster study, which allowed for the evaluation of whether neonatal
effects were due to maternal care/maternal toxicity or to a direct effect on the pups. An additional
strength of the study is that it evaluated several endpoints (e.g., lung morphology and lung glycogenstores) that could elucidate the mechanisms of action for fetal deaths. Luebker et al. (2005a) measured
serum and liver PFOS levels, which allowed for validation of the Wambaugh et al. (2013) model’s
predicted serum TWA PFOS level. Although the study was designed to evaluate four PFOS dose levels,
high mortality in the F1 offspring at the two highest dose levels resulted in a discontinuation of these doselevels, which limits the amount of data that can be used to establish dose-response relationships.
Calculations of Internal Dosimetric: TWA serum PFOS concentrations corresponding to external doses
and exposure durations were predicted from a pharmacokinetic model (Wambaugh et al. 2013) using
animal species-, strain-, and sex-specific parameters (see MRL approach section for details).
Human Equivalent Dose: HEDs were calculated based on the assumption that humans would have
similar effects as the laboratory animal at a given serum concentration. HEDs that would result in steadystate serum concentrations of PFOS equal to the serum concentration selected as the POD were calculatedusing the first order single-compartment model (see MRL approach section for details).
Uncertainty Factor and Modifying Factor: The NOAELHED is divided by a total uncertainty factor (UF)of 30 and modifying factor (MF) of 10:• 3 UF for extrapolation from animals to humans with dosimetric adjustment• 10 UF for human variability• 10 MF for concern that immunotoxicity may be a more sensitive endpoint of PFOS toxicity thandevelopmental toxicity
MRL = NOAELHED ÷ (UFs x MF)
0.000515 mg/kg/day ÷ ((3 x 10) x 10) = 2x10-6 mg/kg/day
Although pharmacokinetic model parameters were not available for the strain/sex of the animals tested in
the immunotoxicity studies, most of the studies did provide measured serum PFOS levels. The serum
PFOS levels at the NOAEL and LOAEL doses are presented in Table A-17. The measured serum PFOS
levels associated with altered immune responses are approximately 1–10 times lower than the serum
concentration predicted to occur at the NOAEL dose. These data suggest that immunotoxicity may be amore sensitive effect than developmental toxicity.

Table A-17. Measured Serum PFOS Levels at the NOAEL and LOAEL Doses for
Immunological Effects

Effect, species andexposure duration
Impaired response to sRBC in NOAEL
mice exposed for 60 days
LOAEL

Dose
(mg/kg/day)
0.00830.083

Measured mean
serum PFOS(µg/mL)
Reference
0.674
7.132

Dong et al. 2009

PERFLUOROALKYLS

A-48
APPENDIX A

Table A-17. Measured Serum PFOS Levels at the NOAEL and LOAEL Doses for
Immunological Effects

Effect, species andexposure duration
Impaired response to sRBC in NOAEL
mice exposed for 60 days
LOAEL
Decreased resistance to
NOAEL
influenza virus in mice
LOAEL
exposed for 21 days
Suppressed response to sRBC NOAEL
in mice exposed for 28 days
LOAEL

Dose
(mg/kg/day)

Measured mean
serum PFOS(µg/mL)
Reference

0.0167
0.083
0.005
0.025

2.36
10.75
0.189
0.670

Dong et al. 2011

0.000160.00166

0.01780.0915Peden-Adams etal. 2008

Guruge et al.
2009

PFOS = perfluorooctane sulfonic acid; sRBC = sheep red blood cell

A candidate MRL was calculated using the NOAEL of 0.0167 mg/kg/day identified in the Dong et al.
(2011). This study was selected over the other immunotoxicity studies because it identified the highest
NOAEL for immunotoxicity and it had the longest exposure duration; the Peden-Adams et al. (2008) was
not selected because the LOAEL of 0.00166 mg/kg/day is not supported by the other three studies. A
TWA concentration was estimated using a similar approach described for PFHxS and PFNA in the MRL
approach section. The estimated TWA concentration was 1.2 µg/mL for the 0.0167 mg/kg/day; thisestimated TWA concentration was used to calculate a HED of 0.000083 mg/kg/day. A candidate MRL of
3x10-6 was calculated using an uncertainty factor of 30 (3 for extrapolation from animals to humans using
dosimetric adjustments and 10 for human variability). This MRL is similar to the MRL calculated fromthe Luebker et al. (2005a) study and lends support to using the additional modifying factor of 10 toaccount for the lack of pharmacokinetic modeling parameters for the mouse strains tested for
immunotoxicity.
Other Additional Studies or Pertinent Information that Lend Support to this MRL: A discussion of thefindings from epidemiological studies is presented in the MRL introduction section.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-49
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctane sulfonic acid (PFOS)
1763-23-1
March 2020
Final
Oral
Chronic

MRL Summary: ATSDR did not identify an adequate study with an exposure duration of ≥365 days.
Although adequate data are available for intermediate-duration exposure, ATSDR does not extrapolate
across exposure duration.
Rationale for Not Deriving an MRL: Immune function was not examined following chronic-duration
oral exposure in laboratory animal studies; the only chronic-duration oral study (Butenhoff et al. 2012b;
Thomford 2002b), did not find histological alterations in immune tissues (lymph nodes, spleen, andthymus) in rats at doses as high as 1.04 mg/kg/day. Impaired immune function was the most sensitive
endpoint in intermediate-duration mouse studies. Given the concern that immunotoxicity may occur at
lower doses than liver toxicity, a chronic-duration oral MRL for PFOS is not recommended at this time.
One study has evaluated the chronic toxicity of PFOS in laboratory animals. Histological alterations in
the liver were the primary effects observed in rats exposed to PFOS in the diet for 2 years (Butenhoff et
al. 2012b; Thomford 2002b). Centrilobular hepatocellular hypertrophy was observed in rats exposed to≥0.1 mg/kg/day. At 1.04 mg/kg/day, increases in the incidence of single cell necrosis and cystic
degeneration were observed in the liver. Decreases in body weight were observed at 1.04 mg/kg/day infemale rats. Thus, the 1.04 mg/kg/day dose was identified as the lowest LOAEL for this study.
Epidemiological data (Dalsager et al. 2016; Dong et al. 2013; Fei et al. 2010; Grandjean et al. 2012, 2016;
Granum et al. 2013; Kielsen et al. 2016; Mogensen et al. 2015a; Stein et al. 2016a; Zhu et al. 2016)
suggest that the immune system is a sensitive target of PFOS toxicity following long-term exposures,
which is supported by intermediate-duration PFOS laboratory animal studies (Dong et al. 2009, 2011;
Guruge et al. 2009; Peden-Adams et al. 2008).
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-50
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexane sulfonic acid (PFHxS)
355-46-4
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFHxS.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFHxS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-51
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexane sulfonic acid (PFHxS)
355-46-4
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFHxS.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFHxS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-52
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexane sulfonic acid (PFHxS)
355-46-4
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFHxS.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFHxS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-53
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexane sulfonic acid (PFHxS)
355-46-4
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFHxS.
Rationale for Not Deriving an MRL: The acute oral database for PFHxS was not considered adequate
for derivation of an MRL due to the short duration of the only available study and the lack ofpharmacokinetic model parameters for calculating an HED.
In the only available study of PFHxS in laboratory animals, Viberg et al. (2013) reported altered
spontaneous behavior and habituation in adult mice administered a single gavage dose of 9.2 mg/kg/day
PFHxS on PND 10; no alterations were observed at 6.1 mg/kg/day. This single exposure study was notconsidered adequate as the basis of an acute-duration MRL for PFHxS due to the uncertainty of whether
an MRL based on this study would be protective for repeated exposures or for other potential sensitive
endpoints, such as immunotoxicity.
For perfluoroalkyls, ATSDR has used the approach of predicting TWA serum perfluoroalkyl levels inlaboratory animals and calculating HEDs for these serum concentrations. For PFOA and PFOS, theWambaugh et al. (2013) pharmacokinetic model was utilized for predicting the TWA serum
perfluoroalkyl concentrations. However, strain-, sex-, and compound-specific model parameters are notavailable for other perfluoroalkyls, thus precluding deriving MRLs for other perfluoroalkyls. Other
approaches such as “read across” (i.e., using data for a particular endpoint from one chemical to predict
the same endpoint for another chemical that has similar chemical structure or mechanisms of action) or
equivalency factors were considered for the other perfluoroalkyls; however, there are limited data
available that would allow for comparison of the toxicity and toxicokinetic properties of different
perfluoroalkyls. Peters and Gonzalez (2011) noted that the toxic equivalency factor approach would not
be suitable for perfluoroalkyls because the current data suggest that the toxicity of these compounds
appear to be mediated by multiple receptors, including PPARα, CAR, and PXR, and that there may be
species differences in the response mediated by different receptors. Additionally, available data suggestthat there are qualitative differences in the toxicities of various perfluoroalkyls.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-54
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:
MRL:
Critical Effect:
Reference:
Point of Departure:
Uncertainty Factor:
Modifying Factor:
LSE Graph Key:Species:

Perfluorohexane sulfonic acid (PFHxS)
355-46-4
March 2020
Final
Oral
Intermediate
2x10-5 mg/kg/day
Thyroid follicular epithelial hypertrophy/hyperplasia
Butenhoff et al. 2009a0.0047 mg/kg/day
30
10
33
Rat

MRL Summary: An intermediate-duration oral MRL of 2x10-5 mg/kg/day was derived for PFHxS basedon thyroid follicular epithelial hypertrophy/hyperplasia in adult male rats administered via gavage PFHxS
for a minimum of 42 days (Butenhoff et al. 2009a). The MRL is based on a HED NOAEL of 0.0047
mg/kg/day and a total uncertainty factor of 30 (3 for extrapolation from animals to humans withdosimetric adjustments and 10 for human variability) and a modifying factor of 10 for databaselimitations.
Selection of the Critical Effect: Four intermediate-duration studies in laboratory animals have been
identified for PFHxS. In a developmental toxicity study, increased incidences of thyroid follicular cells
hypertrophy/hyperplasia were observed in F0 male rats administered ≥3 mg/kg/day (Butenhoff et al.
2009a). Increased liver weight and centrilobular hepatocellular hypertrophy were also observed in themales at ≥3 mg/kg/day. Consistent with the Hall et al. (2012), the liver effects were not considered a
relevant endpoint for humans. Although there is uncertainty regarding the exact, and possibly multiple,
mechanism(s) for these liver effects, peroxisome proliferation is a likely contributor, a mechanism thatcannot be reliably extrapolated to humans (Hall et al. 2012). Therefore, increases in liver weight andhepatic lipid levels and alterations in serum lipid levels observed in rats and mice, in the absence of otherdegenerative lesions, were not considered appropriate endpoints for deriving MRLs.
No reproductive or developmental effects were reported in the Butenhoff et al. (2009a) study. A second
developmental toxicity study reported decreases in serum thyroxine levels in rat dams and pups
administered 5 mg/kg/day PFHxS on GDs 7–22 (Ramhøj et al. 2018); no alterations in pup birth weightor weight gain were observed. In a 1-generation reproductive/developmental toxicity study, decreases in
the number of pups per litter were observed in the offspring of mice administered 1 mg/kg/day (Chang etal. 2018). At 3 mg/kg/day, single cell necrosis and microvascular fatty changes were observed at
3 mg/kg/day. Liver effects (decreases in serum lipids, increases in hepatic triglyceride levels, andincreases in liver weight) were also observed in mice exposed to 6 mg/kg/day PFHxS in the diet for 4–6
weeks (Bijland et al. 2011) and mice administered 0.3 mg/kg/day (Chang et al. 2018). Using the Hall etal. (2012) criteria (see Section 2.9 for a discussion of the criteria), the liver effects were not considered
relevant for human risk assessment. Thus, the lowest LOAEL identified in intermediate-duration studies
was 3 mg/kg/day for thyroid effects.
There is some uncertainty regarding the selection of thyroid alterations as the critical effect. Butenhoff etal. (2009a) suggested that the histological alterations in the thyroid may be secondary to the liver effects

PERFLUOROALKYLS

A-55
APPENDIX A(hepatocellular hypertrophy). The alteration may be due to binding competition between PFHxS andthyroid hormones and possible induction of thyroid hormone metabolism by the liver. Ramhøj et al.
(2018) reported decreases in serum T4 levels but did not evaluate possible thyroid gland histologicalalterations. The Chang et al. (2018) 1-generation reproduction study did not find alterations in serum
TSH levels in mice.
A limited number of epidemiological studies have examined potential thyroid effects. Two
epidemiological studies have examined thyroid disease associated with PFHxS exposure (Chan et al.
2011; Wen et al. 2013); one study found increased risk of subclinical hypothyroidism and subclinicalhyperthyroidism among women (Wen et al. 2013) and the second study did not find an increased risk ofhypothyroxinemia (Chan et al. 2011). The small number of studies precludes evaluating the possible
association between PFHxS exposure and thyroid disease in humans. A meta-analysis of epidemiological
data (Kim et al. 2018) found an inverse correlation between serum PFHxS levels and total T4 levels in thegeneral population; there was no correlation among pregnant women. No associations were found forfree T4, total T3, or TSH.
Species-related differences in thyroid parameters between rats and humans also add to the uncertainty.
Some differences include higher rate of T4 production in rats than in humans, and very low levels of
thyroxine binding globulin compared to high levels in humans, and sex-related differences in serum TSH
levels (higher levels in males compared to females) in rats, but not in humans (Choksi et al. 2003). It is
not known if these species differences would influence the relative toxicity of PFHxS.
Selection of the Principal Study: Since the liver effects were not considered relevant to humans, thelowest LOAEL identified for PFHxS was 1 mg/kg/day for decreases in the number of pups per litter
identified in the Chang et al. (2018) study. The investigators noted that the toxicological significance of
this alteration was uncertain because there was no clear dose-response and no alterations in the number of
implantation sites, number of viable pups, or pup to implant ratios. Thus, the Butenhoff et al. (2009a)
study, which reported thyroid effects in male rats at LOAEL of 3 mg/kg/day, with a NOAEL of
1 mg/kg/day, was selected as the principal study.
Summary of the Principal Study:
Butenhoff JL, Chang SC, Ehresman DJ, et al. 2009a. Evaluation of potential reproductive anddevelopmental toxicity of potassium perfluorohexanesulfonate in Sprague Dawley rats. Reprod Toxicol
27:331-341. (Results from this study are also reported in Hoberman and York 2003.)
The reproductive/developmental effects of PFHxS were studied in Sprague-Dawley rats (15/sex/group).
Doses of 0, 0.3, 1, 3, or 10 mg/kg/day PFHxS were administered by gavage in an aqueous vehicle. Male
rats were dosed beginning 14 days before cohabitation and continued until 1 day before sacrifice (aminimum of 42 days). Females were dosed beginning 14 days before cohabitation and continued until
1 day before sacrifice on PND 21 or GD 25 (rats that did not deliver a litter). Endpoints evaluatedincluded: body weight, food consumption, estrous cycling, functional observational battery (FOB; tests ofautonomic function, reactivity and sensitivity, excitability, gait and sensorimotor coordination, grip
strength, and clinical signs), hematology and clinical chemistry, gross necropsy, organ weights,
histopathology, and sperm evaluations. At parturition, litters were evaluated for size and viability; weightof the pups was also recorded. Pups were sacrificed on PND 22.
The following are findings for male F0 rats. Treatment with PFHxS did not affect survival and did not
induce clinical signs that could be attributed to the chemical. Terminal body weight in the 10 mg/kg/day
groups was approximately 6% lower than controls. Food consumption was not affected. Necropsy did
not reveal any treatment-related changes. Histopathological effects were restricted to the liver andPERFLUOROALKYLS

A-56
APPENDIX A

thyroid of males treated with 3 and 10 mg/kg/day. Liver effects consisted of minimal to moderate
hypertrophy of centrilobular hepatocytes. The affected hepatocytes were enlarged with an increased
amount of dense eosinophilic granular cytoplasm. In the thyroid, the changes consisted of hypertrophy
and/or hyperplasia of follicular cells. These effects could have been associated with the liver effects.
Significant organ weight changes consisted of increased absolute and relative liver weight at 3 and10 mg/kg/day and decreased heart/brain weight at 10 mg/kg/day. Significant hematology changes
consisted of decreased hemoglobin at 1 mg/kg/day, decreased red cell count and hematocrit at
3 mg/kg/day, and increased prothrombin time at 0.3 mg/kg/day. Increases in albumin, BUN, alkaline
phosphatase, calcium, and albumin/globulin ratio were seen at 10 mg/kg/day. The investigators notedthat the alterations in prothrombin time were slight and did not follow a specific trend and the values were
within the normal range. There were no significant effects on the FOB or on motor activity and no
significant effects on sperm parameters. There were no significant effects in any parameter monitored in
F0 females or in pups. Treatment with PFHxS had no significant effect on the gross or microscopic
morphology of the spleen, thymus, or lymph nodes. There were no significant effects on sex organ
weights or gross or microscopic lesions in the reproductive organs of males and females. Fertility was
not affected by treatment with PFHxS and there were no significant effects on sperm parameters. Estrous
cycling was not affected by dosing with PFHxS. Treatment with PFHxS did not significantly affect anyof the developmental parameters evaluated including gestation length, number of dams delivering litters,
averages for implantation sites per delivered litter, number of dams with stillborn pups, number of dams
with no live pups, dams with all pups dying, number of pups surviving per litter, sex ratios, litter size, or
pup weight. Also, necropsy of the pups showed no treatment-related effects, and pup liver weight was notaffected. Treatment with PFHxS had no significant effect on the FOB or motor activity. The battery
tested autonomic functions, reactivity and sensitivity to stimuli, excitability, gait and sensorimotor
coordination, limb grip strength, and abnormal clinical signs.
Strengths and Weaknesses: The Butenhoff et al. (2009a) study is a well-designed study evaluating maleand female reproductive endpoints and developmental endpoints. An adequate number of animals were
exposed to three PFHxS dose levels. An additional strength of the study is the inclusion of parametersthat evaluated potential neurobehavioral effects, hematological and clinical chemistry parameters, andhistopathological examination of the liver and thyroid. Measurement of serum PFHxS levels allowed for
estimation of a TWA serum concentration that could be used to calculate a HED. One weakness of thestudy is that thyroid hormone levels were not measured; these data could have been useful in evaluating
the observed histological alterations in the thyroid gland.
Selection of the Point of Departure for the MRL: The HED of the NOAEL of 1 mg/kg/day identified in
the Butenhoff et al. (2009a) developmental toxicity study was selected as the POD for the MRL. A TWA
serum PFHxS concentration of 73.22 µg/mL was estimated for the adult males exposed to 1 mg/kg/day(Butenhoff et al. 2009a).
Human Equivalent Dose: The HED was calculated based on the assumption that humans would have
similar effects as the laboratory animal at a given serum concentration. HEDs that would result in steadystate serum concentrations of PFHxS equal to the estimated TWA serum concentration selected as the
POD were calculated using the first-order single-compartment model (see MRL approach section for
details). The HED was calculated using Equation A-6 where Css is 73.22 µg/mL, Ke=2.23x10-4;
Vd=0.287, and AF=1. The NOAELHED is 0.0047 mg/kg/day
Uncertainty Factor and Modifying Factor: The NOAELHED is divided by a total uncertainty factor (UF)of 30 and a modifying factor (MF) of 10:• 3 UF for extrapolation from animals to humans with dosimetric adjustment• 10 UF for human variability

PERFLUOROALKYLS

A-57
APPENDIX A•

10 MF for database limitations to account for small number of studies examining the toxicity of
PFHxS following intermediate-duration exposure and the limited scope of these studies inparticular studies examining immunotoxicity, a sensitive endpoint for other perfluoroalkyls.
MRL = NOAELHED ÷ (UFs x MF)
0.0047 mg/kg/day ÷ ((10 x 3) x 10) = 2x10-5 mg/kg/day

Other Additional Studies or Pertinent Information that Lend Support to this MRL: A discussion of thefindings from epidemiological studies is presented in the MRL introduction section. An empirical steadystate model was used to estimate the HED from a POD based on a 42-day exposure of adult rats. The
resulting HED is lower than the daily 42-day human dose that would be expected to achieve the POD
serum concentration.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

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APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexane sulfonic acid (PFHxS)
355-46-4
March 2020
Final
Oral
Chronic

MRL Summary: No chronic duration studies were identified for PFHxS. Although adequate data are
available for intermediate-duration exposure, ATSDR does not extrapolate across exposure duration.
Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals wereidentified for PFHxS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

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APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorononanoic acid (PFNA)
375-95-1
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFNA.
Rationale for Not Deriving an MRL: The only available inhalation exposure study for PFNA (Kinney etal. 1989) was not considered suitable for derivation of an inhalation MRL due to its lack ofhistopathological examination and short exposure duration.
In the only available inhalation exposure study for PFNA, Kinney et al. (1989) noted labored breathing inrats during and after a 4-hour nose-only exposure to 590 mg/m3 exposure; the study also reported anincrease in relative liver weight 5 days after exposure to ≥67 mg/m3.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

