Toxicological Profile for

Perfluoroalkyls

Draft for Public Comment 

June 2018 
PERFLUOROALKYLS ii

***DRAFT FOR PUBLIC COMMENT***

FOREWORD 

This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary.

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for these toxic substances described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is 

also presented, but is described in less detail than the key studies. The profile is not intended to be an 

exhaustive document; however, more comprehensive sources of specialty information are referenced. 

The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile 

begins with a relevance to public health discussion which would allow a public health professional to 

make a real-time determination of whether the presence of a particular substance in the environment 

poses a potential threat to human health. The adequacy of information to determine a substance's health 

effects is described in a health effects summary. Data needs that are of significance to the protection of 

public health are identified by ATSDR and EPA. 

Each profile includes the following:

(A) The examination, summary, and interpretation of available toxicologic information and

epidemiologic evaluations on a toxic substance to ascertain the levels of significant human

exposure for the substance and the associated acute, intermediate, and chronic health effects;

(B) A determination of whether adequate information on the health effects of each substance is

available or in the process of development to determine the levels of exposure that present a

significant risk to human health due to acute, intermediate, and chronic duration exposures;

and

(C) Where appropriate, identification of toxicologic testing needed to identify the types or levels

of exposure that may present significant risk of adverse health effects in humans.

The principal audiences for the toxicological profiles are health professionals at the Federal, State, and 

local levels; interested private sector organizations and groups; and members of the public. ATSDR plans 

to revise these documents in response to public comments and as additional data become available. 

Therefore, we encourage comments that will make the toxicological profile series of the greatest use.

Electronic comments may be submitted via: www.regulations.gov. Follow the on-line instructions for 

submitting comments. 

Written comments may also be sent to: Agency for Toxic Substances and Disease Registry

Division of Toxicology and Human Health Sciences

Environmental Toxicology Branch

Regular Mailing Address: Physical Mailing Address:

1600 Clifton Road, N.E. 4770 Buford Highway

Mail Stop F-57 Building 102, 1st floor, MS F-57

Atlanta, Georgia 30329-4027 Chamblee, Georgia 30341
 

PERFLUOROALKYLS iii 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 

104(i)(1) directs the Administrator of ATSDR to “...effectuate and implement the health related 

authorities” of the statute. This includes the preparation of toxicological profiles for hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List (NPL) and that 

pose the most significant potential threat to human health, as determined by ATSDR and the EPA. 

Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a 

toxicological profile for each substance on the list. In addition, ATSDR has the authority to prepare 

toxicological profiles for substances not found at sites on the NPL, in an effort to “...establish and 

maintain inventory of literature, research, and studies on the health effects of toxic substances” under 

CERCLA Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and as 

otherwise necessary to support the site-specific response actions conducted by ATSDR. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal scientists have 

also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and is being made available for public review. Final responsibility for the contents and views expressed 

in this toxicological profile resides with ATSDR. 

Patrick N. Breysse, Ph.D., CIH 

Director, National Center for Environmental Health and 

Agency for Toxic Substances and Disease Registry 

Centers for Disease Control and Prevention 

***DRAFT FOR PUBLIC COMMENT*** 
PERFLUOROALKYLS iv

***DRAFT FOR PUBLIC COMMENT***

VERSION HISTORY 

Date Description

June 2018 

August 2015 

May 2009 

Draft for public comment toxicological profile released 

Draft for public comment toxicological profile released 

Draft for public comment toxicological profile released 
PERFLUOROALKYLS v 

***DRAFT FOR PUBLIC COMMENT***

CONTRIBUTORS & REVIEWERS 

CHEMICAL MANAGER TEAM

Selene Chou, Ph.D. (Lead) Lisa Ingerman, Ph.D., DABT

Dennis Jones, DVM, Ph.D. Lynn Barber, M.S.

Hana R. Pohl, M.D., Ph.D. Heather Carlson-Lynch, M.S., DABT

Patricia Ruiz, Ph.D. Mario Citra, Ph.D.

Franco Scinicariello, M.D., M.P.H. Gary L. Diamond, Ph.D.

Melanie Buser, M.P.H. Julie Klotzbach, Ph.D.

Fernando T. Llados, Ph.D.

Daniel J. Plewak, B.S.

ATSDR, Division of Toxicology and Human Health 

Sciences, Atlanta, GA

SRC, Inc., North Syracuse, NY

REVIEWERS

Interagency Minimal Risk Level Workgroup: 

Includes ATSDR; National Center for Environmental Health (NCEH); National Institute of 

Occupational 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. David A. Savitz, Ph.D., Professor of Epidemiology, Professor of Obstetrics and Gynecology, Brown

University, Providence, Rhode Island

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 York

3. 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, University of

Pennsylvania, Philadelphia, Pennsylvania

These experts collectively have knowledge of toxicology, chemistry, and/or health effects. All reviewers 

were selected in conformity with Section 104(I)(13) of the Comprehensive Environmental Response, 

Compensation, and Liability Act, as amended. 

ATSDR scientists review peer reviewers’ comments and determine whether changes will be made to the 

profile based on comments. The peer reviewers’ comments and responses to these comments are part of 

the administrative record for this compound. 

The listing of peer reviewers should not be understood to imply their approval of the profile's final 

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

***DRAFT FOR PUBLIC COMMENT***

CONTENTS

FOREWORD................................................................................................................................................ii

VERSION HISTORY..................................................................................................................................iv

CONTRIBUTORS & REVIEWERS............................................................................................................v

CONTENTS.................................................................................................................................................vi

LIST OF FIGURES .....................................................................................................................................ix

LIST OF TABLES......................................................................................................................................xii

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...........................................................................................................21

2.1 INTRODUCTION........................................................................................................................21

2.2 DEATH ......................................................................................................................................106

2.3 BODY WEIGHT........................................................................................................................109

2.4 RESPIRATORY.........................................................................................................................121

2.5 CARDIOVASCULAR ...............................................................................................................123

2.6 GASTROINTESTINAL.............................................................................................................135

2.7 HEMATOLOGICAL .................................................................................................................137

2.8 MUSCULOSKELETAL ............................................................................................................141

2.9 HEPATIC...................................................................................................................................146

2.10 RENAL.......................................................................................................................................202

2.11 DERMAL...................................................................................................................................219

2.12 OCULAR....................................................................................................................................220

2.13 ENDOCRINE.............................................................................................................................221

2.14 IMMUNOLOGICAL .................................................................................................................244

2.15 NEUROLOGICAL.....................................................................................................................293

2.16 REPRODUCTIVE......................................................................................................................300

2.17 DEVELOPMENTAL .................................................................................................................340

2.18 OTHER NONCANCER.............................................................................................................406

2.19 CANCER....................................................................................................................................418

2.20 MECHANISM OF TOXICITY..................................................................................................433

2.20.1 Cellular Mechanisms of Toxicity........................................................................................434

2.20.2 Hepatic Toxicity Mechanisms.............................................................................................441

2.20.3 Developmental Toxicity Mechanisms.................................................................................443

2.20.4 Immunotoxicity Mechanisms..............................................................................................444

2.20.5 Endocrine Mechanisms.......................................................................................................445

2.20.6 Cancer Mechanisms............................................................................................................446

2.21 GENOTOXICITY......................................................................................................................447

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, 

CHEMICAL INTERACTIONS .......................................................................................450

3.1 TOXICOKINETICS...................................................................................................................450

3.1.1 Absorption...........................................................................................................................451

3.1.2 Distribution .........................................................................................................................455

3.1.3 Metabolism..........................................................................................................................469

3.1.4 Excretion .............................................................................................................................469
PERFLUOROALKYLS vii

***DRAFT FOR PUBLIC COMMENT***

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ........... 493

3.1.5.1 Loccisano et al. (2012a, 2012b) Rat Models ............................................................... 494

3.1.5.2 Loccisano et al. (2011, 2013) Monkey and Human Models ........................................ 500

3.1.5.3 Rodriguez et al. (2009) Mouse Model ......................................................................... 504

3.1.5.4. Wambaugh et al. 2013 (Andersen et al. 2006) Model ................................................. 506

3.1.5.5 Harris and Barton (2008) Rat Model ........................................................................... 509

3.1.5.6 Worley and Fisher (2015a, 2015b) Rat Model ............................................................ 512

3.1.5.7 Worley et al. (2017b) Human Model ........................................................................... 513

3.1.5.8 Fàbrega et al. (2014, 2016) Human Model .................................................................. 513

3.1.6 Animal-to-Human Extrapolations ....................................................................................... 514

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ... 515

3.3 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................... 518

3.3.1 Biomarkers of Exposure ...................................................................................................... 519

3.3.2 Biomarkers of Effect ........................................................................................................... 520

3.4 INTERACTIONS WITH OTHER CHEMICALS ..................................................................... 520

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION .......................................................... 521

4.1 CHEMICAL IDENTITY ............................................................................................................ 521

4.2 PHYSICAL AND CHEMICAL PROPERTIES ......................................................................... 521

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ...................................................................... 533

5.1 OVERVIEW ............................................................................................................................... 533

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ................................................ 537

5.2.1 Production ........................................................................................................................... 537

5.2.2 Import/Export ...................................................................................................................... 545

5.2.3 Use ...................................................................................................................................... 545

5.2.4 Disposal ............................................................................................................................... 546

5.3 RELEASES TO THE ENVIRONMENT ................................................................................... 546

5.3.1 Air ....................................................................................................................................... 551

5.3.2 Water ................................................................................................................................... 552

5.3.3 Soil ...................................................................................................................................... 554

5.4 ENVIRONMENTAL FATE ...................................................................................................... 555

5.4.1 Transport and Partitioning ................................................................................................... 555

5.4.2 Transformation and Degradation ........................................................................................ 559

5.5 LEVELS IN THE ENVIRONMENT ......................................................................................... 561

5.5.1 Air ....................................................................................................................................... 564

5.5.2 Water ................................................................................................................................... 571

5.5.3 Sediment and Soil ............................................................................................................... 582

5.5.4 Other Media ........................................................................................................................ 587

5.6 GENERAL POPULATION EXPOSURE .................................................................................. 596

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 623

CHAPTER 6. ADEQUACY OF THE DATABASE ............................................................................... 628

6.1 Existing Information on Health Effects ...................................................................................... 628

6.2 Identification of Data Needs ....................................................................................................... 632

6.3 Ongoing Studies ......................................................................................................................... 642

CHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................ 644

CHAPTER 8. REFERENCES ................................................................................................................. 647
PERFLUOROALKYLS viii

***DRAFT FOR PUBLIC COMMENT***

APPENDICES

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND 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 
PERFLUOROALKYLS ix

***DRAFT FOR PUBLIC COMMENT***

LIST OF FIGURES 

1-1. Health Effects Found in Animals Following Oral Exposure to PFOA ................................................. 7

1-2. Health Effects Found in Animals Following Oral Exposure to PFOS ................................................. 8

1-3. Health Effects Found in Animals Following Oral Exposure to Other Perfluoroalkyls ........................ 9

1-4. Summary of Sensitive Targets of PFOA – Oral ................................................................................. 17

1-5. Summary of Sensitive Targets of PFOS – Oral .................................................................................. 18

2-1. Overview of the Number of Studies Examining PFOA Health Effects .............................................. 27

2-2. Overview of the Number of Studies Examining PFOS Health Effects .............................................. 28

2-3. Overview of the Number of Studies Examining Other Perfluoroalkyls Health Effects ..................... 29

2-4. Levels of Significant Exposure to PFOA – Inhalation ....................................................................... 32

2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Inhalation ............................................... 34

2-6. Levels of Significant Exposure to PFOA – Oral ................................................................................ 58

2-7. Levels of Significant Exposure to PFOS – Oral ................................................................................. 81

2-8. Levels of Significant Exposure to Other Perfluoroalkyls – Oral ........................................................ 99

2-9. Serum Total Cholesterol Levels Relative to Serum PFOA Levels ................................................... 173

2-10. Risk of Abnormal Cholesterol Levels Relative to PFOA Levels (Presented as Adjusted 

Ratios) ............................................................................................................................................ 174

2-11. Serum LDL Cholesterol Levels Relative to Serum PFOA Levels ................................................. 175

2-12. Risk of Abnormal LDL Cholesterol Levels Relative to PFOA Levels (Presented as 

Adjusted Ratios) ............................................................................................................................. 176

2-13. Serum Total Cholesterol Levels Relative to Serum PFOS Levels ................................................. 189

2-14. Risk of Abnormal Cholesterol Levels Relative to PFOS Levels (Presented as Adjusted 

Ratios) ............................................................................................................................................ 190

2-15. Serum LDL Cholesterol Levels Relative to Serum PFOS Levels .................................................. 191

2-16. Risk of Abnormal LDL Cholesterol Levels Relative to PFOS Levels (Presented as 

Adjusted Ratios) ............................................................................................................................. 192

2-17. Risk of Hyperuricemia Relative to PFOA Levels (Presented as Adjusted Odds Ratios) ............... 213

2-18. Risk of Hyperuricemia Relative to PFOS Levels (Presented as Adjusted Odds Ratios) ................ 215
PERFLUOROALKYLS x 

***DRAFT FOR PUBLIC COMMENT***

2-19. Antibody Responses Relative to Serum PFOA Levels in Epidemiology Studies .......................... 270

2-20. Risk of Asthma Diagnosis Relative to PFOA Levels (Presented as Adjusted Odds Ratios) .......... 272

2-21. Antibody Responses Relative to Serum PFOS Levels in Epidemiology Studies ........................... 278

2-22. Risk of Asthma Diagnosis Relative to PFOS Levels (Presented as Adjusted Odds Ratios) .......... 280

2-23. Antibody Responses Relative to Serum PFHxS Levels in Epidemiology Studies ......................... 283

2-24. Risk of Asthma Diagnosis Relative to PFHxS Levels (Presented as Adjusted Odds Ratios) ........ 285

2-25. Antibody Responses Relative to Serum PFNA Levels in Epidemiology Studies .......................... 287

2-26. Risk of Asthma Diagnosis Relative to PFNA Levels (Presented as Adjusted Odds Ratios) .......... 288

2-27. Antibody Responses Relative to Serum PFDeA Levels in Epidemiology Studies ........................ 290

2-28. Risk of Asthma Diagnosis Relative to PFDeA Levels (Presented as Adjusted Odds Ratios) ........ 292

2-29. Fecundability Relative to PFOA Levels (Presented as Adjusted Fecundability Ratios) ................ 326

2-30. Infertility Relative to PFOA Levels (Presented as Adjusted Odds Ratios) .................................... 327

2-31. Fecundability Relative to PFOS Levels (Presented as Adjusted Fecundability Ratios) ................. 333

2-32. Infertility Relative to PFOS Levels (Presented as Adjusted Odds Ratios) ..................................... 334

2-33. Risk of Low Birth Weight Infant Relative to PFOA Levels (Presented as Adjusted Odds 

Ratios) ............................................................................................................................................ 379

2-34. Risk of Small For Gestational Age Infant Relative to PFOA Levels (Presented as Adjusted 

Odds Ratios) ................................................................................................................................... 380

2-35. Risk of Low Birth Weight Infant Relative to PFOS Levels (Presented as Adjusted Odds 

Ratios) ............................................................................................................................................ 391

2-36. Risk of Small for Gestational Age Infant Relative to PFOS Levels (Presented as Adjusted 

Odds Ratios) ................................................................................................................................... 392

2-37. Diabetes Risk Relative to Serum PFOA Levels (Presented as Adjusted Ratios) ........................... 415

2-38. Diabetes Risk Relative to Serum PFOS Levels (Presented as Adjusted Odds Ratios) ................... 417

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 ........................................................................................................ 458

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 ........................... 459
PERFLUOROALKYLS xi

***DRAFT FOR PUBLIC COMMENT***

3-3. Structure of PBPK Model of PFOA and PFOS in the Rat ................................................................ 495

3-4. PBPK Model Structure for Simulating PFOA and PFOS Exposure During Gestation in the 

Rat (Dam, Left; Fetus, Right) ........................................................................................................... 496

3-5. PBPK Model Structure for Simulating PFOA/PFOS Exposure During Lactation in the Rat 

(Dam, Left; Pup, Right) .................................................................................................................... 497

3-6. Structure of PBPK Model for PFOA and PFOS in Monkeys and Humans ...................................... 501

3-7. Renal Resorption Pharmacokinetic Model of Gestation and Lactation used in the Analysis of 

CD-1 Mice ........................................................................................................................................ 505

3-8. Andersen et al. (2006) Pharmacokinetic Model with Oral Absorption ............................................ 507

3-9. Conceptual Representation of a Physiologically Based Pharmacokinetic Model for PFOS 

Exposure in Rats ............................................................................................................................... 510

5-1. Number of NPL Sites with Perfluoroalkyls Contamination ............................................................. 533

5-2. Timeline of Important Events in the History of Polyfluorinated Compounds.................................. 539

6-1. Summary of Existing Health Effects Studies on PFOA By Route and Endpoint ............................. 629

6-2. Summary of Existing Health Effects Studies on PFOS By Route and Endpoint ............................. 630

6-3. Summary of Existing Health Effects Studies on Other Perfluoroalkyls By Route and 

Endpoint ........................................................................................................................................... 631
PERFLUOROALKYLS xii

***DRAFT FOR PUBLIC COMMENT***

LIST OF TABLES 

1-1. Summary of Estimated Elimination Half-lives for Select Perfluoroalkyls ........................................... 4

1-2. Overview of Provisional Minimal Risk Levels Derived for Perfluoroalkyl Compounds ................... 15

1-3. Provisional Minimal Risk Levels (MRLs) for PFOA ......................................................................... 19

1-4. Provisional Minimal Risk Levels (MRLs) for PFOS ......................................................................... 19

1-5. Provisional Minimal Risk Levels (MRLs) for PFHxS ....................................................................... 20

1-6. Provisional Minimal Risk Levels (MRLs) for PFNA ......................................................................... 20

2-1. Levels of Significant Exposure to PFOA – Inhalation ....................................................................... 30

2-2. Levels of Significant Exposure to Other Perfluoroalkyls – Inhalation ............................................... 33

2-3. Levels of Significant Exposure to PFOA – Oral ................................................................................ 35

2-4. Levels of Significant Exposure to PFOS – Oral ................................................................................. 62

2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Oral ........................................................ 85

2-6. Levels of Significant Exposure to PFOA – Dermal ......................................................................... 104

2-7. Summary of Childhood Growth in Humans ..................................................................................... 110

2-8. Summary of Cardiovascular Outcomes in Humans .......................................................................... 125

2-9. Summary of Skeletal Outcomes in Humans ..................................................................................... 142

2-10. Summary of Liver Disease in Humans ........................................................................................... 148

2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humans ................. 150

2-12. Summary of Serum Lipid Outcomes in Humans ............................................................................ 156

2-13. Summary of Renal Outcomes in Humans....................................................................................... 203

2-14. Summary of Uric Acid Outcomes in Humans ................................................................................ 206

2-15. Summary of Thyroid Outcomes in Humans ................................................................................... 223

2-16. Summary of Immunological Outcomes in Humans ....................................................................... 245

2-17. Summary of Neurological Outcomes in Humans ........................................................................... 294

2-18. Summary of Alterations in Reproductive Hormone Levels in Humans ......................................... 301

2-19. Summary of Male Reproductive Outcomes in Humans ................................................................. 308
PERFLUOROALKYLS xiii

***DRAFT FOR PUBLIC COMMENT***

2-20. Summary of Female Reproductive Outcomes in Humans..............................................................313

2-21. Summary of Fertility Outcomes in Humans...................................................................................318

2-22. Summary of Pregnancy Outcomes in Humans...............................................................................341

2-23. Summary of Birth Outcomes in Humans........................................................................................344

2-24. Summary of Neurodevelopmental Outcomes in Humans ..............................................................360

2-25. Summary of Effects on the Development of the Reproductive System in Humans.......................371

2-26. Summary of Outcomes Related to Diabetes in Humans.................................................................407

2-27. Summary of Cancer Outcomes in Humans.....................................................................................419

2-28. Transactivation of Human and Mouse PPARα in Transfected Cos-1 Cells Exposed to 

Perfluoroalkyl Compounds (In Order of Decreasing C20max in the Mouse)....................................436

2-29. Gene Expression Changes Induced by Perfluoroalkyl Compounds...............................................439

2-30. Hepatic Effects of Perfluoroalkyl Compounds in Wild-Type and PPARα-Null Mice 

Exposed Orally ...............................................................................................................................442

3-1. Tissue Distribution and Excretion of 14C-Radioactivity from Both Sexes of Rats, Mice, 

Hamsters, and Rabbits Dosed with 14C-Labeled APFO ...................................................................461

3-2. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant Pairs................................463

3-3. Matched Serum (or Plasma) and Breast Milk Concentrations in Humans.......................................467

3-4. Excretory Clearance of PFOA and PFOS in Humans ......................................................................471

3-5. Summary Elimination Half-Lives for Perfluoroalkyls Estimated in Humans and 

Experimental Animals......................................................................................................................473

3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated in Experimental Animals.................481

3-7. Estimated and Assumed Pharmacokinetic Parameters for the Modified Andersen et al. 

(2006) Model for PFOA and PFOS..................................................................................................508

4-1. Chemical Identity of Perfluoroalkyls................................................................................................522

4-2. Physical and Chemical Properties of Perfluoroalkyls.......................................................................527

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........541

5-2. U.S. Production Volume Ranges for Perfluoroalkyls (1986–2002) Reported under the EPA 

Inventory Update Rule......................................................................................................................545
PERFLUOROALKYLS xiv

***DRAFT FOR PUBLIC COMMENT***

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..........................547

5-4. Global Historical PFCA Production and Emissions Estimates from 1951 to 2004..........................550

5-5. Biological Monitoring of PFOA and PFOS in the Arctic.................................................................556

5-6. Lowest Limit of Detection Based on Standards...............................................................................562

5-7. Summary of Environmental Levels of Perfluoroalkyls....................................................................562

5-8. Perfluoroalkyls Levels in Water, Soil, and Air of National Priorities List (NPL) Sites...................563

5-9. Concentrations of Perfluoroalkyl in Outdoor Air.............................................................................565

5-10. Concentrations of Perfluoroalkyl in Indoor Air..............................................................................568

5-11. Concentration (ng/g) of Perfluoroalkyls in 39 Dust Samples.........................................................570

5-12. Concentrations of PFOA and PFOS in Surface Water (ng/L)........................................................572

5-13. Concentrations of Other Perfluoroalkyls in Surface Water............................................................574

5-14. Concentrations of Perfluoroalkyls in Surface Water and Groundwater at Fluorochemical 

Industrial Facilities.........................................................................................................................576

5-15. Concentrations of PFOA and PFOS in Ocean Water .....................................................................578

5-16. Concentrations of Perfluoroalkyls in Soil and Sediment at Fluorochemical Industrial 

Facilities .........................................................................................................................................583

5-17. Summary of Perfluoroalkyl Compounds Detected in Soil, Sediment, Surface Water, and 

Groundwater at 10 Military Installations........................................................................................586

5-18. Detections of PFOA in 31 U.S. Food Items ...................................................................................588

5-19. Detections of Perfluoroalkyls in Fish from U.S. Lakes and Rivers................................................589

5-20. Fluorotelomer Alcohols Detected in Microwaveable Popcorn Bags Produced in China and 

the United States.............................................................................................................................594

5-21. Concentrations of PFOA and PFOS in Human Serum Collected in the United States ..................597

5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collected in the United States...........600

5-23. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for Occupationally Exposed 

Individuals......................................................................................................................................608

5-24. Percent Detection and Levels of PFOA and PFOS in Children’s Serum, Umbilical Cord 

Blood, and Breast Milk...................................................................................................................611
PERFLUOROALKYLS xv

***DRAFT FOR PUBLIC COMMENT***

5-25. Percent Detection and Levels of Other Perfluoroalkyls in Children’s Serum, Umbilical 

Cord Blood, and Breast Milk .......................................................................................................... 616

5-26. Blood Serum Levels for 69,030 Current and Former Residents of Six Water Districts in the 

Mid-Ohio Valley (2005–2006) ....................................................................................................... 625

6-1. Ongoing Studies on Perfluoroalkyls ................................................................................................. 642

7-1. Regulations and Guidelines Applicable to Perfluoroalkyls .............................................................. 644

7-2. Select State Drinking Water and Daily Intake Levels for Perfluoroalkyls ....................................... 646
PERFLUOROALKYLS 1

***DRAFT FOR PUBLIC COMMENT***

CHAPTER 1. RELEVANCE TO PUBLIC HEALTH

This toxicological profile on perfluoroalkyls discusses information on 14 perfluoroalkyl compounds that 

have been measured 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. These compounds include: 

Perfluorobutyric acid (PFBA)

Perfluorohexanoic acid (PFHxA)

Perfluoroheptanoic acid (PFHpA)

Perfluorooctanoic acid (PFOA)

Perfluorononanoic acid (PFNA)

Perfluorodecanoic acid (PFDeA)

Perfluoroundecanoic acid (PFUA)

Perfluorobutane sulfonic acid (PFBuS)

Perfluorohexane sulfonic acid (PFHxS)

Perfluorooctane sulfonic acid (PFOS) 

Perfluorododecanoic acid (PFDoA)

Perfluorooctane sulfonamide (PFOSA)

2-(N-Methyl-perfluorooctane sulfonamide) acetic acid (Me-PFOSA-AcOH) 

2-(N-Ethyl-perfluorooctane sulfonamide) acetic acid (Et-PFOSA-AcOH)

The term “perfluoroalkyls” used throughout the toxicological profile is referring to these 

14 compounds and the information may not be applicable to other perfluoroalkyl compounds.

1.1 OVERVIEW AND U.S. EXPOSURES

The perfluoroalkyl compounds discussed in this profile primarily consist of perfluorinated aliphatic 

carboxylic acids (PFCAs), perfluorinated aliphatic sulfonic acids (PFSAs), and some polyfluorinated 

substances that may degrade or be metabolized to some important perfluorinated substances such as 

PFOA or PFOS. These substances have been used extensively in surface coating and protectant 

formulations due to their unique surfactant properties (Kissa 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 of fluoropolymers such as nonstick coatings on 

cookware (DuPont 2008; EPA 2008a).
PERFLUOROALKYLS 2

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

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 companies began 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 are no longer manufactured or imported into the United States; 

however, there could be some imported goods containing trace amounts of these substances as impurities. 

Information 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 processes has not been located. In the environment, some of the perfluoroalkyls discussed 

in this profile can also be formed from environmental 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 that can degrade to long-chain perfluoroalkyls such as 

PFOA, and higher homologues from emissions and products (EPA 2008a, 2016a). 

Due to their chemical structure, perfluoroalkyls are very stable in the environment and are resistant to 

biodegradation, photoxidation, 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 are 

mobile 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 high levels of exposure to PFOA, PFOS, and other perfluoroalkyls for

some populations residing near fluoropolymer manufacturing facilities (ATSDR 2008; Emmett et al. 
PERFLUOROALKYLS 3

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

2006a; Steenland et al. 2009b). Median PFOA serum levels of in 45,276 non-occupationally exposed 

individuals residing in southeastern Ohio and West Virginia who were exposed to PFOA via 

contaminated drinking water were approximately 6 times greater than the median concentration of the 

general population when compared to NHANES data (Shin et al. 2011). Serum levels of PFOA and 

PFOS in the general population of the United States have decreased dramatically in recent years as U.S. 

production of these substances ceased (CDC 2018). 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, 

but have decreased to 1.94 ng/mL (PFOA) and 4.99 ng/mL (PFOS) in 2013–2014 (CDC 2018).

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 impregnated 

clothes, and dust ingestion. This includes exposure to 8:2 fluorotelomer alcohol in food packaging and 

air, 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 

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 et 

al. 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 to 

perfluorocarboxylate homologues for different populations and also concluded that dietary intake was the 

primary background exposure pathway for the general population, while inhalation of indoor air was the 

main exposure pathway for occupationally exposed individuals with estimated intakes >150 ng/kg/day.

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–

0.639 and 0.210–0.490 ng/mL, respectively (Kärrman et al. 2007; So et al. 2006b; Völkel et al. 2008). 

Maximum concentrations of other perfluoroalkyl compounds were <0.18 ng/mL. In most umbilical cord 

samples, the concentrations of PFOS and PFOA ranged from 4.9 to 11.0 and from 1.6 to 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.
PERFLUOROALKYLS 4

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

1.2 SUMMARY OF HEALTH EFFECTS 

Perfluoroalkyls are ubiquitous chemicals in the environment; they are readily absorbed following 

inhalation or oral exposure and are not metabolized in humans or laboratory animals. The toxicity of 

perfluoroalkyl compounds, particularly PFOA and PFOS, has been extensively evaluated in humans and 

laboratory animals. However, comparison of the toxicity of perfluoroalkyls across species is problematic 

due to differences in elimination half-lives, lack of adequate mechanistic data, species differences in the 

mechanism of toxicity for some endpoints, and differences in measurement of exposure levels between 

epidemiology and experimental studies. Substantial differences in the rate of elimination of 

perfluoroalkyls exist across species. Table 1-1 lists half-lives for PFOA, PFOS, PFHxS, PFBuS, and

PFBA for human, nonhuman primates, rats, and mice to illustrate some of the species differences. For 

example, for PFOA, the estimated elimination half-life ranges from 8 years in humans to 1.9 hours in 

female rats. 

Table 1-1. Summary of Estimated Elimination Half-lives for Select Perfluoroalkyls

Humans Nonhuman primates Ratsa Micea

PFOA 8 years 

(Olsen et al. 2007a)

20.1–32.6 days 

(Butenhoff et al. 

2004c)

Males: 44–322 hours

Females: 1.9–16.2 hours

PFOS 5.4 years

(Olsen et al. 2007a)

110–170 days 

(Chang et al. 2012; 

Seacat et al. 2002)

179–1,968 hours 731–1,027 hours

PFHxS 8.5 years 

(Olsen et al. 2007a)

87–141 days 

(Sundström et al. 

2012)

Males: 382–688 hours 

Females: 1.03–41.28 hours 

597–643 hours

PFBuS 665 hours 

(Olsen et al. 2009)

8.0–95.2 hours 

(Chengelis et al. 2009; 

Olsen et al. 2009)

2.1–7.42 hours 

PFBA 72 hours 

(Chang et al. 2008b)

40.3–41.0 hours 

(Chang et al. 2008b)

1.03–9.22 hours 2.79–13.34 hours

aSee Section 3.1.4 for citations.

The mechanisms of toxicity of perfluoroalkyl compounds have not been fully elucidated. There is strong 

evidence that some effects observed in rodents, such as hepatotoxicity, immunotoxicity, and 

developmental toxicity, involve the activation of peroxisome proliferator-activated receptor-α (PPARα); 

however, humans and nonhuman primates are less responsive to PPARα agonists than rodents. 

Additionally, PPARα-independent mechanisms are also involved and it is not known if species 
PERFLUOROALKYLS 5

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

differences exist for these mechanisms. In general, epidemiology studies use serum perfluoroalkyl levels 

as a biomarker of exposure, which contrasts with experimental 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 comparisons between administered doses in laboratory animals and serum 

concentrations in humans.

Effects in Humans. Perfluoroalkyl compounds have been detected in the serum of workers, residents 

living near perfluoroalkyl facilities, and the general population. A large number of epidemiology studies 

have evaluated possible associations between perfluoroalkyl exposure and a wide range of adverse health 

outcomes. Most of the studies have focused on PFOA and/or PFOS; fewer studies have evaluated a 

smaller number of potential health outcomes for the remaining 12 perfluoroalkyls included in this 

toxicological profile. Most of the epidemiology studies lack exposure monitoring data, and there is a 

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 are 

occupational exposure studies, studies of communities living near a PFOA manufacturing facility with 

high levels of PFOA in the drinking water, and studies of populations exposed to background levels of 

perfluoroalkyl compounds (referred to as general population studies). Of the three categories of subjects, 

workers have the highest potential exposure to perfluoroalkyls, followed by the highly-exposed residents 

in the Mid-Ohio Valley, 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 highly-exposed residents (without occupational exposure) near this 

facility was 423 ng/mL in 2004–2005 (Emmett et al. 2006a). By comparison, the geometric mean 

concentration of PFOA in the U.S. population was 3.92 ng/mL in 2005–2006 (CDC 2013). Although a 

large number of epidemiology studies have examined the potential of perfluoroalkyl compounds to induce 

adverse health effects, most of the studies are cross-sectional in design and do not establish causality. 

Based on a number of factors (described in Section 2.1) including the consistency of findings across 

studies, the available epidemiology studies suggest associations between perfluoroalkyl exposure and 

several health outcomes:

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

• Liver damage, as evidenced by increases in serum enzymes and decreases in serum bilirubin 

levels (PFOA, PFOS, PFHxS)
PERFLUOROALKYLS 6

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

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

cholesterol (PFOA, PFOS, PFNA, PFDeA)

• Increased risk of thyroid disease (PFOA, PFOS)

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

• Increased risk of asthma diagnosis (PFOA)

• Increased risk of decreased fertility (PFOA, PFOS)

• Small (<20 g or 0.7 ounces per 1 ng/mL increase in blood perfluoroalkyl 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 kidney 

cancer have been observed in highly exposed humans.

There is also some suggestive evidence for associations between perfluoroalkyls and additional health 

outcomes; there is less certainty in these associations due to the higher degree of inconsistencies across 

studies and/or a smaller 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, PFUA, PFDoA). Additionally, associations between serum PFOA and PFOS and 

decreases in glomerular 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 and not perfluoroalkyl toxicity.

Effects in Laboratory Animals. Most of the information regarding the effects of perfluoroalkyl 

compounds in animals is derived from oral studies; considerably less information is available from 

inhalation and dermal exposure studies. PFOA and PFOS are the most studied perfluoroalkyl 

compounds, with considerably less data for the other compounds. Of the 187 animal studies reviewed in 

this toxicological profile, 48% examined PFOA, 34% examined PFOS, and 18% examined other 

perfluoroalkyls (4 studies on PFHxS, 16 studies on PFNA, 1 study on PFUA, 4 studies on PFBuS, 

6 studies on PFBA, 6 studies on PFDeA, 2 studies on PFDoA, 1 study on PFOSA, and 3 studies on 

PFHxA). The primary effects observed in laboratory animals exposed to perfluoroalkyl compounds are 

liver toxicity, developmental toxicity, and immune toxicity (see Figures 1-1, 1-2, and 1-3; not all of these 

effects have been observed or examined for all perfluoroalkyl compounds. Based on limited data, the 
PERFLUOROALKYLS 7

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

Figure 1-1. Health Effects Found in Animals Following Oral Exposure to PFOA
PERFLUOROALKYLS 8

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

Figure 1-2. Health Effects Found in Animals Following Oral Exposure to PFOS
PERFLUOROALKYLS 9 

1. RELEVANCE TO PUBLIC HEALTH 

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

Perfluoroalkyls 

***DRAFT FOR PUBLIC COMMENT*** 
PERFLUOROALKYLS 10

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

toxicity of perfluoroalkyl compounds does not appear to be specific to the route of administration. It 

should be noted that, for the most part, adverse health effects in studies in animals have been associated 

with exposure concentrations or doses that resulted in blood levels of perfluoroalkyl compounds that were 

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 and 

experimental animals. The elimination t1/2 of PFOA is approximately 4 years in humans compared with 

days or hours in rodents. These factors, plus issues related to the mode of action of perfluoroalkyls (see 

below), make it somewhat difficult at this time to determine the true relevance of some effects reported in 

animal studies to human health.

Many of the adverse health effects observed in laboratory animals result from the ability of these 

compounds (with some structural restrictions) to activate the PPARα, which can mediate a broad range of 

biological responses (Issemann and Green 1990). Species differences in the response to PPARα agonists 

have been found; 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 a 

functional PPARα. Several explanations for these species differences have been suggested (e.g., 

differences in the ability of PPARα to be induced after exposure to a peroxisome proliferator and 

differences in the pattern and level of tissue-specific expression of PPARα). Activation of this receptor in 

rodents initiates a characteristic sequence of morphological and biochemical events, principally, but not 

exclusively, in the liver (Cattley et al. 1998; Kennedy et al. 2004; Klaunig et al. 2003). The proliferation 

of peroxisomes has been associated with a variety of effects, including hepatocellular hypertrophy, 

alterations in lipid metabolism, and decreased pup survival and immune effects. Studies in PPARα-null 

mice provide evidence that PPARα-independent mechanisms are also involved in PFOA and PFOS 

toxicity, including liver and immune toxicity. A more complete discussion of the mechanisms of PFOA 

and PFOS toxicity is presented in Section 2.20.

Liver Effects. Many studies have described morphological and biochemical alterations in the liver from 

rodents 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 and 

triglyceride levels (e.g., Butenhoff et al. 2004b; Liu et al. 1996; Pastoor et al. 1987; Yang et al. 2001). 

The observed hepatomegaly and hypertrophy are likely due to expansion of the smooth endoplasmic 

reticulum and proliferation of peroxisomes, as confirmed by increased 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, 
PERFLUOROALKYLS 11

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

absolute liver weight and fatty acid β-oxidation activity were significantly 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 with PFOA have shown that the hepatic 

effects are reversible once dosing ceases and that recovery tends to parallel 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 treated with ≥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, and 

decreases in serum cholesterol and triglyceride levels in rodents (e.g., Elcombe et al. 2012a, 2012b; Era et 

al. 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 proliferation 

and 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 perfluoroalkyl compounds 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; Hoberman 

and York 2003; Kudo et al. 2000, 2006; Permadi et al. 1992, 1993; van Otterdijk 2007a, 2007b). 

Significant peroxisome activity seems to require 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 mouse COS-1 cells, PFOA had the lowest 

effective concentration needed for PPARα activation followed by PFNA and PFDeA, 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 PFBuS. Wolf et al. (2008a) also found that carboxylate 

perfluoroalkyls activated PPARα at lower concentrations than the sulfonate perfluoroalkyls. Studies have 

shown that the differential activity is also related to differential accumulation of the perfluoroalkyl 

compound in the liver (Kudo and Kawashima 2003; Kudo et al. 2000, 2006). Hydrophobicity, which 
PERFLUOROALKYLS 12

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

increases as carbon length increases, seems to favor biliary enterohepatic recirculation, resulting in a more 

protracted toxicity (Goecke-Flora and Reo 1996).

Developmental Effects. PFOA and PFOS have induced developmental effects in rodents. Most studies 

with PFOA have been conducted in mice, probably because of the relatively short half-life for PFOA in 

female rats, which would prevent accumulation of PFOA during the dosing period. Specific effects 

reported include prenatal loss, reduced neonate weight and viability, neurodevelopment toxicity, 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 mice treated with as low as 0.6 mg/kg/day PFOA on gestation days (GDs) 1–17 (Abbott et al. 

2007). This dose level 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 were administered a single gavage dose of PFOA at the age of 10 days (Johansson et al. 2008). 

Increases in motor activity were also observed following in utero exposure to PFOA (Cheng et al. 2013; 

Onishchenko et al. 2011). A cross-fostering study showed that the delays in mammary gland 

development were observed following in utero exposure and following lactation-only exposure (White et 

al. 2009); however, the results of a 2-generation study showed that the delayed development did not 

appear to affect lactational support (White et al. 2011). No fetal toxicity or teratogenicity was reported in 

offspring of rabbits exposed to up to 50 mg/kg/day PFOA on GDs 6–18 (Gortner et al. 1982), suggesting 

that rabbits are less susceptible than mice to the developmental effects of PFOA, although comparing 

administered doses is probably not very informative. There were significant increases in body weight 

gain in mice aged 10–40 weeks that were exposed to low levels of PFOA (0.01–0.3 mg/kg/day) on 

GDs 1–17 (Hines et al. 2009). Increases in serum insulin and leptin 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, and brown fat weight at age 18 months (Hines 

et al. 2009). 
PERFLUOROALKYLS 13

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

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 to 

mediate 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 in 

both 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 are 

insufficient 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. Dosing rats late during gestation (GDs 17–20) 

caused significantly more lethality than dosing early (GDs 2–5) (Grasty et al. 2003). Since pups had 

difficulty breathing within minutes of birth and their lungs showed evidence of delayed lung maturation 

and other histological alterations (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; Chen et 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 when mice were placed in a novel environment (Fuentes et al. 2007a; Onishchenko et al. 2011); 

another study 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, and 

alterations 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 PFDeA 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, PFBuS, or PFHxS 
PERFLUOROALKYLS 14

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

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 

observed in mice exposed to PFHxS on PND 10 (Viberg et al. 2013); no alterations were observed in 

mice similarly exposed to PFDeA (Johansson et al. 2008).

Immunological Effects. A number of studies have examined the immunotoxicity of perfluoroalkyls in 

rats and mice; these data suggest that mice are considerably more sensitive than rats. PFOA- and 

PFOS-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 et 

al. 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 IgE 

levels following a challenge with ovalbumin relative to mice treated with ovalbumin alone, which led the 

investigators to suggest that PFOA may increase the IgE response to environmental allergens (Fairley et 

al. 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), PFDeA 

(Harris et al. 1989), PFBuS (3M 2001), or PFBA (3M 2007a; Butenhoff et al. 2012a; van Otterdijk 2007a, 

2007b).

Cancer Effects. PFOA, as many other PPARα agonists, induced hepatocellular adenomas, Leydig cell 

adenomas, and pancreatic acinar cell adenomas in rats (Biegel et al. 2001). Liver tumors induced by 

PFOA are believed to be mediated largely through PPARα activation, and considered to be of limited 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, 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 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 through 
PERFLUOROALKYLS 15

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

decreased biosynthesis, or via the conversion of testosterone to estradiol via the enzyme aromatase, both 

of 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 human 

relevance (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 of 

action is limited to information demonstrating increased biliary excretion of PFOA in wild-type and 

PPARα 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 preclude a conclusion regarding 

the human relevance of PFOA-induced pancreatic tumors (EPA 2016h). 

1.3 MINIMAL RISK LEVELS (MRLs)

A summary of the provisional MRLs derived for perfluoroalkyl compounds is presented in Table 1-2. 

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 not 

adequate for identifying the most sensitive targets of toxicity or establishing dose-response relationships. 

No inhalation data are available for other perfluoroalkyl compounds.

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

Perfluoroalkyl Compounds

Compound

Inhalation MRLs Oral MRLs

Acute Intermediate Chronic Acute Intermediate Chronic

PFOA Xa X X X 3x10-6 mg/kg/day

(Table 1-3)

X

PFOS X X X X 2x10-6 mg/kg/day

(Table 1-4)

X

PFHxS X X X X 2x10-5 mg/kg/day

(Table 1-5)

X

PFNA X X X X 3x10-6 mg/kg/day

(Table 1-6)

X

PFDeA X X X X X X

PFUA X X X X X X

PFHpA X X X X X X
PERFLUOROALKYLS 16

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

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

Perfluoroalkyl Compounds

Compound

Inhalation MRLs Oral MRLs

Acute Intermediate Chronic Acute Intermediate Chronic

PFBuS X X X X X X

PFBA X X X X X X

PFDoA X X X X X X

PFHxA X X X X X X

PFOSA X X X X X X

Me-PFOSA-AcOH X X X X X X

Et-PFOSA-AcOH X X X X X X

aX indicates that no MRL was derived.

Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; Me-PFOSA-AcOH = 2-(N-methylperfluorooctane sulfonamide); acetic acid; PFBA = perfluorobutyric acid; PFBuS = perfluorobutane sulfonic acid; 

PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; 

PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; 

PFUA = perfluoroundecanoic acid

The oral databases were considered adequate for derivation of provisional intermediate-duration oral 

MRLs for PFOA, PFOS, PFHxS, and PFNA based on laboratory animal data. The databases were not 

considered adequate for derivation of MRLs for the other perfluoroalkyl compounds. Hepatic, immune, 

and developmental endpoints were the most sensitive targets in laboratory animals exposed to PFOA (see 

Figure 1-4) and PFOS (see Figure 1-5), respectively. The most sensitive targets were hepatic and thyroid 

endpoints for PFHxS and body weight and developmental endpoints for PFNA. The provisional 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 detail in Appendix A.
PERFLUOROALKYLS 17

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

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.
PERFLUOROALKYLS 18

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

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.
PERFLUOROALKYLS 19

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

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

Exposure 

duration MRL Critical effect

Point of 

departure Uncertainty factor Reference

Inhalation exposure

Acute Insufficient data for MRL derivation

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

Oral exposure (mg/kg/day)

Acute Insufficient data for MRL derivation

Intermediate 3x10-6 Neurodevelopmental 

and skeletal effects in 

mice

0.000821 

(LOAELHED)

300 Koskela et al. 

2016; 

Onishchenko 

et al. 2011

Chronic Insufficient data for MRL derivation

aSee Appendix A for additional information.

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

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

Exposure 

duration MRL Critical effect

Point of 

departure

Uncertainty and 

modifying factors Reference

Inhalation exposure

Acute Insufficient data for MRL derivation

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

Oral exposure (mg/kg/day)

Acute Insufficient data for MRL derivation

Intermediate 2x10-6 Delayed eye opening 

and decreased pup 

weight in rats

0.000515 

(NOAELHED)b

30

10

Luebker et 

al. 2005a

Chronic Insufficient data for MRL derivation

aSee Appendix A for additional information.

HED = human equivalent dose; NOAEL = no-observed-adverse-effect level; PFOS = perfluorooctane sulfonic acid
PERFLUOROALKYLS 20

1. RELEVANCE TO PUBLIC HEALTH

***DRAFT FOR PUBLIC COMMENT***

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

Exposure 

duration MRL Critical effect

Point of 

departure

Uncertainty and 

modifying factors Reference

Inhalation exposure

Acute Insufficient data for MRL derivation

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

Oral exposure (mg/kg/day)

Acute Insufficient data for MRL derivation

Intermediate 2x10-5 Thyroid follicular cell 

damage in rats 

0.0047 

(NOAELHED)

30

10

Butenhoff et 

al. 2009a

Chronic Insufficient data for MRL derivation

aSee Appendix A for additional information.

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

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

Exposure 

duration MRL Critical effect

Point of 

departure

Uncertainty and 

modifying factors Reference

Inhalation exposure

Acute Insufficient data for MRL derivation

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

Oral exposure (mg/kg/day)

Acute Insufficient data for MRL derivation

Intermediate 3x10-6 Decreased body weight 

and developmental 

delays in mice

0.001 

(NOAELHED)

30

10

Das et al. 

2015

Chronic Insufficient data for MRL derivation

aSee Appendix A for additional information.

HED = human equivalent dose; NOAEL = no-observed-adverse-effect level; PFNOA = perfluorononanoic acid 
PERFLUOROALKYLS 21

***DRAFT FOR PUBLIC COMMENT***

CHAPTER 2. HEALTH EFFECTS

2.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of perfluoroalkyls. 

It contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.

This document discusses information on perfluoroalkyl compounds that have been measured in the serum 

collected from a representative U.S. population ≥12 years of age in the 2003–2004 NHANES (Calafat et 

al. 2007b), as well as 2 compounds (PFBA and PFHxA) that have been identified in other monitoring 

studies. These compounds include: 

Perfluorooctanoic acid (PFOA)

Perfluorooctane sulfonic acid (PFOS) 

Perfluorohexane sulfonic acid (PFHxS) 

Perfluorononanoic acid (PFNA) 

Perfluorodecanoic acid (PFDeA) 

Perfluoroundecanoic acid (PFUA)

Perfluoroheptanoic acid (PFHpA)

Perfluorobutane sulfonic acid (PFBuS)

Perfluorobutyric acid (PFBA)

Perfluorododecanoic acid (PFDoA)

Perfluorohexanoic acid (PFHxA)

Perfluorooctane sulfonamide (PFOSA)

2-(N-Methyl-perfluorooctane sulfonamide) acetic acid (Me-PFOSA-AcOH) 

2-(N-Ethyl-perfluorooctane sulfonamide) acetic acid (Et-PFOSA-AcOH)

The term perfluoroalkyls used throughout the profile is referring to these 14 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 of 

route of exposure (inhalation, oral, and dermal) and three exposure periods: acute (≤14 days), intermediate 

(15–364 days), and chronic (≥365 days).
PERFLUOROALKYLS 22

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

As discussed in Appendix B, a literature search was conducted to identify relevant studies examining health 

effect endpoints. Figures 2-1, 2-2, and 2-3 provide an overview of the database of studies in humans 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.

Summaries of the epidemiology studies, including details on the study design and results, are presented in 

tables in the Supporting Document for Epidemiological Studies for Perfluoroalkyls; briefer summaries of 

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. 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 in Tables 2-1 and 2-2, respectively. The oral data for PFOA, PFOS, and 

other perfluoroalkyls are presented in Tables 2-3, 2-4, and 2-5, respectively. The dermal data for PFOA 

is presented in Table 2-6. In addition, the NOAEL and LOAEL values from inhalation and oral studies 

are graphically presented in Figures 2-4, 2-5, 2-6, 2-7, and 2-8.

Levels of significant exposure (LSEs) for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (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 cause significant 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 in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant 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 an attempt at distinguishing 

between "less serious" and "serious" effects. The distinction between "less serious" 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 
PERFLUOROALKYLS 23

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 health 

effect section begins with an overview, which contains a brief discussion of the available data and 

conclusions that can be drawn from the data. Compound-specific discussions follow the overview; the 

perfluoroalkyls are discussed in the following order: PFOA, PFOS, PFHxS, PFNA, PFDeA, PFUA, 

PFHpA, PFBuS, PFBA, PFDoA, PFHpA, PFOSA, Me-PFOSA-AcOH, and Et-PFOSA-AcOH. It is 

noted that for most health effects, there are no data for a number of the perfluoroalkyl compounds. The 

compound-specific discussions are further divided into Epidemiology Studies and Laboratory Animal 

Studies; for data-rich endpoints, a compound-specific summary is also included. Each perfluoroalkyl is 

treated separately in this chapter. Although there is some evidence of similar health outcomes for some 

compounds, 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 epidemiology and animal 

studies; the literature search framework for identifying these studies is discussed in Appendix B. As 

illustrated in Figures 2-1, 2-2, and 2-3, most of the health effects data come from epidemiology studies. 

For PFOA, PFOS, and other perfluoroalkyls, 67, 70, and 73%, respectively, of the health effect studies 

were in humans; it is noted that a number of epidemiology studies examined more than one perfluoroalkyl 

compound. Three population categories were examined in epidemiology studies: workers at facilities 

involved in the production or use of perfluoroalkyls (most of the studies involved workers at two U.S.

facilities), communities living near a PFOA manufacturing facility with high levels of PFOA in the 

drinking water (almost all of the studies involved residents living near a PFOA production facility in 

West Virginia), and populations exposed to background levels of perfluoroalkyl compounds (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 were collected from over 

69,000 participants who lived, worked, or attended school in six contaminated water districts surrounding 
PERFLUOROALKYLS 24

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 an average age of 

39.1 years. 

Serum perfluoroalkyl levels were used as the biomarker of exposure in almost all of the epidemiology 

studies. 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 a mean 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). Most of the epidemiology studies provided a single serum perfluoroalkyl 

concentration, which has been shown to be a reliable biomarker of recent exposure; however, it does not 

provide information on historical exposure. The lack of historical exposure data is a particular limitation 

of the occupational and community population studies where past exposures were typically higher than 

current exposures. Another limitation of the epidemiology studies involves co-exposure to multiple 

perfluoroalkyl compounds. A number of the epidemiology studies have found strong correlations 

between serum levels of different perfluoroalkyl compounds. In vitro studies (Carr et al. 2013; Wolf et al. 

2014) have shown that at lower concentrations, binary pairs of perfluoroalkyl compounds demonstrate 

concentration and response additivity, but deviate from additivity at higher concentrations (Wolf et al. 

2014). These possible interactions (or dose additivity) complicate the interpretation of the epidemiology 

data.

Although a large number of epidemiology studies have examined the potential of perfluoroalkyl 

compounds to induce adverse health effects, most of the studies are cross-sectional in design and do not 

establish causality. ATSDR used a weight-of-evidence approach to evaluate whether the available data 

supported a link between perfluoroalkyl exposure and a particular health effect. This weight-of-evidence 

approach takes into consideration the consistency of the findings across studies, the quality of the studies, 

dose-response, and plausibility. 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 may be within the normal limits or not indicative of an adverse health outcome. Plausibility 
PERFLUOROALKYLS 25

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

depends primarily on experimental toxicology studies that establish a plausible biological mechanism for 

the observed effects.

The available epidemiology studies suggest links between perfluoroalkyl exposure and several health 

outcomes:

• Hepatic effects. Increases in serum enzymes and decreases in serum bilirubin, observed in 

studies of PFOA, PFOS, and PFHxS, are suggestive of liver damage. In addition, the results of 

epidemiology studies of PFOA, PFOS, PFNA, and PFDeA suggest a link between perfluoroalkyl 

exposure and increases in serum lipid levels, particularly total cholesterol and LDL cholesterol.

• Cardiovascular effects. There is suggestive epidemiological evidence for an association 

between serum PFOA and PFOS and pregnancy-induced hypertension and/or pre-eclampsia.

• Endocrine effects. Epidemiology studies provide suggestive evidence of a link between serum 

PFOA and PFOS and an increased risk of thyroid disease.

• Immune effects. Evidence is suggestive of a link between serum PFOA, PFOS, PFHxS, and 

PFDeA levels and decreased antibody responses to vaccines. A possible link between serum 

PFOA levels and increased risk of asthma diagnosis has also been found.

• Reproductive effects. A suggestive link between serum PFOA and PFOS levels and an 

increased risk of decreased fertility has been found.

• Developmental effects. Evidence is suggestive of a link between serum PFOA and PFOS 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.

As presented in Figures 2-1, 2-2, and 2-3, most of the available literature on the health effects of 

perfluoroalkyl compounds 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, and 

monkeys indicates that the liver is a sensitive target of PFOA, PFOS, PFHxS, PFNA, PFDeA, 

PFUA, PFBA, PFBuS, PFDoA, and PFHpA toxicity. The effects include increases in liver 

weight, hepatocellular hypertrophy, and decreases in serum lipid levels. The effects were 

considered specific to rodents and were not considered relevant to humans. Some degenerative 

and necrotic effects that are likely relevant to humans have also been observed for PFOA, PFOS,

and PFHpA.
PERFLUOROALKYLS 26

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

• 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 was 

observed in the one study of PFNA. Immune function has not been tested for the other 

perfluoroalkyl compounds examined in this profile.

• Reproductive effects. Decreases in mammary gland development have been observed in mice 

orally exposed to PFOA. In general, studies of PFOA and PFOS have not found alterations in 

fertility.

• Developmental effects. Evidence from acute and intermediate oral studies in rats and/or mice 

indicates that developmental endpoints are targets of PFOA, PFOS, PFHxS, PFNA, PFDeA, 

PFUA, and PFBA toxicity. The developmental effects include decreases in pup body weight, 

decreases in pup survival, and alterations in locomotor activity.
PERFLUOROALKYLS 27

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-1. 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 outcomes

More studies evaluated health effects in humans than animals (counts represent studies examining endpoint)

 

*Includes studies discussed in Chapter 2. A total of 271 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.
PERFLUOROALKYLS 28

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-2. Overview of the Number of Studies Examining PFOS Health Effects* 

 

Developmental, hepatic, and reproductive effects of PFOS were the most widely examined potential toxicity outcomes

More studies evaluated health effects in humans than animals (counts represent studies examining endpoint)

 

*Includes studies discussed in Chapter 2. A total of 218 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.
PERFLUOROALKYLS 29

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-3. 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 outcomes

More studies evaluated health effects in humans than animals (counts represent studies examining endpoint)

*Includes studies discussed in Chapter 2. A total of 127 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.
PERFLUOROALKYLS 30

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-1. Levels of Significant Exposure to PFOA – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/m3)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

ACUTE EXPOSURE

1 Rat

(albino)

5 M,F

1 hour

(NS)

18,600 CS, BW, GN, 

HP

Resp 18,600 Red nasal discharge; dry rales

Ocular 18,600 Red material around the eyes; lacrimation

Neuro 18,600 Excessive salivation

Griffith and Long 1980

APFO

2 Rat

(CD)

36 M

4 hours 380, 810, 

830, 2,200, 

4,800, 

5,700

CS, HE, BI, 

GN, HP

Death 980 M LC50

Bd Wt 380 M Weight loss for 1–2 days after exposure

(data not shown)

Resp 380 M Pulmonary edema

Gastro 380 M Stomach irritation

Hepatic 810 Liver enlargement at 810 mg/m3; no 

histological alterations

Ocular 380 M 810 M Corneal opacity and corrosion

Kennedy et al. 1986

APFO

3 Rat

(CD)

24 M

2 weeks

6 hours/day

5 days/week

0, 1, 7.6, 

84

CS, HE, BI, 

GN, HP

Bd Wt 7.6 84 7% lower body weight on exposure day 5

Resp 84 

Cardio 84 

Gastro 84 

Hemato 84 

Musc/skel 84 

Hepatic 84 Increased absolute and relative liver weight; 

hepatocellular hypertrophy at 7.6 mg/m3

Renal 84 

Dermal 84 

Ocular 84 

Endocr 84 

Neuro 84 No histological alterations

Repro 84 No histological alterations

Kennedy et al. 1986
PERFLUOROALKYLS 31

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-1. Levels of Significant Exposure to PFOA – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/m3)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

APFO

4 Rat

(SpragueDawley)

12 F

GDs 6–15

6 hours/day

0, 0.1, 1, 

10, 25

MX, DX, OW, 

CS, HP

Death 25 3/12 deaths on GDs 12, 13, and 17

Bd Wt 1 10 12% decrease weight gain on GDs 6–15

Hepatic 25 18% increase absolute liver weight at 

25 mg/m3

Develop 10 25 10% decreased neonatal body weight on 

PND 1

Staples et al. 1984

APFO

aThe number corresponds to entries in Figure 2-4.

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 = hematology; HP = histopathology; LC50 = lethal concentration, 50% kill; LE = lethality; LOAEL = lowest-observed-adverse-effect level; 

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 32

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-4. Levels of Significant Exposure to PFOA – Inhalation

Acute (≤14 days)
PERFLUOROALKYLS 33

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/m3)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

ACUTE EXPOSURE

PFNA

1 Rat

(CD)

6 M

4 hours 67–4,600 LE Death 820 14-day LC50

Kinney et al. 1989

Exposure was nose-only.

2 Rat

(CD)

10 M

4 hours 0, 67, 590 BW, OW Bd Wt 67 590 Reduced 18% 5 days after exposure

Resp 67 590 Lung noise; labored breathing during and 

after exposure

Hepatic 67 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 2-5.