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APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorononanoic acid (PFNA)
375-95-1
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFNA.
Rationale for Not Deriving an MRL: No intermediate-duration inhalation studies in laboratory animals
were identified for PFNA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-61
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorononanoic acid (PFNA)
375-95-1
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFNA.
Rationale for Not Deriving an MRL: No chronic-duration inhalation studies in laboratory animals wereidentified for PFNA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-62
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorononanoic acid (PFNA)
375-95-1
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFNA.
Rationale for Not Deriving an MRL: An acute-duration oral MRL cannot be derived for PFNA because
the study identifying the lowest dose for a non-hepatic effect (Fang et al. 2009) did not measure serum
PFNA levels, which are needed for estimating an HED.
A number of studies examined the toxicity of PFNA in rats and mice exposed for acute durations. Thesestudies reported immune, liver, and body weight effects. Immune effects included increases in thymus
weight in rats at 1 mg/kg/day (Fang et al. 2009), decreases in thymus and spleen weights in rats at
3 mg/kg/day (Fang et al. 2009, 2010), and an alteration in splenic lymphocyte phenotypes in mice at
1 mg/kg/day (Fang et al. 2008). In the only study examining immune function, no alterations in splenic
lymphocyte response to ConA were observed at doses as high as 5 mg/kg/day in mice (Fang et al. 2008).
Liver effects included increases in hepatic lipid levels at ≥0.2 mg/kg/day (Wang et al. 2015a), increases inliver weights at ≥0.2 mg/kg/day (Wang et al. 2015a; Kennedy 1987), serum lipid levels at ≥1 mg/kg/day(Fang et al. 2012a, 2012b), hepatocellular vacuolation at 5 mg/kg/day (Fang et al. 2012b), and increases
in serum aminotransferases at 5 mg/kg/day (Wang et al. 2015a). Although there is uncertainty regarding
the exact, and possibly multiple, mechanism(s) for these liver effects, peroxisome proliferation is a likely
contributor, a mechanism that cannot be reliably extrapolated to humans (Hall et al. 2012). Therefore,
increases in liver weight and hepatic lipid levels and alterations in serum lipid levels observed in rats andmice, in the absence of other degenerative lesions, were not considered appropriate endpoints for deriving
MRLs.
Decreases in body weight were observed in rats and mice administered 5 mg/kg/day (Hadrup et al. 2016;
Wang et al. 2015a).
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

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APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:
MRL:
Critical Effect:
Reference:
Point of Departure:
Uncertainty Factor:
Modifying Factor:
LSE Graph Key:Species:

Perfluorononanoic acid (PFNA)
375-95-1
March 2020
Final
Oral
Intermediate
3x10-6 mg/kg/day
Decreased body weight and developmental delays
Das et al. 2015
0.001 mg/kg/day
30
10
39
Mouse

MRL Summary: An intermediate-duration oral MRL of 3x10-6 mg/kg/day was derived for PFNA basedon decreased body weight gain and developmental delays in the offspring of mice administered via
gavage PFNA on GDs 1–17 (Das et al. 2015). The MRL is based on a HED NOAEL of 0.001 mg/kg/day
and a total uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetricadjustments and 10 for human variability), and a modifying factor of 10 for database limitations.
Selection of the Critical Effect: The intermediate-duration database consists of three developmental
toxicity studies in rats and mice and a 90-day study in mice. The lowest LOAEL for developmental
toxicity was 1.1 mg/kg/day in mice administered PFNA on GDs 1–18; at this dose, decreases in litter sizeand pup survival were observed (Wolf et al. 2010). At higher doses (2–5 mg/kg/day), decreases in pup
body weight, delays in postnatal development (Das et al. 2015; Rogers et al. 2014; Wolf et al. 2010),
increases in pup systolic blood pressure (Rogers et al. 2014), and reduced nephron endowment (Rogers etal. 2014) were observed. A study of PPARα knockout mice did not find alterations pup body weight or
postnatal development at 2 mg/kg/day (Wolf et al. 2010). In the 90-day study, decreased sperm motility,
viability, and number; degenerative changes in seminiferous tubules; and decreased litter size (males
mated to unexposed females) were observed at 0.5 mg/kg/day; no changes were observed at
0.2 mg/kg/day (Singh and Singh 2018). A summary of the observed effects is presented in Table A-18.

Table A-18. Summary of the Adverse Effects Observed in Laboratory Animals
Following Intermediate-Duration Oral Exposure to PFNA
Species and exposure
duration
Parkes mouse
90 daysDose(mg/kg/day)
0.2
0.5

EffectReference

No effects reported
Singh and Singh
Decreased sperm motility, viability, 2018
and number; degenerative changes
in seminiferous tubules; decreased
litter size

PERFLUOROALKYLS

A-64
APPENDIX A

Table A-18. Summary of the Adverse Effects Observed in Laboratory Animals
Following Intermediate-Duration Oral Exposure to PFNA
Species and exposure
durationDose(mg/kg/day)

129S1/svlm mouse
GDs 1–18(offspring followed until
PND 21)0.83
1.1

CD-1 mouse
GDs 1–17(offspring followed until
PND 287)

1
3

1.5
2.0

5
10
5

Sprague-Dawley rat
GDs 1–20
offspring followed throughPND 434)

EffectReference

No effects reported
Wolf et al. 2010
Decreased litter size and pup
survival
No effects reported
Decreased number of live pups per
litter and decreased pup bodyweight gainNo effects reported
Das et al. 2015
Decreased body weight gain anddelayed eye opening, preputial
separation, and vaginal opening
Decreased postnatal survival, 80%
mortality between PND 2 and 10
Full litter resorption
Decreased birth weight, increased Rogers et al. 2014
blood pressure at 10 weeks of age;
reduced nephron endowment

GD = gestation day; PFNA = perfluorononanoic acid; PND = postnatal day

Selection of the Principal Study: The lowest LOAEL was 0.5 mg/kg/day identified in the Singh andSingh (2018) reproductive toxicity study. However, this study could not be used to derive an MRL for
PFNA because the investigators did not measure serum PFNA levels. Developmental toxicity, including
decreases in pup survival, developmental delays, and decreases in birth weight have been observed inthree studies. A comparison of the estimated TWA serum PFNA levels (Table A-19) for the Wolf et al.
(2010) and Das et al. (2015) studies (measured serum levels were not available from the Rogers et al.
2014 study) showed that the lowest LOAEL for developmental effects was 10.9 µg/mL (Das et al. 2015);
this study reported a NOAEL of 6.8 µg/mL. Thus, the Das et al. (2015) study was selected as theprincipal study for the MRL.

Table A-19. Summary of Estimated TWA Serum PFNA levels in Laboratory
Animals Following Intermediate-Duration Oral Exposure

Species andexposure duration
Parkes mouse
90 days

Estimated
TWA serum
Dose
PFNA(mg/kg/day) (µg/mL)
Effect0.2
0.5

Notcalculated

Reference

No effects reported
Singh andSingh 2018
Decreased sperm motility, viability,and number; degenerative changes inseminiferous tubules; decreased littersize

PERFLUOROALKYLS

A-65
APPENDIX A

Table A-19. Summary of Estimated TWA Serum PFNA levels in Laboratory
Animals Following Intermediate-Duration Oral Exposure

Species andexposure duration

Estimated
TWA serum
Dose
PFNA(mg/kg/day) (µg/mL)
EffectReference

129S1/svlm mouse
GDs 1–18(offspring followed
until PND 21)

0.83
1.1
1.5
2.0

4.47
11.6
10.5
17.6

No effects reported
Wolf et al.
Decreased litter size and pup survival 2010
No effects reported
Decreased number of live pups per
litter and decreased pup body weightgain

CD-1 mouse
GDs 1–17(offspring followed
until PND 287

1
3

6.8
10.9

5

39.7

10
5

NA
Not
calculated

No effects reported
Decreased body weight gain anddelayed eye opening, preputial
separation, and vaginal opening
Decreased postnatal survival, 80%
mortality between PND 2 and 10
Full litter resorption
Decreased birth weight, increased
blood pressure at 10 weeks of age;
reduced nephron endowment

Sprague-Dawley rat
GDs 1–20(offspring followed
through PND 434)

Das et al.
2015

Rogers etal. 2014

GD = gestation day; PFNA perfluorononanoic acid; PND = postnatal day

Summary of the Principal Study:
Das KP, Grey BE, Rosen MB, et al. 2015. Developmental toxicity of perfluorononanoic acid in mice.
Reprod Toxicol 51:133-144.
Groups of 8–10 timed-pregnant female CD-1 mice were administered via gavage 0, 1, 3, 5, or
10 mg/kg/day PNFA at a dosing volume of 10 ml/kg body weight in deionized water on GDs 1–17. On
GD 17, selected mice from each group were sacrificed for maternal and fetal examination, while theremaining mice were allowed to give birth. Pups were observed for postnatal survival up to PND 24 aswell as growth and development up to PND 287. The following parameters were used to assess toxicity:
clinical observations, maternal body weight, pup body weight (pre- and postnatal), organ weights (liver,gravid uterus weight), number of implantation sites, percent of live fetuses, percent of prenatal loss per
litter, and morphological changes (eye opening, vaginal opening, preputial separation).
Maternal weight loss beginning on GD 8 was observed at 10 mg/kg/day; on GD 13, the 10 mg/kg/day
group weighed approximately 30% less than controls. The 10 mg/kg/day group was terminated on
GD 13. Significant increases in full litter resorptions occurred at 10 mg/kg/day (7/7 compared to 2/8 incontrols). There were no adverse effects on pregnancy outcome following in utero exposure to 5 mg/kg.
Statistically significant dose-related increases in absolute and relative liver weights were observed indams in the 1, 3, and 5 mg/kg/day groups examined on GD 17, as well as in dams examined on postweaning day 28. There were no effects on the number of implants, number of live fetuses, or fetal bodyweight. Relative and absolute fetal liver weight were significantly increased; however, the increase did
not appear to be dose-related. Visceral and skeletal examination of fetuses revealed no treatment-relatedPERFLUOROALKYLS

A-66
APPENDIX A

effects. Increases in postnatal deaths were observed in the 5 mg/kg/day offspring between PND 2 and 10;
postnatal survival was approximately 20% on PND 10. Weight gain was significantly reduced in pups
from the 3 and 5 mg/kg dose groups from PND 1 to 24. The changes in males were dose-related andpersisted from PND 25 to 287. Weight reduction in females was less substantial in comparison withmales and returned to control levels by 7 weeks of age. Relative pup liver weights were significantly
increased at all doses up to PND 24 and at 3 and 5 mg/kg/day on PND 42. No significant effects on liver
weight were detectable by PND 70. Postnatal development (eye opening, preputial separation, andvaginal opening) was significantly delayed (by 2–7 days) at 3 and 5 mg/kg/day.
The serum PFNA levels (means±standard error of the mean) in the pregnant dams (measured at term)
were 0.015±0.003, 13.67±1.45, 21.85±3.17, and 79.48±22.69 µg/mL in the 0. 1, 3, and 5 mg/kg/day
groups (serum concentrations were provided to ATSDR by C. Lau).
Strengths and Weaknesses: Das et al. (2015) is a well-designed developmental toxicity study in mice.
One strength of the study is that it included evaluation of potential anomalies in fetuses, as well as
monitoring postnatal growth and development through PND 70. An additional strength of the study is theinclusion of serum and liver PFNA measurements, which allow for cross-species evaluations. Inclusionof measurement of the expression of genes related to PPARα, CAR, and PXR provides valuable
mechanisms-of-action data. Although the study tested four PFNA dose levels, increases in maternal
morbidity at 10 mg/kg/day and pup lethality at 5 mg/kg/day limited the data available to establish doseresponse relationships.
Selection of the Point of Departure for the MRL: The HED of the NOAEL of 1 mg/kg/day identified in
the Das et al. (2015) developmental toxicity study was selected as the POD for the MRL. A TWA serum
PFNA concentration was estimated for dams using the serum concentration in the control group(0.015 µg/mL) as the baseline concentrations and the terminal concentration for the 1 mg/kg/day group(13.67 µg/mL) resulting in an estimated TWA serum concentration of 6.8 µg/mL.
Human Equivalent Dose: The HED was calculated based on the assumption that humans would have
similar effects as the laboratory animal at a given serum concentration. HEDs that would result in steadystate serum concentrations of PFNA equal to the estimated TWA serum concentration selected as the
POD were calculated using the first-order single-compartment model (see MRL approach section for
details). The HED was calculated using Equation A-6 where Css is 6.8 µg/mL, Ke=7.59x10-4; Vd=0.2, and
AF=1. The Ke was calculated using the 2.5-year elimination half-life in young women; this value wasselected over the 4.3-year value for the combined group of males and older females because the MRL isbased on a developmental toxicity study. The NOAELHED is 0.001 mg/kg/day.
Uncertainty Factor and Modifying Factor: The NOAELHED is divided by a total uncertainty factor (UF)of 30 and modifying factor (MF) of 10:• 3 UF for extrapolation from animals to humans with dosimetric adjustment• 10 UF for human variability• 10 MF for database limitations to account for small number of studies examining the toxicity of
PFNA following intermediate-duration exposure and the limited scope of these studies. The
available data suggest that reproductive toxicity may be a more sensitive endpoint thandevelopmental toxicity; however, this endpoint could not be used to derive the MRL because theSingh and Singh (2018) study did not measure serum PFNA levels. Additionally, intermediateduration studies for other perfluoroalkyls suggest that immune function is a sensitive target of
toxicity; however, this potential endpoint has not been examined in intermediate-duration PFNA
studies.
MRL = NOAELHED ÷ (UFs x MF)

PERFLUOROALKYLS

A-67
APPENDIX A

0.001 mg/kg/day ÷ ((10 x 3) x 10) = 3x10-6 mg/kg/day
Other Additional Studies or Pertinent Information that Lend Support to this MRL: A discussion of thefindings from epidemiological studies is presented in the MRL introduction section.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-68
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorononanoic acid (PFNA)
375-95-1
March 2020
Final
Oral
Chronic

MRL Summary: No chronic-duration studies were identified for PFNA. Although adequate data are
available for intermediate-duration exposure, ATSDR does not extrapolate across exposure duration.
Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals wereidentified for PFNA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-69
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorodecanoic acid (PFDA)
335-76-2
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFDA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFDA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

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APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorodecanoic acid (PFDA)
335-76-2
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFDA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFDA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-71
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorodecanoic acid (PFDA)
335-76-2
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFDA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFDA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-72
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorodecanoic acid (PFDA)
335-76-2
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFDA.
Rationale for Not Deriving an MRL: The available acute oral database for PFDA was not consideredadequate for derivation of an MRL because the study identifying the lowest adverse effect level did notmeasure serum PFDA levels, which are needed to estimate HEDs.
Several laboratory animal studies have examined the acute oral toxicity of PFDA; most were limited inscope. The lowest LOAEL was 1 mg/kg/day for decreases in fetal weight in mice administered PFDA on
GDs 6–15 (Harris and Birnbaum 1989). At 12.8 mg/kg/day, decreases in the number of live fetuses per
litter were observed; maternal weight loss was also observed at this dose level (Harris and Birnbaum1989). Another developmental toxicity study did not report alterations in performance onneurobehavioral tests in 2–4-month-old mice administered 10.8 mg/kg/day PFDA on PND 10 (Johansson
et al. 2008). Other effects observed in acute exposure studies include decreases in maternal weight gain
at 6.4 mg/kg/day (Harris and Birnbaum 1989), weight loss at ≥9.5 mg/kg/day in rats (Kawashima et al.
1995) and mice (Harris and Birnbaum 1989; Permadi et al. 1992, 1993), increases in T3 and T4 levels inmice at 80 mg/kg/day (Harris et al. 1989), decreases in spleen weight in mice at 80 mg/kg/day (Harris etal. 1989), and atrophy and lymphoid depletion in thymus and spleen in mice at 160 mg/kg/day (Harris etal. 1989). Liver effects included increases in liver weight at ≥2.4 mg/kg/day (Brewster and Birnbaum
1989; Harris et al. 1989; Kawashima et al. 1995; Permadi et al. 1992, 1993), increases in hepatic lipid
levels at ≥9.5 mg/kg/day (Brewster and Birnbaum 1989; Kawashima et al. 1995), and hepatocellular
hypertrophy at ≥20 mg/kg/day (Harris et al. 1989). Although there is uncertainty regarding the exact, andpossibly multiple, mechanism(s) for these liver effects, peroxisome proliferation is a likely contributor, amechanism that cannot be reliably extrapolated to humans (Hall et al. 2012). Therefore, increases in liver
weight and hepatic lipid levels and alterations in serum lipid levels observed in rats and mice, in theabsence of other degenerative lesions, were not considered appropriate endpoints for deriving MRLs.
To derive MRLs for perfluoroalkyls, ATSDR used the approach of predicting TWA serum perfluoroalkyl
levels in laboratory animals or measured serum perfluoroalkyl levels and calculating HEDs for theseserum concentrations. For PFOA and PFOS, the Wambaugh et al. (2013) pharmacokinetic model was
utilized for predicting the TWA serum perfluoroalkyl concentrations. However, strain-, sex-, andcompound-specific model parameters are not available for other perfluoroalkyls. The Harris andBirnbaum (1989) study, which identified the lowest adverse effect level, did not measure maternal serum
PFDA levels. Thus, HEDs could not be calculated using animal serum PFDA levels. Other approaches
such as “read across” or equivalency factors were considered; however, there are limited data available
that would allow for comparison of the toxicity and toxicokinetic properties of different perfluoroalkyls.
Peters and Gonzalez (2011) noted that the toxic equivalency factor approach would not be suitable for
perfluoroalkyls because the current data suggest that the toxicity of these compounds appear to be
mediated by multiple receptors, including PPARα, CAR, and PXR, and that there may be species
differences in the response mediated by different receptors. Additionally, available data suggest that there
are qualitative differences in the toxicities of various perfluoroalkyls.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-73
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorodecanoic acid (PFDA)
335-76-2
March 2020
Final
Oral
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for
PFDA.
Rationale for Not Deriving an MRL: Two studies conducted by Frawley et al. (2018) evaluated theintermediate-duration toxicity of PFDA. In a 28-day study in rats, increases in mean corpuscularhemoglobin and mean corpuscular hemoglobin concentration and decreases in phagocytosis by fixedtissue macrophages in the liver were observed in female rats administered 0.25 mg/kg/day PFDA. At
0.5 mg/kg/day, single cell necrosis was observed. In the second study, decreases in splenic T-cells andmacrophages were observed in mice administered 1.25 mg/kg PFDA once a week for 4 weeks.
The Frawley et al. (2018) study was not considered for the principal study since it did not measure serum
PFDA levels.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-74
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorodecanoic acid (PFDA)
335-76-2
March 2020
Final
Oral
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFDA.
Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals wereidentified for PFDA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-75
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroundecanoic acid (PFUnA)
2058-94-8
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFUnA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFUnA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-76
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroundecanoic acid (PFUnA)
2058-94-8
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFUnA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFUnA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-77
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroundecanoic acid (PFUnA)
2058-94-8
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFUnA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFUnA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-78
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroundecanoic acid (PFUnA)
2058-94-8
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFUnA.
Rationale for Not Deriving an MRL: No acute-duration oral studies in laboratory animals wereidentified for PFUnA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-79
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroundecanoic acid (PFUnA)
2058-94-8
March 2020
Final
Oral
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for
PFUnA.
Rationale for Not Deriving an MRL: Intermediate-duration oral database was considered inadequate forderivation of an MRL for PFUnA because the only available study did not measure serum PFUnA levels,
which are needed to calculated HEDs (see MRL approach in Appendix A introduction).
One study was identified that examined the oral toxicity of PFUnA in laboratory animals. In this study,
decreases in body weight, hematological alterations, increases in liver weight, and centrilobular
hypertrophy were observed in rat dams administered 1.0 mg/kg/day for 41–46 days (Takahashi et al.
2014). The study also found decreases in pup body weight on PNDs 0 and 4 at 1.0 mg/kg/day.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-80
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroundecanoic acid (PFUnA)
2058-94-8
March 2020
Final
Oral
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFUnA.
Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals wereidentified for PFUnA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-81
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroheptanoic acid (PFHpA)
375-85-9
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFHpA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFHpA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-82
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroheptanoic acid (PFHpA)
375-85-9
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFHpA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFHpA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-83
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroheptanoic acid (PFHpA)
375-85-9
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFHpA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFHpA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-84
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroheptanoic acid (PFHpA)
375-85-9
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFHpA.
Rationale for Not Deriving an MRL: No oral studies in laboratory animals were identified for PFHpA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-85
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroheptanoic acid (PFHpA)
375-85-9
March 2020
Final
Oral
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for
PFHpA.
Rationale for Not Deriving an MRL: No oral studies in laboratory animals were identified for PFHpA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-86
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluoroheptanoic acid (PFHpA)
375-85-9
March 2020
Final
Oral
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFHpA.
Rationale for Not Deriving an MRL: No oral studies in laboratory animals were identified for PFHpA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-87
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutane sulfonic acid (PFBS)
375-73-5
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFBS.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFBS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-88
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutane sulfonic acid (PFBS)
375-73-5
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFBS.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFBS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-89
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutane sulfonic acid (PFBS)
375-73-5
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFBS.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFBS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-90
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutane sulfonic acid (PFBS)
375-73-5
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFBS.
Rationale for Not Deriving an MRL: No acute-duration oral studies in laboratory animals wereidentified for PFBS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-91
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutane sulfonic acid (PFBS)
375-73-5
March 2020
Final
Oral
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for
PFBS.
Rationale for Not Deriving an MRL: Several studies have evaluated the toxicity of PFBS followingintermediate-duration oral exposure and have identified several targets of toxicity. However, none ofthese studies included measurement of serum PFBS levels that are needed to calculate a HED and MRL
derivation.
Limited data available on the toxicity of PFBS in laboratory animals have identified the liver, kidneys,
stomach, and hematological systems and the developing organism as targets of toxicity. Decreases inhemoglobin and hematocrit levels were observed in male rats administered 200 mg/kg/day PFBS for
90 days (Lieder et al. 2009a); decreases in erythrocyte levels were observed at 600 mg/kg/day.
Administration of 600 mg/kg/day for 90 days also resulted in tubular and ductal papillary epithelial
hyperplasia in the kidneys and necrosis and hyperplasia/hyperkeratosis in the forestomach (Lieder et al.
2009a). Effects in the liver consisted of decreases in plasma triglyceride levels in mice exposed to
30 mg/kg/day for 4–6 weeks (Bijland et al. 2011), increases in absolute and relative liver weight in malerats administered 300 mg/kg/day for at least 70 days (Lieder et al. 2009b) or 900 mg/kg/day for 28 days
(3M 2001), and hepatocellular hypertrophy in rats administered 1,000 mg/kg/day in a 2-generation study(Lieder et al. 2009b). In general, no biologically relevant alterations in performance on FOB tests or
motor activity tests were observed in rats administered 900 mg/kg/day PFBS for 28 days (3M 2001) or
600 mg/kg/day for 90 days (Lieder et al. 2009a).
Decreases in fetal body weight were observed in two studies involving administration of PFBS to rats on
GDs 6–20 (York 2002, 2003a); one study reported a LOAEL of 1,000 mg/kg/day (York 2002) and theother a LOAEL of 2,000 mg/kg/day with a NOAEL of 1,000 mg/kg/day (York 2003a). In adevelopmental toxicity mouse study, decreases in pup body weight, developmental delays (eye opening
and vaginal opening), impaired development of the reproductive system (delay in first estrous, decreases
in ovarian follicles, decreases in uterine endometrial and myometrial thickness), and decreases in total T4
and T3 and increases in TSH were observed in the offspring of mice administered 200 mg/kg/day PFBS
(Feng et al. 2017). Decreases in maternal total T4, free T4, and total T3 and increases in TSH wereobserved at 200 mg/kg/day.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-92
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutane sulfonic acid (PFBS)
375-73-5
March 2020
Final
Oral
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFBS.
Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals wereidentified for PFBS.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-93
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutanoic acid (PFBA)
375-22-4
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFBA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFBA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-94
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutanoic acid (PFBA)
375-22-4
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFBA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFBA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-95
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutanoic acid (PFBA)
375-22-4
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFBA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFBA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-96
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutanoic acid (PFBA)
375-22-4
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFBA.
Rationale for Not Deriving an MRL: Laboratory animal studies for other perfluoroalkyls have identified
immunotoxicity and developmental toxicity as sensitive endpoints following acute-duration oral
exposure; these potential targets have not been investigated for PFBA. Thus, the database was consideredinadequate for identifying a critical endpoint and evaluating dose-response relationships.
Three studies have examined the acute toxicity of PFBA in laboratory animals for a limited number ofpotential endpoints. Ikeda et al. (1985) reported that administration of approximately 20 mg/kg/day
PFBA in the diet to male rats for 2 weeks did not significantly affect relative liver weight, but increased
catalase activity in liver homogenates by 42% and induced peroxisome proliferation, as assessed byelectron microscopy. In a similar study, dietary administration of approximately 78 mg/kg/day PFBA tomale mice for 10 days induced a 63% increase in absolute liver weight (Permadi et al. 1992). The
increase in liver weight was accompanied by changes in enzymes involved in drug metabolism and/or indeactivation of reactive oxygen species; however, PFBA did not have a significant effect on parameters ofperoxisomal fatty acid β-oxidation (Permadi et al. 1993). In a more comprehensive study, no significant
effect on a wide range of endpoints including body and organ weights, hematology and clinical chemistry,and histopathology were observed in rats administered 184 mg/kg/day for 5 days (3M 2007a).
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-97
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutanoic acid (PFBA)
375-22-4
March 2020
Final
Oral
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for
PFBA.
Rationale for Not Deriving an MRL: The available intermediate-duration database was not consideredadequate for derivation of an MRL. Although the available studies have examined potentially sensitive
endpoints and developmental toxicity and both studies measured serum PFBA levels, the database is
missing a reliable estimate of elimination half-life in humans. Chang et al. (2008b) reported serum halflives in small groups of subjects (<10 subjects); only 2 of the subjects were females. Because
developmental toxicity is one of the more sensitive endpoints, data from females is needed in order toestimate the HED.
The intermediate-duration oral database for PFBA consists of a developmental study in mice (Das et al.
2008) and 28- and 90-day gavage studies in rats (Butenhoff et al. 2012a; van Otterdijk 2007a, 2007b). In
the developmental study, PFBA administered to pregnant mice on GDs 1–17 did not affect newborn
weight gain or viability (Das et al. 2008). The most sensitive response was a delay in eye opening in thepups at maternal doses of PFBA of 35 mg/kg/day. In the 28- and 90-day studies, hyperplasia/hypertrophyof the follicular epithelium of the thyroid and hepatocellular hypertrophy were observed at ≥30 mg/kg/day(Butenhoff et al. 2012a; van Otterdijk 2007a, 2007b). In addition, the 90-day study reported
hematological alterations in male rats dosed with 30 mg/kg/day PFBA. The NOAEL for these effects was
6 mg/kg/day.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-98
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorobutanoic acid (PFBA)
375-22-4
March 2020
Final
Oral
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFBA.
Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals wereidentified for PFBA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-99
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorododecanoic acid (PFDoDA)
307-55-1
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFDoDA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFDoDA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-100
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorododecanoic acid (PFDoDA)
307-55-1
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFDoDA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFDoDA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-101
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorododecanoic acid (PFDoDA)
307-55-1
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFDoDA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
PFDoDA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-102
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorododecanoic acid (PFDoDA)
307-55-1
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFDoDA.
Rationale for Not Deriving an MRL: The database was considered inadequate for derivation of an MRL.
Two studies have examined the acute-oral toxicity of PFDoDA. Shi et al. (2007) reported decreases inbody weight and decreases in serum testosterone and estradiol levels in rats following a 14-day gavage
administration of 5 mg/kg/day (Shi et al. 2007). The study also reported an increase in serum cholesterollevels at 10 mg/kg/day. In the second study, Zhang et al. (2008) found increases in liver weight andhepatic triglyceride and cholesterol levels in rats administered via gavage ≥5 mg/kg/day for 14 days; theseliver effects were not considered relevant to humans. Given the limited number of endpoints examined in
Shi et al. (2007) this study, including the lack of histopathological examination, this study was notconsidered suitable for the derivation of an MRL.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-103
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorododecanoic acid (PFDoDA)
307-55-1
March 2020
Final
Oral
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for
PFDoDA.
Rationale for Not Deriving an MRL: Three intermediate-duration studies examined the oral toxicity of
PFDoDA. Decreases in serum estradiol and increases in serum cholesterol were observed in pubertal
females exposed to 3 mg/kg/day PFDoDA on PNDs 24–72 (Shi et al. 2009b). In a second study by thisgroup, decreases in serum testosterone levels were observed in male rats administered 0.2 mg/kg/day
PFDoDA for 110 days (Shi et al. 2009a). In a one-generation reproductive/developmental toxicity study,
increases in maternal deaths were observed in rats administered 2.5 mg/kg/day PFDoDA prior to mating
and throughout gestation, and lactation days 1–5 (Kato et al. 2015). Other effects observed in the maleand female parental animals administered 2.5 mg/kg/day included decreases in body weight, decreases inmean corpuscular volume and reticulocytes, single cell hepatocellular necrosis (females only), pancreaticinterstitial edema (females only), atrophy of the thymic cortex (females only), atrophy of the adrenal
cortex (males only), decrease forelimb grip strength (males only), hemorrhage at the implantation site,and continuous diestrus in unmated females (Kato et al. 2015). The study also reported decreases in pup
body weight in the only litter with live pups.
The Shi et al. (2009a) study identified the lowest LOAEL of 0.5 mg/kg/day. However, this study was notconsidered suitable for MRL derivation because it examined a limited number of endpoints (body weightand reproductive toxicity in males). The Kato et al. (2015) study examined a wide range of endpoints, buteffects were only observed at a lethal dose.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-104
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorododecanoic acid (PFDoDA)
307-55-1
March 2020
Final
Oral
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFDoDA.
Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals wereidentified for PFDoDA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-105
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanesulfonamide (FOSA)
754-91-6
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
FOSA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
FOSA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-106
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanesulfonamide (FOSA)
754-91-6
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for FOSA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
FOSA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-107
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanesulfonamide (FOSA)
754-91-6
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
FOSA.
Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for
FOSA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-108
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanesulfonamide (FOSA)
754-91-6
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for FOSA.
Rationale for Not Deriving an MRL: The acute-duration database for FOSA was not consideredadequate for identifying critical targets of toxicity because the Seacat and Luebker (2000) study only
examined a limited number of potential endpoints and the potential developmental and immunologicaleffects (sensitive targets for other perfluoroalkyls) were not examined.
One laboratory animal study evaluated the acute oral toxicity of FOSA. Seacat and Luebker (2000) did
not find alterations in body weight or liver weight in rats administered a single dose of 5 mg/kg/day
FOSA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-109
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanesulfonamide (FOSA)
754-91-6
March 2020
Final
Oral
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for
FOSA.
Rationale for Not Deriving an MRL: No intermediate-duration oral studies in laboratory animals wereidentified for FOSA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-110
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorooctanesulfonamide (FOSA)
754-91-6
March 2020
Final
Oral
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for FOSA.
Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals wereidentified for FOSA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-111
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexanoic acid (PFHxA)
307-24-4
March 2020
Final
Inhalation
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for
PFHxA.
Rationale for Not Deriving an MRL: No acute-duration inhalation studies in laboratory animals wereidentified for PFHxA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-112
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexanoic acid (PFHxA)
307-24-4
March 2020
Final
Inhalation
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL
for PFHxA.
Rationale for Not Deriving an MRL: No intermediate-duration inhalation studies in laboratory animals
were identified for PFHxA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-113
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexanoic acid (PFHxA)
307-24-4
March 2020
Final
Inhalation
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for
PFHxA.
Rationale for Not Deriving an MRL: No chronic-duration inhalation studies in laboratory animals wereidentified for PFHxA.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-114
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexanoic acid (PFHxA)
307-24-4
March 2020
Final
Oral
Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFHxA.
Rationale for Not Deriving an MRL: The acute database for PFHxA was not considered adequate forderivation of an MRL because serum PFHxA levels at the lowest LOAEL were below the detection limit
and an elimination half-life has not been estimated for humans; both of these toxicokinetic parameters areneeded to estimate HEDs.
Two developmental toxicity studies conducted by Iwai and Hoberman (2014) examined the acute toxicityof PFHxA following gavage administration. Increases in stillborn pups and decreases in pup body weight
were observed at 175 mg/kg/day; no effects were observed at 35 mg/kg/day. In the second study,
decreases in birth weight and delayed eye opening was observed at 350 mg/kg/day; the NOAEL was
100 mg/kg/day. These studies were not considered adequate for derivation of an MRL because themeasured serum PFHxA levels at 35 and 175 mg/kg/day groups were below the limit of detection.
Additionally, the elimination half-life has not been estimated in humans.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-115
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexanoic acid (PFHxA)
307-24-4
March 2020
Final
Oral
Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for
PFHxA.
Rationale for Not Deriving an MRL: Five studies have evaluated the intermediate-duration toxicity of
PFHxA in rats. A summary of the adverse effects observed in these studies is presented in Table A-20.
These studies identify several targets of toxicity including the respiratory tract, erythrocytes, thyroid,
thymus, and developing organism; the lowest LOAEL is 100 mg/kg/day for nasal lesions and decrease inbody weight gain in males. None of the available studies evaluated immune function, which has been
identified as a sensitive target in intermediate oral studies for other perfluoroalkyls.
The data are considered inadequate for MRL derivation because an elimination half-life has not been
estimated in humans. Thus, a HED cannot be calculated and an MRL cannot be derived.

Table A-20. Summary of the Adverse Effects Observed in Laboratory Animals
Following Intermediate-Duration Oral Exposure to PFHxASpecies and exposure Doseduration(mg/kg/day) EffectRat
92–93 days (GW)
30 M, 30 F

20
100
500

Rat
110–120 days
(premating, gestation,lactation) (GW)
20 M, 20 F
Rat
90 days (GW)
10 M, 10 F

20
100
500

10
50
200

No effects observed
Degeneration/atrophy of nasal
olfactory epithelium
Respiratory metaplasia, decreased
RBC, hemoglobin, and hematocrit;increased reticulocytes; thyroid
follicular epithelial hypertrophy
No effect observed
Decreased weight gain in males
Decreased maternal weight gain,
decreased pup body weight duringlactation period

Reference
Loveless et al. 2009

Loveless et al. 2009

No effects observed
Chengelis et al. 2009b
No effects observed
Slight decrease in RBC, hemoglobin,
and hematocrit and increase in
reticulocytes

PERFLUOROALKYLS

A-116
APPENDIX A

Table A-20. Summary of the Adverse Effects Observed in Laboratory Animals
Following Intermediate-Duration Oral Exposure to PFHxASpecies and exposure Doseduration(mg/kg/day) EffectRat
32–44 days (GW)
10–15 M, 10–15 F

50
150
315 (TWA
dose)

Rat
GDs 1–20 (GW)
22 F

20
100
500

Reference

No effects observed
Kirkpatrick 2005
Decreased hemoglobin levels (males
only)
Decreased hemoglobin levels (males
only), increased reticulocyte levels(males only), thymic atrophy (females
only)
No effect observed
No effect observed
Decreased maternal weight gain;
decreased fetal body weight

Loveless et al. 2009

F = female(s); GD = gestation day; (GW) = gavage in water; M = male(s); RBC = red blood cell; TWA = timeweighted average

Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

A-117
APPENDIX AMINIMAL RISK LEVEL (MRL) WORKSHEET
Chemical Name:
CAS Numbers:
Date:Profile Status:
Route:
Duration:

Perfluorohexanoic acid (PFHxA)
307-24-4
March 2020
Final
Oral
Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFHxA.
Rationale for Not Deriving an MRL: The chronic duration oral database for PFHxA is not consideredadequate for derivation of a chronic MRL because the only study available did not measure serum PFHxAlevels and elimination half-life data are not available for humans. These toxicokinetic data are needed toderive HEDs.
One study has evaluated the chronic oral toxicity of PFHxA in laboratory animals (Klaunig et al. 2015).
Exposure to female rats to 200 mg/kg/day resulted in hematological alterations (decreases in red blood
cells and hemoglobin levels and increases in reticulocyte counts), renal effects (tubular degeneration,
necrosis, increased urine volume and reduced specific gravity), and liver effects (necrosis); no adverse
alterations were observed at 30 mg/kg/day or at 100 mg/kg/day in males. This study was not considered
suitable for derivation of an MRL because serum PFHxA levels were not measured. Additionally, anelimination half-life has not been estimated in humans.
Agency Contacts (Chemical Managers): Melanie BuserPERFLUOROALKYLS

B-1

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR
PERFLUOROALKYLS
The objective of the toxicological profile is to evaluate the potential for human exposure and the potential
health hazards associated with inhalation, oral, or dermal/ocular exposure to perfluoroalkyls.
B.1 LITERATURE SEARCH AND SCREEN
A literature search and screen was conducted to identify studies examining health effects, toxicokinetics,
mechanisms of action, susceptible populations, biomarkers, chemical interactions, physical and chemical
properties, production, use, environmental fate, environmental releases, and environmental and biologicalmonitoring data for perfluoroalkyls. ATSDR primarily focused on peer-reviewed articles without
publication date or language restrictions. Non-peer-reviewed studies that were considered relevant to theassessment of the health effects of perfluoroalkyls have undergone peer review by at least three ATSDRselected experts who have been screened for conflict of interest. The inclusion criteria used to identify
relevant studies examining the health effects of perfluoroalkyls are presented in Table B-1.

Table B-1. Inclusion Criteria for the Literature Search and Screen
Health Effects
Species
Human
Laboratory mammals
Route of exposure
Inhalation
Oral
Dermal (or ocular)
Parenteral (these studies will be considered supporting data)
Health outcome
Death
Systemic effects
Body weight effects
Respiratory effects
Cardiovascular effects
Gastrointestinal effects
Hematological effects
Musculoskeletal effects
Hepatic effects
Renal effects
Dermal effects
Ocular effects
Endocrine effects
Immunological effects
Neurological effects
Reproductive effects
Developmental effects

PERFLUOROALKYLS

B-2
APPENDIX B

Table B-1. Inclusion Criteria for the Literature Search and Screen
Other noncancer effects
CancerToxicokinetics
Absorption
Distribution
Metabolism
ExcretionPBPK models
Biomarkers
Biomarkers of exposure
Biomarkers of effectInteractions with other chemicals
Potential for human exposure
Releases to the environment
Air
Water
Soil
Environmental fateTransport and partitioning
Transformation and degradation
Environmental monitoring
Air
Water
Sediment and soil
Other media
Biomonitoring
General populations
Occupation populations

B.1.1 Literature Search
The current literature search was intended to update the draft toxicological profile for perfluoroalkyls
released for public comment in 2015. The following main databases were searched in March 2008,
September/October 2013, May 2016, and September 2018:•••

PubMedNational Library of Medicine’s TOXLINE
Scientific and Technical Information Network’s TOXCENTER

The search strategy used the chemical names, Chemical Abstracts Service (CAS) numbers,
synonyms, and Medical Subject Headings (MeSH) terms for perfluoroalkyls. The query strings used
for the literature search are presented in Table B-2.

PERFLUOROALKYLS

B-3
APPENDIX B

The search was augmented by searching the Toxic Substances Control Act Test Submissions (TSCATS),NTP website, and National Institute of Health Research Portfolio Online Reporting Tools Expenditures
and Results (NIH RePORTER) databases using the queries presented in Table B-3. Additional databases
were searched in the creation of various tables and figures, such as the TRI Explorer, the Substancepriority list (SPL) resource page, and other items as needed. Regulations applicable to perfluoroalkyls
were identified by searching international and U.S. agency websites and documents.
Review articles were identified and used for the purpose of providing background information andidentifying additional references. ATSDR also identified reports from the grey literature, which included
unpublished research reports, technical reports from government agencies, conference proceedings andabstracts, and theses and dissertations.

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
PubMed
9/11/2018((1763-23-1[rn] OR 2058-94-8[rn] OR 2355-31-9[rn] OR 2991-50-6[rn] OR 307-55-1[rn] OR 335-671[rn] OR 335-76-2[rn] OR 355-46-4[rn] OR 375-22-4[rn] OR 375-73-5[rn] OR 375-85-9[rn] OR 37595-1[rn] OR 754-91-6[rn] OR "perfluorododecanoic acid"[nm] OR "perfluorobutanesulfonic acid"[nm]OR "1,1,2,2,3,3,4,4,4-Nonafluoro-1-butanesulfonic acid"[tw] OR "1,1,2,2,3,3,4,4,4-Nonafluorobutane1-sulphonic acid"[tw] OR "1,1,2,2,3,3,4,4,5,5,6,6,6-Tridecafluorohexane-1-sulfonic acid"[tw] OR "1Perfluorobutanesulfonic acid"[tw] OR "2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-Nonanoic
acid"[tw] OR "2-(N-Ethyl-perfluorooctane sulfonamido) acetic acid"[tw] OR "2-(N-Methylperfluorooctane sulfonamido) acetic acid"[tw] OR "C11-PFA"[tw] OR "et-pfosa-acoh"[tw] OR"Glycine, N-ethyl-N-((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctyl)sulfonyl)-"[tw] OR"Henicosafluoroundecanoic acid"[tw] OR "heptadecafluoro-1-octane sulfonic acid"[tw] OR"Heptadecafluoro-1-octanesulfonic acid"[tw] OR "heptadecafluorooctane sulfonic acid"[tw] OR"Heptadecafluorooctane-1-sulphonic acid"[tw] OR "Heptadecafluorooctanesulphonamide"[tw] OR"Heptafluoro-1-butanoic acid"[tw] OR "Heptafluorobutanoic acid"[tw] OR "Heptafluorobutyric acid"[tw]OR "me-pfosa-acoh"[tw] OR "N-Ethyl-N-((heptadecafluorooctyl)sulphonyl)glycine"[tw] OR "Ndfda"[tw]OR "Nonadecafluoro-n-decanoic acid"[tw] OR "Nonadecafluorodecanoic acid"[tw] OR "Nonafluoro-1butanesulfonic acid"[tw] OR "Nonafluorobutanesulfonic acid"[tw] OR "Pentadecafluoro-1-octanoic
acid"[tw] OR "Pentadecafluoro-n-octanoic acid"[tw] OR "Pentadecafluorooctanoic acid"[tw] OR"Pentyl perfluorobutanoate"[tw] OR "Perfluoro-n-decanoic acid"[tw] OR "Perfluoro-n-heptanoic
acid"[tw] OR "Perfluoro-n-nonanoic acid"[tw] OR "Perfluoro-n-undecanoic acid"[tw] OR"Perfluorobutane sulfonic acid"[tw] OR "Perfluorobutanesulfonic acid"[tw] OR "Perfluorobutanoic
acid"[tw] OR "Perfluorobutyric acid"[tw] OR "Perfluorocaprylic acid"[tw] OR "Perfluoroctanoic acid"[tw]OR "Perfluoroctylsulfonamide"[tw] OR "Perfluorodecanoic acid"[tw] OR "Perfluorododecanoic
acid"[tw] OR "Perfluorododecanoic acid "[tw] OR "Perfluoroheptanecarboxylic acid"[tw] OR"Perfluoroheptanoic acid"[tw] OR "Perfluorohexane sulfonic acid"[tw] OR "Perfluorohexane-1sulphonic acid"[tw] OR "perfluorohexanesulfonate"[tw] OR "perfluorohexanesulfonic acid"[tw] OR"Perfluorolauric acid"[tw] OR "Perfluorononan-1-oic acid"[tw] OR "Perfluorononanoic acid"[tw] OR"Perfluorooctane sulfonamide"[tw] OR "Perfluorooctane sulfonate"[tw] OR "Perfluorooctane sulfonicacid "[tw] OR "perfluorooctane sulphonic acid"[tw] OR "Perfluorooctanesulfonamide"[tw] OR"Perfluorooctanesulfonate"[tw] OR "perfluorooctanesulfonic acid"[tw] OR "Perfluorooctanesulfonicacid amide"[tw] OR "Perfluorooctanoic acid"[tw] OR "Perfluorooctylsulfonic acid"[tw] OR"Perfluoropropanecarboxylic acid"[tw] OR "Perfluoroundecanoic acid"[tw] OR "pfbus"[tw] OR"PFDA"[tw] OR "pfdea"[tw] OR "pfdoa"[tw] OR "Pfhpa"[tw] OR "PFHS cpd"[tw] OR "pfhxs"[tw] OR"pfna"[tw] OR "PFOA"[tw] OR "PFOS"[tw] OR "pfsoa"[tw] OR "Pfua"[tw] OR"Tricosafluorododecanoic acid"[tw] OR "Tridecafluoro-1-heptanoic acid"[tw] OR"Tridecafluoroheptanoic acid"[tw]) AND (2015/05/01:3000[dp] OR 2016/05/01:3000[mhda] OR
2016/05/01:3000[crdat] OR 2016/05/01:3000[edat])) AND (to[sh] OR po[sh] OR ae[sh] OR pk[sh] ORai[sh] OR ci[sh] OR bl[sh] OR cf[sh] OR ur[sh] OR "pharmacology"[sh:noexp] OR "environmental
exposure"[mh] OR "endocrine system"[mh] OR "hormones, hormone substitutes, and hormone
antagonists"[mh] OR "endocrine disruptors"[mh] OR "Computational biology"[mh] OR "Medical
Informatics"[mh] OR Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR