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 34

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-5. Levels of Significant Exposure to Other Perfluoroalkyls – Inhalation

Acute (≤14 days)
PERFLUOROALKYLS 35

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

ACUTE EXPOSURE

1 Monkey

(Rhesus)

10 M,F

2 weeks

(G) 

0, 3, 10, 30, 

100

LE, CS, HE, 

BI, GN, HP

Death 100 Unspecified number out of 4 died 

on week 2

Griffith and Long 1980

APFO

2 Rat

(CD)

10 M

14 days

(GW)

0, 25 BI, OW Repro 25 184% increase in serum estradiol

Biegel et al. 1995

APFO

3 Rat

(CD)

75 M

14 days

(GW)

0, 1, 10, 25,

50

BW, OW, BI, 

HP

Bd Wt 10 25 14% reduction in final body weight

Hepatic 50 46% increase in relative liver 

weight at ≥10 mg/kg/day

Repro 1 10 63% increase in serum estradiol

Cook et al. 1992

APFO

4 Rat

(Sprague-Dawley)

18 M

1 or 7 days

(F)

0, 18, 23 Hepatic 23 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

Once 

(GO)

100, 215, 

464, 1,000, 

2,150

Death 680 M

430 F

LD50

LD50

Griffith and Long 1980

APFO
PERFLUOROALKYLS 36

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

6 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

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)

8 M

7 days

ad lib 

(F)

0, 16 BW, OW, BI, 

EA

Bd Wt 16 

Hepatic 16 66% increase in absolute liver 

weight

Haughom and Spydevold 1992

APFO

8 Rat (SpragueDawley)

3 M

14 days

(F)

0, 20 OW, EA Hepatic 20 45% increase in relative liver 

weight

Ikeda et al. 1985

PFOA

9 Rat (SpragueDawley)

16 M

14 days

(GW)

0, 0.5, 5, 50 BW, OW, CS, 

HE, BI

Bd Wt 50 

Hepatic 50 2-fold increased mean relative liver 

weight at 50 mg/kg/day

Immuno 50 No alterations in spleen weight or 

splenocyte phenotype

Iwai and Yamashita 2006

APFO
PERFLUOROALKYLS 37

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

10 Rat

(Wistar)

5–12 M

Once

(GO)

0, 50 BW, FX BW 50

Neuro 50 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

BW, OW, EA, 

HP

Bd Wt 38 

Hepatic 9.5 Significant increase in absolute 

and relative 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, 

BW, OW, BC Bd Wt 1 3 24% decrease in overall body 

weight gain

Hepatic 30 Decreased serum cholesterol 

levels at ≥0.3 mg/kg/day

Loveless et al. 2006

APFO

13 Rat

(CD)

15 M

14 days

(G)

0, 0.2, 2, 20, 

40

BW, OW, EA Bd Wt 2 20 14% lower final body weight

Hepatic 40 34% increase in absolute and 

relative liver weight at 

≥2 mg/kg/day

Repro 0.2 2 2-fold increase in serum estradiol

Liu et al. 1996

APFO

14 Rat

(Sprague-Dawley)

24 M

1, 3, 7 days

(GW)

0, 50 BW, BI, EA, 

HP

Bd Wt 50 17% weight loss

Hepatic 50 2-fold increase in relative and 

absolute liver weight

Pastoor et al. 1987

APFO
PERFLUOROALKYLS 38

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

15 Rat

(Sprague-Dawley)

12 or 25 F

GDs 6–15 

(GO)

0, 100 DX, MX, BW Bd Wt 100 33% reduced maternal body weight 

gain 

Develop 100 No alterations in fetal body weight 

or teratology

Staples et al. 1984

APFO

16 Mouse

(SV129 wild type)

4 M

7 days

(G)

0, 10 BW, HP Bd Wt 10

Hepatic 10 Hepatocellular hypertrophy, 

steatosis, and increased hepatic 

triglyceride levels

Das et al. 2017

PFOA

17 Mouse

(C57BL/6N)

6 F

10 days

(W)

0, 3.75, 7.5, 

15

FX Immuno 7.5 15 Altered response to sRBC

DeWitt et al. 2009

PFOA

18 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 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

19 Mouse

(C57BL/6N)

16 F

GDs 6–17

(DW)

0, 0.5, 1 Bd Wt 1 

Develop 0.5 7–10% decrease in litter weight on 

PND 2

Hu et al. 2010

APFO
PERFLUOROALKYLS 39

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

20 Mouse

(CD-1)

10 M

Once

(G)

0, 0.58, 8.70 CS, OF, DX Develop 0.58 Decreased spontaneous activity 

and altered response to cholinergic 

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

21 Mouse 

(CD-1)

5 M,F

14 days

(F)

0, 5.3, 54, 

537

OW Hepatic 537 123–155% increase in absolute 

liver weight in 14 days at 

≥5.3 mg/kg/day

Kennedy 1987

APFO

22 Mouse

(CD-1)

10 M

14 days

(GW)

0, 0.3, 1, 3, 

10, 30, 

BW, OW, BC Bd Wt 3 10 6–12% decreased in body weight 

gain

Hepatic 30 Decreased serum cholesterol 

levels at ≥0.3 mg/kg/day

Loveless et al. 2006

APFO

23 Mouse

(C57BL/6N)

3 M

2–10 days

(F)

0, 78, 390 BW, OW, EA Bd Wt 78 25% body weight loss after 

10 days of treatment

Hepatic 390 74% increase in absolute liver 

weight at ≥78 mg/kg/day

Permadi et al. 1992

PFOA

24 Mouse

(C57BL/6N)

4 M

2–10 days

(F)

0, 78, 390 BW, OW, EA Bd Wt 78 25% body weight loss after 5 days 

of treatment

Hepatic 390 74% increase in absolute liver 

weight in 5 days at ≥78 mg/kg/day

Permadi et al. 1993

PFOA
PERFLUOROALKYLS 40

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

25 Mouse

(BALB/c)

5 F

7 days

(GW)

20 BW, OW, BC Bd wt 20 36% decrease in body weight gain

Hepatic 20 32% increase in relative liver 

weight

Immuno 20 Inhibition of T-and B-lymphocyte 

proliferation in 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

PFOA

26 Mouse

(CD-1)

14 F

GDs 8–17

GDs 1217

(GW) 

0, 5 DX, GN Develop 5 Altered mammary gland 

development in female pups; 

reduced pup weight on PND 20

White et al. 2007

APFO
PERFLUOROALKYLS 41

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

27 Mouse

(CD-1)

56 F

GDs 8–17

(GW)

0, 5 Bd Wt 5 

Hepatic 5 40–120% increased relative liver 

weight in lactating dams on 

PNDs 1–10

Repro 5 Immature mammary gland 

morphology in lactating dams on 

PNDs 1–10

Develop 5 Delayed mammary gland 

development (30–60%) in female 

pups on PNDs 1–10

White et al. 2009

APFO

28 Mouse

(CD-1)

12–14 F

GDs 7–17

GDs 10–17

GDs 13–17

GDs 15–17

0, 5 Develop 5 Delayed mammary gland 

development (31–47%) in female 

pups on PNDs 22–32 and at 

18 months

White et al. 2009

APFO

29 Mouse

(CD-1)

6–14 F

GDs 7–17, 

GDs 10–17 

GDs 13–17 

GDs 15–17 

(GW)

0, 5, 20 DX, MX, BW, 

OW

Bd Wt 20 No alterations in dams dosed on 

GDs 15–17

Hepatic 20 Increase in relative liver weight in 

dams dosed on GDs 13–17, 10–

17, or 7–17 at ≥5 mg/kg/day

Develop 5 Reduced pup body weight at 

weaning, 43% in males and 35% in 

females

Wolf et al. 2007

APFO

30 Mouse

(C57BL/6N)

8 M

7 days

(F)

0, 24 CS, BW, OW, 

BI

Bd Wt 24 >10% reduced final body weight

Hepatic 24 2-fold increase in absolute liver 

weight

Xie et al. 2003

PFOA
PERFLUOROALKYLS 42

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

31 Mouse

(C57BL/6N)

8 M

10 days

(F)

0, 30 BW, OW, BI, 

CS

Bd Wt 30 17% decrease in final body weight

Hepatic 30 >90% increase in absolute and 

relative liver weight

Immuno 30 86% reduction in absolute thymus 

weight; 30% reduction in absolute 

spleen weight

Yang et al. 2000

PFOA

32 Mouse

(C57BL/6N)

8 M

10 days

(F)

0, 1, 3.5, 

11.5, 23, 58

CS, BW, OW, 

OF, BI

Hepatic 1 35% increase in absolute liver 

weight at ≥1 mg/kg/day

Immuno 11.5 40–50% decrease in spleen and 

thymus weights

Yang et al. 2001

PFOA

33 Mouse

(C57BL/6N)

8–12 M

7 days

(F)

0, 24 CS, BW, BI, 

OF

Immuno 24 Decreased humoral response to 

immunization with horse red blood 

cells

Yang et al. 2002a

PFOA

34 Mouse

(C57BL/6N)

16 M

7 days

ad lib

(F)

0, 33 BW, OW, BI, 

OF

Bd Wt 33 14% decreased mean body weight

Hepatic 33 86% increase in absolute liver 

weight

Immuno 33 40% reduction in spleen weight 

and 79% reduction in thymus 

weight

Yang et al. 2002b

PFOA

Experiments with PPARα-null mice suggested PPARα-dependent and -independent immune effects

35 Rabbit

(New Zealand)

18 F

GDs 6–18

1 time/day

(GW)

0, 1.5, 5, 50 CS, MX, DX, 

BW

Develop 50 

Gortner et al. 1982

PFOA
PERFLUOROALKYLS 43

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

INTERMEDIATE EXPOSURE

36 Monkey

(Cynomolgus)

4–6 M

26 weeks

1 time/day

(C)

0, 3, 10, 

30/20

BC, BW, CS, 

EA, FI, GN, 

HE, HP, LE, 

OP, OW, UR

Bd Wt 10 20 12% decrease by week 10

Resp 20 

Cardio 20 

Gastro 20 

Hemato 20 

Musc/skel 20 

Hepatic 3 36% increase in absolute liver 

weight at ≥3 mg/kg/day; increased 

serum triglyceride levels at 

30/20 mg/kg/day

Renal 20 

Dermal 20 

Ocular 20 

Endocr 3 10 Significant decrease in serum TT4

(27–35%) and FT4 (30–38%)

Immuno 20 No histological alterations

Neuro 20 No histological alterations

Repro 20 No histological alterations

Butenhoff et al. 2002

APFO

37 Monkey

(Rhesus)

10 M,F

90 days

1 time/day

(G)

0, 3, 10, 30, 

100

LE, CS, HE, 

BI, GN, HP

Death 30 One male and two females died 

during weeks 7–12

Bd Wt 10 30 33% body weight loss by week 6

Cardio 10

Gastro 10 30 Emesis

Hemato 30

Hepatic 10

Renal 10

Immuno 10 30 Atrophy of lymphoid follicles in 

spleen and lymph nodes

Neuro 10 30 Hypoactivity and prostration
PERFLUOROALKYLS 44

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Repro 100 No histological alterations in testes 

or ovaries

Griffith and Long 1980

APFO

38 Monkey

(Cynomolgus)

8 M

30 day

1 time/day

(C)

0, 2, 20 CS, BW, FI, 

BI, HE, EA, 

GN, HP

Bd Wt 20 

Hemato 20 

Hepatic 20 

Endocr 20 No alterations in serum levels of 

thyroid hormones and TSH and 

histopathology of adrenals

Repro 20 No alterations in serum estradiol, 

estriol, or histopathology of the 

testes

Thomford 2001

APFO

39 Rat

(CD)

156 M

1 year

ad lib

(F)

0, 13.6 CS, BW, FI, 

OW, GN, HP

Bd Wt 13.6 >10% reduced weight gain

Hepatic 13.6 Increased relative liver weight

Repro 13.6 Significant increase in serum 

estradiol at 1, 3, 6, 9, and 

12 months (~100–180%); prolactin 

was decreased at all time points, 

but not always significantly

Biegel et al. 2001

APFO

40 Rat

(Sprague-Dawley)

30 M,F

70–90 days

1 time/day

(GW)

0, 1, 3, 10, 30 MX, DX, OF, 

BW, GN, HP

Bd Wt 3 10 >11% reduced body weight

Hepatic 1 3 Increased absolute and relative 

liver weight in P-generation (36%) 

and F1-generation (30%) males;

hepatocellular hypertrophy and 

less commonly necrosis in F1 

males (incidence not reported)

Renal 3 Increased absolute and relative 

kidney weight in P-generation 

(14%) and F1-generation (11%)

males
PERFLUOROALKYLS 45

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Endocr 10 30 Vacuolation of zona glomerulosa of 

adrenal gland

Repro 30 No alteration in reproductive 

performance in P0 or F1 

generation

Develop 10 30 Increased number of dead pups on 

PNDs 6–8

Butenhoff et al. 2004b

APFO

41 Rat

(Wistar)

5 F

GD 1 to 

PND 21

ad lib

(W)

0, 1.6 Develop 1.6 17–18% reduced motor 

coordination and increased 

locomotor activity in pups on 

PNDs 34–35

Cheng et al. 2013

PFOA

42 Rat

(Sprague-Dawley)

10 M

Daily

28 days

(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 and 

congestion in the hepatic sinusoid 

or central vein at 20 mg/kg/day

Neuro 5 Cachexia and lethargy

Cui et al. 2009

PFOA

43 Rat

(Sprague-Dawley)

10 M

28 days

(F)

0, 18 Hepatic 18 Increased liver weight (43% on 

day 29), decreased serum 

cholesterol (39% on day 29) and

triglyceride (73% on day 29), 

hepatocellular hypertrophy and 

hyperplasia

Elcombe et al. 2010

APFO
PERFLUOROALKYLS 46

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

44 Rat

(CD)

40 M,F

28 days

ad lib

(F)

M: 0, 3, 10, 

30, 100, 300, 

1,000, 3,000; 

F: 0, 3.4, 

11.3, 34, 113, 

340, 1,130, 

3,400

BW, FI, HP Bd Wt 10 M 30 M 100 M 30 mg/kg/day: 11% reduction in 

final body weight; 100 mg/kg/day: 

33% reduction in final body weight

Hepatic 3 M Hepatocyte hypertrophy

Griffith and Long 1980

APFO

45 Rat

(CD)

30 M,F

90 days

ad lib

(F)

M: 0, 1, 3, 10, 

30, 100; F: 0, 

1.1, 3.4, 11, 

34, 110

CS, BW, FI, 

HE BI, GN, 

HP, OW

Bd Wt 30 M

110 F

100 M 33% reduction in final mean body 

weight

Resp 100 F

Cardio 110 F

Gastro 110 F

Musc/skel 110 F

Hepatic 100 M Hepatocyte hypertrophy; 50% 

increase in absolute liver weight

Renal 110 F

Dermal 110 F

Ocular 110 F

Endocr 110 F

Immuno 110 F

Neuro 110 F No histological alterations

Repro 100 M

110 F

No histological alterations

Griffith and Long 1980

APFO

46 Rat

(Sprague-Dawley)

10 dams; 12–

13 pups

GDs 12–18

(GO)

0, 5, and 20 BC, BW, DX, 

OW

Bd Wt 5 20 30% reduction in body weight of 

dams

Develop 5 20 13% reduction in body weight of 

male pups

Li et al. 2016

PFOA
PERFLUOROALKYLS 47

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

47 Rat

(CD)

10 M

28 days

(G)

0, 0.29, 0.96, 

9.6, 29

Bd Wt 0.96 9.6 10% decrease in final body weight

Hemato 29 

Hepatic 0.29 29 34% decrease in serum triglyceride 

levels, minimal hepatocellular 

hypertrophy at ≥0.29 mg/kg/day; 

minimal focal necrosis at 

29 mg/kg/day

Immuno 29 

Loveless et al. 2008

APFO

48 Rat

(CD)

55 M

13 weeks

ad lib

(F)

0, 0.06, 0.64, 

1.94, 6.5

CS, BW, FI, 

OW, GN, HP

Bd Wt 6.5

Resp 6.5 

Hepatic 6.5 Minimal to moderate hepatocellular 

hypertrophy at ≥0.64 mg/kg/day

Neuro 6.5 No histological alterations

Repro 6.5 No histological alterations

Perkins et al. 2004

APFO

49 Mouse

(129S1/SvlmJ 

WT)

17 F

GDs 1–17

(GW)

0, 0.1, 0.3, 

0.6, 1, 3, 5, 

10, 20

MX, DX, BW Bd Wt 10 F

Hepatic 20 Increased absolute and relative 

liver weight of dams on PND 22 at 

≥1 mg/kg/day

Develop 0.3 0.6 Significantly reduced pup survival

(46%) from birth to weaning

Abbott et al. 2007

APFO

Body weight NOAEL is for changes during pregnancy.

50 Mouse

(wild-type Sv/129)

5–6 F

GDs 1–17

1 time/day

(GW)

0, 3 Hepatic 3 28% increased liver weight,

hepatocellular hypertrophy with 

increased peroxisomes

Develop 3 31.5% reduced pups per litter on 

PND 20

Albrecht et al. 2013

PFOA
PERFLUOROALKYLS 48

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

51 Mouse

(C57BL/6N)

8 F

15 days

ad lib

(W)

0, 0.94, 1.88, 

3.75, 7.5, 15, 

30

BW, OW, OF Bd Wt 7.5 15 Weight loss (~5%)

Immuno 1.88 3.75 Reduced sRBC-specific response 

to IgM antibody titers

DeWitt et al. 2008

APFO

52 Mouse

(wild-type 

C57BL/6-Tac and 

PPARα knockout)

8 F

15 days

(W)

0, 7.5, 30 BW, OW, BC Bd Wt 30 14–20% decrease in body weight 

in wild-type mice

Immuno 7.5 30 16 and 14% reduction in sRBCspecific antibody response in wildtype and PPARα knockout mice, 

respectively; 29.8% decrease in 

relative spleen weight in wild-type 

mice

DeWitt et al. 2016

PFOA

53 Mouse 

(C57BL/6N)

8 F

15 days

(W)

0, 0.94, 1.88, 

3.75, 7.5

BW, OW, BC Bd Wt 7.5 

Immuno 0.94 1.88 Decrease in DNP-specific IgM 

antibody responses; decreases in 

relative spleen (17%) and thymus 

weights (14%) at 7.5 mg/kg/day

DeWitt et al. 2016

PFOA

54 Mouse

(C57BL/6N)

8 F

10, 13, 

15 days

(W)

0, 3.75, 7.5 BC Bd Wt 7.5 

DeWitt et al. 2016

PFOA
PERFLUOROALKYLS 49

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

55 Mouse

(CD-1)

6–14 dams; 21–

37 F offspring

GDs 1–17

(GW)

0, 0.01, 0.1, 

0.3, 1, 5 

HP Hepatic 0.3 1 Increase in severity of chronic 

inflammation at ≥1 mg/kg/day; Ito 

cell hypertrophy and centrilobular 

hepatocellular hypertrophy at 

5 mg/kg/day

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

56 Mouse

(129/Sv WT)

3–7 dams; 6–10 F 

offspring

GDs 1–17

(GW)

0, 0.1, 0.3, 

0.6, 1 

HP Hepatic 1 Increased severity of centrilobular 

hepatocyte hypertrophy at 

≥0.3 mg/kg/day

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

57 Mouse

(129/Sv PPARαknockout)

5–9 dams; 6–10 F 

offspring

GDs 1–17

(GW)

0, 0.1, 0.3, 1, 

3 

HP Hepatic 1 3 Centrilobular hepatocyte 

hypertrophy and bile duct 

hyperplasia at 3 mg/kg/day

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

(CD)

40 M,F

28 days

ad lib

(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

BW, FI, HP Death 54 M

58 F

4/5 died before end of 4th week

5/5 died before 4th week of study

Bd Wt 5.4 M 5.8 F Males: final body weight 20% lower 

than controls; females: final body 

weight 25% lower than controls

Hepatic 18 3-fold or greater increased 

absolute and relative liver weight 

and hepatocellular hypertrophy at 

≥5.4 mg/kg/day

Griffith and Long 1980

APFO
PERFLUOROALKYLS 50

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

59 Mouse

(CD-1)

5–14F

GDs 1–17

(GW)

0, 0.01, 0.1, 

0.3, 1, 3, 5

BW FX Develop 5 F Decreased birth weight

(approximately 8%) and body 

weight at weaning (24%)

Hines et al. 2009

APFO

60 Mouse

(CD-1)

5 M,F

21 days

ad lib

(F)

0, 0.0018, 

0.0054, 

0.018, 0.054, 

0.18, 0.54, 

1.8, 5.4

OW Hepatic 5.4 39–41% increase in absolute liver 

weight at ≥5.4 mg/kg/day

Kennedy 1987

APFO

61 Mouse

(C57BL/6)

6 F

GDs 1–21

(F)

0.3 BW, DX Develop 0.3b Altered femur and tibial bone 

morphology, decreased tibial 

mineral density

Koskela et al. 2016

PFOA

Offspring were examined at 13 and 17 months of age

62 Mouse

(CD-1)

9–45 M

GDs 1–17

1 time/day

(GW)

0, 1, 3, 5, 10, 

20, 40

MX, DX, BW, 

OW

Bd Wt 5 10 32% reduced weight gain during 

pregnancy

Hepatic 1 38% increase in absolute liver 

weight at ≥1 mg/kg/day

Develop 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

Lau et al. 2006

APFO
PERFLUOROALKYLS 51

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

63 Mouse

(CD)

20 M

28 days

(G)

0, 0.29, 0.96, 

9.6, 29

Bd Wt 0.96 9.6 Weight loss (86% of controls)

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

Immuno 0.96 M 9.6 M Decreased response to sRBC, 

decreased number of splenic and 

thymic lymphocytes 

Loveless et al. 2008

APFO

64 Mouse

(CD-1)

13 F

GDs 1–17

(G)

0, 0.3, 1.0, 

3.0 

DX Develop 0.3 Impaired development of 

mammary glands in offspring

Macon et al. 2011

PFOA

65 Mouse

(CD-1)

13 F

GDs 10–17

(G)

0, 0.01, 0.1, 

1.0 

DX Develop 0.01 Developmental delays in mammary 

gland development

Macon et al. 2011

PFOA

66 Mouse

(C57BL/6JApc+/+)

20–21 F

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 

births

Ngo et al. 2014

PFOA

67 Mouse

(C57BL/6/

Bk1)

6 F

GDs 1–21

ad lib

(F)

0, 0.3 Develop 0.3b Increased locomotor activity in 

adult offspring

Onishchenko et al. 2011

PFOA
PERFLUOROALKYLS 52

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

68 Mouse

(CD-1)

17–21 F dams; 4–

6 M,F pups

GDs 1–17

(GW)

0, 0.01, 0.1, 

0.3, 1 

BI, BW, HP, 

OF, OW

Hepatic 0.01 Increased severity of 

hepatocellular hypertrophy at 

PND 91 and periportal 

inflammation on PND 21 at 

≥0.01 mg/kg/day (incidence was 

not reported); decreased serum 

total cholesterol, LDL, and HDL 

levels in high-fat fasted animals on 

PND 91 at ≥0.3 mg/kg/day

Quist et al. 2015a, 2015b

PFOA

Subgroup of female offspring were fed a high-fat diet (50% calories from diet) for 6 weeks

69 Mouse

(C57BL/6)

6 M,F

6 weeks

(F)

0.55 BC, BW, FI, 

OW

Hepatic 0.55 66–67% increase in relative liver 

weight in males; increased plasma 

cholesterol levels in males (35%) 

and females (70%)

Rebholz et al. 2016

PFOA

70 Mouse

(BALB/c)

6 M,F

6 weeks

(F)

0.55 BC, BW, FI, 

OW

Hepatic 0.55 54–65% increase in relative liver 

weight; 20% increase in plasma 

cholesterol in males 

Rebholz et al. 2016

PFOA

71 Mouse

(C57BL/6)

6 F

GD 7 to 

PND 21

(F)

0, 0.1 BH, BW Develop 0.1 Increased horizontal and 

ambulatory locomotor activity and 

decreased resting time in males; 

decrease in novel object 

recognition in males and females

Sobolewski et al. 2014

PFOA
PERFLUOROALKYLS 53

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

72 Mouse

(ICR)

10 M

21 days

ad lib

(W)

0, 0.5, 2.6, 

18, 47

BW, OW, 

GN, HP

Bd Wt 2.6 18 17% decrease in weight gain

Hepatic 18 47 27% increase in relative liver 

weight at ≥0.5 mg/kg/day; 

increases in ALT at 

≥2.6 mg/kg/day; hepatocytomegaly 

at 18 mg/kg/day; necrosis at 

47 mg/kg/day

Renal 47 

Son et al. 2008

APFO

73 Mouse

(ICR)

10 M

21 days

(W)

0, 0.49, 2.64, 

17.63, 47.21

FX HP Immuno 47.21 Marked hyperplasia in spleen white 

pulp and thymic atrophy

Son et al. 2009

PFOA

74 Mouse

(C57BL/6N)

7–8 M

3 weeks

(F)

0, 5 HP Hepatic 5 Hepatocellular hypertrophy and 

degeneration

Tan et al. 2013

PFOA

75 Mouse

(CD-1)

4–12 F

GDs 1–17

(GW)

0, 0.01, 0.1, 

0.3, 1.0

BW, DX, OW Develop 0.01 Developmental delays in the 

mammary glands on PNDs 35 

(26%) and 56 (30%)

Tucker et al. 2015

PFOA

76 Mouse

(C57BL/6)

2–6 F

GDs 1–17

(GW)

0, 0.01, 0.1, 

0.3, 1.0 

BW, DX, OW Develop 0.1 0.3 Developmental delays in the 

mammary glands on PNDs 21 

(38%) and 61 (25%)

Tucker et al. 2015

PFOA
PERFLUOROALKYLS 54

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

77 Mouse

(CD-1)

14–16 F

GDs 1–17

GDs 8–17 

1 time/day

GDs 12–17 

(GW)

0, 5 MX, DX, GN, 

HP

Repro 5 Delayed mammary gland 

differentiation

White et al. 2007

APFO

78 Mouse

(CD-1)

14 F

GDs 1–17

1 time/day

(GW)

0, 5 DX, GN Develop 5 Increased prenatal loss; 40% 

reduced neonatal body weight on 

PNDs 5 and 10

White et al. 2007

APFO

79 Mouse

(CD-1)

28–48 F

GDs 1–17

1 time/day

(GW)

0, 3, 5 Develop 3 Delayed mammary gland 

development in female pups on 

PNDs 22–63 and at 18 months

White et al. 2009

APFO

80 Mouse

(CD-1)

10–12 F

GDs 1–17

1 time/day

(GW)

0, 1, 5 Repro 1 Delayed mammary gland 

lactational differentiation in dams 

on PND 22

Develop 1 5 323% increased prenatal loss, 

16.7% decreased live fetuses, 

24.3% decreased neonatal survival

White et al. 2011

APFO

81 Mouse

(CD-1)

10–12 F

GDs 1–17

1 time/day

(GW)

GD 7 to 

PND 22

(W); 

3-generation 

study

0, 0.0024, 

1.0024

Repro 0.0024 Delayed mammary gland 

lactational differentiation in dams 

on PND 22

Develop 0.0024 Delayed mammary gland 

development in female pups on 

PNDs 22–63

White et al. 2011

APFO
PERFLUOROALKYLS 55

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

82 Mouse

(CD-1)

28–48 F

GDs 1–17

1 time/day

(GW)

0, 3, 5 CS, BW, MX, 

DX, OW

Bd Wt 5

Hepatic 5 Significant increase in relative and 

absolute maternal liver weight on 

PND 22 at ≥3 mg/kg/day

Develop 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

83 Mouse

(ICR)

5–10 F

GDs 0–17 or 

GDs 0–18

(GW)

0, 1, 5, 10 BW, FI, WI, 

OW, HP, DX

Hepatic 1 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

Renal 1 35% increased maternal relative 

kidney weight with renal 

hypertrophy

Develop 1 5 14% increased neonatal mortality,

9.5% reduced fetal body weight

Yahia et al. 2010

PFOA
PERFLUOROALKYLS 56

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

CHRONIC EXPOSURE

84 Rat

(Sprague-Dawley)

65 M,F

2 years

ad lib

(F)

0, 1.5, 15 CS, FI, BW, 

OW, HE, BI, 

GN, HP

Bd Wt 1.5 F 15 F 10.3% lower terminal body weight

Resp 1.5 M 15 M Lung hemorrhage

Cardio 15

Gastro 15

Hemato 15

Hepatic 1.5 15 Increased serum ALT and AST and 

hepatocellular hypertrophy at 

≥1.5 mg/kg/day; hepatocellular 

necrosis at 15 mg/kg/day after 

1 year of exposure

Renal 15

Ocular 15

Endocr 15

Immuno 15

Neuro 15

Repro 1.5 M 15 M

1.5 F

Vascular mineralization in the 

testes

Tubular hyperplasia in the ovaries

Other 

noncancer

1.5 M Inflammation of the salivary gland

Cancer No significant increases in the 

incidence of neoplastic lesions

3M 1983

PFOA
PERFLUOROALKYLS 57

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-3. Levels of Significant Exposure to PFOA – Oral

Figure 

keya

Species (strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

85 Rat 

(CD)

156 M

2 years

ad lib

(F)

0, 13.6 CS, BW, FI, 

OW, GN, HP

Bd Wt 13.6 >10% reduction in weight gain 

most of the study

Hepatic 13.6 Increased relative liver weight

Repro 13.6 Increased incidence of Leydig cell 

hyperplasia; elevated serum LH at 

18 months

Other 

noncancer

13.6 Increased incidence of acinar cell 

hyperplasia in pancreas

Cancer No significant increases in the 

incidence of neoplastic lesions

Biegel et al. 2001

APFO

aThe number corresponds to entries in Figure 2-6. 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).

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 = hematology; 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-effect level; OF = organ function; 

OP = ophthalmology; OW = organ weight; PFOA = perfluorooctanoic acid; PND = postnatal day; PPARα = peroxisome proliferator-activated receptor-α; 

Repro = reproductive; Resp = respiratory; sRBC = sheep red blood cell; TSH = thyroid-stimulating hormone; TT4 = total thyroxine; TWA = time-weighted 

average; UR = urinalysis; W = water; WI = water intake
PERFLUOROALKYLS 58

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-6. Levels of Significant Exposure to PFOA – Oral

Acute (≤14 days)
PERFLUOROALKYLS 59

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-6. Levels of Significant Exposure to PFOA – Oral

Intermediate (15–364 days)
PERFLUOROALKYLS 60

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-6. Levels of Significant Exposure to PFOA – Oral

Intermediate (15–364 days)
PERFLUOROALKYLS 61

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-6. Levels of Significant Exposure to PFOA – Oral

Chronic (≥365 days)
PERFLUOROALKYLS 62

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

ACUTE EXPOSURE

1 Rat

(SpragueDawley)

5–15 F

Once

(GW)

0, 15 BI, OF Endocr 15 Transient decrease in serum TT4 (24, 

38, and 53% after 2, 6, and 24 hours, 

respectively)

Chang et al. 2008b

PFOS potassium salt

2 Rat

(SpragueDawley)

30 M

1 day

(F)

0, 1.97, 10.3 HP Hepatic 10.3 

Endocr 10.3 

Elcombe et al. 2012a

PFOS potassium salt

3 Rat

(SpragueDawley)

30 M

7 day

(F)

0, 0, 1.72, 

8.17 

HP Hepatic 8.17 Decreased serum cholesterol (38%) 

and triglyceride (55%) levels at 

8.17 mg/kg/day

Endocr 8.17 

Elcombe et al. 2012a

PFOS potassium salt

4 Rat

(SpragueDawley)

10 M

7 day

(F)

0, 1.79, 8.96 HP Hepatic 8.96 Hepatocellular hypertrophy, incr liver 

weight, decreased serum cholesterol at 

≥1.79 mg/kg/day

Endocr 8.96 

Elcombe et al. 2012b

PFOS potassium salt

5 Rat

(SpragueDawley)

NS F

2 day

GDs 19–20 

1 x/d 

(GW)

0, 25, 50 BW, MX, DX Develop 25 Decreased neonatal survival (82% of 

controls on PND 1)

Grasty et al. 2003

PFOS potassium salt
PERFLUOROALKYLS 63

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

6 Rat

(SpragueDawley)

NS F

4 days

GDs 2–5, 6–

9, 10–13, 

14–17, or 

17–20 

(GW)

0, 25 MX, DX Bd Wt 25 Weight loss during treatment when 

treated on GDs 2–5 (22%) or 6–9

(17%)

Develop 25 Decreased neonatal survival (90% 

survival on GDs 2–5; 30% survival on 

GDs 17–20)

Grasty et al. 2003

PFOS potassium salt

7 Rat

(SpragueDawley)

NS F

2 days

GDs 19–20

1 x/d

(G)

0, 25, 50 Develop 25 Increased neonatal mortality

Grasty et al. 2005

PFOS potassium salt

8 Rat

(Wistar)

8 M

7 days

ad lib

(F)

0, 15 BW, OW, BI, 

EA

Hepatic 15 40% increase in absolute liver weight

Haughom and Spydevold 1992

PFOS potassium salt

9 Mouse

(wild-type 

129S1/Svlm)

8–20 F

GDs 15–18

1 time/day

(GW)

0, 4.5, 6.5, 

8.5, 10.5

DX Develop 4.5 31% reduced percentage of live pups 

per litter on PND 15

Abbott et al. 2009

PFOS potassium salt

10 Mouse

(ICR)

5–7 F

GDs 11–15 

1 time/day

(GW)

0, 50 BW, OW, DX Hepatic 50 103% increased maternal relative liver 

weight

Develop 50 6.1% increased cleft palate and 12.7% 

reduced body weight in fetuses

Era et al. 2009

PFOS potassium salt
PERFLUOROALKYLS 64

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

11 Mouse

(CD-1)

10–11 F

GDs 6–18

1 time/day

(GW)

0, 1.5, 3, 6 MX, DX, BW, 

CS, OW

Bd Wt 6 

Hepatic 6 21% increase in absolute liver weight at 

≥3 mg/kg/day

Endocr 6 No alterations in serum T3 or T4 levels

Develop 6

Fuentes et al. 2006

PFOS potassium salt

12 Mouse

(CD-1)

8–10 F

GDs 12–18 

(GW)

0, 6 CS, BW, BH, 

MX, DX

Bd Wt 6 

Develop 6 Reduced body weight of pups on 

PNDs 4 and 8

Fuentes et al. 2007b

PFOS potassium salt

13 Mouse

(CD-1)

8–10 F

GDs 12–18 

(GW)

0, 6 DX Develop 6 Decreased distanced traveled in open 

field test at 3 months of age

Fuentes et al. 2007a

PFOS potassium salt

14 Mouse

(NMRI)

12 M pups

Single dose

(GO)

0, 11.3 BH, BW, OF Develop 11.3 Altered spontaneous behavior (≤60, 

87.5, or 60% changes in total activity, 

rearing, and locomotion)

Hallgren et al. 2015

PFOS

15 Mouse

(CD-1)

10 M pups

Once

(G)

0, 0.75, 11.3 CS, OF, DX Develop 0.75 M 24% decreased total spontaneous

activity at 2 months of age; no 

significant alteration at 4 months

Johansson et al. 2008

PFOS potassium salt
PERFLUOROALKYLS 65

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

16 Mouse

(CD-1)

10 F

GDs 11–16

(G)

0, 0.5, 2.0, 

8.0 

BC, BW, DX, 

HP

Bd Wt 8.0 21% reduction in maternal body weight 

gain on GDs 14–17

Repro 0.5 Decreases in mean fetal placental 

weight and placental capacity

Develop 0.5 2.0 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

Lee et al. 2015a

PFOS

17 Mouse

(BALB/c)

5 F

7 days

(GW)

20 BW, OW, BC Bd Wt 20 41% decrease body weight gain

Hepatic 20 59% increase in relative liver weight

Immuno 20 Inhibition of T lymphocyte proliferation 

in 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

18 Mouse

(CD-1)

4 M

14 days 

1 time/day 

(GO)

0, 1, 5, 10 Bd Wt 10 

Hepatic 10 ~70% increased absolute liver weight 

at ≥5 mg/kg/day

Repro 10 

Wan et al. 2011

PFOS potassium salt

19 Mouse

(C57BL/6)

10 M

1 day

(GO)

0, 300, 400, 

500, 600, 700 

BW, CS, HP, 

LE

Death 579 LD50

Xing et al. 2016

PFOS
PERFLUOROALKYLS 66

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

20 Mouse

(C57BL/6N)

12 M

7 days

(G)

0, 5, 20, 40 FX Immuno 5 Impaired response to T-cell mitogens; 

suppressed response to sRBC

Zheng et al. 2009

PFOS

21 Rabbit

(New Zealand)

22 F

GDs 6–20 

1 time/day 

(GW)

0, 0.1, 1.0, 

2.5, 3.75

MX, DX, BW, 

CS

Bd wt 0.1 1 F 21% decreased mean maternal body 

weight gain on GDs 7–21; no effect on 

food consumption

Develop 1 2.5 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

Case et al. 2001

PFOS potassium salt

INTERMEDIATE

22 Monkey

(Cynomolgus)

4–6 M, 4–6 F

26 weeks

1 time/day

(C)

0, 0.03, 0.15, 

0.75

CS, BW, OW, 

HE, BI, GN, 

HP

Bd Wt 0.15 M

0.75 F

0.75 M 13.5% reduction in final body weight

Resp 0.75

Cardio 0.75

Gastro 0.75

Hemato 0.75

Musc/skel 0.75

Hepatic 0.15 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

Renal 0.75

Dermal 0.75
PERFLUOROALKYLS 67

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Ocular 0.75

Endocr 0.15 0.75 Increased TSH and decreased total T3

Immuno 0.75

Neuro 0.75 No histological alterations

Repro 0.15 0.75 M Significant decrease in serum estradiol 

on days 62 (48%), 91 (42%), and 182

(96%); no histological alterations

Seacat et al. 2002

PFOS potassium salt

23 Monkey

(Cynomolgus)

6 M,F

4 weeks

1 time/day

(C)

0, 0.02, 2 CS, BW, FC, 

HE, BI, GN, 

HP, EA

Bd Wt 2

Resp 2

Hemato 2

Hepatic 2

Renal 2

Ocular 2

Endocr 2

Immuno 2 No histological alteration

Repro 2 No histological alterations

Thomford 2002a

PFOS potassium salt

24 Rat

(SpragueDawley)

25 F

GD 0 to 

PND 20

1 time/day

(GW)

0, 0.1, 0.3, 1 Repro 1 

Develop 0.3 1 ~30% increased locomotor activity and 

concurrent failure to habituate to test 

environment in male pups on PND 17

Butenhoff et al. 2009b

PFOS potassium salt

25 Rat

(SpragueDawley)

25 F

GD 0 to 

PND 20

1 time/day

(GW)

0, 0.1, 0.3, 1 Develop 1 2.1-fold increased fetal thyroid cell 

proliferation on GD 20

Chang et al. 2009

PFOS potassium salt
PERFLUOROALKYLS 68

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

26 Rat

(SpragueDawley)

10 F

GDs 1–21

1 time/day

(GW)

0, 0.1, 2 Develop 0.1 2 ~5-fold increased postnatal mortality 

and severe lung histopathology in pups

Chen et al. 2012b

PFOS

27 Rat

(SpragueDawley)

10 M

Daily

28 days 

(G)

0, 5, 20 HP Death 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

Cui et al. 2009

PFOS

28 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 

Cardio 5.89 M

Hemato 3.47 F 7.01 F Decreased red blood cells (8.9%), 

hemoglobin (10%), hematocrit (8.8%)

Hepatic 5.89 M Increased relative liver weight; 

hepatocellular hypertrophy in males at 

5.89 mg/kg/day

Renal 5.89 M

Endocr 0.14 1.23 Decreased T4 level (82% in males; 

48% in females)

Curran et al. 2008

PFOS potassium salt

29 Rat

(SpragueDawley)

30 M

28 days

(F) 

0, 1.54, 7.34 HP Hepatic 7.34 Hepatocellular hypertrophy and 

decreased serum cholesterol levels at 

≥1.54 mg/kg/day

Endocr 7.34 

Elcombe et al. 2012a

PFOS potassium salt
PERFLUOROALKYLS 69

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

30 Rat 

(Wistar)

5–6 M

Daily

28 days

(G)

0, 0.12, 0.5, 

2.0, 8.5 

FX Neuro 2 8.5 Tonic convulsions in response to 

stimuli

Kawamoto et al. 2011

PFOS

31 Rat

(SpragueDawley)

NS

GDs 2–21

(GW)

0, 1, 2, 3, 5, 

10

Develop 1 2 Reduced serum T4 in pups at 

1 mg/kg/day; approximately 60% 

survival at weaning versus 80% in 

controls at 2 mg/kg/day

Lau et al. 2003

PFOS potassium salt

32 Rat

(SpragueDawley)

15M, 15F

28 days

(F)

M: 0, 0.14, 

1.33, 3.21, 

6.34; F: 0, 

0.15, 1.43, 

3.73, 7.58

OW, BW Bd Wt 1.33 M 3.21 M 12% decrease in terminal body weight

Hepatic 6.34 M Increased relative liver weight at 

≥0.14 mg/kg/day

Immuno 6.34 M

Lefebvre et al. 2008

PFOS

33 Rat

(SpragueDawley)

19 M

28 days

(GO)

0, 0.5, 1.0, 

3.0, 6.0 

BC, BW, HP, 

OF, OW

Neuro 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

Lopez-Doval et al. 2014

PFOS
PERFLUOROALKYLS 70

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

34 Rat

(SpragueDawley)

35 M,F

84 days 

(6 weeks 

prior to 

mating GD 0 

to PND 21)

1 time/day

(GW)

0, 0.1, 0.4, 

1.6, 3.2

MX, DX, BW, 

OW, OF, GN, 

HP, FC

Bd Wt 1.6 3.2 >10% reduction in body weight

Repro 3.2 No alterations in mating and fertility 

parameters

Develop 0.1b 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

Luebker et al. 2005a

PFOS potassium salt

35 Rat

(SpragueDawley)

50 F

90 day

1 time/day

0, 1.6 MX, DX, BW, 

OW, OF, GN

Develop 1.6 Increased pup mortality during 

PNDs 1–4

Luebker et al. 2005a

PFOS potassium salt

Cross-foster study 

36 Rat

(SpragueDawley)

20 F

62–67 days

42 days 

prior to 

mating 

through 

GD 20 or 

PND 4

(G)

0, 0.4, 0.8, 1, 

1.2, 1.6, 2

MX, DX, BW, 

CS, BI

Bd Wt 1.6 2 22% reduction in body weight gain 

during premating; food consumption 

reduced 5.8%

Hepatic 2 16% reduction in serum total 

cholesterol on PND 5 at 

≥0.4 mg/kg/day Increased liver weight 

in dams at ≥0.8 mg/kg/day;

Endocr 0.4 46% reduction in total T4 on PND 5

Repro 2 No alteration in fertility

Develop 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

Luebker et al. 2005b

PFOS potassium salt
PERFLUOROALKYLS 71

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

37 Rat

(SpragueDawley)

10 M

25 days

(GW)

0, 0.5, 1.0, 

3.0 and 6.0 

OF, OW 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%),

Pereiro et al. 2014

PFOS

38 Rat

(SpragueDawley)

21 dams; 10–

12 M,F 

pups/litter

GDs 2–6

(G)

0, 18.75 BW, OF, OW Bd Wt 18.75 Reduced body weight in dams; 

approximately 98% on GD 8 and 33% 

on GD 20

Develop 18.75 Decreased birth weight in females only 

(approximately 11%); increased 

systolic blood pressure in male 

offspring at 7 and 52 weeks and in 

female offspring at 37 and 65 weeks; 

reduced nephron endowment

Rogers et al. 2014

PFOS

39 Rat

(SpragueDawley)

7 M

28 days

(GW)

0, 3.0, and 

6.0

BI, BW, OW Bd Wt 6 

Endocr 3 Decreased serum prolactin (~78%) and 

estradiol concentrations (~18%)

Salgado et al. 2015

PFOS
PERFLUOROALKYLS 72

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

40 Rat

(SpragueDawley)

25 M,F

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, 

HE, BI, GN, 

HP

Bd Wt 1.77 F

Hemato 1.77 F

Hepatic 1.77 F

Renal 1.77 F

Ocular 1.77 F

Immuno 1.77 F No histological alterations

Neuro 1.77 F No histological alterations

Repro 1.51 M

1.77 F

No histological alterations

Seacat et al. 2003

PFOS potassium salt

41 Rat

(SpragueDawley)

25 M,F

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, 

HE, BI, GN, 

HP

Bd Wt 1.56 F

Hemato 0.34 M 1.33 M 45% increase in non-segmented 

neutrophils

Hepatic 1.33 M Increased absolute and relative liver 

weight; increased serum ALT; 

hepatocyte hypertrophy and 

vacuolation at 1.33/1.55 mg/kg/day

Renal 1.56 F

Ocular 1.56 F

Endocr 1.56 F

Immuno 1.56 F No histological alterations

Neuro 1.56 F No histological alterations

Repro 1.33 M

1.56 F

No histological alterations

Seacat et al. 2003

PFOS potassium salt
PERFLUOROALKYLS 73

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

42 Rat

(SpragueDawley)

25–50 F

GDs 2–20

(GW)

0, 1, 2, 3, 5, 

10

MX, DX, BW, 

FI, WI, OW, 

BI

Bd Wt 1 2 Decreased mean body weight gain, 

10% at 2 mg/kg/day and 33% at 

5 mg/kg/day 

Hepatic 10 

Endocr 1 Reduced total and free T4 and T3

Develop 10 Increased incidences of cleft palate

Thibodeaux et al. 2003

PFOS potassium salt

43 Rat

(Wistar)

10 or 15 dams; 

6–10 M,F pups

GD 1 to 

PND 1, 

PNDs 1–7 

or 35, 

or GD 1 to 

PND 7 or 35

0, 0.8, 2.4 DX Develop 0.8 Decreased spatial learning ability in 

prenatally or postnatally exposed 

offspring at ≥0.8 mg/kg/day and in 

offspring exposure pre- and postnatally 

at 2.4 mg/kg/day; decreased memory 

ability in offspring exposure pre- and 

postnatally at 2.4 mg/kg/day

Wang et al. 2015c

PFOS

44 Rat

(SpragueDawley)

10 F

GDs 2–21

1 time/day

(GW)

0, 0.1, 0.6, 2 Develop 0.6 2 5-fold increased neonatal mortality on 

PNDs 1–3

Xia et al. 2011

PFOS

45 Rat

(SpragueDawley)

8–10 M

91 days

(W)

0, 0.27, 0.79, 

2.37 

BC Endocr 0.27 M 42% decrease in total T4 levels

Develop 3.2 F 19–36% reduced serum T4 levels in 

pups on PNDs 21–35 after gestationand/or postnatal-only exposure

Yu et al. 2009a

PFOS potassium salt
PERFLUOROALKYLS 74

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

46 Mouse

(E3L CETP)

6–8 M

4–6 weeks

(F)

0, 3 BW, FI, BC, 

OW 

Bd wt 3

Hepatic 3 Decreased plasma triglyceride, total 

cholesterol, non-HDL cholesterol, and 

HDL cholesterol levels; increased 

hepatic triglyceride levels, increased 

liver weight

Bijland et al. 2011

PFOS

47 Mouse

(C57BL/6N)

10 M

60 days

(G)

0, 0.00833, 

0.08333, 

0.41667, 

0.83333, 

2.0833

FX Immuno 0.0083 0.0833 Impaired response to sRBC

Dong et al. 2009

PFOS potassium salt

48 Mouse

(C57BL/6N)

12 M

60 days

(G)

0, 0.00833, 

0.0167, 

0.0833, 

0.4167, 

0.8333

FX Immuno 0.0167 0.0833 Impaired response to sRBC

Dong et al. 2011

PFOS potassium salt

49 Mouse

(ICR)

6–8 F

GDs 1–17

1 time/day

(GW)

0, 20 Bd Wt 20 35% reduced maternal body weight

Develop 20 89% increased cleft palate, 25% 

reduced body weight in fetuses

Era et al. 2009

PFOS potassium salt

50 Mouse (CD-1)

10 M

4 weeks

(GW)

0, 3, 6 CS, BW, BH, 

MX, DX

Develop 3 Impaired retention of the task in the 

water maze test

PFOS potassium salt

Fuentes et al. 2007c
PERFLUOROALKYLS 75

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

51 Mouse

(B6C3F1)

30 F

21 days

(G)

0, 0.005, 

0.025

Immuno 0.005 0.025 Decreased host resistance to influenza 

virus

Guruge et al. 2009

PFOS

52 Mouse

(B6C3F1)

10–12 F

GDs 1–17

1 time/day

(GW)

0, 0.1, 1, 5 MX, DX, BW, 

CS, OF

Develop 0.1 1 42.5% reduced NK cell activity in male 

pups at 8 weeks of age

Keil et al. 2008

PFOS potassium salt

53 Mouse

(CD-1)

21–22 F

GDs 1–17

1 time/day

(GW)

0, 1, 5, 10, 

15, 20

DX, OW, BI Develop 1 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

54 Mouse

(CD-1)

4 dams; 

8 fetuses

GDs 1–17

(GO)

3 BC, EA, OF Hepatic 3 No alteration in maternal hepatic lipid 

levels

Develop 3 Significant increase in cholesterol 

levels in fetal livers

Lee et al. 2015b

PFOS

55 Mouse

(C57BL/6)

15 M,F

Daily

3 months

(G)

0, 0.43, 2.15, 

10.75 

FX Neuro 0.43 2.15 Impaired spatial learning and memory

Long et al. 2013

PFOS
PERFLUOROALKYLS 76

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

56 Mouse

(BALB/c)

28 M

3 weeks 0, 2.5, 5 and 

10 

BW, OF, OW Bd Wt 10 M ~15% reduction in body weight during 

the recovery period

Immuno 2.5 M 5 M ~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-cell 

proliferation during recovery

Lv et al. 2015

PFOS

57 Mouse

(C57BL/6JApc+/+)

20–21 F

GDs 1–7

(GW)

0, 0.01, 0.1, 

3.0 

BC, BW, FI, 

HE, OW

Develop 0.1 3 Decrease in number of successful 

births

Ngo et al. 2014

PFOS

58 Mouse

(C57BL/6/

Bk1)

6 F

GDs 1–21

ad lib

0, 0.3 Develop 0.3 Decreased locomotion, muscle strength 

and motor coordination in adult 

offspring

Onishchenko et al. 2011

PFOS, potassium salt

59 Mouse

(B6C3F1)

5M, 5F

28 days

(G)

0, 0.000166, 

0.00166, 

0.00331, 

0.0166, 

0.0331, 0.166

OW, FX Immuno 0.000166 M 0.00166 M Suppressed response to sRBC (~60%)

Peden-Adams et al. 2008

PFOS potassium salt
PERFLUOROALKYLS 77

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

60 Mouse

(B6C3F1)

5 M

28 days

(F)

0.20 NS Bd Wt 0.2 21% reduction in body weight

Immuno 0.2 No alterations in thymic lymphocyte 

phenotypes, response to sRBC, or IgM 

antibodies to LPS

Qazi et al. 2010b

PFOS

61 Mouse

(CD-1)

5 F

GDs 1–17

1 time/day

(GW)

0, 5, 10 Develop 5 Peroxisome proliferation in fetal liver at 

≥5 mg/kg/day

Rosen et al. 2009

PFOS, potassium salt

62 Mouse

(CD-1)

60–80 F

GDs 1–17

(GW)

0, 1, 5, 10, 

15, 20

BW, OW, BI, 

DX

Bd Wt 20 

Hepatic 20 Increase in absolute and relative liver 

weight and decreased serum 

triglycerides at ≥5 mg/kg/day

Endocr 15 20 Decreased total T4 on GD 6

Develop 1 5 20 Increased incidences of sternal defects 

at ≥5 mg/kg/day; reduced percentage 

of live fetuses (9%) at 20 mg/kg/day

Thibodeaux et al. 2003

PFOS potassium salt

63 Mouse

(CD-1)

4 M

21 days

1 time/day

(GO)

0, 1, 5, 10 BW, BI, OW, 

HP

Bd Wt 5 10 ~15% reduced body weight

Hepatic 10 Increased absolute liver weight at 

≥5 mg/kg/day

Repro 5 10 ~17% reduced serum testosterone, 

~38% reduced epididymal sperm count

Wan et al. 2011

PFOS potassium salt
PERFLUOROALKYLS 78

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

64 Mouse

(CD-1)

6 F (dams)

GD 3 to 

PND 21 or

GD 3 to 

PND 63

(GO)

0, 0.3, 3 BW, OF, OW Hepatic 3 ~24% increase in relative liver weight in 

dams at 3 mg/kg/day

Develop 3 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%)

Develop 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%) and 

females (~85%)increased response to 

oral glucose tolerance test, increased 

HOMA-IR index, and 33% increased 

relative liver weight at 3 mg/kg/day

Other 

noncancer 

3 F No significant alteration in fasting 

serum insulin or glucose levels; 

significant increase in HOMA-IR index 

at 0.3 and 3 mg/kg/day

Wan et al. 2014b

PFOS

65 Mouse

(C57BL/6)

10 M

30 days

(GO)

0, 2.5, 5, 10 BW, HP, OF, 

OW

Bd Wt 10 31% reduction in body weight 

(correlated with 68% reduction in feed 

consumption)

Hepatic 2.5 Increased liver weight (35%) and 

serum 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, and 

hepatocellular hypertrophy observed, 

but no incidence data provided

Renal 10 

Xing et al. 2016

PFOS
PERFLUOROALKYLS 79

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

66 Mouse

(ICR)

5 F

GDs 0–17

GDs 0–18

(GW)

0, 1, 10, 20 Hepatic 20 60% increased absolute liver weight at 

≥10 mg/kg/day

Develop 1 20 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

Develop 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

67 Rat

(SpragueDawley)

70 M,F

104 weeks

ad lib

(F)

0, 0.025, 

0.10, 0.25, 

1.04

CS, BW, FC, 

GN, HP, BI

Bd Wt 0.25 F 1.04 F 14% reduction in final body weight

Resp 1.04

Cardio 1.04

Gastro 1.04

Hemato 1.04

Musc/skel 1.04

Hepatic 0.25 M 1.04 M Hepatocellular hypertrophy at 

≥0.1 mg/kg/day; single cell necrosis 

and cystic degeneration at 

1.04 mg/kg/day

Renal 1.04

Dermal 1.04

Ocular 1.04

Endocr 1.04

Immuno 1.04 No histological alterations
PERFLUOROALKYLS 80

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-4. Levels of Significant Exposure to PFOS – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Neuro 1.04 No histological alterations

Repro 1.04 No histological alterations

Butenhoff et al. 2012b; Thomford 2002b

PFOS potassium salt

aThe number corresponds to entries in Figure 2-7. 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.

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 = hematology; 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-observed-adverse-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; sRBC = sheep red blood cell; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroidstimulating hormone; TT4 = total thyroxine; TWA = time-weighted average; W = water
PERFLUOROALKYLS 81

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-7. Levels of Significant Exposure to PFOS – Oral

Acute (≤14 days)
PERFLUOROALKYLS 82

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-7. Levels of Significant Exposure to PFOS – Oral

Intermediate (15–364 days)
PERFLUOROALKYLS 83

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-7. Levels of Significant Exposure to PFOS – Oral

Intermediate (15–364 days)
PERFLUOROALKYLS 84

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-7. Levels of Significant Exposure to PFOS – Oral

Chronic (≥365 days)
PERFLUOROALKYLS 85

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

ACUTE EXPOSURE

PFHxS

1 Mouse

(SV129 WT 

and PPARα 

null)

4 M

7 days

(G)

0, 10

PFHxS

BW, HP Bd Wt 10

Hepatic 10 Hepatocellular hypertrophy, steatosis, 

and increased hepatic triglyceride levels

Das et al. 2017

2 Mouse

(NMRI)

14–18 M,F

PND 10

Once

(GO)

0, 0.61, 6.1, 

9.2 

PFHxS

Develop 6.1 9.2 Altered spontaneous behavior and 

habituation in adults exposed as 

neonates

Viberg et al. 2013

PFNA

3 Rat

(SpragueDawley)

10 M

14 days

(GW)

0, 1, 3, 5 

PFNA

BC, BW, OW Bd wt 1 3 Decreases in body weight at 3 and 

5 mg/kg/day (18 and 39%)

Immuno 1 24% increase in relative thymus weight 

at 1 mg/kg/day; 20% decrease in thymus 

weight at 3 or 5 mg/kg/day, increases in 

thymic cortex:medulla ratios, alterations 

in cytokine levels at ≥3 mg/kg/day 

Fang et al. 2009

4 Rat

(SpragueDawley)

10 M

14 days

(GW)

0, 1, 3, 5 

PFNA

BC, OW Immuno 3 5 Decreased relative spleen weight and

increases in cytokine levels

Fang et al. 2010

5 Rat

(SpragueDawley)

6 M

14 days

(GW)

0, 0.2, 1, 5 

PFNA

BC Hepatic 5 Decreased HDL levels at ≥1 mg/kg/day

Other 

noncancer 

(glucose)

0.2 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)

6 M

14 days

(GW)

0, 0.2, 1, 5 

PFNA

HP Hepatic 5 Hepatocellular vacuolation and lipid 

accumulation at 5 mg/kg/day

Fang et al. 2012b
PERFLUOROALKYLS 86

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

7 Rat

(SpragueDawley)

6 M

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

Feng et al. 2009

8 Rat

(SpragueDawley)

6 M

14 days

(GW)

0, 1, 3, 5

PFNA

HP Repro 3 5 Large vacuoles between testicular Sertoli 

cells and spermatogonia

Feng et al. 2010

9 Rat

(Wistar)

14 days

(GO)

8 or 10M

0, 0.0125, 

0.25, 5

PFNA

BI, BW, OW, 

GN, HP

Bd Wt 5 Decreased body weight; magnitude of 

effect was not reported

Endocr 5 Decreased androstenedione and 

testosterone concentrations (data not 

shown)

Hadrup et al. 2016

10 Mouse

(SV129 WT 

and PPARα 

null)

4 M

7 days

(G)

0, 10

PFNA

BW, HP Bd Wt 10

Hepatic 10 Hepatocellular hypertrophy, steatosis, 

and increased hepatic triglyceride levels

Das et al. 2017

11 Mouse

(BALB/c)

6 M

14 days

(G)

0, 1, 3, 5

PFNA

FX Immuno 1 Decreases in the percentages of F4/80+ 

and CD49b+ cells in the spleen; no 

alteration in the response of splenic 

lymphocytes to ConA at ≤5 mg/kg/day 

Fang et al. 2008

12 Mouse

(CD-1)

5 M,F

14 days

(F)

0, 0.5, 1.8, 

5.3, 54, 537

PFNA

LE, OW Death 54 100% mortality before day 14

Hepatic 5.3 50–70% increase in absolute liver weight 

at ≥0.5 mg/kg/day

Kennedy 1987
PERFLUOROALKYLS 87

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

13 Mouse

(BALB/c)

8 M

14 days

(G)

0, 0.2, 1, 5

PFNA

BW, OW, BC Bd Wt 1 5 ~25% decrease in body weight

Hepatic 1 5 Increases in liver weight (~160%) and 

increases 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

PFDeA

14 Rat

(Wistar)

5–12 M

Once

(GO)

0, 50 

PFDeA

BW, FX BW 50 8% weight loss was observed 10-days 

post-exposure

Neuro 50 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, 9.5

PFDeA

BE, OW, EA Bd Wt 4.7 9.5 ~32% weight loss

Hepatic 9.5 Increases in liver weight at 

≥2.4 mg/kg/day; increases in hepatic 

cholesterol at 9.5 mg/kg/day

Kawashima et al. 1995

16 Mouse

(C57BL/6N)

4 F

Once

(GO)

0, 40, 80, 

100, 120, 160

PFDeA

OW, EA Hepatic 160 Increase in hepatic lipids and liver weight 

2 days post-exposure at 40 mg/kg/day

Brewster and Birnbaum 1989

17 Mouse

(C57BL/6N)

12–14 F

GDs 6–15

(GO)

0, 0.03, 0.1, 

0.3, 1, 3, 6.4, 

12.8

PFDeA

MX, DX, BW, 

OW

Bd Wt 3 6.4 12.8 No weight gain at 6.4 mg/kg/day and 

weight loss at 12.8 mg/kg/day (net 

change of -2.4)

Develop 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)

Harris and Birnbaum 1989
PERFLUOROALKYLS 88

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

18 Mouse

(C57BL/6N)

10 F

Once

(GO)

0, 20, 40, 80, 

160, 320

PFDeA

BW, OW, 

GN, HP

Death 120 LD50 in 30-day observation period

Bd Wt 40 80 12% decreased body weight 30 days 

post-exposure

Cardio 80 No histological alterations in the heart 

30 days post-exposure; decreased 

relative heart weight at 80 mg/kg/day

Hepatic 80 Increases in liver weight and pancellular 

hypertrophy at ≥20 mg/kg/day 30 days 

post-exposure 

Renal 80 No histological alterations 30 days postexposure

Endocr 40 80 2-fold increase in T3 and 4-fold increase 

in T4 levels 30 days post-exposure

Immuno 40 80 160 28% decrease in relative spleen weight 

at 80 mg/kg/day; atrophy and lymphoid 

depletion in thymus and spleen at 

160 mg/kg/day

Harris et al. 1989

19 Mouse

(CD-1)

10 M

Once on

PND 10

(G)

0, 0.72, 10.8

PFDeA

CS, DX Develop 10.8 No alteration in spontaneous activity or 

habituation at 2–4 months of age

Johansson et al. 2008

20 Mouse

(C57BL/6N)

4 M

10 days

(F)

0, 78

PFDeA

BW, OW, EA Bd Wt 78 33% weight loss

Hepatic 78 36% increase in liver weight

Permadi et al. 1992, 1993

PFBA

21 Rat

(SpragueDawley)

3 M,F

5 days

1 time/day

(GW)

0, 18, 58, 184

PFBA

CS, BW, OW, 

HE, BI, GN, 

HP

Bd Wt 184

Resp 184

Cardio 184

Gastro 184

Hemato 184

Musc/skel 184

Hepatic 184

Renal 184
PERFLUOROALKYLS 89

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Endocr 184

Immuno 184 No histological alterations

Neuro 184 No histological alterations

Repro 184 No histological alterations

3M 2007a

22 Rat

(SpragueDawley)

3 M

14 days

ad lib

(F)

0, 20

PFBA

OW, EA Hepatic 20 Biochemical and ultrastructural evidence 

of peroxisome proliferation

Ikeda et al. 1985

23 Mouse

(C57BL/6N)

4 M

10 days

(F)

0, 78

PFBA

BW, OW, EA Bd Wt 78 

Hepatic 78 63% increase in absolute liver weight

Permadi et al. 1992, 1993

PFDoA

24 Rat

(Wistar)

5–12 M

Once

(GO)

0, 5, 20, 50 

PFDoA

BW, FX BW 50 44% decrease in body weight gain 

(measured 10-days post-exposure)

Neuro 50 Impaired performance on novel object 

recognition test

Kawabata et al. 2017

25 Rat

(Wistar)

10 M

Once

(GO)

0, 50 

PFDoA

FX Neuro 50 No alterations in open field activity

Kawabata et al. 2017

26 Rat

(Wistar)

8 M

Once

(GO)

0, 50 

PFDoA

FX Neuro 50 No alterations in tests of working memory 

or depressive behavior.

Kawabata et al. 2017
PERFLUOROALKYLS 90

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

27 Rat

(SpragueDawley)

10 M

14 days

1 time/day

(GW)

0, 1, 5, 10

PFDoA

BW, OW, BI Bd Wt 1 5 25% reduction in final body weight

Hepatic 10 35% increase in total serum cholesterol 

at 10 mg/kg/day

Repro 1 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%)

Shi et al. 2007

28 Rat

(SpragueDawley)

10 M

14 days

1 time/day

(GW)

0, 1, 5, 10

PFDoA

OW, BI, HP Hepatic 10 Increased liver weight, increase in 

increased hepatic triglyceride and 

cholesterol levels at ≥5 mg/kg/day; 

increased serum triglyceride levels at 

10 mg/kg/day

Zhang et al. 2008

PFOSA

29 Rat

(SpragueDawley)

15 M

Once

(GO)

0, 5

PFOSA

BW, OW Bd Wt 5 

Hepatic 5 No alterations in liver weight

Seacat and Luebker 2000

PFHxA

30 Mouse

(CD1)

20 F

GDs 6–18

(GW)

0, 100, 350, 

500

PFHxA

CS, DX Develop 100 350 12.5% decrease in birth weight and 

delayed eye opening at ≥350 mg/kg/day; 

increased pup mortality (PND 0–3) and 

decreased pup survival at 500 mg/kg/day

Iwai and Hoberman 2014

31 Mouse

(CD1)

20 F

GDs 6–18

(GW)

0, 7, 35, 175

PFHxA

CS, DX Develop 35 175 Increase in stillborn pups and 12.5% 

decrease in birth weight

Iwai and Hoberman 2014
PERFLUOROALKYLS 91

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

INTERMEDIATE EXPOSURE

PFHxS

32 Rat

(SpragueDawley)

15 M,F

42–56 days

1 time/day

(GW)

0, 0.3, 1, 3, 

10

PFHxS

CS, BW, MX, 

DX, OW, OF, 

BI, HE, GN, 

HP, FI

Bd Wt 10

Resp 10

Cardio 10

Gastro 10

Hemato 10 F 0.3 M 6% increase in prothrombin time in males 

at ≥0.3 mg/kg/day; decreases in 

hemoglobin (4%), hematocrit (3%), and 

RBC levels (2.4%) in males at 

≥3 mg/kg/day

Hepatic 10 Increased liver weight; centrilobular 

hepatocellular hypertrophy in males at 

≥3 mg/kg/day

Renal 3 M 10 M 31% increase in BUN in males

Endocr 1b M

10 F

3 M Hypertrophy and hyperplasia of thyroid 

follicular cells in males

Immuno 10 No histological alterations

Neuro 10 No histological alterations

Repro 10 No histological alterations or effects on 

fertility

Develop 10 F

Butenhoff et al. 2009a; Hoberman and York 2003

33 Mouse

(E3L CETP)

6–8 M

4–6 weeks

(F)

0, 6

PFHxS

BW, FI, BC, 

OW 

Bd wt 6

Hepatic 6 Decreased plasma triglyceride, 

cholesterol, non-HDL cholesterol, and 

HDL cholesterol levels; increased hepatic 

triglyceride levels, increased liver weight

Bijland et al. 2011
PERFLUOROALKYLS 92

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

PFNA

34 Rat

(SpragueDawley)

18 dams; 

10–12 M,F 

pups/litter

GDs 1–20

(GW)

5 

PFNA

BW, OF, OW Bd Wt 5 Reduced maternal body weight; 

approximately 33% on GD 7 and 10% on 

GD 20

Develop 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

35 Mouse

(CD-1)

8–10F

GDs 1–17

(GW)

1, 3, 5, 10

PFNA

BC, DX, FX, 

MX, OW

Bd Wt 10 43% maternal weight loss at GD 13

Hepatic 10 Increases in absolute and relative liver 

weights in dams on GD 17 and on postweaning day 28 at ≥1 mg/kg/day

Develop 1c 3 5 Delayed postnatal development [eye 

opening, preputial separation and vaginal 

opening] and decreased body weight 

gain 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

36 Mouse

(129S1/

Svlm)

8 F

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 Increase in dam liver weight at 

≥0.83 mg/kg/day 

Develop 0.83c 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 litter 

and decreased pup body weight gain in 

females at 2 mg/kg/day; increased pup 

liver weight at ≥0.83 mg/kg/day 

Wolf et al. 2010
PERFLUOROALKYLS 93

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

37 Mouse

(PPARα 

knockout)

8 F

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

Develop 2.0 No alterations in the number of live pups 

per litter, birth weight, pup survival, day 

of eye opening, or pup body weight gain; 

no increases in pup liver weight were 

observed

Wolf et al. 2010

PFUA

38 Rat

(Crl:CD[SD])

12 M,F 

(main); 

5 M,F 

(other)

41–46 days 

(GO)

0, 0.1, 0.3, 

1.0 

PFUA

BH, BW, CS, 

HP, OF, OW, 

UR

Bd Wt 0.3 1.0 Decreased body weight (~10%) in males 

during exposure and recovery and in 

satellite females during dosing (~23% on 

day 40) and recovery (~10%)

Hemato 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%) and 

fibrinogen (19%); main study females: 

increased MCV (10%) and MCH (10%) 

and decreased fibrinogen (32%)

Hepatic 1.0 Increased absolute and relative liver 

weight and centrilobular hypertrophy at 

1.0 mg/kg/day

Renal 0.3 1.0 Increased BUN (61%) and ALP (140%); 

decreased total protein (11%) and 

albumin (7%) in main group males 

Develop 0.3 F 1.0 F Decreased body weight in pups on 

PNDs 0 and 4 (13–19% in males and 

12–16% in females)

Takahashi et al. 2014
PERFLUOROALKYLS 94

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

PFBuS

39 Rat

(SpragueDawley)

28 days

1 time/day

(GO)

0, 100, 300, 

900

PFBuS

CS, BW, FI, 

HE, BI, GN, 

HP, OF

Bd Wt 900

Resp 900

Cardio 900

Gastro 900

Hemato 900

Musc/Skel 900

Hepatic 900 Increased absolute and relative liver 

weight at 900 mg/kg/day

Renal 900 

Ocular 900

Endocr 900

Immuno 900 No histological alterations

Neuro 900 No histological alterations

Repro 900 No histological alterations

3M 2001

40 Rat

(SpragueDawley)

10 NS

90 days

(G)

0, 60, 200, 

600 

PFBuS

LT, BW, OW, 

GN, HP, BC, 

CS, BI, BH, 

HE

Resp 600

Cardio 600

Gastro 200 600 Necrosis of individual squamous cells in 

forestomach and hyperplasia and 

hyperkeratosis of limiting ridge

Hemato 60 M 200 M Decreased hemoglobin (4.9%) and 

hematocrit (5.2%)

Musc/skel 600

Hepatic 600

Renal 200 600 Hyperplasia of medullary and papillary 

tubules and medullary ducts and focal 

papillary edema 

Endocr 600

Neuro 600

Lieder et al. 2009a
PERFLUOROALKYLS 95

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

41 Rat

(SpragueDawley)

P0: starting 

70 days 

prior to 

mating; 

F1: starting 

at weaning

(G)

0, 30, 100, 

300, 1,000

PFBuS 

BW, OW, FI, 

GN, HP, FX, 

MX, DX, TG

Bd Wt 1,000

Hepatic 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

Lieder et al. 2009b

42 Mouse

(E3L CETP)

6–8 M

4–6 weeks

(F)

0, 30

PFBuS

BW, FI, BC, 

OW 

Bd wt 30

Hepatic 30 Decreased plasma triglyceride levels 

Bijland et al. 2011

PFBA

43 Rat

(SpragueDawley)

10 M,F

28 days

1 time/day

0, 6, 30, 150

PFBA

CS, BW, OW, 

FI, BI, HE, 

GN, HP, OF

Bd Wt 150

Resp 150

Cardio 150

Gastro 150

Hemato 150

Musc/skel 150

Hepatic 150 Increased absolute and relative liver 

weight and decreased serum cholesterol 

in males at ≥30 mg/kg/day; 

hepatocellular hypertrophy in males at 

150 mg/kg/day

Renal 150

Dermal 150

Ocular 150

Endocr 6 M 30 M Hyperplasia/hypertrophy of follicular 

epithelium of the thyroid

Immuno 150 No histological alterations

Neuro 30 M 150 M Delayed pupillary reflex

Repro 150 No histological alterations

Butenhoff et al. 2012a; van Otterdijk 2007a
PERFLUOROALKYLS 96

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

44 Rat

(SpragueDawley)

10 M,F

90 days

1 time/day

0, 1.2, 6, 30

PFBA

CS, BW, FI, 

OW, BI, HE, 

GN, HP

Bd Wt 30

Resp 30

Cardio 30

Gastro 30

Hemato 6 30 M Reduced erythrocyte counts (3.8%), 

hemoglobin (5.7%), and hematocrit

(4.5%)

Musc/skel 30

Hepatic 30 Diffuse panlobular hepatocyte 

hypertrophy at 30 mg/kg/day in males

Renal 30

Dermal 30

Ocular 30

Endocr 6 M 30 M Hypertrophy/hyperplasia of follicular 

epithelium of the thyroid gland

Immuno 30 No histological alterations

Neuro 30 No histological alterations

Repro 30 No histological alterations

Butenhoff et al. 2012a; van Otterdijk 2007b

45 Mouse

(CD-1)

18 days

GDs 1–17

1 time/day

(GW)

0, 35, 175, 

350

PFBA

BW, MX, DX Hepatic 350 Significant increase in absolute and 

relative liver weight at ≥175 mg/kg/day

Develop 35 Eye opening delayed approximately 

1 day

Das et al. 2008

PFDoA

46 Rat

(SpragueDawley)

8 F

28 days

PNDs 24–72

1 time/day

(GW)

0, 0.5, 1.5, 3

PFDoA

Develop 1 3 40% reduced serum estradiol and 20% 

increased serum cholesterol in pubertal 

females

Shi et al. 2009
PERFLUOROALKYLS 97

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

CHRONIC EXPOSURE

PFHxA

47 Rat

(SpragueDawley)

60 or 70 M,F

104 weeks

(GW)

M: 0, 2.5, 15, 

100 F: 0, 5, 

30, 200 

PFHxA

BC, BW, CS, 

GN, HP, LE, 

OP, OW, UR

Death 200 F 36, 43, 33, and 22% survival rate in 

females at 0, 5, 30, and 200 mg/kg/day, 

respectively

Bd Wt 100 M

200 F

Hemato 100 M 200 F 8.1% reduction in mean red blood cell 

count and 5.2% reduction in hemoglobin 

at 51 weeks; 23.6 and 53.6% increase in 

reticulocyte counts at weeks 25 and 51, 

respectively

Hepatic 100 M

30F

200 F Males: 42% decrease in triglycerides, 

19% decrease in free fatty acids in males 

at 100 mg/kg/day; hepatocellular 

necrosis; 66% increase in triglycerides, 

44% decrease in non-HDL cholesterol in 

females at 200 mg/kg/day
PERFLUOROALKYLS 98

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Renal 100 M 200 F Mild renal tubular degeneration and mild 

to severe papillary necrosis; increased 

mean urine volume (109%) and reduced 

specific gravity (0.96%)

Neuro 100 M

200 F

Klaunig et al. 2015

aThe number corresponds to entries in Figure 2-8. 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 dose 

and 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 from 

animals 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 and 

an 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.

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; 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 = hematology; HP = histopathology; Immuno = immunotoxicological; LD50 = lethal dose, 50% kill; LE = lethality; LOAEL = lowestobserved-adverse-effect level; M = male(s); MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; Musc/skel = musculoskeletal; 

MX = maternal toxicity; Neuro = neurological; NOAEL = no observed-adverse-effect level; NS = not specified; OF = organ function; OP = ophthalmology; 

OW = organ weight; PFBA = perfluorobutyric acid; PFBuS = perfluorobutane sulfonic acid; PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; 

PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOSA = perfluorooctane sulfonamide; 

PFUA = perfluoroundecanoic acid; PPARα = peroxisome proliferator-activated receptor-α; Repro = reproductive; Resp = respiratory; TG = teratogenicity; 

UR = urinalysis
PERFLUOROALKYLS 99

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-8. Levels of Significant Exposure to Other Perfluoroalkyls – Oral

Acute (≤14 days)
PERFLUOROALKYLS 100

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-8. Levels of Significant Exposure to Other Perfluoroalkyls – Oral

Acute (≤14 days)
PERFLUOROALKYLS 101

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-8. Levels of Significant Exposure to Other Perfluoroalkyls – Oral

Intermediate (15–364 days)
PERFLUOROALKYLS 102

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-8. Levels of Significant Exposure to Other Perfluoroalkyls – Oral

Intermediate (15–364 days)
PERFLUOROALKYLS 103

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-8. Levels of Significant Exposure to Other Perfluoroalkyls – Oral

Chronic (≥365 days)
PERFLUOROALKYLS 104

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-6. Levels of Significant Exposure to PFOA – Dermal

Species 

(strain)

No./group

Exposure 

parameters Doses

Parameters 

monitored Endpoint NOAEL 

Less 

serious 

LOAEL 

Serious 

LOAEL Effect

ACUTE EXPOSURE

Rat

(CD)

15 M,F

Once 3,000, 5,000, 

7,500 mg/kg

CS, LE Death 7,000 M 14-day LD50

Bd Wt 3,000 M F 5–7% transient weight loss

Dermal 3,000 M F 5,000 M F Mild skin irritation

Kennedy 1985

APFO

LD50 in females was >7,500 mg/kg

Rat

(CD)

60 M

2 weeks

6 hours/day

5 days/week

0, 20, 200, 

2,000 mg/kg/day

CS, BW, 

HE, BI, 

GN, HP

Bd Wt 20 M 200 M 14% weight loss

Resp 2,000 M

Cardio 2,000 M

Gastro 2,000 M

Hemato 2,000 M

Hepatic 20 M Foci of coagulative necrosis

Renal 2,000 M

Dermal 20 M 200 M 2,000 M Skin irritation; acute necrotizing dermatitis

Ocular 2,000 M

Endocr 2,000 M

Immuno 2,000 M

Neuro 2,000 M

Repro 2,000 M

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

(BALB/c)

35 F

4 days

1 time/day

0, 0.25, 2.5, 

6.25, 12.5, 25, 

50 mg/kg/day

BW, OW, 

OF

Bd Wt 50 F

Hepatic 2.5 F 6.25 F 52% increase in absolute liver weight

Fairley et al. 2007

PFOA
PERFLUOROALKYLS 105

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-6. Levels of Significant Exposure to PFOA – Dermal

Species 

(strain)

No./group

Exposure 

parameters Doses

Parameters 

monitored Endpoint NOAEL 

Less 

serious 

LOAEL 

Serious 

LOAEL Effect

Mouse

(BALB/c)

35 F

4 days

1 time/day

0, 12.5, 18.8, 25, 

50 mg/kg/day

BW, OW, 

OF

Immuno 12.5 18.8 Increased serum IgE following ovalbumin 

challenge

Fairley et al. 2007

PFOA

Rabbit 

(albino)

6 NS

Once

(NS)

100 mg CS Ocular 100 Moderate eye irritation

Griffith and Long 1980

APFO

Rabbit 

(albino)

6 NS

24 hours

(NS)

500 mg CS Dermal 500

Griffith and Long 1980

APFO

Rabbit

(New Zealand)

17 M

Once 1,500, 3,000, 

5,000, 

7,500 mg/kg

CS, LE Death 4,300 14-day LD50

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 = hematology; HP = histopathology; Immuno = immunotoxicological; LD50 = lethal 

dose, 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
PERFLUOROALKYLS 106

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

2.2 DEATH

Overview. There are limited data regarding the lethality of perfluoroalkyls in humans; the available data 

primarily come from cohort mortality studies in workers. Laboratory animal studies have measured LC50

and LD50 values and reported deaths following inhalation, oral, or dermal exposure to perfluoroalkyls. 

These data are presented in Tables 2-1, 2-2, 2-3, 2-4, 2-5, and 2-6 and Figures 2-4, 2-5, 2-6, 2-7, and 2-8.

PFOA

Epidemiology Studies. Five occupational exposure studies at two PFOA manufacturing facilities have 

examined 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-specific 

mortality have been observed; these data are discussed in subsequent sections of this chapter.

Laboratory Animal Studies. Limited data are available regarding death in animals following inhalation 

exposure to perfluoroalkyl compounds. 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 in 

groups exposed to ≤10 mg/m3 (Staples et al. 1984). The cause of death was not reported.

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); all 

animals 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, all 

rats (males and females) in groups receiving approximately 1,000–1,130 mg/kg/day APFO died before 
PERFLUOROALKYLS 107

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

the end of the first week (Griffith and Long 1980). In a similar study in mice, all mice receiving doses of 

approximately 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 face 

and 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 bone 

marrow, moderate atrophy of the lymphoid follicles of the spleen, and moderate atrophy of the lymphoid 

follicles of the lymph nodes. No deaths occurred at 10 mg/kg/day. Deaths were also reported in 

intermediate-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 of 

pulmonary 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 area 

of the skin, which immediately was covered with gauze pads and wrapped with rubber sheeting around 

the trunk. The contact period was 24 hours, at which time the application site was washed with water and 

the 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 

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.
PERFLUOROALKYLS 108

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFOS

Epidemiology Studies. One occupational exposure study evaluated the potential of PFOS to increase 

lethality; 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 from 

1,890 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 water 

in Sherman-Wistar albino rats was >50 and <1,500 mg/kg. An oral LD50 value of 579 mg/kg/day was 

reported 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 of

neurotoxicity (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 capsule 

died or were sacrificed due to morbidity (Seacat et al. 2002). The cause of death in one monkey was 

pulmonary inflammation; the cause of morbidity in the second monkey was not determined, but the 

animal did have hyperkalemia.

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 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 (Kennedy 1987).
PERFLUOROALKYLS 109

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFDeA

Laboratory Animal Studies. An LD50 of 120 mg/kg was estimated for PFDeA in female C57BL/6N mice 

administered single doses between 20 and 320 mg/kg/day PFDeA 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 PFDeA. 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 

PFDeA in male Fischer-344 rats was 57 mg/kg.

PFHxA

Laboratory Animal Studies. 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. Animals in the 200 mg/kg/day dose group had rales and 

increased incidence of struggling behavior. 

2.3 BODY WEIGHT

Overview. Epidemiology studies have examined the possible associations between in utero and/or early 

life exposure to perfluoroalkyls and body weight, body mass index (BMI), 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 epidemiology 

studies are summarized in Table 2-7, with more detailed descriptions presented in the Supporting

Document for Epidemiological Studies for Perfluoroalkyls, Table 1. 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 in Tables 2-1, 2-2, 2-3, 2-4, 2-5, and 2-6 and 

Figures 2-4, 2-5, 2-6, 2-7, and 2-8.

PFOA

Epidemiology 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. 
PERFLUOROALKYLS 110

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-7. Summary of Childhood Growth in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Barry et al. 2014

Community (C8) (n=8,764 20–40 year olds)

164.6 and 194.3 ng/mL 

(estimated early life median 

PFOA)

Overweight or obesity at 

age 20–40 years

OR 0.9 (0.7–1.1), males

OR 0.9 (0.7–1.1), females

Andersen et al. 2010 

General population (n=1,010 infants)

5.21 ng/mL (maternal median 

PFOA)

Body weight (age 5 and 

12 months)

Inverse association (p<0.05)*, boys

NS (p>0.05), girls

BMI (age 5 and 12 months) Inverse association (p<0.05)*, boys

NS (p>0.05), girls

Height (age 5 and 

12 months)

NS (p>0.05), boys

NS (p>0.05), girls

Andersen et al. 2013 

General population (n=811 children aged 

7 years)

5.25 ng/mL (maternal median 

PFOA)

BMI NS (p>0.05)

Waist circumference NS (p>0.05)

Braun et al. 2016a, 2016b

General population (n=204 children)

5.3 ng/mL (maternal median 

PFOA)

Changes in BMI scores 

between 2 and 8 years of 

age

Association (p=0.03)*

Overweight/obesity risk RR 1.54 (0.77–3.07), 3rd tertile

de Cock et al. 2014

General population (n=89 infants aged 1–

11 months)

0.9402 ng/mL (cord blood 

mean PFOA)

Weight NS (p=0.350)

Height NS (p=0.045)

BMI NS (p=0.813)

Head circumference NS (p=0.774)

Halldorsson et al. 2012

General population (n=665 20 year olds)

3.7 and 5.8 ng/mL (maternal 

median PFOA and 4th quartile 

median)

BMI Association (p=0.001)*, females

Waist circumference Association (p=0.006)*, females

Overweight risk RR 3.1 (1.4–6.9)*, females 

4th quartile

High waist circumference RR 3.0 (1.3–6.8)*, females 

4th quartile
PERFLUOROALKYLS 111

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-7. Summary of Childhood Growth in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Høyer et al. 2015b

General population (n=1,122 children aged 5–

9 years; n=531 for Greenland cohort and 

n=491 for Ukraine cohort)

2.2–5.1 and 1.1–9.8 ng/mL 

(maternal 3rd tertile PFOA for 

Greenland and Ukraine 

cohorts)

Overweight

Greenland cohort

Ukraine cohort

RR 1.23 (0.87–1.74), 3rd tertile

RR 0.78 (0.47–1.29), 3rd tertile

Waist-to-height ratio >0.5 

Greenland cohort

Ukraine cohort

RR 1.18 (0.80–1.74), 3rd tertile

RR 1.11 (0.48–2.57), 3rd tertile

Timmermann et al. 2014

General population (n=499 8–10-year-old 

children) 

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

increase 

Wang et al. 2016

General population (n=117 boys and 106 girls 

examined at 2, 5, 8, and 11 years of age) 

2.37 and 2.34 ng/mL (median 

maternal PFOA for boys and 

girls) 

Growth during childhood NS (p>0.05)

PFOS

Andersen et al. 2010

General population (n=1,010 infants)

33.8 ng/mL (maternal median 

PFOS)

Body weight (age 5 months) NS (p>0.05), boys

NS (p>0.05), girls

Body weight (age 

12 months)

Inverse association (p<0.05)*, boys

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 and 

12 months)

NS (p>0.05), boys

NS (p>0.05), girls

Andersen et al. 2013 

General population (n=811 children aged 

7 years)

33.8 ng/mL (maternal median 

PFOS)

BMI NS (p>0.05)

Waist circumference NS (p>0.05)
PERFLUOROALKYLS 112

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-7. Summary of Childhood Growth in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Braun et al. 2016a, 2016b

General population (n=204 children)

13 ng/mL (maternal median 

PFOS)

Changes in BMI scores 

between 2 and 8 years of 

age 

NS (p>0.23)

Overweight/obesity risk RR 1.08 (0.59–1.95), 3rd tertile

Halldorsson et al. 2012

General population (n=665 20 year olds)

21.5 and 5.8 ng/mL (maternal 

median PFOS)

BMI NS (p>0.56)

Waist circumference NS (p>0.56)

Høyer et al. 2015b

General population (n=1,122 children aged 5–

9 years; n=531 for Greenland cohort and 

n=491 for Ukraine cohort)

23.9–87.3 and 5.9–

18.1 ng/mL (maternal 3rd

tertile PFOS for Greenland 

and Ukraine cohorts)

Overweight

Greenland cohort

Ukraine cohort

RR 0.84 (0.61–1.14), 3rd tertile

RR 0.89 (0.57–1.37), 3rd tertile

Waist-to-height ratio >0.5 

Greenland cohort

Ukraine cohort

RR 1.22 (0.86–1.74), 3rd tertile

RR 1.44 (0.62–3.31), 3rd tertile

Maisonet et al. 2012

General population (n=447 girls)

>23.0 ng/mL (maternal PFOS 

3rd tertile) 

Body weight at 20 months 

(adjusted for birth weight)

β 438.4 g (71.09–805.65 g, 

p=0.0195)*, 3rd tertile

Timmermann et al. 2014

General population (n=499 8–10-year-old 

children) 

41.5 ng/mL (mean PFOS) Adiposity markers NS (p>0.05), per 10 ng/mL PFOS 

increase 

PFHxS

Braun et al. 2016a, 2016b

General population (n=204 children)

1.4 ng/mL (maternal median 

PFHxS)

Changes in BMI scores 

between 2 and 8 years of 

age 

NS (p>0.23)

Overweight/obesity risk RR 1.48 (0.75–2.96), 3rd tertile

Maisonet et al. 2012

General population (n=447 girls)

1.6 ng/mL (maternal median 

PFHxS) 

Body weight at 20 months NS (p=0.4375 for trend)
PERFLUOROALKYLS 113

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-7. Summary of Childhood Growth in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFNA

Braun et al. 2016a, 2016b

General population (n=204 children)

0.9 ng/mL (maternal median 

PFNA)

Changes in BMI scores 

between 2 and 8 years of 

age 

NS (p>0.23)

Overweight/obesity risk RR 1.26 (0.64–2.48), 3rd tertile

Halldorsson et al. 2012

General population (n=665 20 year olds)

0.3 ng/mL (maternal median 

PFNA)

BMI NS (p>0.56)

Waist circumference NS (p>0.56)

Wang et al. 2016

General population (n=117 boys and 106 girls 

examined at 2, 5, 8, and 11 years of age) 

1.55 and 1.58 ng/mL (median 

maternal PFNA for boys and 

girls) 

Growth during childhood NS (p>0.05)

PFDeA

Wang et al. 2016

General population (n=117 boys and 106 girls 

examined at 2, 5, 8, and 11 years of age) 

0.46 and 0.43 ng/mL (median 

maternal PFDeA for boys and 

girls) 

Growth during childhood

Weight

Height

Inverse association (p<0.05)*, girls

Inverse association (p<0.05)*, girls

PFUA

Wang et al. 2016

General population (n=117 boys and 106 girls 

examined at 2, 5, 8, and 11 years of age) 

3.52 and 3.31 ng/mL (median 

maternal PFUA for boys and 

girls) 

Growth during childhood

Weight

Height

Inverse association (p<0.05)*, girls 

Inverse association (p<0.05)*, girls

PFDoA

Wang et al. 2016

General population (n=117 boys and 106 girls 

examined at 2, 5, 8, and 11 years of age) 

0.37 and 0.37 ng/mL (median 

maternal PFDoA for boys and 

girls) 

Growth during childhood

Weight

Height

Inverse association (p<0.05)*, girls 

Inverse association (p<0.05)*, girls
PERFLUOROALKYLS 114

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-7. Summary of Childhood Growth in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOSA

Halldorsson et al. 2012

General population (n=665 20 year olds)

1.1 ng/mL (maternal median 

PFOSA)

BMI NS (p>0.56)

Waist circumference NS (p>0.56)

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

BMI = body mass index; HR = hazard ratio; NR = not reported; NS = not significant; OR = odds ratio; PFDeA = perfluorodecanoic acid; 

PFDoA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; 

PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid; RR = relative risk
PERFLUOROALKYLS 115

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

A study by de Cock et al. (2014) of infants 1–11 months of age did not find associations between cord 

blood PFOA levels and weight, height, or BMI. One study of children (Braun et al. 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. Other studies in children (2–

11 years of age) found no associations between maternal PFOA or cord blood PFOA and growth during 

childhood (Wang et al. 2016), risk of being overweight (Andersen et al. 2013; Braun et al. 2016a; Høyer 

et al. 2015b), 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).

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 and 

waist 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 of 

age) when estimated early life PFOA exposure was used as the exposure metric (Barry et al. 2014).

Overall, the available epidemiology data do not suggest a connection between serum PFOA levels and 

body weight or risk of being overweight/obese.

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 in 

body weight 5 and 12 days after exposure, respectively (Kinney et al. 1989). Inhalation exposure to 

67 mg/m3 had no significant effect on body weight. In a developmental study, inhalation exposure of 

pregnant rats to 25 mg/m3 APFO dusts during GDs 6–15 induced a 37% reduction in body weight gain 

relative to controls during the exposure period (Staples et al. 1984); in a pair-fed group, the reduction of 

weight gain during the same period was 61% relative to ad libitum controls.
PERFLUOROALKYLS 116

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Reductions in body weight or body weight gain are typical, although not particularly sensitive, responses 

of rodents to oral exposure to perfluoroalkyl compounds. 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, in acute-duration 

studies, rats administered 25 mg/kg/day APFO for 14 days had a mean terminal body weight 14% lower 

than controls (Cook et al. 1992). 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 PPARα-null mice did not cause a reduction 

in weight gain, suggesting that the effect on body weight is a specific effect 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 to 

controls at the 1 year mark and at termination (Biegel et al. 2001). Similar observations have been made 

in mice dosed with approximately ≥18 mg/kg/day APFO for 28 days (Griffith and Long 1980) 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 the 

treatment period (14 and 24%, respectively, on test day 10), but body weights were comparable to control 

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).
PERFLUOROALKYLS 117

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFOS

Epidemiology Studies. General population studies have evaluated body weight, height, and BMI in 

infants, children, and adults to assess whether there were links between growth and maternal serum PFOS 

levels. Andersen et al. (2010) found that maternal PFOS levels were inversely related to body weight and 

BMI in 12-month-old male infants; no associations were found in females at 12 months of age or in males 

and females at 5 months of age. The magnitude of the effect on body weight in the boys was small, 9 g 

per 1 ng/mL increase in maternal serum PFOS level. 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) 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, adiponectin levels, and leptin levels) were found 

in a study of children aged 8–10 years (Timmermann et al. 2014). Overall, the epidemiology studies do 

not suggest a connection between serum PFOS and body weight or the risk of being overweight/obese.

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 of 

pregnant rats with 25 mg/kg/day PFOS on GDs 2–5 or 6–9 resulted in weight loss during treatment, 

whereas treatment on GDs 10–13, 14–17, or 17–20 resulted in significant reductions in 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). 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).

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 food 

consumption (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 were 

associated 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 a 

capsule, 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 body 

weight, at which time the mean concentration of PFOS in serum was 172 μg/mL (Seacat et al. 2002). In a 
PERFLUOROALKYLS 118

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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; 

Thomford 2002b). No significant effect (<10% difference with controls) was seen in females dosed with 

≤0.25 mg/kg/day PFOS. 

PFHxS

Epidemiology Studies. Two studies have evaluated the influence of in utero PFHxS exposure on 

childhood growth and found no associations between maternal PFHxS levels and body weight at 

20 months of age (Maisonet et al. 2012), changes in BMI scores between 2 and 8 years of age (Braun et 

al. 2016a), or the risk of childhood overweight/obesity (Braun et al. 2016a).

Laboratory Animal Studies. Treatment of rats with up to 10 mg/kg/day PFHxS by gavage for 40–

60 days did not significantly affect body weight (Butenhoff et al. 2009a; Hoberman and York 2003); the 

mean terminal body weights were within 10% of the body weight of the control group. Food 

consumption was not affected by treatment with PFHxS.

PFNA

Epidemiology Studies. Several studies have examined the influence of maternal PFNA levels on 

childhood growth. These studies did not find associations between maternal PFNA levels and growth 

during childhood (Wang et al. 2016), BMI (Braun et al. 2016a; Halldorsson et al. 2012), or overweight/

obesity risk (Braun et al. 2016a).

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 for 

both species. In intermediate-duration developmental toxicity studies, decreases in body weight were 

observed 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).
PERFLUOROALKYLS 119

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFDeA

Epidemiology Studies. One study examined the effect of PFDeA levels on childhood growth; Wang et al. 

(2016) reported decreases in weight and height in girls associated with increasing maternal serum PFDeA 

levels. 

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 

PFDeA in the diet resulted in a 32% weight loss in rats (Kawashima et al. 1995); the NOAEL was 

4.7 mg/kg/day.

Body weight of female C57BL/6N mice administered a single gavage dose of 80 mg/kg PFDeA was 

reduced 12% relative to controls 30 days after dosing (Harris et al. 1989); no significant effect was seen at 

40 mg/kg PFDeA. In a developmental study, pregnant mice dosed with 6.4 mg/kg/day PFDeA on 

GDs 6–15 gained 92% less weight (adjusted weight) on GDs 6–18 than controls; mice dosed with 

12.8 mg/kg/day lost weight (Harris and Birnbaum 1989). Food consumption data were not provided in 

any of these studies. Weight loss was also observed in C57BL/6N mice exposed to 78 mg/kg/day PFDeA 

in the diet for 10 days (Permadi et al. 1992, 1993).

PFUA

Epidemiology Studies. Wang et al. (2016) found an inverse association between maternal serum PFUA 

levels and weight and height in girls.

Laboratory Animal Studies. Decreases in body weight gain (10% in males and 23% in females) were 

observed in rats exposed to 1.0 mg/kg/day in a 41–46-day developmental toxicity study (Takahashi et al. 

2014).

PFBuS

Laboratory Animal Studies. No significant alterations in body weight gain were observed in SpragueDawley rats administered ≤900 mg/kg/day PFBuS via gavage for 28 days (3M 2001) or in SpragueDawley rats administered ≤1,000 mg/kg/day PFBuS via gavage for at least 70 days (Lieder et al. 2009b).
PERFLUOROALKYLS 120

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 to 

78 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).

PFDoA

Epidemiology Studies. Wang et al. (2016) found an inverse association between maternal serum PFDoA 

levels and growth (weight and height) in girls.

Laboratory Animal Studies. Dosing of Sprague-Dawley rats with 5 mg/kg/day PFDoA by gavage for 

14 days resulted in a 25% reduction in final body weight relative to a control group or 7% loss of body 

weight 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 PFDoA (Kawabata et al. 2017).

PFHxA

Laboratory Animal Studies. Gavage administration of 100 or 200 mg/kg/day for 2 years did not result in 

alterations in body weight gain in male or female rats, respectively (Klaunig et al. 2015).

PFOSA

Epidemiology Studies. Halldorsson et al. (2012) did not find associations between maternal serum 

PFOSA 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 PFOSA (Seacat and Luebker 2000).
PERFLUOROALKYLS 121

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

2.4 RESPIRATORY

Overview. A small number of epidemiology studies have examined the potential of perfluoroalkyl 

compounds to damage the respiratory tract; detailed descriptions of these studies are presented in the 

Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 2. 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 

histological lesions in the lungs following inhalation (see Tables 2-1 and 2-2) or oral exposure (see 

Tables 2-3, 2-4, and 2-5).

PFOA

Epidemiology 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 this 

facility 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 noise 

and labored breathing during exposure and throughout a 12-day recovery period (Kinney et al. 1989). 
PERFLUOROALKYLS 122

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Oral dosing of male and female CD rats with ≤110 mg/kg/day APFO did not induce gross or microscopic 

changes 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). The 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 statistically significant difference (p<0.05). 

In a study in monkeys administered up to 20 mg/kg/day APFO, administered via a capsule, for 26 weeks, 

no signs of respiratory 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 between 1,890 and 45,970 mg/m3 for 1 hour induced dry rales 

and other breathing disturbances. 

Dosing of Cynomolgus monkeys with up to 2 mg/kg/day PFOS for 4 weeks had no effect of the gross or 

microscopic morphology of the lungs (Thomford 2002a). Administration of doses 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).

PFHxS

Laboratory Animal Studies. Examination of the respiratory tract of rats administered ≤10 mg/kg/day 

PFHxS by gavage in a reproductive study (40–60 days of dosing) showed no treatment-related effects 

(Butenhoff et al. 2009a; Hoberman and York 2003).
PERFLUOROALKYLS 123

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFNA

Laboratory Animal Studies. Labored breathing during and after a 4-hour nose-only exposure to 

590 mg/m3 PFNA was reported in rats (Kinney et al. 1989).

PFBuS

Laboratory Animal Studies. Administration of PFBuS at gavage doses of ≤900 mg/kg/day for 28 days or 

600 mg/kg/day for 90 days had no significant effect on the gross or microscopic morphology of the lungs 

or trachea in rats (3M 2001; Lieder et al. 2009a); 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 morphological 

alterations in the respiratory tract.

2.5 CARDIOVASCULAR

Overview. Epidemiology and laboratory animal studies have evaluated the toxicity of perfluoroalkyls to 

the cardiovascular system. The epidemiology 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, and 

general population studies have not consistently found increases in the risk of heart disease or stroke that

were associated with serum PFOA levels. Considerably less epidemiology data are available for other 

perfluoroalkyls; general population studies for PFOS, PFHxS, PFNA, PFDeA, PFUA, and PFHpA have 

not found increases in the risk of cardiovascular disease. Most of the available epidemiology studies did 

not find a link between serum PFOA and hypertension, and the one study for PFOS did not find an 

association. Although mixed results were found in studies of highly exposed community residents, the 

strongest methodological study (Darrow et al. 2013) found an increased risk of pregnancy-induced 
PERFLUOROALKYLS 124

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

hypertension that was associated with serum PFOA levels. Increases in the risk of pregnancy-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 PFDeA and pre-eclampsia; one 

study on PFUA found an inverse association.

Examination of the cardiovascular system in laboratory animals primarily consists of inhalation, oral, and 

dermal studies examining the heart for morphological alterations (see Tables 2-1, 2-3, 2-4, 2-5, and 2-6). 

The laboratory animal studies did not find increases in the incidence of histological alterations in the heart 

following exposure to PFOA, PFOS, PFHxS, PFDeA, PFBuS, or PFBA.

PFOA

Epidemiology 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 found 

increases in deaths from all heart disease, cerebrovascular disease, or ischemic heart disease when 

compared 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 with 

definite 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 risks 

of self-reported cardiovascular disease (Anderson-Mahoney et al. 2008), angina (Anderson-Mahoney et 

al. 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 measure 

serum PFOA levels; the incidences of self-reported diseases were compared to NHANES rates. Another 

community study of residents in this area did not find an increased risk of coronary artery disease 

(Winquist and Steenland 2014a). Two 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 of 

coronary artery disease in subjects with median serum PFOA levels of 4.2 ng/mL (cases) or 4.0 ng/mL 
PERFLUOROALKYLS 125

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-8. Summary of Cardiovascular Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Leonard 2006

Occupational (n=6,027)

5–9,550 ng/mL (PFOA 

range)

Heart disease deaths SMR 110 (98–123)

Cerebrovascular disease 

deaths

SMR 86 (60–120)

Ischemic heart disease 

deaths

SMR 109 (96–124)

Lundin et al. 2009

Occupational (n=3,993)

2,600–5,200 ng/mL (range of 

definite exposure group)

Heart disease deaths SMR 0.7 (0.5–1.3)

Cerebrovascular disease 

deaths

SMR 1.6 (0.5–3.7)

Ischemic heart disease 

deaths

SMR 0.8 (0.5–1.4)

Cerebrovascular disease 

risk

HR 4.6 (1.3–17.0)* workers with 

definite exposure of ≥6 months

HR 2.1 (1.0–4.6)* workers with 

definite exposure ≥5 years

Raleigh et al. 2014

Occupational (n=9,027)

Cumulative PFOA exposure Ischemic heart disease 

deaths

SMR 0.84 (0.74–0.95)*

Cerebrovascular disease SMR 0.81 (0.61–1.05)

Ischemic heart disease 

risk

HR 0.89 (0.66–1.21), 4th quartile

Cerebrovascular disease 

risk

HR 0.98 (0.53–1.81), 4th quartile

Sakr et al. 2009

Occupational (n=4,747)

NR Ischemic heart disease 

risk

NS (p=0.16 for trend)
PERFLUOROALKYLS 126

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-8. Summary of Cardiovascular Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Steenland et al. 2015 

Occupational (n=3,713)

Cumulative PFOA exposure Coronary artery disease 

risk

NS (p=0.78 for trend), no lag

NS (p=0.75 for trend), 10-year lag

Hypertension NS (p=0.95 for trend), no lag

NS (p=0.54 for trend), 10-year lag

Stroke NS (p=0.35 for trend), no lag

NS (p=0.64 for trend), 10-year lag

Steenland and Woskie 2012

Occupational (n=1,084)

7,800 ng/mL-years (mean 

cumulative PFOA exposure)

Ischemic heart disease 

deaths

SMR 0.93 (0.72–1.19), no lag

Anderson-Mahoney et al. 2008

Community (n=566)

NR Cardiovascular disease 

(self-reported)

SPR 4.29 (3.47–5.29)*

Angina (self-reported) SPR 8.07 (6.54–9.95)*

Myocardial infarction SPR (1.91 (1.40–2.62)* 

Stroke SPR 2.17 (1.47–3.21)*

Hypertension SPR 1.18 (0.97–1.43)

Darrow et al. 2013

Community (C8) (n=1,330)

6.9–<11.1 ng/mL (2nd PFOA 

quintile)

Pregnancy-induced 

hypertension

OR 2.39 (1.05–5.46)* (2nd quintile)

Nolan et al. 2009

Community (C8) (n=1,555 women) 

NR Pregnancy-induced 

hypertension

LHWA residents

Partial LHWA residents

OR 1.2 (0.7–2.0), unadjusted

OR 0.8 (0.5–1.4), unadjusted

Savitz et al. 2012a

Community (C8) (n=11,737 pregnant women)

6.8–<16.6 ng/mL (2nd PFOA 

quartile, estimated)

Pre-eclampsia OR 1.2 (1.0–1.5)*

Savitz et al. 2012b

Community (C8) (n=224 cases of pregnancyinduced hypertension)

21.0–717.6 ng/mL (5th PFOA 

quintile, estimated)

Pregnancy induced 

hypertension

OR 1.0 (0.7–1.3), 5th quintile
PERFLUOROALKYLS 127

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-8. Summary of Cardiovascular Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Savitz et al. 2012b

Community (C8) (n=4,547 pregnant women)

21.0–717.6 ng/mL (5th PFOA 

quintile, estimated)

Pregnancy induced 

hypertension

OR 1.1 (0.8–1.5)

Simpson et al. 2013

Community (C8) (n=28,541; 11% also had 

occupational exposure)

>178–319 ng/mL 

(cumulative, estimated 2nd

PFOA quintile)

Stroke OR 1.39 (1.11–1.76)*, 2nd quintile

Stein et al. 2009

Community (C8) (n=5.262 pregnant women)

120.6–894.4 ng/mL (4th

PFOA quartile)

Pre-eclampsia OR 0.9 (0.5–1.8)

Winquist and Steenland 2014a

Community (C8) (n=28,541; 11% also had 

occupational exposure)

≥3,579 ng/mL (cumulative, 

estimated 5th PFOA quintile)

Hypertension HR 0.98 (0.91–1.06), 5th quintile

Coronary artery disease HR 1.07 (0.93–1.23), 5th quintile

Geiger et al. 2014a

General population (NHANES) (n=1,655 

adolescents)

>5.4 ng/mL (4th quartile 

PFOA)

Hypertension OR 0.69 (0.41–1.17), 4th quartile

Lin et al. 2013a, 2013b

General population (n=644)

3.49 ng/mL (median PFOA) Carotid intima media 

thickness

NS (p=0.285 for trend)

Mattsson et al. 2015

General population (n=231 cases with CHD, 

231 controls)

4.2 and 4.0 ng/mL (median 

PFOA in cases and controls)

Coronary artery disease OR 0.88 (0.50–1.55), 4th quartile

Melzer et al. 2010

General population (NHANES) (n=3,966 adults)

10.39 and 9.47 ng/mL (mean 

4th quartile PFOA)

Coronary artery disease, 

angina, and/or heart 

attack

OR 1.08 (0.70–1.69, p=0.715), 4th

quartile

Min et al. 2012

General population (NHANES) (n=2,208)

4.00 ng/mL (geometric mean 

PFOA)

Systolic blood pressure Association (p=0.0004)* 

Hypertension risk OR 1.71 (1.23–2.36)*, 4th quartile
PERFLUOROALKYLS 128

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-8. Summary of Cardiovascular Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Shankar et al. 2012

General population (NHANES) (n=1,216)

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 

disease

OR 1.78 (1.03–3.08)*, 4th quartile

Coronary heart disease OR 2.24 (1.02–4.94)*, 4th quartile

Stroke OR 4.26 (1.84–9.89)*, 4th quartile

Starling et al. 2014b

General population (n=976 pregnant women)

2.78 ng/mL (median PFOA) Pre-eclampsia HR 0.89 (0.65–1.22), per ln unit

PFOS

Darrow et al. 2013

Community (C8) (n=1,330)

12.1–<15.9 ng/mL (3rd PFOS 

quintile)

Pregnancy-induced 

hypertension

OR 2.71 (1.33–5.52)* (3rd quintile)

Stein et al. 2009

Community (C8) (n=5,262 pregnant women)

23.2–83.4 ng/mL (4th PFOS 

quartile)

Pre-eclampsia OR 1.6 (1.2–2.3)*

Geiger et al. 2014a

General population (NHANES) 

(n=1,655 adolescents)

>25.5 ng/mL (4th PFOS 

quartile)

Hypertension OR 0.77 (0.37–1.61), 4th quartile

Lin et al. 2013a, 2013b

General population (n=644)

8.65 ng/mL (median PFOS) Carotid intima media 

thickness

Association (p<0.001 for trend)*

Mattsson et al. 2015

General population (n=231 cases with CHD, 

231 controls)

22.8 and 22.0 ng/mL (median 

PFOS in cases and controls)

Coronary artery disease OR 1.07 (0.60–1.92), 4th quartile

Melzer et al. 2010

General population (NHANES) (n=3,966 adults)

57.73 and 50.96 ng/mL 

(mean 4th quartile PFOS)

Coronary artery disease, 

angina, and/or heart 

attack

OR 0.91 (0.570–1.64, p=0.745), 4th

quartile

Starling et al. 2014b

General population (n=976 pregnant women)

12.87 ng/mL (median PFOS) Pre-eclampsia HR 1.13 (0.84–1.52), per ln unit
PERFLUOROALKYLS 129

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-8. Summary of Cardiovascular Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFHxS

Mattsson et al. 2015

General population (n=231 cases with CHD, 

231 controls)

1.6 ng/mL (median PFHxS in 

cases and controls)

Coronary artery disease OR 0.95 (0.54–1.67), 4th quartile

Starling et al. 2014b

General population (n=976 pregnant women)

0.69 ng/mL (median PFHxS) Pre-eclampsia HR 0.91 (0.72–1.14), per ln unit

PFNA

Lin et al. 2013a, 2013b

General population (n=644)

0.38 ng/mL (median PFNA) Carotid intima media 

thickness

Inverse association (p=0.014 for 

trend)*

Mattsson et al. 2015

General population (n=231 cases with CHD, 

231 controls)

0.5 ng/mL (median PFNA in 

cases and controls)

Coronary artery disease OR 0.68 (0.39–1.20), 4th quartile

Starling et al. 2014b

General population (n=976 pregnant women)

0.54 ng/mL (median PFNA) Pre-eclampsia HR 0.90 (0.70–1.16), per ln unit

PFDeA

Mattsson et al. 2015

General population (n=231 cases with CHD, 

231 controls)

0.2 ng/mL (median PFDeA in 

cases and controls)

Coronary artery disease OR 0.92 (0.53–1.60), 4th quartile

Starling et al. 2014b

General population (n=976 pregnant women)

0.10 ng/mL (median PFDeA) Pre-eclampsia HR 0.88 (0.75–1.04), per ln unit

PFUA

Lin et al. 2013a, 2013b

General population (n=644)

6.59 ng/mL (median PFUA) Carotid intima media 

thickness

NS (p=0.953 for trend)
PERFLUOROALKYLS 130

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-8. Summary of Cardiovascular Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Mattsson et al. 2015

General population (n=231 cases with CHD, 

231 controls)

0.2 ng/mL (median PFUA in 

cases and controls)

Coronary artery disease OR 0.88 (0.51–1.51), 4th quartile

Starling et al. 2014b

General population (n=976 pregnant women)

0.17 ng/mL (median PFUA) Pre-eclampsia HR 0.78 (0.66–0.92)*, per ln unit

PFHpA

Mattsson et al. 2015

General population (n=231 cases with CHD, 

231 controls)

0.06 and 0.04 ng/mL 

(median PFHpA in cases and 

controls)

Coronary artery disease OR 2.58 (1.39–4.78)*, 3rd quartile

OR 1.73 (0.94–3.16), 4th quartile

PFDoA

Mattsson et al. 2015

General population (n=231 cases with CHD, 

231 controls)

0.02 ng/mL (median PFDoA 

in cases and controls)

Coronary artery disease OR 0.63 (0.35–1.11), 4th quartile

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

CHD = coronary heart disease; HR = hazard ratio; LHWA = Little Hocking Water Authority; NHANES = National Health and Nutrition Examination Survey; 

NR = not reported; NS = not significant; OR = odds ratio; PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; 

PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; 

PFUA = perfluoroundecanoic acid; SMR = standardized mortality ratio; SPR = standard prevalence ratio
PERFLUOROALKYLS 131

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

(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 

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, another NHANES study did not find an association between serum 

PFOA and physician-diagnosed coronary artery disease, angina, and/or heart attack (Melzer et al. 2010). 

A general population study did not find an association between serum PFOA levels and carotid intima 

media thickness (Lin et al. 2013a).

Epidemiology Studies—Hypertension. Occupational, community, and general population exposure 

studies have investigated the possible association between PFOA and blood pressure, the risk of 

hypertension, and the risk of pregnancy-induced hypertension and/or pre-eclampsia. A study by Min et 

al. (2012) utilizing NHANES data found an increase in hypertension risk among participants with serum 

PFOA levels in the 4th quartile. In contrast, no increases in the risk of hypertension were observed 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). 

There is some epidemiological evidence 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 found increases 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. The fourth study (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 preeclampsia in C8 Health Project participants with elevated PFOA levels. Another study of participants in 

the C8 Health Project that used measured serum perfluoroalkyl levels found significant increases in the 

odds ratios (ORs) for pregnancy-induced hypertension in women with higher PFOA (≥6.9 ng/mL) levels 

(Darrow et al. 2013). A third study of highly exposed residents reported a weak association between 
PERFLUOROALKYLS 132

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

serum PFOA and 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 and serum 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 pre-eclampsia among C8 Health 

Project participants categorized by serum PFOA levels. Another study of residents 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 and the risk of pre-eclampsia 

(Starling et al. 2014a).

Laboratory Animal Studies. 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). No morphological alterations were seen 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, and 

risk of hypertension has been evaluated in workers, community members living near a PFOA facility, and 

the general population. In general, occupational exposure studies have not found increases in the risks of 

deaths 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 in 

areas 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 

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.
PERFLUOROALKYLS 133

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFOS

Epidemiology 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 the 

risk of physician-diagnosed coronary artery disease, angina, and/or heart attack among NHANES 

participants. In a case-control study (Mattsson et al. 2015), no alterations in the risk of coronary 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.

Epidemiology Studies—Hypertension. No increases in the risk of hypertension associated with serum 

PFOS levels were observed in adolescent NHANES participants (Geiger et al. 2014a). Two studies found 

increases in the risk of pregnancy-induced hypertension (Darrow et al. 2013) or pre-eclampsia (Stein et al. 

2009) associated with serum PFOS levels among C8 participants. No increase in the risk of preeclampsia was observed in a general population study (Starling et al. 2014b).

Laboratory Animal Studies. 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 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

Epidemiology Studies. Two 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 pre-eclampsia (Starling et al. 2014b) were found.

Laboratory Animal Studies. Dosing of rats with≤10 mg/kg/day PFHxS by gavage for 40–60 days did not 

cause morphological alterations in the heart (Butenhoff et al. 2009a; Hoberman and York 2003).

PFNA

Epidemiology 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 
PERFLUOROALKYLS 134

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

finding may be secondary to an interaction between higher serum PFOS levels and lower serum PFNA 

levels in the study population. Other general population studies have not found increases in the risk of 

coronary heart disease (Mattsson et al. 2015) or pre-eclampsia (Starling et al. 2014b) associated with 

increasing serum PFNA levels.

PFDeA

Epidemiology Studies. The risks of coronary artery disease (Mattsson et al. 2015) and pre-eclampsia 

(Starling et al. 2014b) were not associated with serum PFDeA levels in general population studies.

Laboratory Animal Studies. Death in female C57BL/6N mice following administration of a single lethal 

dose of 160 or 320 mg/kg PFDeA by gavage was associated with mural thrombosis of the left ventricle of 

the heart (Harris et al. 1989). Doses ≤80 mg/kg did not cause gross or microscopic alterations in the 

heart, assessed 30 days after dosing, but 80 mg/kg significantly decreased relative heart weight (Harris et 

al. 1989).

PFUA

Epidemiology Studies. Starling et al. (2014b) found an inverse association between serum PFUA levels 

and the risk of pre-eclampsia in pregnant women. No association between serum PFUA levels and 

carotid intima artery thickness was observed in a general population study (Lin et al. 2013a). A third 

general population study (Mattsson et al. 2015) did not find an increase in the risk of coronary artery 

disease associated with serum PFUA levels.

PFHpA

Epidemiology 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 those 

with serum levels in the 4th quartile.
PERFLUOROALKYLS 135

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFBuS

Laboratory Animal Studies. No morphological alterations were reported in the heart or aorta from rats 

dosed with ≤900 mg/kg/day PFBuS by gavage for 28 days (3M 2001) or ≤600 mg/kg/day PFBuS for 

90 days (Lieder et al. 2009a).

PFBA

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).

PFDoA

Epidemiology Studies. No increase in the risk of coronary heart disease associated with serum PFDoA 

levels was found in a general population study (Mattsson et al. 2015).

2.6 GASTROINTESTINAL

Overview. Available epidemiology 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. 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 other perfluoroalkyls 

(Table 2-5); the NOAELs and LOAELs are presented in Figures 2-4, 2-6, and 2-7. Studies on PFOA and 

PFBuS 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, or PFBA.
PERFLUOROALKYLS 136

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFOA

Laboratory Animal Studies. 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 or

female 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). The same investigators also reported that emesis occurred in 

Rhesus monkeys exposed to lethal doses (30 and 100 mg/kg/day) of APFO by gavage 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 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

Epidemiology 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 (estimated 

serum 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 high 

potential 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 diet 
PERFLUOROALKYLS 137

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

for 2 years did not induce morphological alterations in the gastrointestinal tract (Butenhoff et al. 2012b; 

Thomford 2002b).

PFHxS

Laboratory Animal Studies. No morphological alterations were observed in the gastrointestinal tract of 

rats administered ≤10 mg/kg/day PFHxS via gavage for 42–56 days (Butenhoff et al. 2009a; Hoberman 

and York 2003).

PFBuS

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 PFBuS via gavage for 90 days (Lieder et al. 2009a); these lesions were likely due to 

irritation from the repeated gavage administration with PFBuS. In another study, no morphological 

alterations were observed in the gastrointestinal tract of rats administered ≤900 mg/kg/day PFBuS 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 morphological 

alterations in the gastrointestinal tract (3M 2007a; Butenhoff et al. 2012a; van Otterdijk 2007a, 2007b).

2.7 HEMATOLOGICAL

Overview. A small number of epidemiology studies have evaluated hematological endpoints in workers 

exposed to PFOA or PFOS and in a community exposure study; these studies did not find alterations in 

hematological indices. Details of these studies are presented in the Supporting Document for 

Epidemiological Studies for Perfluoroalkyls, Table 5. Laboratory animal studies have evaluated potential 

alterations in hematological endpoints for a variety of perfluoroalkyl compounds (Tables 2-1, 2-3, 2-4, 

2-5, and 2-6). Some laboratory animal studies have reported alterations in hematological indices 

following exposure to higher doses of PFOA, PFOS, PFHxS, PFUA, PFBuS, PFBA, or PFHxA.
PERFLUOROALKYLS 138

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFOA

Epidemiology Studies. Information on effects on hematological parameters is available from a study of 

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 of 

serum PFOA levels of 5–9,550 ng/mL (Sakr et al. 2007b).

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, and 

differential leukocyte counts.

No significant hematological alterations were reported in male and female rats orally dosed with 

approximately 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 a 

capsule (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 not 

always dose-related or consistent among sexes and were within acceptable ranges for the rat (3M 1983). 

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

Epidemiology Studies. Two occupational exposure studies (Olsen et al. 1998a, 2003a) have examined 

the potential association between serum PFOS and hematological parameters (including hematocrit, 
PERFLUOROALKYLS 139

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 hematological 

parameters (Seacat et al. 2003). Oral dosing with 1.3–1.6 mg/kg/day for 14 weeks resulted in a 

significant increase (45%) in non-segmented neutrophils (Seacat et al. 2003). The biological significance 

of 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 the 

study, the only significant effect was a 9% decrease in hemoglobin in 0.75 mg/kg/day males at 

termination (Seacat et al. 2002). The investigators considered this a treatment-related effect, but not 

biologically significant given that the value was within the published range and there was no evidence of 

blood in the stools. No significant hematological effects were reported in a 2-year study in rats dosed 

with approximately 1.04 mg/kg/day PFOS in the diet (Butenhoff et al. 2012b; Thomford 2002b).

PFHxS

Laboratory Animal Studies. Treatment of male rats with doses ≥0.3 mg/kg/day PFHxS by gavage for at 

least 42 days significantly increased prothrombin time (Butenhoff et al. 2009a; Hoberman and York 

2003). Doses ≥1 mg/kg/day significantly decreased hemoglobin concentration, whereas ≥3 mg/kg/day 

decreased erythrocyte count and 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 hematological parameters (Butenhoff et al. 2009a; Hoberman and York 2003).

PFUA

Laboratory Animal Studies. Treatment of rats with 1.0 mg/kg/day PFUA 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%), activated 

partial thromboplastin time (APTT) (16–25%), and fibrinogen (19–33%), and increased platelet counts 
PERFLUOROALKYLS 140

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

(13%) and white blood cells (7%). In females, there were increases in MCV (10%) and MCH (10%) and 

a decrease in fibrinogen (32%). The NOAEL was 0.3 mg/kg/day.

PFBuS

Laboratory Animal Studies. A 90-day exposure to PFBuS 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 PFBuS 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 or up to 150 mg/kg/day for 28 days did not result in significant alterations in hematological 

parameters (3M 2007a; Butenhoff et al. 2012a; van Otterdijk 2007a). 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, and 

hematocrit, and an increase in red cell distribution width in male rats (Butenhoff et al. 2012a; van 

Otterdijk 2007b). This dose level also caused a reduction in MCH and reduced MCH concentration in 

male 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 marrow 

or the spleen.

PFHxA

Laboratory Animal Studies. In a 104-week gavage study, treatment of female Sprague-Dawley rats 

(60 or 70/dose) with 200 mg/kg/day PFHxA resulted in significant decreases in mean red blood cell 

counts (8.1%) and hemoglobin (5.2%), as well as significant increases in reticulocyte counts at weeks 25 

and 51 (23.6 and 53.6%, respectively) (Klaunig et al. 2015). There were no alterations in hematological 

parameters in males. The NOAEL was 100 mg/kg/day.
PERFLUOROALKYLS 141

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

2.8 MUSCULOSKELETAL

Overview. Several epidemiology 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 of 

mostly male workers. Mixed results were found in studies of PFOS, with studies finding a decreased risk

of 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 a link between perfluoroalkyl exposure and osteoarthritis is complicated by the 

lack of mechanistic data to support this association and it is noted that there are a number of factors that 

contribute to the osteoarthritis risk, and that some of these factors may be affected by perfluoroalkyls, 

including elevations in uric acid levels. No morphological alterations were noted in bone or skeletal 

muscle in laboratory animals following exposure to PFOA, PFOS, PFBuS, or PFBA; these data are 

summarized in Tables 2-1, 2-3, 2-4, and 2-5 and Figures 2-4, 2-6, 2-7, and 2-8.

PFOA

Epidemiology 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 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 (Khalil et al. 2016; Uhl et al. 2013); there were no associations in men. When 

stratified by age, the associations were found in women 20–49 years of age, but not in older women (50–

84 years old) (Uhl et al. 2013). Two studies of adult NHANES participants found no associations 
PERFLUOROALKYLS 142

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-9. Summary of Skeletal Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Steenland et al. 2015

Occupational (n=3,713 workers)

Cumulative exposure Osteoarthritis risk NS (p=0.92 for trend), no lag

NS (p=0.13 for trend), 10-year lag 

Innes et al. 2011

Community (C8) (n=49,432 adults) 

13.6–28.0 ng/mL (2nd PFOA 

quartile) 

Osteoarthritis risk 

(physician diagnosed)

OR 1.16 (1.03–1.31)*, 2nd quartile 

OR 1.22 (1.02–1.45)*, 2nd quartile 

participants <55 years of age

Khalil et al. 2016

General population (NHANES) 

(n=1,914 participants) 

3.7 ng/mL (mean PFOA) Total femur neck mineral 

density 

β -0.017 (-0.033 to -0.001)*, women

β 0.001 (-0.025–0.022), men 

Osteoarthritis risk 

(women)

OR 1.84 (1.17–2.90; p=0.008)*, per lnPFOA increase

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 bone 

mineral density

NS (p>0.01), premenopausal women, 

postmenopausal women, men

Total hip bone mineral 

density

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

Hip fracture 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

Wrist fracture 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
PERFLUOROALKYLS 143

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-9. Summary of Skeletal Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Spine fracture 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 

Uhl et al. 2013

General population (NHANES) (n=1,888 male 

and 1,921 female adults)

>5.89 ng/mL (4th PFOA 

quartile)

Osteoarthritis risk (selfreported)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

PFOS

Innes et al. 2011

Community (C8) (n=49,432 adults) 

≥29.4 ng/mL (4th PFOS 

quartile) 

Osteoarthritis risk 

(physician diagnosed)

OR 0.76 (0.68–0.85)*, 4th quartile

Khalil et al. 2016

General population (NHANES) 

(n=1,914 participants) 

12.7 ng/mL (mean PFOS) Total femur neck mineral 

density 

β -0.016 (-0.029 to -0.002)*, women

β -0.013 (-0.024 to -0.002)*, men

Osteoarthritis risk 

(women)

OR 1.14 (0.68–1.94; p=0.619), per 

ln-PFOS increase

Lin et al. 2014

General population (NHANES) 

(n=2,339 participants)

19.23 and 12.09 ng/mL 

(geometric mean PFOS in 

males and females)

Total lumbar spine bone 

mineral density

β -0.022 (-0.038 to -0.007)*, 

premenopausal women

NS (p>0.01), postmenopausal women

NS (p>0.01), men

Total hip bone mineral 

density

NS (p>0.01), premenopausal women, 

postmenopausal women, men

All fracture types 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
PERFLUOROALKYLS 144

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-9. Summary of Skeletal Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Hip fracture 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

Wrist fracture 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

PFHxS

Khalil et al. 2016

General population (NHANES) 

(n=1,914 participants) 

2.5 ng/mL (mean PFHxS) Total femur bone mineral 

density 

β -0.014 (-0.074 to -0.014)*, women

β -0.026 (-0.065–0.013), men 

Osteoarthritis risk 

(women)

OR 1.64 (1.14–2.38; p=0.008)*, per 

ln-PFHxS increase

PFNA

Khalil et al. 2016

General population (NHANES) (n=1,914 

participants) 

1.9 ng/mL (mean PFNA) Total femur bone mineral 

density 

β -0.040 (-0.077 to -0.003)*, women

β 0.007 (-0.031–0.045), men 

Osteoarthritis risk

(women)

OR 1.45 (1.02–2.05; p=0.001)*, per 

ln-PFNA increase.

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 compound; 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

1
PERFLUOROALKYLS 145

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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. 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 PFOA resulted in morphometrical alterations in 

the femur (increases in the periosteal area) and decreases in bone mineral density in the tibia of 13- or 

17-month-old mice (Koskela et al. 2016). No alterations in biomechanical properties were found. The 

investigators noted that PFOA concentrations were 4–5 times higher in the PFOA-exposed animals than 

in controls.

PFOS

Epidemiology Studies. Several epidemiology studies have evaluated the potential of PFOS to induce 

skeletal damage. In the participants of the C8 Health Study, a decreased risk of osteoarthritis was found 

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 osteoarthritis in women. 

However, the study did find an inverse association between serum PFOS and femur neck bone mineral 

density, but no associations with total femur or lumbar spine bone mineral density.

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 appearance 

of the femur, sternum, or thigh skeletal muscle (Seacat et al. 2002). Similar observations were made in 

rats treated with up to 1.04 mg/kg/day PFOS in the diet for 2 years (Butenhoff et al. 2012b; Thomford 

2002b).
PERFLUOROALKYLS 146

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFHxS

Epidemiology Studies. A study of NHANES participants found an increase in the risk of osteoarthritis 

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).

PFNA

Epidemiology Studies. Khalil et al. (2016) found an increase in the risk of osteoarthritis 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.

PFBuS

Laboratory Animal Studies. Treatment of rats with up to 900 mg/kg/day PFBuS by gavage for 28 or 

90 days did not induce morphological alterations in skeletal muscle (3M 2001; Lieder et al. 2009a).

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).

2.9 HEPATIC

Overview. Epidemiology studies on perfluoroalkyls have examined three potential hepatic outcomes: 

liver disease, alterations in serum enzyme and bilirubin levels, and alterations in serum lipid levels. 

Summaries of the epidemiology studies examining these outcomes are presented in Tables 2-10, 2-11, and
PERFLUOROALKYLS 147

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

2-12, with more detailed descriptions presented in the Supporting Document for Epidemiological Studies 

for Perfluoroalkyls, Table 7. There are limited epidemiology data on potential associations between 

serum perfluoroalkyls and risk of liver disease. Occupational exposure and community studies did not 

find increased risk of liver disease associated with PFOA or PFOS. As assessed by serum enzyme and 

bilirubin levels, the epidemiology studies provide suggestive evidence of liver damage. Increases in 

aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase 

(GGT) levels and decreases in serum bilirubin levels have been reported in occupational, community,

and/or general population studies. Although there is considerable variability across studies, the evidence

is adequate for PFOA, PFOS, and PFHxS, particularly for ALT levels; consistent results were not found 

for PFNA. The results of available epidemiology studies suggest associations between increases in serum 

lipids, particularly total cholesterol and LDL cholesterol, and serum PFOA, PFOS, PFNA, and PFDeA. 

For PFHxS, PFUA, PFHpA, PFBuS, PFBA, and PFDoA, there are too few studies or the results are too 

inconsistent to determine if they also would affect serum lipid levels at environmental exposure levels.

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 2-4, 2-5, 2-6, 2-7, and 2-8. The 

results of these studies provide strong evidence that the liver is a sensitive target of PFOA, PFOS, PFHxS, 

PFNA, PFUA, PFBuS, and PFBA toxicity. Observed effects in rodents include increases in liver weight; 

hepatocellular hypertrophy, hyperplasia, and necrosis; and decreases 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).

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 be 

considered adaptive responses and of little relevance to humans. According to the ESTP criteria, 
PERFLUOROALKYLS 148

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-10. Summary of Liver Disease in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Anderson-Mahoney et al. 2008

Community (n=566)

NR Liver problems (selfreported)SPR 1.01 (0.64–1.59) 

Darrow et al. 2016

Community (C8) (n=28,831)

Cumulative 

16.5 ng/mL (median 

2005/2006)

Liver disease HR 0.97 (0.92–1.03), no lag per ln 

increase in PFOA

HR 0.98 (0.93–1.04), 10-year lag

Enlarged liver, fatty liver, 

or cirrhosis

HR 0.97 (0.91–1.04), no lag per ln 

increase in PFOA 

HR 1.00 (0.94–1.07), 10-year lag 

Steenland et al. 2015

Occupational (n=3,713)

Cumulative Non-hepatitis liver disease 

risk 

NS (p=0.86), no lag

NS (p=0.40), 10-year lag

PFOS

Alexander et al. 2003

Occupational (n=2,083)

NR Liver cirrhosis deaths SMR 0.81 (0.10–2.94)

Grice et al. 2007

Occupational (n=1,400)

1,300–1,970 ng/mL (high 

potential workers)

Liver disease OR 1.21 (0.56–2.60)

Cholelithiasis OR 0.91 (0.57–1.46)

Cholecystitis OR 1.15 (0.65–2.06)
PERFLUOROALKYLS 149

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-10. Summary of Liver Disease in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Olsen et al. 2004a

Occupational (n=652 exposed, n=659 for nonexposed)

NR Cholelithiasis or acute 

cholecystitis

RREpC 8.6 (1.1–>100)*

RREpC 25 (2.1–>100)*, workers with 

≥10 years high exposure potential

Liver disease RREpC 1.2 (0.2–8.6) 

Biliary duct disorders RREpC 1.6 (0.8–2.9) 

RREpC 2.6 (1.2–5.5)*, workers with 

≥10 years high exposure potential

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 compound; 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 150

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Costa et al. 2009

Occupational (n=37 current workers; 

n=16 former workers; n=107 non-exposed 

workers)

12,930 ng/mL (mean PFOA 

current workers)

6,810 ng/mL (mean former 

workers)

AST NS (p>0.05) (34 current workers)

ALT NS (p>0.05) (34 current workers)

Association (p<0.01)* (56 current, 

former, non-exposed workers)

GGT NS (p>0.05) (34 current workers)

Association (p<0.01)* (56 current, 

former, non-exposed workers)

Total bilirubin Inverse association (p<0.01)* 

(56 current, former, non-exposed 

workers)

Gilliland and Mandel 1996

Occupational (n=115)

NR (serum fluorine levels used 

as surrogate for serum PFOA)

ALT NS (p=0.32)

AST NS (p=0.80)

GGT NS (p=0.81)

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, and 

1997) 

Workers divided into three

groups: 0–<1,000, 1,000–

<10,000, and ≥10,000 ng/mL

ALT NS (p=0.82, 0.30, 0.73) differences 

between exposure groups for each 

measurement period

AST NS (p=0.33, 0.45, 0.83) differences 

between exposure groups for each 

measurement period

GGT NS (p=0.24, 0.41, 0.78) differences 

between exposure groups for each 

measurement period

Total bilirubin NS (p=0.48, 0.11, 0.58) differences 

between exposure groups for each 

measurement period

Direct bilirubin NS (p=0.82, 0.05, 0.74) differences 

between exposure groups for each 

measurement period
PERFLUOROALKYLS 151

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Olsen and Zobel 2007

Occupational (n=552)

2170 ng/mL (mean 8th PFOA 

decile)

12,150 ng/mL (mean 10th PFOA 

decile)

GGT

Elevated GGT

Association (p=0.05)*

OR 1.0 (0.3–2.9), 10th decile

Total bilirubin Inverse association (p=0.001)*

ALT

Elevated ALT

NS (p=0.06)

OR 1.2 (0.5–3.4), 10th decile 

AST NS (p=0.55)

Sakr et al. 2007a

Occupational (n=454)

1,130 ng/mL (mean PFOA) Total bilirubin Association (p=0.006)*

AST Association (p=0.009)*

ALT NS (p>0.05)

GGT NS (p>0.05)

Sakr et al. 2007b

Occupational (n=1,025)

428 ng/mL (mean PFOA) GGT Association (p=0.016)*

AST NS (p=0.317)

ALT NS (p=0.124)

Bilirubin NS (p=0.590)

Wang et al. 2012

Occupational (n=55)

2,157.74 ng/mL (mean PFOA) AST Association (p=0.02)*

ALT NS (p=0.38)

Darrow et al. 2016

Community (C8) (n=28,831)

Cumulative 

16.5 ng/mL (median PFOA in 

2005/2006)

ALT Association (p<0.0001 for trend)*, 

cumulative levels

Association (p<0.0001 for trend)*, 

2005/2006 levels

GGT NS (p=0.1021), cumulative levels

NS (p=0.1552), 2005/2006 levels 

Bilirubin Inverse association (p=0.0029 for 

trend)*, cumulative levels

Inverse association (p=0.0036 for 

trend)*, 2005/2006 levels
PERFLUOROALKYLS 152

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Emmett et al. 2006b

Community (n=371)

354 ng/mL (median PFOA) ALT

Abnormal ALT

NS (p>0.05)

NS (p>0.05)

AST

Abnormal AST

NS (p>0.05)

Inverse association (p=0.03)*

GGT

Abnormal GGT

NS (p>0.05)

NS (p>0.05) 

Gallo et al. 2012

Community (C8) (n=46,452)

NR ALT

Abnormal ALT

Correlation (p<0.001)*

OR 1.19 (1.03–1.37)*, 3rd decile

GGT

Abnormal GGT

Correlation (p<0.001)*

NS (p=0.213 for trend)

Direct bilirubin

Abnormal bilirubin

NS (p>0.05)

NS (p=0.496 for trend)

Wang et al. 2012

Community (n=132)

378.30 ng/mL (mean PFOA) ALT NS (p=0.05)

AST NS (p=0.22)

Gleason et al. 2015

General population (NHANES) (n=4,333)

3.7 ng/mL (median PFOA) ALT Association (p<0.001)*

Elevated ALT Association (p=0.007 for trend)*

AST Association (p<0.01)*

Elevated AST NS (p=0.058 for trend).