PERFLUOROALKYLS

B-4
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR
Phenotype[mh] OR genetics[mh] OR genotype[mh] OR Transcriptome[mh] OR ("Systems
Biology"[mh] AND ("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh] ORanalysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR "Transcriptional
activation"[mh] OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND (RNA[mh] OR DNA[mh]))
OR "RNA, Messenger"[mh] OR "RNA, Transfer"[mh] OR "peptide biosynthesis"[mh] OR "protein
biosynthesis"[mh] OR "Reverse Transcriptase Polymerase Chain Reaction"[mh] OR "BaseSequence"[mh] OR "Trans-activators"[mh] OR "Gene Expression Profiling"[mh] OR cancer[sb] OR"pharmacology"[sh:noexp] OR toxicokinetics[mh:noexp] OR (me[sh] AND ("humans"[mh] OR"animals"[mh])))(("FC-143 surfactant"[nm] OR 307-24-4[rn] OR 3825-26-1[rn] OR "Hexanoic acid,
2,2,3,3,4,4,5,5,6,6,6-undecafluoro-"[tw] OR "Hexanoic acid, undecafluoro-"[tw] OR"Perfluorohexanoic acid"[tw] OR "Undecafluoro-1-hexanoic acid"[tw] OR "Undecafluorohexanoic
acid"[tw] OR "Ammonium pentadecafluorooctanoate"[tw] OR "Ammonium perfluorocaprilate"[tw] OR"Ammonium perfluorocaprylate"[tw] OR "Ammonium perfluorooctanoate"[tw] OR "FC 143"[tw] OR"Octanoic acid, 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluoro-, ammonium salt"[tw] OR "Octanoic
acid, pentadecafluoro-, ammonium salt"[tw] OR "Pentadecafluoro-1-octanoic acid, ammonium
salt"[tw] OR "Pentadecafluorooctanoic acid, ammonium salt"[tw] OR "Perfluoroammonium
octanoate"[tw] OR "Perfluorooctanoic acid, ammonium salt"[tw]) NOT (1763-23-1[rn] OR 2058-948[rn] OR 2355-31-9[rn] OR 2991-50-6[rn] OR 307-55-1[rn] OR 335-67-1[rn] OR 335-76-2[rn] OR 35546-4[rn] OR 375-22-4[rn] OR 375-73-5[rn] OR 375-85-9[rn] OR 375-95-1[rn] OR 754-91-6[rn] OR"perfluorododecanoic acid"[nm] OR "perfluorobutanesulfonic acid"[nm] OR "1,1,2,2,3,3,4,4,4Nonafluoro-1-butanesulfonic acid"[tw] OR "1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulphonic acid"[tw]OR "1,1,2,2,3,3,4,4,5,5,6,6,6-Tridecafluorohexane-1-sulfonic acid"[tw] OR "1-Perfluorobutanesulfonicacid"[tw] OR "2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-Nonanoic acid"[tw] OR "2-(N-Ethylperfluorooctane sulfonamido) acetic acid"[tw] OR "2-(N-Methyl-perfluorooctane sulfonamido) acetic
acid"[tw] OR "C11-PFA"[tw] OR "et-pfosa-acoh"[tw] OR "Glycine, N-ethyl-N((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctyl)sulfonyl)-"[tw] OR "Henicosafluoroundecanoic
acid"[tw] OR "heptadecafluoro-1-octane sulfonic acid"[tw] OR "Heptadecafluoro-1-octanesulfonicacid"[tw] OR "heptadecafluorooctane sulfonic acid"[tw] OR "Heptadecafluorooctane-1-sulphonicacid"[tw] OR "Heptadecafluorooctanesulphonamide"[tw] OR "Heptafluoro-1-butanoic acid"[tw] OR"Heptafluorobutanoic acid"[tw] OR "Heptafluorobutyric acid"[tw] OR "me-pfosa-acoh"[tw] OR "NEthyl-N-((heptadecafluorooctyl)sulphonyl)glycine"[tw] OR "Ndfda"[tw] OR "Nonadecafluoro-ndecanoic acid"[tw] OR "Nonadecafluorodecanoic acid"[tw] OR "Nonafluoro-1-butanesulfonic acid"[tw]OR "Nonafluorobutanesulfonic acid"[tw] OR "Pentadecafluoro-1-octanoic acid"[tw] OR"Pentadecafluoro-n-octanoic acid"[tw] OR "Pentadecafluorooctanoic acid"[tw] OR "Pentyl
perfluorobutanoate"[tw] OR "Perfluoro-n-decanoic acid"[tw] OR "Perfluoro-n-heptanoic acid"[tw] OR"Perfluoro-n-nonanoic acid"[tw] OR "Perfluoro-n-undecanoic acid"[tw] OR "Perfluorobutane sulfonicacid"[tw] OR "Perfluorobutanesulfonic acid"[tw] OR "Perfluorobutanoic acid"[tw] OR "Perfluorobutyricacid"[tw] OR "Perfluorocaprylic acid"[tw] OR "Perfluoroctanoic acid"[tw] OR"Perfluoroctylsulfonamide"[tw] OR "Perfluorodecanoic acid"[tw] OR "Perfluorododecanoic acid"[tw]OR "Perfluorododecanoic acid "[tw] OR "Perfluoroheptanecarboxylic acid"[tw] OR"Perfluoroheptanoic acid"[tw] OR "Perfluorohexane sulfonic acid"[tw] OR "Perfluorohexane-1sulphonic acid"[tw] OR "perfluorohexanesulfonate"[tw] OR "perfluorohexanesulfonic acid"[tw] OR"Perfluorolauric acid"[tw] OR "Perfluorononan-1-oic acid"[tw] OR "Perfluorononanoic acid"[tw] OR"Perfluorooctane sulfonamide"[tw] OR "Perfluorooctane sulfonate"[tw] OR "Perfluorooctane sulfonicacid "[tw] OR "perfluorooctane sulphonic acid"[tw] OR "Perfluorooctanesulfonamide"[tw] OR"Perfluorooctanesulfonate"[tw] OR "perfluorooctanesulfonic acid"[tw] OR "Perfluorooctanesulfonicacid amide"[tw] OR "Perfluorooctanoic acid"[tw] OR "Perfluorooctylsulfonic acid"[tw] OR"Perfluoropropanecarboxylic acid"[tw] OR "Perfluoroundecanoic acid"[tw] OR "pfbus"[tw] OR"PFDA"[tw] OR "pfdea"[tw] OR "pfdoa"[tw] OR "Pfhpa"[tw] OR "PFHS cpd"[tw] OR "pfhxs"[tw] OR"pfna"[tw] OR "PFOA"[tw] OR "PFOS"[tw] OR "pfsoa"[tw] OR "Pfua"[tw] OR"Tricosafluorododecanoic acid"[tw] OR "Tridecafluoro-1-heptanoic acid"[tw] OR"Tridecafluoroheptanoic acid"[tw])) AND (to[sh] OR po[sh] OR ae[sh] OR pk[sh] OR ai[sh] OR ci[sh]OR bl[sh] OR cf[sh] OR ur[sh] OR "pharmacology"[sh:noexp] OR "environmental exposure"[mh] OR"endocrine system"[mh] OR "hormones, hormone substitutes, and hormone antagonists"[mh] OR

PERFLUOROALKYLS

B-5
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string

05/24/2016"endocrine disruptors"[mh] OR "Computational biology"[mh] OR "Medical Informatics"[mh] OR
Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR Metabolomics[mh] OR
Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR Phenotype[mh] OR genetics[mh]OR genotype[mh] OR Transcriptome[mh] OR ("Systems Biology"[mh] AND ("Environmental
Exposure"[mh] OR "Epidemiological Monitoring"[mh] OR analysis[sh])) OR "Transcription, Genetic"[mh] OR "Reverse transcription"[mh] OR "Transcriptional activation"[mh] OR "Transcription
factors"[mh] OR ("biosynthesis"[sh] AND (RNA[mh] OR DNA[mh])) OR "RNA, Messenger"[mh] OR"RNA, Transfer"[mh] OR "peptide biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "Reverse
Transcriptase Polymerase Chain Reaction"[mh] OR "Base Sequence"[mh] OR "Trans-activators"[mh]OR "Gene Expression Profiling"[mh] OR cancer[sb] OR "pharmacology"[sh:noexp] OR
toxicokinetics[mh:noexp] OR (me[sh] AND ("humans"[mh] OR "animals"[mh])))((((("1,1,2,2,3,3,4,4,4-Nonafluoro-1-butanesulfonic acid"[tw] OR "1,1,2,2,3,3,4,4,4-Nonafluorobutane1-sulphonic acid"[tw] OR "1,1,2,2,3,3,4,4,5,5,6,6,6-Tridecafluorohexane-1-sulfonic acid"[tw] OR "1Perfluorobutanesulfonic acid"[tw] OR "2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-Nonanoic
acid"[tw] OR "2-(N-Ethyl-perfluorooctane sulfonamido) acetic acid"[tw] OR "2-(N-Methylperfluorooctane sulfonamido) acetic acid"[tw] OR "C11-PFA"[tw] OR "et-pfosa-acoh"[tw] OR"Glycine, N-ethyl-N-((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctyl)sulfonyl)-"[tw] OR"Henicosafluoroundecanoic acid"[tw] OR "heptadecafluoro-1-octane sulfonic acid"[tw] OR"Heptadecafluoro-1-octanesulfonic acid"[tw] OR "heptadecafluorooctane sulfonic acid"[tw] OR"Heptadecafluorooctane-1-sulphonic acid"[tw] OR "Heptadecafluorooctanesulphonamide"[tw] OR"Heptafluoro-1-butanoic acid"[tw] OR "Heptafluorobutanoic acid"[tw] OR "Heptafluorobutyric acid"[tw]OR "me-pfosa-acoh"[tw] OR "N-Ethyl-N-((heptadecafluorooctyl)sulphonyl)glycine"[tw] OR "Ndfda"[tw]OR "Nonadecafluoro-n-decanoic acid"[tw] OR "Nonadecafluorodecanoic acid"[tw] OR "Nonafluoro-1butanesulfonic acid"[tw] OR "Nonafluorobutanesulfonic acid"[tw] OR "Pentadecafluoro-1-octanoic
acid"[tw] OR "Pentadecafluoro-n-octanoic acid"[tw] OR "Pentadecafluorooctanoic acid"[tw] OR"Pentyl perfluorobutanoate"[tw] OR "Perfluoro-n-decanoic acid"[tw] OR "Perfluoro-n-heptanoic
acid"[tw] OR "Perfluoro-n-nonanoic acid"[tw] OR "Perfluoro-n-undecanoic acid"[tw] OR"Perfluorobutane sulfonic acid"[tw] OR "Perfluorobutanesulfonic acid"[tw] OR "Perfluorobutanoic
acid"[tw] OR "Perfluorobutyric acid"[tw] OR "Perfluorocaprylic acid"[tw] OR "Perfluoroctanoic acid"[tw]OR "Perfluoroctylsulfonamide"[tw] OR "Perfluorodecanoic acid"[tw] OR "Perfluorododecanoic acid"[tw] OR "Perfluorododecanoic acid"[tw] OR "Perfluoroheptanecarboxylic acid"[tw] OR"Perfluoroheptanoic acid"[tw] OR "Perfluorohexane sulfonic acid"[tw] OR "Perfluorohexane-1sulphonic acid"[tw] OR "perfluorohexanesulfonate"[tw] OR "perfluorohexanesulfonic acid"[tw] OR"Perfluorolauric acid"[tw] OR "Perfluorononan-1-oic acid"[tw] OR "Perfluorononanoic acid"[tw] OR"Perfluorooctane sulfonamide"[tw] OR "Perfluorooctane sulfonate"[tw] OR "Perfluorooctane sulfonicacid "[tw] OR "perfluorooctane sulphonic acid"[tw] OR "Perfluorooctanesulfonamide"[tw] OR"Perfluorooctanesulfonate"[tw] OR "Perfluorooctanesulfonic acid amide"[tw] OR"perfluorooctanesulfonic acid"[tw] OR "Perfluorooctanoic acid"[tw] OR "Perfluorooctylsulfonicacid"[tw] OR "Perfluoropropanecarboxylic acid"[tw] OR "Perfluoroundecanoic acid"[tw] OR "pfbus"[tw]OR "PFDA"[tw] OR "pfdea"[tw] OR "pfdoa"[tw] OR "Pfhpa"[tw] OR "PFHS cpd"[tw] OR "pfhxs"[tw] OR"pfna"[tw] OR "PFOA"[tw] OR "PFOS"[tw] OR "pfsoa"[tw] OR "Pfua"[tw] OR"Tricosafluorododecanoic acid"[tw] OR "Tridecafluoro-1-heptanoic acid"[tw] OR"Tridecafluoroheptanoic acid"[tw]) AND (2013/09/01:3000[crdat] OR 2013/09/01:3000[edat])) NOT
medline[sb])))) OR (((("1,1,2,2,3,3,4,4,4-Nonafluoro-1-butanesulfonic acid"[tw] OR "1,1,2,2,3,3,4,4,4Nonafluorobutane-1-sulphonic acid"[tw] OR "1,1,2,2,3,3,4,4,5,5,6,6,6-Tridecafluorohexane-1-sulfonicacid"[tw] OR "1-Perfluorobutanesulfonic acid"[tw] OR "2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9heptadecafluoro-Nonanoic acid"[tw] OR "2-(N-Ethyl-perfluorooctane sulfonamido) acetic acid"[tw] OR"2-(N-Methyl-perfluorooctane sulfonamido) acetic acid"[tw] OR "C11-PFA"[tw] OR "et-pfosa-acoh"[tw]OR "Glycine, N-ethyl-N-((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctyl)sulfonyl)-"[tw] OR"Henicosafluoroundecanoic acid"[tw] OR "heptadecafluoro-1-octane sulfonic acid"[tw] OR"Heptadecafluoro-1-octanesulfonic acid"[tw] OR "heptadecafluorooctane sulfonic acid"[tw] OR"Heptadecafluorooctane-1-sulphonic acid"[tw] OR "Heptadecafluorooctanesulphonamide"[tw] OR"Heptafluoro-1-butanoic acid"[tw] OR "Heptafluorobutanoic acid"[tw] OR "Heptafluorobutyric acid"[tw]OR "me-pfosa-acoh"[tw] OR "N-Ethyl-N-((heptadecafluorooctyl)sulphonyl)glycine"[tw] OR "Ndfda"[tw]OR "Nonadecafluoro-n-decanoic acid"[tw] OR "Nonadecafluorodecanoic acid"[tw] OR "Nonafluoro-1butanesulfonic acid"[tw] OR "Nonafluorobutanesulfonic acid"[tw] OR "Pentadecafluoro-1-octanoic

PERFLUOROALKYLS

B-6
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query stringacid"[tw] OR "Pentadecafluoro-n-octanoic acid"[tw] OR "Pentadecafluorooctanoic acid"[tw] OR"Pentyl perfluorobutanoate"[tw] OR "Perfluoro-n-decanoic acid"[tw] OR "Perfluoro-n-heptanoic
acid"[tw] OR "Perfluoro-n-nonanoic acid"[tw] OR "Perfluoro-n-undecanoic acid"[tw] OR"Perfluorobutane sulfonic acid"[tw] OR "Perfluorobutanesulfonic acid"[tw] OR "Perfluorobutanoic
acid"[tw] OR "Perfluorobutyric acid"[tw] OR "Perfluorocaprylic acid"[tw] OR "Perfluoroctanoic acid"[tw]OR "Perfluoroctylsulfonamide"[tw] OR "Perfluorodecanoic acid"[tw] OR "Perfluorododecanoic acid"[tw] OR "Perfluorododecanoic acid"[tw] OR "Perfluoroheptanecarboxylic acid"[tw] OR"Perfluoroheptanoic acid"[tw] OR "Perfluorohexane sulfonic acid"[tw] OR "Perfluorohexane-1sulphonic acid"[tw] OR "perfluorohexanesulfonate"[tw] OR "perfluorohexanesulfonic acid"[tw] OR"Perfluorolauric acid"[tw] OR "Perfluorononan-1-oic acid"[tw] OR "Perfluorononanoic acid"[tw] OR"Perfluorooctane sulfonamide"[tw] OR "Perfluorooctane sulfonate"[tw] OR "Perfluorooctane sulfonicacid "[tw] OR "perfluorooctane sulphonic acid"[tw] OR "Perfluorooctanesulfonamide"[tw] OR"Perfluorooctanesulfonate"[tw] OR "Perfluorooctanesulfonic acid amide"[tw] OR"perfluorooctanesulfonic acid"[tw] OR "Perfluorooctanoic acid"[tw] OR "Perfluorooctylsulfonicacid"[tw] OR "Perfluoropropanecarboxylic acid"[tw] OR "Perfluoroundecanoic acid"[tw] OR "pfbus"[tw]OR "PFDA"[tw] OR "pfdea"[tw] OR "pfdoa"[tw] OR "Pfhpa"[tw] OR "PFHS cpd"[tw] OR "pfhxs"[tw] OR"pfna"[tw] OR "PFOA"[tw] OR "PFOS"[tw] OR "pfsoa"[tw] OR "Pfua"[tw] OR"Tricosafluorododecanoic acid"[tw] OR "Tridecafluoro-1-heptanoic acid"[tw] OR"Tridecafluoroheptanoic acid"[tw] OR 1763-23-1[rn] OR 2058-94-8[rn] OR 2355-31-9[rn] OR 299150-6[rn] OR 307-55-1[rn] OR 335-67-1[rn] OR 335-76-2[rn] OR 355-46-4[rn] OR 375-22-4[rn] OR
375-73-5[rn] OR 375-85-9[rn] OR 375-95-1[rn] OR 754-91-6[rn]) AND (2013/09/01:3000[mhda] OR
2013/09/01:3000[crdat] OR 2013/09/01:3000[edat])) AND (to[sh] OR po[sh] OR ae[sh] OR pk[sh] ORai[sh] OR ci[sh] OR bl[sh] OR cf[sh] OR ur[sh] OR "pharmacology"[sh:noexp] OR "environmental
exposure"[mh] OR "endocrine system"[mh] OR "hormones, hormone substitutes, and hormone
antagonists"[mh] OR "endocrine disruptors"[mh] OR "Computational biology"[mh] OR "Medical
Informatics"[mh] OR Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR
Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR
Phenotype[mh] OR genetics[mh] OR genotype[mh] OR Transcriptome[mh] OR ("Systems
Biology"[mh] AND ("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh] ORanalysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR "Transcriptional
activation"[mh] OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND (RNA[mh] OR DNA[mh]))
OR "RNA, Messenger"[mh] OR "RNA, Transfer"[mh] OR "peptide biosynthesis"[mh] OR "protein
biosynthesis"[mh] OR "Reverse Transcriptase Polymerase Chain Reaction"[mh] OR "BaseSequence"[mh] OR "Trans-activators"[mh] OR "Gene Expression Profiling"[mh] OR cancer[sb] OR(me[sh] AND ("humans"[mh] OR "animals"[mh])))10/03/2013("Computational biology"[mh] OR "Medical Informatics"[mh] OR Genomics[mh] OR Genome[mh] OR
Proteomics[mh] OR Proteome[mh] OR Metabolomics[mh] OR Metabolome[mh] OR Genes[mh] OR"Gene expression"[mh] OR Phenotype[mh] OR genetics[mh] OR genotype[mh] OR
Transcriptome[mh] OR ("Systems Biology"[mh] AND ("Environmental Exposure"[mh] OR"Epidemiological Monitoring"[mh] OR analysis[sh])) OR "Transcription, Genetic "[mh] OR "Reverse
transcription"[mh] OR "Transcriptional activation"[mh] OR "Transcription factors"[mh] OR("biosynthesis"[sh] AND (RNA[mh] OR DNA[mh])) OR " RNA, Messenger "[mh] OR " RNA,Transfer"[mh] OR "peptide biosynthesis"[mh] OR "protein biosynthesis"[mh] OR "Reverse
Transcriptase Polymerase Chain Reaction"[mh] OR "Base Sequence"[mh] OR "Trans-activators"[mh]OR "Gene Expression Profiling"[mh]) AND ((335-67-1[rn] OR 1763-23-1[rn] OR 355-46-4[rn] OR
2991-50-6[rn] OR 2355-31-9[rn] OR 335-76-2[rn] OR 375-73-5[rn] OR 375-85-9[rn] OR 375-95-1[rn]OR 754-91-6[rn] OR 2058-94-8[rn] OR 307-55-1[rn] OR 375-22-4[rn] OR 80AM718FML[rn]) AND
2007/05/01:2013/10/03[dp])09/19/2013(((335-67-1[rn] OR 1763-23-1[rn] OR 355-46-4[rn] OR 2991-50-6[rn] OR 2355-31-9[rn] OR 335-762[rn] OR 375-73-5[rn] OR 375-85-9[rn] OR 375-95-1[rn] OR 754-91-6[rn] OR 2058-94-8[rn] OR 30755-1[rn] OR 375-22-4[rn] OR 80AM718FML[rn]) AND 2007/05/01:2013/09/19[dp]) AND(((Caprylates/metabolism[MeSH Terms] OR Fluorocarbons/metabolism[MeSH Terms] OR"Alkanesulfonic Acids/metabolism"[MeSH Terms] OR "Sulfonic Acids/metabolism"[MeSH Terms] OR"Decanoic Acids/metabolism"[MeSH Terms] OR "Heptanoic Acids/metabolism"[MeSH Terms] OR"Hydrocarbons, Fluorinated/metabolism"[MeSH Terms] OR "Fatty Acids/metabolism"[MeSH Terms]