GGT Association (p<0.01)*

Elevated GGT Association (p=0.042 for trend)*

Total bilirubin Association (p<0.01)*

Elevated bilirubin Association (p<0.001 for trend)*

Lin et al. 2010

General population (NHANES) (n=2,216)

5.05 and 4.06 ng/mL (geometric 

mean PFOA in males and 

females)

ALT Association (p=0.005)*

GGT Association (p=0.019)*

Total bilirubin NS (p=0.645)

Yamaguchi et al. 2013

General population (n=608)

2.1 ng/mL (mean PFOA) ALT Association (p=0.02)*

AST Association (p=0.001)*

GGT Association (p=0.03)*
PERFLUOROALKYLS 153

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOS

Grice et al. 2007

Occupational (n=1,400)

1,300–1,970 ng/mL (high 

potential workers)

Cholelithiasis OR 0.91 (0.57–1.46)

Cholecystitis OR 1.15 (0.65–2.06)

Olsen et al. 1999

Occupational (n=178 in 1995; n=149 in 

1997)

2,440 and 1,930 ng/mL (mean 

PFOS in 1995 in DeCatur and 

Antwerp)

1,960 and 1,480 ng/mL (mean 

PFOS in 1997 in DeCatur and 

Antwerp)

AST NS (p=0.14 for trend), 1995

NS (p=0.67 for trend), 1997

ALT NS (p=0.38 for trend), 1995

NS (p=0.46 for trend), 1997

GGT NS (p=0.71 for trend), 1995

NS (p=0.34 for trend), 1997

Olsen et al. 2003a

Occupational (n=518)

2460 ng/mL (median 4th PFOS 

quartile)

AST NS (p>0.05), no adjustments

ALT

Risk of abnormal ALT

Higher levels (p<0.05)*, males only 

with no adjustments

OR 2.1 (0.6–7.3) 

GGT

Risk of abnormal GGT

Difference (p<0.05)*, females only 

with no adjustments

OR 2.0 (0.7–5.8)

Gallo et al. 2012

Community (C8) (n=46,452)

NR ALT

Abnormal ALT

Correlation (p<0.001)*

OR 1.19 (1.04–1.37)*, 5th decile

GGT

Abnormal GGT

NS (p>0.05)

Association (p=0.047 for trend)*

Direct bilirubin

Abnormal bilirubin

Correlation (p<0.001)*

Association (p=0.015 for trend)*
PERFLUOROALKYLS 154

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Gleason et al. 2015

General population (NHANES) (n=4,333)

11.3 ng/mL (median PFOS) ALT NS (p>0.01)

Elevated ALT NS (p=0.370 for trend)

AST NS (p>0.01)

Elevated AST NS (p=0.438 for trend)

GGT NS (p>0.01)

Elevated GGT NS (p=0.654 for trend)

Total bilirubin NS (p>0.01)

Elevated bilirubin Association (p=0.028 for trend)*

Lin et al. 2010

General population (NHANES) (n=2,216)

27.39 and 22.20 ng/mL 

(geometric mean PFOS in males 

and females)

ALT NS (p=0.066)

GGT NS (p=0.808)

Total bilirubin NS (p=0.223)

Yamaguchi et al. 2013

General population (n=608)

5.8 ng/mL (mean PFOS) ALT Association (p=0.03)*

AST Association (p=0.01)*

GGT Association (p=0.03)*

PFHxS

Gleason et al. 2015

General population (NHANES) (n=4,333)

1.8 ng/mL (median PFHxS) ALT Association (p<0.01)*

Elevated ALT NS (p=0.484 for trend)

AST Association (p<0.001)*

Elevated AST NS (p=0.230 for trend)

GGT NS (p>0.01)

Elevated GGT NS (p=0.415 for trend)

Total bilirubin Association (p<0.01)*

Elevated bilirubin Association (p=0.041 for trend)*

Lin et al. 2010

General population (NHANES) (n=2,216)

2.29 and 1.72 ng/mL (geometric 

mean PFHxS in males and 

females)

ALT NS (p=0.691)

GGT NS (p=0.898)

Total bilirubin NS (p=0.063)
PERFLUOROALKYLS 155

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-11. Summary of Alterations in Serum Hepatic Enzymes and Bilirubin Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFNA

Mundt et al. 2007

Occupational (n=592)

NR ALT NS, longitudinal analysis

AST NS, longitudinal analysis

GGT NS, longitudinal analysis

Bilirubin NS, longitudinal analysis

Gleason et al. 2015

General population (NHANES) (n=4,333)

1.4 ng/mL (median PFNA) ALT Association (p<0.001)*

Elevated ALT NS (p=0.042 for trend)

AST NS (p>0.01)

Elevated AST NS (p=0.516 for trend)

GGT Association (p<0.01)*

Elevated GGT NS (p=0.126 for trend)

Total bilirubin NS (p>0.01)

Elevated bilirubin NS (p=0.614 for trend)

Lin et al. 2010

General population (NHANES) (n=2,216)

0.89 and 0.72 ng/mL (geometric 

mean PFNA in males and 

females)

ALT NS (p=0.131)

GGT NS (p=0.857)

Total bilirubin 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 compound; 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 and 

Nutrition Examination Survey; NR = not reported; NS = not significant; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid
PERFLUOROALKYLS 156

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Costa 2004

Occupational (n=35)

NR Total cholesterol Association (p=0.03)*

Non-HDL cholesterol Association (p=0.03)*

HDL cholesterol NS (p>0.05)

LDL cholesterol NS (p>0.05)

Total triglycerides NS (p>0.05)

Costa et al. 2009

Occupational (n=37 current workers; n=16 

former workers; n=107 non-exposed workers)

12,930 ng/mL (mean PFOA in 

current workers)

6,810 ng/mL (mean PFOA in 

former workers)

Total cholesterol Association (p=0.005)* (current 

workers)

Association (p<0.05)* (56 current, 

former, non-exposed workers)

HDL cholesterol NS (p>0.05) (34 current workers)

Triglycerides NS (p>0.05)

Gilliland and Mandel 1996

Occupational (n=115)

NR (serum fluorine levels 

used as surrogate for serum 

PFOA)

Total cholesterol NS (p=0.62)

Total LDL NS (p=0.87)

Total HDL NS (p=0.66)

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, and 1997) 

Workers divided into three 

groups: 0–<1,000, 1,000–

<10,000, and ≥10,000 ng/mL

Total cholesterol NS (p=0.45, 0.48, 0.08) differences 

between exposure groups for each 

measurement period

LDL cholesterol NS (p=0.84, 0.96, 0.11) differences 

between exposure groups for each 

measurement period

HDL cholesterol NS (p=0.32, 0.70, 0.40) differences 

between exposure groups for each 

measurement period

Triglycerides NS (p=0.77, 0.07, 0.13) differences 

between exposure groups for each 

measurement period
PERFLUOROALKYLS 157

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Olsen and Zobel 2007

Occupational (n=552)

2,170 ng/mL (mean of 

8th PFOA decile)

12,150 ng/mL (mean of 

10th PFOA decile)

Total cholesterol NS (p=0.20)

Elevated total cholesterol OR 1.1 (0.5–2.6), 10th decile

LDL cholesterol NS (p=0.81)

Elevated LDL- cholesterol OR 1.2 (0.5–2.8), 10th decile

HDL cholesterol Association (p=0.01)*

Decreased HDL 

cholesterol

OR 1.8 (0.7–4.8), 10th decile 

Triglycerides Association (p=0.0001)*

Elevated triglycerides OR 1.8 (0.8–4.4), 10th decile

Sakr et al. 2007a

Occupational (n=454)

1,130 ng/mL (mean PFOA) Total cholesterol Association (p=0.011)*

LDL cholesterol NS (p>0.05)

HDL cholesterol NS (p>0.05)

Triglycerides NS (p>0.05)

Total bilirubin Association (p=0.006)*

Sakr et al. 2007b

Occupational (n=1,025)

428 ng/mL (mean PFOA) Total cholesterol Association (p=0.002)*

LDL cholesterol Association (p=0.008)*

VLDL cholesterol Association (p=0.031)*

HDL cholesterol NS (p=0.680)

Triglycerides NS (p=0.384)

Steenland et al. 2015

Occupational (n=3,713)

Cumulative PFOA Elevated cholesterol NS (p=0.56), no lag

NS (p=0.62), 10-year lag

Wang et al. 2012

Occupational (n=55)

2,157.74 ng/mL (mean 

PFOA)

Total cholesterol NS (p=0.36)

LDL cholesterol NS (p=0.43)

HDL cholesterol Inverse association (p=0.01)*

Triglycerides NS (p=0.37)

Emmett et al. 2006b

Community (n=371)

354 ng/mL (median PFOA) Total cholesterol

Abnormal cholesterol

NS (p>0.05)

NS (p>0.05)
PERFLUOROALKYLS 158

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Fitz-Simon et al. 2013

Community (C8) (n=560 adults) 

140.1 and 68.2 ng/mL (mean 

PFOA at first and second 

examinations) 

Total cholesterol -1.65% (-0.32 to -2.97)*, 50% 

decrease in PFOA

LDL cholesterol -3.58% (-1.47 to -5.66)*, 50% 

decrease in PFOA

HDL cholesterol -1.33% (0.21 to -2.85), 50% decrease 

in PFOA

Triglycerides 0.78% (5.34 to -3.58), 50% decrease 

in PFOA

Frisbee et al. 2010

Community (C8) (n=12,476 children and 

adolescents)

77.7 ng/mL (mean PFOA in 

children)

61.8 ng/mL (mean PFOA in 

adolescents)

Total cholesterol Association (p<0.001)*, children 

5th quintile

Association (p<0.001)*, adolescents 

5th quintile

Abnormal cholesterol OR 1.1 (1.0–1.3), 2nd quintile 

LDL cholesterol Association (p=0.001)*, children 

5th quintile

Association (p=0.004)*, adolescents 

5th quintile

Abnormal LDL levels OR 1.2 (1.0–1.5), 2nd quintile

HDL cholesterol NS (p=0.88), children 5th quintile 

NS (p=0.20), adolescents 5th quintile

Triglycerides NS (p=0.1), children 5th quintile 

NS (p=0.1), adolescents 5th quintile

Steenland et al. 2009b

Community (C8) (n=46,294)

80.3 ng/mL (mean PFOA)

13.2–26.5 ng/mL (2nd PFOA 

quartile)

Total cholesterol Association (p<0.001 for trend)*

Abnormal cholesterol OR 1.21 (1.12–1.31)*, 2nd quartile

LDL cholesterol Association (p<0.05 for trend)*

HDL cholesterol NS (p>0.05)

Triglycerides Association (p<0.05 for trend)*
PERFLUOROALKYLS 159

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Wang et al. 2012

Community (n=132)

378.30 ng/mL (mean PFOA) Total cholesterol NS (p=0.85) 

LDL cholesterol NS (p=0.97)

Triglycerides NS (p=0.73)

HDL cholesterol NS (p=0.39)

Winquist and Steenland 2014a

Community (C8) (n=28,541) 

142–<234 ng/mL (estimated 

2nd quintile for cumulative 

PFOA) 

Hypercholesterolemia HR 1.24 (1.15–1.33)*, 2nd quintile for 

cumulative exposure

Eriksen et al. 2013

General population (n=753) 

7.1 ng/mL (mean PFOA) Total cholesterol Association (p=0.01)* 

Fisher et al. 2013

General population (n=2,368)

2.46 ng/mL (mean PFOA) Total cholesterol NS (p=0.22) 

High cholesterol levels OR 1.5 (0.86–2.62), 4th quartile

Non HDL cholesterol NS (p=0.13)

LDL cholesterol NS (p=0.63)

HDL cholesterol NS (p=0.96)

Fu et al. 2014a

General population (n=133) 

1.43 ng/mL (median PFOA) Total cholesterol Association (p=0.015)* 

Elevated cholesterol OR 0.55 (0.09–3.31) 

LDL cholesterol Association (p=0.022)*

Elevated LDL OR 0.71 (0.14–3.49)

HDL cholesterol NS (p=0.260)

Elevated HDL OR 0.67 (0.13–3.51)

Triglycerides NS (p=0.298)

Elevated triglyceride OR 1.97 (0.59–6.55)
PERFLUOROALKYLS 160

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Geiger et al. 2014b

General population (NHANES) (n=815 12–

18-year-old adolescents)

4.2 ng/mL (mean PFOA) Total cholesterol Association (p=0.0170 for trend)*

Elevated cholesterol OR 1.44 (1.11–1.88, p=0.0253 for 

trend)*, log transformed PFOA 

LDL cholesterol Association (p=0.0027 for trend)*

Elevated LDL NS (p=0.0539 for trend) 

HDL cholesterol NS (p=0.1769 for trend)

Decreased HDL NS (p=0.1493 for trend)

Triglycerides NS (p=0.9943 for trend)

Elevated triglycerides NS (p=0.5975 for trend)

Maisonet et al. 2015a

General population (n=111 for 7-year-old and 

n=88 for 15-year-old girls

1.1–3.1, 3.2–4.4, and 4.5–

16.4 ng/mL (maternal PFOA 

for 1st, 2nd, and 3rd tertiles)

Total cholesterol in 7 year 

olds

Association (β 13.75, 0.05–27.45)*, 

1st tertile

NS, 2nd and 3rd tertiles

Total cholesterol in 

15 year olds

Association (β 17.19, 0.405–33.93)*, 

1st tertile

NS, 2nd and 3rd tertiles

LDL cholesterol in 7 year 

olds

Association (β 14.01, 3.26–24.76)*, 

1st tertile

NS, 2nd and 3rd tertiles

LDL cholesterol in 15 year 

olds

Association (β 14.261, 0.25–28.26)*, 

1st tertile

NS, 2nd and 3rd tertiles

HDL cholesterol 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

Triglycerides 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
PERFLUOROALKYLS 161

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Nelson et al. 2010

General population (NHANES) (n=860)

4.6 ng/mL (mean PFOA) Total cholesterol NS (p=0.07) 

LDL cholesterol NS (p=0.84)

Non-HDL cholesterol Association (p=0.05)*

β 1.38 (0.12–2.65), per ng/mL 

increase in PFOA

HDL cholesterol NS (p=0.34)

Skuladottir et al. 2015

General population (n=854 pregnant women) 

4.1 ng/mL (mean PFOA) Total cholesterol Association (p=0.01 for trend)* 

Starling et al. 2014a

General population (n=854 pregnant women) 

2.25 ng/mL (50th PFOA 

percentile)

Total cholesterol NS (β 2.58; -4.32–9.47), per ln-unit 

increase in PFOA 

LDL cholesterol NS (β 0.35 -3.97–8.48), per ln-unit 

increase in PFOA

HDL cholesterol Association (β 3.42 0.56–6.28)*, 

4th quartile

Triglycerides NS (β 0.00 (-0.07–0.06), per ln-unit 

increase in PFOA 

Timmermann et al. 2014

General population (n=499 children, 8–10 years

old)

9.3 ng/mL (median PFOA) Triglycerides NS (p=0.91), normal weight children

Association (p=0.002)*, obese 

children

Zeng et al. 2015

General population (n=225 adolescents, 12–

15 years old)

1.1 and 0.92 ng/mL (mean 

PFOA in boys and girls)

Total cholesterol Association (p=0.001)*

LDL cholesterol Association (p=0.002)*

HDL cholesterol NS (p=0.06)

Triglycerides Association (p<0.001)*
PERFLUOROALKYLS 162

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOS

Olsen et al. 1999

Occupational (n=178 in 1995; n=149 in 1997)

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 DeCatur 

and Antwerp)

Total cholesterol NS (p=0.96 for trend), 1995

Association (p=0.006 for trend)*, 

1997

LDL cholesterol NS (p=0.87 for trend), 1995

Association (p=0.01 for trend)*, 

1997

HDL cholesterol Inverse association (p=0.04 for 

trend)*, 1995

NS (p=0.34) 1997

Triglycerides NS (p=0.35 for trend), 1995

NS (p=0.67 for trend), 1997

Olsen et al. 2003a

Occupational (n=518)

2,460 ng/mL (median 4th

PFOS quartile)

Total cholesterol NS (p>0.05), no adjustments

Association (p=0.04)*, with 

adjustments

HDL cholesterol NS (p>0.05), no adjustments

Triglycerides Higher levels (p<0.05)*, males only 

with no adjustments 

Association (p=0.01)*, with 

adjustments

Frisbee et al. 2010

Community (C8) (n=12,476 children and 

adolescents)

23.6 ng/mL (mean PFOS in 

children)

21.9 ng/mL (mean PFOS in 

adolescents)

Total cholesterol Association (p<0.001)*, children 

5th quintile

Association (p<0.001)*, adolescents 

5th quintile

Abnormal cholesterol OR 1.3 (1.1–1.4)*, 2nd quintile 

LDL cholesterol Association (p=0.002)*, children 

5th quintile

Association (p<0.001)*, adolescents 

5th quintile

Abnormal LDL levels OR 1.2 (1.0–1.5)*, 2nd quintile
PERFLUOROALKYLS 163

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

HDL cholesterol Association (p=0.007)*, children 

5th quintile 

Association (p=0.001)*, adolescents 

5th quintile

Triglycerides NS (p=0.1), children 5th quintile 

NS (p=0.1), adolescents 5th quintile

Steenland et al. 2009b

Community (C8) (n=46,294)

22.4 ng/mL (mean PFOS)

13.3–19.5 ng/mL (2nd quartile)

Total cholesterol Association (p<0.001 for trend)*

Abnormal cholesterol OR 1.14 (1.05–1.23)*, 2nd quartile

LDL cholesterol Association (p<0.05 for trend)*

HDL cholesterol NS (p>0.05)

Triglycerides Association (p<0.05 for trend)*

Châtaeu-Degat et al. 2010

General population (n=723) 

25.7 ng/mL (mean PFOS) Total cholesterol NS (p=0.086)

LDL cholesterol NS (p=0.242)

HDL cholesterol Association (p<0.001)*, men

Association (p=0.001)*, women

Triglycerides NS (p=0.162), men

Inverse association (p=0.040)*. 

women

Eriksen et al. 2013

General population (n=753) 

36.1 ng/mL (mean PFOS) Total cholesterol Association (p=0.02)* 

Fisher et al. 2013

General population (n=2,368)

8.04 ng/mL (mean PFOS) Total cholesterol NS (p=0.35)

High cholesterol levels OR 1.36 (0.87–2.12), 4th quartile

Non HDL cholesterol NS (p=0.14)

LDL cholesterol NS (p=0.42)

HDL cholesterol NS (p=0.33)
PERFLUOROALKYLS 164

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Fu et al. 2014a

General population (n=133) 

1.47 ng/mL (median PFOS) Total cholesterol NS (p=0.287)

Elevated cholesterol OR 2.27 (0.47–10.92)

LDL cholesterol NS (p=0.357)

Elevated LDL OR 2.27 (0.50–10.37)

HDL cholesterol NS (p=0.260)

Elevated HDL OR 0.29 (0.06–1.50)

Triglycerides NS (p=0.711)

Elevated triglyceride OR 1.26 (0.41–3.90)

Geiger et al. 2014b

General population (NHANES) (n=815 12–

18-year-old adolescents)

17.7 ng/mL (mean PFOS) Total cholesterol NS (p=0.0512 for trend)

Elevated cholesterol OR 1.35 (1.11–1.64, p=0.0183 for 

trend)*, log transformed PFOS

LDL cholesterol Association (p=0.0081 for trend)*

Elevated LDL OR 1.48 (1.15–1.90, p=0.0178 for 

trend)*, log transformed PFOS

HDL cholesterol NS (p=0.9703)

Decreased HDL NS (p=0.9873 for trend)

Triglycerides NS (p=0.1104 for trend)

Elevated triglycerides NS (p=0.2418 for trend)

Maisonet et al. 2015b

General population (n=111 for 7-year-old and 

n=88 for 15-year-old girls)

23.5–94.5 ng/mL (3rd tertile 

maternal PFOS)

Total cholesterol NS (β -0.10, -0.73–0.54), 7 year olds

Association (β -0.77, -1.40 

to -0.13)*, 15 year olds

LDL cholesterol NS (β 0.02, -0.48–0.53), 7 year olds

Association (β -0.54, -1.08 

to -0.003)*, 15 year olds

HDL cholesterol NS (β -0.04, -0.33–0.25), 7 year olds 

NS (β -0.18, -0.47–0.12), 15 year olds

Triglycerides NS (β -0.004, -0.015–0.006), 7 year 

olds

NS (β -0.004, -0.011–0.004), 15 year 

olds
PERFLUOROALKYLS 165

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Nelson et al. 2010

General population (NHANES) (n=860)

25.3 ng/mL (mean PFOS) Total cholesterol Association (p=0.01)*

LDL cholesterol NS (p=0.27)

Non-HDL cholesterol Association (p=0.02)*

HDL cholesterol NS (p=0.78)

Skuladottir et al. 2015

General population (n=854 pregnant women) 

22.3 ng/mL (mean PFOS) Total cholesterol Association (p=0.01 for trend)* 

Starling et al. 2014a

General population (n=854 pregnant women) 

13.03 ng/mL (50th PFOS 

percentile)

Total cholesterol Association (p<0.05)* 

LDL cholesterol NS (β 6.48, -0.07–13.03), per ln-unit 

increase in PFOS 

HDL cholesterol Association (β 4.39, 2.37–6.42)*, per 

ln-unit increase in PFOS

Triglycerides NS (β -0.02, -0.09–0.04), per ln-unit 

increase in PFOS 

Timmermann et al. 2014

General population (n=499 children, 8–10 years

old)

41.5 ng/mL (median PFOS) Triglycerides NS (p=0.78), normal weight children

Association (p=0.002)*, obese 

children

Zeng et al. 2015

General population (n=225 children, 12–

15 years old)

32.4 and 34.2 ng/mL (mean 

PFOS in boys and girls)

Total cholesterol Association (p<0.001)*

LDL cholesterol Association (p<0.001)*

HDL cholesterol NS (p=0.72)

Triglycerides Association (p=0.05)*

PFHxS

Fisher et al. 2013

General population (n=2,368)

2.18 ng/mL (mean PFHxS) Total cholesterol Association (p=0.005)*

High cholesterol levels OR 1.27 (1.11–1.45)*, 4th quartile

Non HDL cholesterol Association (p=0.002)*

LDL cholesterol Association (p=0.02)*

HDL cholesterol NS (p=0.67)
PERFLUOROALKYLS 166

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Nelson et al. 2010

General population (NHANES) (n=860)

2.6 ng/mL (mean PFHxS) Total cholesterol NS (p=0.07)

LDL cholesterol NS (p=0.10)

Non-HDL cholesterol Association (p=0.04)*

HDL cholesterol NS (p=0.11)

Starling et al. 2014a

General population (n=854 pregnant women) 

0.60 ng/mL (50th PFHxS 

percentile)

Total cholesterol NS (β 3.00, -1.75–7.76), per ln-unit 

increase in PFHxS

LDL cholesterol NS (β 1.92, -2.50–6.33), per ln-unit 

increase in PFHxS 

HDL cholesterol Association (β 1.46; 0.19–2.73)*, per 

ln-unit increase in PFHxS

Triglycerides NS (β -0.01, -0.05–0.03), per ln-unit 

increase in PFHxS 

Zeng et al. 2015

General population (n=225 children, 12–

15 years old)

2.1 and 2.1 ng/mL (mean 

PFHxS in boys and girls)

Total cholesterol NS (p=0.23)

LDL cholesterol NS (p=0.17)

HDL cholesterol NS (p=0.54)

Triglycerides NS (p=0.15)

PFNA

Mundt et al. 2007

Occupational (n=592)

NR Total cholesterol NS, longitudinal analysis

Triglycerides NS, longitudinal analysis

Fu et al. 2014a

General population (n=133) 

0.37 ng/mL (median PFNA) Total cholesterol Association (p=0.002)*

Elevated cholesterol OR 1.03 (0.24–4.46)

LDL cholesterol Association (p=0.004)

Elevated LDL OR 2.51 (0.59–10.74)

HDL cholesterol NS (p=0.191)

Lowered HDL OR 1.06 (0.20–5.57)

Triglycerides NS (p=0.460)

Elevated triglycerides OR 0.80 (0.26–2.49)
PERFLUOROALKYLS 167

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Nelson et al. 2010

General population (NHANES) (n=860)

1.3 ng/mL (mean PFNA) Total cholesterol Association (p=0.04)*

LDL cholesterol NS (p=0.08)

Non-HDL cholesterol Association (p=0.04)*

HDL cholesterol NS (p=0.31)

Starling et al. 2014a

General population (n=854 pregnant women) 

0.39 ng/mL (50th PFNA 

percentile)

Total cholesterol NS (β 0.01, -5.98–6.00), per ln-unit 

increase in PFNA

LDL cholesterol NS (β -2.15, -7.31–3.02), per ln-unit 

increase in PFNA 

HDL cholesterol Association (β 2.84; 0.97–4.71)*, per 

ln-unit increase in PFNA

Triglycerides NS (β -0.02, -0.07–0.03), per ln-unit 

increase in PFNA 

Zeng et al. 2015

General population (n=225 children, 12–

15 years old)

0.8 and 0.9 ng/mL (mean 

PFNA in boys and girls)

Total cholesterol Association (p=0.04)*

LDL cholesterol Association (p=0.05)*

HDL cholesterol NS (p=0.37)

Triglycerides Association (p=0.007)*

PFDeA

Fu et al. 2014a

General population (n=133) 

0.19 ng/mL (median PFDeA) Total cholesterol Association (p=0.048)*

Elevated cholesterol OR 3.84 (0.87–16.95)

LDL cholesterol NS (p=0.251)

Elevated LDL OR 2.17 (0.52–9.04)

HDL cholesterol Association (p=0.007)*

Elevated HDL OR 2.21 (0.49–10.07)

Triglycerides NS (p=0.317)

Elevated triglycerides OR 0.51 (0.17–1.58)
PERFLUOROALKYLS 168

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Starling et al. 2014a

General population (n=854 pregnant women) 

0.09 ng/mL (50th PFDeA 

percentile)

Total cholesterol NS (β 1.84, -2.12–5.79), per ln-unit 

increase in PFDeA

LDL cholesterol NS (β 0.19, -3.30–3.69), per ln-unit 

increase in PFDeA 

HDL cholesterol Association (β 2.54, 1.22–3.87)*, per 

ln-unit increase in PFDeA

Triglycerides NS (β -0.03, -0.07–0.01), per ln-unit 

increase in PFDeA 

Zeng et al. 2015

General population (n=225 children, 12–

15 years old)

1.0 and 1.0 ng/mL (mean 

PFDeA in boys and girls)

Total cholesterol NS (p=0.74)

LDL cholesterol NS (p=0.85)

HDL cholesterol NS (p=0.47)

Triglycerides NS (p=0.92)

PFUA

Fu et al. 2014a

General population (n=133) 

0.26 ng/mL (median PFUA) Total cholesterol NS (p=0.184)

Elevated cholesterol OR 3.70 (0.76–18.03)

LDL cholesterol NS (p=0.270)

Elevated LDL OR 4.16 (0.96–18.00)

HDL cholesterol NS (p=0.279)

Elevated HDL OR 0.54 (0.11–2.57)

Triglycerides NS (p=0.755)

Elevated triglycerides OR 0.74 (0.25–2.21)

Starling et al. 2014a

General population (n=854 pregnant women) 

0.22 ng/mL (50th PFUA 

percentile)

Total cholesterol NS (β 0.89, -3.28–5.06), per ln-unit 

increase in PFUA

LDL cholesterol NS (β -2.36, -5.97–1.25), per ln-unit 

increase in PFUA 

HDL cholesterol Association (β 4.05, 2.75–5.35)*, per 

ln-unit increase in PFUA

Triglycerides NS (β -0.04, -0.08–0.00), per ln-unit 

increase in PFUA 
PERFLUOROALKYLS 169

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-12. Summary of Serum Lipid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFHpA

Fu et al. 2014a

General population (n=133) 

0.04 ng/mL (median PFHpA) Total cholesterol NS (p>0.05)

LDL cholesterol NS (p>0.05)

HDL cholesterol NS (p>0.05)

Triglycerides NS (p>0.05)

PFBuS

Zeng et al. 2015

General population (n=225 children, 12–

15 years old)

0.5 and 0.4 ng/mL (mean 

PFBuS in boys and girls)

Total cholesterol Association (p=0.04)*

LDL cholesterol NS (p=0.14)

HDL cholesterol NS (p=0.15)

Triglycerides NS (p=0.81)

PFBA

Fu et al. 2014a

General population (n=133) 

0.11 ng/mL (median PFBA) Total cholesterol NS (p>0.05)

LDL cholesterol NS (p>0.05)

HDL cholesterol NS (p>0.05)

Triglycerides NS (p>0.05)

PFDoA

Zeng et al. 2015

General population (n=225 children, 12–

15 years old)

4.5 and 4.4 ng/mL (mean 

PFDoA in boys and girls)

Total cholesterol NS (p=0.37)

LDL cholesterol NS (p=0.44)

HDL cholesterol NS (p=0.68)

Triglycerides NS (p=0.40)

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 compound; 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 = not 

significant; OR = odds ratio; PFBA = perfluorobutyric acid; PFBuS = perfluorobutane sulfonic acid; PFDeA = perfluorodecanoic acid; 

PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUA = perfluoroundecanoic acid; VLDL = very low-density lipoprotein
PERFLUOROALKYLS 170

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 cell 

proliferation, 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 of 

histological 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 clinical 

pathology marker indicating liver dysfunction (albumin, bilirubin, bile acids, coagulation factors, 

cholesterol, triglycerides, etc.). ATSDR has adapted the criteria from Hall et al. (2012) for determining 

the adversity of the liver effects reported in the rodent perfluoroalkyl studies. Doses associated with 

increases in liver weight and hepatocellular hypertrophy were not considered adverse effect levels unless 

hepatocellular degenerative or necrotic changes or evidence of biliary or other liver cell damage were also 

present. 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

Epidemiology Studies—Liver Disease. Three studies of highly exposed populations have examined 

possible 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, 

estimated cumulative serum PFOA levels were not associated with any liver disease or enlarged liver, 

fatty liver, or cirrhosis (Darrow et al. 2016).

Epidemiology 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 find 

associations 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), 
PERFLUOROALKYLS 171

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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) did not find associations between serum fluorine levels (used as a 

surrogate for serum PFOA) and ALT, AST, or GGT levels in workers. 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 in total 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 a cross-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 more 

measurements 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 

PFOA who had a decrease in serum PFOA levels during the study period, there was a significant increase 

in 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 the 

occupational exposure studies, several studies of populations living near PFOA facilities have found 

inconsistent results. Darrow et al. (2016) found associations between ALT and bilirubin (inverse 

association) and 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 GGT activity. Gallo 
PERFLUOROALKYLS 172

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 from 

NHANES, 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 epidemiology studies have found associations between serum PFOA and serum 

hepatic enzyme and bilirubin levels, many of the investigators noted that liver biomarker levels were 

typically 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 et 

al. (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 

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 of 

elevated bilirubin levels, whereas Gallo et al. (2012) did not find this association in the higher exposed 

population.

Epidemiology Studies—Serum Lipids. Occupational, community, and general population studies have 

examined the possible associations between serum PFOA levels and serum lipid levels; the results of 

these studies are presented in Table 2-12. Summaries of the changes in serum total cholesterol and LDL 

cholesterol levels, as well as the risk associated with elevated serum cholesterol and LDL cholesterol 

levels, are presented in Figures 2-9, 2-10, 2-11, and 2-12.
PERFLUOROALKYLS 173

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-9. Serum Total Cholesterol Levels Relative to Serum PFOA Levels 

(Presented as percent change in cholesterol levels)
PERFLUOROALKYLS 174

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-10. Risk of Abnormal Cholesterol Levels Relative to PFOA Levels (Presented as Adjusted Ratios)
PERFLUOROALKYLS 175

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-11. Serum LDL Cholesterol Levels Relative to Serum PFOA Levels 

(Presented as percent change in LDL cholesterol levels)
PERFLUOROALKYLS 176

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-12. Risk of Abnormal LDL Cholesterol Levels Relative to PFOA Levels (Presented as Adjusted Ratios)
PERFLUOROALKYLS 177

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

A study of workers at a manufacturing facility in Italy found higher total cholesterol and non- highdensity 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 not exposed 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 HDL 

cholesterol levels. No associations were found for HDL cholesterol or triglyceride levels. In another 

small 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) examined workers at the Cottage Grove facility in 1990 and found no associations 

between serum fluorine levels (used as a surrogate for PFOA) and total cholesterol, 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, 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 by blood 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 cholesterol-lowering 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 and inversely associated with HDL 

cholesterol levels (Olsen and Zobel 2007). The study did not find increases 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 with serum PFOA levels in the highest 

deciles. In addition to these cross-sectional studies, two longitudinal studies were conducted at these 

facilities. Using data for 174 workers with medical surveillance data in 2000 and 1997 and/or 1995, 

Olsen et al. (2003a) found that serum PFOA was a significant predictor of cholesterol and triglyceride 

levels, which was primarily due to 21 workers at the Antwerp facility (mean serum level 8,400 ng/mL)

whose serum PFOA levels increased over time. In a longitudinal study, Olsen et 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 mean baseline serum PFOA levels 
PERFLUOROALKYLS 178

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

were 881 ng/mL in 14 3M workers with prior PFOA or PFOS exposure and 28.9 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-exposure serum 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 total 

cholesterol, 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 the 

occurrence of elevated cholesterol levels that required medication. In a longitudinal study of workers 

who had at least two serum PFOA measurements between 1979 and 2004, Sakr et al. (2007a) found a 

positive 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 by 

Emmett 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 of 

participants 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 relationship 

between serum PFOA and serum lipids was nonlinear, with greater increases in lipids observed at the
PERFLUOROALKYLS 179

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

lower serum PFOA levels. Similar findings were reported in a study of >46,000 adults with a median 

serum 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 total 

cholesterol, LDL cholesterol, and non-HDL cholesterol; a positive association between serum PFOA and 

triglycerides was also found. No associations between serum PFOA levels and HDL cholesterol levels 

were found. Increased risks of having high cholesterol (≥240 mg/dL) were found in subjects with serum 

PFOA levels in the 2nd, 3rd, and 4th quartiles. The investigators noted that the odds of high cholesterol 

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 cholesterol-lowering

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 

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 cumulative exposure levels ≥142 ng/mL. In a longitudinal study by Fitz-Simon 

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 LDL cholesterol 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 HDL cholesterol 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 and did not 

include an adjustment for the use of cholesterol-lowering medication.

General population studies were conducted in the United States, Canada, Denmark, Norway, Japan, 

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 
PERFLUOROALKYLS 180

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 not found 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 HDL cholesterol 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 HDL cholesterol. 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.

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. Associations between serum PFOA levels and 

total cholesterol levels were also found in a study of Danish 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 found associations 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 elevated total cholesterol, LDL cholesterol, or triglycerides or 

decreased HDL cholesterol associated with serum PFOA. A study of pregnant women in Denmark also 

found an association between serum PFOA (mean serum PFOA level of 4.1 ng/mL at gestation 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.
PERFLUOROALKYLS 181

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

A number of epidemiology 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 et 

al. 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 

other investigators have not found associations in worker populations (Gilliland and Mandel 1996; Olsen 

et 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 in 

a ≥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 (results only available as an abstract), administration of APFO to patients with advanced refractory 

solid tumors at doses of 50–1,200 mg weekly for 6 weeks resulted in decreases in serum LDL cholesterol

levels (it is unclear if this effect was observed at all dose levels) (MacPherson et al. 2011). 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 a steep doseresponse 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 2-12). Several investigators have explored whether PFOA and cholesterol 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 the issues 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 

that this was not a non-causal factor. The Steenland et al. (2009b) study found slightly lower serum 
PERFLUOROALKYLS 182

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 

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 the 

84 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 were 

unremarkable 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 of 

recovery. 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 perfluoroalkyl compounds in animals following short- or long-term 

oral exposures. The hepatic response to exposure to many perfluoroalkyl compounds, particularly in 

rodents, is initiated by the activation of the nuclear hormone receptor, PPARα, which triggers a 

characteristic sequence of morphological 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 the liver via a method independent of PPARα. The most sensitive liver effect 

observed in rats and mice after acute oral exposure to PFOA is an increase in 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 
PERFLUOROALKYLS 183

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 the first dose; however, the relative liver 

weight was not significantly different from controls (Pastoor et al. 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 for 7 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 histological examinations 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 was observed at 10 mg/kg/day (Wolf et al. 2008a). 

Qazi et al. (2010a) reported hepatocellular hypertrophy in mice 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 in 

absolute 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). 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 
PERFLUOROALKYLS 184

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 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 (29 mg/kg/day in rats and 

0.96 mg/kg/day in mice exposed for 28 days) (Loveless et al. 2008). Fatty changes were observed in rats 

administered 20 mg/kg/day for 28 days (Cui et al. 2009) and mice administered 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 in decreases 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 mice administered 9.6 or 29 mg/kg/day (Loveless et al. 2008). Similarly, 

serum triglyceride levels were decreased 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 hepatomegalocytosis, hepatocellular necrosis, and portal 

mononuclear cell infiltration after a 1-year exposure to 15 mg/kg/day in the diet (3M 1983). A 2-year 

exposure to 15 mg/kg/day resulted in hepatomegalocytosis, cystoid degeneration, and portal mononuclear 

cell infiltration (3M 1983). 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 to 13.6 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 toxicity. 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 increase 

in 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 
PERFLUOROALKYLS 185

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

20 mg/kg/day via capsules for 30 days (Thomford 2001) or Rhesus monkeys administered 3 or 

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 statistically 

significant 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 observed 

in the Thomford (2001) study.

Several studies have examined PPARα-null mice to assess whether PFOA-induced liver effects can also 

occur via a mechanism not involving peroxisome proliferation. 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 the 

same 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 in 

hepatocellular cytoplasmic vacuoles at ≥1 mg/kg/day and suggested that the increase in liver weight was 

due 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-null 

mice (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 in 

both the wild-type and PPARα-null mice, but noted that the effect was more intensive in the PPARα-null 

mice. No significant alterations in steatosis or triglyceride accumulation were observed in PPARα-null 

mice 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 and 

increases at 20.7 mg/kg/day were observed in the PPARα-null mice; significant decreases in total 

cholesterol 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).
PERFLUOROALKYLS 186

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Intermittent application of 20, 200, or 2,000 mg/kg APFO to the skin of rats for 2 weeks resulted in the 

presence 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 were 

markedly 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 of 

five 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 was 

seen for AST activity, but achieving statistical significance in the high-dose group. The blood 

concentrations 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. Epidemiology studies examining the hepatotoxicity of PFOA have examined three

outcomes—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 epidemiology 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 were typically 

within the normal range. Four studies examined the risk of serum enzyme levels outside of the normal 

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 cholesterol levels; several 

studies have also found no associations. Studies examining the change in cholesterol levels 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 found between serum PFOA and HDL 

cholesterol or triglyceride levels. Studies in laboratory animals have found strong associations between 

PFOA exposure and hepatotoxicity. Liver effects have been observed in rats exposed to airborne APFO 
PERFLUOROALKYLS 187

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 epidemiology studies, an experimental study in 

humans exposed to PFOA (MacPherson et al. 2011) and human exposure to other PPARα agonists, such 

as fibrates (Staels et al. 1998), suggest that hypolipidemic effects, similar to those observed in rodents, 

may occur in humans exposed to PFOA, although humans may not be as sensitive as rodents.

PFOS

Epidemiology 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 found in 

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 duct 

disorders (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 and 

for 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 et 

al. 2007).

Epidemiology Studies—Hepatic Serum Enzymes and Bilirubin Levels. A series of studies conducted by 

Olsen and associates evaluated liver function (as assessed by serum liver enzymes) in workers at several 

3M facilities involved in PFOS production. Using health data collected in 1995 and 1997, Olsen et 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 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 the same plants, 

but that included women and a longitudinal analysis of the workers, reported that, after adjusting for 
PERFLUOROALKYLS 188

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 bilirubin 

levels. 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.

Epidemiology Studies—Serum Lipids. Occupational, community, and general population studies have 

examined possible associations between serum PFOS levels and serum lipids; these data are summarized 

in 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 are 

presented in Figures 2-13, 2-14, 2-15, and 2-16.

In the Olsen occupational studies, significantly higher serum total cholesterol levels were found in 

workers 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 level was 

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 

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). Similar 
PERFLUOROALKYLS 189

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-13. Serum Total Cholesterol Levels Relative to Serum PFOS Levels 

(Presented as percent change in cholesterol levels)
PERFLUOROALKYLS 190

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-14. Risk of Abnormal Cholesterol Levels Relative to PFOS Levels (Presented as Adjusted Ratios)
PERFLUOROALKYLS 191

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-15. Serum LDL Cholesterol Levels Relative to Serum PFOS Levels 

(Presented as percent change in LDL cholesterol levels)
PERFLUOROALKYLS 192

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-16. Risk of Abnormal LDL Cholesterol Levels Relative to PFOS Levels (Presented as Adjusted Ratios)
PERFLUOROALKYLS 193

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

findings 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. The investigators noted that the odds of high 

cholesterol from the 1st to the 5th quartile 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 et 

al. 2010); inverse associations between serum PFOS and HDL cholesterol (Starling et al. 2014a) and 

triglycerides (Châtaeu-Degat et al. 2010) were also found. However, other studies in adults have not 

found associations between serum PFOS and total cholesterol (Châtaeu-Degat et al. 2010; Eriksen et al. 

2013; Fisher et al. 2013; Fu et al. 2014a), non-HDL cholesterol (Fisher et al. 2013), LDL cholesterol 

(Châtaeu-Degat et al. 2010; Fisher et al. 2013; Fu et al. 2014a; Starling et al. 2014a), HDL cholesterol

(Fisher et al. 2013; Fu et al. 2014a), or triglycerides (Fu et al. 2014a; Starling et al. 2014a). Additionally, 

two studies 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). Overall, studies of children and adolescents 

have found associations for serum lipid levels. Geiger et al. (2014b) found increases in the risk of 

elevated cholesterol and LDL cholesterol in children and adolescents aged 12–18 years; an association 

between serum PFOS and LDL cholesterol levels was also found. Zeng et al. (2015) found associations 

between serum PFOS and serum total cholesterol, LDL cholesterol, and triglyceride levels in children 

aged 12–15 years. Timmermann et al. (2014) also found an association between serum PFOS and 

triglycerides only in obese Danish children (8–10 years of age), but not in normal weight children. In 
PERFLUOROALKYLS 194

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

contrast, Maisonet et al. (2015b) found an inverse association between maternal serum PFOS and total 

cholesterol and LDL cholesterol in 15-year-old girls; no association was found when the girls were 

7 years of age.

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 in 

varying 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 for 

increased 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 find 

significant 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).

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 cholesterol 

levels 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 VLDL 

and 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 
PERFLUOROALKYLS 195

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 a 

significant increase in relative liver weight in female rats, but not male rats, exposed to PFOS in the diet 

for 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 and 

hepatocellular 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, and 

decreased 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, centrilobular 

eosinophilic 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 the 

incidence 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) and 

unscheduled deaths were included with animals sacrificed at exposure termination, the incidence of 

centrilobular 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 

in male rats exposed to ≥0.025 mg/kg/day. However, this was mainly due to a high incidence in 

unscheduled deaths; among animals sacrificed at exposure termination, the incidence was only increased 

in males exposed to 1.04 mg/kg/day. An increased incidence of single cell necrosis was observed in 

males 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 moderate 

smooth endoplasmic reticulum hyperplasia and minimal to mild hepatocellular hypertrophy primarily in 

rats dosed with 1.5 mg/kg/day PFOS, the highest dose tested.
PERFLUOROALKYLS 196

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Treatment of Cynomolgus monkeys with up to 2 mg/kg/day PFOS administered via a capsule for 4 weeks 

did not induce gross or microscopic morphological alterations in the liver and did not increase cell 

proliferation (Thomford 2002a). In a 26-week study in Cynomolgus monkeys, exposure to 

0.75 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 cholesterol

levels 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 centrilobular 

vacuolation, 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 HDL 

cholesterol levels returned to pretreatment levels after 61 days of recovery.

Summary. Epidemiology studies have examined the possible associations between PFOS exposure and 

liver disease in workers and hepatocellular damage and alterations in serum lipid levels in workers and 

the general population. The available occupational exposure studies or general population studies do not 

consistently suggest an association between PFOS exposure and increases in the risk of liver disease or 

biliary 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 epidemiology 

studies 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 found 

elevated 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 total 

cholesterol 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 cholesterol 

levels in general population studies. Associations have been found between serum PFOS levels and 

serum 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 
PERFLUOROALKYLS 197

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

levels. A small number of studies also reported focal necrosis and centrilobular hepatocytic 

vacuolization. The applicability of the hepatic hypertrophy and serum lipid alterations observed in rodent 

studies to humans has been questioned due to species differences in PPARα receptor activation, the 

presumed mechanism of action for these effects in rodents.

PFHxS

Epidemiology Studies—Hepatic Serum Enzymes and Bilirubin Levels. Lin et al. (2010) did not find

associations between serum ALT and GGT levels with serum PFHxS levels in a general population study 

using the NHANES data set.

Epidemiology Studies—Serum Lipids. Four 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 and 

non-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 a 

geometric mean serum PFHxS level of 2.16 ng/mL, associations were found for total cholesterol, LDL 

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. In pregnant women in Norway with median serum 

PFHxS levels of 0.60 ng/mL, serum PFHxS levels were associated 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).

Laboratory Animal Studies. Acute-duration gavage administration of PFHxS resulted in increases in 

liver weight, steatosis, and increases in hepatic triglyceride levels in mice; increases in liver weight and 

steatosis were also observed in similarly exposed PPARα-null mice (Das et al. 2017). An intermediateduration study with PFHxS in rats reported that gavage doses ≥3 mg/kg/day induced a significant increase 

in absolute and relative liver weight in males (Butenhoff et al. 2009a; Hoberman and York 2003). Light 

microscopy revealed minimal to moderate enlargement of centrilobular hepatocytes. Clinical chemistry 

tests showed a 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. In male mice, 

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 
PERFLUOROALKYLS 198

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

hepatic production of VLDL (Bijland et al. 2011). Increases in liver weight and hepatic triglyceride 

levels were also observed.

PFNA

Epidemiology Studies—Hepatic Serum Enzymes and Bilirubin Levels. A health evaluation of workers 

at a U.S. polymer production facility using PFNA did not find alterations in ALT, AST, GGT, or bilirubin 

levels related to increases in exposure intensity score in a longitudinal analysis (Mundt et al. 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. The Gleason et al. (2015) study also did not find increased risks for elevated ALT, AST, GGT, 

or bilirubin.

Epidemiology 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 (Zeng 

et al. 2015); one study in pregnant women did not find an association (Starling et al. 2014a). Several 

studies have also found associations with LDL cholesterol (Fu et al. 2014a; 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; 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; Zeng et al. 2015) or triglycerides (Fu et al. 2014a; 

Starling et al. 2014a). Exceptions were the Starling et al. (2014a) study of pregnant women, which found 

a positive association for HDL cholesterol, 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. Nine studies have evaluated the hepatic toxicity of PFNA. The observed 

effects are consistent with effects observed for other perfluoroalkyl compounds. Alterations in serum 

lipid levels consisted of decreases in serum HDL cholesterol levels in rats administered via gavage

≥1 mg/kg/day for 14 days (Fang et al. 2012a) and decreases in serum triglyceride and cholesterol levels in 

mice receiving gavage doses of ≥1 mg/kg/day (Wang et al. 2015a). Increases in liver weight were 

observed in rats nose-only exposed to ≥67 mg/m3 (Kinney et al. 1989), in mice administered via gavage 
PERFLUOROALKYLS 199

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

10 mg/kg/day PFNA for 7 days (Das et al. 2017), in mice exposed to 0.5 mg/kg/day PFNA in the diet 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). Hepatocellular vacuolation was observed in mice administered 

via gavage 5 mg/kg/day 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 for 18 days, but were not 

found in pregnant animals (Wolf et al. 2010). Das et al. (2017) found increases in liver weight, steatosis, 

and increases in liver triglyceride levels in PPARα-null mice administered 10 mg/kg/day for 10 days.

PFDeA

Epidemiology Studies—Serum Lipids. Three general population studies have evaluated the potential 

relationships between serum PFDeA and serum lipids and reported inconsistent results. Fu et al. (2014a) 

found an association between serum PFDeA and total cholesterol in adults; studies in pregnant women 

(Starling et al. 2014a) and children (Zeng et al. 2015) did not find associations. Both Fu et al. (2014a) 

and Starling et al. (2014a) found positive associations with HDL cholesterol; this was not found in the 

Zeng et al. (2015) study. None of the studies found associations between serum PFDeA and LDL 

cholesterol or triglycerides (Fu et al. 2014a; Starling et al. 2014a; Zeng et al. 2015). Only the Fu et al. 

(2014a) study looked for alterations in the risk of elevated cholesterol, 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 PFDeA include 

alterations in liver weight and morphology. Increases in liver weight have been observed in mice 

following a single gavage dose of PFDeA; the alterations were observed 2 days after exposure to 

40 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 PFDeA 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. Oral 

doses ≥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 associated 

with hepatocellular hypertrophy and evidence of peroxisome proliferation. Thirty days after a single 

gavage dose of ≥20 mg/kg/day PFDeA, effects included periportal to panlobular hepatocellular 

hypertrophy characterized by swollen hepatocytes with abundant granular eosinophilic cytoplasm and 

enlarged and hyperchromatic nuclei (Harris et al. 1989).
PERFLUOROALKYLS 200

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFUA

Epidemiology Studies—Serum Lipids. Neither of the two studies (Fu et al. 2014a; Starling et al. 2014a) 

examining possible relationships between serum PFUA and serum lipids found associations between 

serum PFUA and for total cholesterol, LDL cholesterol, or triglyceride levels. Starling et al. (2014a) 

found an association of serum PFUA 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 the 

adults examined by Fu et al. (2014a).

Laboratory Animal Studies. Only one animal study was identified that examined the liver following oral 

exposure to PFUA. In an intermediate-duration study of rats administered PFUA 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, and mild 

to moderate centrilobular hepatocellular hypertrophy was observed in males and females at 1.0 mg/kg/day 

(Takahashi et al. 2014).

PFHpA

Epidemiology Studies—Serum Lipids. Epidemiology data on PFHpA are limited to a study in adults 

conducted by Fu et al. (2014a), which found no associations between serum PFHpA and total cholesterol, 

LDL cholesterol, HDL cholesterol, or triglyceride levels.

PFBuS

Epidemiology Studies—Serum Lipids. In the only epidemiology study examining serum lipids and 

possible associations with serum PFBuS, Zeng et al. (2015) found an association with total cholesterol 

levels in children. No associations were found between serum PFBuS and LDL cholesterol, HDL 

cholesterol, or triglycerides.

Laboratory Animal Studies. Treatment of male rats with 900 mg/kg/day PFBuS 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 liver 

function were unremarkable and there were no chemical-related microscopic alterations. The NOAEL for 

liver weight effects was 300 mg/kg/day. No alterations in liver weight, serum chemistry parameters 

(ALT, AST, cholesterol), or liver morphology were observed in rats administered gavage doses as high as 
PERFLUOROALKYLS 201

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

600 mg/kg/day PFBuS 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

Epidemiology Studies—Serum Lipids. Only one epidemiology study examined hepatic outcomes; this 

study (Fu et al. 2014a) did not find any associations between serum PFBA levels and total cholesterol, 

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 male 

mice for 10 days induced a 63% increase in absolute liver weight (Permadi et al. 1992, 1993).

PFBA intermediate-duration studies have consistently found increases in liver weight and histological 

alterations. Dosing rats with by gavage for 28 days resulted in significant increases in absolute and 

relative 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 

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 resulted in increased absolute liver 

weight and panlobular hepatocyte hypertrophy (Butenhoff et al. 2012a; van Otterdijk 2007b); no liver 

effects were observed at 6 mg/kg/day. None of the liver alterations were observed after a 21-day recovery 

period. 
PERFLUOROALKYLS 202

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFDoA

Epidemiology Studies—Serum Lipids. A general population study of adolescents (Zeng et al. 2015) did 

not find any associations between serum PFDoA and total cholesterol, LDL cholesterol, HDL cholesterol, 

or triglyceride levels.

Laboratory Animal Studies. Dosing of male Sprague-Dawley rats with 10 mg/kg/day PFDoA by gavage 

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 in 

rats dosed via gavage with 1 or 5 mg/kg/day PFDoA, 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 liver cholesterol levels were 

increased at ≥5 mg/kg/day. Single doses ≥1 mg/kg/day significantly induced the expression of PPARα 

and PPARγ and their target genes to enhance fatty acid β-oxidation. 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 body weight (shown in Shi et al. [2007], but not in Zhang et al. [2008]).

PFHxA

Laboratory Animal Studies. 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.

PFOSA

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 PFOSA.

2.10 RENAL

Overview. Epidemiology 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 epidemiology studies evaluating 

kidney disease and renal function are summarized in Table 2-13; Table 2-14 contains the studies 
PERFLUOROALKYLS 203

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-13. Summary of Renal Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Costa et al. 2009

Occupational 

(n =53)

12,930 ng/mL (mean PFOA 

in current workers)

Serum urea NS (p>0.05)

Serum creatinine NS (p>0.05)

Total proteins NS (p>0.05)

α1 globulins, α2 

globulins, β globulins, or 

γ globulins

NS (p>0.05)

α2 globulins Association (p<0.01), current, 

former and non-exposed workers.

Lundin et al. 2009

Occupational (n=3,992)

NR Nephritis and nephrosis 

deaths

SMR 5.2 (0.6–18.9)

Raleigh et al. 2014

Occupational (n=9,027)

NR Chronic kidney disease 

deaths

HR 0.73 (0.21–2.48), 4th quartile

Steenland et al. 2015

Occupational (n=3,713)

Cumulative PFOA Chronic kidney disease 

risk

NS (p=0.92), no lag

NS (p=0.99), 10-year lag

Steenland and Woskie 2012

Occupational (n=1,084)

7,800 ng/mL-year (mean 

PFOA)

Chronic kidney disease 

deaths

SMR 3.79 (1.03–9.71)*, 2nd quartile

Anderson-Mahoney et al. 2008

Community (n=566)

NR Kidney disease (selfreported)SPR 2.26 (1.45–3.51)*

Dhingra et al. 2016b

Community (C8) (n=28,541)

Cumulative PFOA Chronic kidney disease 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

Emmett et al. 2006b

Community (n=371)

354 ng/mL (median PFOA) Serum creatinine NS (p>0.05)

BUN NS (p>0.05)

Total serum proteins NS (p>0.05)
PERFLUOROALKYLS 204

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-13. Summary of Renal Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Watkins et al. 2013

Community (C8) (9,660 children)

28.3 ng/mL (median PFOA) GFR Inverse association (p=0.02)*

Kataria et al. 2015

General population (NHANES) 

(n=1,960 adolescents)

≥4.7 ng/mL (4th PFOA 

quartile)

GFR Inverse association (p<0.01)*, 

4th quartile

Serum uric acid Association (p<0.01)*

Shankar et al. 2011a

General population (NHANES) (n=4,587)

>5.9 ng/mL (4th PFOA 

quartile)

GFR Inverse association (p<0.001 for 

trend)*

Chronic kidney disease OR 1.73 (1.04–2.88)*, 4th quartile

PFOS

Olsen et al. 1998a

Occupational (n=178 in 1995; n=149 in 1997)

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 DeCatur 

and Antwerp)

Serum creatinine Association (p<0.06)*, 1997 only 

BUN NS (p>0.1)

Watkins et al. 2013

Community (C8) (9,660 children)

20.0 ng/mL (median PFOS) GFR Inverse association (p=0.0001)*

Kataria et al. 2015

General population (NHANES) 

(n=1,960 adolescents)

7.9–12.8 ng/mL (2nd PFOS 

quartile)

≥19.4 ng/mL (4th PFOS 

quartile)

GFR Inverse association (p<0.05)*, 

2nd quartile

Shankar et al. 2011a

General population (NHANES) (n=4,587)

>29.5 ng/mL (4th PFOS 

quartile)

11.2–17.8 ng/mL (2nd PFOS 

quartile)

GFR Inverse association (p<0.001 for 

trend)*

Chronic kidney disease OR 1.82 (1.02–3.27)*, 4th quartile

PFHxS

Watkins et al. 2013

Community (C8) (9,660 children)

5.2 ng/mL (median PFHxS) GFR Inverse association (p=0.003)*
PERFLUOROALKYLS 205

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-13. Summary of Renal Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Kataria et al. 2015

General population (NHANES) 

(n=1,960 adolescents)

≥4 ng/mL (4th PFHxS 

quartile)

GFR NS (p>0.05)

PFNA

Mundt et al. 2007

Occupational (n=592)

NR BUN

Creatinine

Small, but not clinically significant

Watkins et al. 2013

Community (C8) (9,660 children)

1.5 ng/mL (median PFNA) GFR Inverse association (p=0.002)*

Kataria et al. 2015

General population (NHANES) 

(n=1,960 adolescents)

≥1.5 ng/mL (4th PFNA 

quartile)

GFR NS (p>0.05)

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 compound; 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 206

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-14. Summary of Uric Acid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Costa et al. 2009

Occupational (n=53)

12,930, ng/mL (mean PFOA 

in current workers)

Serum uric acid Association (p=0.039)*

Sakr et al. 2007b

Occupational (n=1,025)

490 ng/mL (median PFOA) Serum uric acid Association (reported by 

investigator)*

Steenland et al. 2010b

Community (n=54,591)

11.5–20.6 ng/mL (2nd quintile 

PFOA)

Hyperuricemia risk OR 1.33 (1.24–1.43)* (2nd quintile)

Gleason et al. 2015

General population (NHANES) 

(n=4,333 adolescents)

3.7 ng/mL (median PFOA) Serum uric acid Association (p<0.001)*

Hyperuricemia risk Association (p<0.001)*

Geiger et al. 2013

General population (NHANES) 

(n=1,772 adolescents and adults)

4.3 ng/mL (mean PFOA), 

>5.4 ng/mL (4th PFOA 

quartile)

Serum uric acid Association (p=0.0001)*

Hyperuricemia risk OR 1.62 (1.10–2.37)* (4th quartile)

Kataria et al. 2015

General population (NHANES) 

(n=1,960 adolescents)

≥4.7 ng/mL (4th PFOA 

quartile)

Serum uric acid Association (p<0.01)*

Qin et al. 2016

General population (n=225 adolescents)

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)

Shankar et al. 2011b

General population (NHANES) (n=3,883 adults)

3.5–5.1 ng/mL (3rd PFOA 

quartile)

Serum uric acid Association (p<0.0001)*

Hyperuricemia risk OR 1.90 (1.35–2.69)*, 3rd quartile

PFOS

Steenland et al. 2010b

Community (n=54,591)

17.5–23,26 ng/mL (3rd PFOS 

quintile)

Hyperuricemia risk OR 1.11 (1.04–1.20)* (3rd quintile)
PERFLUOROALKYLS 207

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-14. Summary of Uric Acid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Gleason et al. 2015

General population (NHANES, 

n=4,333 adolescents)

11.3 ng/mL (median PFOS) Serum uric acid Association (p<0.01)*

Hyperuricemia risk NS (p=0.502)

Geiger et al. 2013

General population (NHANES) 

(n=1,772 adolescents and adults)

18.4 ng/mL (mean PFOS), 

>25.5 ng/mL (4th PFOS 

quartile)

Serum uric acid NS (p=0.0575)

Hyperuricemia risk OR 1.65 (1.10–2.49)* (4th quartile)

Kataria et al. 2015

General population (NHANES) 

(n=1,960 adolescents)

≥19.4 ng/mL (4th PFOS 

quartile)

Serum uric acid Association (p<0.05)*

Qin et al. 2016

General population (n=225 adolescents)

28.9 ng/mL (median PFOS) Serum uric acid NS (p>0.05)

Hyperuricemia risk OR 1.35 (0.95–1.93) (full cohort)

Shankar et al. 2011b

General population (NHANES) (n=3,883 adults)

11.2–17.8 ng/mL (2nd PFOS 

quartile)

Serum uric acid Association (p=0.0018)*

Hyperuricemia risk OR 1.46 (1.11–1.91)*, 2nd quartile

PFHxS

Gleason et al. 2015

General population (NHANES) (n=4,333)

1.8 ng/mL (median PFHxS) Serum uric acid NS (p>0.01)

Hyperuricemia risk NS (p=0.110 for trend)

Kataria et al. 2015

General population (NHANES) 

(n=1,960 adolescents)

≥4 ng/mL (4th PFHxS 

quartile)

Serum uric acid NS (p>0.05)

Qin et al. 2016

General population (n=225 adolescents)

1.3 ng/mL (median PFHxS) Serum uric acid Association (p<0.05)*

Hyperuricemia risk OR 1.39 (0.93–2.07)

PFNA

Mundt et al. 2007

Occupational (n=592)

NR Serum uric acid Small, but not clinically significant
PERFLUOROALKYLS 208

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-14. Summary of Uric Acid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Gleason et al. 2015

General population (NHANES) (n=4,333)

1.4 ng/mL (median PFNA) Serum uric acid Association (p<0.001)*

Hyperuricemia risk NS (p=0.42 for trend)

Kataria et al. 2015

General population (NHANES) 

(n=1,960 adolescents)

≥1.5 ng/mL (4th PFNA 

quartile)

Serum uric acid NS (p>0.05)

Qin et al. 2016

General population (n=225 adolescents)

0.8 ng/mL (median PFNA) Serum uric acid NS (p>0.05)

Hyperuricemia risk OR 1.28 (0.83–1.96)

PFDeA

Qin et al. 2016

General population (n=225 adolescents)

0.9 ng/mL (median PFDeA) Serum uric acid NS (p>0.05)

Hyperuricemia risk OR 1.26 (0.82–1.92)

PFBuS

Qin et al. 2016

General population (n=225 adolescents)

0.5 ng/mL (median PFBuS) Serum uric acid NS (p>0.05)

Hyperuricemia risk OR 1.23 (0.86–1.75)

PFDoA

Qin et al. 2016

General population (n=225 adolescents)

2.7 ng/mL (median PFDoA) Serum uric acid NS (p>0.05)

Hyperuricemia risk OR 0.93 (0.65–1.34)
PERFLUOROALKYLS 209

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-14. Summary of Uric Acid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFHxA

Qin et al. 2016

General population (n=225 adolescents)

0.2 ng/mL (median PFHxA) Serum uric acid NS (p>0.05)

Hyperuricemia risk OR 1.08 (0.77–1.61)

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 compound; 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; PFBuS = perfluorobutane sulfonic acid; 

PFDoA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; 

PFOS = perfluorooctane sulfonic acid
PERFLUOROALKYLS 210

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

evaluating alterations in uric acid levels. More detailed descriptions of these studies can be found in the 

Supporting Document for Epidemiological Studies for Perfluoroalkyls, Table 8. Although there are a 

couple of studies finding associations between PFOA exposure and kidney disease, the results are not 

consistent across study populations. However, there is some indication that perfluoroalkyls may affect 

renal 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 epidemiology 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 and 

uric acid. Based on the small number of epidemiology studies or the inconsistency of the results, possible 

associations between other perfluoroalkyls (PFHxS, PFNA, PFDeA, PFBuS, or PFDoA) and renal 

functions cannot be assessed.

Laboratory animal studies have primarily evaluated kidney morphology; these studies are summarized in 

Tables 2-1, 2-3, 2-4, 2-5, and 2-6. The NOAEL and LOAEL values for these studies are illustrated in 

Figures 2-4, 2-6, 2-7, and 2-8. In general, the laboratory animal studies have not found evidence of 

impaired renal function or morphological damage following exposure to PFOA, PFOS, PFHxS, PFDeA, 

PFUA, PFBuS, PFBA, or PFHxA.

PFOA

Epidemiology Studies—Kidney Disease. Several epidemiology studies have examined the possible 

association between PFOA exposure and increased risk of kidney disease. In a cohort mortality study of

workers at the DuPont PFOA facility in West Virginia, Steenland and Woskie (2012) found an increase in 

deaths from chronic renal disease when compared to DuPont workers at other regional facilities. When

cumulative PFOA exposure was estimated based on the worker’s job history and data from a 

biomonitoring survey conducted from 1979 to 2004, there was a significant positive trend for 

nonmalignant 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 in 

deaths from chronic kidney disease (Raleigh et al. 2014) or nephritis and nephrosis (Lundin et al. 2009) as 

compared to mortality rates for the state of Minnesota. Similar results were found when chronic kidney 

disease deaths were compared to those in 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 cumulative PFOA exposure and 

the risk of chronic kidney disease. Another study of the community living near the Washington Works 
PERFLUOROALKYLS 211

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

facility found a higher prevalence of self-reported kidney disease as compared to rates reported in 

NHANES (Anderson-Mahoney et al. 2008).

Epidemiology Studies—Biomarkers of Renal Function. Several biomarkers of renal function have been 

evaluated in epidemiology 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 exposure studies by 

Olsen et al. (2003a) or Costa et al. (2009) or a community exposure study by Emmett et al. (2006b).

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 kidney 

disease, 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 with 

serum 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 kidney 

disease, suggesting that it was not due to reverse causality. In another study utilizing NHANES data, an 

inverse 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 in 

children 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 estimated 

glomerular filtration rates may be a consequence of reverse causation because no associations were found 

between 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.

Epidemiology 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 and 

serum 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 
PERFLUOROALKYLS 212

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

risks of hyperuricemia (>6.0 mg/dL for women, >6.8 mg/dL for men) were observed for subjects with 

serum 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 2-17.