PERFLUOROALKYLS

B-7
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
OR Sulfonamides/metabolism[MeSH Terms]) AND ("humans"[MeSH Terms] OR "animals"[MeSH
Terms])) OR ((Caprylates[MeSH Terms] OR Fluorocarbons[MeSH Terms] OR "Alkanesulfonic
Acids"[MeSH Terms] OR "Sulfonic Acids"[MeSH Terms] OR "Decanoic Acids"[MeSH Terms] OR"Heptanoic Acids"[MeSH Terms] OR "Hydrocarbons, Fluorinated"[MeSH Terms] OR "Fatty
Acids"[MeSH Terms] OR Sulfonamides[MeSH Terms]) AND (Endocrine System[mh] OR
Hormones[mh] OR Endocrine disruptors[mh])) OR ((Caprylates[MeSH Terms] OR
Fluorocarbons[MeSH Terms] OR "Alkanesulfonic Acids"[MeSH Terms] OR "Sulfonic Acids"[MeSH
Terms] OR "Decanoic Acids"[MeSH Terms] OR "Heptanoic Acids"[MeSH Terms] OR "Hydrocarbons,
Fluorinated"[MeSH Terms] OR "Fatty Acids"[MeSH Terms] OR Sulfonamides[MeSH Terms]) AND"environmental exposure"[MeSH Terms]) OR ((Caprylates[MeSH Terms] OR Fluorocarbons[MeSH
Terms] OR "Alkanesulfonic Acids"[MeSH Terms] OR "Sulfonic Acids"[MeSH Terms] OR "Decanoic
Acids"[MeSH Terms] OR "Heptanoic Acids"[MeSH Terms] OR "Hydrocarbons, Fluorinated"[MeSH
Terms] OR "Fatty Acids"[MeSH Terms] OR Sulfonamides[MeSH Terms]) AND "chemicallyinduced"[MeSH Subheading]) OR ((((((((((("caprylates/adverse effects"[MeSH Terms] OR"caprylates/antagonists and inhibitors"[MeSH Terms] OR "caprylates/blood"[MeSH Terms] OR"caprylates/cerebrospinal fluid"[MeSH Terms] OR "caprylates/pharmacokinetics"[MeSH Terms] OR"caprylates/poisoning"[MeSH Terms] OR "caprylates/toxicity"[MeSH Terms] OR"caprylates/urine"[MeSH Terms]))) OR (("fluorocarbons/adverse effects"[MeSH Terms] OR"fluorocarbons/antagonists and inhibitors"[MeSH Terms] OR "fluorocarbons/blood"[MeSH Terms] OR"fluorocarbons/pharmacokinetics"[MeSH Terms] OR "fluorocarbons/poisoning"[MeSH Terms] OR"fluorocarbons/toxicity"[MeSH Terms] OR "fluorocarbons/urine"[MeSH Terms]))) OR(("alkanesulfonic acids/adverse effects"[MeSH Terms] OR "alkanesulfonic acids/antagonists andinhibitors"[MeSH Terms] OR "alkanesulfonic acids/blood"[MeSH Terms] OR "alkanesulfonicacids/cerebrospinal fluid"[MeSH Terms] OR "alkanesulfonic acids/pharmacokinetics"[MeSH Terms]
OR "alkanesulfonic acids/poisoning"[MeSH Terms] OR "alkanesulfonic acids/toxicity"[MeSH Terms]
OR "alkanesulfonic acids/urine"[MeSH Terms]))) OR (("sulfonic acids/adverse effects"[MeSH Terms]
OR "sulfonic acids/antagonists and inhibitors"[MeSH Terms] OR "sulfonic acids/blood"[MeSH Terms]
OR "sulfonic acids/cerebrospinal fluid"[MeSH Terms] OR "sulfonic acids/pharmacokinetics"[MeSH
Terms] OR "sulfonic acids/poisoning"[MeSH Terms] OR "sulfonic acids/toxicity"[MeSH Terms] OR"sulfonic acids/urine"[MeSH Terms]))) OR (("decanoic acids/adverse effects"[MeSH Terms] OR"decanoic acids/antagonists and inhibitors"[MeSH Terms] OR "decanoic acids/blood"[MeSH Terms]
OR "decanoic acids/pharmacokinetics"[MeSH Terms] OR "decanoic acids/poisoning"[MeSH Terms]
OR "decanoic acids/toxicity"[MeSH Terms] OR "decanoic acids/urine"[MeSH Terms]))) OR(("heptanoic acids/adverse effects"[MeSH Terms] OR "heptanoic acids/antagonists andinhibitors"[MeSH Terms] OR "heptanoic acids/blood"[MeSH Terms] OR "heptanoic
acids/cerebrospinal fluid"[MeSH Terms] OR "heptanoic acids/pharmacokinetics"[MeSH Terms] OR"heptanoic acids/poisoning"[MeSH Terms] OR "heptanoic acids/toxicity"[MeSH Terms] OR"heptanoic acids/urine"[MeSH Terms]))) OR (("hydrocarbons, fluorinated/adverse effects"[MeSH
Terms] OR "hydrocarbons, fluorinated/antagonists and inhibitors"[MeSH Terms] OR "hydrocarbons,fluorinated/blood"[MeSH Terms] OR "hydrocarbons, fluorinated/cerebrospinal fluid"[MeSH Terms]
OR "hydrocarbons, fluorinated/pharmacokinetics"[MeSH Terms] OR "hydrocarbons,fluorinated/toxicity"[MeSH Terms] OR "hydrocarbons, fluorinated/urine"[MeSH Terms]))) OR (("fatty
acids/adverse effects"[MeSH Terms] OR "fatty acids/antagonists and inhibitors"[MeSH Terms] OR"fatty acids/blood"[MeSH Terms] OR "fatty acids/cerebrospinal fluid"[MeSH Terms] OR "fatty
acids/pharmacokinetics"[MeSH Terms] OR "fatty acids/poisoning"[MeSH Terms] OR "fatty
acids/toxicity"[MeSH Terms] OR "fatty acids/urine"[MeSH Terms]))) OR (("sulfonamides/adverse
effects"[MeSH Terms] OR "sulfonamides/antagonists and inhibitors"[MeSH Terms] OR"sulfonamides/blood"[MeSH Terms] OR "sulfonamides/cerebrospinal fluid"[MeSH Terms] OR"sulfonamides/pharmacokinetics"[MeSH Terms] OR "sulfonamides/poisoning"[MeSH Terms] OR"sulfonamides/toxicity"[MeSH Terms] OR "sulfonamides/urine"[MeSH Terms]))))) OR(("Perfluorooctanoic acid"[tw] OR "Pentadecafluoro-1-octanoic acid"[tw] OR "Pentadecafluoro-noctanoic acid"[tw] OR "Pentadecafluorooctanoic acid"[tw] OR "Perfluorocaprylic acid"[tw] OR"Perfluoroctanoic acid"[tw] OR "Perfluoroheptanecarboxylic acid"[tw] OR "Perfluorooctanoic acid"[tw]OR "Pentadecafluorooctanoic acid"[tw] OR "Perfluorooctanoic acid"[tw] OR "Perfluorooctane sulfonicacid "[tw] OR "Heptadecafluoro-1-octanesulfonic acid"[tw] OR "heptadecafluoro-1-octane sulfonicacid"[tw] OR "Heptadecafluorooctane-1-sulphonic acid"[tw] OR "heptadecafluorooctane sulfonicPERFLUOROALKYLS

B-8
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query stringacid"[tw] OR "Perfluorooctane sulfonate"[tw] OR "Perfluorooctylsulfonic acid"[tw] OR"perfluorooctane sulphonic acid"[tw] OR "perfluorooctanesulfonic acid"[tw] OR"Perfluorooctanesulfonate"[tw] OR "Heptadecafluorooctane-1-sulphonic acid1Perfluorooctanesulfonic acid"[tw] OR "Perfluorohexane sulfonic acid"[tw] OR "pfhxs"[tw] OR"perfluorohexanesulfonic acid"[tw] OR "perfluorohexanesulfonate"[tw] OR "1,1,2,2,3,3,4,4,5,5,6,6,6Tridecafluorohexane-1-sulfonic acid"[tw] OR "Perfluorohexane-1-sulphonic acid"[tw] OR "PFHS
cpd"[tw] OR "2-(N-Ethyl-perfluorooctane sulfonamido) acetic acid"[tw] OR "et-pfosa-acoh"[tw] OR "NEthyl-N-((heptadecafluorooctyl)sulphonyl)glycine"[tw] OR "Glycine, N-ethyl-N((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctyl)sulfonyl)-"[tw] OR "2-(N-Methylperfluorooctane sulfonamido) acetic acid"[tw] OR "me-pfosa-acoh"[tw] OR "Perfluorodecanoic
acid"[tw] OR "Nonadecafluoro-n-decanoic acid"[tw] OR "Nonadecafluorodecanoic acid"[tw] OR"Perfluoro-N-decanoic acid"[tw] OR "Perfluoro-n-decanoic acid"[tw] OR "Perfluorodecanoic acid"[tw]OR "Nonadecafluorodecanoic acid"[tw] OR "Perfluoro-N-decanoic acid"[tw] OR "Perfluorobutane
sulfonic acid"[tw] OR "Perfluorobutanesulfonic acid"[tw] OR "1,1,2,2,3,3,4,4,4-Nonafluoro-1butanesulfonic acid"[tw] OR "1-Perfluorobutanesulfonic acid"[tw] OR "Nonafluoro-1-butanesulfonicacid"[tw] OR "Nonafluorobutanesulfonic acid"[tw] OR "Pentyl perfluorobutanoate"[tw] OR"1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulphonic acid"[tw] OR "Nonafluoro-1-butanesulfonic acid"[tw]OR "Perfluoroheptanoic acid"[tw] OR "Tridecafluoro-1-heptanoic acid"[tw] OR "Perfluoro-n-heptanoic
acid"[tw] OR "Perfluoroheptanoic acid"[tw] OR "Tridecafluoroheptanoic acid"[tw] OR"Perfluorononanoic acid"[tw] OR "Perfluoro-n-nonanoic acid"[tw] OR"2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-Nonanoic acid"[tw] OR "Perfluorononan-1-oic
acid"[tw] OR "Perfluorooctane sulfonamide"[tw] OR "Perfluorooctanesulfonamide"[tw] OR"Perfluoroctylsulfonamide"[tw] OR "Perfluorooctanesulfonic acid amide"[tw] OR"Heptadecafluorooctanesulphonamide"[tw] OR "Perfluoroundecanoic acid"[tw] OR "Perfluoro-nundecanoic acid"[tw] OR "Henicosafluoroundecanoic acid"[tw] OR "Perfluorododecanoic acid "[tw]OR "Perfluorododecanoic acid"[tw] OR "Tricosafluorododecanoic acid"[tw] OR "Perfluorolauricacid"[tw] OR "Perfluorobutyric acid"[tw] OR "Heptafluorobutyric acid"[tw] OR "Heptafluoro-1-butanoic
acid"[tw] OR "Heptafluorobutanoic acid"[tw] OR "Heptafluorobutyric acid"[tw] OR "Perfluorobutanoic
acid"[tw] OR "Perfluoropropanecarboxylic acid"[tw]) NOT medline[sb]) OR (("PFOA"[tw] OR"PFOS"[tw] OR "Pfua"[tw] OR "pfdoa"[tw] OR "C11-PFA"[tw] OR "pfsoa"[tw] OR "pfna"[tw] OR"Pfhpa"[tw] OR "pfbus"[tw] OR "PFDA"[tw] OR "pfdea"[tw] OR "Ndfda"[tw]) NOT medline[sb])Toxcenter9/11/2018

FILE 'TOXCENTER' ENTERED AT 15:57:25 ON 11 SEP 2018
CHARGED TO COST=EH011.10.LB.01.05
L17667 SEA FILE=TOXCENTER 1763-23-1 OR 2058-94-8 OR 2355-31-9 OR
2991-50-6 OR 307-55-1 OR 335-67-1 OR 335-76-2 OR 355-46-4 OR
375-22-4 OR 375-73-5 OR 375-85-9 OR 375-95-1 OR 754-91-6
L21413 SEA FILE=TOXCENTER 307-24-4 OR 3825-26-1
L4
189 SEA FILE=TOXCENTER L2 NOT L1
L57856 SEA FILE=TOXCENTER L1 OR L2
L67800 SEA FILE=TOXCENTER L5 NOT TSCATS/FS
L77460 SEA FILE=TOXCENTER L6 NOT PATENT/DT
ACTIVATE TOXQUERY/Q--------L8
QUE (CHRONIC OR IMMUNOTOX? OR NEUROTOX? OR TOXICOKIN? OR
BIOMARKER? OR NEUROLOG?)
L9
QUE (PHARMACOKIN? OR SUBCHRONIC OR PBPK OR EPIDEMIOLOGY/ST,CT,IT)
L10QUE (ACUTE OR SUBACUTE OR LD50# OR LD(W)50 OR LC50# OR
LC(W)50)
L11QUE (TOXICITY OR ADVERSE OR POISONING)/ST,CT,IT
L12QUE (INHAL? OR PULMON? OR NASAL? OR LUNG? OR RESPIR?)
L13
QUE ((OCCUPATION? OR WORKPLACE? OR WORKER?) AND EXPOS?)
L14
QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET OR DIETS ORDIETARY OR DRINKING(W)WATER?)PERFLUOROALKYLS

B-9
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
L15
L16
L17

QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR PERMISSIBLE))

QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?)
QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM? OROVUM?)L18
QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?)
L19
QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? ORTERATOGEN?)
L20
QUE (SPERM OR SPERMAC? OR SPERMAG? OR SPERMATI? OR SPERMAS? OR
SPERMATOB? OR SPERMATOC? OR SPERMATOG?)
L21
QUE (SPERMATOI? OR SPERMATOL? OR SPERMATOR? OR SPERMATOX? OR
SPERMATOZ? OR SPERMATU? OR SPERMI? OR SPERMO?)
L22
QUE (NEONAT? OR NEWBORN? OR DEVELOPMENT OR DEVELOPMENTAL?)
L23
QUE (ENDOCRIN? AND DISRUPT?)L24
QUE (ZYGOTE? OR CHILD OR CHILDREN OR ADOLESCEN? OR INFANT?)
L25
QUE (WEAN? OR OFFSPRING OR AGE(W)FACTOR?)
L26
QUE (DERMAL? OR DERMIS OR SKIN OR EPIDERM? OR CUTANEOUS?)
L27
QUE (CARCINOG? OR COCARCINOG? OR CANCER? OR PRECANCER? OR
NEOPLAS?)
L28
QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR CARCINOM?)
L29
QUE (GENETOX? OR GENOTOX? OR MUTAGEN? OR GENETIC(W)TOXIC?)
L30
QUE (NEPHROTOX? OR HEPATOTOX?)
L31
QUE (ENDOCRIN? OR ESTROGEN? OR ANDROGEN? OR HORMON?)
L32
QUE (OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?)
L33
QUE L8 OR L9 OR L10 OR L11 OR L12 OR L13 OR L14 OR L15 OR L16
OR L17 OR L18 OR L19 OR L20 OR L21 OR L22 OR L23 OR L24 OR L25
OR L26 OR L27 OR L28 OR L29 OR L30 OR L31 OR L32
L34
QUE (RAT OR RATS OR MOUSE OR MICE OR GUINEA(W)PIG? OR MURIDAE
OR DOG OR DOGS OR RABBIT? OR HAMSTER? OR PIG OR PIGS OR SWINE
OR PORCINE OR MONKEY? OR MACAQUE?)
L35
QUE (MARMOSET? OR FERRET? OR GERBIL? OR RODENT? OR LAGOMORPHA
OR BABOON? OR CANINE OR CAT OR CATS OR FELINE OR MURINE)L36
QUE L33 OR L34 OR L35
L37
QUE (HUMAN OR HUMANS OR HOMINIDAE OR MAMMALS OR MAMMAL? OR
PRIMATES OR PRIMATE?)
L38
QUE L36 OR L37--------L39
5371 SEA FILE=TOXCENTER L7 AND L38
L401566 SEA FILE=TOXCENTER L39 AND MEDLINE/FS
L41
1116 SEA FILE=TOXCENTER L39 AND BIOSIS/FS
L422649 SEA FILE=TOXCENTER L39 AND CAPLUS/FS
L43
40 SEA FILE=TOXCENTER L39 NOT (L40 OR L41 OR L42)
L443543 DUP REM L40 L41 L43 L42 (1828 DUPLICATES REMOVED)ANSWERS '1-3543' FROM FILE TOXCENTER
L*** DEL 1566 S L39 AND MEDLINE/FS
L*** DEL 1566 S L39 AND MEDLINE/FS
L45
1566 SEA FILE=TOXCENTER L44
L*** DEL 1116 S L39 AND BIOSIS/FS
L*** DEL 1116 S L39 AND BIOSIS/FS
L46
594 SEA FILE=TOXCENTER L44
L*** DEL 2649 S L39 AND CAPLUS/FS
L*** DEL 2649 S L39 AND CAPLUS/FS
L471350 SEA FILE=TOXCENTER L44
L*** DEL 40 S L39 NOT (L40 OR L41 OR L42)
L*** DEL 40 S L39 NOT (L40 OR L41 OR L42)
L48
33 SEA FILE=TOXCENTER L44

PERFLUOROALKYLS

B-10
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
L49

05/25/2016

865 SEA FILE=TOXCENTER (L45 OR L46 OR L47 OR L48) AND (ED>20160401
OR PY>2015)
L*** DEL 1566 S L39 AND MEDLINE/FS
L*** DEL 1566 S L39 AND MEDLINE/FS
L50
1566 SEA FILE=TOXCENTER L44
L*** DEL 1116 S L39 AND BIOSIS/FS
L*** DEL 1116 S L39 AND BIOSIS/FS
L51
594 SEA FILE=TOXCENTER L44
L*** DEL 2649 S L39 AND CAPLUS/FS
L*** DEL 2649 S L39 AND CAPLUS/FS
L521350 SEA FILE=TOXCENTER L44
L*** DEL 40 S L39 NOT (L40 OR L41 OR L42)
L*** DEL 40 S L39 NOT (L40 OR L41 OR L42)
L53
33 SEA FILE=TOXCENTER L44
L542678 SEA FILE=TOXCENTER (L50 OR L51 OR L52 OR L53) NOT L49
L55
43 SEA FILE=TOXCENTER L54 AND L4
L56
908 SEA FILE=TOXCENTER L49 OR L55
SAVE TEMP L56 PFOA/Q
D SCAN L56
FILE 'TOXCENTER' ENTERED AT 08:37:55 ON 25 MAY 2016
L15994 SEA 335-67-1 OR 1763-23-1 OR 355-46-4 OR 2991-50-6 OR 2355-31-9
OR 335-76-2 OR 375-73-5 OR 375-85-9 OR 375-95-1 OR 754-91-6
OR 2058-94-8 OR 307-55-1 OR 375-22-4
L25967 SEA L1 NOT TSCATS/FS
L35731 SEA L2 NOT PATENT/DT
L4
1847 SEA L3 AND ED>=20130701
ACT TOXQUERY/Q
L5
QUE (CHRONIC OR IMMUNOTOX? OR NEUROTOX? OR TOXICOKIN? OR
BIOMARKER? OR NEUROLOG?)
L6
QUE (PHARMACOKIN? OR SUBCHRONIC OR PBPK OR EPIDEMIOLOGY/ST,CT,IT)
L7QUE (ACUTE OR SUBACUTE OR LD50# OR LD(W)50 OR LC50# OR
LC(W)50)
L8QUE (TOXICITY OR ADVERSE OR POISONING)/ST,CT,IT
L9
QUE (INHAL? OR PULMON? OR NASAL? OR LUNG? OR RESPIR?)
L10
QUE ((OCCUPATION? OR WORKPLACE? OR WORKER?) AND EXPOS?)
L11
QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET OR DIETS ORDIETARY OR DRINKING(W)WATER?)
L12
QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR PERMISSIBLE))
L13
QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?)
L14
QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM? OROVUM?)L15
QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?)
L16
QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? ORTERATOGEN?)
L17
QUE (SPERM OR SPERMAC? OR SPERMAG? OR SPERMATI? OR SPERMAS? OR
SPERMATOB? OR SPERMATOC? OR SPERMATOG?)
L18
QUE (SPERMATOI? OR SPERMATOL? OR SPERMATOR? OR SPERMATOX? OR
SPERMATOZ? OR SPERMATU? OR SPERMI? OR SPERMO?)
L19
QUE (NEONAT? OR NEWBORN? OR DEVELOPMENT OR DEVELOPMENTAL?)
L20
QUE (ENDOCRIN? AND DISRUPT?)L21
QUE (ZYGOTE? OR CHILD OR CHILDREN OR ADOLESCEN? OR INFANT?)L22
QUE (WEAN? OR OFFSPRING OR AGE(W)FACTOR?)
L23
QUE (DERMAL? OR DERMIS OR SKIN OR EPIDERM? OR CUTANEOUS?)
L24
QUE (CARCINOG? OR COCARCINOG? OR CANCER? OR PRECANCER? OR
NEOPLAS?)PERFLUOROALKYLS