Laboratory Animal Studies. No gross or microscopic alterations were observed in the kidneys from male 

rats 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 evaluation 

of 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 the 

kidneys, 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 morphological 

alterations 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, and 

blood 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). 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. Epidemiology studies have examined possible associations between exposure to PFOA and 

increases 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 and 
PERFLUOROALKYLS 213

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-17. Risk of Hyperuricemia Relative to PFOA Levels (Presented as Adjusted Odds Ratios) 
PERFLUOROALKYLS 214

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

glomerular filtration rate; however, there is suggestive evidence that this association may be due to 

reverse causation rather than a direct effect. Associations between serum PFOA levels and serum uric 

acid levels have been consistently observed in occupational, community, and general populations. 

Laboratory animal studies have not found evidence of alterations in renal function or histological 

alterations.

PFOS

Epidemiology 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 estimated glomerular 

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 those with 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.

Epidemiology 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, and 

5th quintiles. Similar findings were found in NHANES adult participants (Shankar et al. 2011b). Two 

studies of adolescent NHANES participants also found associations between serum PFOS and serum uric 

acid levels (Gleason et al. 2015; Kataria et al. 2015); a third 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; this was not found in the Gleason et al. (2015) study. A study of 

Taiwanese adolescents did not find associations between serum PFOS and uric acid or an increased risk 

of hyperuricemia (Qin et al. 2016). The ORs for the risk of hyperuricemia in these studies are 

summarized in Figure 2-18.
PERFLUOROALKYLS 215

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-18. Risk of Hyperuricemia Relative to PFOS Levels (Presented as Adjusted Odds Ratios) 
PERFLUOROALKYLS 216

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 (potassium 

salt) (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. 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

Epidemiology Studies—Biomarkers of Renal Function. A small number of epidemiology studies have 

evaluated biomarkers of renal function. In a study of C8 Health Project participants, an inverse 

association between serum PFHxS and estimated glomerular filtration rate was observed (Watkins et al. 

2013). A study of adolescent participants in NHANES did not find this association (Kataria et al. 2015). 

A comparison between the reported median PFHxS level in the Watkins et al. (2013) study (5.2 ng/mL) 

and the lower end of the 4th quartile serum PFHxS level in the Kataria et al. (2015) study (≥4 ng/mL) 

suggests that the serum PFHxS levels were higher in the Watkins et al. (2013) study.

Epidemiology Studies—Alterations in Uric Acid Levels. In adolescent NHANES participants, no 

associations between serum PFHxS levels and serum uric acid levels (Gleason et al. 2015; Kataria et al. 

2015) 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 acid levels, 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; Hoberman and York 2003); the NOAEL was 

3 mg/kg/day. No significant effect on BUN was reported in female rats.
PERFLUOROALKYLS 217

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFNA

Epidemiology Studies—Biomarkers of Renal Function. Two epidemiology studies have evaluated the 

possible associations between serum PFNA and alterations in renal function biomarkers. In a study of 

children participating in the C8 Health Project, an inverse association between serum PFNA and 

estimated 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.

Epidemiology Studies—Alterations in Uric Acid Levels. Gleason et al. (2015) found an association 

between serum PFNA and serum uric acid levels in adolescents; this association was not found in other 

studies of adolescents (Kataria et al. 2015; Qin et al. 2016). Studies by Gleason et al. (2015) and Qin et 

al. (2016) did not find increases in the risk of hyperuricemia associated with serum PFNA levels.

PFDeA

Epidemiology Studies—Alterations in Uric Acid Levels. Epidemiology studies examining renal 

outcomes are limited to a study of Taiwanese adolescents that found no association between serum 

PFDeA 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 PFDeA 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.

PFUA

Laboratory Animal Studies. Treatment of male and female rats with 1.0 mg/kg/day PFUA via gavage for 

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.
PERFLUOROALKYLS 218

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFBuS

Epidemiology Studies—Alterations in Uric Acid Levels. Serum PFBuS levels were not associated with 

serum uric acid levels or increases in the risk of hyperuricemia in a study of adolescents in Taiwan (Qin et 

al. 2016).

Laboratory Animal Studies. Treatment of female rats with 900 mg/kg/day PFBuS 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 weight 

effects was 300 mg/kg/day PFBuS. In a 90-day rat study, PFBuS did not result in alterations in kidney 

weights, 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 to 

moderate 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).

PFDoA

Epidemiology Studies—Alterations in Uric Acid Levels. In adolescents, no associations between serum 

PFDoA levels and serum uric acid levels or the risk of hyperuricemia were observed (Qin et al. 2016).

PFHxA

Epidemiology 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).
PERFLUOROALKYLS 219

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Laboratory Animal Studies. 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 kidneys of 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 the 

abdominal 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 of 

rats, and left in place covered for 24 hours produced mild skin irritation (Kennedy 1985); no irritation was 

apparent with a dose of 3,000 mg/kg. In a 2-week dermal exposure study, skin irritation was observed in 

rats exposed to 200 mg/kg/day (Kennedy 1985). Acute necrotizing dermatitis was observed in two out of 

five 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 and 

48 hours later (Griffith and Long 1980).
PERFLUOROALKYLS 220

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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; van 

Otterdijk 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 the 

eye (see Tables 2-1 and 2-6). However, ocular effects have not been found following oral exposure to 

PFOA, PFOS, PFBuS, or PFBA (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 and 

lacrimation 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 et 

al. 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 from 

these rats at termination and following a recovery period of up to 42 days was unremarkable.

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 and 

Long 1980). Similar results were reported in rats that received dietary doses up to 15 mg/kg/day APFO 

for 2 years (3M 1983) and in monkeys dosed with up to 20 mg/kg/day APFO for 26 weeks (Butenhoff et 

al. 2002).
PERFLUOROALKYLS 221

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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-related 

changes. In a study in rabbits, 0.1 g APFO was instilled once in the conjunctival sac of the right eye and 

examinations 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 were 

immediate 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 were 

reported 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).

PFBuS

No gross and microscopic alterations were observed in the eyes of rats administered ≤900 mg/kg/day 

PFBuS via gavage for 28 days (3M 2001). 

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).

2.13 ENDOCRINE

Overview. Epidemiology studies have examined a number of endocrine targets including thyroid gland 

and hormones, reproductive hormones, and insulin levels. A discussion of the thyroid effects is included 
PERFLUOROALKYLS 222

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

in this section; the reproductive hormone effects are discussed in Section 2.16, Reproductive, and the 

insulin effects (as well as other effects associated with glucose metabolism and utilization) are discussed 

in Section 2.18, Other Noncancer. Summaries of results of epidemiology 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. The results of 

community and general population studies suggest an association between serum PFOA and an increased 

risk of thyroid disease. There is also limited support of an association between serum PFOS and thyroid 

disease. Although some associations between serum PFOA or PFOS and thyroid stimulating hormone 

(TSH), triiodothyronine (T3), or thyroxine (T4) levels have been found, the results are not consistent 

across studies. A small number of studies have evaluated PFHxS, PFNA, and PFDeA and most studies 

have not found consistent associations between serum perfluoroalkyl levels and thyroid hormone levels.

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. Some 

alterations in thyroid hormone levels have been observed in laboratory animals exposed to PFOA, PFOS, 

or PFDeA. Histopathological alterations have been observed in the thyroid of some laboratory animal 

studies for PFHxS and PFBA; the investigators noted that these effects were likely secondary to the 

hepatocellular hypertrophy. In general, the pituitary, parathyroid, thyroid, and adrenal glands do not 

appear to be sensitive targets following exposure to PFOA, PFOS, or PFBuS.

PFOA

Epidemiology Studies. A number of epidemiology studies have examined the potential of PFOA to 

damage the thyroid. Steenland et al. (2015) did not find an association between serum PFOA and the risk 

of 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. Another study reported an association 

between serum PFOA and TSH, but this was only observed at one time point (Olsen et al. 1998b). A 

fourth occupational study reported that TSH, T4, and T3 levels were within the reference range (Sakr et 

al. 2007b).
PERFLUOROALKYLS 223

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Olsen et al. 1998b

Occupational (n=111 in 1993 and n=80 in 1995)

10,000–<30,000 ng/mL 

(PFOA range)

TSH NS (p=0.09 for trend), 1993 group

Association (p=0.002), 1995 group

Sakr et al. 2007b

Occupational (n=1,025) 

428 ng/mL (mean PFOA) TSH The investigators noted that the levels 

were within the reference range T4

T3

Steenland et al. 2015

Occupational (n=3,713)

Cumulative PFOA Thyroid disease risk 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

Olsen and Zobel 2007

Occupational (n=552)

2,210 ng/mL (mean PFOA) Free T4 Association (p=0.01)*

T4 NS (p=0.29)

T3 Association (p=0.05)*

TSH NS (p=0.08)

Anderson-Mahoney et al. 2008

Community (n=566)

NR Self-reported thyroid 

problems

SPR 1.56 (1.22–1.98)*

Emmett et al. 2006b

Community (n=371)

354 ng/mL (median PFOA) TSH NS (p>0.05)
PERFLUOROALKYLS 224

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Knox et al. 2011a

Community (n=50,113 adults ≥20 years of age)

52.6, 91.0, 98.6, and 

124.3 ng/mL (mean PFOA in 

women ≤50 year, men 

≤50 years, women 

>50 years, men >50 years)

T4 Association (p≤0.0001)*, women 

≤50 years

Association (p<0.001), men and 

women >50 years

T3 uptake Inverse association (p=0.0001)* 

women ≤50 years

Inverse association (p=0.005)*, 

women >50 years

Inverse association (p=0.037)*, men 

>50 years

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 OR 1.44 (1.02–2.03)*, per 

interquartile shift

Hypothyroidism OR 1.54 (1.00–2.37)*, per 

interquartile shift 

Subclinical 

hypothyroidism

OR 0.98 (0.86–1.15), per interquartile 

shift 

Subclinical 

hyperthyroidism

OR 0.81 (0.58–1.15), per interquartile 

shift

TSH β -1.1 (-5.3–3.4), 4th quartile 

Total T4 β -0.1 (-1.7–1.4), 4th quartile

Winquist and Steenland 2014b

Community (C8 and occupational) (n=28,541)

114.7–<202.2 ng/mL-year 

(2nd quintile cumulative 

PFOA)

Functional thyroid 

disease

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 

analysis
PERFLUOROALKYLS 225

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Hyperthyroidism 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

Hypothyroidism 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

Bloom et al. 2010

General population (n=31)

1.33 ng/mL (geometric mean 

PFOA)

TSH NS (p=0.871)

Free T4 NS (p=0.896)

Chan et al. 2011

General population (n=94 women with 

hypothryoxinemia and 175 matched controls)

1.28 and 1.37 ng/mL 

(geometric mean PFOA in 

cases and controls) 

Hypothyroxinemia risk OR 0.94 (0.74–1.18)

Jain 2013

General population (NHANES) (n=1,525)

NR Total T3 Association (p=0.013)*

TSH NS (p>0.05)

Free T3 NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Thyroglobulin NS (p>0.05)

Ji et al. 2012

General population (n=633)

2.74 ng/mL (median PFOA) TSH NS (p=0.4055)

T4 NS (p=0.2221)
PERFLUOROALKYLS 226

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Lewis et al. 2015

General population (NHANES) (n=1,682)

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 NS (p>0.05)

Free T3 Association (p<0.05)*, 60–80-yearold females

Total T3 Association (p<0.05)*, 60–80-yearold females

Melzer et al. 2010

General population (NHANES) (n=3,966)

9.47 and 10.39 ng/mL 

(4th PFOA quartile mean in 

women and men)

Thyroid disease risk OR 1.64 (1.09–2.46)*, females

OR 1.58 (0.74–3.39), males

Raymer et al. 2012

General population (n=256)

10.4 ng/mL (mean PFOA) TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)

Shrestha et al. 2015

General population (n=87 with thyroid disease)

9.17 ng/mL (geometric mean 

PFOA)

TSH NS (p=0.176)

Free T4 NS (p=0.536)

T4 NS (p=0.097)

T3 NS (p=0.208)

Wang et al. 2013a

General population (n=903 pregnant women)

2.13 ng/mL (geometric mean 

PFOA)

TSH NS (p>0.05)

Elevated TSH risk NS (p>0.05)

Wang et al. 2014

General population (n=285 pregnant women)

2.39 ng/mL (median PFOA) TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Total T3 NS (p>0.05)
PERFLUOROALKYLS 227

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Webster et al. 2016

General population (NHANES) (n=1,525)

4.2 ng/mL (geometric mean 

PFOA)

TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 Association (p<0.05)*

Total T3 NS (p<0.05)

Wen et al. 2013

General population (NHANES) (n=1,181)

4.15 ng/mL (geometric mean 

PFOA)

TSH 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

Subclinical 

hypothyroidism risk

OR1.29 (0.40–4.10), men

OR 7.42 (1.14–48.12, p<0.05), women

Subclinical 

hyperthyroidism risk

OR 0.38 (0.16–0.95, p<0.05)*, men

OR 0.99 (0.13–7.59), women

Yang et al. 2016a

General population (n=157 pregnant women)

1.95 ng/mL (mean PFOA) TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

PFOS

Olsen et al. 1998a

Occupational (n=327)

1,480–2,440 ng/mL (range of 

mean PFOS)

TSH NS (p=0.95)

Cortisol NS (p=0.45)

Olsen et al. 2003a

Occupational (n=518)

1,320 and 800 ng/mL (mean 

PFOS)

T3 Association (p=0.04)*
PERFLUOROALKYLS 228

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Knox et al. 2011a

Community (n=50,113 adults ≥20 years of age)

17.3, 24.8, 25.7, and 

29.1 ng/mL (mean PFOA in 

women ≤50 year, men 

≤50 years, women >50 

years, men >50 years)

T4 Association (p<0.0001)*, women ≤50 

or >50 years

Association (p=0.0001)*, men ≤50 or 

>50 years

T3 uptake 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

Lopez-Espinosa et al. 2012

Community (n=10,725 children aged 1–

17 years)

20.0 ng/mL (median PFOS) Thyroid disease OR 0.8 (0.62–1.08), per interquartile 

shift

Hypothyroidism OR 0.91 (0.63–1.31), per interquartile 

shift

Subclinical 

hypothyroidism

OR 0.99 (0.86–1.13), per interquartile 

shift 

Subclinical 

hyperthyroidism

OR 0.80 (0.62–1.02), per interquartile 

shift

TSH β -1.0 (-0.3–2.3), per interquartile shift 

Total T4 β 1.1 (0.6–1.5), per interquartile shift

Berg et al. 2015

General population (n=391)

8.1–11.0 ng/mL (3rd PFOS 

quartile)

TSH Association (p=0.03)*, 3rd quartile

Bloom et al. 2010

General population (n=31)

19.57 ng/mL (geometric 

mean PFOS)

TSH NS (p=0.896)

Free T4 NS (p=0.623)

Chan et al. 2011

General population (n=94 women with 

hypothyroxinemia and 175 matched controls)

7.59 and 7.08 ng/mL 

(geometric mean PFOS in 

cases and controls) 

Hypothyroxinemia risk OR 0.88 (0.63–1.24)
PERFLUOROALKYLS 229

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Dallaire et al. 2009

General population (n=623)

18.28 ng/mL (geometric 

mean PFOS)

TSH Inverse association (p≤0.05)*

T3 Inverse association (p≤0.05)*

T4-binding globulin Inverse association (p≤0.01)*

Free T4 Association (p≤0.05)*

Jain 2013

General population (NHANES) (n=1,525)

NR TSH NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Thyroglobulin NS (p>0.05)

Ji et al. 2012

General population (n=633)

7.96 ng/mL (median PFOS) TSH NS (p=0.3537)

T4 NS (p=0.1134)

Lewis et al. 2015

General population (NHANES) (n=1,682)

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

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

Melzer et al. 2010

General population (NHANES) (n=3,966)

57.73 and 50.96 ng/mL 

(4th PFOS quartile mean in 

women and men)

Thyroid disease risk 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 and 

2nd quartiles

Raymer et al. 2012

General population (n=256)

37.4 ng/mL (mean PFOS) TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)
PERFLUOROALKYLS 230

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Shrestha et al. 2015

General population (n=87 with thyroid disease)

31.6 ng/mL (geometric mean 

PFOS)

TSH NS (p=0.094)

Free T4 Association (p=0.044)*

T4 Association (p=0.001)*

T3 NS (p=0.287)

Wang et al. 2013a

General population (903 pregnant women)

12.77 ng/mL (geometric 

mean PFOS)

TSH Association (p=0.03)*

Elevated TSH risk NS (p>0.05)

Wang et al. 2014

General population (285 pregnant women)

12.73 ng/mL (median PFOS) TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Total T3 NS (p>0.05)

Webster et al. 2016

General population (NHANES) (n=1,525)

13.9 ng/mL (geometric mean 

PFOS)

TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p<0.05)

Wen et al. 2013

General population (NHANES) (n=1,181)

14.2 ng/mL (geometric mean 

PFOS)

TSH NS (p=0.931), men

NS (p=0.358), women

Total T4 NS (p=0.840), men

NS (p=0.433), women

Total T3 NS (p=0.404), men

NS (p=0.384), women

Thyroglobulin NS (p=0.342), men

NS (p=0.061), women

Subclinical 

hypothyroidism risk

OR 1.98 (1.19–3.28, p<0.05)*, men

OR 3.03 (1.14–8.07, p<0.05)*, women 

Subclinical 

hyperthyroidism risk

OR 0.92 (0.19–4.46), men

OR 1.90 (0.33–6.80), women
PERFLUOROALKYLS 231

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Yang et al. 2016a

General population (n=157 pregnant women)

5.08 ng/mL (mean PFOS) TSH Inverse association (p<0.01)*

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

PFHxS

Bloom et al. 2010

General population (n=31)

0.75 ng/mL (geometric mean 

PFHxS)

TSH NS (p=0.956)

Free T4 NS (p=0.567)

Chan et al. 2011

General population (n=94 women with 

hypothyroxinemia and 175 matched controls)

1.28 and 1.37 ng/mL 

(geometric mean PFHxS in 

cases and controls) 

Hypothyroxinemia risk OR 1.12 (0.89–1.41)

Jain 2013

General population (NHANES) (n=1,525)

NR TSH NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Thyroglobulin NS (p>0.05)

Ji et al. 2012

General population (n=633)

1.51 ng/mL (median PFHxS) TSH NS (p=0.8144)

T4 NS (p=0.5147)

Lewis et al. 2015

General population (NHANES) (n=1,682)

0.69–1.81 ng/mL (range of 

median PFHxS for different 

age groups)

TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

Wang et al. 2013a

General population (n=903 pregnant women)

0.62 ng/mL (geometric mean 

PFHxS)

TSH NS (p>0.05)

Elevated TSH risk NS (p>0.05)
PERFLUOROALKYLS 232

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Wang et al. 2014

General population (n=285 pregnant women)

0.81 ng/mL (median PFHxS) TSH Association (p<0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Total T3 NS (p>0.05)

Webster et al. 2016

General population (NHANES) (n=1,525)

1.9 ng/mL (geometric mean 

PFHxS)

TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

Wen et al. 2013

General population (NHANES) (n=1,181)

2.0 ng/mL (geometric mean 

PFHxS)

TSH NS (p=0.608), men

NS (p=0.720), women

Total T4 NS (p=0.641), men

Association (p=0.022)*, women

Total T3 NS (p=0.917), men

Association (p<0.001)*, women

Thyroglobulin NS (p=0.455), men

NS (p=0.725), women

Subclinical 

hypothyroidism risk

OR 1.57 (0.76–3.25), men

OR 3.10 (1.22–7.86, p<0.05)*, women 

Subclinical 

hyperthyroidism risk

OR 0.56 (0.24–1.20.92), men

OR 12.27 (1.07–4.80.90)*,women

Yang et al. 2016a

General population (n=157 pregnant women)

0.63 ng/mL (mean PFHxS) TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)
PERFLUOROALKYLS 233

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFNA

Mundt et al. 2007

Occupational (n=592)

NR TSH Investigators noted differences 

between groups was small and not 

clinically relevant

T4

T3

Lopez-Espinosa et al. 2012

Community (n=10,725 children aged 1–

17 years)

1.5 ng/mL (median PFNA) Thyroid disease OR 1.05 (0.78–1.41), per interquartile 

shift

Hypothyroidism OR 1.11 (0.77–1.60), per interquartile 

shift

Subclinical 

hypothyroidism

OR 0.99 (0.88–1.12), per interquartile 

shift 

Subclinical 

hyperthyroidism

OR 0.78 (0.61–1.01), per interquartile 

shift

TSH β -1.1 (CI 0.7–1.5), per interquartile 

shift 

Total T4 Β 0.8 (-0.4–2.0), per interquartile shift

Bloom et al. 2010

General population (n=31)

0.79 ng/mL (geometric mean 

PFNA)

TSH NS (p=0.789)

Free T4 NS (p=0.424)

Jain 2013

General population (NHANES) (n=1,525)

NR TSH NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Thyroglobulin NS (p>0.05)

Ji et al. 2012

General population (n=633)

2.09 ng/mL (median PFNA) TSH NS (p=0.1354)

T4 NS (p=0.7436)

Wang et al. 2013a

General population (n=903 pregnant women)

0.37 ng/mL (geometric mean 

PFNA)

TSH NS (p>0.05)

Elevated TSH risk NS (p>0.05)
PERFLUOROALKYLS 234

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Wang et al. 2014

General population (n=285 pregnant women)

1.51 ng/mL (median PFNA) TSH NS (p>0.05)

Free T4 Inverse association (p<0.001)*

Total T4 Inverse association (p<0.001)*

Total T3 NS (p>0.05)

Webster et al. 2016

General population (NHANES) (n=1,525)

1.5 ng/mL (geometric mean 

PFNS)

TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

Wen et al. 2013

General population (NHANES) (n=1,181)

1.54 ng/mL (geometric mean 

PFNA)

TSH NS (p=0.973), men

NS (p=0.407), women

Total T4 NS (p=0.097), men

NS (p=0.632), women

Total T3 NS (p=0.063), men

NS (p=0.258), women

Thyroglobulin NS (p=0.537), men

NS (p=0.395), women

Subclinical 

hypothyroidism risk

OR 1.30 (0.65–2.60), men

OR 2.54 (0.40–16.05), women 

Subclinical 

hyperthyroidism risk

OR 2.41 (0.48–12.04), men

OR 1.91 (0.83–4.38), women

Yang et al. 2016a

General population (n=157 pregnant women)

0.52 ng/mL (mean) TSH Inverse association (p<0.05)*

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

PFDeA

Berg et al. 2015

General population (n=391 pregnant women)

0.31–2.34 ng/mL (4th PFDeA 

quartile)

T3 Association (p=0.03) (4th quartile)
PERFLUOROALKYLS 235

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Bloom et al. 2010

General population (n=31)

0.21 ng/mL (geometric mean 

PFDeA)

TSH NS (p=0.365)

Free T4 NS (p=0.107)

Jain 2013

General population (NHANES) (n=1,525)

NR TSH NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Thyroglobulin NS (p>0.05)

Ji et al. 2012

General population (n=633)

0.91 ng/mL (median PFDeA) TSH NS (p=0.2721)

T4 NS (p=0.2176)

Wang et al. 2013a

General population (903 pregnant women)

0.09 ng/mL (geometric mean 

PFDeA)

TSH NS (p>0.05)

Elevated TSH risk NS (p>0.05)

Wang et al. 2014

General population (285 pregnant women)

0.46 ng/mL (median PFDeA) TSH NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Total T3 Association (p<0.01)*

Yang et al. 2016a

General population (n=157 pregnant women)

0.45 ng/mL (mean PFDeA) TSH Inverse association (p<0.01)*

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

PFUA

Berg et al. 2015

General population (n=391)

0.4–0.96 ng/mL (4th PFUA 

quartile)

Free T3 Association (p=0.00)*, 4th quartile
PERFLUOROALKYLS 236

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Bloom et al. 2010

General population (n=31)

0.20 ng/mL (geometric mean 

PFUA)

TSH NS (p=0.527)

Free T4 NS (p=0.204)

Ji et al. 2012

General population (n=633)

1.75 ng/mL (median PFUA) TSH NS (p=0.5368)

T4 NS (p=0.0642)

Wang et al. 2013a

General population (n=903 pregnant women)

0.20 ng/mL (geometric mean 

PFUA)

TSH NS (p>0.05)

Elevated TSH risk NS (p>0.05)

Wang et al. 2014

General population (n=285 pregnant women)

3.26 ng/mL (median PFUA) TSH NS (p>0.05)

Free T4 Inverse association (p<0.001)*

Total T4 Inverse association (p<0.001)*

Total T3 NS (p>0.05)

Yang et al. 2016a

General population (n=157 pregnant women)

0.45 ng/mL (mean PFUA) TSH Inverse association (p<0.05)*

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

PFDoA

Ji et al. 2012

General population (n=633)

0.92 ng/mL (median PFDoA) TSH NS (p=0.6925)

T4 NS (p=0.7153)

Wang et al. 2014

General population (285 pregnant women)

0.36 ng/mL (median PFDoA) TSH NS (p>0.05)

Free T4 Inverse association (p<0.001)*

Total T4 Inverse association (p<0.01)*

Total T3 NS (p>0.05)
PERFLUOROALKYLS 237

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-15. Summary of Thyroid Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Yang et al. 2016a

General population (n=157 pregnant women)

0.046 ng/mL (mean PFDoA) TSH Inverse association (p<0.01)*

Free T4 Inverse association (p<0.05)*

Total T4 Inverse association (p<0.05)*

Free T3 Inverse association (p<0.01)*

Total T3 Inverse association (p<0.01)*

Me-PFOSA-AcOH

Jain 2013

General population (NHANES) (n=1,525)

NR TSH NS (p>0.05)

Free T3 NS (p>0.05)

Total T3 NS (p>0.05)

Free T4 NS (p>0.05)

Total T4 NS (p>0.05)

Thyroglobulin NS (p>0.05)

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 compound; 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; 

PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUA = perfluoroundecanoic acid; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid 

stimulating hormone
PERFLUOROALKYLS 238

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 cumulative serum PFOA and hyperthyroidism or hypothyroidism were found in 

retrospective analysis (Winquist and Steenland 2014b). However, in prospective analysis, an association 

between 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 the 

general 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, and 

a decreased risk of subclinical hyperthyroidism among men, but not women. A case-control study of 

women did not find that serum PFOA levels were associated with the risk of hypothyroxinemia (Chan et 

al. 2011). Although four studies found associations between serum PFOA and T3 levels (Jain 2013; 

Lewis et al. 2015; Webster et al. 2016; Wen et al. 2013), four other studies did not find these associations 

(Raymer et al. 2012; Shrestha et al. 2015; Wang et al. 2014; Yang et al. 2016a). No associations between 

serum PFOA and TSH or T4 (Bloom et al. 2010; Jain 2013; Ji et al. 2012; Lewis et al. 2015; 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) levels were found in the general population studies, with the exception of the study by Lewis et al. 

(2015), which found an association for TSH and T4 levels.

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 
PERFLUOROALKYLS 239

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

rats dosed with up to 15 mg/kg/day APFO in the diet for 2 years, there were no significant morphological 

alterations in the adrenals (3M 1983). 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. This dose level was lethal to 

some monkeys; no such effect was seen in monkeys dosed with 10 mg/kg/day.

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, and 

parathyroid glands from male and female rats dosed with up to 15 mg/kg/day APFO in the diet for 2 years 

(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). Serum 

T4 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 of 

rats following dermal application of up to 2,000 mg/kg/day APFO for 2 weeks in the Kennedy (1985) 

study.

PFOS

Epidemiology Studies. A number of epidemiology 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 in men or 

women (Lewis et al. 2015; Melzer et al. 2010). Melzer et al. (2010) did find an increase in the risk 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. Although some studies have 

found alterations in thyroid hormone levels, the results are not consistent across studies. Associations 

between serum PFOS and TSH levels were observed in two general population studies (Berg et al. 2015; 

Wang et al. 2014). In contrast, two other studies found inverse associations for TSH (Dallaire et al. 2009; 
PERFLUOROALKYLS 240

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Yang et al. 2016a). An occupational exposure study (Olsen et al. 1998a) and eight general population 

studies (Bloom et al. 2010; Jain 2013; Ji et al. 2012; 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 (Jain 2013; Lewis et al. 2015; 

Raymer et al. 2012; Shrestha et al. 2015; Wang et al. 2014; Webster et al. 2016; Wen et al. 2013; Yang et 

al. 2016a). Most studies did not find an association with T4 levels (Jain 2013; Ji et al. 2012; Lewis et al. 

2015; Raymer et al. 2012; 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, and increases in TSH levels (Webster et al. 

2016).

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 dose 

level 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 induce 

a 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 affect 

maternal 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 

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 in 

mice 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 
PERFLUOROALKYLS 241

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

(Curran et al. 2008); T3 levels were decreased in female rats exposed to 50 or 100 mg/kg/day and in male 

rats at 100 mg/kg/day. No histological alterations were observed in the thyroid. Another study with 

PFOS 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 no 

changes 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. In a study in Cynomolgus monkeys, T3 

was numerically lower than controls 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 based on 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).

PFHxS

Epidemiology Studies. Ten general population studies have evaluated possible associations between 

serum PFHxS levels and alterations in thyroid hormone levels. With the exception of a study of pregnant 

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 epidemiology studies did not find associations for TSH, T3, or T4 (Bloom 

et al. 2010; Jain 2013; Ji et al. 2012; Lewis et al. 2015; Wang et al. 2013a, 2014; Webster et al. 2016; 

Yang et al. 2016a). Chan et al. (2011) did not find an increase in the risk of hypothyroxinemia associated 
PERFLUOROALKYLS 242

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

with serum PFHxS levels, but Wen et al. (2013) found increases in the risk of subclinical hypothyroidism 

and subclinical hyperthyroidism among women, but not men.

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; 

Hoberman and York 2003). The NOAEL was 1 mg/kg/day. The investigators noted that the observed 

changes in rats are consistent with the known effects of inducers of microsomal enzymes where the 

hepatocellular hypertrophy results in a compensatory hypertrophy and hyperplasia of the thyroid due to an 

increase in plasma turnover of T4 and associated stimulation of TSH. Neither thyroid hormones nor TSH 

were measured in the study.

PFNA

Epidemiology 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 

levels (Bloom et al. 2010; Jain 2013; Ji et al. 2012; Lopez-Espinosa et al. 2012; 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). 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) or in NHANES 

participants (Wen et al. 2013). 

PFDeA

Epidemiology Studies. Most general population studies did not find associations between serum PFDeA 

levels and TSH, T3, or T4 levels (Bloom et al. 2010; Ji et al. 2012; Wang et al. 2013a, 2014; Yang et al. 

2016a). The exceptions were studies by Berg et al. (2015) and Wang et al. (2014), which found 

associations with T3 levels in pregnant women, and a study by Yang et al. (2016a), which found an 

inverse association with TSH levels in pregnant women.
PERFLUOROALKYLS 243

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Laboratory Animal Studies. Administration of a single dose of 80 mg/kg PFDeA 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).

PFUA

Epidemiology Studies. Inverse associations between serum PFUA and serum TSH (Yang et al. 2016a) or 

T4 (Wang et al. 2014) have been reported in pregnant women; another study found an association 

between PFUA and T3 levels (Berg et al. 2015). However, other general population studies have not 

found association between PFOA and TSH, T4, or T3 levels (Bloom et al. 2010; Ji et al. 2012; Wang et 

al. 2013a, 2014; Yang et al. 2016a).

PFBuS

Laboratory Animal Studies. Treatment of rats with up to 900 mg/kg/day PFBuS 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.

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 the 

hypertrophic hepatocytes. None of these studies measured thyroid hormones or TSH in serum.

PFDoA

Epidemiology Studies. Three general population studies have evaluated the effect of PFDoA on thyroid 

hormone levels. Wang et al. (2014) reported inverse associations between serum PFDoA and free T4 and 

total T4 in pregnant women; no associations were found for TSH or total T3. In another study of 
PERFLUOROALKYLS 244

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 PFDoA and TSH or 

T4.

Me-PFOSA-AcOH

Epidemiology Studies. In the only available study examining thyroid outcomes, Jain (2013) found no 

associations between serum Me-PFOSA-AcOH levels and TSH, T3, or T4 levels in NHANES 

participants.

2.14 IMMUNOLOGICAL

Overview. Epidemiology 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 epidemiology 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. In general, the epidemiology studies identify the 

immune system as a target of perfluoroalkyl toxicity. The strongest evidence of the immunotoxicity of 

perfluoroalkyls in humans comes from epidemiology studies finding associations evaluating the antibody 

response to vaccines. Associations have been found for PFOA, PFOS, PFHxS, and PFDeA. There is also 

some limited evidence for decreased antibody response for PFNA, PFUA, and PFDoA, 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. Epidemiology studies have also found increases in 

the asthma diagnosis that were associated with serum PFOA levels. There is also marginal evidence for 

PFOS, PFHxS, PFNA, PFDeA, PFBuS, and PFDoA; 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 autoimmunity; epidemiology 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 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
PERFLUOROALKYLS 245

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Ashley-Martin et al. 2015

General population (1,258 women) 

NR IL-33/TSLP (cord blood) OR 1.1 (0.6–1.8)

IgE (cord blood) OR 1.1 (0.6–1.9)

Buser and Scinicariello 2016

General population (NHANES) (n=637 and 

701 adolescents in 2005–2006 and 2007–

2010) 

3.59 and 3.27 ng/mL 

(geometric mean 2005–2006 

and 2007–2010)

>4.47 ng/mL (4th quartile)

Food allergies OR 9.09 (3.52–24.90)*, 4th quartile

Food sensitization NS (p=0.74 for trend)

Dalsager et al. 2016

General population (n=359 1–4-year-old 

children)

2.04–10.12 ng/mL (maternal 

3rd tertile PFOA)

Risk of number of days 

above the median

Fever

Cough

Nasal discharge

Diarrhea

Vomiting

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)

Risk of number of days 

Fever

Cough

Nasal discharge

Diarrhea

Vomiting

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)

Dong et al. 2013

General population (n=231 asthmatic and 

225 non-asthmatic children) 

This is the same group of children 

evaluated by Zhu et al. (2016)

1.5 and 1.0 ng/mL (mean 

serum PFOA levels in the 

asthmatic and non-asthmatic 

children, respectively; serum 

levels were not reported for 

full cohort)

Asthma diagnosis OR 2.67 (1.49–4.79)*, 3rd quartile

IgE 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 
PERFLUOROALKYLS 246

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Fei et al. 2010

General population. (n=1,400 pregnant 

women and young children)

5.6 ng/mL (maternal PFOA) Risk of hospitalization for 

infectious disease in young 

children

IRR 0.96 (0.87–1.06) for trend

IRR 1.21 (1.04–1.42)* for trend, girls

IRR 0.83 (0.73–0.95)* for trend, boys

Grandjean et al. 2012; Mogensen et al. 

2015a

General population (n=456 and 

n=464 children 5 and 7 years of age)

4.1 and 4.4 ng/mL (median

PFOA at age 5 and 7 years)

3.20 ng/mL (geometric mean 

maternal PFOA)

Tetanus antibody levels at 

age 5

NS, maternal PFOA

NS, PFOA at age 5 

Tetanus antibody levels at 

age 7

NS, maternal PFOA

β -35.8% (-51.9 to -14.2)*, per 2-fold 

increase in PFOA levels at age 5 

NS, PFOA at age 7 

Diphtheria antibody levels 

at age 5

NS, maternal PFOA

NS (p=0.69), PFOA at age 5 

Diphtheria antibody levels 

at age 7

NS, maternal PFOA

β -25.2% (-42.9 to -2.0)*, per 2-fold 

increase in PFOA levels at age 5

β -25.4% (-40.9 to -5.8)*, per 2-fold 

increase in PFOA levels, PFOA at 

age 7 

Grandjean et al. 2017

General population (n=516 children 

examined at age 7 and 13 years)

4.4 and 2.0 ng/mL (median 

PFOA at age 7 and 13 years)

Tetanus antibody levels at 

age 13

NS (p=0.637), PFOA at age 7 

NS (p=0.856), PFOA at age 13

Diphtheria antibody levels 

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 
PERFLUOROALKYLS 247

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Granum et al. 2013

General population (n=56 children age 

3 years)

1.1 ng/mL (mean maternal 

PFOA)

Rubella antibody levels Inverse association (p=0.001)*

Hemophilus influenza type 

B antibody levels

NS (p>0.05)

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 

media

NS (p>0.05)

Number of episodes of 

common cold

Association (p<0.001)*

Number of episodes of 

gastroenteritis

Association (p=0.048)*

Humblet et al. 2014

General population (NHANES) 

(n=1,877 adolescents)

4.3 and 4.0 ng/mL (median 

PFOA in asthmatics and 

nonasthmatics)

Asthma episode in last 

12 months

OR 1.18 (1.01–1.39)*, per doubling 

PFOA

Current asthma NS (p=0.26)

Wheezing NS (p=0.98)

Kielsen et al. 2016

General pop. (n=12 adults) 

1.69 ng/mL (median PFOA) Diphtheria antibody levels NS (p=0.250), unadjusted 

Tetanus antibody levels NS (p=0.970), unadjusted.

Looker et al. 2014

Community (C8) (n=411)

33.74 ng/mL (geometric 

mean)

13.8–31.5 ng/mL (2nd quartile)

Seroprotection from 

influenza A H3N2 virus

OR 0.34 (0.14–0.83)*, 2nd quartile

Seroprotection from 

influenza A H1N1 virus 

NS (p=0.02)

Seroprotection from 

influenza type B virus 

NS (p=0.68)

Cold or flu infection NS (p>0.05)

Frequency of colds NS (p>0.05)
PERFLUOROALKYLS 248

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Okada et al. 2012

General population (n=343 pregnant 

women)

1.3 ng/mL (maternal median 

PFOA)

Cord IgE levels

Males

Females

NS (p>0.05)

Inverse association (p<0.05)*

Infant food allergy OR 1.67 (0.52–5.37)

Eczema OR 0.96 (0.23–4.02)

Wheezing OR 1.27 (0.27–6.05)

Otitis media OR 1.51 (0.45–5.12)

Okada et al. 2014

General population (n=2,603 infants)

2.67 ng/mL (maternal mean 

PFOA)

Risk of allergic diseases

Males

Females

OR 0.63 (0.63–1.37), 4th quartile

OR 0.64 (0.42–0.97)*, 4th quartile

Eczema

Males

Females

OR 0.75 (0.48–1.18), 4th quartile

OR 0.65 (0.39–1.09), 4th quartile

Smit et al. 2015

General population (n=1,024 children)

0.97 and 1.79 ng/mL 

(maternal mean PFOA in 

Ukraine and Greenland 

cohorts)

Ever having asthma OR 0.80 (0.62–1.04), whole cohort

Ever having eczema OR 0.97 (0.81–1.17), whole cohort

Current eczema OR 1.01 (0.79–1.29), whole cohort

Ever having wheezing OR 0.91 (0.76–1.10), whole cohort

Current wheezing OR 0.97 (0.71–1.33), whole cohort

Steenland et al. 2013

Community (C8) (28,441)

Cumulative Ulcerative colitis OR 1.76 (1.04–2.99)*, 2nd quartile

Rheumatoid arthritis NS (p>0.05)

Crohn’s disease NS (p>0.05)

Type I diabetes NS (p>0.05)

Lupus NS (p>0.05)

Multiple sclerosis NS (p>0.05)
PERFLUOROALKYLS 249

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Steenland et al. 2015

Occupational (n=3,713)

Cumulative Asthma NS (p=0.27), with no lag

NS (p=0.53), with 10-year lag

Positive categorical trend (p=0.05)*, 

with no lag

Ulcerative colitis RR 6.57 (1.47–29.40)*, with 10-year lag

Rheumatoid arthritis Positive categorical trend (p=0.04)*, 

with no lag

Stein et al. 2016a

General population (NHANES) 

(n=1,191 adolescents)

4.13 ng/mL (geometric mean) Measles antibody titers NS (95% CI included unity)

Mumps antibody titers NS (95% CI included unity), whole cohort

β -6.6% (-11.7 to -1.5)*, per 2-fold 

increase in PFOA levels, seropositive 

subcohort 

Rubella antibody titers NS (95% CI included unity), whole cohort

β -8.9% (-14.6 to -2.9)*, per 2-fold 

increase in PFOA levels, seropositive 

subcohort 

Stein et al. 2016a

General population (NHANES)

(n=640 adolescents)

3.59 ng/mL (geometric mean) Rhinitis OR 1.35 (1.10–1.66)*

Current asthma OR 1.28 (0.81–2.04)

Wheeze OR 0.94 (0.51–1.73)

Allergy OR 1.12 (0.85–1.47)

Allergic sensitization

Plants

Dust mites

Pets

Cockroach or shrimp

Rodents

Mold

Food

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)
PERFLUOROALKYLS 250

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Stein et al. 2016b

General population (n=78 adults receiving 

influenza vaccine)

2.28 ng/mL (geometric mean) Seroconversion

Hemagglutinin

Immunohistochem.

NS (p=0.07 for trend)

NS (p=0.27 for trend)

Serum cytokine levels NS (p>0.05 for trend)

Serum chemokine levels NS (p>0.05 for trend)

Nasal cytokine levels NS (p>0.05 for trend)

Nasal chemokine levels NS (p>0.05 for trend)

Serum IgA levels NS (p>0.05 for trend)

Wang et al. 2011

General population (n=244 children aged 

2 years) 

1.71 ng/mL (median cord 

PFOA) 

Serum IgE levels NS (p=0.870) 

Cord blood IgE levels Association (p=0.047)* 

Atopic dermatitis NS (p>0.05)

Zhu et al. 2016

General population (n=231 asthmatic and 

225 non-asthmatic children)

This is the same group of children 

evaluated by Dong et al. (2013)

1.51 and 1.00 ng/mL (mean in 

asthmatics and nonasthmatics)

Asthma diagnosis OR 4.24 (1.91–9.42)*, males 4th quartile

OR 3.68 (1.43–9.48)*, females 4th

quartile

T-helper cytokines

IL-4

IL-5

IFN-γ

IL-2

Association (p=0.001 for trend)*

Association (p=0.004 for trend)*

NS (p>0.05 for trend)

NS (p>0.05 for trend)

Serum IgE NS (p>0.05 for trend)

PFOS

Ashley-Martin et al. 2015

General population (1,258 women) 

NR IL-33/TSLP (cord blood) 1.1 (0.6–1.9)

IgE (cord blood) OR 1.1 (0.6–1.9)

Buser and Scinicariello 2016

General population (NHANES) (n=637 and 

701 adolescents in 2005–2006 and 2007–

2010) 

14.98 and 8.74 ng/mL 

(geometric mean PFOS 

2005–2006 and 2007–2010)

9.17–13.75 ng/mL 

(3rd quartile)

Food allergies OR 2.43 (1.05–5.59)*, 3rd quartile 

(trend not significant, p=0.27)

Food sensitization NS (p=0.49 for trend)
PERFLUOROALKYLS 251

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Dalsager et al. 2016

General population (n=359 1–4-year-old 

children)

10.19–25.10 ng/mL (maternal 

3rd tertile PFOS)

Risk of number of days 

above the median

Fever

Cough

Nasal discharge

Diarrhea

Vomiting

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)

Risk of number of days 

Fever

Cough

Nasal discharge

Diarrhea

Vomiting

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)

Dong et al. 2013

General population (n=231 asthmatic and 

225 non-asthmatic children) 

This is the same group of children 

evaluated by Zhu et al. (2016)

45.5 and 33.4 ng/mL (mean 

serum PFOS levels in the 

asthmatic and non-asthmatic 

children, respectively; serum 

levels were not reported for 

full cohort)

Asthma diagnosis OR 2.63 (1.48–4.69)*, 4th quartile

Asthma severity Association (p=0.045 for trend)*

IgE 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 

Fei et al. 2010

General population (n=1,400 pregnant 

women and young children)

35.3 ng/mL (maternal PFOS) Risk of hospitalization for 

infectious disease in young 

children

IRR 1.00 (0.91–1.09) for trend

IRR 1.18 (1.03–1.36)* for trend, girls

IRR 0.90 (0.80–1.12) for trend, boys

Grandjean et al. 2012; Mogensen et al. 

2015a

General population (n=456 and 

n=464 children 5 and 7 years of age)

17.3 and 15.5 ng/mL (median 

PFOS at age 5 and 7 years)

27.3 ng/mL (geometric mean 

maternal PFOS)

Tetanus antibody levels at 

age 5

NS, maternal PFOS

β -28.5% (-45.5 to -6.1)*, per 2-fold 

increase in PFOS levels at age 5 

Tetanus antibody levels at 

age 7

NS, maternal PFOS

NS, PFOS at ages 5 and 7 

Diphtheria antibody levels 

at age 5

NS, maternal PFOS

NS, PFOS at age 5 
PERFLUOROALKYLS 252

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Diphtheria antibody levels 

at age 7

β -27.6% (-45.8 to -3.3)*, per 2-fold 

increase in PFOS levels at age 5 

β -30.3% (47.3 to -7.8)*, per 2-fold 

increase in PFOS levels at age 7

Grandjean et al. 2017

General population (n=516 children 

examined at age 7 and 13 years)

15.3 and 6.7 ng/mL (median 

at age 7 and 13 years)

Tetanus antibody levels at 

age 13

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 at 

age 7 

NS (p=0.144), PFOS at age 13

Diphtheria antibody levels 

at age 13

NS (p=0.07), age 7

NS (p=0.454), age 13

Granum et al. 2013

General population (n=56 children age 3 

years)

5.6 ng/mL (mean maternal 

PFOS)

Rubella antibody levels Inverse association (p=0.007)*

Hemophilus influenza

type B antibody levels

NS (p>0.05)

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 

media

NS (p>0.05)

Number of episodes of 

common cold

NS (p=0.501)

Number of episodes of 

gastroenteritis

NS (p=0.367)

Humblet et al. 2014

General population (NHANES) 

(n=1,877 adolescents)

17.0 and 16.8 ng/mL (median 

PFOS in asthmatics and nonasthmatics)

Asthma episode in last 

12 months

NS (p=0.13), per doubling PFOS

Current asthma NS (p=0.24)

Wheezing NS (p=0.08)
PERFLUOROALKYLS 253

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Kielsen et al. 2016

General population (n=12 adults) 

9.52 ng/mL (median PFOS) Diphtheria antibody levels Inverse association (p=0.044)*, 

unadjusted 

Tetanus antibody levels NS (p=0.420), unadjusted

Looker et al. 2014

Community (C8) (n=411)

8.32 ng/mL (geometric mean 

PFOS)

Response to influenza A 

H3N2 virus vaccine

NS (p>0.05)

Response to influenza A 

H1N1 virus vaccine

NS (p>0.05)

Response to influenza 

type B virus vaccine 

NS (p>0.05)

Cold or flu infection NS (p>0.05)

Frequency of colds NS (p>0.05)

Okada et al. 2012

General population (n=343 infants)

5.2 ng/mL (maternal median 

PFOS)

Cord IgE levels NS (p>0.05) 

Infant food allergy OR 3.72 (0.81–17.10)

Eczema OR 0.87 (0.15–5.08)

Wheezing OR 2.68 (0.39–18.30)

Otitis media OR 1.40 (0.33–6.00)

Okada et al. 2014

General population (n=2,603 infants)

5.56 ng/mL (maternal mean 

PFOS)

Risk of allergic diseases

Males

Females

OR 0.95 (0.65–1.37), 4th quartile

OR 0.79 (0.53–1.17), 4th quartile

Eczema

Males

Females

OR 0.98 (0.63–1.53), 4th quartile

OR 0.84 (0.51–1.38), 4th quartile

Smit et al. 2015

General population (n=1,024 children)

4.88 and 20.6 ng/mL 

(maternal mean PFOS in 

Ukraine and Greenland 

cohorts)

Ever having asthma OR 0.86 (0.67–1.10), whole cohort

Ever having eczema OR 0.98 (0.88–1.18), whole cohort

Current eczema OR 1.05 (0.82–1.33), whole cohort

Ever having wheezing OR 0.83 (0.69–1.00), whole cohort

Current wheezing 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
PERFLUOROALKYLS 254

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Stein et al. 2016a

General population (NHANES) 

(n=1,191 adolescents)

20.8 ng/mL (geometric mean 

PFOS)

Measles antibody titers NS (95% CI included unity)

Mumps antibody titers β -7.4% (-12.8 to -1.7)*, per 2-fold 

increase in PFOS levels, whole cohort 

β -5.9% (-9.9 to -1.6)*, per 2-fold 

increase in PFOS levels, seropositive 

subcohort

Rubella antibody titers NS (95% CI included unity), whole cohort

β -13.3% (-19.9–6.2)*, per 2-fold 

increase in PFOS levels, seropositive 

subcohort 

Stein et al. 2016a

General population (NHANES) 

(n=640 adolescents)

15.0 ng/mL (geometric mean) Rhinitis OR 1.16 (0.90–1.50)

Current asthma OR 1.20 (0.88–1.63)

Wheeze OR 0.76 (0.45–1.19) 

Allergy OR 1.05 (0.80–1.37)

Allergic sensitization

Plants

Dust mites

Pets

Cockroach or shrimp

Rodents

Mold

Food

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)

Stein et al. 2016b

General population (n=78 adults receiving 

influenza vaccine)

5.22 ng/mL (geometric mean) Seroconversion

Hemagglutinin

Immunohistochemistry

NS (p=0.81 for trend)

NS (p=0.12 for trend)

Serum cytokine levels NS (p>0.05 for trend)

Serum chemokine levels NS (p>0.05 for trend)

Nasal cytokine levels NS (p>0.05 for trend)

Nasal chemokine levels NS (p>0.05 for trend)

Serum IgA levels NS (p>0.05 for trend)
PERFLUOROALKYLS 255

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Wang et al. 2011

General population (n=244 children aged 

2 years) 

5.50 ng/mL (median cord 

PFOS) 

Serum IgE levels NS (p=0.179) 

Cord blood IgE levels Association (p=0.017)* 

Atopic dermatitis NS (p>0.05)

Zhu et al. 2016

General population (n=231 asthmatic and 

225 non-asthmatic children)

This is the same group of children 

evaluated by Dong et al. (2013)

45.86 and 33.9 ng/mL (mean 

in asthmatics and nonasthmatics)

Asthma diagnosis OR 4.38 (2.02–9.50)*, males 4th quartile

NS (p=0.899 for trend), females 

T-helper cytokines

IL-4

IL-5

IFN-γ

IL-2

NS (p>0.05 for trend)

NS (p>0.05 for trend)

NS (p>0.05 for trend)

NS (p>0.05 for trend)

Serum IgE NS (p>0.05 for trend)

PFHxS

Ashley-Martin et al. 2015

General population (1,258 women) 

NR IL-33/TSLP (cord blood) 1.0 (0.7–1.4)

IgE (cord blood) OR 1.0 (0.7–1.4)

Buser and Scinicariello 2016

General population (NHANES) (n=637 and 

701 adolescents in 2005–2006 and 2007–

2010) 

2.09 and 2.19 ng/mL 

(geometric mean 2005–2006 

and 2007–2010)

>4.00 ng/mL (4th quartile) 

Food allergies OR 3.06 (1.35–6.93)*, 4th quartile (trend 

not significant, p=0.11)

Food sensitization NS (p=0.72 for trend)

Dalsager et al. 2016

General population (n=359 1–4-year-old 

children)

0.32 ng/mL (maternal median 

PFHxS)

Risk of number of days 

above the median

Fever

Cough

Nasal discharge

Diarrhea

Vomiting

NS (p>0.05)

NS (p>0.05)

NS (p>0.05)

NS (p>0.05)

NS (p>0.05)
PERFLUOROALKYLS 256

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Risk of number of days 

Fever

Cough

Nasal discharge

Diarrhea

Vomiting

NS (p>0.05)

NS (p>0.05)

NS (p>0.05)

NS (p>0.05)

NS (p>0.05)

Dong et al. 2013

General population (n=231 asthmatic and 

225 non-asthmatic children) 

This is the same group of children 

evaluated by Zhu et al. (2016)

3.9 and 2.1 ng/mL (mean 

serum PFHxS levels in the 

asthmatic and non-asthmatic 

children, respectively; serum 

levels were not reported for 

full cohort)

Asthma diagnosis OR 2.94 (1.65–5.25)*, 3rd quartile

Asthma severity NS (p=0.722 for trend)

IgE 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 Association (p<0.05)*, asthmatics

NS (p>0.05), non-asthmatics 

Grandjean et al. 2012; Mogensen et al. 

2015a

General population (n=456 and n=464 

children 5 and 7 years of age)

0.6 and 0.5 ng/mL (median 

PFHxS at age 5 and 7 years)

4.41 ng/mL (geometric mean 

maternal PFHxS)

Tetanus antibody levels at 

age 5

NS, maternal PFHxS

-19.0% (-29.8 to -6.6)*, per 2-fold 

increase in PFHxS levels at age 5 

Tetanus antibody levels at 

age 7

NS, maternal PFHxS

β -19.7% (-31.6 to -5.7)*, per 2-fold 

increase PFHxS levels at age 5

β -22.3% (-36.3 to -5.2)*, per 2-fold 

increase PFHxS levels at age 7

Diphtheria antibody levels 

at age 5

NS, maternal PFHxS

NS, PFHxS at age 5 

Diphtheria antibody levels 

at age 7

NS, maternal PFHxS

NS, PFHxS at age 5 or 7

Grandjean et al. 2017

General population (n=516 children 

examined at age 7 and 13 years)

0.5 and 0.4 ng/mL (median 

PFHxS at age 7 and 

13 years) 

Tetanus antibody levels at 

age 13

NS (p=0.334), PFHxS at age 7 

NS (p=0.568), PFHxS at age 13

Diphtheria antibody levels 

at age 13

NS (p=0.264), PFHxS at age 7

NS (p=0.583), PFHxS at age 13
PERFLUOROALKYLS 257

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Granum et al. 2013

General population (n=56 children age 

3 years)

0.3 ng/mL (mean maternal 

PFHxS levels)

Rubella antibody levels Inverse association (p=0.008)*

Hemophilus influenza

type B antibody levels

NS (p>0.05)

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 

media

NS (p>0.05)

Number of episodes of 

common cold

NS (p=0.078)

Number of episodes of 

gastroenteritis

Association (p=0.007)*

Humblet et al. 2014

General population (NHANES) 

(n=1,877 adolescents)

2.2 and 2.0 ng/mL (median 

PFHxS in asthmatics and 

nonasthmatics)

Asthma episode in last 

12 months

NS (p=0.66), per doubling PFHxS

Current asthma NS (p=0.99)

Wheezing NS (p=0.92)

Kielsen et al. 2016

General population (n=12 adults) 

0.37 ng/mL (median PFHxS) Diphtheria antibody levels NS (p=0.055), unadjusted 

Tetanus antibody levels NS (p=0.390), unadjusted

Okada et al. 2014

General population (n=2,603 infants)

0.324 ng/mL (maternal mean 

PFHxS)

Risk of allergic diseases

Males

Females

OR 0.81 (0.56–1.16), 4th quartile

OR 1.13 (0.75–1.69), 4th quartile

Eczema

Males

Females

OR 0.78 (0.51–1.19), 4th quartile

OR 0.82 (0.49–1.36), 4th quartile
PERFLUOROALKYLS 258

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Smit et al. 2015

General population (n=1,024 children)

1.53 and 2.14 ng/mL 

(maternal mean PFHxS in 

Ukraine and Greenland 

cohorts)

Ever having asthma OR 0.91 (0.69–1.18), whole cohort

Ever having eczema OR 1.03 (0.86–1.24), whole cohort

Current eczema OR 0.93 (0.73–1.20), whole cohort

Ever having wheezing OR 0.96 (0.79–1.17), whole cohort

Current wheezing OR 0.93 (0.68–1.27), whole cohort

Stein et al. 2016a

General population (NHANES) 

(n=1,191 adolescents)

2.47 ng/mL (geometric mean 

PFHxS)

Measles antibody titers NS (95% CI included unity)

Mumps antibody titers NS (95% CI included unity)

Rubella antibody titers NS (95% CI included unity), whole cohort

β -6.0% (-9.6 to -2.2)*, per 2-fold 

increase PFHxS levels, seropositive 

subcohort

Stein et al. 2016a

General population (NHANES) 

(n=640 adolescents)

2.09 ng/mL (geometric mean 

PFHxS)

Rhinitis OR 0.81 (0.57–1.16)

Current asthma OR 0.98 (0.51–1.87)

Wheeze OR 0.99 (0.68–1.44) 

Allergy OR 0.83 (0.59–1.17)

Allergic sensitization

Plants

Dust mites

Pets

Cockroach or shrimp

Rodents

Mold

Food

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)

Stein et al. 2016b

General population (n=78 adults receiving 

influenza vaccine)

1.1 ng/mL (geometric mean 

PFHxS)

Seroconversion

Hemagglutinin

Immunohistochem.

NS (p=0.22 for trend)

NS (p=0.34 for trend)

Serum cytokine levels

IFN-γ

IFN-α2

TNF-α

IP-10

Association (p=0.05 for trend)*

NS (p=0.09 for trend)

Association (p=0.04 for trend)*

NS (p=0.59 for trend)
PERFLUOROALKYLS 259

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Serum chemokine levels NS (p>0.05 for trend)

Nasal cytokine levels NS (p>0.05 for trend)

Nasal chemokine levels NS (p>0.05 for trend)

Serum IgA levels NS (p>0.05 for trend)

Zhu et al. 2016

General population (n=231 asthmatic and 

225 non-asthmatic children)

This is the same group of children 

evaluated by Dong et al. (2013)

3.86 and 2.10 ng/mL (mean 

PFHxS in asthmatics and 

non-asthmatics)

Asthma diagnosis OR 2.97 (1.33–6.64)*, males 4th quartile

OR 5.02 (2.05–12.30)*, females 

4th quartile

T-helper cytokines

IL-4

IL-5

IFN-γ

IL-2

NS (p>0.05 for trend)

NS (p>0.05 for trend)

NS (p>0.05 for trend)

NS (p>0.05 for trend)

Serum IgE NS (p>0.05 for trend)

PFNA

Buser and Scinicariello 2016

General population (NHANES) (n=637 and 

701 adolescents in 2005–2006 and 2007–

2010) 

0.93 and 1.13 ng/mL 

(geometric mean PFNA 

2005–2006 and 2007–2010)

>1.36 ng/mL (4th quartile) 

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)

Dalsager et al. 2016

General population (n=359 1–4-year-old 

children)

0.56–0.81 and 0.82–

3.64 ng/mL (maternal 2nd and 

3rd tertile PFNA)

Risk of number of days 

above the median

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)

Risk of number of days 

Fever

Cough

Nasal discharge

Diarrhea

Vomiting

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 260

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Dong et al. 2013

General population (n=231 asthmatic and 

225 non-asthmatic children) 

This is the same group of children 

evaluated by Zhu et al. (2016)

1.1 and 0.9 ng/mL (mean 

serum PFNA levels in the 

asthmatic and non-asthmatic 

children, respectively; serum 

levels were not reported for 

full cohort)

Asthma diagnosis OR 2.56 (1.41–4.65)*, 4th quartile

Asthma severity NS (p=0.217 for trend)

IgE 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 

Grandjean et al. 2012

General population (n=456 and 

n=464 children 5 and 7 years of age)

1.00 ng/mL (geometric mean 

PFNA at age 5 years)

0.60 ng/mL (geometric mean 

PFNA at age 7 years)

Tetanus antibody levels at 

age 5 

NS, maternal PFNA

NS, PFNA at age 5 

Tetanus antibody levels at 

age 7

NS, maternal PFNA

NS, PFNA at age 5

Diphtheria antibody levels 

at age 5

NS, maternal PFNA

β -16.1% (-28.8 to -1.0)*, per 2-fold 

increase PFNA levels at age 5 

Diphtheria antibody levels 

at age 7

NS, maternal PFNA

NS, PFNA at age 5

Grandjean et al. 2017

General population (n=516 children 

examined at age 7 and 13 years)

1.1 and 0.7 ng/mL (median 

PFNA at age 7 and 13 years) 

Tetanus antibody levels at 

age 13

NS (p=0.075), PFNA at age 7 

NS (p=0.394), PFNA at age 13

Diphtheria antibody levels 

at age 13

NS (p=0.243), PFNA at age 7

NS (p=0.693), PFNA at age 13

Granum et al. 2013

General population (n=56 children age 

3 years)

0.3 ng/mL (mean maternal 

PFNA levels)

Rubella antibody levels Inverse association (p=0.007)*

Hemophilus influenza

type B antibody levels

NS (p>0.05)

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 

media

NS (p>0.05)
PERFLUOROALKYLS 261

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Number of episodes of 

common cold

Association (p=0.035)*

Number of episodes of 

gastroenteritis

NS (p=0.883)

Humblet et al. 2014

General population (NHANES) 

(n=1,877 adolescents)

0.9 and 0.8 ng/mL (median 

PFNA in asthmatics and 

nonasthmatics)

Asthma episode in last 

12 months

NS (p=0.92), per doubling PFNA

Current asthma NS (p=0.97)

Wheezing NS (p=0.94)

Kielsen et al. 2016

General population

(n=12 adults) 

0.66 ng/mL (median PFNA) Diphtheria antibody levels Inverse association (p=0.004)*, 

unadjusted 

Tetanus antibody levels NS (p=0.250), unadjusted

Okada et al. 2014

General population (n=2,603 infants)

1.36 ng/mL (maternal mean 

PFNA)

Risk of allergic diseases

Males

Females

OR 0.95 (0.66–1.38), 4th quartile

OR 0.55 (0.36–0.82)*, 4th quartile

Eczema

Males

Females

OR 0.96 (0.61–1.52), 4th quartile

OR 0.63 (0.38–1.02), 4th quartile

Smit et al. 2015

General population (n=1,024 children)

0.62 and 0.73 ng/mL 

(maternal mean PFNA in 

Ukraine and Greenland 

cohorts)

Ever having asthma OR 0.90 (0.70–1.14), whole cohort

Ever having eczema OR 0.94 (0.78–1.14), whole cohort

Current eczema OR 1.03 (0.82–1.30), whole cohort

Ever having wheezing OR 0.91 (0.75–1.09), whole cohort

Current wheezing OR 0.90 (0.66–1.23), whole cohort

Stein et al. 2016a

General population (NHANES) 

(n=1,191 adolescents)

0.765 ng/mL (geometric 

mean)

Measles antibody titers NS (95% CI included unity)

Mumps antibody titers NS (95% CI included unity)

Rubella antibody titers NS (95% CI included unity)

Stein et al. 2016a

General population (NHANES) 

(n=640 adolescents)

0.929 ng/mL (geometric 

mean)

Rhinitis OR 1.24 (0.97–1.60)

Current asthma OR 1.26 (0.79–2.01)

Wheeze OR 0.99 (0.58–1.68) 

Allergy OR 1.12 (0.85–1.47)
PERFLUOROALKYLS 262

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Allergic sensitization

Plants

Dust mites

Pets

Cockroach or shrimp

Rodents

Mold

Food

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)

Stein et al. 2016b

General pop. (n=78 adults receiving 

influenza vaccine)

0.77 ng/mL (geometric mean 

PFNA)

Seroconversion

Hemagglutinin

Immunohistochem.