B-11
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
L25
L26
L27
L28
L29
L30

QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR CARCINOM?)
QUE (GENETOX? OR GENOTOX? OR MUTAGEN? OR GENETIC(W)TOXIC?)QUE (NEPHROTOX? OR HEPATOTOX?)QUE (ENDOCRIN? OR ESTROGEN? OR ANDROGEN? OR HORMON?)QUE (OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?)
QUE L5 OR L6 OR L7 OR L8 OR L9 OR L10 OR L11 OR L12 OR L13 OR
L14 OR L15 OR L16 OR L17 OR L18 OR L19 OR L20 OR L21 OR L22 OR
L23 OR L24 OR L25 OR L26 OR L27 OR L28 OR L29
L31
QUE (RAT OR RATS OR MOUSE OR MICE OR GUINEA(W)PIG? OR MURIDAE
OR DOG OR DOGS OR RABBIT? OR HAMSTER? OR PIG OR PIGS OR SWINE
OR PORCINE OR MONKEY? OR MACAQUE?)
L32
QUE (MARMOSET? OR FERRET? OR GERBIL? OR RODENT? OR LAGOMORPHA
OR BABOON? OR CANINE OR CAT OR CATS OR FELINE OR MURINE)L33
QUE L30 OR L31 OR L32
L34
QUE (NONHUMAN MAMMALS)/ORGN
L35
QUE L33 OR L34
L36
QUE (HUMAN OR HUMANS OR HOMINIDAE OR MAMMALS OR MAMMAL? OR
PRIMATES OR PRIMATE?)
L37
QUE L35 OR L36
L381318 SEA L4 AND L37
L391148 SEA L4 AND L30
L40
356 SEA L38 AND MEDLINE/FS
L41
297 SEA L38 AND BIOSIS/FS
L42
664 SEA L38 AND CAPLUS/FS
L43
1 SEA L38 NOT (MEDLINE/FS OR BIOSIS/FS OR CAPLUS/FS)
L44
931 DUP REM L40 L41 L43 L42 (387 DUPLICATES REMOVED)
L*** DEL 356 S L38 AND MEDLINE/FS
L*** DEL 356 S L38 AND MEDLINE/FS
L45
356 SEA L44
L*** DEL 297 S L38 AND BIOSIS/FS
L*** DEL 297 S L38 AND BIOSIS/FS
L46
190 SEA L44
L*** DEL 664 S L38 AND CAPLUS/FS
L*** DEL 664 S L38 AND CAPLUS/FS
L47
385 SEA L44
L48
575 SEA (L45 OR L46 OR L47) NOT MEDLINE/FS
D SCAN L48
09/19/2013

FILE 'TOXCENTER' ENTERED AT 09:10:51 ON 19 SEP 2013
L13993 SEA 335-67-1 OR 1763-23-1 OR 355-46-4 OR 2991-50-6 OR 2355-31-9
OR 335-76-2 OR 375-73-5 OR 375-85-9 OR 375-95-1 OR 754-91-6
OR 2058-94-8 OR 307-55-1 OR 375-22-4
L2
3966 SEA L1 NOT TSCATS/FS
L33782 SEA L2 NOT PATENT/DT
L42796 SEA L3 AND PY>2006
ACTIVATE TOXBROAD/Q
L5
QUE (CHRONIC OR IMMUNOTOX? OR NEUROTOX? OR TOXICOKIN? OR
BIOMARKER? OR NEUROLOG?)
L6
QUE (PHARMACOKIN? OR SUBCHRONIC OR PBPK OR EPIDEMIOLOGY/ST,CT)
L7
QUE (ACUTE OR SUBACUTE OR LD50 OR LC50)
L8QUE (TOXICITY OR ADVERSE OR POISONING)/ST,CT
L9
QUE (INHAL? OR PULMON? OR NASAL? OR LUNG? OR RESPIR?)
L10
QUE (VAPOR? OR VAPOUR? OR AEROSOL?)L11
QUE ((OCCUPATION? OR WORKPLACE? OR WORKER?) AND EXPOS?)
L12QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET? OR DRINKING(W)WATER?)
L13
QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR PERMISSIBLE))PERFLUOROALKYLS

B-12
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
L14
L15

QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?)
QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM? OROVUM?)L16
QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?)
L17
QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? ORTERATOGEN?)
L18
QUE (SPERM? OR NEONAT? OR NEWBORN? OR DEVELOPMENT OR
DEVELOPMEN
TAL?)
L19
QUE (ENDOCRIN? AND DISRUPT?)L20
QUE (ZYGOTE? OR CHILD OR CHILDREN OR ADOLESCEN? OR INFANT?)L21
QUE (WEAN? OR OFFSPRING OR AGE(W)FACTOR?)
L22
QUE (DERMAL? OR DERMIS OR SKIN OR EPIDERM? OR CUTANEOUS?)
L23
QUE (CARCINOG? OR COCARCINOG? OR CANCER? OR PRECANCER? OR
NEOPLAS?)
L24
QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR CARCINOM?)
L25
QUE (GENETOX? OR GENOTOX? OR MUTAGEN?)
L26
QUE GENETIC(W)TOXIC?
L27
QUE L5 OR L6 OR L7 OR L9 OR L10 OR L11 OR L12 OR L13 OR L14 OR
L15 OR L16 OR L17 OR L18 OR L19 OR L20 OR L21
L28
QUE L27 OR L22 OR L23 OR L24 OR L25 OR L26
L29
QUE L28 OR L8
L30
QUE NEPHROTOX? OR HEPATOTOX? OR ENDOCRIN? OR ESTROGEN? OR
ANDROGEN? OR HORMON?
L31
QUE L29 OR L30
L32
QUE RAT OR RATS OR MOUSE OR MICE OR GUINEA PIG OR MURIDAE OR
DOG OR DOGS OR RABBIT? OR HAMSTER? OR PIG OR PIGS OR SWINE OR
PORCINE OR GOAT OR GOATS OR SHEEP OR MONKEY? OR MACAQUE?
L33
QUE MARMOSET? OR FERRET? OR GERBIL? OR HAMSTER? OR RODENT? OR
LAGOMORPHA OR BABOON? OR BOVINE OR CANINE OR CAT OR CATS OR
FELINE OR PIGEON?
L34
QUE OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?
L35
QUE L31 OR L32 OR L33 OR L34
L36
QUE NONHUMAN MAMMALS/ORGN
L37
QUE L35 OR L36
L38
QUE HUMAN? OR HOMINIDAE OR MAMMAL? OR PRIMATE?
L39
QUE L37 OR L38
L40
2012 SEA L4 AND L39
L41
619 SEA L40 AND MEDLINE/FS
L42
417 SEA L40 AND BIOSIS/FS
L43
975 SEA L40 AND CAPLUS/FS
L44
1 SEA L40 NOT (MEDLINE/FS OR BIOSIS/FS OR CAPLUS/FS)
L45
1308 DUP REM L41 L42 L44 L43 (704 DUPLICATES REMOVED)
L*** DEL 619 S L40 AND MEDLINE/FS
L*** DEL 619 S L40 AND MEDLINE/FS
L46
619 SEA L45
L*** DEL 417 S L40 AND BIOSIS/FS
L*** DEL 417 S L40 AND BIOSIS/FS
L47
217 SEA L45
L*** DEL 975 S L40 AND CAPLUS/FS
L*** DEL 975 S L40 AND CAPLUS/FS
L48
471 SEA L45
L*** DEL
1 S L40 NOT (MEDLINE/FS OR BIOSIS/FS OR CAPLUS/FS)
L*** DEL
1 S L40 NOT (MEDLINE/FS OR BIOSIS/FS OR CAPLUS/FS)
L49
1 SEA L45
L50
689 SEA (L46 OR L47 OR L48 OR L49) NOT MEDLINE/FSPERFLUOROALKYLS

B-13
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
L51
L52
L53
L54
L55
L56
ToxLine9/11/2018

SAVE TEMP L50 PERFLUOROALKYLS/A PFOA/A
217 SEA L50 AND BIOSIS/FS
471 SEA L50 AND CAPLUS/FS
220 SEA L52 AND 4-?/CC
1 SEA L50 NOT (MEDLINE/FS OR BIOSIS/FS OR CAPLUS/FS)
438 SEA L51 OR L53 OR L54
689 SEA L55 OR L52
D SCAN L55( 1763-23-1 [rn] OR 2058-94-8 [rn] OR 2355-31-9 [rn] OR 2991-50-6 [rn] OR 307-55-1 [rn] OR 33567-1 [rn] OR 335-76-2 [rn] OR 355-46-4 [rn] OR 375-22-4 [rn] OR 375-73-5 [rn] OR 375-85-9 [rn] OR
375-95-1 [rn] OR 754-91-6 [rn] ) AND 2015:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS[org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR HMTC[org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] ORPESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org] AND NOT pubdart [org]( "perfluoro n heptanoic acid" OR "perfluoro n nonanoic acid" OR "perfluoro n undecanoic acid" OR"perfluorobutane sulfonic acid" OR "perfluorobutanesulfonic acid" OR "perfluorobutanoic acid" OR"perfluorobutyric acid" OR "perfluorocaprylic acid" OR "perfluoroctanoic acid" OR"perfluoroctylsulfonamide" OR "perfluorodecanoic acid" OR "perfluorododecanoic acid" OR"perfluorododecanoic acid " OR "perfluoroheptanecarboxylic acid" OR "perfluoroheptanoic acid" OR"perfluorohexane sulfonic acid" OR "perfluorohexane 1 sulphonic acid" OR"perfluorohexanesulfonate" OR "perfluorohexanesulfonic acid" OR "perfluorolauric acid" OR"perfluorononan 1 oic acid" OR "perfluorononanoic acid" OR "perfluorooctane sulfonamide" OR"perfluorooctane sulfonate" OR "perfluorooctane sulfonic acid " OR "perfluorooctane sulphonic acid"
OR "perfluorooctanesulfonamide" OR "perfluorooctanesulfonate" OR "perfluorooctanesulfonic acid"
OR "perfluorooctanesulfonic acid amide" OR "perfluorooctanoic acid" OR "perfluorooctylsulfonicacid" OR "perfluoropropanecarboxylic acid" OR "perfluoroundecanoic acid" OR "pfbus" OR "pfda"
OR "pfdea" OR "pfdoa" OR "pfhpa" OR "pfhs cpd" OR "pfhxs" OR "pfna" OR "pfoa" OR "pfos" OR"pfsoa" OR "pfua" OR "tricosafluorododecanoic acid" OR "tridecafluoro 1 heptanoic acid" OR"tridecafluoroheptanoic acid" ) AND 2015:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS[org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR HMTC[org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] ORPESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org] AND NOT pubdart [org]( "1 1 2 2 3 3 4 4 4 nonafluoro 1 butanesulfonic acid" OR "1 1 2 2 3 3 4 4 4 nonafluorobutane 1sulphonic acid" OR "1 1 2 2 3 3 4 4 5 5 6 6 6 tridecafluorohexane 1 sulfonic acid" OR "1
perfluorobutanesulfonic acid" OR "2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 9 heptadecafluoro nonanoic acid"OR "2 ( n ethyl perfluorooctane sulfonamido ) acetic acid" OR "2 ( n methyl perfluorooctane
sulfonamido ) acetic acid" OR "c11 pfa" OR "et pfosa acoh" OR "glycine n ethyl n ( ( 1 1 2 2 3 3 4 4 5
5 6 6 7 7 8 8 8 heptadecafluorooctyl ) sulfonyl ) " OR "henicosafluoroundecanoic acid" OR"heptadecafluoro 1 octane sulfonic acid" OR "heptadecafluoro 1 octanesulfonic acid" OR"heptadecafluorooctane sulfonic acid" OR "heptadecafluorooctane 1 sulphonic acid" OR"heptadecafluorooctanesulphonamide" OR "heptafluoro 1 butanoic acid" OR "heptafluorobutanoic
acid" OR "heptafluorobutyric acid" OR "me pfosa acoh" OR "n ethyl n ( ( heptadecafluorooctyl )sulphonyl ) glycine" OR "ndfda" OR "nonadecafluoro n decanoic acid" OR "nonadecafluorodecanoic
acid" OR "nonafluoro 1 butanesulfonic acid" OR "nonafluorobutanesulfonic acid" OR"pentadecafluoro 1 octanoic acid" OR "pentadecafluoro n octanoic acid" OR"pentadecafluorooctanoic acid" OR "pentyl perfluorobutanoate" OR "perfluoro n decanoic acid" )AND 2015:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC
[org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR
RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB[org] ) AND NOT PubMed [org] AND NOT pubdart [org]( 307-24-4 [rn] OR 3825-26-1 [rn] OR "hexanoic acid 2 2 3 3 4 4 5 5 6 6 6-undecafluoro-" OR"hexanoic acid undecafluoro-" OR "perfluorohexanoic acid" OR "undecafluoro-1-hexanoic acid" OR"undecafluorohexanoic acid" OR "ammonium pentadecafluorooctanoate" OR "ammonium

PERFLUOROALKYLS

B-14
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
perfluorocaprilate" OR "ammonium perfluorocaprylate" OR "ammonium perfluorooctanoate" OR "fc
143" OR "octanoic acid 2 2 3 3 4 4 5 5 6 6 7 7 8 8 8-pentadecafluoro- ammonium salt" OR "octanoic
acid pentadecafluoro- ammonium salt" OR "pentadecafluoro-1-octanoic acid ammonium salt" OR"pentadecafluorooctanoic acid ammonium salt" OR "perfluoroammonium octanoate" OR"perfluorooctanoic acid ammonium salt" ) AND 1900:2017 [yr] AND ( ANEUPL [org] OR BIOSIS [org]
OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR
HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] ORPESTAB [org] OR PPBIB [org] ) AND NOT PubMed [org] AND NOT pubdart [org]05/24/2016((("C11-PFA" OR "et-pfosa-acoh" OR "Henicosafluoroundecanoic acid" OR "heptadecafluoro-1octane sulfonic acid" OR "Heptadecafluoro-1-octanesulfonic acid" OR "heptadecafluorooctane
sulfonic acid" OR "Heptadecafluorooctane-1-sulphonic acid" OR "Heptadecafluorooctane-1-sulphonicacid1-Perfluorooctanesulfonic acid" OR "Heptadecafluorooctanesulphonamide" OR "Heptafluoro-1butanoic acid" OR "Heptafluorobutanoic acid" OR "Heptafluorobutyric acid" OR "me-pfosa-acoh" OR"N-Ethyl-N-((heptadecafluorooctyl)sulphonyl)glycine" OR "Ndfda" OR "Nonadecafluoro-n-decanoic
acid" OR "Nonadecafluorodecanoic acid" OR "Nonafluoro-1-butanesulfonic acid" OR"Nonafluorobutanesulfonic acid" OR "Pentadecafluoro-1-octanoic acid" OR "Pentadecafluoro-noctanoic acid" OR "Pentadecafluorooctanoic acid" OR "Pentyl perfluorobutanoate" OR "Perfluoro-ndecanoic acid" OR "Perfluoro-n-heptanoic acid" OR "Perfluoro-n-nonanoic acid" OR "Perfluoro-nundecanoic acid" OR "Perfluorobutane sulfonic acid" OR "Perfluorobutanesulfonic acid" OR"Perfluorobutanoic acid" OR "Perfluorobutyric acid" OR "Perfluorocaprylic acid" OR "Perfluoroctanoic
acid" OR "Perfluoroctylsulfonamide" OR "Perfluorodecanoic acid" OR "Perfluorododecanoic acid "OR "Perfluorododecanoic acid" OR "Perfluoroheptanecarboxylic acid" OR "Perfluoroheptanoic acid"
OR "Perfluorohexane sulfonic acid" OR "Perfluorohexane-1-sulphonic acid" OR"perfluorohexanesulfonate" OR "perfluorohexanesulfonic acid" OR "Perfluorolauric acid" OR"Perfluorononan-1-oic acid" OR "Perfluorononanoic acid" OR "Perfluorooctane sulfonamide" OR"Perfluorooctane sulfonate" OR "Perfluorooctane sulfonic acid " OR "perfluorooctane sulphonic acid"
OR "Perfluorooctanesulfonamide" OR "Perfluorooctanesulfonate" OR "Perfluorooctanesulfonic acidamide" OR "perfluorooctanesulfonic acid" OR "Perfluorooctanoic acid" OR "Perfluorooctylsulfonicacid" OR "Perfluoropropanecarboxylic acid" OR "Perfluoroundecanoic acid" OR "pfbus" OR "PFDA"
OR "pfdea" OR "pfdoa" OR "Pfhpa" OR "PFHS cpd" OR "pfhxs" OR "pfna" OR "PFOA" OR "PFOS"
OR "pfsoa" OR "Pfua" OR "Tricosafluorododecanoic acid" OR "Tridecafluoro-1-heptanoic acid" OR"Tridecafluoroheptanoic acid") AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org]
OR EMIC [org] OR EPIDEM [org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org]
OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) OR ("176323-1" OR "2058-94-8" OR "2355-31-9" OR "2991-50-6" OR "307-55-1" OR "335-67-1" OR "335-76-2"
OR "355-46-4" OR "375-22-4" OR "375-73-5" OR "375-85-9" OR "375-95-1" OR "754-91-6") AND (ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR
HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org]
OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ))) AND 2013:2016 [yr]("1,1,2,2,3,3,4,4,4-Nonafluoro-1-butanesulfonic acid" OR "1,1,2,2,3,3,4,4,4-Nonafluorobutane-1sulphonic acid" OR "1,1,2,2,3,3,4,4,5,5,6,6,6-Tridecafluorohexane-1-sulfonic acid" OR "1Perfluorobutanesulfonic acid" OR "2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-Nonanoic acid"OR "2-(N-Ethyl-perfluorooctane sulfonamido) acetic acid" OR "2-(N-Methyl-perfluorooctane
sulfonamido) acetic acid" OR "Glycine, N-ethyl-N-((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8heptadecafluorooctyl)sulfonyl)-") AND 2013:2016 [yr] AND ( ANEUPL [org] OR BIOSIS [org] OR CIS[org] OR DART [org] OR EMIC [org] OR EPIDEM [org] OR HEEP [org] OR HMTC [org] OR IPA [org]
OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB[org] )

09/18/2013( "perfluorooctanoic acid" OR "pentadecafluoro 1 octanoic acid" OR "pentadecafluoro n octanoic
acid" OR "pentadecafluorooctanoic acid" OR "perfluorocaprylic acid" OR "perfluoroctanoic acid" OR"perfluoroheptanecarboxylic acid" OR "perfluorooctanoic acid" OR "pentadecafluorooctanoic acid"
OR "perfluorooctanoic acid" OR "perfluorooctane sulfonic acid " OR "heptadecafluoro 1
octanesulfonic acid" OR "heptadecafluoro 1 octane sulfonic acid" OR "heptadecafluorooctane 1sulphonic acid" OR "heptadecafluorooctane sulfonic acid" OR "perfluorooctane sulfonate" OR"perfluorooctylsulfonic acid" OR "perfluorooctane sulphonic acid" OR "perfluorooctanesulfonic acid"PERFLUOROALKYLS

B-15
APPENDIX B

Table B-2. Database Query Strings Post Public Comment Searches
Databasesearch date Query string
OR "perfluorooctanesulfonate" OR "heptadecafluorooctane 1 sulphonic acid1 perfluorooctanesulfonicacid" OR "perfluorohexane sulfonic acid pfhxs " OR "perfluorohexanesulfonic acid" OR"perfluorohexanesulfonate" OR "perfluorohexane 1 sulphonic acid" OR "pfhs cpd" OR "2 ( n ethyl
perfluorooctane sulfonamido ) acetic acid" OR "et pfosa acoh" OR "n ethyl n ( ( heptadecafluorooctyl) sulphonyl ) glycine" OR "2 ( n methyl perfluorooctane sulfonamido ) acetic acid" OR "me pfosaacoh" OR "perfluorodecanoic acid" OR "nonadecafluoro n decanoic acid" OR"nonadecafluorodecanoic acid" OR "perfluoro n decanoic acid" OR "perfluoro n decanoic acid" OR"perfluorodecanoic acid" OR "nonadecafluorodecanoic acid" OR "perfluoro n decanoic acid" OR"perfluorobutane sulfonic acid" OR "perfluorobutanesulfonic acid" OR OR "pentyl perfluorobutanoate"
OR "nonafluoro 1 butanesulfonic acid" OR "perfluoroheptanoic acid" OR "tridecafluoro 1 heptanoic
acid" OR "perfluoro n heptanoic acid" OR "perfluoroheptanoic acid" OR "tridecafluoroheptanoic acid"
OR "perfluorononanoic acid" OR "perfluoro n nonanoic acid" OR "perfluorononan 1 oic acid" OR"perfluorooctane sulfonamide" OR "perfluorooctanesulfonamide" OR "perfluoroctylsulfonamide" OR"perfluorooctanesulfonic acid amide" OR "heptadecafluorooctanesulphonamide" OR"perfluoroundecanoic acid" OR "perfluoro n undecanoic acid" OR "hennone ) AND 2007:2013 [yr]AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR NIH RePORTER [org] OR DART [org] OR
EMIC [org] OR EPIDEM [org] OR FEDRIP [org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR
RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB[org] ) NOT PubMed [org] NOT pubdart [org]