NS (p=0.33 for trend)

NS (p=0.40 for trend)

Serum cytokine levels NS (p>0.05 for trend)

Serum chemokine levels NS (p>0.05 for trend)

Nasal cytokine levels NS (p>0.05 for trend)

Nasal chemokine levels NS (p>0.05 for trend)

Serum IgA levels NS (p>0.05 for trend)

Wang et al. 2011

General population (n=244 children aged 

2 years) 

2.30 ng/mL (median cord 

PFNA) 

Serum IgE levels NS (p=0.837) 

Cord blood IgE levels NS (p=0.908)

Atopic dermatitis NS (p>0.05)

Zhu et al. 2016

General population (n=231 asthmatic and 

225 non-asthmatic children)

This is the same group of children 

evaluated by Dong et al. (2013)

1.07 and 0.87 ng/mL (mean 

PFNA in asthmatics and nonasthmatics)

Asthma diagnosis OR 3.33 (1.46–7.58)*, males 4th quartile

NS (p=0.142 for trend), females

T-helper cytokines

IL-4

IL-5

IFN-γ

IL-2

Association (p=0.031 for trend)*

Association (p=0.011 for trend)*

NS (p>0.05 for trend)

NS (p>0.05 for trend)

Serum IgE Association (p=0.008 for trend)*
PERFLUOROALKYLS 263

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFDeA

Dalsager et al. 2016

General population (n=359 children aged 

1–4 years) 

0.27 ng/mL (median maternal 

serum PFDeA level

Symptoms of infection NS (p>0.05) 

Dong et al. 2013

General population (n=231 asthmatic and 

225 non-asthmatic children) 

This is the same group of children 

evaluated by Zhu et al. (2016)

1.2 and 1.0 ng/mL (mean 

serum PFDeA levels in the 

asthmatic and non-asthmatic 

children, respectively; serum 

levels were not reported for 

full cohort)

Asthma diagnosis OR 3.22 (1.75–5.94)*, 4th quartile

Asthma severity Association (p=0.005 for trend)*

IgE 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

Grandjean et al. 2012

General population (n=456 and 

n=464 children 5 and 7 years of age)

0.28 ng/mL (geometric mean 

PFDeA at age 5 years)

0.28 ng/mL (geometric mean 

maternal PFDeA)

Tetanus antibody levels at 

age 5

NS, maternal PFDeA

β -19.9% (-33.1 to -3.9), per 2-fold 

increase PFDeA levels at age 5 

Tetanus antibody levels at 

age 7

NS, maternal PFDeA

β -22.3 (-35.8 to -5.8), per 2-fold 

increase PFDeA levels at age 5

Diphtheria antibody levels 

at age 5

NS, maternal PFDeA

NS, PFDeA at age 5 

Diphtheria antibody levels 

at age 7

NS, maternal PFDeA

NS, PFDeA at age 5 

Grandjean et al. 2017

General population (n=516 children 

examined at age 7 and 13 years)

0.4 and 0.3 ng/mL (median at 

age 7 and 13 years) 

Tetanus antibody levels at 

age 13

Association (p=0.022)*, PFDeA at 

age 7 

NS (p=0.258), PFDeA at age 13

Diphtheria antibody levels 

at age 13

Association (p=0.008)*, PFDeA at 

age 7

NS (p=0.726), PFDeA at age 13
PERFLUOROALKYLS 264

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Kielsen et al. 2016

General population (n=12 adults) 

0.30 ng/mL (median PFDeA) Diphtheria antibody levels Inverse association (p=0.009)*, 

unadjusted 

Tetanus antibody levels NS (p=0.130), unadjusted

Okada et al. 2014

General population (n=2,603 infants)

0.563 ng/mL (maternal mean 

PFDeA)

Risk of allergic diseases

Males

Females

OR 1.13 (0.78–1.64), 4th quartile

OR 0.70 (0.47–1.04), 4th quartile

Eczema

Males

Females

OR 0.93 (0.60–1.44), 4th quartile

OR 0.78 (0.49–1.25), 4th quartile

Smit et al. 2015

General population (n=1,024 children)

0.16 and 0.42 ng/mL 

(maternal mean PFDeA in 

Ukraine and Greenland 

cohorts)

Ever having asthma OR 0.92 (0.73–1.16), whole cohort 

Ever having eczema OR 0.88 (0.73–1.06), whole cohort

Current eczema OR 0.95 (0.75–1.20), whole cohort

Ever having wheezing OR 0.85 (0.70–1.01), whole cohort

Current wheezing OR 0.76 (0.56–1.04), whole cohort

Zhu et al. 2016

General population (n=231 asthmatic and 

225 non-asthmatic children)

This is the same group of children 

evaluated by Dong et al. (2013)

1.24 and 1.02 ng/mL (mean in 

asthmatics and nonasthmatics)

Asthma diagnosis OR 3.45 (1.51–7.88)*, males 4th quartile

OR 3.68 (1.43–9.48)*, females 4th

quartile

T-helper cytokines

IL-4

IL-5

IFN-γ

IL-2

NS (p>0.05 for trend)

NS (p>0.05 for trend)

NS (p>0.05 for trend)

NS (p>0.05 for trend)

Serum IgE Association (p=0.002 for trend)*

PFUA

Kielsen et al. 2016

General population (n=12 adults) 

0.21 ng/mL (median PFUA) Diphtheria antibody levels Inverse association (p=0.036)*, 

unadjusted 

Tetanus antibody levels Inverse association (p=0.039)*, 

unadjusted
PERFLUOROALKYLS 265

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Okada et al. 2014

General population (n=2,603 infants)

1.50 ng/mL (maternal mean 

PFUA)

Risk of allergic diseases

Males

Females

OR 1.13 (0.79–1.63), 4th quartile

OR 0.58 (0.39–0.86)*, 4th quartile

Eczema

Males

Females

OR 1.16 (0.75–10.81), 4th quartile

OR 0.50 (0.30–0.81)*, 4th quartile

Smit et al. 2015

General population (n=1,024 children)

0.16 and 0.68 ng/mL 

(maternal mean PFUA in 

Ukraine and Greenland 

cohorts)

Ever having asthma OR 0.96 (0.77–1.21), whole cohort 

Ever having eczema OR 0.95 (0.79–1.15), whole cohort

Current eczema OR 1.07 (0.85–1.34), whole cohort

Ever having wheezing OR 0.84 (0.70–1.00), whole cohort

Current wheezing OR 0.87 (0.65–1.17), whole cohort

PFHpA

Kielsen et al. 2016

General population (n=12 adults) 

0.12 ng/mL (median PFHpA) Diphtheria antibody levels NS (p=0.750), unadjusted 

Tetanus antibody levels NS (p=0.280), unadjusted

Smit et al. 2015

General population (n=1,024 children)

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 OR 0.93 (0.78–1.11), whole cohort

Current eczema OR 0.90 (0.70–1.15), whole cohort

Ever having wheezing OR 1.03 (0.84–1.25), whole cohort

Current wheezing 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
PERFLUOROALKYLS 266

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFBuS

Dong et al. 2013

General population (n=231 asthmatic and 

225 non-asthmatic children) 

This is the same group of children 

evaluated by Zhu et al. (2016)

0.5 and 0.5 ng/mL (mean 

serum PFBuS levels in the 

asthmatic and non-asthmatic 

children, respectively; serum 

levels were not reported for 

full cohort)

Asthma diagnosis OR 1.90 (1.08–3.37)*, 4th quartile

Asthma severity NS (p=0.092 for trend)

IgE 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 

Zhu et al. 2016

General population (n=231 asthmatic and 

225 non-asthmatic children)

This is the same group of children 

evaluated by Dong et al. (2013)

0.53 and 0.48 ng/mL (mean 

serum PFBuS in asthmatics 

and non-asthmatics)

Asthma diagnosis OR 2.59 (1.14–5.87)*, males 4th quartile

NS (p=0.505 for trend), females 

T-helper cytokines

IL-4

IL-5

IFN-γ

IL-2

NS (p>0.05 for trend)

Association (p=0.023 for trend)*

NS (p>0.05 for trend)

NS (p>0.05 for trend)

Serum IgE NS (p>0.05 for trend)

PFDoA

Dong et al. 2013

General population (n=231 asthmatic and 

225 non-asthmatic children) 

5.8 and 4.5 ng/mL (mean 

serum PFDoA levels in the 

asthmatic and non-asthmatic 

children, respectively; serum 

levels were not reported for 

full cohort)

Asthma diagnosis OR 1.81 (1.02–3.23)*, 4th quartile

Asthma severity Association (p=0.024 for trend)*

IgE 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 

Kielsen et al. 2016

General population (n=12 adults) 

0.039 ng/mL (median PFDoA) Diphtheria antibody levels Inverse association (p=0.038)*, 

unadjusted 

Tetanus antibody levels Inverse association (p=0.038)*, 

unadjusted
PERFLUOROALKYLS 267

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-16. Summary of Immunological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Okada et al. 2014

General population (n=2,603 infants)

0.188 ng/mL (maternal mean 

PFDoA)

Risk of allergic diseases

Males

Females

OR 0.93 (0.65–1.34), 4th quartile

OR 0.58 (0.39–0.85)*, 4th quartile

Eczema

Males

Females

OR 1.00 (0.64–1.55), 4th quartile

OR 0.73 (0.45–1.18), 4th quartile

Smit et al. 2015

General population (n=1,024 children)

0.04 and 0.13 ng/mL 

(maternal mean PFDoA in 

Ukraine and Greenland 

cohorts)

Ever having asthma OR 1.03 (0.81–1.30), whole cohort 

Ever having eczema OR 0.90 (0.75–1.08), whole cohort

Current eczema OR 0.88 (0.70–1.14), whole cohort

Ever having wheezing OR 0.97 (0.80–1.16), whole cohort

Current wheezing OR 0.87 (0.64–1.18), whole cohort

PFHxA

Dong et al. 2013

General population (n=231 asthmatic and 

225 non-asthmatic children) 

0.3 and 0.2 ng/mL (mean 

serum PFHxA levels in the 

asthmatic and non-asthmatic 

children, respectively; serum 

levels were not reported for 

full cohort)

Asthma diagnosis OR 1.60 (0.90–2.86), 4th quartile

Asthma severity NS (p=0.854) 

IgE NS (p>0.05), asthmatics

NS (p>0.05), non-asthmatics 

Absolute eosinophil counts NS (p>0.05), asthmatics

NS (p>0.05), non-asthmatics 

Eosinophil cationic protein NS (p>0.05), asthmatics

NS (p>0.05), non-asthmatics

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 compound; 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; 

PFBuS = perfluorobutane sulfonic acid; PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; 

PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; 

PFUA = perfluoroundecanoic acid; RR= relative risk; TNF-α =tumor necrosis factor-α
PERFLUOROALKYLS 268

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 2-6, 2-7, and 2-8. 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 and thymus 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 PFDeA. 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 was

noted that the strongest evidence is for suppression of the antibody response and increased 

hypersensitivity (PFOA only).

PFOA

Epidemiology 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 

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. However, other studies have not found 

associations between PFOA levels and the frequency of the common 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), or between maternal PFOA and the risk of number of days with cough, 

nasal discharge, diarrhea, or vomiting (Dalsager et al. 2016).
PERFLUOROALKYLS 269

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 2-19. 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 an 

altered 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 associated 

with serum PFOA levels (Kielsen et al. 2016). Increasing current serum PFOA levels were associated 

with lower antibody levels for mumps and rubella, but not for measles, in a cross-sectional study of 

adolescents (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 with 

serum 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 were 

associated 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 noted 

that 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 

Islands (Heilmann et al. 2010). Lower levels of rubella antibodies at age 3 were associated with 

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).

Epidemiology Studies—Hypersensitivity Outcomes. Of the different types of hypersensitivity effects, 

the most widely studied endpoint is asthma; the possible association between exposure to PFOA and 

asthma 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 et 

al. 2013; Humblet et al. 2014) and adults (Anderson-Mahoney et al. 2008; Zhu et al. 2016).
PERFLUOROALKYLS 270

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-19. Antibody Responses Relative to Serum PFOA Levels in Epidemiology Studies

(Presented as percent difference in antibody concentration per 2-fold increase in serum PFOA)
PERFLUOROALKYLS 271

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

However, other studies have found no association between estimated cumulative serum PFOA levels and 

incidence of asthma being treated with medication in workers (Steenland et al. 2015) or asthma in the 

general 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) or 5–

9-year-old children (Smit et al. 2015), 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), or children 5–9 years of age (Smit et al. 2015) 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 graphically presented in Figure 2-20. 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).

No association between current serum PFOA levels and risks of allergy or allergic sensitization were 

found in adults (Stein et al. 2016a). Two studies examining the possible association between current 

serum PFOA levels in adults and food allergies have found mixed results, with one study finding an

association (Buser and Scinicariello 2016) 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 IgE levels, 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 with 

asthma 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 in 

female 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 et 
PERFLUOROALKYLS 272

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-20. Risk of Asthma Diagnosis Relative to PFOA Levels (Presented as Adjusted Odds Ratios) 

1age 5–9 years 2males, age 9–16 years 3females age 9–16 years 4age 10–15 years 5age 12–19 years 6adult
PERFLUOROALKYLS 273

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

al. 2015). NTP (2016b) concluded that there is low confidence that exposure to PFOA during childhood 

is associated with increased hypersensitivity responses. 

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 with 

asthma 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 in 

female 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 et 

al. 2015). NTP (2016b) concluded that there is low confidence that exposure to PFOA during childhood 

is associated with increased hypersensitivity responses. 

Epidemiology 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, and 

multiple sclerosis). A third study examined neural- and non-neural-specific antibodies and found no 

associations 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. 

Laboratory Animal Studies. The results of several mouse studies support the epidemiology data 

suggesting 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 were 

observed 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; no 
PERFLUOROALKYLS 274

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

alterations in IgM levels were observed 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 associated 

with alterations in IgM or IgG levels in the offspring (Hu et al. 2010). Limited data suggest that 

alterations 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 affect 

the 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 to 

30 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 the 

dorsal 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 results 

of the dermal study, no increases in airway hyperresponsiveness were observed in ovalbumin-sensitized 

mice 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 and 

thymus, 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), and 

severe 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).

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 intermediate 

studies were 3.75 mg/kg/day PFOA for decreases in absolute spleen weight (DeWitt et al. 2008) and 

9.6 mg/kg/day for decreases in absolute and relative thymus weight (Loveless et al. 2008). In rats, no 
PERFLUOROALKYLS 275

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

alterations in spleen weight were observed following chronic exposure to 15 mg/kg/day in the diet (3M 

1983).

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 bone 

marrow 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 the 

greatest 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-lymphoid 

cells was observed. Significant increases in CD4-CD8- and CD4-CD8+ thymic lymphocytes were 

observed in mice exposed to 47.21 mg/kg/day for 21 days; increases in CD4+CD8+ lymphocytes were 

observed 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 and 

increases 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 in 

total 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 to 

concavalin 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 to 

Cynomolgus 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 

monkeys for 90 days induced atrophy of lymphoid follicles in the spleen and lymph nodes and slight to 

moderate hypocellularity of the bone marrow (Griffith and Long 1980). No histological alterations were 

observed 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 
PERFLUOROALKYLS 276

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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).

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 alterations 

in 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, the 

magnitudes 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 high 

confidence 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 moderate 

confidence that PFOA is associated with increased hypersensitivity.

Summary. Epidemiology studies have evaluated several aspects of immunotoxicity including 

immunosuppression, hypersensitivity, and autoimmunity. A number of general populations studies have 

found 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 tests 

of 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 or 

allergic 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 

serum PFOA and an increased risk of ulcerative colitis, but not for other autoimmune diseases. Animal 

studies suggest that the immune system is a sensitive target of PFOA toxicity. A number of studies in 

mice 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. 
PERFLUOROALKYLS 277

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFOS

Epidemiology Studies—Immunosuppression Outcomes. Several epidemiology studies have evaluated 

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). However, associations 

between the number of days with symptoms of infection and maternal PFOS levels were observed in 

children (Dalsager et al. 2016).

Other studies evaluating immunosuppression found significant alterations in the response to vaccines; the 

changes in the response to antibody levels relative to serum PFOS levels are graphically presented in 

Figure 2-21. In children receiving a tetanus vaccination at age 5, there were associations between serum 

PFOS levels at age 5 and tetanus antibody levels at age 5 (Grandjean et al. 2012) and between serum 

PFOS levels at age 7 and tetanus 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 (Grandjean et al. 2012; Mogensen et al. 2015a), or between tetanus 

antibody levels at age 14 and child PFOS levels at age 13 (Grandjean et al. 2017). Similarly, diphtheria 

antibody levels at age 7 were 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 (Grandjean et al. 2012) and antibody levels at age 13 were not associated with 

child PFOS levels at age 7 or 13 (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 were inversely associated with mumps and rubella antibody levels, but not with 

measles antibody levels (Stein et 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).
PERFLUOROALKYLS 278

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-21. Antibody Responses Relative to Serum PFOS Levels in Epidemiology Studies 

(Presented as percent difference in antibody concentration per 2-fold increase in serum PFOS)
PERFLUOROALKYLS 279

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 associated 

with increased incidence of infectious disease (or lower ability to resist or respond to infectious disease).

Epidemiology Studies—Hypersensitivity Outcomes. Several studies examined the risk of 

hypersensitivity associated with serum PFOS in children and adolescents; however, the results are 

inconsistent. In two case-control studies, increased risks of asthma were observed. Dong et al. (2013) 

reported an increased risk of asthma diagnosis and increased severity of asthma episodes in children with 

PFOS 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. 

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 olds, between maternal PFOS 

and asthma diagnosis in children in adolescence (Humblet et al. 2014; Stein et al. 2016a). Data 

evaluating associations between serum PFOS and the risk of asthma diagnosis are presented in 

Figure 2-22.

No associations between maternal PFOS and eczema, atopic dermatitis, or wheezing have been found in 

children (Granum et al. 2013; 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 Scinicariello 2016; Stein et al. 2016a) or maternal PFOS levels and food allergies in infants (Okada et 

al. 2012) were observed. However, in a cross-sectional study of adolescents, recent PFOS levels were 

associated with mold 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 with 

changes 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. 
PERFLUOROALKYLS 280

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-22. Risk of Asthma Diagnosis Relative to PFOS Levels (Presented as Adjusted Odds Ratios)

1age 5–9 years 2males, age 9–16 years 3females age 9–16 years 4age 10–15 years 5age 12–19 years

Smit et al. 2015

Zhu et al. 2016

Dong et al. 2013

Humblet et al. 2014

Stein et al. 2016a

Reference

1 SD change in maternal PFOS

2nd quartile

3rd quartile

4th quartile

2nd quartile

3rd quartile

4th quartile

2nd quartile

3rd quartile

4th quartile

doubling PFOS

doubling PFOS

shift from 25th to 75th percentile

Exposure Metric

Ever having asthma1

Asthma diagnosis2

Asthma diagnosis2

Asthma diagnosis2

Asthma diagnosis3

Asthma diagnosis3

Asthma diagnosis3

Asthma diagnosis4

Asthma diagnosis4

Asthma diagnosis4

Asthma episode in last 12 months5

Current asthma5

Current asthma5

Outcome

-1 -0.5 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 9.5

OR (95% CI)

Ever having asthma

Asthma Diagnosis

Current or Episode in last 12m
PERFLUOROALKYLS 281

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 the 

innate 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; no 

alterations were observed in mice exposed to a 20-fold lower dose.

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 and 

thymus 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). 

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 high 

confidence that exposure to PFOS is associated with suppression of the antibody response, moderate 

confidence 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 epidemiology studies have examined the potential immunotoxicity of PFOS. 

The database provides convincing evidence of an association between serum PFOS levels and 

immunosuppression, particularly impaired antibody responses to vaccines in adults and children. Mixed 

results have been observed in studies evaluating infectious disease resistance. Similarly, inconsistent 
PERFLUOROALKYLS 282

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 the 

immunotoxicity of PFOS. The strongest evidence comes from studies reported impaired antibody 

responses resulting in 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 in 

splenic and thymic cellularity and bone marrow cells.

PFHxS

Epidemiology Studies—Immunosuppression Outcomes. Several epidemiology studies have examined 

the potential of PFHxS to suppress the immune system. Altered antibody responses relative to serum 

PFHxS levels are graphically presented in Figure 2-23. Inverse associations were observed between 

tetanus antibody levels in 5 and 7 year olds and serum PFHxS levels at age 5 or 7 years (Grandjean et al. 

2012; Mogensen et al. 2015a); but there were no associations between serum PFHxS levels 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 no associations 

between diphtheria antibody levels at ages 5, 7, or 13 and serum PFHxS levels in the mother or in the 

children. A study in 3-year-old children found an inverse association between maternal PFHxS levels 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); one 

study found an association between maternal PFHxS levels and the number of episodes of gastroenteritis 

in children (Granum et al. 2013).
PERFLUOROALKYLS 283

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-23. Antibody Responses Relative to Serum PFHxS Levels in Epidemiology Studies 

(Presented as percent difference in antibody concentration per 2-fold increase in serum PFHxS)
PERFLUOROALKYLS 284

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Epidemiology Studies—Hypersensitivity Outcomes. Data evaluating associations between serum PFHxS 

and the risk of asthma diagnosis are presented in Figure 2-24. No associations were observed between 

asthma diagnosis, wheezing, and/or eczema in children and maternal serum PFHxS levels (Granum et al. 

2013; Smit et al. 2015) or with recent PFHxS levels in adolescents (Humblet et al. 2014; Okada et al. 

2014). In contrast, case-control studies in asthmatic children did find associations between recent PFHxS 

serum levels and asthma diagnosis (Dong et al. 2013; Zhu et al. 2016), but no association with asthma 

severity (Dong et al. 2013). Dong et al. (2013) also reported associations between serum PFHxS levels 

and eosinophil counts and eosinophil cationic protein levels in asthmatic children, but not in nonasthmatics. 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 to 

foods, 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; Hoberman and York 2003) 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

Epidemiology 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). Some studies 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 and 

diphtheria 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 
PERFLUOROALKYLS 285

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-24. Risk of Asthma Diagnosis Relative to PFHxS Levels (Presented as Adjusted Odds Ratios)

1age 5–9 years 2males, age 9–16 years 3females age 9–16 years 4age 10–15 years 5age 12–19 years
PERFLUOROALKYLS 286

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 2-25.

Overall, the epidemiology data do not suggest an association between decreased infectious disease 

resistance and serum 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. 

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).

Epidemiology Studies—Hypersensitivity Outcomes. Case-control studies of asthmatic children have 

reported associations between serum PFNA and asthma diagnosis (Dong et al. 2013; Zhu et al. 2016), but 

no association with asthma severity (Dong et al. 2013). However, cross-sectional or retrospective studies 

(Humblet et al. 2014; Smit et al. 2015; Stein et al. 2016a) have not found associations. Data evaluating 

associations between serum PFNA and the risk of asthma diagnosis are presented in Figure 2-26. No 

associations were found in adolescents between 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 in adolescents (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).

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 were 

observed in the serum at ≥3 mg/kg/day (Fang et al. 2009) and spleen at 5 mg/kg/day (Fang et al. 2010). 
PERFLUOROALKYLS 287

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-25. Antibody Responses Relative to Serum PFNA Levels in Epidemiology Studies 

(Presented as percent difference in antibody concentration per 2-fold increase in serum PFNA)
PERFLUOROALKYLS 288

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-26. Risk of Asthma Diagnosis Relative to PFNA Levels (Presented as Adjusted Odds Ratios)

1age 5–9 years 2males, age 9–16 years 3females age 9–16 years 4age 10–15 years 5age 12–19 years
PERFLUOROALKYLS 289

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

No alterations were observed in the response of splenic T lymphocytes to ConA at 5 mg/kg/day (Fang et 

al. 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 relative spleen weight and

splenic leukocyte counts, alterations in splenic T-lymphoctye phenotypes (increased ratios of CD4+ and 

CD8+ 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 more 

sensitive than males (Rockwell et al. 2017).

PFDeA

Epidemiology Studies—Immunosuppression Outcomes. Studies examining possible associations 

between serum PFDeA levels and response to vaccines have reported mixed results; see Figure 2-27 for a 

graphical presentation of the antibody response relative to PFDeA levels. Inverse associations were 

observed between serum PFDeA levels at age 5 and tetanus antibody levels at ages 5 and 7 (Grandjean et 

al. 2012) and serum PFDeA levels at age 7 and antibody levels at age 13 (Grandjean et al. 2017). 

Similarly, diphtheria antibody levels at age 13 were inversely associated with serum PFDeA levels at 

age 7 (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 PFDeA levels, but there 

was no association for tetanus antibody levels (Kielsen et al. 2016); this study did not adjust for potential 

confounders. In the only study examining the possible association between serum PFDeA levels and 

infectious disease resistance, no association was found between maternal serum PFDeA levels and 

symptoms of infection in children aged 1–4 years (Dalsager et al. 2016).

Epidemiology 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 
PERFLUOROALKYLS 290

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-27. Antibody Responses Relative to Serum PFDeA Levels in Epidemiology Studies 

(Presented as percent difference in antibody concentration per 2-fold increase in serum PFDeA)
PERFLUOROALKYLS 291

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

were also observed. A cross-sectional study of children did not find associations between maternal 

PFDeA 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 PFDeA levels 

(Okada et al. 2014). Data evaluating associations between serum PFDeA and the risk of asthma diagnosis 

are presented in Figure 2-28.

Laboratory Animal Studies. A single gavage dose of 80 mg/kg PFDeA 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 lymphoid 

depletion in both the thymus and spleen.

PFUA

Epidemiology Studies. Three epidemiology studies have evaluated the potential immunotoxicity of 

PFUA in humans. Kielsen et al. (2016) reported inverse associations between serum PFUA (unadjusted 

for potential confounders) and diphtheria and tetanus antibody levels in adults. No significant 

associations between maternal PFUA levels and the risk of asthma diagnosis, eczema, or wheezing were 

observed in children (Smit et al. 2015). The third study (Okada et al. 2012) found inverse associations 

between maternal serum PFUA and risk of allergies or eczema in female infants, but not in males.

PFHpA

Epidemiology Studies. In general, the two available human immunotoxicity studies did not find 

associations between serum PFHpA levels and diphtheria or tetanus antibody levels in adults (Kielsen et 

al. 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.

PFBuS

Epidemiology Studies. The epidemiology database for PFBuS consists of two case-control studies in 

asthmatic children (Dong et al. 2013; Zhu et al. 2016). Both studies reported increases in asthma 

diagnosis, but no association with serum IgE levels.
PERFLUOROALKYLS 292

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-28. Risk of Asthma Diagnosis Relative to PFDeA Levels (Presented as Adjusted Odds Ratios)

1age 5–9 years 2males, age 9–16 years 3females age 9–16 years 4age 10–15 years
PERFLUOROALKYLS 293

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Laboratory Animal Studies. No significant histological alterations were observed in spleen, thymus, or 

lymph nodes of rats administered via gavage 900 mg/kg/day 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).

PFDoA

Epidemiology Studies. Four epidemiology studies examining potential immunotoxic endpoints were 

identified. Kielsen et al. (2016) found inverse associations between recent serum PFDoA levels (not 

adjusted for potential confounders) and diphtheria and tetanus antibody levels in adults. Associations 

between serum PFDoA levels and the risk of asthma diagnosis, severity of asthma, serum IgE levels, 

absolute eosinophil counts, and eosinophil cationic protein levels were observed in a case-control study of 

asthmatic children (Dong et al. 2013). A cross-sectional study of children did not find associations 

between maternal serum PFDoA levels and risk of asthma diagnosis, eczema, or wheezing (Smit et al. 

2015). Another study did not find associations between maternal serum PFDoA levels and the risk of 

allergic disease or eczema in infants (Okada et al. 2014).

PFHxA

Epidemiology Studies. In the only epidemiology study examining potential immunotoxic endpoints, 

Dong et al. (2013) found no associations between serum PFHxA levels in asthmatic and nonasthmatic 

children and asthma diagnosis, asthma severity, or IgE levels.

2.15 NEUROLOGICAL

Overview. There are limited data on the neurotoxicity of perfluoroalkyls in humans or laboratory 

animals; epidemiology data come from two 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 294

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-17. Summary of Neurological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Gallo et al. 2013

Community (C8) (n=21,024 older adults; 

>50 years of age)

14.1–27.0 ng/mL (2nd PFOA 

quintile)

Memory loss (selfreported)OR 0.88 (0.79–0.97)*, 2nd quintile

Power et al. 2013

General population (NHANES) (n=1,766 older 

adults aged 60–<85 years)

4.08 ng/mL (median PFOA) Difficulty remembering or 

periods of confusion (selfreported)

OR 0.92 (0.78–1.09)

PFOS

Gallo et al. 2013

Community (C8) (n=21,024 older adults; 

>50 years of age)

20.5–27.1 ng/mL (3rd PFOS 

quintile)

Memory loss (selfreported)OR 0.86 (0.78–0.96)*, 3rd quintile

Power et al. 2013

General population (NHANES) (n=1,766 older 

adults aged 60–<85 years)

22.63 ng/mL (median PFOS) Difficulty remembering or 

periods of confusion (selfreported)

OR 0.90 (0.78–1.03)

PFHxS

Gallo et al. 2013

Community (C8) (n=21,024 older adults; 

>50 years of age)

5.7–232.6 ng/mL (5th PFHxS 

quintile)

Memory loss (selfreported)OR 0.89 (0.79–0.99)*, 5th quintile

Power et al. 2013

General population (NHANES) (n=1,766 older 

adults aged 60–<85 years)

2.05 ng/mL (median PFHxS) Difficulty remembering or 

periods of confusion (selfreported)

OR 0.93 (0.82–1.06)

PFNA

Gallo et al. 2013

Community (C8) (n=21,024 older adults; 

>50 years of age)

1.0–1.2 ng/mL (2nd PFNA 

quintile)

Memory loss (selfreported)OR 0.86 (0.78–0.96)*, 2nd quintile
PERFLUOROALKYLS 295

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-17. Summary of Neurological Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Power et al. 2013

General population (NHANES) (n=1,766 older 

adults aged 60–<85 years)

1.01 ng/mL (median PFNA) Difficulty remembering or 

periods of confusion (selfreported)

OR 0.91 (0.79–1.04)

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 compound; 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

1
PERFLUOROALKYLS 296

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Perfluoroalkyls, Table 11. 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. There are limited epidemiology data on the neurotoxicity of 

perfluoroalkyls. The two available studies found decreases in the risk of memory loss associated with 

serum PFOA, PFOS, PFHxS, and PFNA.

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 2-4, 2-6, 2-7, and 2-8. No morphological alterations in the brain and nerves were observed in 

studies of PFOA, PFOS, PFBuS, or PFBA. No alterations in neurological function tests were observed in 

studies of PFHxS, PFHxA, PFBA, or PFDoA. Impaired learning and memory was observed in a study of 

PFOS and decreases in grip strength were observed in a study of PFUA.

PFOA

Epidemiology 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. When 

the participants were categorized by diabetic status, the risk of memory loss was higher among the 

diabetics 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. In 

a second 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 mice 

administered up to 1,000 mg/kg PFOA via gavage and observed for 14 days (Sato et al. 2009). Exposure 

of rats to up to approximately 110 mg/kg/day PFOA via the diet for 90 days did not induce gross or 
PERFLUOROALKYLS 297

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 

1983). 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 treatmentrelated 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 morphological alterations 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

Epidemiology Studies. Two studies have examined the influence of serum PFOS levels on self-reported 

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).

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 dosed 

with 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 ultrasonic 

stimulation were observed in rats exposed to 8.5 mg/kg/day PFOS in the diet for 6 weeks (Kawamoto et 

al. 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 

PFOS for 4 weeks (Fuentes et al. 2007c). Histopathological examination of the hypothalamus in male 

Sprague-Dawley rats administered PFOS via gavage for 28 days revealed degeneration of gonadotropic 
PERFLUOROALKYLS 298

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

cells of the pituitary gland at ≥1.0 mg/kg/day and dense chromatin, condensed ribosomes, and loss of 

morphology in the hypothalamus at ≥3.0 mg/kg/day (López-Doval et al. 2014).

PFHxS

Epidemiology Studies. A decrease in the risk of self-reported memory loss was observed in older adult 

participants 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 of 

confusion 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 in 

females on postpartum day 17 (Butenhoff et al. 2009a; Hoberman and York 2003). 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

Epidemiology 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 of 

confusion (Power et al. 2013). 

PFUA

Laboratory Animal Studies. In the only study located for PFUA, a decrease in grip strength was 

observed in male and female rats administered 1.0 mg/kg/day PFUA for 41–46 days and allowed to 

recover for 14 days (Takahashi et al. 2014). No other alterations in performance on FOB tests were 

found.
PERFLUOROALKYLS 299

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFBuS

Laboratory Animal Studies. A significant decrease in tail flick latency to a thermal stimulus was 

observed in all groups of male rats administered via gavage PFBuS for 28 days. However, other tests of 

sensory reactivity to stimuli, grip strength, and motor activity were not affected (3M 2001), and the 

significance of this isolated finding is difficult to ascertain. Gross and microscopic examination of the 

brain, 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 in 

rats at PFBuS 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; van 

Otterdijk 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, pupillary 

reflex tests conducted in weeks 8 and 12 showed delayed dilation under dark conditions in rats dosed with 

30 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 considered 

biologically 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.

PFDoA

Laboratory Animal Studies. Single-dose administration of 50 mg/kg resulted in impaired performance 

on 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).
PERFLUOROALKYLS 300

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFHxA

Laboratory Animal Studies. Treatment with 100 or 200 mg/kg/day PFHxA in male and female SpragueDawley rats via gavage for 104 weeks had no effect on locomotion or performance in the FOB test 

(Klaunig et al. 2015).

2.16 REPRODUCTIVE

Overview. A number of epidemiology studies have evaluated the reproductive toxicity of perfluoroalkyls; 

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 epidemiology 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 found associations 

with PFOA, PFOS, or PFUA levels, the findings are not consistent across studies or there are too few 

studies to interpret the results. Alterations in reproductive hormone levels have not been found in studies 

of PFHxS, PFNA, PFDeA, or PFOSA. Some associations between serum perfluoroalkyls (PFOA, PFOS, 

PFHxS, PFNA, PFDeA) 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 an earlier onset of menopause would 

result in a decrease in the removal of perfluoroalkyls in menstrual blood. Epidemiology studies of PFOA 

and PFOS provide evidence of impaired fertility (increased risks of longer time to pregnancy and 

infertility); there is also some evidence for PFHxS and PFNA, but the results are not consistent across

studies. The small number of studies evaluating fertility for PFDeA, PFUA, PFOSA, Me-PFOSA-AcOH, 

and Et-PFOSA-AcOH did not find associations.

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 
PERFLUOROALKYLS 301

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Olsen et al. 1998b

Occupational (n=111 males in 1993 and 

80 males in 1995)

0–80,000 ng/mL (PFOA 

range)

Prolactin Association (p=0.01 for trend)*, 

1993

NS (p=0.58 for trend), 1995

Estradiol NS (p=0.66 and 0.56 for trend), 1993 

and 1995

17α-Hydroxyprogesterone NS (p=0.21 and 0.18 for trend), 1993 

and 1995

Bound testosterone NS (p=0.07 and 0.85 for trend), 1993 

and 1995

Free testosterone. NS (p=0.15 or 0.82 for trend), 1993 

and 1995

Sakr et al. 2007b

Occupational (n=1,025)

428 ng/mL (mean PFOA) Estradiol Association (p=0.017)*, males

Testosterone Association (p=0.034)*, males

Knox et al. 2011

Community (C8) (n=25,957 women)

11.3–19.8 ng/mL (2nd PFOA 

quintile)

Estradiol concentration NS (p>0.05), menopausal and 

perimenopausal subgroups

Barrett et al. 2015

General population (n=178 women)

3.61 and 2.31 ng/mL (mean 

PFOA in nulliparous and 

parous women)

Follicular estradiol NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Luteal progesterone NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Joensen et al. 2013

General population (n=247 young men; mean 

age 19.6 years)

3.46 ng/mL (mean PFOA) Total testosterone NS (p>0.05)

Free testosterone NS (p>0.05)

Free androgen index NS (p>0.05)

LH NS (p>0.05)

Estradiol NS (p>0.05)

SHBG NS (p>0.05)

FSH NS (p>0.05)
PERFLUOROALKYLS 302

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Raymer et al. 2012

General population (n=256 men)

10.4 ng/mL (mean PFOA) Estradiol NS (p=0.751)

Prolactin NS (p=0.349)

FSH NS (p=0.581)

LH Correlation (p=0.011)*

Free testosterone Correlation (p=0.015)*

Total testosterone NS (p=0.440)

Specht et al. 2012

General population (n=604 men)

1.3–4.8 (range of PFOA 

means of different sites)

SHBG NS (p=0.39 for trend)

Tsai et al. 2015

General population (n=540 adolescents and 

young adults aged 12–30 years)

2.74 ng/mL (geometric mean 

PFOA)

SHGB Association (p<0.05)*, females 12–

17 years old

FSH NS (p>0.05)

Testosterone NS (p>0.05)

Vested et al. 2013

General population (n=169 males aged 19–

21 years)

3.8 ng/mL (median maternal 

PFOA) 

Testosterone NS (p>0.05)

Estradiol NS (p>0.05)

Inhibin B NS (p>0.05)

SHBG NS (p>0.05)

Free antigen index NS (p>0.05)

LH Association (p=0.03)*

FSH Association (p=0.01)*

PFOS

Olsen et al. 1998a

Occupational (n=327)

1,480–2,440 ng/mL (range of 

PFOS means at different time 

periods)

DHEAS NS (p=0.60)

FSH NS (p=0.91)

17-HP NS (p=0.99)

LH NS (p=0.69)

Prolactin NS (p=0.25)

SHBG NS (p=0.77)

Free testosterone NS (p=0.90)
PERFLUOROALKYLS 303

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Bound testosterone NS (p=035)

Estradiol NS (p=0.14), after removal of 1 outlier

Knox et al. 2011

Community (C8) (n=25,957 women)

11.9–17.0 and 17.1–

22.4 ng/mL (2nd and 3rd PFOS 

quintiles)

Estradiol concentration 

Perimenopausal 

subgroup

Menopausal subgroup

Inverse association (p=0.0001)*

Inverse association (p=0.007)*

Barrett et al. 2015

General population (n=178 women)

16.44 and 14.18 ng/mL 

(mean PFOS in nulliparous 

and parous women)

Follicular estradiol 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

Luteal progesterone NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Joensen et al. 2013

General population (n=247 young men; mean 

age 19.6 years)

8.46 ng/mL (mean PFOS) Total testosterone Inverse association (p<0.05)*

Free testosterone Inverse association (p<0.05)*

Free androgen index Inverse association (p<0.05)*

LH NS (p>0.05)

Estradiol NS (p>0.05)

SHBG NS (p>0.05)

FSH NS (p>0.05)

Raymer et al. 2012

General population (n=256 men)

37.4 ng/mL (mean PFOS) Estradiol NS (p>0.05)

Prolactin NS (p>0.05)

FSH NS (p>0.05)

LH NS (p>0.05)

Free testosterone NS (p>0.05)

Total testosterone NS (p>0.05)
PERFLUOROALKYLS 304

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Tsai et al. 2015

General population (n=540 male and female 

adolescents and young adults aged 12–

30 years)

7.78 ng/mL (geometric mean 

PFOS)

SHGB NS (p>0.05)

FSH Inverse association (p<0.05)*, males 

12–17 years old

Testosterone Inverse association (p<0.05)*, 

females 12–17 years old

Vested et al. 2013

General population (n=169 males aged 19–

21 years)

21.2 ng/mL (median maternal 

PFOS) 

Testosterone NS (p>0.05)

Estradiol NS (p>0.05)

Inhibin B NS (p>0.05)

SHBG NS (p>0.05)

Free antigen index NS (p>0.05)

LH NS (p>0.05) 

FSH NS (p>0.05) 

PFHxS

Barrett et al. 2015

General population (n=178 women)

1.22 and 1.65 ng/mL (mean 

PFHxS in nulliparous and 

parous women)

Follicular estradiol NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Luteal progesterone NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Joensen et al. 2013

General population (n=247 young men; mean 

age 19.6 years)

0.81 ng/mL (mean PFHxS) Total testosterone NS (p>0.05)

Free testosterone NS (p>0.05)

Free androgen index NS (p>0.05)

LH NS (p>0.05)

Estradiol NS (p>0.05)

SHBG NS (p>0.05)

FSH NS (p>0.05)
PERFLUOROALKYLS 305

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFNA

Barrett et al. 2015

General population (n=178 women)

0.67 and 0.60 ng/mL (mean 

PFNA in nulliparous and 

parous women)

Follicular estradiol NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Luteal progesterone NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Joensen et al. 2013

General population (n=247 young men; mean 

age 19.6 years)

1.23 ng/mL (mean PFNA) Total testosterone NS (p>0.05)

Free testosterone NS (p>0.05)

Free androgen index NS (p>0.05)

LH NS (p>0.05)

Estradiol Association (p<0.05)*

SHBG NS (p>0.05)

FSH NS (p>0.05)

Tsai et al. 2015

General population (n=540 male and female 

adolescents and young adults aged 12–

30 years)

1.10 ng/mL (geometric mean 

PFNA)

SHBG NS (p>0.05)

FSH NS (p>0.05)

Testosterone NS (p>0.05)

PFDeA

Barrett et al. 2015

General population (n=178 women)

0.25 and 0.24 ng/mL (mean 

PFDoA in nulliparous and

parous women)

Follicular estradiol NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Luteal progesterone NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts
PERFLUOROALKYLS 306

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Joensen et al. 2013

General population (n=247 young men; mean 

age 19.6 years)

0.38 ng/mL (mean PFDeA) Total testosterone NS (p>0.05)

Free testosterone NS (p>0.05)

Free androgen index NS (p>0.05)

LH NS (p>0.05)

Estradiol NS (p>0.05)

SHBG NS (p>0.05)

FSH NS (p>0.05)

PFUA

Barrett et al. 2015

General population (n=178 women)

0.40 and 0.42 ng/mL (mean 

PFUA in nulliparous and parous 

women)

Follicular estradiol NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Luteal progesterone NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Tsai et al. 2015

General population (n=540 males and females

aged 12–30 years)

5.84 ng/mL (geometric mean 

PFUA)

SHBG NS (p>0.05)

FSH Inverse association (p<0.05)*, 

females 12–17 years old

Testosterone NS (p>0.05)
PERFLUOROALKYLS 307

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-18. Summary of Alterations in Reproductive Hormone Levels in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOSA

Barrett et al. 2015

General population (n=178 women)

0.25 and 0.23 ng/mL (mean 

PFOSA in nulliparous and 

parous women)

Follicular estradiol NS (95% CI included unity), whole 

cohort and parous and nulliparous 

subcohorts

Luteal progesterone NS (95% CI included unity), whole 

cohort 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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

CI = confidence interval; DHEAS = dihydroepiandrosterone sulfate; FSH = follicle stimulating hormone; LH = luteinizing hormone; NS = not significant; 

PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; 

PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid; SHBG = sex hormone binding globulin
PERFLUOROALKYLS 308

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-19. Summary of Male Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Buck Louis et al. 2015

General population (n=96 Michigan and 366 in 

Texas)

4.6 and 5.3 ng/mL (median 

PFOA in Michigan and 

Texas)

Sperm viability NS (p>0.05)

Sperm count NS (p>0.05)

Sperm motility

↑ curvilinear velocity

Other parameters

Association (p<0.05)*

NS (p>0.05)

Sperm morphology

↑ percentage of sperm 

head acrosome area

↓ percentage sperm 

with coiled tails

Other parameters

Association (p<0.05)*

Association (p<0.05)*

NS (p<0.05)

Joensen et al. 2013

General population (n=247 young men; mean 

age of 19.6 years)

3.46 ng/mL (mean PFOA) Sperm volume NS (p>0.05)

Sperm concentration NS (p>0.05)

Sperm count NS (p>0.05)

Percentage progressive 

motile sperm

NS (p>0.05)

Sperm morphology NS (p>0.05)

Kvist et al. 2012

General population (n=588 men)

1.91–5.19 ng/mL (range of 

PFOA means)

Y-X chromosome ratio NS (p>0.05)

Raymer et al. 2012

General population (n=256 men)

10.4 ng/mL (mean PFOA) Semen volume NS (p>0.05)

Semen pH NS (p>0.05)

Sperm motility NS (p>0.05)

Sperm concentration NS (p>0.05)

Toft et al. 2012

General population (n=588 males)

3.8 ng/mL (median PFOA) ↑ percent motile sperm Association (p<0.05)*

Sperm concentration NS (p>0.05)

Sperm volume NS (p>0.05)

Sperm count NS (p>0.05)

Sperm morphology NS (p>0.05)
PERFLUOROALKYLS 309

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-19. Summary of Male Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Vested et al. 2013

General population (n=169 males aged 19–

21 years)

3.8 ng/mL (median maternal 

PFOA) 

Sperm concentration Inverse association (p=0.01)* 

Total sperm count Inverse association (p=0.001)*

Semen volume NS (p>0.05)

Percentage progressive 

spermatozoa

NS (p>0.05)

Percentage 

morphologically normal 

spermatozoa

NS (p>0.05)

Mean testicular volume NS (p>0.05)

PFOS

Buck Louis et al. 2015

General population (n=96 Michigan and 366 in 

Texas)

19.15 and 21.6 ng/mL 

(median PFOS in Michigan 

and Texas)

Sperm viability NS (p>0.05)

Sperm count NS (p>0.05)

Sperm motility

↑ distance travelled

Other parameters

Association (p<0.05)*

NS (p>0.05)

Sperm morphology NS (p<0.05)

Joensen et al. 2013

General population (n=247 young men; mean 

age of 19.6 years)

8.46 ng/mL (mean PFOS) Sperm volume NS (p>0.05)

Sperm concentration NS (p>0.05)

Sperm count NS (p>0.05)

Percentage progressive 

motile sperm

NS (p>0.05)

Kvist et al. 2012

General population (n=588 men)

8.20–51.65 ng/mL (range of 

mean PFOS)

51.65 ng/mL (mean for 

Greenland subcohort)

Y-X chromosome ratio Association (p<0.05)*, whole cohort

Inverse association (p=0.044 for 

trend)*, Greenland subcohort

Raymer et al. 2012

General population (n=256 men)

37.4 ng/mL (mean PFOS) Semen volume NS (p>0.05)

Semen pH NS (p>0.05)

Sperm motility NS (p>0.05)

Sperm concentration NS (p>0.05)
PERFLUOROALKYLS 310

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-19. Summary of Male Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Toft et al. 2012

General population (n=588 males)

18.4 ng/mL (median PFOS) Percent motile sperm NS (p>0.05)

Sperm concentration NS (p>0.05)

Sperm volume NS (p>0.05)

Sperm count NS (p>0.05)

Percent normal sperm Inverse association (p<0.05)*

Vested et al. 2013

General population (n=169 males aged 19–

21 years)

21.2 ng/mL (median 

maternal PFOS) 

Sperm concentration NS (p>0.05) 

Total sperm count NS (p>0.05)

Semen volume NS (p>0.05)

Percentage progressive 

spermatozoa

NS (p>0.05)

Percentage 

morphologically normal 

spermatozoa

NS (p>0.05)

Mean testicular volume NS (p>0.05)

PFHxS

Joensen et al. 2013

General population (n=247 young men; mean 

age of 19.6 years)

0.81 ng/mL (mean PFHxS) Sperm volume NS (p>0.05)

Sperm concentration NS (p>0.05)

Sperm count NS (p>0.05)

Percentage progressive 

motile sperm

NS (p>0.05)

Sperm morphology NS (p>0.05)

Toft et al. 2012

General population (n=588 males)

1.1 ng/mL (median PFHxS) Percent motile sperm NS (p>0.05)

Sperm concentration NS (p>0.05)

Sperm volume NS (p>0.05)

Sperm count NS (p>0.05)

Percent normal sperm Inverse association (p<0.05)*
PERFLUOROALKYLS 311

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-19. Summary of Male Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFNA

Buck Louis et al. 2015

General population (n=96 Michigan and 366 in 

Texas)

1.0 and 1.65 ng/mL (median 

PFNA in Michigan and 

Texas)

Sperm viability NS (p>0.05)

Sperm count NS (p>0.05)

Sperm motility NS (p>0.05)

Sperm morphology

↑ percentage of normal 

sperm 

↓ percentage sperm 

with coiled tails

Other parameters

Association (p<0.05)*

Association (p<0.05)*

NS (p<0.05)

Joensen et al. 2013

General population (n=247 young men; mean 

age of 19.6 years)

1.23 ng/mL (mean PFNA) Sperm volume NS (p>0.05)

Sperm concentration NS (p>0.05)

Sperm count NS (p>0.05)

Percentage progressive 

motile sperm

NS (p>0.05)

Sperm morphology NS (p>0.05)

Toft et al. 2012

General population (n=588 males)

1.2 ng/mL (median PFNA) Percent motile sperm NS (p>0.05)

Sperm concentration NS (p>0.05)

Sperm volume NS (p>0.05)

Sperm count NS (p>0.05)

Percent normal sperm NS (p>0.05)

PFDeA

Buck Louis et al. 2015

General population (n=96 Michigan and 366 in 

Texas)

0.3 and 0.5 ng/mL (median 

PFDeA in Michigan and 

Texas)

Sperm viability NS (p>0.05)

Sperm count NS (p>0.05)

Sperm motility NS (p>0.05)

Sperm morphology

↑ sperm head length 

↓ percentage sperm 

with coiled tails

Other parameters

Association (p<0.05)*

Association (p<0.05)*

NS (p<0.05)
PERFLUOROALKYLS 312

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-19. Summary of Male Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Joensen et al. 2013

General population (n=247 young men; mean 

age of 19.6 years)

0.38 ng/mL (mean PFDeA) Sperm volume NS (p>0.05)

Sperm concentration NS (p>0.05)

Sperm count NS (p>0.05)

Percentage progressive 

motile sperm

NS (p>0.05)

Sperm morphology NS (p>0.05)

Me-PFOSA-AcOH

Buck Louis et al. 2015

General population (n=96 Michigan and 366 in 

Texas)

0.4 and 0.25 ng/mL (median 

Me-PFOSA-AcOH in Michigan 

and Texas)

Sperm viability NS (p>0.05)

Sperm count NS (p>0.05)

Sperm motility NS (p>0.05)

Sperm morphology

↑ percentage of 

neck/midpiece 

abnormalities

↑ immature sperm

Other parameters

Association (p<0.05)*

Association (p<0.05)*

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

Me-PFOSA-AcOH = 2-(N-methyl-perfluorooctane sulfonamide) acetic acid; NS = not significant; PFDeA = perfluorodecanoic acid; PFHxS = perfluorohexane 

sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid
PERFLUOROALKYLS 313

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-20. Summary of Female Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Dhingra et al. 2016a

Community (C8) (n=8,759; retrospective 

analysis)

>2,130 ng/mL∙year 

(cumulative PFOA exposure 

5th quintile)

Menopause age HR 1.11 (0.97–1.26, p=0.14), 

5th quintile

Early menopause risk 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 

Dhingra et al. 2016a

Community (C8) (n=3,334, prospective analysis)

>4,670 ng/mL∙year 

(cumulative PFOA exposure 

5th quintile)

>80.8 ng/mL (measured 5th

PFOA quintile)

Menopause age 

(cumulative)

HR 1.10 (0.84–1.43, p=0.51), 

5th quintile

Menopause age 

(measured)

HR 1.12 (0.86–1.45, p=0.40), 

5th quintile

Knox et al. 2011b

Community (C8) (n=25,957)

11.3–19.8 ng/mL (2nd PFOA 

quintile)

Early menopause risk 

(menopausal subgroup)

OR 1.5 (1.1–2.1)*, 2nd quintile

Early menopause risk 

(perimenopausal 

subgroup)

OR 1.4 (1.1–1.8)*, 2nd quintile

Buck Louis et al. 2012

General population (n=473)

2.65 and 2.15 ng/mL 

(geometric mean PFOA in 

women with or without 

endometriosis)

Endometriosis OR 1.89 (1.17–3.06)*, without parity 

adjustment

OR 1.62 (0.99–2.66), with parity 

adjustment

Risk of moderate to 

severe endometriosis

OR 2.58 (1.18–5.64)*, without parity 

adjustment

OR 1.86 (0.81–4.24) with parity 

adjustment

Fei et al. 2010

General population (n=1,347 pregnant women)

3.91–5.20 ng/mL (2nd quartile 

for maternal PFOA)

Breastfeeding duration 

≤3 months

OR 1.98 (1.17–3.24)*, 2nd quartile

Breastfeeding duration 

≤6 months

OR 1.88 (1.31–2.72)*, 2nd quartile
PERFLUOROALKYLS 314

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-20. Summary of Female Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Lyngsø et al. 2014

General population (n=1,623 pregnant women) 

1.5 ng/mL (median PFOA) Irregular menstrual cycle OR 1.4 (0.9–2.2)

Long menstrual cycle OR 1.7 (1.1–2.6)*

Short menstrual cycle OR 0.7 (0.3–1.5)

Romano et al. 2016

General population (n=336 women) 

5.5–7.6 ng/mL (maternal 

3rd quartile PFOA)

Breastfeeding duration 

≤3 months

RR 1.63 (1.16–2.28)*, 3rd quartile

Breastfeeding duration 

≤6 months

RR 1.38 (1.06–1.79)*, 3rd quartile

Taylor et al. 2014

General population (n=2,151 women)

>2.5–4.4 and >4.4 ng/mL 

(2nd and 3rd PFOA tertiles)

Menopause HR 1.36 (1.05–1.75)*, 3rd tertile 

Hysterectomy HR 1.83 (1.31–2.56)*, 2nd tertile

Vagi et al. 2014 

General population (n=52 cases and 

50 controls)

4.1 and 2.3 ng/mL (geometric 

mean PFOA for cases and 

controls)

Polycystic ovary 

syndrome risk

OR 6.93 (1.79–29.92, p=0.003)*, 

3rd tertile

PFOS

Knox et al. 2011b

Community (C8) (n=25,957)

11.9–17.0 and 17.1–

22.4 ng/mL (2nd and 3rd PFOS 

quintiles)

Early menopause risk 

(menopausal subgroup)

OR 1.5 (1.1–2.1)*, 2nd quintile

Early menopause risk 

(perimenopausal 

subgroup)

OR 1.1 (1.1–1.8)*, 3rd quintile

Buck Louis et al. 2012

General population (n=473)

7.20 and 6.11 ng/mL 

(geometric mean PFOS in 

women with or without 

endometriosis)

Endometriosis OR 1.39 (0.98–1.98), without parity 

adjustment

OR 1.25 (0.87–1.80), with parity 

adjustment

Risk of moderate to 

severe endometriosis

OR 1.86 (1.05–3.30)*, without parity 

adjustment

OR 1.50 (0.82–2.74) with parity 

adjustment

Fei et al. 2010

General population (n=1,347 pregnant women)

3.91–5.20 ng/mL (2nd quartile 

for maternal PFOA)

Breastfeeding duration 

≤3 months

OR 1.89 (1.19–3.01)*, 4th quartile

Breastfeeding duration 

≤6 months

OR 1.56 (1.10–2.22)*, 2nd quartile
PERFLUOROALKYLS 315

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-20. Summary of Female Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Lyngsø et al. 2014

General population (n=1,623 pregnant women) 

8.0 ng/mL (median PFOS) Irregular menstrual cycle OR 1.0 0.6–1.6)

Long menstrual cycle OR 0.7 (0.4–1.2)

Short menstrual cycle OR 0.7 (0.3–1.5)

Romano et al. 2016

General population (n=336 women) 

13.9 ng/mL (maternal median 

PFOS)

Breastfeeding duration 

≤3 months

NS (p=0.065 for trend) 

Breastfeeding duration 

≤6 months

NS (p=0.111 for trend)

Taylor et al. 2014

General population (n=2,151 women)

>9–18.4 and >18.4 ng/mL 

(2nd and 3rd PFOS tertiles)

Menopause HR 1.16 (0.91–1.48), 3rd tertile 

Hysterectomy HR 1.44 (1.12–1.85)*, 2nd tertile

Vagi et al. 2014

General population (n=52 cases and 

50 controls)

8.2 and 4.9 ng/mL (geometric 

mean PFOS for cases and 

controls)

Polycystic ovary 

syndrome risk

OR 5.79 (1.58–24.12, p=0.005)*, 

3rd tertile

PFHxS

Buck Louis et al. 2012

General population (n=473)

0.48 and 0.43 ng/mL 

(geometric mean PFHxS in 

women with or without 

endometriosis)

Endometriosis OR 1.14 (0.58–2.24), without parity 

adjustment

OR 0.85 (0.42–1.73), with parity 

adjustment

Risk of moderate to 

severe endometriosis

OR 2.12 (0.85–5.27), without parity 

adjustment

OR 1.24 (0.47–3.31) with parity 

adjustment

Romano et al. 2016

General population (n=336 women) 

1.5 ng/mL (maternal median 

PFHxS)

Breastfeeding duration 

≤3 months

NS (p=0.124 for trend) 

Breastfeeding duration 

≤6 months

NS (p=0.087 for trend)

Taylor et al. 2014

General population (n=2,151 women)

>0.9–1.8 and >1.8 ng/mL 

(2nd and 3rd PFHxS tertiles)

Menopause HR 1.42 (1.08–7.87)*, 2nd tertile 

Hysterectomy HR 2.22 (1.66–2.98)*, 2nd tertile
PERFLUOROALKYLS 316

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-20. Summary of Female Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Vagi et al. 2014

General population (n=52 cases and 

50 controls)

1.1 and 0.7 ng/mL (geometric 

mean PFHxS for cases and 

controls)

Polycystic ovary 

syndrome risk

OR 1.20 (0.35–4.07), 3rd tertile

PFNA

Buck Louis et al. 2012

General population (n=473)

0.69 and 0.58 ng/mL 

(geometric mean PFNA in 

women with or without 

endometriosis)

Endometriosis OR 2.20 (1.02–4.75)*, without parity 

adjustment

OR 1.99, 0.91–4.33), with parity 

adjustment

Risk of moderate to 

severe endometriosis

OR 1.21 (0.35–4.19), without parity 

adjustment

OR 0.99 (0.27–3.65) with parity 

adjustment

Romano et al. 2016

General population (n=336 women) 

0.9 ng/mL (maternal median 

PFNA)

Breastfeeding duration 

≤3 months

NS (p=0.591 for trend) 

Breastfeeding duration 

≤6 months

NS (p=0.349 for trend)

Taylor et al. 2014

General population (n=2,151 women)

>0.80–1.5 and >1.5 ng/mL 

(2nd and 3rd PFNA tertiles)

Menopause HR 1.47 (1.14–1.90)*, 3rd tertile 

Hysterectomy HR 1.39 (1.08–1.80)*, 2nd tertile

Vagi et al. 2014

General population (n=52 cases and 

50 controls)

1.2 and 0.9 ng/mL (geometric 

mean PFNA for cases and 

controls)

Polycystic ovary 

syndrome risk

OR 2.25 (0.67–8.00), 3rd tertile
PERFLUOROALKYLS 317

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-20. Summary of Female Reproductive Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFDeA

Buck Louis et al. 2012

General population (n=473)

0.20 and 0.18 ng/mL 

(geometric mean PFDeA in 

women with or without 

endometriosis)

Endometriosis OR 2.95 (0.72–12.1), without parity 

adjustment

OR 2.60 (0.62–10.9), with parity 

adjustment

Risk of moderate to 

severe endometriosis

OR 0.72 (0.06–8.09), without parity 

adjustment

OR 0.58 (0.04–7.42) with parity 

adjustment

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

HR = hazard ratio; OR = odds ratio; NS = not significant; PFDeA = perfluorodecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic 

acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; RR = risk ratio
PERFLUOROALKYLS 318

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-21. Summary of Fertility Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Bach et al. 2015a

General population (n=1,372 pregnant women)

2.0 ng/ml (median maternal

PFOA)

Fecundability FR 1.00 (0.99–1.01), per 0.1 ng/mL

Infertility risk OR 1.00 (0.98–1.01), per 0.1 ng/mL

Bach et al. 2015b, 2015c

General population (n=440 pregnant women)

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 subgroup

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

Bach et al. 2015b, 2015c

(re-analysis of Fei et al. 2009, 2012 data)

General population (n=1,161 pregnant women)

4.1–5.4 ng/mL (2nd PFOA 

quartile)

7.2–41.5 ng/mL (4th PFOA 

quartile)

Fecundability

Parous subgroup

Nulliparous subgroup

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

Infertility 

Parous subgroup

Nulliparous subgroup

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

Fei et al. 2009

General population (n=1,240 pregnant women)

3.91–5.20 ng/mL (2nd PFOA 

quartile, maternal)

Fecundability FOR 0.72 (0.57–0.90)*, 2nd quartile

Infertility OR 2.06 (1.22–3.51)*, 2nd quartile

Fei et al. 2012 

(re-analysis of Fei et al. 2009 data)

General population (n=1,240 pregnant women)

3.91–5.20 and ≥6.97 ng/mL 

(2nd and 4th PFOA quartiles, 

maternal)

Fecundability

Parous subgroup

Nulliparous subgroup

FOR 0.61 (0.46–0.80)*, 2nd quartile

FOR 0.63 (0.39–1.04), 4th quartile

Infertility

Parous subgroup

Nulliparous subgroup

OR 3.39 (1.75–6.53)*, 2nd quartile

OR 1.30 (0.52–3.21; p=0.082 for 

trend), 4th quartile

Jørgensen et al. 2014a, 2014b

General population (n=938 pregnant women) 

1.65 ng/mL (median PFOA) Fecundability

Primiparous subgroup

FR1.04 (0.87–1.25) 

FR 1.31 (1.03–1.68)*

Infertility OR 1.11 (0.74–1.66) 

Vélez et al. 2015

General population (n=1,743 pregnant women)

1.7 ng/mL (median maternal 

PFOA)

Fecundability FOR 0.89 (0.83–0.94, p<0.001)* 

Infertility OR 1.31 (1.11–1.53, p=0.001)*
PERFLUOROALKYLS 319

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-21. Summary of Fertility Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Vestergaard et al. 2012

General population (n=222 nulliparous couples)

5.58 and 5.61 ng/mL 

(median PFOA in women 

with no pregnancy and 

pregnant)

Fecundability OR 1.18 (0.78–1.78)

Not becoming pregnant 

within first six cycles

OR 1.21 (0.67–2.18)

Whitworth et al. 2012b

General population (n=416 subfecund pregnant 

women and 474 controls)

1.66–2.24, 2.25–3.02, and 

≥3.02 ng/mL (2nd, 3rd, and 

4th PFOA quartiles)

Infertility

Parous subgroup

Primiparous subgroup

OR 1.6 (1.1–2.3)*, 2nd quartile

OR 2.4 (1.4–4.1)*, 3rd quartile

OR 0.5 (0.2–1.2), 4th quartile

PFOS

Bach et al. 2015a

General population (n=1,372 pregnant women)

8.3 ng/ml (median maternal 

PFOS)

10.85–36.10 ng/mL 

(4th PFOS quartile)

Fecundability FR 1.09 (0.92–1.30), 4th quartile

Infertility risk OR 0.71 (0.47–1.07), 4th quartile

Bach et al. 2015b, 2015c

General population (n=440 pregnant women)

36.3–103.8 ng/mL (4th PFOS 

quartile)

Fecundability

Parous subgroup

Nulliparous subgroup

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

Infertility 

Parous subgroup

Nulliparous subgroup

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

Bach et al. 2015b, 2015c

(re-analysis of Fei et al. 2009, 2012 data)

General population (n=1,161)

27.0–34.2, 34.3–43.8, and 

43.9–106.7 ng/mL (2nd, 3rd, 

and 4th PFOS quartiles)

Fecundability

Parous subgroup

Nulliparous subgroup

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

Infertility 

Parous subgroup

Nulliparous subgroup

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

Fei et al. 2009

General population (n=1,240 pregnant women)

26.1–33.3 ng/mL (2nd PFOS 

quartile, maternal)

Fecundability OR 0.70 (0.56–0.87)*, 2nd quartile

Infertility OR 1.70 (1.01–2.86)*, 2nd quartile
PERFLUOROALKYLS 320

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-21. Summary of Fertility Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Fei et al. 2012 

(re-analysis of Fei et al. 2009 data)

General population (n=1,240 pregnant women)

26.1–33.3 and 33.4–43.2 

ng/mL (2nd and 3rd PFOS 

quartiles, maternal)

Fecundability

Parous subgroup

Nulliparous subgroup

NS (p=0.32 for trend)

FOR 0.63 (0.43–0.91)*, 3rd quartile

Infertility

Parous subgroup

Nulliparous subgroup

NS (p=0.26 for trend)

OR 2.50 (1.16–5.37, p=0.36 for 

trend)*, 3rd quartile

Jørgensen et al. 2014a, 2014b

General population (n=938 pregnant women) 

10.60 ng/mL (median PFOS) Fecundability FR 0.90 (0.76–1.07) 

Infertility OR 1.39 (0.93–2.07) 

Vélez et al. 2015

General population (n=1,743 pregnant women)

4.7 ng/mL (median maternal 

PFOS)

Fecundability FOR 0.96 (0.91–1.02, p=0.17)

Infertility OR 1.14 (0.98–1.34, p=0.09)

Vestergaard et al. 2012

General population (n=222 nulliparous couples)

35.75 and 36.29 ng/mL 

(median PFOS in women 

with no pregnancy and 

pregnant)

Fecundability NS (p=0.29)

Not becoming pregnant 

within first six cycles

OR 0.98 (0.54–1.77)

Whitworth et al. 2012b

General population (n=416 subfecund women 

and 474 controls)

10.34–16.60 and 

≥16.61 ng/mL (3rd and 

4th PFOS quartile)

Infertility

Parous subgroup

Primiparous subgroup

OR 1.4 (1.0–2.0)*, 3rd quartile

OR 2.1 (1.2–3.8)*, 4th quartile

OR 0.7 (0.4–1.3), 4th quartile

PFHxS

Bach et al. 2015a

General population (n=1,372 pregnant women)

0.5 ng/ml (median maternal 

PFHxS)

Fecundability FR 1.00 (0.99–1.01), per 0.1 ng/mL

Infertility risk OR 0.98 (0.93–1.03), per 0.1 ng/mL

Jørgensen et al. 2014a, 2014b

General population (n=938 pregnant women) 

1.94 ng/mL (median PFHxS) Fecundability FR 0.97 (0.85–1.11) 

Infertility OR 0.99 (0.73–1.33) 

Vélez et al. 2015

General population (n=1,743 pregnant women)

1 ng/mL (median maternal 

PFHxS)

Fecundability FOR 0.91 (0.86–0.97, p=0.002)* 

Infertility OR 1.27 (1.09–1.48, p=0.003)*
PERFLUOROALKYLS 321

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-21. Summary of Fertility Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Vestergaard et al. 2012

General population (n=222 nulliparous couples)

1.12 and 1.22 ng/mL 

(median PFHxS in women 

with no pregnancy and 

pregnant)

Fecundability OR 1.33 (1.01–1.75)*

Not becoming pregnant 

within first six cycles

OR 0.67 (0.37–1.20)

PFNA

Bach et al. 2015a

General population (n=1,372 pregnant women)

0.8 ng/mL (median maternal) Fecundability FR 1.00 (0.98–1.02), per 0.1 ng/mL

Infertility risk OR 0.99 (0.95–1.03), per 0.1 ng/mL

Jørgensen et al. 2014a, 2014b

General population (n=938 pregnant women) 

0.64 ng/mL (median PFNA) Fecundability

Primiparous subgroup

FR 0.80 (0.69–0.94)* 

FR 0.99 (0.88–1.22)

Infertility OR 1.53 (1.08–2.15)*

Vestergaard et al. 2012

General population (n=222 nulliparous couples)

0.45 and 0.51 ng/mL 

(median PFNA in women 

with no pregnancy and 

pregnant)

Fecundability OR 1.17 (0.88–1.54)

Not becoming pregnant 

within first six cycles

OR 0.67 (0.37–1.25)

PFDeA

Bach et al. 2015a

General population (n=1,372 pregnant women)

0.3 ng/mL (median maternal 

PFDeA)

Fecundability FR 1.00 (0.97–1.03), per 0.1 ng/mL

Infertility risk OR 0.99 (0.92–1.07), per 0.1 ng/mL

Vestergaard et al. 2012

General population (n=222 nulliparous couples)

0.10 and 0.11 ng/mL 

(median PFDeA in women 

with no pregnancy and 

pregnant)

Fecundability OR 1.15 (0.89–1.49)

Not becoming pregnant 

within first six cycles

OR 0.61 (0.33–1.12)

PFUA

Bach et al. 2015a

General population (n=1,372 pregnant women)

0.3 ng/mL (median maternal 

PFUA)

Fecundability FR 1.01 (0.98–1.03), per 0.1 ng/mL

Infertility risk OR 0.98 (0.92–1.04), per 0.1 ng/mL

PFOSA

Vestergaard et al. 2012

General population (n=222 nulliparous couples)

0.10 and 0.11 ng/mL 

(median PFOSA in women 

with no pregnancy and 

pregnant)

Fecundability OR 1.01 (0.86–1.18)

Not becoming pregnant 

within first six cycles

OR 0.81 (0.45–1.46)
PERFLUOROALKYLS 322

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-21. Summary of Fertility Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Me-PFOSA-AcOH

Vestergaard et al. 2012

General population (n=222 nulliparous couples)

0.45 and 0.39 ng/mL 

(median Me-PFOSA-AcOH 

in women with no pregnancy 

and pregnant)

Fecundability OR 0.99 (0.82-–1.18)

Not becoming pregnant 

within first six cycles

OR 1.23 (0.68–2.20)

Et-PFOSA-AcOH

Vestergaard et al. 2012

General population (n=222 nulliparous couples)

2.12 and 1.79 ng/mL 

(median Et-PFOSA-AcOH in 

women with no pregnancy 

and pregnant)

Fecundability OR 0.79 (0.62–1.00)

Not becoming pregnant 

within first six cycles

OR 1.53 (0.85–2.77)

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; FOR = fecundability odds ratio; FR = fecundability ratio (probability of conceiving during a 

given menstrual cycle); OR = odds ratio; Me-PFOSA-AcOH = 2-(N-methyl-perfluorooctane sulfonamide) acetic acid; NS = not significant;

PFDeA = perfluorodecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; 

PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid
PERFLUOROALKYLS 323

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

are presented in Tables 2-1, 2-3, 2-4, 2-5, and 2-6 and in Figures 2-4, 2-6, 2-7, and 2-8. Multigeneration 

studies on PFOA, PFOS, and PFBuS have not found alterations in reproductive parameters in animals; 

similarly, no effect on fertility was observed for PFHxS. An increase in the incidence of Leydig cell 

hyperplasia (reclassified as gonodal stromal hyperplasia) has been observed in animals exposed to PFOA; 

one study for PFDoA reported ultrastructural alterations in the testes. Studies on PFOS, PFHxS, PFBuS, 

and PFBA have not found histological alterations. Delays in mammary gland development have been 

observed in mice exposed to PFOA; this effect has also been observed in perinatally exposed mice (see 

Section 2.17, Developmental).

PFOA

Epidemiology Studies—Reproductive Hormone Levels. Two studies have evaluated potential effects of 

PFOA exposure on reproductive hormone levels in workers (Olsen et al. 1998b; Sakr et al. 2007b). Sakr 

et al. (2007b) found associations between serum PFOA and estradiol and testosterone levels male workers 

at the Washington Works 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 in workers 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 young men 

(median age 19 years) (Joensen et al. 2013) or adolescents and young men (12–30 years of age) (Tsai et 

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.

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 either 

group.
PERFLUOROALKYLS 324

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Epidemiology Studies—Effects on Sperm. Six general population studies have evaluated the potential 

alterations in sperm parameters associated with PFOA exposure. Although some associations have been 

found, the results are not consistent across studies. Buck Louis et al. (2015) reported an increase in 

curvilinear 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 motile sperm in men with 

serum 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 in 

motility 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).

Epidemiology Studies—Effects on Menstrual Cycle Length, Menopause Onset, Endometriosis, and 

Breastfeeding Duration. One study examined possible associations between serum PFOA levels and 

alterations in menstrual cycle length (Lyngsø et al. 2014). 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 a continuous variable. No alterations in the risk of having a short menstrual cycle (≤24 days) or 

irregular menstrual cycles (≥7 days difference between cycles) were observed. 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) and menopausal (>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. An analysis by Taylor et 

al. (2014) of possible reverse causality showed that serum PFOA levels increased after menopause. In 

contrast, no alterations in the risk of early menopause or age of menopause were associated with 

cumulative serum PFOA levels in retrospective and prospective studies of C8 Health Study participants 

(Dhingra et al. 2016a); age of menopause was also not associated with measured serum PFOA levels in 

the prospective study (Dhingra et al. 2016a). 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 in confidence intervals that included unity. A case-control study 

(Vagi et al. 2014) found an increased risk of polycystic ovary syndrome among women with serum PFOA 

levels in the 3rd tertile.
PERFLUOROALKYLS 325

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Two studies have evaluated a possible link between maternal PFOA levels and breastfeeding duration. 

Both studies found increases in the risk of breastfeeding ≤3 or 6 months that were associated with 

maternal PFOA levels (Fei et al. 2010; Romano et al. 2016). When the women were segregated by parity, 

the associations were only found in multiparous women (Fei et al. 2010). This finding may be due to 

reverse causality since shorter breastfeeding would likely result in lower maternal transfer of PFOA.

Epidemiology Studies—Effects on Fertility. Several general population studies have examined the 

possible association between female serum PFOA levels and decreased fertility or infertility; the results 

are graphically presented in Figures 2-29 and 2-30, respectively. With the exception of the Vestergaard et 

al. (2012) study, all of the women were pregnant; thus, couples with unresolved infertility are 

underrepresented in these analyses. No studies were identified that used paternal serum PFOA levels as 

the biomarker of exposure. Most of 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 in 

fecundability and an increase in infertility were observed in women with serum PFOA (measured at 

gestation week 12) levels ≥3.91 ng/mL (Fei et al. 2009). When the women were categorized by parity, 

decreased fecundability OR and increased infertility OR were only found in the parous group; the ORs for 

the nulliparous women included unity (Fei et al. 2009). A second re-analysis of these data (Bach et al. 

2015a) using a different statistical approach confirmed the results of the whole group and the parous

subgroup; this re-analysis also found a decrease in the fecudability risk among the nulliparous women. In 

another set of women participating in the Danish National Birth Cohort study (Bach et al. 2015b), no 

alterations in fecudability or infertility risk were observed in the whole cohort or when the women were 

categorized into parous and nulliparous subcohorts. It was noted that the median serum 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 fecudability (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. 
PERFLUOROALKYLS 326

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-29. Fecundability Relative to PFOA Levels (Presented as Adjusted Fecundability Ratios)
PERFLUOROALKYLS 327

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-30. Infertility Relative to PFOA Levels (Presented as Adjusted Odds Ratios)
PERFLUOROALKYLS 328

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Other studies have not found alterations in fecudability and/or infertility (Bach et al. 2015a; Jørgensen et 

al. 2014a; Vestergaard et al. 2012).

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 cells 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 not 

reveal 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 not 

altered by 50 mg/kg/day PFOA, but androstenedione levels were reduced 2-fold. The data suggested that 

the 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 the 

liver. 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 

ultimately produce Leydig cell hyperplasia and adenoma by acting as a mitogen or enhancing growth 

factor secretion. A study of the dose-response relationship for PFOA and serum estradiol reported a 

significant increase in serum estradiol in rats dosed with ≥2 mg/kg/day, which was well correlated with 

total hepatic aromatase activity (Liu et al. 1996). Significant increases in serum estradiol were also 
PERFLUOROALKYLS 329

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 to 

13.6 mg/kg/day PFOA in the diet for 2 years (Biegel et al. 2001). Another 2-year study found an 

increased incidence of vascular mineralization in the testes of rats exposed to 15 mg/kg/day PFOA in the 

diet; no effects were observed at 1.5 mg/kg/day (3M 1983). 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). A peer review of the histological slides from 3M (1983) 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, no statistically significant increases in the occurrence of gonadal stromal 

hyperplasia were observed in either group; 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 and 

Long 1980), and rats with up to approximately 100–110 mg/kg/day PFOA for 13 weeks (Griffith and 

Long). Serum levels of estradiol and estriol were not significantly altered in the 4-week study conducted 

by 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 

1.5 mg/kg/day increased the incidence of tubular hyperplasia in the ovaries (3M 1983).
PERFLUOROALKYLS 330

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 gland 

differentiation 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; the 

morphology 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 gland 

structure was similar to mammary gland tissue at or near the peak of lactation (PND 10). Necrosis was 

observed in the placenta of mice administered via gavage 10 or 25 mg/kg/day PFOA on GDs 11–16 (Suh 

et al. 2011); no alterations were observed at 2 mg/kg/day.

No gross or microscopic alterations were reported in the testes from rats dermally exposed to 

2,000 mg/kg/day APFO (Kennedy 1985).

Summary. Epidemiology studies have examined a several types of reproductive endpoints. Due to 

inconsistent 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 is 

based on the findings of two studies (a third study did not find an association). Several general 

population studies found associations between serum PFOA and impaired fertility (increased time to 

pregnancy and/or infertility). The results of a multi-generational study in rats do not suggest that the 

reproductive system is a sensitive target of PFOA toxicity. Additionally, histological alterations have not 

been observed in monkeys or rats following intermediate and/or chronic oral exposure.

PFOS

Epidemiology 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 in 

adolescent 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
PERFLUOROALKYLS 331

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 associated 

with 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 adolescent 

females; no association was found in older females (Tsai et al. 2015).

Epidemiology 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 Louis

et al. 2015; Joensen et al. 2013; Raymer et al. 2012; Toft et al. 2012; Vested et al. 2013). A multinational 

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 a 

single measurement of PFOS, and are not adequate for establishing causality.

Epidemiology Studies—Effects on Menstrual Cycle Length, Menopause Onset, Endometriosis, and 

Breastfeeding 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). A 

study of C8 Health Study participants found increases in the risk of early menopause 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 find an association between serum PFOS 

and the risk of early menopause (Taylor et al. 2014). The risk of endometriosis was not associated with 

serum PFOS levels (Buck Louis et al. 2012). 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 
PERFLUOROALKYLS 332

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

examined in one study and the evidence is inconclusive to determine whether there is an association 

between PFOS exposure and these female reproductive 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). When the women were segregated by parity, the 

associations were only found in multiparous women (Fei et al. 2010). This finding may be due to reverse 

causality since longer breastfeeding would likely result in lower maternal PFOS levels.

Epidemiology Studies—Effects on Fertility. Several general population studies have evaluated whether 

there is a possible link 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 2-31 and 2-32, respectively. A couple of studies

have found associations, but most have not found associations. Fei et al. (2009) found decreases 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), the decrease in 

fecundability and increase in infertility risk were only observed in nulliparous women with serum PFOS 

levels in the 3rd and 4th quartiles; no alterations were observed among parous women. A re-analysis of 

these data using a different statistical approach (Bach et al. 2015b) resulted in the same findings of 

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 found alterations in fecundability or fertility associated 

with maternal serum PFOS levels (Bach et al. 2015a, 2015b; Jørgensen et al. 2014a; Vélez et al. 2015; 

Vestergaard et al. 2012).

Laboratory Animal Studies. A significant decrease in serum testosterone levels and epididymal sperm 

count was observed in mice administered 10 mg/kg/day PFOS for 21 days (Wan et al. 2011). No 

alterations were observed in mice administered 5 mg/kg/day PFOS or in mice administered 5 or 

10 mg/kg/day PFOS for 14 days. 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. Multigeneration studies with PFOS in 
PERFLUOROALKYLS 333

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-31. Fecundability Relative to PFOS Levels (Presented as Adjusted Fecundability Ratios) 
PERFLUOROALKYLS 334

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-32. Infertility Relative to PFOS Levels (Presented as Adjusted Odds Ratios) 
PERFLUOROALKYLS 335

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

rats did not provide indications of reproductive toxicity. Exposure of 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 with PFOS had no 

significant effect on cell proliferation in the testes. Serum estradiol also was lower than in controls in one 

male and one female monkey dosed with 2 mg/kg/day PFOS for 4 weeks, but little can be concluded 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 have been 

observed.

PFHxS

Epidemiology Studies—Reproductive Hormone Levels. Two general population studies evaluated 

possible 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 luteal 

progesterone were observed in women (Barrett et al. 2015).

Epidemiology 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.

Epidemiology Studies—Effects on Menstrual Cycle Length, Menopause Onset, Endometriosis, and 

Breastfeeding Duration. Four general population studies have evaluated possible associations between 

serum PFHxS levels and female reproductive outcomes. Taylor et al. (2014) reported increases in the risk 

of earlier menopause in women with serum PFHxS levels in the 3rd tertile and the risk of hysterectomy in 

women with serum PFHxS levels in the 2nd and 3rd tertiles. Other studies did not find associations with 
PERFLUOROALKYLS 336

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

the risk and severity of endometriosis (Buck Louis et al. 2012) or polycystic ovary syndrome (Vagi et al. 

2014). Romano et al. (2016) did not find associations between maternal PFHxS levels and the risk of 

breastfeeding ≤3 or 6 months.

Epidemiology Studies—Effects on Fertility. Four 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 fecudability 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. Studies by Bach et al. (2015a) and 

Jørgensen et al. (2014a) did not find alterations in time to pregnancy 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 not 

deliver a litter) (exposure began 14 days prior to cohabitation) (Butenhoff et al. 2009a; Hoberman and 

York 2003). Fertility was not affected by treatment with PFHxS and there were no significant effects on 

sperm parameters. Also, estrous cycling was not affected by dosing with PFHxS.

PFNA

Epidemiology Studies—Reproductive Hormone Levels. Reproductive hormone alterations associated 

with serum PFNA levels are limited to a finding for estradiol in young men (Joensen et al. 2013); no 

associations with other reproductive hormones were found in this study. In another study of adolescent 

and 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). A third study did not find alterations in follicular estradiol or luteal progesterone levels in women 

(Barrett et al. 2015).

Epidemiology 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 with 
PERFLUOROALKYLS 337

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

coiled tails. No associations were found for other sperm parameters (Buck Louis et al. 2015; Joensen et 

al. 2013; Toft et al. 2012).

Epidemiology Studies—Effects on Menstrual Cycle Length, Menopause Onset, Endometriosis, and 

Breastfeeding Duration. Increases in the risk of earlier menopause and hysterectomy 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 increase in the risk of 

endometriosis was associated with serum PFNA levels in a general population study (Buck Louis et al. 

2012); however, adjustment for parity resulted in OR CIs that included unity. Vagi et al. (2014) did not 

find an increased risk of polycystic syndrome that was associated with serum PFNA levels. No 

associations between maternal PFNA levels and the risk of breastfeeding ≤3 or 6 months were found in a 

general population study (Romano et al. 2016).

Epidemiology Studies—Effects on Fertility. Jørgensen et al. (2014a) found increases in time to 

pregnancy (measured as a decrease in fecundability ratio) and an increase in infertility risk in a study of 

pregnant women. In sensitivity analysis, the fecundability ratio for primiparous women was 0.99 and the 

95% CI range included unity (0.88–1.22). Studies by Bach et al. (2015a) and Vestergaard et al. (2012) 

did not find associations between serum PFNA levels and fecundability ratio; Bach et al. (2015a) also did 

not find an increase in the 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; these changes as well as increases in serum Mullerian 

inhibiting substance and decreases in serum inhibin B cells were suggestive of damage to the secretory 

function of the Sertoli cells (Feng et al. 2010).

PFDeA

Epidemiology Studies—Reproductive Hormone Levels. No associations were found between serum 

PFDeA levels and testosterone, free androgen index, LH, estradiol, sex hormone binding globulin, or FSH
PERFLUOROALKYLS 338

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

levels in young men (Joensen et al. 2013). Similarly, no alterations in follicular estradiol or luteal 

progesterone levels were observed in women (Barrett et al. 2015).

Epidemiology Studies—Effects on Sperm. Two general population studies evaluated potential effects of 

PFDeA exposure on sperm parameters. Buck Louis et al. (2015) found associations between serum 

PFDeA 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 morphological 

alterations (Buck Louis et al. 2015; Joensen et al. 2013).

Epidemiology Studies—Effects on Menstrual Cycle Length, Menopause Onset, and Endometriosis. 

Only one study examined alterations in female reproductive outcomes associated with serum PFDeA 

levels. In this study, no associations between serum PFDeA levels and the risk or severity of 

endometriosis were found (Buck Louis et al. 2012).

Epidemiology Studies—Effects on Fertility. Two studies have examined the potential for PFDeA to alter 

fertility. No alterations in time to pregnancy (measured as fecundability ratio) or risk of infertility were 

observed in pregnant women (Bach et al. 2015a). Another study (Vestergaard et al. 2012) also found no 

association between female serum PFDeA levels and time to pregnancy.

PFUA

Epidemiology Studies—Reproductive Hormone Levels. An inverse association between serum PFUA 

levels and FSH levels was observed in adolescent girls (Tsai et al. 2015). The study did not find 

alterations 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).

Epidemiology Studies—Effects on Fertility. Only one study evaluated possible associations between 

maternal serum PFUA levels and fertility; no alterations in time to pregnancy (measured as a 

fecundability ratio) or infertility risk were observed in pregnant women (Bach et al. 2015a).
PERFLUOROALKYLS 339

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFBuS

Laboratory Animal Studies. Administration of up to 900 mg/kg/day PFBuS to rats by gavage for 28 days 

did not cause any significant gross or microscopic alterations in primary or secondary sex organs from 

males or females (3M 2001). A 2-generation study in which rats were exposed to gavage doses of 

potassium PFBuS 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 and 

secondary reproductive organs 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).

PFDoA

Laboratory Animal Studies. Treatment of male rats with 1, 5, or 10 mg/kg/day PFDoA 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 a 

significant 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 

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 transport 

and 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 total 

cholesterol 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.
PERFLUOROALKYLS 340

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFOSA

Epidemiology Studies. One study examined reproductive hormone levels and did not find an association 

between serum PFOSA and follicular estradiol or luteal progesterone levels in women (Barrett et al. 

2015). The only epidemiology study evaluating fertility did not find an increase in time to pregnancy, as 

measured as a fecundability ratio, or decrease in the likelihood of becoming pregnant within the first six

menstrual cycles (Vestergaard et al. 2012).

Me-PFOSA-AcOH

Epidemiology Studies. In the only study identified that examined sperm parameters associated with 

Me-PFOSA-AcOH, increases in the percentage of sperm with neck/midpiece abnormalities and increases 

in the number of immature sperm were found (Buck Louis et al. 2015). No associations with sperm 

viability, count, or motility were found. One study examining fertility did not find associations between 

serum Me-PFOSA-AcOH levels in women and time to pregnancy (Vestergaard et al. 2012).

Et-PFOSA-AcOH

Epidemiology Studies. No associations between serum Et-PFOSA-AcOH levels in females and the time 

to pregnancy were observed in a study of nulliparous couples (Vestergaard et al. 2012).

2.17 DEVELOPMENTAL

Overview. A large number of epidemiology 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. The discussion of these developmental outcomes is divided into four 

categories: pregnancy outcome, birth outcome, neurodevelopment, and sexual maturation. The 

epidemiology studies examining pregnancy outcome are summarized in Table 2-22; the pregnancy 

outcomes include miscarriage, stillbirth, preterm birth, and gestation age. Table 2-23 summarizes the 

epidemiology studies examining birth outcomes, which include birth weight, birth size, low birth weight, 

small for gestational age, birth defects, and sex ratio. Epidemiology studies examining 

neurodevelopmental endpoints, particularly risks for ADHD, are summarized in Table 2-24. Studies 

evaluating possible links between serum perfluoroalkyl levels and development of the reproductive

system are summarized in Table 2-25. Further details on these studies are presented in the Supporting
PERFLUOROALKYLS 341

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-22. Summary of Pregnancy Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Darrow et al. 2013

Community (C8) (n=1,330 women)

≥37.2 ng/mL (5th PFOA 

quintile)

Preterm birth OR 1.01 (0.55–1.86)

Darrow et al. 2014

Community (C8) (n=1,129 women)

>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

Savitz et al. 2012a

Community (C8) (11,737 singleton infants)

63.1–934.3 ng/mL 

(4th maternal PFOA quartile)

Miscarriage OR 0.9 (0.7–1.0) 

Stillbirth OR 1.0 (0.5–1.8)

Savitz et al. 2012b

Community (13,243 cases stillbirth, preterm 

birth, low birth weight or small for gestational 

age)

21.0–717.6 ng/mL 

(5th maternal PFOA quintile)

Stillbirth OR 0.8 (0.5–1.5)

Preterm birth (<37 weeks) OR 1.0 (0.9–1.2)

Preterm birth (<32 weeks) OR 1.0 (0.7–1.3)

Savitz et al. 2012b

Community (4,547 infants)

83.3–921.3 ng/mL 

(5th maternal PFOA quintile)

Preterm birth (<37 weeks) OR 1.2 (0.9–1.6)

Preterm birth (<32 weeks) OR 1.4 (0.5–3.6)

Stein et al. 2009

Community (C8) (n=1,845 pregnancies)

48.8 ng/mL (maternal mean 

PFOA) 

Miscarriage OR 0.9 (0.5–1.6), >90th percentile

Preterm birth OR 0.9 (0.6–1.5), >90th percentile

Apelberg et al. 2007b

General population (n=341 singleton births)

1.6 ng/mL (cord serum 

median PFOA)

Gestational age NS (p>0.05)

Chen et al. 2012a

General population (n=429 infants)

1.84 ng/mL (cord blood 

geometric mean PFOA)

Gestational age NS (p>0.05)

Preterm birth OR 0.64 (0.40–1.02)

Hamm et al. 2010

General population (n=252 pregnant women)

>2.1–18 ng/mL (maternal 

3rd PFOA tertile)

Preterm birth RR 1.31 (0.38–4.45), 3rd tertile
PERFLUOROALKYLS 342

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-22. Summary of Pregnancy Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Jensen et al. 2015

General population (n=56 cases and 

336 controls)

1.58 ng/mL (maternal median 

PFOA)

Miscarriage before gestation 

week 12

OR 0.64 (0.36–1.18)

Whitworth et al. 2012a

General population (n=901 infants) 

≥3.04 ng/mL (maternal 

4th PFOA quartile)

Preterm birth OR 0.1 (0.03–0.6)*, 4th quartile

PFOS

Darrow et al. 2013

Community (C8) (n=1,330 women)

15.6 ng/mL (mean PFOS) Preterm birth OR 1.07 (0.58–1.95)

Darrow et al. 2014

Community (C8) (n=1,129 women)

>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

Stein et al. 2009

Community (C8) (n=5,262 infants)

23.2–83.4 ng/mL 

(>90th PFOS percentile)

Miscarriage OR 0.9 (0.7–1.3), >90th percentile

Preterm birth OR 1.4 (1.1–1.7)*, >90th percentile

Chen et al. 2012a

General population (n=429 infants)

5.94 ng/mL (cord blood 

geometric mean PFOS)

Preterm birth OR 2.45 (1.47–4.08)*

Fei et al. 2007, 2008a

General population (n=1,400 pregnant women)

35.3 ng/mL (maternal median 

PFOS)

Gestation length NS (p>0.01)

Preterm birth OR 1.43 (0.50–4.11), 4th quartile

Hamm et al. 2010

General population (n=252 pregnant women)

>10–35 ng/mL (maternal 

3rd tertile PFOS)

Preterm birth RR 1.11 (0.36–3.38), 3rd tertile

Jensen et al. 2015

General population (n=56 cases and 

336 controls)

8.10 ng/mL (maternal median 

PFOS)

Miscarriage before gestation 

week 12

OR 1.16 (0.59–1.29)

Whitworth et al. 2012a

General population (n=901 infants) 

13.0 and ≥16.59 ng/mL 

(maternal median and 

4th quartile PFOS)

Preterm birth OR 0.3 (0.1–1.0, p=0.03)*, 

4th quartile
PERFLUOROALKYLS 343

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-22. Summary of Pregnancy Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFHxS

Hamm et al. 2010

General population (n=252 pregnant women)

>1.4–43 ng/mL (maternal 

3rd tertile PFHxS)

Preterm birth RR 0.31 (0.11–0.90)*, 3rd tertile

Jensen et al. 2015

General population (n=56 cases and 

336 controls)

0.298 ng/mL (maternal 

median PFHxS)

Miscarriage before gestation 

week 12

OR 1.53 (0.99–2.38)

PFNA

Chen et al. 2012a

General population (n=429 infants)

2.36 ng/mL (cord blood 

geometric mean PFNA)

Preterm birth OR 0.88 (0.71–1.11)

Jensen et al. 2015

General population (n=56 cases and 

336 controls)

0.72 ng/mL (maternal median 

PFNA)

Miscarriage before gestation 

week 12

OR 16.46 (7.39–36.62)*

PFDeA

Jensen et al. 2015

General population (n=56 cases and 

336 controls)

0.27 ng/mL (maternal median 

PFDeA)

Miscarriage before gestation 

week 12

OR 2.30 (1.18–4.47)*

PFUA

Chen et al. 2012a

General population (n=429 infants)

10.26 ng/mL (cord blood 

geometric mean PFUA)

Preterm birth OR 0.87 (0.64–1.16)

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

OR = odds ratio; NS = not significant; PFDeA = perfluorodecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFUA = perfluoroundecanoic acid; RR= risk ratio
PERFLUOROALKYLS 344

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Darrow et al. 2013

Community (C8) (n=1,330 women)

≥37.2 ng/mL (5th PFOA 

quintile)

Birth weight NS (p=0.70 for trend)

Low birth weight OR 0.92 (0.44–1.95)

Nolan et al. 2009

Community (n=1,555 singleton infants)

NR Birth weight NS (p>0.05)

Low birth weight OR 0.37 (0.16–0.86)*

Nolan et al. 2010

Community (n=1,548 singleton infants)

NR Congenital anomalies OR 1.1 (0.34–3.3)

Savitz et al. 2012a

Community (C8) (11,737 singleton infants)

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)

Savitz et al. 2012b

Community (13,243 cases stillbirth, preterm 

birth, low birth weight or small for gestational 

age)

7.7 ng/mL (estimated 

maternal median PFOA)

Birth weight β -14.80 (-42.28–13.68), per 

100 ng/mL increase in PFOA

Low birth weight OR 1.0 (0.86–1.15), per 100 ng/mL 

increase in PFOA

Small for gestational age OR 0.86 (0.67–1.11), per 100 ng/mL 

increase in PFOA

Savitz et al. 2012b

Community (4,547 infants)

13.4 ng/mL (estimated 

maternal median PFOA)

Low birth weight OR 1.07 (0.96–1.18), per 100 ng/mL 

increase in PFOA

Small for gestational age 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

Birth weight OR -12.76 (-26.08–0.57), per 

100 ng/mL increase in PFOA

Stein et al. 2009

Community (C8) (n=1,845 pregnancies)

50.0–<120.6 and 120.6–

894.4 ng/mL (3rd and 4th

maternal PFOA quartile)

Low birth weight OR 0.8 (0.3–1.9), 4th quartile

Birth defects OR 1.7 (0.8–3.6), 4th quartile
PERFLUOROALKYLS 345

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Stein et al. 2014c

Community (C8) (n=10,262 infants)

61.3 ng/mL (estimated in 

utero mean PFOA)

Brain defects OR 2.6 (1.3–5.1), interquartile range

Gastrointestinal defects OR 0.7 (0.3–1.4), interquartile range

Kidney defects OR 0.7 (0.3–1.8), interquartile range

Craniofacial defects OR 0.6 (0.3–1.3), interquartile range

Eye defects OR 1.1 (0.6–2.1), interquartile range

Limb defects OR 1.2 (0.7–2.0), interquartile range

Genitourinary defects OR 1.0 (0.6–1.7), interquartile range

Heart defects OR 1.2 (0.8–1.7), interquartile range

Apelberg et al. 2007b

General population (n=341 singleton births)

1.6 ng/mL (cord serum 

median PFOA)

Birth weight NS (p>0.05)

Birth length NS (p>0.05)

Head circumference Inverse association (p>0.05)*

Ponderal index Inverse association (p>0.05)*

Ashley-Martin et al. 2016

General population (n=1,723 pregnant women)

1.70 and 0.39 ng/mL 

(maternal and cord median 

PFOA)

Gestational weight gain NS (p>0.1), serum PFOA

OR 1.04 (1.02–1.06)*, cord PFOA

Bach et al. 2016

General population (n=1,507 nulliparous 

women)

2.0 ng/mL (median PFOA) Birth weight NS, investigators noted no consistent 

alterations across PFOA quartiles

Birth length NS, investigators noted no consistent 

alterations across PFOA quartiles

Head circumference NS, investigators noted no consistent 

alterations across PFOA quartiles

Bae et al. 2015

General population (n=233 couples)

5.01 and 4.05 ng/mL and 

5.00 and 2.54 ng/mL 

(geometric mean PFOA in 

male and female nulliparous 

parents and male and female 

parous parents, respectively)

Male birth OR 0.93 (0.68–1.26), maternal PFOA

OR 0.94 (0.72–1.23), paternal PFOA
PERFLUOROALKYLS 346

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Chen et al. 2012a

General population (n=429 infants)

1.84 ng/mL (cord blood 

geometric mean PFOA)

Birth weight NS (p>0.05)

Birth length NS (p>0.05)

Head circumference NS (p>0.05)

Ponderal index NS (p>0.05)

Small for gestational age OR 1.24 (0.75–2.05)

Low birth weight OR 0.53 (0.18–1.55)

Fei et al. 2007, 2008a

General population (n=1,400 pregnant women)

5.6 ng/mL (maternal median 

PFOA)

Birth weight β -10.63 (-20.79 to -0.47)*

Birth length β -0.069 (-0.113 to -0.024)*

Abdominal circumference β -0.059 (-0.106 to -0.012)*

Head circumference β-0.030 (-0.064–0.004)

Low birth weight OR 2.44 (0.27–22.25), 4th quartile

Small for gestation age OR 0.97 (0.55–1.70), 4th quartile

Govarts et al. 2016

General population (n=202 infants)

1.52 ng/mL (cord blood 

geometric mean PFOA)

Birth weight NS (p=0.473)

Hamm et al. 2010

General population (n=252 pregnant women)

>2.1–18 ng/mL (maternal 3rd

tertile PFOA)

Birth weight Change in weight 14.80 (-107.29–

136.89), 3rd tertile

Small for gestational age RR 0.99 (0.25–3.92), 3rd tertile

Kim et al. 2011

General population (n=44 pregnant women)

1.46 ng/mL (maternal median 

PFOA)

Birth weight NS (p>0.05)

Cord TSH Association (p<0.05)*

Cord T3 NS (p>0.05)

Cord T4 NS (p>0.05)

Kim et al. 2016a

General population (n=27 infants with 

congenital hypothyroidism; n=13 controls)

5.398 and 2.12 ng/mL (mean 

PFOA in cases and controls)

Thyroid stimulating 

immunoglobulin levels

Inverse association (p<0.05)*

TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)
PERFLUOROALKYLS 347

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Lee et al. 2013

General population (n=59 pregnant women)

2.73 ng/mL (maternal mean 

PFOA) 

Birth weight OR 0.54 (0.17–3.03)

Birth length OR 0.44 (0.12–1.58)

Ponderal index OR 0.56 (0.16–2.01)

Head circumference OR 0.82 (0.24–13.65)

Lee et al. 2016

General population (n=85 infants)

1.11 ng/mL (cord blood mean 

PFOA) 

Birth weight NS (p>0.05)

Lenters et al. 2016a, 2016b

General population (n=513 infants in 

Greenland subcohort, n=557 infants in Ukraine

subcohort, and n=180 infants in Poland 

subcohort

1.84, 0.96, and 2.51 ng/mL 

(maternal median PFOA for 

Greenland, Ukraine, and

Poland subcohorts) 

Birth weight β -63.77 (-122.83 to -4.71, 

p=0.035)*. 2 SD increase in lntransformed PFOA 

Maisonet et al. 2012

General population (n=447 girls)

3.7 ng/mL (maternal median 

PFOA) 

Birth weight Inverse association (p=0.0120 for 

trend)*

Birth length NS (p=0.0978)

Ponderal index NS (p=0.5920)

Body weight at 20 months NS (p=0.4147)

Monroy et al. 2008

General population (n=101 pregnant women)

1.81 and 1.58 ng/mL 

(maternal and cord median 

PFOA)

Birth weight NS (p>0.05), maternal serum and 

cord blood PFOA

Robledo et al. 2015a, 2015b

General population (n=234 couples)

3.16 and 5.00 ng/mL 

(maternal and paternal 

geometric mean PFOA)

Birth weight NS (p>0.05), maternal or paternal 

Birth length NS (p>0.05), maternal or paternal 

Head circumference NS (p>0.05), maternal or paternal 

Ponderal index NS (p>0.05), maternal or paternal 

Wang et al. 2016

General population (n=117 boys and 106 girls 

examined at 2, 5, 8, and 11 years of age) 

2.37 and 2.34 ng/mL (median 

maternal PFOA for boys and 

girls) 

Birth weight NS (p>0.05)

Birth length NS (p>0.05)

Head circumference NS (p>0.05)

Small for gestational age NS (p>0.05)
PERFLUOROALKYLS 348

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Washino et al. 2009

General population (n=428 infants)

1.3 ng/mL (maternal median 

PFOA) 

Birth weight NS (p=0.207)

Birth length NS (p=0.631)

Chest circumference NS (p=0.460)

Head circumference NS (p=0.823)

Whitworth et al. 2012a

General population (n=901 infants) 

2.2 and ≥3.04 ng/mL 

(maternal median and 

4th quartile PFOA)

Birth weight NS (p=0.12) 

Small for gestational age NS (p=0.92)

Large for gestational age NS (p=0.33)

PFOS

Grice et al. 2007

Occupational (n=263 females)

1,300–1,970 ng/mL (range of 

PFOS)

Birth weight NS (p=0.15)

Darrow et al. 2013

Community (C8) (n=1,330 women)

15.6 ng/mL (mean PFOS) Birth weight NS (p=0.045 for trend), whole cohort

Association (p=0.006), women 

(n=783) who conceived after blood 

sample collection

Low birth weight OR 1.33 (0.60–2.96)

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 OR 1.6 (1.1–2.3)*, 75th-90th

percentile

Birth defects OR 1.3 (0.8–2.1)

Apelberg et al. 2007b

General population (n=341 singleton births)

5 ng/mL (PFOS cord serum 

median)

Gestational age NS (p>0.05)

Birth weight NS (p>0.05)

Birth length NS (p>0.05)

Head circumference Inverse association (p>0.05)*

Ponderal index Inverse association (p>0.05)*

Ashley-Martin et al. 2016

General population (1,723 pregnant women)

4.60 and 0.15 ng/mL 

(maternal and cord PFOS 

median)

Gestational weight gain Association (p<0.1), serum PFOS in 

underweight/normal weight subjects

OR 1.03 (1.00–1.05)*, cord PFOS
PERFLUOROALKYLS 349

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Bach et al. 2016

General population (n=1,507 nulliparous 

women)

8.3 ng/mL (PFOS median) Birth weight Inverse association reported by 

investigators 

Birth length NS, investigators noted no consistent 

alterations across PFOS quartiles

Head circumference NS, investigators noted no consistent 

alterations across PFOS quartiles

Bae et al. 2015

General population (233 couples)

21.7 and 14.5 ng/mL and 

21.5 and 10.8 ng/mL 

(geometric mean PFOS in 

male and female nulliparous 

parents and male and female 

parous parents, respectively)

Male birth OR 1.16 (0.88–1.53), maternal PFOS

OR 1.01 (0.78–1.33), paternal PFOS

Chen et al. 2012a

General population (n=429 infants)

5.94 ng/mL (cord blood 

geometric mean PFOS)

Gestational age Inverse association (p<0.001)*

Birth weight β -110.2 g (-176.0 to -44.5, 

p<0.001)*, per ln PFOS

Birth length NS (p>0.05)

Head circumference β -0.25 cm (-0.46–0.05 cm, 

p<0.05)*, per ln PFOS

Ponderal index NS (p>0.05)

Small for gestational age OR 2.27 (1.25–4.15)*

Low birth weight OR 2.61 (0.185–8.03)

de Cock et al. 2014

General population (n=89 infants)

1.611 ng/mL (cord blood 

mean PFOS)

Weight NS (p=0.802)

Height NS (p=0.975)

BMI NS (p=0.586)

Head circumference NS (p=0.649)

Fei et al. 2007, 2008a

General population (n=1,400 pregnant women)

35.3 ng/mL (maternal median 

PFOS)

Birth weight β -0.46 (-2.34–1.41)

Birth length β-0.002 (-0.011–0.006) 

Abdominal circumference β -0.003 (-0.012–0.005)

Head circumference β 0.000 (-0.006–0.007)

Gestation length NS (p>0.01)
PERFLUOROALKYLS 350

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Low birth weight OR 4.82 (0.56–41.16), 4th quartile

Small for gestation age OR 0.98 (0.58–1.65), 4th quartile

Govarts et al. 2016

General population (n=202 infants)

2.63 ng/mL (cord blood 

geometric mean PFOS)

Birth weight NS (p=0.798)

Hamm et al. 2010

General population (n=252 pregnant women)

>10–35 ng/mL (maternal 3rd

tertile PFOS)

Birth weight Change in weight 71.25 (54.97–

197.48), 3rd tertile

Small for gestational age RR 0.26 (0.10–0.70)*, 3rd tertile

Kim et al. 2011

General population (n=44 pregnant women)

2.93 ng/mL (maternal median 

PFOS)

Birth weight NS (p>0.05)

Cord TSH NS (p>0.05)

Cord T3 Inverse association (p<0.05)*

Cord T4 NS (p>0.05)

Kim et al. 2016a

General population (n=27 infants with 

congenital hypothyroidism; N=13 controls)

5.326 and 4.05 ng/mL (mean 

PFOS in cases and controls)

Thyroid stimulating 

immunoglobulin levels

NS (p>0.05)

TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)

Lee et al. 2013

General population (n=59 pregnant women)

10.77 ng/mL (maternal mean 

PFOS) 

Birth weight OR 0.98 (0.32–3.03)

Birth length OR 0.97 (0.29–3.27)

Ponderal index OR 0.22 (0.05–0.90)*

Head circumference OR 1.34 (0.20–8.90)

Lee et al. 2016

General population (n=85 infants)

0.87 ng/mL (cord blood mean 

PFOS) 

Birth weight NS (p>0.05)

Lenters et al. 2016a, 2016b

General population (n=513 infants in 

Greenland subcohort, n=557 infants in Ukraine

subcohort, and n=180 infants in Poland 

subcohort)

20.09, 5.04, and 7.81 ng/mL 

(maternal median PFOS for 

Greenland, Ukraine, and

Poland subcohorts) 

Birth weight NS (p=0.109)
PERFLUOROALKYLS 351

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Liew et al. 2014

General population (n=156 children diagnosed 

with congenital cerebral palsy (cases) and 

550 controls) 

28.90 and 27.50 ng/mL 

(maternal median PFOS in 

boy and girl cases)

27.60 and 26.20 ng/mL 

(maternal median PFOS in 

boy and girl controls)

Congenital cerebral palsy

Boys

Girls 

RR 1.7 (1.0–2.8)*

RR 0.7 (0.4–1.4)

Maisonet et al. 2012

General population (n=447 girls)

19.6 ng/mL (maternal median 

PFOS) 

Birth weight 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 NS (p=0.1120) 

Monroy et al. 2008

General population (n=101 pregnant women)

14.54 mg/mL and 6.08 ng/mL 

(maternal and cord median 

PFOS)

Birth weight NS (p>0.05), maternal serum and 

cord blood PFOA

Robledo et al. 2015a, 2015b

General population (n=234 couples)

12.44 and 21.6 ng/mL 

(maternal and paternal 

geometric mean PFOS)

Birth weight NS (p>0.05), maternal or paternal 

Birth length NS (p>0.05), maternal or paternal 

Head circumference NS (p>0.05), maternal or paternal 

Ponderal index NS (p>0.05), maternal or paternal 

Washino et al. 2009

General population (n=428 infants)

5.2 ng/mL (maternal median 

PFOS) 

Birth weight 

Males

Females 

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

Birth length NS (p=0.167)

Chest circumference NS (p=0.718)

Head circumference NS (p=0.488)

Whitworth et al. 2012a

General population (n=901 infants) 

13.0 and ≥16.59 ng/mL 

(maternal median and 4th

quartile PFOS)

Birth weight NS (p=0.10) 

Small for gestational age NS (p=0.51)

Large for gestational age NS (p=0.33)
PERFLUOROALKYLS 352

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFHxS

Ashley-Martin et al. 2016

General population (n=1,723 pregnant women)

1.00 and 0.10 ng/mL 

(maternal and cord PFHxS 

median)

Gestational weight gain NS (p>0.1), serum PFHxS

OR 1.01 (10.99–1.03), cord PFHxS

Bach et al. 2016

General population (n=1,507 nulliparous 

women)

0.5 ng/mL (maternal PFHxS 

median)

Birth weight Inverse association reported by 

investigators 

Birth length NS, investigators noted no consistent 

alterations across PFHxS quartiles

Head circumference NS, investigators noted no consistent 

alterations across PFHxS quartiles

Hamm et al. 2010

General population (n=252 pregnant women)

>1.4–43 ng/mL (maternal 

3rd tertile PFHxS)

Birth weight Change in weight (25.99, 95%

CI -95.25–147.23), 3rd tertile

Small for gestational age RR 2.35 (0.63–8.72), 3rd tertile

Kim et al. 2011

General population (n=44 pregnant women)

0.55 ng/mL (maternal median 

PFHxS)

Birth weight NS (p>0.05)

Cord TSH NS (p>0.05)

Cord T3 NS (p>0.05)

Cord T4 NS (p>0.05)

Kim et al. 2016a

General population (n=27 infants with 

congenital hypothyroidism; n=13 controls)

1.228 and 1.17 ng/mL (mean 

PFHxS in cases and controls)

Thyroid stimulating 

immunoglobulin levels

Association (p<0.05)*

TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)

Lee et al. 2013

General population (n=59 pregnant women)

1.35 ng/mL (maternal mean 

PFHxS) 

Birth weight OR 0.57 (0.19–1.75)

Birth length OR 0.44 (0.12–1.58)

Ponderal index OR 0.64 (0.19–2.23)

Head circumference OR 0.90 (0.13–6.13)

Lee et al. 2016

General population (n=85 infants)

0.60 ng/mL (cord blood mean 

PFHxS) 

Birth weight NS (p>0.05)
PERFLUOROALKYLS 353

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Lenters et al. 2016a, 2016b

General population (n=513 infants in 

Greenland subcohort, n=557 infants in Ukraine

subcohort, and n=180 infants in Poland 

subcohort)

2.05, 1.56, and 2.28 ng/mL 

(maternal median PFHxS for 

Greenland, Ukraine, and

Poland subcohorts) 

Birth weight NS (p=0.801) 

Liew et al. 2014

General population (n=156 children diagnosed 

with congenital cerebral palsy (cases) and 

550 controls) 

0.96 and 0.90 ng/mL 

(maternal median PFHxS in 

boy and girl cases)

0.92 and 0.92 ng/mL 

(maternal median PFHxS in 

boy and girl controls)

Congenital cerebral palsy

Boys

Girls 

RR 1.2 (0.9–1.7)

RR 1.1 (0.6–1.9)

Maisonet et al. 2012

General population (n=447 girls)

1.6 ng/mL (maternal median 

PFHxS) 

Birth weight Inverse association (p=0.0314 for 

trend)*

Birth length Inverse association (p=0.0008 for 

trend)*

Ponderal index NS (p=0.6802 for trend) 

Monroy et al. 2008

General population (n=101 pregnant women)

1.62 mg/mL (maternal 

median PFHxS)

Birth weight NS (p>0.05)

PFNA

Bach et al. 2016

General population (n=1,507 nulliparous 

women)

0.8 ng/mL (PFNA median) Birth weight NS, investigators noted no consistent 

alterations across PFNA quartiles

Birth length NS, investigators noted no consistent 

alterations across PFNA quartiles

Head circumference NS, investigators noted no consistent 

alterations across PFNA quartiles

Bae et al. 2015

General population (233 couples)

1.60 and 1.37 ng/mL and 

1.55 and 1.09 ng/mL 

(geometric mean PFNA in 

male and female nulliparous 

parents and male and female 

parous parents, respectively)

Male birth OR 0.94 (0.70–1.26), maternal PFNA

OR 0.94 (0.71–1.24), paternal PFNA
PERFLUOROALKYLS 354

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Chen et al. 2012a

General population (n=429 infants)

2.36 ng/mL (cord blood 

geometric mean PFNA)

Gestational age NS (p>0.05)

Birth weight NS (p>0.05)

Birth length Association (p<0.01)*

Head circumference NS (p>0.05)

Ponderal index Inverse association (p<0.05)

Small for gestational age OR 0.97 (0.74–1.26)

Low birth weight OR 0.76 (0.47–1.23)

Kim et al. 2016a

General population (n=27 infants with 

congenital hypothyroidism; n=13 controls)

1.931 and 0.633 ng/mL

(mean PFNA in cases and 

controls)

Thyroid stimulating 

immunoglobulin levels

NS (p>0.05)

TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)

Lee et al. 2016

General population (n=85 infants)

0.36 ng/mL (cord blood mean 

PFNA) 

Birth weight NS (p>0.05)

Lenters et al. 2016a, 2016b

General population (n=513 infants in 

Greenland subcohort, n=557 infants in Ukraine 

subcohort, and n=180 infants in Poland 

subcohort)

0.69, 0.61, and 0.56 ng/mL 

(maternal median PFNA for 

Greenland, Ukraine, and 

Poland subcohorts) 

Birth weight NS (p=0.065)

Liew et al. 2014

General population (n=156 children diagnosed 

with congenital cerebral palsy (cases) and 

550 controls) 

0.46 and 0.39 ng/mL 

(maternal median PFNA in 

boy and girl cases)

0.44 and 0.41 ng/mL 

(maternal median PFNA in 

boy and girl controls)

Congenital cerebral palsy

Boys

Girls 

RR 1.2 (0.6–2.5)

RR 0.6 (0.3–1.2)

Monroy et al. 2008

General population (n=101 pregnant women)

0.69 mg/mL (maternal 

median PFNA)

Birth weight NS (p>0.05)
PERFLUOROALKYLS 355

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Robledo et al. 2015a, 2015b

General population (n=234 couples)

1.211 and 1.566 ng/mL 

(maternal and paternal 

geometric mean PFNA)

Birth weight NS (p>0.05), maternal or paternal 

Birth length NS (p>0.05), maternal or paternal 

Head circumference NS (p>0.05), maternal or paternal 

Ponderal index NS (p>0.05), maternal or paternal 

Wang et al. 2016

General population (n=117 boys and 106 girls 

examined at 2, 5, 8, and 11 years of age) 

1.55 and 1.58 ng/mL (median 

maternal PFNA for boys and 

girls) 

Birth weight Inverse association (p>0.05)*, girls 

only

Birth length NS (p>0.05)

Head circumference NS (p>0.05)

Small for gestational age NS (p>0.05)

Growth during childhood NS (p>0.05)

PFDeA

Bach et al. 2016

General population (n=1,507 nulliparous 

women)

0.3 ng/mL (PFDeA median) Birth weight NS, investigators noted no consistent 

alterations across PFDeA quartiles

Birth length NS, investigators noted no consistent 

alterations across PFDe quartiles

Head circumference NS, investigators noted no consistent 

alterations across PFDeA quartiles

Bae et al. 2015

General population (233 couples)

0.46 and 0.38 ng/mL and 

0.49 and 0.46 ng/mL 

(geometric mean PFDeA in 

male and female nulliparous 

parents and male and female 

parous parents, respectively)

Male birth OR 1.07 (0.81–1.42), maternal 

PFDeA

OR 1.02 (0.78–1.34), paternal 

PFDeA

Kim et al. 2016a

General population (n=27 infants with 

congenital hypothyroidism; n=13 controls)

0.523 and 0.298 ng/mL 

(mean PFDeA in cases and 

controls)

Thyroid stimulating 

immunoglobulin levels

NS (p>0.05)

TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)

Lee et al. 2016

General population (n=85 infants)

0.14 ng/mL (cord blood mean 

PFDeA) 

Birth weight NS (p>0.05)
PERFLUOROALKYLS 356

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Lenters et al. 2016a, 2016b

General population (n=513 infants in 

Greenland subcohort, n=557 infants in Ukraine 

subcohort, and n=180 infants in Poland 

subcohort)

0.40, 0.16, and 0.22 ng/mL 

(maternal median PFDeA for 

Greenland, Ukraine, and 

Poland subcohorts) 

Birth weight NS (p=0.158) 

Liew et al. 2014

General population (n=156 children diagnosed 

with congenital cerebral palsy (cases) and 

550 controls) 

0.18 and 0.16 ng/mL 

(maternal median PFDeA in 

boy and girl cases)

0.17 and 0.16 ng/mL 

(maternal median PFDeA in 

boy and girl controls)

Congenital cerebral palsy

Boys

Girls 

RR 1.1 (0.7–1.7)

RR 0.6 (0.3–1.1)

Robledo et al. 2015a, 2015b

General population (n=234 couples)

0.402 and 0.458 ng/mL 

(maternal and paternal 

geometric mean PFDeA)

Birth weight NS (p>0.05), maternal or paternal 

Birth length NS (p>0.05), maternal or paternal 

Head circumference NS (p>0.05), maternal or paternal 

Ponderal index NS (p>0.05), maternal or paternal 

Wang et al. 2016

General population (n=117 boys and 106 girls 

examined at 2, 5, 8, and 11 years of age) 

0.46 and 0.43 ng/mL (median 

maternal PFDeA for boys and 

girls) 

Birth weight Inverse association (p>0.05)*, girls 

only

Birth length NS (p>0.05)

Head circumference NS (p>0.05)

Small for gestational age OR 3.14 (1.07–9.19)*, girls only

PFUA

Bach et al. 2016

General population (n=1,507 nulliparous 

women)

0.3 ng/mL (PFUA median) Birth weight NS, investigators noted no consistent 

alterations across PFUA quartiles

Birth length NS, investigators noted no consistent 

alterations across PFUA quartiles

Head circumference NS, investigators noted no consistent 

alterations across PFUA quartiles

Chen et al. 2012a

General population (n=429 infants)

10.26 ng/mL (cord blood 

geometric mean PFUA)

Gestational age NS (p>0.05)

Birth weight NS (p>0.05)

Birth length NS (p>0.05)
PERFLUOROALKYLS 357

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Head circumference NS (p>0.05)

Ponderal index NS (p>0.05)

Small for gestational age OR 0.93 (0.65–1.33)

Low birth weight OR 1.01 (0.53–1.91)

Kim et al. 2016a

General population (n=27 infants with 

congenital hypothyroidism; n=13 controls)

0.982 and 0.438 ng/mL 

(mean PFUA in cases and 

controls)

Thyroid stimulating 

immunoglobulin levels

NS (p>0.05)

TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)

Lee et al. 2016

General population (n=85 infants)

0.22 ng/mL (cord blood mean 

PFUA) 

Birth weight NS (p>0.05)

Lenters et al. 2016a, 2016b

General population (n=513 infants in 

Greenland subcohort, n=557 infants in Ukraine 

subcohort, and n=180 infants in Poland 

subcohort)

0.70, 0.16, and 0.13 ng/mL 

(maternal median PFUA for 

Greenland, Ukraine, and 

Poland subcohorts) 

Birth weight NS (p=0.275) 

Wang et al. 2016

General population (n=117 boys and 106

girls examined at age 2, 5, 8, and 11 years 

of age) 

3.52 and 3.31 ng/mL (median 

maternal PFUA for boys and 

girls) 

Birth weight Inverse association (p<0.05)*, girls 

only

Birth length NS (p>0.05)

Head circumference NS (p>0.05)

Small for gestational age OR 1.83 (1.01–3.32)*, girls only

PFHpA

Kim et al. 2016a

General population (n=27 infants with 

congenital hypothyroidism; n=13 controls)

0.284 and 0.324 ng/mL 

(mean PFHpA in cases and 

controls)

Thyroid stimulating 

immunoglobulin levels

NS (p>0.05)

TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)
PERFLUOROALKYLS 358

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFBA

Kim et al. 2016a

General population (n=27 infants with 

congenital hypothyroidism; n=13 controls)

0.464 and 0.220 ng/mL 

(mean PFBA in cases and 

controls)

Thyroid stimulating 

immunoglobulin levels

NS (p>0.05)

TSH NS (p>0.05)

T3 NS (p>0.05)

T4 NS (p>0.05)

PFDoA

Lee et al. 2016

General population (n=85 infants)

0.14 ng/mL (cord blood mean 

PFDoA) 

Birth weight NS (p>0.05)

Lenters et al. 2016a, 2016b

General population (n=513 infants in 

Greenland subcohort, n=557 infants in 

Ukraine subcohort, and n=180 infants in 

Poland subcohort)

0.13, 0.04, and 0.05 ng/mL 

(maternal median PFDoA for 

Greenland, Ukraine, and 

Poland subcohorts) 

Birth weight NS (p=0.440) 

Wang et al. 2016

General population (n=117 boys and 106 girls 

examined at 2, 5, 8, and 11 years of age) 

0.37 and 0.37 ng/mL (median 

maternal PFDoA for boys and 

girls) 

Birth weight Inverse association (p<0.05)*, girls 

only

Birth length NS (p>0.05)

Head circumference Inverse association (p<0.05)*, girls 

only

Small for gestational age NS (p>0.05)

PFOSA

Bae et al. 2015

General population (233 couples)

0.11 and 0.10 ng/mL and 

0.10 and 0.12 ng/mL 

(geometric mean PFOSA in 

male and female nulliparous 

parents and male and female 

parous parents, respectively)

Male birth OR 1.07 (0.81–1.41), maternal 

PFOSA

OR 1.14 (0.86–1.51), paternal 

PFOSA
PERFLUOROALKYLS 359

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Robledo et al. 2015a, 2015b

General population (n=234 couples)

0.112 and 0.114 ng/mL 

(maternal and paternal 

geometric mean PFOSA)

Birth weight

Boys

Girls

Inverse association (p<0.05)*, 

maternal only

NS (p>0.05), maternal or paternal 

Birth length NS (p>0.05), maternal or paternal 

Head circumference NS (p>0.05), maternal or paternal 

Ponderal index NS (p>0.05), maternal or paternal 

Me-PFOSA-AcOH

Bae et al. 2015

General population (233 couples)

0.29 and 0.28 ng/mL and 

0.28 and 0.32 ng/mL 

(geometric mean Me-PFOSAAcOH in male and female 

nulliparous parents and male 

and female parous parents,

respectively)

Male birth OR 0.98 (0.75–1.28), maternal 

Me-PFOSA-AcOH

OR 0.80 (0.60–1.06), paternal 

Me-PFOSA-AcOH

Female birth OR 0.34 (0.13–0.89)*, paternal 

Me-PFOSA-AcOH 3rd tertile

Robledo et al. 2015a, 2015b

General population (n=234 couples)

0.301 and 0.324 ng/mL 

(maternal and paternal 

geometric mean Me-PFOSAAcOH)

Birth weight NS (p>0.05), maternal or paternal 

Birth length NS (p>0.05), maternal or paternal 

Head circumference NS (p>0.05), maternal or paternal 

Ponderal index NS (p>0.05), maternal or paternal 

Et-PFOSA-AcOH

Bae et al. 2015

General population (233 couples)

0.11 and 0.10 ng/mL and 

0.10 and 0.11 ng/mL 

(geometric mean Et-PFOSAAcOH in male and female 

nulliparous parents and male 

and female parous parents, 

respectively)

Male birth OR 1.22 (0.92–1.60), maternal 

Et-PFOSA-AcOH

OR 0.98 (0.75–1.29, paternal 

Et-PFOSA-AcOH
PERFLUOROALKYLS 360

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-23. Summary of Birth Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Robledo et al. 2015a, 2015b

General population (n=234 couples)

0.109 and 0.105 ng/mL 

(maternal and paternal 

geometric mean Et-PFOSAAcOH)

Birth weight NS (p>0.05), maternal or paternal 

Birth length NS (p>0.05), maternal or paternal 

Head circumference NS (p>0.05), maternal or paternal 

Ponderal index β -0.09 (-0.16 to -0.02)*, maternal

NS (p>0.05), paternal 

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

BMI = body mass index; Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; FSH = follicle stimulating hormone; HR = hazard ratio; 

LH = luteinizing hormone; Me-PFOSA-AcOH = 2-(N-methyl-perfluorooctane sulfonamide) acetic acid; NS = not significant; NR = not reported; OR = odds ratio; 

PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid; RR = relative 

risk; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Stein et al. 2013

Community (C8) (n=320 children 6–12 years 

old)

115.9 ng/mL (estimated in 

utero mean PFOA)

Full scale IQ β 4.61 (0.68–8.54)*, 4th quartile

Reading and math skills NS

Scores on tests of ADHD 

(improvement)

β -8.49 (-16.14 to -0.84)*, 4th

quartile

Stein et al. 2014a, 2014b

Community (C8) (n=321 children 6–12 years 

old)

94.1–838.6 ng/mL (4th PFOA 

quartile measured 3–4 years 

prior to behavioral 

assessment)

Executive function scores 

(mother completed survey)

β -6.39 (-11.43 to -1.35)*, 4th

quartile boys

β -6.39 (-0.03–8.87), 4th quartile girls

Executive function scores 

(teacher completed survey)

β -6.42 (-13.29–0.45), 4th quartile 

boys

β -1.92 (-10.39–6.55), 4th quartile 

girls
PERFLUOROALKYLS 361

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

ADHD-like behaviors 

(mother completed survey)

β -3.82 (-8.96–1.31), 4th quartile boys

β 6.99 (2.47–11.51)*, 4th quartile 

girls

β 2.30 (-1.18–5.77), 4th quartile boys 

and girls

ADHD-like behaviors 

(teacher completed survey)

β -9.25 (-18.78–0.27), 4th quartile 

boys

β -3.65 (-10.85–3.51) 4th quartile girls

β -6.03 (-11.40 to -0.66)*, 4th

quartile boys and girls

Behavioral problems and 

emotional disturbances 

(mother completed survey)

β -1.55 (-5.91–2.82), 4th quartile boys

β 4.63 (0.72–8.53)*, 4th quartile girls

Behavioral problems and 

emotional disturbances 

(teacher completed survey)

β -2.47 (-8.24–3.30), 4th quartile boys

β -0.91 (-6.19–4.37), 4th quartile girls

Stein and Savitz 2011

Community (C8) (n=10,546 children aged 5–

18 year)

65.3–2,070.6 ng/mL 

(4th PFOA quartile)

ADHD OR 0.76 (0.64–0.90)*, 4th quartile

Learning problems

12–15 years old

5–18 years old

OR 0.96 (0.73–1.26), 4th quartile

OR 0.90 (0.76–1.06), 4th quartile

Braun et al. 2014

General population (n=175 children 4 and 

5 years old)

5.5 ng/mL (maternal median 

PFOA)

Social responsiveness scale 

score (measure of autistic 

behaviors)

β -2.0 (-4.4–0.4)

Chen et al. 2013

General population (239 children 2 years of 

age)

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
PERFLUOROALKYLS 362

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Donauer et al. 2015

General population (n=349 infants at 5 weeks 

of age)

5.49 ng/mL (maternal 

geometric mean PFOA)

Social/easy going NS (p>0.05)

Hypotonic OR 3.79 (1.1–12.8)* per 10-fold 

increase in PFOA

High arousal/difficult NS (p=0.3533)

Fei et al. 2008b

General population (n=1,400 infants)

5.6 ng/mL (maternal median 

PFOA)

Apgar scores <10 OR 1.14 (0.57–2.25)

Motor and mental 

development at 6 months 

NS (p>0.05)

Neurobehavioral milestones 

at 18 months

NS (p>0.05)

Fei and Olsen 2011

General population (n=526–787 7-year-old 

children)

5.4 ng/mL (maternal median 

PFOA)

Behavioral problems NS (p>0.15 for trend)

Motor coordination NS (p=0.89 for trend)

Forns et al. 2015

General population (n=843 infants) 

40 ng/L (median PFOA 

breast milk level)

Risk of an abnormal score 

on neurobehavioral 

assessment questionnaire 

OR 1.05 (0.77-1.44) at 6 months of 

age

OR 1.0 (0.78-1.28) at 24 months of 

age

Goudarzi et al. 2016

General population (n=173 infants at 6 months 

and 133 at 18 months)

1.2 ng/mL (maternal median 

PFOA)

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 of 

age

NS (p>0.05)

Gump et al. 2011

General population (n=83 children aged 9–

11 years)

3.23 ng/mL (mean PFOA) Performance on task 

requiring behavioral 

inhibition

NS (p>0.05)

Hoffman et al. 2010

General population (NHANES) (n=571 children 

12–15 years)

4.4 ng/mL (median PFOA) ADHD (parent reported) OR 1.12 (1.01–1.23)*, per 1 ng/mL 

PFOA
PERFLUOROALKYLS 363

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Høyer et al. 2015a

General population (n=1,106 children aged 5–

9 years)

1.4 and 1.9–9.8 ng/mL 

(maternal median and 

3rd tertile PFOA)

Motor skills β -0.2 (-1.2–0.9) 

Abnormal behavior OR 2.7 (1.2–6.3)*, 3rd tertile

Hyperactivity OR 3.1 (1.3–7.2)*, 3rd tertile

Lien et al. 2016

General population (n=282 children aged 

7 years)

1.55 ng/mL (cord blood 

weighted average PFOA)

Inattention NS (p=0.7758)

Hyperactivity/impulsivity NS (p=0.2997)

Emotional symptoms NS (p=0.691)

Conduct problems NS (p=0.2664)

Hyperactivity/inattention NS (p=0.774)

Liew et al. 2015

General population (n=215, ADHD cases, 

213 autism cases, 545 controls)

4.06, 3.88, and 4.00 ng/mL 

(maternal median PFOA for 

ADHD, autism, and controls)

ADHD RR 0.98 (0.82–1.16) 

Autism RR 0.98 (0.73–1.31)

Ode et al. 2014

General population (n=206 children with ADHD 

and 206 controls; children were 5–17 years old 

at time of diagnosis)

1.80 and 1.83 ng/mL (cord 

blood median PFOA in cases 

and controls)

ADHD OR 0.98 (0.91–1.02), per 1 ng/mL 

increase in PFOA

Quaak et al. 2016

General population (n=76 infants 18 months of 

age)

0.9056 ng/mL (cord mean 

PFOA)

Score on test evaluating 

ADHD

Males

Females

NS (p=0.72), 3rd tertile

NS (p=0.22), 3rd tertile

NS (p=0.31), 3rd tertile

Scores on test evaluating 

externalizing problem

Males

Females

NS (p=0.31), 3rd tertile

Association (p=0.05 and 0.09)*, 

2nd and 3rd tertiles

NS (p=0.74), 3rd tertile

Strøm et al. 2014

General population (n=876 adults age 

20 years) 

3.7 ng/mL (median maternal 

PFOA)

ADHD NS (p=0.45 for trend of 3rd tertile)

Depression NS (p=0.28 for trend of 3rd tertile)

Scholastic achievement NS (p=0.21 for trend of 3rd tertile)
PERFLUOROALKYLS 364

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Vuong et al. 2016

General population (n=256 children aged 5 or 

8 years)

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)

Wang et al. 2015b

General population (n=120 children age 

5 years and 120 children aged 8 years) 

2.50 and 2.50 ng/mL 

(maternal median PFOA for 

5 and 8 year olds) 

IQ score

Age 5 years

Age 8 years

NS

NS 

PFOS

Stein and Savitz 2011

Community (C8) (n=10,546 children aged 5–

18 years)

14.8–<20.2, 20.22–<27.9, 

and 27.9–202.1 ng/mL (2nd, 

3rd, and 4th PFOS quartiles)

ADHD OR 0.99 (0.76–1.30), 4th quartile

Learning problems

5–18 years old

12–15 years old

OR 0.83 (0.70–0.98)*, 2nd quartile

OR 0.68 (0.52–0.89)*, 3rd quartile

Braun et al. 2014

General population (n=175 children 4 and 

5 years old)