Table B-3. Strategies to Augment the Literature Search
SourceQuery and number screened when available

TSCATSa
9/11/2018
5/23/2016
9/18/2013

Compounds searched: 1763-23-1; 2058-94-8; 2355-31-9; 2991-50-6; 307-55-1; 335-67-1; 33576-2; 355-46-4; 375-22-4; 375-73-5; 375-85-9; 375-95-1; 754-91-6; 307-24-4; 3825-26-1

NTP
9/11/2018

Content types: Reports & Publications; Systematic Reviews; ROC Profiles, Reviews or
Candidates; Testing Status"1763-23-1" "2058-94-8" "2355-31-9" "2991-50-6" "307-55-1" "335-67-1" "335-76-2" "355-46-4""375-22-4" "375-73-5" "375-85-9" "375-95-1" "754-91-6""Henicosafluoroundecanoic acid" "heptadecafluoro-1-octane sulfonic acid" "Heptadecafluoro-1octanesulfonic acid" "heptadecafluorooctane sulfonic acid" "Heptadecafluorooctane-1-sulphonicacid" "Heptadecafluorooctanesulphonamide" "Heptafluoro-1-butanoic acid" "Heptafluorobutanoic
acid" "Heptafluorobutyric acid" "me-pfosa-acoh" "N-Ethyl-N((heptadecafluorooctyl)sulphonyl)glycine" "Ndfda" "Nonadecafluoro-n-decanoic acid""Nonadecafluorodecanoic acid" "Nonafluoro-1-butanesulfonic acid" "Nonafluorobutanesulfonicacid" "Pentadecafluoro-1-octanoic acid" "Pentadecafluoro-n-octanoic acid""Pentadecafluorooctanoic acid" "Pentyl perfluorobutanoate" "Perfluoro-n-decanoic acid""Perfluoro-n-heptanoic acid" "Perfluoro-n-nonanoic acid" "Perfluoro-n-undecanoic acid""Perfluorobutane sulfonic acid" "Perfluorobutanesulfonic acid" "Perfluorobutanoic acid""Perfluorobutyric acid" "Perfluorocaprylic acid" "Perfluoroctanoic acid" "Perfluoroctylsulfonamide""Perfluorodecanoic acid" "Perfluorododecanoic acid" "Perfluorododecanoic acid ""Perfluoroheptanecarboxylic acid" "Perfluoroheptanoic acid" "Perfluorohexane sulfonic acid""Perfluorohexane-1-sulphonic acid" "perfluorohexanesulfonate" "perfluorohexanesulfonic acid""Perfluorolauric acid" "Perfluorononan-1-oic acid" "Perfluorononanoic acid" "Perfluorooctane
sulfonamide" "Perfluorooctane sulfonate" "Perfluorooctane sulfonic acid " "perfluorooctane
sulphonic acid" "Perfluorooctanesulfonamide" "Perfluorooctanesulfonate""perfluorooctanesulfonic acid" "Perfluorooctanesulfonic acid amide" "Perfluorooctanoic acid""Perfluorooctylsulfonic acid" "Perfluoropropanecarboxylic acid" "Perfluoroundecanoic acid""pfbus" "PFDA" "pfdea" "pfdoa" "Pfhpa" "PFHS cpd" "pfhxs" "pfna" "PFOA" "PFOS" "pfsoa"

PERFLUOROALKYLS

B-16
APPENDIX B

Table B-3. Strategies to Augment the Literature Search
Source

5/23/2016

Query and number screened when available"Pfua" "Tricosafluorododecanoic acid" "Tridecafluoro-1-heptanoic acid" "Tridecafluoroheptanoicacid""307-24-4" "3825-26-1""Perfluorohexanoic acid" "Undecafluoro-1-hexanoic acid" "Undecafluorohexanoic acid""Ammonium pentadecafluorooctanoate" "Ammonium perfluorocaprilate" "Ammonium
perfluorocaprylate" "Ammonium perfluorooctanoate" "FC 143" "Octanoic acid, pentadecafluoro-,ammonium salt" "Pentadecafluoro-1-octanoic acid, ammonium salt" "Pentadecafluorooctanoic
acid, ammonium salt" "Perfluoroammonium octanoate" "Perfluorooctanoic acid, ammonium salt""335-67-1" OR "1763-23-1" OR "355-46-4" OR "2991-50-6" OR "2355-31-9" OR "335-76-2" OR"375-73-5" OR "375-85-9" OR "375-95-1" OR "754-91-6" OR "2058-94-8" OR "307-55-1" OR"375-22-4" OR "Perfluorooctanoic acid" OR "PFOA" OR "Pentadecafluoro-1-octanoic acid" OR"Pentadecafluorooctanoic acid" OR "Perfluoroctanoic acid" OR "Perfluorooctane sulfonic acid"OR "Heptadecafluorooctane-1-sulphonic acid" OR "PFOS" OR "Perfluorooctane sulfonate" OR"Perfluorooctylsulfonic acid" OR "perfluorooctane sulphonic acid" OR "perfluorooctanesulfonicacid" OR "Perfluorooctanesulfonate" OR "Heptadecafluorooctane-1-sulphonic acid" OR"1,1,2,2,3,3,4,4,5,5,6,6,6-Tridecafluorohexane-1-sulfonic acid" OR "Perfluorohexane sulfonicacid" OR "Perfluorohexane-1-sulphonic acid" OR "perfluorohexanesulfonate" OR"perfluorohexanesulfonic acid" OR "pfhxs" OR "Ndfda" OR "Nonadecafluorodecanoic acid" OR"Nonadecafluoro-n-decanoic acid" OR "Perfluorodecanoic acid" OR "Perfluoro-n-decanoic acid"
OR "PFDA" OR "pfdea" OR "1-Perfluorobutanesulfonic acid" OR "Nonafluoro-1-butanesulfonicacid" OR "Perfluorobutane sulfonic acid" OR "Perfluorobutanesulfonic acid" OR "pfbus" OR"Perfluorononanoic acid" OR "pfna" OR "Perfluorooctanesulfonamide" OR "Perfluorododecanoic
acid" OR "pfdoa" OR "Heptafluorobutyric acid" OR "Perfluorobutanoic acid" OR "Perfluorobutyricacid"
Screened: 146 hits
"1,1,2,2,3,3,4,4,4-Nonafluoro-1-butanesulfonic acid" OR "1,1,2,2,3,3,4,4,4-Nonafluorobutane-1sulphonic acid" OR "Nonafluorobutanesulfonic acid" OR "Pentyl perfluorobutanoate" OR"Pentadecafluoro-n-octanoic acid" OR "Perfluorocaprylic acid" OR "Perfluoroheptanecarboxylic
acid" OR "Heptadecafluoro-1-octanesulfonic acid" OR "heptadecafluoro-1-octane sulfonic acid"OR "heptadecafluorooctane sulfonic acid" OR "1-Perfluorooctanesulfonic acid" OR "PFHS cpd"
OR "2-(N-Ethyl-perfluorooctane sulfonamido) acetic acid" OR "et-pfosa-acoh" OR "N-Ethyl-N((heptadecafluorooctyl)sulphonyl)glycine" OR "Glycine, N-ethyl-N((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctyl)sulfonyl)-" OR "2-(N-Methylperfluorooctane sulfonamido) acetic acid" OR "me-pfosa-acoh" OR "Perfluoroheptanoic acid" OR"Perfluoro-n-heptanoic acid" OR "Pfhpa" OR "Tridecafluoro-1-heptanoic acid" OR"Tridecafluoroheptanoic acid" OR "2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluoro-Nonanoic
acid" OR "Perfluoro-n-nonanoic acid" OR "Perfluorononan-1-oic acid" OR"Heptadecafluorooctanesulphonamide" OR "Perfluoroctylsulfonamide" OR "Perfluorooctane
sulfonamide" OR "Perfluorooctanesulfonic acid amide" OR "Pfsoa" OR "C11-PFA" OR"Henicosafluoroundecanoic acid" OR "Perfluoro-n-undecanoic acid" OR "Perfluoroundecanoic
acid" OR "Pfua" OR "Perfluorolauric acid" OR "Tricosafluorododecanoic acid" OR "Heptafluoro1-butanoic acid" OR "Heptafluorobutanoic acid" OR "Perfluoropropanecarboxylic acid"
Screened: 0 hits

PERFLUOROALKYLS

B-17
APPENDIX B

Table B-3. Strategies to Augment the Literature Search
Source
NIH RePORTER
2/28/2017

Query and number screened when available
Text Search: "1,1,2,2,3,3,4,4,4-Nonafluoro-1-butanesulfonic acid" OR "1,1,2,2,3,3,4,4,4Nonafluorobutane-1-sulphonic acid" OR "1,1,2,2,3,3,4,4,5,5,6,6,6-Tridecafluorohexane-1sulfonic acid" OR "1-Perfluorobutanesulfonic acid" OR "2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9heptadecafluoro-Nonanoic acid" OR "2-(N-Ethyl-perfluorooctane sulfonamido) acetic acid" OR"2-(N-Methyl-perfluorooctane sulfonamido) acetic acid" OR "C11-PFA" OR "et-pfosa-acoh" OR"Glycine, N-ethyl-N-((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluorooctyl)sulfonyl)-" OR"Henicosafluoroundecanoic acid" OR "heptadecafluoro-1-octane sulfonic acid" OR"Heptadecafluoro-1-octanesulfonic acid" OR "heptadecafluorooctane sulfonic acid" OR"Heptadecafluorooctane-1-sulphonic acid" OR "Heptadecafluorooctanesulphonamide" OR"Heptafluoro-1-butanoic acid" OR "Heptafluorobutanoic acid" OR "Heptafluorobutyric acid" OR"me-pfosa-acoh" OR "N-Ethyl-N-((heptadecafluorooctyl)sulphonyl)glycine" OR "Ndfda" OR"Nonadecafluoro-n-decanoic acid" OR "Nonadecafluorodecanoic acid" OR "Nonafluoro-1butanesulfonic acid" OR "Nonafluorobutanesulfonic acid" OR "Pentadecafluoro-1-octanoic acid"
OR "Pentadecafluoro-n-octanoic acid" OR "Pentadecafluorooctanoic acid" OR "Pentyl
perfluorobutanoate" OR "Perfluoro-n-decanoic acid" OR "Perfluoro-n-heptanoic acid" OR"Perfluoro-n-nonanoic acid" OR "Perfluoro-n-undecanoic acid" OR "Perfluorobutane sulfonicacid" OR "Perfluorobutanesulfonic acid" OR "Perfluorobutanoic acid" OR "Perfluorobutyric acid"
OR "Perfluorocaprylic acid" OR "Perfluoroctanoic acid" OR "Perfluoroctylsulfonamide" OR"Perfluorodecanoic acid" OR "Perfluorododecanoic acid" OR "Perfluorododecanoic acid" OR"Perfluoroheptanecarboxylic acid" OR "Perfluoroheptanoic acid" OR "Perfluorohexane sulfonicacid" OR "Perfluorohexane-1-sulphonic acid" OR "perfluorohexanesulfonate" OR"perfluorohexanesulfonic acid" OR "Perfluorolauric acid" OR "Perfluorononan-1-oic acid" OR"Perfluorononanoic acid" OR "Perfluorooctane sulfonamide" OR "Perfluorooctane sulfonate" OR"Perfluorooctane sulfonic acid" OR "perfluorooctane sulphonic acid" OR"Perfluorooctanesulfonamide" OR "Perfluorooctanesulfonate" OR "Perfluorooctanesulfonic acidamide" OR "perfluorooctanesulfonic acid" OR "Perfluorooctanoic acid" OR"Perfluorooctylsulfonic acid" OR "Perfluoropropanecarboxylic acid" OR "Perfluoroundecanoic
acid" OR "pfbus" OR "PFDA" OR "pfdea" OR "pfdoa" OR "Pfhpa" OR "PFHS cpd" OR "pfhxs"
OR "pfna" OR "PFOA" OR "PFOS" OR "pfsoa" OR "Pfua" OR "Tricosafluorododecanoic acid"OR "Tridecafluoro-1-heptanoic acid" OR "Tridecafluoroheptanoic acid" (Advanced), Search in:
Projects Admin IC: All, Fiscal Year: Active Projects, 2017, 2016, 2015, 2014, 2013, 2012
Screened: 80

4/7/2014

Compounds searched: 335-67-1; 1763-23-1; 355-46-4; 2991-50-6; 2355-31-9; 335-76-2; 375-735; 375-85-9; 375-95-1; 754-91-6; 2058-94-8; 307-55-1; 375-22-4
Screened: 82 hits

Other

Identified throughout the assessment process

aSeveral versions of the TSCATS database were searched, as needed, by CASRN including TSCATS1 via Toxline(no date limit), TSCATS2 via https://yosemite.epa.gov/oppts/epatscat8.nsf/ReportSearch?OpenForm (date restricted
by EPA receipt date), and TSCATS via CDAT (date restricted by ‘Mail Received Date Range’), as well as google forrecent TSCA submissions.

The September 2018 results were:• Number of records identified from PubMed, TOXLINE, and TOXCENTER (after duplicate
removal): 941• Number of records identified from other strategies: 153• Total number of records to undergo literature screening: 1,094

PERFLUOROALKYLS

B-18
APPENDIX B

B.1.2 Literature Screening
A two-step process was used to screen the literature search to identify relevant studies on perfluoroalkyls:••

Title and abstract screen
Full text screen

Title and Abstract Screen. Within the reference library, titles and abstracts were screened manually forrelevance. Studies that were considered relevant (see Table B-1 for inclusion criteria) were moved to thesecond step of the literature screening process. Studies were excluded when the title and abstract clearly
indicated that the study was not relevant to the toxicological profile.
••Number of titles and abstracts screened: 1,094
Number of studies considered relevant and moved to the next step: 1,408

Full Text Screen. The second step in the literature screening process was a full text review of individual
studies considered relevant in the title and abstract screen step. Each study was reviewed to determine
whether it was relevant for inclusion in the toxicological profile.
••Number of studies undergoing full text review: 1,408
Total number of health effects studies cited in the profile: 452

A summary of the results of the literature search and screening is presented in Figure B-1.

PERFLUOROALKYLS

B-19
APPENDIX B

Figure B-1. September 2018 Literature Search Results and Screen for
Perfluoroalkyls

PERFLUOROALKYLS

C-1

APPENDIX C. USER'S GUIDE
Chapter 1. Relevance to Public HealthThis chapter provides an overview of U.S. exposures, a summary of health effects based on evaluations ofexisting toxicologic, epidemiologic, and toxicokinetic information, and an overview of the minimal risk
levels. This is designed to present interpretive, weight-of-evidence discussions for human healthendpoints by addressing the following questions:
1. What effects are known to occur in humans?
2. What effects observed in animals are likely to be of concern to humans?
3. What exposure conditions are likely to be of concern to humans, especially around hazardous
waste sites?
Minimal Risk Levels (MRLs)
Where sufficient toxicologic information is available, ATSDR derives MRLs for inhalation and oralroutes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are notmeant to support regulatory action, but to acquaint health professionals with exposure levels at which
adverse health effects are not expected to occur in humans.
MRLs should help physicians and public health officials determine the safety of a community living neara hazardous substance emission, given the concentration of a contaminant in air or the estimated daily
dose in water. MRLs are based largely on toxicological studies in animals and on reports of humanoccupational exposure.
MRL users should be familiar with the toxicologic information on which the number is based.
Section 1.2, Summary of Health Effects, contains basic information known about the substance. Other
sections, such as Section 3.2 Children and Other Populations that are Unusually Susceptible andSection 3.4 Interactions with Other Substances, provide important supplemental information.
MRL users should also understand the MRL derivation methodology. MRLs are derived using amodified version of the risk assessment methodology that the Environmental Protection Agency (EPA)
provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure.
To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement,
represents the most sensitive human health effect for a given exposure route and duration. ATSDR
cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available
for all potential systemic, neurological, and developmental effects. If this information and reliable
quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive
species (when information from multiple species is available) with the highest no-observed-adverse-effectlevel (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, alowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factorof 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability toprotect sensitive subpopulations (people who are most susceptible to the health effects caused by thesubstance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL,
these individual uncertainty factors are multiplied together. The product is then divided into theinhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a

PERFLUOROALKYLS

C-2
APPENDIX C

substance-specific MRL are provided in the footnotes of the levels of significant exposure (LSE) tables
that are provided in Chapter 2. Detailed discussions of the MRLs are presented in Appendix A.
Chapter 2. Health Effects
Tables and Figures for Levels of Significant Exposure (LSE)
Tables and figures are used to summarize health effects and illustrate graphically levels of exposure
associated with those effects. These levels cover health effects observed at increasing doseconcentrations and durations, differences in response by species and MRLs to humans for noncancer
endpoints. The LSE tables and figures can be used for a quick review of the health effects and to locate
data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction
with the text. All entries in these tables and figures represent studies that provide reliable, quantitative
estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs).
The legends presented below demonstrate the application of these tables and figures. Representative
examples of LSE tables and figures follow. The numbers in the left column of the legends correspond to
the numbers in the example table and figure.
TABLE LEGEND
See Sample LSE Table (page C-5)
(1)

Route of exposure. One of the first considerations when reviewing the toxicity of a substanceusing these tables and figures should be the relevant and appropriate route of exposure.
Typically, when sufficient data exist, three LSE tables and two LSE figures are presented in the
document. The three LSE tables present data on the three principal routes of exposure(i.e., inhalation, oral, and dermal). LSE figures are limited to the inhalation and oral routes. Not
all substances will have data on each route of exposure and will not, therefore, have all five of thetables and figures. Profiles with more than one chemical may have more LSE tables and figures.

(2)

Exposure period. Three exposure periods—acute (<15 days), intermediate (15–364 days), andchronic (≥365 days)—are presented within each relevant route of exposure. In this example, twooral studies of chronic-duration exposure are reported. For quick reference to health effects
occurring from a known length of exposure, locate the applicable exposure period within the LSE
table and figure.

(3)

Figure key. Each key number in the LSE table links study information to one or more data points
using the same key number in the corresponding LSE figure. In this example, the study
represented by key number 51 identified NOAELs and less serious LOAELs (also see the three"51R" data points in sample LSE Figure 2-X).

(4)

Species (strain) No./group. The test species (and strain), whether animal or human, are identified
in this column. The column also contains information on the number of subjects and sex pergroup. Chapter 1, Relevance to Public Health, covers the relevance of animal data to human
toxicity and Section 3.1, Toxicokinetics, contains any available information on comparative
toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated
to equivalent human doses to derive an MRL.

(5)

Exposure parameters/doses. The duration of the study and exposure regimens are provided inthese columns. This permits comparison of NOAELs and LOAELs from different studies. In
this case (key number 51), rats were orally exposed to “Chemical X” via feed for 2 years. For aPERFLUOROALKYLS

C-3
APPENDIX C

more complete review of the dosing regimen, refer to the appropriate sections of the text or theoriginal reference paper (i.e., Aida et al. 1992).
(6)

Parameters monitored. This column lists the parameters used to assess health effects. Parameters
monitored could include serum (blood) chemistry (BC), behavioral (BH), biochemical changes(BI), body weight (BW), clinical signs (CS), developmental toxicity (DX), enzyme activity (EA),
food intake (FI), fetal toxicity (FX), gross necropsy (GN), hematology (HE), histopathology(HP), lethality (LE), maternal toxicity (MX), organ function (OF), ophthalmology (OP), organ
weight (OW), teratogenicity (TG), urinalysis (UR), and water intake (WI).

(7)

Endpoint. This column lists the endpoint examined. The major categories of health endpoints
included in LSE tables and figures are death, body weight, respiratory, cardiovascular,
gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal, ocular, endocrine,
immunological, neurological, reproductive, developmental, other noncancer, and cancer. "Other
noncancer" refers to any effect (e.g., alterations in blood glucose levels) not covered in thesesystems. In the example of key number 51, three endpoints (body weight, hematological, andhepatic) were investigated.

(8)

NOAEL. A NOAEL is the highest exposure level at which no adverse effects were seen in theorgan system studied. The body weight effect reported in key number 51 is a NOAEL at
25.5 mg/kg/day. NOAELs are not reported for cancer and death; with the exception of these two
endpoints, this field is left blank if no NOAEL was identified in the study.

(9)

LOAEL. A LOAEL is the lowest dose used in the study that caused an adverse health effect.
LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help
readers identify the levels of exposure at which adverse health effects first appear and thegradation of effects with increasing dose. A brief description of the specific endpoint used toquantify the adverse effect accompanies the LOAEL. Key number 51 reports a less serious
LOAEL of 6.1 mg/kg/day for the hepatic system, which was used to derive a chronic exposure,oral MRL of 0.008 mg/kg/day (see footnote "c"). MRLs are not derived from serious LOAELs.
A cancer effect level (CEL) is the lowest exposure level associated with the onset ofcarcinogenesis in experimental or epidemiologic studies. CELs are always considered serious
effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may reportdoses not causing measurable cancer increases. If no LOAEL/CEL values were identified in the
study, this field is left blank.

(10)

Reference. The complete reference citation is provided in Chapter 8 of the profile.

(11)

Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are foundin the footnotes. For example, footnote "c" indicates that the LOAEL of 6.1 mg/kg/day in key
number 51 was used to derive an oral MRL of 0.008 mg/kg/day.

FIGURE LEGEND
See Sample LSE Figure (page C-6)
LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help thereader quickly compare health effects according to exposure concentrations for particular exposure
periods.
(13)

Exposure period. The same exposure periods appear as in the LSE table. In this example, healtheffects observed within the chronic exposure period are illustrated.

PERFLUOROALKYLS

C-4
APPENDIX C(14)Endpoint. These are the categories of health effects for which reliable quantitative data exist.
The same health effect endpoints appear in the LSE table.

(15)

Levels of exposure. Concentrations or doses for each health effect in the LSE tables aregraphically displayed in the LSE figures. Exposure concentration or dose is measured on the log
scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in
mg/kg/day.

(16)

LOAEL. In this example, the half-shaded circle that is designated 51R identifies a LOAEL
critical endpoint in the rat upon which a chronic oral exposure MRL is based. The key number
51 corresponds to the entry in the LSE table. The dashed descending arrow indicates theextrapolation from the exposure level of 6.1 mg/kg/day (see entry 51 in the sample LSE table) tothe MRL of 0.008 mg/kg/day (see footnote "c" in the sample LSE table).

(17)

CEL. Key number 59R is one of studies for which CELs were derived. The diamond symbolrefers to a CEL for the test species (rat). The number 59 corresponds to the entry in the LSE
table.

(18)

Key to LSE figure. The key provides the abbreviations and symbols used in the figure.

PERFLUOROALKYLS

C-5
APPENDIX BPERFLUOROALKYLS

C-6
APPENDIX CPERFLUOROALKYLS

D-1

APPENDIX D. QUICK REFERENCE FOR HEALTH CARE PROVIDERS
Toxicological Profiles are a unique compilation of toxicological information on a given hazardous
substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretationof available toxicologic and epidemiologic information on a substance. Health care providers treating
patients potentially exposed to hazardous substances may find the following information helpful for fastanswers to often-asked questions.

Primary Chapters/Sections of Interest
Chapter 1: Relevance to Public Health: The Relevance to Public Health Section provides an overview
of exposure and health effects and evaluates, interprets, and assesses the significance of toxicity
data to human health. A table listing minimal risk levels (MRLs) is also included in this chapter.
Chapter 2: Health Effects: Specific health effects identified in both human and animal studies arereported by type of health effect (e.g., death, hepatic, renal, immune, reproductive), route of
exposure (e.g., inhalation, oral, dermal), and length of exposure (e.g., acute, intermediate, andchronic).
NOTE: Not all health effects reported in this section are necessarily observed in the clinicalsetting.
Pediatrics:
Section 3.2
Section 3.3

Children and Other Populations that are Unusually Susceptible
Biomarkers of Exposure and Effect

ATSDR Information Center
Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY)Internet: http://www.atsdr.cdc.gov
The following additional materials are available online:
Case Studies in Environmental Medicine are self-instructional publications designed to increase primary
health care providers’ knowledge of a hazardous substance in the environment and to aid in theevaluation of potentially exposed patients (see https://www.atsdr.cdc.gov/csem/csem.html).
Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene(prehospital) and hospital medical management of patients exposed during a hazardous materials
incident (see https://www.atsdr.cdc.gov/MHMI/index.asp). Volumes I and II are planning guides
to assist first responders and hospital emergency department personnel in planning for incidents
that involve hazardous materials. Volume III—Medical Management Guidelines for Acute
Chemical Exposures—is a guide for health care professionals treating patients exposed tohazardous materials.
Fact Sheets (ToxFAQs™) provide answers to frequently asked questions about toxic substances (seehttps://www.atsdr.cdc.gov/toxfaqs/Index.asp).

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D-2
APPENDIX D

Other Agencies and Organizations
The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease,
injury, and disability related to the interactions between people and their environment outside theworkplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, GA
30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015 • Web Page:
https://www.cdc.gov/nceh/.
The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational
diseases and injuries, responds to requests for assistance by investigating problems of health andsafety in the workplace, recommends standards to the Occupational Safety and HealthAdministration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains
professionals in occupational safety and health. Contact: NIOSH, 395 E Street, S.W., Suite 9200,
Patriots Plaza Building, Washington, DC 20201 • Phone: 202-245-0625 or 1-800-CDC-INFO(800-232-4636) • Web Page: https://www.cdc.gov/niosh/.
The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency forbiomedical research on the effects of chemical, physical, and biologic environmental agents onhuman health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive,
Research Triangle Park, NC 27709 • Phone: 919-541-3212 • Web Page:
https://www.niehs.nih.gov/.

Clinical Resources (Publicly Available Information)
The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics
in the United States to provide expertise in occupational and environmental issues. Contact:
AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/.
The American College of Occupational and Environmental Medicine (ACOEM) is an association ofphysicians and other health care providers specializing in the field of occupational andenvironmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk
Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266 • Web Page:
http://www.acoem.org/.
The American College of Medical Toxicology (ACMT) is a nonprofit association of physicians withrecognized expertise in medical toxicology. Contact: ACMT, 10645 North Tatum Boulevard,
Suite 200-111, Phoenix AZ 85028 • Phone: 844-226-8333 • FAX: 844-226-8333 • Web Page:
http://www.acmt.net.
The Pediatric Environmental Health Specialty Units (PEHSUs) is an interconnected system of specialists
who respond to questions from public health professionals, clinicians, policy makers, and the
public about the impact of environmental factors on the health of children and reproductive-aged
adults. Contact information for regional centers can be found at http://pehsu.net/findhelp.html.
The American Association of Poison Control Centers (AAPCC) provide support on the prevention andtreatment of poison exposures. Contact: AAPCC, 515 King Street, Suite 510, Alexandria VA
22314 • Phone: 701-894-1858 • Poison Help Line: 1-800-222-1222 • Web Page:
http://www.aapcc.org/.

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E-1

APPENDIX E. GLOSSARY
Absorption—The process by which a substance crosses biological membranes and enters systemic
circulation. Absorption can also refer to the taking up of liquids by solids, or of gases by solids or liquids.
Acute Exposure—Exposure to a chemical for a duration of ≤14 days, as specified in the Toxicological
Profiles.
Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to thesurfaces of solid bodies or liquids with which they are in contact.
Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight oforganic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.
Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase)
divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a
fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil orsediment.
Benchmark Dose (BMD) or Benchmark Concentration (BMC)—is the dose/concentration
corresponding to a specific response level estimate using a statistical dose-response model applied toeither experimental toxicology or epidemiology data. For example, a BMD10 would be the dosecorresponding to a 10% benchmark response (BMR). The BMD is determined by modeling the doseresponse curve in the region of the dose-response relationship where biologically observable data arefeasible. The BMDL or BMCL is the 95% lower confidence limit on the BMD or BMC.
Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms
at a specific time or during a discrete time period of exposure divided by the concentration in thesurrounding water at the same time or during the same period.
Biomarkers—Indicators signaling events in biologic systems or samples, typically classified as markers
of exposure, effect, and susceptibility.
Cancer Effect Level (CEL)—The lowest dose of a chemical in a study, or group of studies, that
produces significant increases in the incidence of cancer (or tumors) between the exposed population andits appropriate control.
Carcinogen—A chemical capable of inducing cancer.
Case-Control Study—A type of epidemiological study that examines the relationship between aparticular outcome (disease or condition) and a variety of potential causative agents (such as toxic
chemicals). In a case-control study, a group of people with a specified and well-defined outcome isidentified and compared to a similar group of people without the outcome.
Case Report—A report that describes a single individual with a particular disease or exposure. These
reports may suggest some potential topics for scientific research, but are not actual research studies.
Case Series—Reports that describe the experience of a small number of individuals with the samedisease or exposure. These reports may suggest potential topics for scientific research, but are not actual
research studies.

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APPENDIX E

Ceiling Value—A concentration that must not be exceeded.
Chronic Exposure—Exposure to a chemical for ≥365 days, as specified in the Toxicological Profiles.
Clastogen—A substance that causes breaks in chromosomes resulting in addition, deletion, or
rearrangement of parts of the chromosome.
Cohort Study—A type of epidemiological study of a specific group or groups of people who have had acommon insult (e.g., exposure to an agent suspected of causing disease or a common disease) and arefollowed forward from exposure to outcome, and who are disease-free at start of follow-up. Often, atleast one exposed group is compared to one unexposed group, while in other cohorts, exposure is acontinuous variable and analyses are directed towards analyzing an exposure-response coefficient.
Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines
the relationship between exposure and outcome to a chemical or to chemicals at a specific point in time.
Data Needs—Substance-specific informational needs that, if met, would reduce the uncertainties ofhuman health risk assessment.
Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result
from exposure to a chemical prior to conception (either parent), during prenatal development, or
postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any pointin the life span of the organism.
Dose-Response Relationship—The quantitative relationship between the amount of exposure to a
toxicant and the incidence of the response or amount of the response.
Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure toa chemical; the distinguishing feature between the two terms is the stage of development during which theeffect occurs. Effects include malformations and variations, altered growth, and in utero death.
Epidemiology—The investigation of factors that determine the frequency and distribution of disease orother health-related conditions within a defined human population during a specified period.
Excretion—The process by which metabolic waste products are removed from the body.
Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication ofaffected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specificalteration of the molecular structure of the genome.
Half-life—A measure of rate for the time required to eliminate one-half of a quantity of a chemical fromthe body or environmental media.
Health Advisory—An estimate of acceptable drinking water levels for a chemical substance derived by
EPA and based on health effects information. A health advisory is not a legally enforceable federal
standard, but serves as technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH)—A condition that poses a threat of life or health, or
conditions that pose an immediate threat of severe exposure to contaminants that are likely to haveadverse cumulative or delayed effects on health.

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E-3
APPENDIX E

Immunotoxicity—Adverse effect on the functioning of the immune system that may result fromexposure to chemical substances.
Incidence—The ratio of new cases of individuals in a population who develop a specified condition to
the total number of individuals in that population who could have developed that condition in a specified
time period.
Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the
Toxicological Profiles.
In Vitro—Isolated from the living organism and artificially maintained, as in a test tube.
In Vivo—Occurring within the living organism.
Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported
to have caused death in humans or animals.
Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure fora specific length of time is expected to cause death in 50% of a defined experimental animal population.
Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation thathas been reported to have caused death in humans or animals.
Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of adefined experimental animal population.
Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical
is expected to cause death in 50% of a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study,
or group of studies, that produces statistically or biologically significant increases in frequency or severityof adverse effects between the exposed population and its appropriate control.
Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as thelymph nodes, spleen, and thymus.
Malformations—Permanent structural changes that may adversely affect survival, development, orfunction.
Metabolism—Process in which chemical substances are biotransformed in the body that could result inless toxic and/or readily excreted compounds or produce a biologically active intermediate.
Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is
likely to be without an appreciable risk of adverse noncancer health effects over a specified route andduration of exposure.
Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk
Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty
factors. The default value for a MF is 1.

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E-4
APPENDIX E

Morbidity—The state of being diseased; the morbidity rate is the incidence or prevalence of a disease ina specific population.
Mortality—Death; the mortality rate is a measure of the number of deaths in a population during a
specified interval of time.
Mutagen—A substance that causes mutations, which are changes in the DNA sequence of a cell’s DNA.
Mutations can lead to birth defects, miscarriages, or cancer.
Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause ofdeath or pathological conditions.
Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to ahazardous substance.
No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no
statistically or biologically significant increases in frequency or severity of adverse effects seen between
the exposed population and its appropriate control. Although effects may be produced at this dose, they
are not considered to be adverse.
Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical
in n-octanol and water, in dilute solution.
Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances
and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence
among subjects exposed to a particular risk factor divided by the incidence among subjects who were notexposed to the risk factor). An odds ratio that is greater than 1 is considered to indicate greater risk of
disease in the exposed group compared to the unexposed group.
Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA)
regulatory limit on the amount or concentration of a substance not to be exceeded in workplace air
averaged over any 8-hour work shift of a 40-hour workweek.
Pesticide—General classification of chemicals specifically developed and produced for use in the controlof agricultural and public health pests (insects or other organisms harmful to cultivated plants or animals).
Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides
the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body.
Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent
chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based
and physiologically-based. A data-based model divides the animal system into a series of compartments,
which, in general, do not represent real, identifiable anatomic regions of the body, whereas thephysiologically-based model compartments represent real anatomic regions of the body.
Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic
endpoints. These models advance the importance of physiologically based models in that they clearly
describe the biological effect (response) produced by the system following exposure to an exogenous
substance.

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E-5
APPENDIX E

Physiologically Based Pharmacokinetic (PBPK) Model—A type of physiologically based doseresponse model that is comprised of a series of compartments representing organs or tissue groups withrealistic weights and blood flows. These models require a variety of physiological information, including
tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates, and possibly
membrane permeabilities. The models also utilize biochemical information, such as blood:air partition
coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry
models.
Prevalence—The number of cases of a disease or condition in a population at one point in time.
Prospective Study—A type of cohort study in which a group is followed over time and the pertinent
observations are made on events occurring after the start of the study.
Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour
workweek.
Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order ofmagnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups)that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime.
The inhalation RfC is expressed in units of mg/m3 or ppm.
Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of thedaily oral exposure of the human population to a potential hazard that is likely to be without risk ofdeleterious noncancer health effects during a lifetime. The oral RfD is expressed in units of mg/kg/day.
Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under
the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). RQs are(1) ≥1 pound or (2) for selected substances, an amount established by regulation either under CERCLA orunder Section 311 of the Clean Water Act. Quantities are measured over a 24-hour period.
Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result
from exposure to a hazardous substance. The toxicity may be directed to the reproductive organs and/or
the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual
behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the
integrity of this system.
Retrospective Study—A type of cohort study based on a group of persons known to have been exposedat some time in the past. Data are collected from routinely recorded events, up to the time the study isundertaken. Retrospective studies are limited to causal factors that can be ascertained from existing
records and/or examining survivors of the cohort.
Reverse Causation—Describes an association where the outcome results in a change in the biomarker of
exposure.
Risk—The possibility or chance that some adverse effect will result from a given exposure to a hazardous
substance.

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E-6
APPENDIX E

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, existing healthcondition, or an inborn or inherited characteristic that is associated with an increased occurrence ofdisease or other health-related event or condition.
Risk Ratio/Relative Risk—The ratio of the risk among persons with specific risk factors compared to therisk among persons without risk factors. A risk ratio that is greater than 1 indicates greater risk of diseasein the exposed group compared to the unexposed group.
Short-Term Exposure Limit (STEL)—A STEL is a 15-minute TWA exposure that should not be
exceeded at any time during a workday.
Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected
number of deaths in a specific standard population.
Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or
physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.
Teratogen—A chemical that causes structural defects that affect the development of an organism.
Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists(ACGIH) concentration of a substance to which it is believed that nearly all workers may be repeatedly
exposed, day after day, for a working lifetime without adverse effect. The TLV may be expressed as aTime-Weighted Average (TLV-TWA), as a Short-Term Exposure Limit (TLV-STEL), or as a ceiling
limit (TLV-C).
Time-Weighted Average (TWA)—An average exposure within a given time period.
Toxicokinetic—The absorption, distribution, metabolism, and elimination of toxic compounds in theliving organism.
Toxics Release Inventory (TRI)—The TRI is an EPA program that tracks toxic chemical releases andpollution prevention activities reported by industrial and federal facilities.
Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL),
Reference Dose (RfD), or Reference Concentration (RfC) from experimental data. UFs are intended toaccount for (1) the variation in sensitivity among the members of the human population, (2) the
uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating fromdata obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data.
A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used;however, a reduced UF of 3 may be used on a case-by-case basis (3 being the approximate logarithmic
average of 10 and 1).
Xenobiotic—Any substance that is foreign to the biological system.

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APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS
AAPCC
ACGIH
ACOEM
ACMT
ADI
ADME
AEGL
AIC
AIHA
ALT
AOEC
AP
APFO
AST
atm
ATSDR
AWQC
BCF
BMD/C
BMDX
BMDLX
BMDS
BMR
BUN
C
CAA
CAS
CDC
CEL
CERCLA
CFR
Ci
CI
cm
CPSC
CWA
DNA
DOD
DOE
DWEL
EAFUS
ECG/EKG
EEG
EPA
ERPG
F
F1
FDA
FIFRA

American Association of Poison Control Centers
American Conference of Governmental Industrial Hygienists
American College of Occupational and Environmental Medicine
American College of Medical Toxicology
acceptable daily intake
absorption, distribution, metabolism, and excretion
Acute Exposure Guideline Level
Akaike’s information criterion
American Industrial Hygiene Association
alanine aminotransferase
Association of Occupational and Environmental Clinics
alkaline phosphataseammonium perfluorooctanoate
aspartate aminotransferase
atmosphere
Agency for Toxic Substances and Disease Registry
Ambient Water Quality Criteria
bioconcentration factor
benchmark dose or benchmark concentrationdose that produces a X% change in response rate of an adverse effect95% lower confidence limit on the BMDXBenchmark Dose Software
benchmark response
blood urea nitrogencentigrade
Clean Air Act
Chemical Abstract Services
Centers for Disease Control and Prevention
cancer effect level
Comprehensive Environmental Response, Compensation, and Liability Act
Code of Federal Regulations
curie
confidence interval
centimeter
Consumer Products Safety Commission
Clean Water Act
deoxyribonucleic acid
Department of Defense
Department of Energy
drinking water exposure level
Everything Added to Food in the United Stateselectrocardiogram
electroencephalogram
Environmental Protection Agency
emergency response planning guidelines
Fahrenheit
first-filial generation
Food and Drug Administration
Federal Insecticide, Fungicide, and Rodenticide Act

F-1

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F-2
APPENDIX F

FR
FSH
g
GC
gd
GGT
GRAS
HEC
HED
HHS
HPLC
HSDB
IARC
IDLH
IRIS
Kd
kg
kkg
Koc
Kow
L
LC
LC50
LCLo
LD50
LDLo
LDH
LH
LOAEL
LSE
LT50
m
mCi
MCL
MCLG
MF
mg
mL
mm
mmHg
mmol
MRL
MS
MSHA
Mt
NAAQS
NAS
NCEH
ND
ng
NHANES

Federal Registerfollicle stimulating hormone
gram
gas chromatography
gestational day
γ-glutamyl transferase
generally recognized as safe
human equivalent concentration
human equivalent dose
Department of Health and Human Services
high-performance liquid chromatography
Hazardous Substance Data BankInternational Agency for Research on Cancer
immediately dangerous to life and healthIntegrated Risk Information Systemadsorption ratio
kilogram
kilokilogram; 1 kilokilogram is equivalent to 1,000 kilograms and 1 metric tonorganic carbon partition coefficientoctanol-water partition coefficientliter
liquid chromatographylethal concentration, 50% killlethal concentration, lowlethal dose, 50% killlethal dose, lowlactic dehydrogenaseluteinizing hormone
lowest-observed-adverse-effect level
Level of Significant Exposure
lethal time, 50% killmeter
millicurie
maximum contaminant level
maximum contaminant level goal
modifying factor
milligrammilliliter
millimeter
millimeters of mercury
millimole
Minimal Risk Level
mass spectrometry
Mine Safety and Health Administration
metric ton
National Ambient Air Quality Standard
National Academy of Science
National Center for Environmental Healthnot detectednanogram
National Health and Nutrition Examination Survey

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F-3
APPENDIX F

NIEHS
NIOSH
NLM
nm
nmol
NOAEL
NPL
NR
NRC
NS
NTP
OR
OSHA
PAC
PAH
PBPD
PBPK
PEHSU
PEL
PEL-C
PFBA
PFBS
PFDA
PFDoDA
PFHpA
PFHxA
PFHxS
PFNA
PFOA
FOSA
PFOS
PFUnA
pg
PND
POD
ppb
ppbv
ppm
ppt
REL
REL-C
RfC
RfD
RNA
SARA
SCE
SD
SE
SGOT
SGPT
SIC

National Institute of Environmental Health Sciences
National Institute for Occupational Safety and HealthNational Library of Medicine
nanometer
nanomole
no-observed-adverse-effect level
National Priorities List
not reported
National Research Council
not specified
National Toxicology Program
odds ratio
Occupational Safety and Health Administration
Protective Action Criteria
polycyclic aromatic hydrocarbon
physiologically based pharmacodynamic
physiologically based pharmacokinetic
Pediatric Environmental Health Specialty Unit
permissible exposure limit
permissible exposure limit-ceiling value
perfluorobutanoic acid
Perfluorobutane sulfonic acidperfluorodecanoic acidperfluorododecanoic acidperfluoroheptanoic acidperfluorohexanoic acidperfluorohexane sulfonic acidperfluorononanoic acidperfluorooctanoic acidperfluorooctane sulfonamide
perfluorooctane sulfonic acidperfluoroundecanoic acidpicogram
postnatal day
point of departureparts per billion
parts per billion by volume
parts per million
parts per trillion
recommended exposure level/limit
recommended exposure level-ceiling valuereference concentrationreference doseribonucleic acid
Superfund Amendments and Reauthorization Act
sister chromatid exchange
standard deviation
standard error
serum glutamic oxaloacetic transaminase (same as aspartate aminotransferase or AST)
serum glutamic pyruvic transaminase (same as alanine aminotransferase or ALT)
standard industrial classification

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F-4
APPENDIX F

SMR
sRBC
STEL
T1/2
TLV
TLV-C
TRI
TSCA
TWA
UF
U.S.
USDA
USGS
USNRC
VOC
WBC
WHO

standardized mortality ratio
sheep red blood cellshort term exposure limit
Half-life
threshold limit value
threshold limit value-ceiling value
Toxics Release Inventory
Toxic Substances Control Act
time-weighted average
uncertainty factor
United States
United States Department of Agriculture
United States Geological Survey
U.S. Nuclear Regulatory Commission
volatile organic compound
white blood cell
World Health Organization

>
≥
=
<
≤
%
α
β
γ
δ
μm
μg
q1*
–
+
(+)
(–)

greater thangreater than or equal toequal toless thanless than or equal topercent
alpha
beta
gamma
delta
micrometer
microgram
cancer slope factor
negative
positive
weakly positive result
weakly negative result