13 ng/mL (maternal PFOS 

median)

Social responsiveness scale 

score (test of autism)

No association

Donauer et al. 2015

General population (n=349 infants)

13.25 ng/mL (maternal 

geometric mean PFOS)

Neurobehavioral outcomes NS (p>0.05)

Hypotonic NS (p=0.3996)

High arousal/difficult NS (p=0.4678)

Fei et al. 2008b

General population (n=1,400 infants)

35.3 ng/mL (maternal median 

PFOS)

Apgar scores <10 OR 1.20 (0.67–2.14)

Neurobehavioral milestones 

Delay in age of sitting

Earlier use of word-like 

sounds

Delays in using 2-word 

sentences

Other milestones

Association (p=0.041 for trend)*

Association (p=0.039 for trend)*

Association (p=0.050 for trend)*

NS (p>0.05)

Motor and mental 

development at 6 months

NS (p>0.05)
PERFLUOROALKYLS 365

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Fei and Olsen 2011

General population (n=526–787 children)

34.4 ng/mL (maternal median 

PFOS)

Behavioral health NS (p>0.39 for trend)

Motor coordination NS (p=0.41 for trend)

Forns et al. 2015

General population (n=843 infants) 

110 ng/L (median PFOS 

breast milk level)

Risk of an abnormal score 

on neurobehavioral 

assessment questionnaire 

OR 0.96 (0.76-1.20) at 6 months of 

age

OR 0.93 (0.74-1.17) at 24 months of 

age

Goudarzi et al. 2016

General population (n=173 at 6 months and 

133 at 18 months)

5.7 ng/mL (maternal median 

PFOS)

MDI/PDI at 6 months of age NS (p>0.05)

MDI/PDI at 18 months of 

age

NS (p>0.05)

Gump et al. 2011

General population (n=83 children aged 9–

11 years)

9.90 ng/mL (mean PFOS) Performance on task 

requiring behavioral 

inhibition

Inverse association (p<0.05)*

Hoffman et al. 2010

General population (NHANES) (n=571 children 

12–15 years)

22.6 ng/mL (median PFOS) ADHD (parent reported) OR 1.03 (1.01–1.05)*, per 1 ng/mL 

PFOS

Høyer et al. 2015a

General population (n=1,106 children)

10.0 and 16.6–87.3 ng/mL 

(maternal median and 3rd

tertile PFOS)

Motor skills β -0.1 (-1.2–1.1) 

Abnormal behavior OR 1.5 (0.5–4.8), 3rd tertile

Hyperactivity OR 1.4 (0.4–4.9), 3rd tertile

Lien et al. 2016

General population (n=282 children aged 

7 years)

4.79 ng/mL (cord blood 

weighted average PFOS)

Inattention NS (p=0.8508)

Hyperactivity/impulsivity NS (p=0.6857)

Emotional symptoms NS (p=0.9431)

Conduct problems NS (p=0.4938)

Hyperactivity/inattention NS (p=0.5226)

Liew et al. 2015

General population (n=215, ADHD cases, 

213 autism cases, 545 controls)

26.80, 25.40, and 

27.40 ng/mL (maternal 

median PFOS for ADHD, 

autism, and controls)

ADHD RR 0.87 (0.74–1.02) 

RR 0.79 (0.64–0.98)*, 4th quartile

Autism RR 0.92 (0.69–1.22)
PERFLUOROALKYLS 366

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Ode et al. 2014

General population (n=206 children with ADHD 

and 206 controls)

6.92 and 6.77 ng/mL (cord 

blood median PFOS in cases 

and controls)

ADHD OR 0.98 (0.92–1.04), per 1 ng/mL 

increase in PFOS

Quaak et al. 2016

General population (n=76 infants 18 months of 

age)

1.5836 ng/mL (cord mean 

PFOS)

Score on test evaluating 

ADHD

Males

Females

NS (p=0.19), 3rd tertile

NS (p=0.35), 3rd tertile

NS (p=0.43), 3rd tertile

Scores on test evaluating 

externalizing problem

Males

Females

NS (p=0.31), 3rd tertile

NS (p=0.74), 3rd tertile

NS (p=0.31), 3rd tertile

Strøm et al. 2014

General population (n=876 adults age 

20 years) 

21.4 ng/mL (median maternal 

PFOS)

ADHD NS (p=0.38 for trend of 3rd tertile)

Depression NS (p=0.14 for trend of 3rd tertile)

Scholastic achievement NS (p=0.59 for trend of 3rd tertile)

Vuong et al. 2016

General population (n=256 children 5 or 

8 years of age)

13.2 ng/mL (maternal median 

PFOS) 

Behavioral regulation β 3.14 (0.68–5.61)*

Metacognition β 3.10 (0.62–5.58)*

Global executive functioning β 3.38 (0.86–5.90)*

Global executive functioning 

composite score >60

OR 2.19 (1.03–4.66)*

Wang et al. 2015b

General population (n=120 children age 

5 years and 120 children aged 8 years) 

13.25 and 12.28 ng/mL 

(maternal median PFOS for 

5 and 8 year olds) 

IQ score

Age 5 years

Age 8 years

NS (p>0.05)

NS (p>0.05)

PFHxS

Stein and Savitz 2011

Community (C8) (n=10,546 children aged 5–

18 years)

2.9–<5.2 and 10.1–

276.4 ng/mL (2nd and 

4th PFHxS quartiles)

ADHD

5–18 years

12–15 years

OR 1.27 (1.06–1.52)*, 2nd quartile

OR 1.46 (1.10–1.93)*, 2nd quartile

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
PERFLUOROALKYLS 367

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Braun et al. 2014

General population (n=175 children 4 and 

5 years old)

1.6 ng/mL (maternal PFHxS 

median)

Social responsiveness scale 

score (test for autism)

No association

Gump et al. 2011

General population (n=83 children aged 9–

11 years)

6.06 ng/mL (mean PFHxS) Performance on task 

requiring behavioral 

inhibition

Inverse association (p<0.01)*

Hoffman et al. 2010

General population (NHANES) (n=571 children 

12–15 years)

2.2 ng/mL (median PFHxS) ADHD (parent reported) OR 1.06 (1.02–1.11)*, per 1 ng/mL 

PFOS

Liew et al. 2015

General population (n=215, ADHD cases, 

213 autism cases, 545 controls)

0.84. 0.92, and 0.92 ng/mL 

(maternal median PFHxS for 

ADHD, autism, and controls)

ADHD RR 0.67 (0.54–0.83)*, 4th quartile

Autism RR 1.10 (0.92–1.33)

Vuong et al. 2016

General population (n=256 children 5 or 

8 years of age)

1.5 ng/mL (maternal median 

PFHxS) 

Behavioral regulation β 1.19 (-0.54–5.40)

Metacognition β 1.31 (-0.43–3.04)

Global executive functioning β 1.36 (-0.41–3.12)

Global executive functioning 

composite score >60

OR 1.71 (1.05–2.77)*

Wang et al. 2015b

General population (n=120 children age 

5 years and 120 children aged 8 years) 

0.69 and 0.69 ng/mL 

(maternal median PFHxS for 

5 and 8 year olds) 

IQ score

Age 5 years

Age 8 years

NS (p>0.05)

NS (p>0.05)

PFNA

Stein and Savitz 2011

Community (C8) (n=10,546 children aged 5–

18 years)

1.2–<1.5, 1.5–<2.0, and 2.0–

24.1 ng/mL (2nd, 3rd, and 

4th PFNA quartiles)

ADHD

5–18 years

12–15 years

OR 0.99 (0.84–1.18), 4th quartile

OR 1.00 (0.75–1.32), 4th quartile

Learning problems

5–18 years old

12–15 years old

OR 0.81 (0.69–0.95)*, 3rd quartile

OR 0.73 (0.55–0.98)*, 4th quartile
PERFLUOROALKYLS 368

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Braun et al. 2014

General population (n=175 children 4 and 

5 years old)

0.9 ng/mL (maternal PFNA 

median)

Social responsiveness scale 

score (tests for autism)

No association

Gump et al. 2011

General population (n=83 children aged 9–

11 years)

0.82 ng/mL (mean PFNA) Performance on task 

requiring behavioral 

inhibition

Inverse association (p<0.05)*

Hoffman et al. 2010

General population (NHANES) (n=571 children 

12–15 years)

0.6 ng/mL (median PFNA) ADHD (parent reported) OR 1.32 (0.86–2.02), per 1 ng/mL 

PFNA

Lien et al. 2016

General population (n=282 children aged 

7 years)

4.49 ng/mL (cord blood 

weighted average PFNA)

Inattention Inverse association (p=0.0129)*

Hyperactivity/impulsivity NS (p=0.0588)

Emotional symptoms NS (p=0.1902)

Conduct problems NS (p=0.6931)

Hyperactivity/inattention Inverse association (p=0.0484)*

Liew et al. 2015

General population (n=215, ADHD cases, 

213 autism cases, 545 controls)

0.42, 0.41, and 0.43 ng/mL 

(maternal median PFNA for 

ADHD, autism, and controls)

ADHD RR 0.80 (0.62–1.03) 

Autism RR 0.80 (0.58–1.11)

Vuong et al. 2016

General population (n=256 children 5 or 

8 years of age)

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)

Wang et al. 2015b

General population (n=120 children age 

5 years and 120 children aged 8 years) 

1.59 and 1.44 ng/mL 

(maternal median PFNA for 

5 and 8 year olds) 

IQ score NS (p>0.05)

IQ scores, age 8 years

Full scale IQ

Visual IQ

Performance IQ

NS (p>0.05)

Association (p<0.05)*

NS (p>0.05)
PERFLUOROALKYLS 369

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFDeA

Gump et al. 2011

General population (n=83 children aged 9–

11 years)

0.26 ng/mL (mean PFDeA) Performance on task 

requiring behavioral 

inhibition

Inverse association (p<0.05)*

Liew et al. 2015

General population (n=215, ADHD cases, 

213 autism cases, 545 controls)

0.15, 0.15, and 0.17 ng/mL 

(maternal median PFDeA for 

ADHD, autism, and controls)

ADHD RR 0.76 (0.64–0.91)*

RR 0.53 (0.43–0.66)*, 4th quartile

Autism RR 0.79 (0.63–1.01)

RR 0.52 (0.35–0.77)*, 4th quartile

Vuong et al. 2016

General population (n=256 children 5 or 

8 years of age)

0.2 ng/mL (maternal median 

PFDeA) 

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)

Wang et al. 2015b

General population (n=120 children age 

5 years and 120 children aged 8 years) 

0.44 and 0.44 ng/mL 

(maternal median PFDeA for 

5 and 8 year olds) 

IQ score

Age 5 years

Age 8 years

NS (p>0.05)

NS (p>0.05)

PFUA

Lien et al. 2016

General population (n=282 children aged 

7 years)

7.96 ng/mL (cord blood 

weighted average PFUA)

Inattention NS (p=0.6177)

Hyperactivity/impulsivity NS (p=0.3642)

Emotional symptoms NS (p=0.0517)

Conduct problems NS (p=0.1207)

Hyperactivity/inattention NS (p=0.9991)

Wang et al. 2015b

General population (n=120 children age 

5 years and 120 children aged 8 years) 

3.42 and 3.13 ng/mL 

(maternal median PFUA for 

5 and 8 year olds) 

IQ score NS (p>0.05)

IQ scores, age 8 years

Full scale IQ

Visual IQ

Performance IQ

NS (p>0.05)

NS (p>0.05) 

Inverse association (p<0.05)*
PERFLUOROALKYLS 370

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-24. Summary of Neurodevelopmental Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFDoA

Wang et al. 2015b

General population (n=120 children age 

5 years and 120 children aged 8 years) 

0.38 and 0.37 ng/mL 

(maternal median PFDoA for 

5 and 8 year olds) 

IQ score

Age 5 years

Age 8 years

NS (p>0.05)

NS (p>0.05)

PFOSA

Gump et al. 2011

General population (n=83 children aged 9–

11 years)

0.75 ng/mL (mean PFOSA) Performance on task 

requiring behavioral 

inhibition

Inverse association (p<0.05)*

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

ADHD = attention deficit hyperactivity disorder; MDI/PDI = mental and psychomotor development indices; NHANES = National Health and Nutrition Examination 

Survey; NS = not significant; OR = odds ratio; PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; 

PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; 

PFUA = perfluoroundecanoic acid
PERFLUOROALKYLS 371

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Lopez-Espinosa et al. 2011

Community (C8) (n=3,076 boys and 2,931 girls 

aged 8–18 years)

26 and 20 ng/mL (median 

PFOA in boys and girls)

Age of puberty

Boys

Girls

OR 0.95 (0.84–0.07)

OR 0.54 (0.35–0.84)*, 2nd quartile

Lopez-Espinosa et al. 2016

Community (C8) (n=1,169 boys and 1,123 girls 

aged 6–9 years)

34.8 and 30.1 ng/mL (median 

PFOA in boys and girls)

Estradiol NS (interquartile difference of 4.3, 

95% CI -0.4–9.1), boys

NS (4.2, 95% CI -0.7–9.4), girls 

Total testosterone Inverse association (-4.9, 95%

CI -8.7 to -0.8)*, boys 

NS (-2.5, 95% CI -6.7–1.8), girls

Insulin-like growth factor-1 NS (-0.4, 95% CI -3.4–2.7), boys

Inverse association (-3.6, 95%

CI -6.6 to -0.5)*, girls

Christensen et al. 2011

General population (n=448 girls)

3.7 ng/mL (maternal median 

PFOA)

Earlier age of menarche OR 1.01 (0.61–1.68)

Itoh et al. 2016

General population (n=189 infants)

1.4 ng/mL (maternal median 

PFOA)

Cord estradiol NS (p>0.05)

Cord testosterone NS (p>0.05)

Cord testosterone: estradiol 

ratio

NS (p>0.05)

Cord progesterone NS (p>0.05)

Cord prolactin NS (p>0.05)

Cord LH NS (p>0.05)

Cord FSH NS (p>0.05)

Cord SHGB NS (p>0.05)

Cord insulin-like factor 3 NS (p>0.05)

Cord inhibin

Males

Females

Association (p=0.040)*

NS (p>0.05)
PERFLUOROALKYLS 372

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Kristensen et al. 2013

General population (n=343 females 

approximately 20 years of age) 

3.6 and 4.4–19.8 ng/mL 

(maternal median PFOA and 

3rd PFOA tertile)

Age of menarche Association (p=0.01)* 

Menstrual cycle length NS (p>0.05)

Total testosterone NS (p>0.05)

SHBG NS (p>0.05)

Free androgen index NS (p>0.05)

Dehydroepiandrosterone 

sulphate

NS (p>0.05)

Anti-Müllerian hormone NS (p>0.05)

Number of follicles/ovary NS (p>0.05)

Maisonet et al. 2015

General population (n=72 girls aged 15 years)

>4.1 ng/mL (maternal 3rd

tertile PFOA) 

Testosterone β 0.24 (0.05–0.43)*, 3rd tertile 

SHBG β 5.02 (-13.07–11.00), 3rd tertile

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)

2.6 and 2.1 ng/mL (median 

cord blood PFOA Denmark 

and Finland cohorts)

Cryptorchidism OR 0.51 (0.21–1.20), whole cohort 

OR 0.35 (0.12–0.99, p=0.04 for 

trend)*, Finland cohort 3rd tertile 

PFOS

Lopez-Espinosa et al. 2011

Community (C8) (n=3,076 boys and 2,931 girls 

aged 8–18)

20 and 18 ng/mL (PFOS 

median in boys and girls)

Age of puberty

Boys

Girls

OR 0.58 (0.37–0.90)*, 3rd quartile

OR 0.55 (0.35–0.86)*, 3rd quartile

Lopez-Espinosa et al. 2016

Community (C8) (n=1,169 boys and 1,123 girls 

aged 6–9 years)

22.4 and 20.9 ng/mL (PFOS 

median in boys and girls)

Estradiol 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 

Total testosterone Inverse association (-5.8, 95%

CI -9.4 to -2.0)*, boys 

Inverse association (-6.6, 95%

CI -10.1 to -2.8)*, girls
PERFLUOROALKYLS 373

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Insulin-like growth factor-1 Inverse association (-5.9, 95%

CI -8.3 to -3.3)*, boys

Inverse association (-5.6, 95%

CI -8.2 to -2.9)*, girls

Christensen et al. 2011

General population (n=448 girls)

19.8 ng/mL (maternal median 

PFOS)

Earlier age of menarche OR 0.68 (0.40–1.13)

Itoh et al. 2016

General population (n=189 infants)

5.2 ng/mL (maternal median 

PFOS)

Cord estradiol

Males

Females

Association (p=0.021)*

NS (p>0.05)

Cord testosterone NS (p>0.05)

Cord testosterone: estradiol 

ratio

Males

Females

Inverse association (p=0.008)*

NS (p>0.05)

Cord progesterone

Males

Females

Association (p=0.043)*

Association (p=0.002)*

Cord prolactin

Males

Females

NS (p>0.05)

Association (p=0.001)*

Cord LH NS (p>0.05)

Cord FSH NS (p>0.05)

Cord SHGB NS (p>0.05)

Cord insulin-like factor 3 NS (p>0.05)

Cord inhibin

Males

Females

Association (p<0.001)*

NS (p>0.05)
PERFLUOROALKYLS 374

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Kristensen et al. 2013

General population (n=343 young women 

approximately 20 years of age)

21.1 ng/mL (maternal median 

PFOS)

Age of menarche NS (p=0.28)

Menstrual cycle length NS (p>0.05)

Total testosterone NS (p>0.05)

SHBG NS (p>0.05)

Free androgen index NS (p>0.05)

Dehydroepiandrosterone 

sulphate

NS (p>0.05)

Anti-Müllerian hormone NS (p>0.05)

Number of follicles/ovary NS (p>0.05)

Toft et al. 2016

General population (270 cases cryptorchidism, 

75 cases hypospadias, and 300 controls) 

>1.4 ng/mL (amniotic fluid 

3rd tertile PFOS)

Cryptorchidism OR 1.01 (0.66–1.53), 3rd tertile 

Hypospadias OR 0.69 (0.35–1.38), 3rd tertile

Testosterone Association (p=0.002)*

Androstendione Association (p=0.001)*

Progesterone Association (p=0.001)*

Cortisol Association (p<0.001)*

DHEAS NS (p=0.93)

Insulin-like factor 3 Inverse association (p<0.001)*

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 (median 

cord blood PFOS Denmark 

and Finland cohorts)

Cryptorchidism OR 0.83 (0.44–1.58), whole cohort 
PERFLUOROALKYLS 375

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFHxS

Lopez-Espinosa et al. 2016

Community (C8) (n=1,169 boys and 1,123 girls 

aged 6–9 years)

8.1 and 7.0 ng/mL (PFHxS 

median in boys and girls)

Estradiol NS (interquartile difference of -1.3, 

95% CI -5.5–3.1), boys

NS (2.1, 95% CI -2.2–6.5), girls 

Total testosterone NS (-2.7, 95% CI -6.4–1.2), boys 

NS (0.2, 95% CI -3.5–4.0), girls

Insulin-like growth factor-1 NS (-2.5, 95% CI -5.2–0.3), boys

NS (-2.1, 95% CI -4.8–0.7), girls

Christensen et al. 2011

General population (n=448 girls)

1.6 ng/mL (maternal median 

PFHxS)

Earlier age of menarche OR 0.89 (0.65–1.22)

Maisonet et al. 2015

General population (n=72 girls aged 15 years)

>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

PFNA

Lopez-Espinosa et al. 2016

Community (C8) (n=1,169 boys and 1,123 girls 

aged 6–9 years)

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 

Total testosterone NS (-2.1, 95% CI -5.5–1.3), boys 

NS (-1.9, 95% CI -5.5–1.9), girls

Insulin-like growth factor-1 Inverse association (-3.5, 95%

CI -6.0 to -1.0)*, boys

Inverse association (-3.8, 95%

CI -6.4 to -1.2)*, girls

Maisonet et al. 2015

General population (n=72 girls aged 15 years)

>0.6 ng/mL (maternal 

3rd tertile PFNA) 

Testosterone β 0.05 (-0.14–0.24), 3rd tertile 

SHBG β 7.91 (-8.69–24.52), 3rd tertile

PFOSA

Christensen et al. 2011

General population (n=448 girls)

0.2 ng/mL (maternal median 

PFOSA)

Earlier age of menarche OR 0.91 (0.67–1.24)

Me-PFOSA-AcOH
PERFLUOROALKYLS 376

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-25. Summary of Effects on the Development of the Reproductive System in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Christensen et al. 2011

General population (n=448 girls)

0.4 ng/mL (maternal median 

Me-PFOSA-AcOH)

Earlier age of menarche OR 0.86 (0.66–1.12)

Et-PFOSA-AcOH

Christensen et al. 2011

General population (n=448 girls)

0.6 ng/mL (maternal median 

Et-PFOSA-AcOH)

Earlier age of menarche OR 1.03 (0.75–1.43)

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

CI = confidence interval; DHEAS = dihydroepiandrosterone sulfate; Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; FSH = follicle 

stimulating hormone; LH = luteinizing hormone; Me-PFOSA-AcOH = 2-(N-methyl-perfluorooctane sulfonamide) acetic acid; NS = not significant; OR = odds ratio; 

PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; SHBG = sex 

hormone binding globulin
PERFLUOROALKYLS 377

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 

epidemiology studies did not find associations between perfluoroalkyl exposure and adverse pregnancy 

outcomes (miscarriage, preterm birth, or gestational age) for PFOA, PFOS, PFHxS, PFNA, or PFUA. 

Mixed results have been found for birth outcomes, particularly birth weight. Some epidemiology studies 

have found associations between maternal PFOA or PFOS exposure and decreases in birth weight, and 

meta-analyses of these data have found that increases in maternal PFOA or PFOS were associated with 

15–19 g or 5 g decreases in birth weight, respectively; accounting for maternal glomerular filtration rates 

attenuated these results by about 50%. No consistent associations for alterations in birth weight were 

found for other perfluoroalkyls (PFHxS, PFNA, PFDeA, PFUA, PFDoA, Me-PFOSA-AcOH, Et-PFOSAAcOH). Overall, no associations were found between serum PFOA, PFOS, PFHxS, PFNA, or PFUA and 

increases in the risk of low birth weight or small for gestational age infants. No consistent results for 

risks of birth defects have been found; these potential endpoints were only examined for a few 

perfluoroalkyls. The available epidemiology data do not suggest associations between perfluoroalkyls 

and IQ or scholastic achievement for PFOA, PFOS, PFHxS, PFNA, PFDeA, PFUA, or PFDoA. 

Similarly, no associations were found between PFOA, PFOS, PFHxS, PFNA, or PFDeA and increased 

risk of ADHD; several studies have 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 2-4, 2-6, 2-7, and 2-8. Laboratory animal studies provide 

strong evidence of the developmental toxicity of a number of perfluoroalkyl compounds. Prenatal losses 

and decreases in pup survival were observed following exposure to PFOA, PFOS, PFNA, and PFDeA; no 

deaths were observed in a single study of PFBuS. Decreases in fetal weights, birth weight, and pup 

weight were observed in studies of PFOA, PFOS, PFNA, PFDeA, and PFUA; no effects on weight were 

observed in studies on PFHxS or PFBuS. 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 PFDeA. Studies in laboratory animals have examined a number of developmental endpoints, including 

pup survival, malformations, birth weight, mammary gland development, and neurodevelopment.
PERFLUOROALKYLS 378

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFOA

Epidemiology Studies—Pregnancy Outcomes. The results of available epidemiology studies of women 

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), or pre-term birth 

(Chen et al. 2012a; Darrow et al. 2013; Hamm et al. 2010; Stein et al. 2009; Whitworth et al. 2012a) were 

found; the Whitworth et al. (2012a) general population studies reported a decrease in the risk of preterm 

births among women with serum PFOA levels in the 4th quartile. Additionally, Apelberg et al. (2007b) 

and Chen et al. (2012a) did not find associations between maternal serum PFOA levels and gestational 

age.

Epidemiology Studies—Birth Outcomes. Community and general population exposure studies have 

evaluated 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; and 

birth defects. In highly exposed populations, no association between maternal serum PFOA levels and 

birth 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), Lenters et al. (2016a), and Maisonet et al. (2012) found an inverse association between 

maternal serum PFOA and birth weight. However, 12 other general population studies did not find 

associations (Bach et al. 2016; Chen et al. 2012a; Govarts et al. 2016; Hamm et al. 2010; Kim et al. 2011; 

Lee et al. 2013, 2016; Monroy et al. 2008; Robledo et al. 2015a; Wang et al. 2016; Washino et al. 2009; 

Whitworth et al. 2012a). As illustrated in Figure 2-33, most studies found no association between 

maternal serum PFOA levels and the risk of low birth weight infants (typically defined as <2,500 g) 

(Chen et al. 2012a; Darrow et al. 2013; Fei et al. 2007, 2008a; 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, 

there were no increases in the risk for small for gestational age (Chen et al. 2012a; Fei et al. 2007, 2008a; 

Hamm et al. 2010; Savitz et al. 2012b; Wang et al. 2016; Whitworth et al. 2012a); these data are 

presented in Figure 2-34. One study (Savitz et al. 2012b) of C8 participants did find an increase in the 

risk 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). Two 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) (Apelberg et al. 2007b; Fei et al. 2007, 2008a). However, most studies did not find 
PERFLUOROALKYLS 379

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-33. Risk of Low Birth Weight Infant Relative to PFOA Levels (Presented as Adjusted Odds Ratios) 
PERFLUOROALKYLS 380

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-34. Risk of Small For Gestational Age Infant Relative to PFOA Levels (Presented as Adjusted Odds 

Ratios)
PERFLUOROALKYLS 381

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

associations between maternal serum PFOA levels and birth length; head, chest, or abdominal 

circumference; or ponderal index (Bach et al. 2016; Chen et al. 2012a; Lee et al. 2013; Maisonet et al. 

2012; Robledo et al. 2015a; Wang et al. 2016).

In a systematic review of 19 epidemiology studies discussed above, Johnson et al. (2014) evaluated the 

possible association between PFOA exposure and fetal growth and concluded that there was sufficient 

evidence 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), and Maisonet 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 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 to evaluate the influence of glomerular filtration rate on 

the association between maternal PFOA and birth weight. Utilizing simulated maternal PFOA levels at 

delivery, a 1 ng/mL increase in PFOA was associated 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 small number of studies have examined the potential associations between PFOA exposure and risks of 

birth 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).

Epidemiology Studies—Neurodevelopmental Outcomes. A number of epidemiology studies have 

evaluated neurodevelopment at various ages using maternal serum PFOA or cord blood PFOA as a 

biometric of exposure. Fei et al. (2008b) did not find an increased risk of Apgar scores of <10 in 

newborns. 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 tests of social/easy 

going or high arousal/difficult. Goudarzi et al. (2016) reported lower scores on tests of mental and 

psychomotor development in female 6-month-old infants; no association was found when male and 

female infants were grouped together. When the infants were tested at 18 months of age, no association 

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 
PERFLUOROALKYLS 382

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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. (2016) studies suggest some delays in neurodevelopment in young infants, more 

research is needed before establishing a possible relationship with PFOA. 

Studies in children have examined possible links 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 or 

math 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. 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 olds or motor skills in 5–9 year olds.

Several studies have examined possible associations between maternal or child PFOA levels and scores 

on tests/surveys that assess behavioral problems. No associations between maternal PFOA levels and 

behavioral problems in 7 year olds (Fei and Olsen 2011) or behavioral regulation problems in 5 or 8 year 

olds (Vuong et al. 2016). Similarly, no associations between serum PFOA levels and performance on 

tasks requiring behavioral inhibition were observed in 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 were observed (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 with maternal 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, the association was only found when the survey was completed by mothers, but not when 

completed by the child’s teacher.

Ten studies have looked for a possible link between PFOA and ADHD in children. Two studies of 

participants of the C8 Health Study found lower scores on tests for ADHD (Stein et al. 2013) or lower 
PERFLUOROALKYLS 383

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 no 

associations 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, the 

association was only found in 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 median maternal 

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 find 

increased 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 

PFOA 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).

Epidemiology Studies—Development of the Reproductive System. Studies exploring possible links 

between PFOA and alterations in the development of the reproductive system have examined several 

outcomes including hormone levels in cord blood, hormone levels in children and adolescents, congenital 

malformations of reproductive organs, and age of puberty in boys and girls.

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 with

maternal 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 Health 
PERFLUOROALKYLS 384

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Study (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 no 

associations 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).

In a community exposure study (Lopez-Espinosa et al. 2011), increasing levels of serum PFOA were 

associated with delays in menarche in girls aged 8–18 years. Serum PFOA levels in the 2nd, 3rd, and 

4th 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 and 

delays 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 

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 and 

variations among the exposed groups and controls was comparable.

In utero exposure to PFOA resulted in prenatal losses and decreases in pup survival. 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 
PERFLUOROALKYLS 385

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 in pup 

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 

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), and

20 mg/kg/day (Lau et al. 2006; Li et al. 2016). A decrease in mean litter weight on PNDs 2–14 was 

observed in mice administered ≥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 crossfostering study, lactation-only exposure (maternal dose of 5 mg/kg/day PFOA) resulted in decreased body 

weight in female pups on some 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 of age, 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 
PERFLUOROALKYLS 386

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

groups. At termination (18 months of 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 to a 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 weight measurements 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 

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 the 

offspring of mice exposed to 0.3 mg/kg/day in the diet on GDs 1–21. An increased percentage of litters 

with 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 high 

as 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; Wolf 

et 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 preputial 

separation at ≥1 mg/kg/day and delayed vaginal opening at 20 mg/kg/day. The effect in 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 this dose.

A series of studies conducted by White and associates found significant delays in mammary gland 

development in the offspring of mice administered 1 mg/kg/day PFOA via gavage on GDs 8–17 (White et 
PERFLUOROALKYLS 387

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

al. 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 in 

timing 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 by 

developmental 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 in 

mammary 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 and 

63, 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 

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 (the 

highest NOAEL for this strain was 0.1 mg/kg/day); it is noted that the serum PFOA concentrations at a 

given dose were lower in the C57Bl/6 mice than in the CD-1 mice.

A consistent finding in the four mouse studies evaluating the neurodevelopmental toxicity of PFOA is an 

increase 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. Significant increases 

in open field activity were observed at PND 36 in the offspring 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 to controls, and a 20-minute period with significantly 

increased spontaneous activity. Similarly, Onishchenko et al. (2011) reported an increase in activity in a 
PERFLUOROALKYLS 388

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

48-hour period in the adult offspring of 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 the cholinergic 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 with an 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 not alter 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 initial novel object exploratory behavior were also observed at 0.1 mg/kg/day, 

but there were no alterations in recognition time for novel objects (Sobolewski et al. 2014).

Although not investigated in mammalian species, studies in chicken embryos and hatchlings demonstrate 

the developmental cardiotoxicity of PFOA (Jiang et al. 2012, 2013, 2016). The effects following in ovo

exposure include thinning of the right ventricular wall in chick embryos and alterations 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 exposure suggest 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. Epidemiology studies have examined a number of potential developmental outcomes in 

communities living near a PFOA facility and in the 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 

reviews of these data have concluded that there was sufficient evidence that maternal PFOA levels are 

associated with reductions in fetal growth. After correcting for glomerular filtration rate, a small decrease 

in birth weight 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 adverse pregnancy outcomes such as miscarriages or stillbirths, most birth outcomes (e.g., risk 

of low birth weight, risk of small for gestational age, birth length, ponderal index, sex ratio, or birth 
PERFLUOROALKYLS 389

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

defects), or neurodevelopmental outcomes (IQ or scholastic achievement, motor skills, and risk of 

ADHD). Animal studies 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, and 

increased motor activity.

PFOS

Epidemiology Studies—Pregnancy Outcomes. No associations between maternal PFOS levels and the 

risk of miscarriages were observed in several studies (Darrow et al. 2014; Jensen et al. 2015; Stein et al. 

2009). Two 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) 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 et al. 2012a). Two other studies did not find associations for preterm birth (Fei et al. 2007, 

2008a; Hamm et al. 2010). 

Epidemiology Studies—Birth Outcomes. Occupational, community, and general population exposure 

studies have examined the possible links between maternal PFOS levels and 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; and birth defects. Most studies did not find 

associations between maternal serum PFOS levels and birth weight (Apelberg et al. 2007b; AshleyMartin et al. 2016; 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; Lee et al. 2013, 2016; Lenters et al. 2016a; Maisonet et al. 2012; 

Monroy et al. 2008; Robledo et al. 2015a; 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). Three studies did find inverse associations 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. 

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). Although these 

studies found decreases in birth weight associated with PFOS levels, no studies found increases in the risk 
PERFLUOROALKYLS 390

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

of low birth weight infants (Chen et al. 2012a; Darrow et al. 2013; Fei et al. 2007, 2008a; Stein et al. 

2009) or small for gestational age infants (Chen et al. 2012a; Fei et al. 2007, 2008a; Hamm et al. 2010; 

Whitworth et al. 2012a). The ORs for low birth weight and small for gestational age risks are presented 

in Figures 2-35 and 2-36. Maternal PFOS was not associated with birth length (Apelberg et al. 2007b; 

Bach et al. 2016; Chen et al. 2012a; Fei et al. 2007, 2008a; Lee et al. 2013; Robledo et al. 2015a;

Washino et al. 2009) with the exception of the finding of a small decrease in birth length (-0.63 cm) that 

was associated with 3rd tertile maternal serum PFOS levels. Two studies reported inverse associations 

between ponderal index and cord blood PFOS levels (Apelberg et al. 2007b) and maternal serum PFOS 

levels (Lee et al. 2013); other studies did not find this effect (Chen et al. 2012a; Maisonet et al. 2012; 

Robledo et al. 2015a). Two studies reported small decreases in head circumference, which were 

associated 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; de Cock et al. 2014; Fei et al. 2007, 

2008a; Lee et al. 2013; Robledo et al. 2015a; Washino et al. 2009). Verner et al. 2015) conducted a metaanalysis 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 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 weight decreased (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. 

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 in 

boys (Liew et al. 2014). Bae et al. (2015) did not find associations between the odds of having a boy and 

paternal or maternal serum PFOS levels. 

Epidemiology Studies—Neurodevelopmental Outcomes. Epidemiology 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 use 

of word-like sounds, and delays in using two- word sentences) were associated with maternal PFOS 

levels. Goudarzi et al. (2016) did not find alterations on mental and psychomotor development in 6- and 

18-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).
PERFLUOROALKYLS 391

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-35. Risk of Low Birth Weight Infant Relative to PFOS Levels (Presented as Adjusted Odds Ratios)
PERFLUOROALKYLS 392

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-36. Risk of Small for Gestational Age Infant Relative to PFOS Levels (Presented as Adjusted Odds 

Ratios) 
PERFLUOROALKYLS 393

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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. Strøm et al. (2014) found no associations between 

scholastic achievement in 20 year olds and maternal PFOS levels. In a study of children 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 associated with

maternal PFOS levels. Three studies have not found links between maternal PFOS levels and behavioral 

health and motor coordination/skills in children (Fei and Olsen 2011; Høyer et al. 2015a) or between 

breast milk PFOS levels and behavioral development in 6- and 24-month-old infants (Forns et al. 2015). 

A third study (Vuong et al. 2016) found an increased risk for problems with behavioral 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 in children 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.

Epidemiology Studies—Development of Reproductive System. Several epidemiology studies have 

examined 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 of 

cryptorchidism (Toft et al. 2016; Vesterholm Jensen et al. 2014) or hypospadias (Toft et al. 2016) were 

found in two studies. Itoh et al. (2016) reported associations between maternal PFOS levels and 

alterations in cord blood hormone levels, in particular 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) found associations 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 insulin-like growth factor 1 were observed. 

Inverse associations between total testosterone and insulin-like growth factor 1 and serum PFOS levels 

were also observed in the girls. A study of young adult women found no associations between 

reproductive hormone levels and maternal PFOS levels (Kristensen et al. 2013). 
PERFLUOROALKYLS 394

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 of 

menarche 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 three 

studies. 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, and 

found 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 have 

also 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 the 

number 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 

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 
PERFLUOROALKYLS 395

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 a 

contributing 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 of 

pups 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). Histological 

damage has also been reported in pups exposed to lower PFOS levels. Lung atelectasis was observed in 

pups 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, and 

focal infiltration of inflammation cells were observed in pups exposed to 2 mg/kg/day on GDs 0–21; no 

lung 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, and 

rabbits 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; Luebker et al. 2005a, 2005b; Rogers et al. 2014; Xia 

et al. 2011; Yahia et al. 2008). In rats, the lowest-adverse-effect level for decrease in fetal body weight 

was 10 mg/kg/day following administration on GDs 2–20 (Thibodeaux et al. 2003) and the highest noeffect 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 and pup 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 
PERFLUOROALKYLS 396

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 observed 

in 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 to 

mating 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 of 

cleft palate was observed in rats exposed to 10 mg/kg/day on GDs 2–20 (Thibodeaux et al. 2003) and in 

mice 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 (Case 

et al. 2001), wavy ribs and spina bifida occulta in mice exposed to 10 mg/kg/day on GDs 1–17 (Yahia et 

al. 2008), and tail abnormalities and delayed ossification of phalanges at 20 mg/kg/day (Yahia et al. 

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 histological 

alterations 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 in 
PERFLUOROALKYLS 397

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

cholesterol levels in fetal livers of mice exposed to PFOA on GDs 1–17 and Wan et al. (2014b) found 

increases in relative liver weights in pups on PND 21.

Neurodevelopmental studies have shown that prenatal and/or postnatal exposure to PFOS can affect 

motor 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 were 

placed 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 and 

increases 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 of 

time 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 

0.3 or 1.0 mg/kg/day PFOS throughout gestation and lactation. However, this effect was only observed in 

male rats on PND 17; no significant alterations were observed on PNDs 13, 21, or 61. An increase in 

locomotion 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-minute 

sequential 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 to 

the 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 habituation 

differed 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 of 

testing, 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 to 
PERFLUOROALKYLS 398

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

nicotine 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 the 

offspring of rats exposed to 3.2 mg/kg/day for 6 weeks prior to mating and throughout gestation and 

lactation (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 in 

rats 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 

1 mg/kg/day (Luebker et al. 2005b). No alterations in thyroid histology or follicular morphology were 

observed in rats exposed to 1 mg/kg/day on GD 0–PND 20 (Chang et al. 2009), and no alterations in TSH 

levels 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, and 

throughout 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 to 

sRBCs 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 epidemiology studies have evaluated developmental outcomes in occupational, 

community (living near a PFOA facility), and general exposure populations. Overall, these studies have 

not found associations between serum PFOS and adverse pregnancy outcomes (miscarriage, preterm 
PERFLUOROALKYLS 399

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 that some 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 and birth weight, a meta-analysis 

did find a small decrease in birth weight was associated with increasing maternal 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 and delayed skeletal 

ossification; and decreases in offspring motor activity.

PFHxS

Epidemiology Studies—Pregnancy Outcomes. Two studies, summarized in Table 2-22 have evaluated 

possible links 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) found a 

decreased risk of preterm births among women with serum PFHxS levels in the 3rd tertile.

Epidemiology 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 et 

al. (2012) reported inverse associations between maternal PFHxS levels and birth weight; however, other 

studies have not found associations (Hamm et al. 2010; Kim et al. 2011; Lee et al. 2013, 2016; Lenters et 

al. 2016a; Monroy et al. 2008). The risk of low birth weight infants was not examined in the available 

epidemiology studies; Hamm et al. (2010) did not find an association between maternal PFHxS level and 

the relative risk of small for gestational age. Several studies did not find associations between maternal 

PFHxS levels and birth length, head circumference, or ponderal index (Bach et al. 2016; Lee et al. 2013). 

Maisonet et al. (2012) found an inverse association for birth length, but no association for ponderal index. 

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.
PERFLUOROALKYLS 400

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Epidemiology Studies—Neurodevelopmental Outcomes. Epidemiology studies, summarized in 

Table 2-24, have examined PFHxS-related alterations in risks of ADHD, autism, IQ, and behavior. Wang 

et al. (2015b) did not find associations between maternal PFHxS levels and IQ in 5- or 8-year-old 

children. However, Vuong et al. (2016) found a higher risk of performing poorly on tests of global 

executive function with increasing maternal PFHxS levels. No association between serum PFHxS levels 

and the risk of learning problems was found in children living in a community with high PFOA levels 

(Stein and Savitz 2011). Gump et al. (2011) found an inverse association between serum PFHxS levels 

and performance on tasks requiring behavioral inhibition; Vuong et al. (2016) did not find alterations in 

behavioral regulation. 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 of autism; 

Braun et al. (2014) also found no association between maternal PFHxS levels and performance on tests 

assessing autism.

Epidemiology 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 of 

age. Christensen et al. (2011) did not find an association between maternal PFHxS levels and risk of an 

earlier menarche. Summaries of these epidemiology studies are presented in Table 2-25.

Laboratory Animal Studies. Administration of 9.2 mg/kg/day PFHxS on PND 10 resulted in a decrease 

in 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 affect 

spontaneous motor activity, which was in contrast to the nicotine-induced increases in spontaneous motor 

activity observed in the controls and lower PFHxS groups. Another study evaluating the developmental 

toxicity of PFHxS did not find alterations in litter size, pup survival, or pup body weight in rats exposed 

to 10 mg/kg/day PFHxS for 14 days prior to mating and throughout gestation and lactation (Butenhoff et 

al. 2009a; Hoberman and York 2003).
PERFLUOROALKYLS 401

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFNA

Epidemiology Studies—Pregnancy Outcomes. Two studies (summarized in Table 2-22) have examined 

pregnancy outcome. 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. No alterations in the risk of 

preterm birth was found in a study conducted by Chen et al. (2012a).

Epidemiology Studies—Birth Outcomes. Several studies have examined the possible link 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; Chen et al. 2012a; 

Lee et al. 2016; Lenters et al. 2016a; Monroy et al. 2008; Robledo et al. 2015a). No alterations in the risk 

of low birth weight or small for gestational age were found in a study conducted by Chen et al. (2012a). 

Wang et al. (2016) did find an inverse association between maternal PFNA levels and birth weight in girls 

only. 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; Robledo et al. 2015a; Wang et al. 2016). Most 

studies did not find alterations in ponderal index or head circumference (Bach et al. 2016; Chen et al. 

2012a; Robledo et al. 2015a; Wang et al. 2016); Chen et al. (2012a) reported an inverse 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 that were associated with 

maternal PFNA levels.

Epidemiology Studies—Neurodevelopmental Outcomes. Several potential neurodevelopmental 

outcomes have been examined in epidemiology 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 olds (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. Vuong et al. (2016) did not find an association between 

maternal PFNA levels and metacognition or global executive functioning in 5 or 8 year olds. 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 et 

al. (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 
PERFLUOROALKYLS 402

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

find an association between maternal PFNA levels and behavior regulation. 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 associated with autism (Braun et al. 

2014; Liew et al. 2015).

Epidemiology 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 

maternal serum PFHxS levels and risk of earlier age of menarche were observed in girls (Christensen et 

al. 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) and in male offspring of mice administered ≥3 mg/kg/day PFNA on 

GDs 1–17 (Das et al. 2015). No skeletal or visceral abnormalities were observed in mouse pups (Das et 

al. 2015). Reductions in nephron endowment (number of functioning 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 were observed at 26 or 52 weeks of age. Delays in eye opening 

and decreased in pup body weight gain were observed 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 day of 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).

PFDeA

Epidemiology Studies—Pregnancy Outcomes. In the only identified epidemiology study examining 

pregnancy outcomes, Jensen et al. (2015) found an increased risk of miscarriage that was associated with 

maternal PFDeA levels.
PERFLUOROALKYLS 403

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Epidemiology Studies—Birth Outcomes. A small number of epidemiology studies examined risks of 

adverse birth outcomes associated with maternal PFDeA exposure; these studies are summarized in 

Table 2-23. Wang et al. (2016) found an inverse association between maternal PFDeA levels and birth 

weight in female infants only. This study also found an increased risk for small for gestational age among 

female infants. Other studies have not found associations (Bach et al. 2016; Lee et al. 2016; Lenters et al. 

2016a; Robledo et al. 2015a). Epidemiology studies have not found associations between birth length, 

ponderal index, and/or head circumference and maternal PFDeA levels (Bach et al. 2016; Robledo et al. 

2015a; Wang et al. 2016). Liew et al. (2014) did not find alterations in the risk of congenital cerebral 

palsy in boys or girls and Bae et al. (2015) did not find alterations in odds of a male birth associated with 

maternal or paternal PFDeA levels. Additionally, Kim et al. (2016b) did not find associations between 

serum PFDeA levels and thyroid parameters.

Epidemiology Studies—Neurodevelopmental Outcomes. Several studies have evaluated the potential of 

PFDeA to adversely affect neurodevelopment; see Table 2-24 for a summary of the studies. Wang et al. 

(2015b) did not find associations between maternal PFDeA 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. Liew et al. (2015) found 

decreases in the risk of ADHD and autism in children.

Laboratory Animal Studies. An increase in fetal mortality was observed in mice exposed to 

12.8 mg/kg/day PFDeA on GDs 6–15 (Harris and Birnbaum 1989); this dose level was also associated 

with 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 in 

fetal body weight/litter were observed at ≥1 mg/kg/day. The study did not find alterations in the 

occurrence of cleft palate, soft tissue malformations, or skeletal malformations. In mice exposed to 

10.8 mg/kg/day PFDeA on PND 10, there was no effect on spontaneous activity, habituation, 

performance on 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 of Viberg et al. (2013) in mice exposed to PFHxS.
PERFLUOROALKYLS 404

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFUA

Epidemiology Studies—Pregnancy Outcomes. Limited epidemiology studies evaluated pregnancy 

outcomes. Jensen et al. (2015) did not find an alteration in the risk of miscarriage before gestation 

week 12.

Epidemiology Studies—Birth Outcomes. The results from a study conducted by Wang et al. (2016) 

found an inverse association between maternal PFUA levels and birth weight and an increased risk of 

small for gestation age among female infants. The remaining epidemiology studies have not found 

alterations in infant size (birth weight, birth length, ponderal index, head circumference) (Bach et al. 

2016; Chen et al. 2012a; Lee et al. 2016; Lenters et al. 2016a) or the risks of low birth weight (Chen et al. 

2012a) or small for gestational age (Chen et al. 2012a). No association between serum PFUA levels and 

thyroid parameters were observed in infants (Kim et al. 2016a). The results of the epidemiology studies 

examining associations between birth outcome and PFUA are presented in Table 2-23.

Epidemiology Studies—Neurodevelopmental Outcomes. The results of two studies examining possible 

associations between neurodevelopmental outcome and PFUA are summarized in Table 2-24. Wang et 

al. (2015b) found no association between maternal PFUA levels and IQ score in 5 and 8 year olds; the 

study did find an inverse association with scores on tests assessing performance IQ. Lien et al. (2016) 

found no associations between cord blood PFUA levels and performance on behavioral tests.

Laboratory Animal Studies. One study was identified that examined the potential developmental toxicity 

of PFUA (Takahashi et al. 2014); the study found decreases in pup body weight at birth and on PND 4 in 

the offspring of rats administered via gavage 1.0 mg/kg/day PFUA.

PFBuS

Laboratory Animal Studies. No alterations in pup survival, body weight, or development were observed 

at doses as high as 1,000 mg/kg/day in a 2-generation rat study of potassium PFBuS (Lieder et al. 2009b).
PERFLUOROALKYLS 405

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFBA

Epidemiology Studies—Birth Outcomes. In the only available epidemiology studies examining birth 

outcomes, no associations were found between serum PFBA levels and thyroid parameters in infants 

(Kim et al. 2016a).

Laboratory Animal Studies. A delay (approximately 1 day) in eye opening was observed in the offspring 

of mice administered via gavage 35 mg/kg/day PFBA on GDs 1–17 (Das et al. 2008).

PFDoA

Epidemiology Studies—Birth Outcomes. General population studies conducted by Lee et al. (2016) and 

Lenters et al. (2016a) did not find associations between cord blood PFDoA or maternal PFDoA levels and 

birth weight. Wang et al. (2016) found an inverse association between maternal PFDoA levels and birth 

weight and head circumference in female infants; no alteration in the risk of small for gestation age was 

found. The results of these three studies are summarized in Table 2-23.

Epidemiology Studies—Neurodevelopmental Outcomes. As summarized in Table 2-24, only one study 

examined neurodevelopmental outcomes. In this study, maternal PFDoA levels were not associated with 

IQ scores in 5- or 8-year-old children (Wang et al. 2015b).

PFOSA

Epidemiology Studies. Robledo et al. (2015a) found an inverse association between maternal PFOSA 

levels and birth weight in boys, but not in girls; paternal PFOSA levels were not associated with birth 

weight. The study did not find alterations in birth length, head circumference, or ponderal index (see 

Table 2-23). Bae et al. (2015) did not find alterations in the odds of a male birth that was associated with 

maternal or paternal PFOSA levels. As summarized in Table 2-24, only one study evaluated possible 

associations between PFOSA and neurodevelopmental outcomes. Gump et al. (2011) reported an inverse 

association between serum PFOSA 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 PFOSA levels and the risk of an earlier age of menarche in girls 

(see Table 2-25).
PERFLUOROALKYLS 406

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Me-PFOSA-AcOH

Epidemiology Studies. Bae et al. (2015) found decreased odds of a female birth that was associated with 

paternal Me-PFOSA-AcOH levels; there were no alterations in the odds of male births associated with 

maternal or paternal Me-PFOSA-AcOH levels. Robledo et al. (2015a) found no associations between 

maternal or paternal Me-PFOSA-AcOH levels and birth weight, birth length, head circumference, or 

ponderal index. The results of these studies are presented in Table 2-23. Christensen et al. (2011) did not 

find an association between maternal Me-PFOSA-AcOH levels and an earlier age of menarche; the results 

of the study are summarized in Table 2-25.

Et-PFOSA-AcOH

Epidemiology Studies. Two epidemiology studies (summarized in Table 2-23) evaluated birth outcomes. 

No associations were found between paternal or maternal Et-PFOSA-ACOH levels and the odds of male 

birth (Bae et al. 2015) or birth weight, birth length, head circumference, or ponderal index (Robledo et al. 

(2015a). An earlier age of menarche was not associated with maternal Et-PFOSA-AcOH levels were 

found in a study conducted by Christensen et al. (2011).

2.18 OTHER NONCANCER

Overview. A number of epidemiology studies have examined the possible associations between 

perfluoroalkyls and outcomes related to diabetes; the results of these studies are summarized in 

Table 2-26, with additional study details presented in the Supporting Document for Epidemiological 

Studies for Perfluoroalkyls, Table 14. Overall, the epidemiology 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, PFDeA, PFUA, 

PFHpA, or PFOSA. Additionally, results of studies on PFOA, PFOS, PFHxS, and Me-PFOSA-AcOH do 

not suggest a link between perfluoroalkyls and gestational diabetes. Only one laboratory animal study

examined other noncancer endpoints (Table 2-5).
PERFLUOROALKYLS 407

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Leonard 2006

Occupational (n=6,027)

>250–≤750 ng/mL PFOA Diabetes deaths SMR 183 (112–283)* (males only)

Leonard et al. 2008

Occupational (n=6,027)

NR Diabetes deaths SMR 197 (123–298)*

Lundin et al. 2009

Occupational (n=3,992)

Probable exposure Diabetes deaths SMR 2.0 (1.2–3.2)*

Raleigh et al. 2014

Occupational (n=9,027)

NR Diabetes deaths SMR 0.76 (0.50–1.11)

Steenland et al. 2015

Occupational (n=3,713)

Cumulative Risk of diabetes RR 1.10 (0.77–1.57) no lag

RR1.12 (0.76–1.66) 10-year lag

Steenland and Woskie 2012

Occupational (n=1,088)

580 ng/mL (median PFOA) Diabetes deaths 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

Anderson-Mahoney et al. 2008

Community (n=566)

NR Self-reported diabetes SPR 1.54 (1.16–2.05)*

Karnes et al. 2014

Community (n=32,254 C8 participants)

Cumulative Self-reported diabetes HR 1.00 (0.99–1.00, p=0.60), 

retrospective analysis

HR 1.00 (1.00–1.01, p=0.31), 

prospective analysis

Fasting blood glucose NS (p>0.05)

MacNeil et al. 2009

Community (n=13,922 C8 participants)

122.7 ng/mL (mean PFOA) Validated diabetes OR 0.72 (0.52–1.00) (10th decile)
PERFLUOROALKYLS 408

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Fisher et al. 2013

General population (n=2,700)

2.46 ng/mL (geometric mean 

PFOA)

Insulin NS (p=0.12)

Blood glucose NS (p=0.17)

HOMA-IR NS (p=0.10)

Lin et al. 2009

General population (NHANES) 

(n=474 adolescents);

General population (NHANES) (n=969 adults)

1.51 ng/mL (mean log PFOA) Insulin NS (p>0.05)

β-cell function NS (p>0.05)

Fasting blood glucose NS (p>0.05)

HOMA-IR NS (p>0.05)

1.48 ng/mL (mean log PFOA) Insulin Association (p<0.05)

β-cell function Association (p<0.05)

Fasting blood glucose NS (p>0.05)

HOMA-IR NS (p>0.05)

Lind et al. 2014

General population (n=1,016)

3.3 ng/mL (median PFOA) Diabetes OR 0.97 (0.61–1.53, p=0.88)

HOMA-IR NS (p=0.20)

Melzer et al. 2010

General population (NHANES) (n=3,966)

10.39 ng/mL (M)

9.47 ng/mL (F) 

(4th PFOA quartile)

Self-reported diabetes OR 0.69 (0.41–1.16, p=0.158)

Nelson et al. 2010

General population (NHANES) 

(n=306 adolescent and 524 adults)

4.6 ng/mL (mean PFOA) HOMA (adolescent) NS (p=0.16) (M), NS (p=0.11) (F)

HOMA (adult) NS (p>0.05)

Shapiro et al. 2016

General population (1,274 pregnant women)

1.68 ng/mL (geometric mean 

PFOA)

Gestational diabetes NS (p=0.86 for trend)

Impaired glucose 

tolerance

NS (p=0.36 for trend)

Su et al. 2016

General population (n=571)

5.8–8.0 ng/mL 

(2nd PFOA quartile)

Diabetes OR 0.39 (0.16–0.96)* (inverse 

association)

Fasting blood glucose Inverse association (p<0.01 for 

trend)*

Glucose tolerance Inverse association (p<0.01 for 

trend)*
PERFLUOROALKYLS 409

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Glycated hemoglobin Inverse association (p=0.04 for 

trend)*

Zhang et al. 2015a

General population (n=258) 

3.07 and 3.94 ng/mL 

(geometric mean PFOA in 

women with or without 

gestational diabetes)

Gestational diabetes OR 1.86 (1.14–3.02)*

PFOS

Fisher et al. 2013

General population (n=2,700)

8.04 ng/mL 

(geometric mean PFOS)

Insulin NS (p=0.88)

Blood glucose NS (p=0.96)

HOMA-IR NS (p=0.25

Lin et al. 2009

General population (NHANES) 

(n=474 adolescents)

General population (NHANES) (969 adults)

3.11 ng/mL (log mean PFOS) Insulin NS (p>0.05)

HOMA-IR NS (p>0.05)

β-cell function NS (p>0.05)

Blood glucose NS (p>0.05)

3.19 ng/mL (log mean PFOS) Insulin Association (p<0.05)*

HOMA-IR Association (p<0.05)*

β-cell function Association (p<0.05)*

Blood glucose NS (p>0.05)

Lind et al. 2014

General population (n=1,016)

13.2 ng/mL (median PFOS) Diabetes OR 1.43 (0.94–22.16, p=0.09)

HOMA NS (p=0.51)

Melzer et al. 2010

General population (NHANES) (n=3,966)

57.73 ng/mL (M)

50.96 ng/mL (F)

(4th quartile mean PFOS)

Self-reported diabetes OR 0.87 (0.57–1.31, p=0.491)

Nelson et al. 2010

General population (NHANES) 

(n=306 adolescent and 524 adults)

25.3 ng/mL (mean PFOS) HOMA (adolescent) NS (p=0.18) (M), NS (p=0.22) (F)

HOMA (adult) NS (p>0.05)

Shapiro et al. 2016

General population (1,274 pregnant women)

4.58 ng/mL (geometric mean 

PFOS)

Gestational diabetes NS (p=0.70 for trend)

Impaired glucose 

tolerance

NS (p=0.74 for trend)
PERFLUOROALKYLS 410

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Su et al. 2016

General population (n=571)

>4.8 ng/mL 

(4th PFOS quartile)

Diabetes OR 3.37 (1.18–9.65)*

Fasting blood glucose Association (p<0.01 for trend)*

Glucose tolerance test Association (p≤0.01 for trend)*

Glycated hemoglobin Association (p=0.04 for trend)*

Zhang et al. 2015a

General population (n=258) 

13.10 and 12.04 ng/mL 

(geometric mean PFOS in 

women with or without 

gestational diabetes)

Gestational diabetes OR 1.13 (0.75–1.72)

PFHxS

Fisher et al. 2013

General population (n=2,700)

2.18 ng/mL (geometric mean 

PFHxS)

Insulin NS (p=0.89)

Blood glucose NS (p=0.98)

HOMA-IR NS (p=0.20)

Lin et al. 2009

General population (NHANES) 

(n=474 adolescents);

General population (NHANES) (n=969 adults)

0.95 ng/mL (log mean) Insulin NS (p>0.05)

HOMA-IR NS (p>0.05)

Β-cell function NS (p>0.05)

Blood glucose NS (p>0.05)

0.60 ng/mL (log mean PFHxS) Insulin NS (p>0.05)

HOMA-IR NS (p>0.05)

Β-cell function NS (p>0.05)

Blood glucose NS (p>0.05)

Lind et al. 2014

General population (n=1,016)

2.1 ng/mL (median PFHxS) Diabetes OR 1.00 (0.74–1.35, p=0.98)

HOMA NS (p=0.29)

Nelson et al. 2010

General population (NHANES)

(n=306 adolescent and 524 adults)

2.6 ng/mL (mean PFHxS) HOMA (adolescent) NS (p=0.20) (M),

Inverse association (p=0.001)* (F)

HOMA (adult) NS (p>0.05)

Shapiro et al. 2016

General population (n=1,274 pregnant women) 

1.02 ng/mL 

(geometric mean PFHxS)

Gestational diabetes NS (p=0.73 for trend)

Impaired glucose 

tolerance

NS (p=0.44 for trend)
PERFLUOROALKYLS 411

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFNA

Lin et al. 2009

General population (NHANES) 

(n=474 adolescents)

General population (NHANES) (n=969 adults) 

0.35 ng/mL (log mean PFNA) Insulin Inverse association (p<0.05)*

HOMA-IR NS (p>0.05)

β-cell function Inverse association (p<0.05)*

Blood glucose NS (p>0.05)

0.21 ng/mL (log mean PFNA) Insulin NS (p>0.05)

HOMA-IR NS (p>0.05)

β-cell function NS (p>0.05)

Blood glucose NS (p>0.05)

Lind et al. 2014

General population (n=1,016)

0.7 ng/mL (median PFNA) Diabetes OR 1.30 (0.85–1.97, p=0.22)

HOMA NS (p=0.90)

Nelson et al. 2010

General population (NHANES) 

(n=306 adolescent and 524 adults)

1.3 ng/mL (mean PFNA) HOMA (adolescent) NS (p=0.83) (M), (p=0.20) (F)

HOMA (adult) NS (p>0.05)

Su et al. 2016

General population (n=571)

>5.1 ng/mL 

(4th PFNA quartile)

Diabetes OR 0.31 (0.11–0.88)* 4th quartile

(inverse association)

Fasting blood glucose NS (p=0.10 for trend) 

Glucose tolerance test Inverse association (p<0.01 for 

trend)*

Glycated hemoglobin NS (p=0.11 for trend) 

Zhang et al. 2015a

General population (n=258) 

1.23 and 1.20 ng/mL 

(geometric mean) PFNA in 

women with or without 

gestational diabetes)

Gestational diabetes OR 1.06 (0.70–1.60)
PERFLUOROALKYLS 412

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFDeA

Zhang et al. 2015a

General population (n=258) 

0.41 and 0.40 ng/mL ng/mL 

(geometric mean PFDeA in 

women with or without 

gestational diabetes) 

Gestational diabetes OR 1.04 (0.70–1.53)

PFUA

Lind et al. 2014

General population (n=1,016)

0.3 ng/mL (median PFUA) Diabetes OR 0.95 (0.59–1.52; p=0.81)

HOMA NS (p=0.32)

Su et al. 2016

General population (n=571)

6.4–9.2 ng/mL 

(3rd PFUA quartile)

Diabetes OR 0.24 (0.08–0.78)* 3rd quartile

(inverse association)

Fasting blood glucose Inverse association (p<0.01 for 

trend)* 

Glucose tolerance test Inverse association (p<0.01 for 

trend)*

Glycated hemoglobin NS (p=0.17 for trend) 

PFHpA

Lind et al. 2014

General population (n=571)

0.05 ng/mL (median PFHpA) Diabetes OR 1.02 (0.77–1.34, p=0.90)

HOMA NS (p=0.56)

PFOSA

Lind et al. 2014

General population (n=571)

0.11 ng/mL (median PFOSA) Diabetes OR 1.07 (0.75–1.53, p=0.71)

HOMA NS (p=0.070)
PERFLUOROALKYLS 413

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-26. Summary of Outcomes Related to Diabetes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Me-PFOSA-AcOH

Zhang et al. 2015a

General population (n=258) 

0.30 and 0.29 ng/mL ng/mL 

(geometric mean Me-PFOSAAcOH in women with or without 

gestational diabetes) 

Gestational diabetes OR 1.05 (0.71–1.54)

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals.

(F) = females; HOMA = homeostatic model assessment; HR = hazard ratio; IR = insulin resistance; (M) = males; Me-PFOSA-AcOH = 2-(N-methyl-perfluorooctane 

sulfonamide) acetic acid; NHANES = National Health and Nutrition Examination Survey; NR = not reported; NS = not significant; OR = odds ratio; 

PFDeA = perfluorodecanoic acid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid; 

SMR = standardized mortality ratio; SPR = standardized prevalence ratio

1
PERFLUOROALKYLS 414

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

1 PFOA

2

3 Epidemiology Studies. A cohort mortality study conducted by Leonard et al. (2008; Leonard 2006) of 

4 workers at the Washington Works facility found a significant increase in deaths from diabetes, as

5 compared to workers at other DuPont facilities in the region. In an update of the Leonard et al. (2008) 

6 study, Steenland and Woskie (2012) found an increased risk of diabetes deaths when compared to other 

7 regional DuPont employees, but not when compared to the U.S. population. However, when the workers 

8 were categorized by estimated cumulative exposure levels, the exposure-response trend was not 

9 statistically significant. Lundin et al. (2009) also found an increase in deaths from diabetes in workers 

10 exposed to APFO at the 3M Cottage Grove facility in Minnesota, as compared to Minnesota death rates. 

11 The increase was only found in workers with probable exposure to APFO, but not with definite exposure; 

12 no deaths from diabetes were observed in the workers with definite exposure to APFO. As noted by 

13 Steenland and Woskie (2012), diabetes mortality may not be a good surrogate for the underlying diabetes 

14 incidence data. Raleigh et al. (2014) did not find an increase in diabetes deaths at the Cottage Grove

15 facility and Steenland et al. (2015) did not find an increased risk of diabetes associated with cumulative 

16 PFOA exposure at the Washington Works facility.

17

18 In community exposure studies, Anderson-Mahoney et al. (2008) found an increased prevalence of self19 reported diabetes in residents living near the Washington Works facility, as compared to expected rates 

20 taken from NHANES. In contrast, Karnes et al. (2014) did not find an increased risk of self-reported 

21 diabetes associated with cumulative PFOA levels and MacNeil et al. (2009) did not find an increased risk 

22 of validated diabetes in C8 Health Study participants. General population studies found either an inverse 

23 association between serum PFOA and risk of diabetes (Su et al. 2016) or no association (Lind et al. 2014; 

24 Melzer et al. 2010). Additionally, general population studies have not found associations between serum 

25 PFOA levels and insulin (Fisher et al. 2013; Lin et al. 2009), blood glucose levels (Fisher et al. 2013; Lin 

26 et al. 2009; Su et al. 2016), homeostatic model assessment for insulin resistance (HOMA-IR) (Fisher et al. 

27 2013; Lin et al. 2009; Lind et al. 2014; Nelson et al. 2010), or glucose tolerance (Su et al. 2016). Two 

28 studies evaluated the risk of gestational diabetes and found mixed results. In a case-control study, Zhang 

29 et al. (2015a) found an increased risk of gestational diabetes associated with serum PFOA, whereas 

30 Shapiro et al. (2016) did not find associations between serum PFOA and gestational diabetes or impaired 

31 glucose tolerance. The ORs for the risk of diabetes and gestational diabetes are graphically presented in 

32 Figure 2-37.

33
PERFLUOROALKYLS 415

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-37. Diabetes Risk Relative to Serum PFOA Levels (Presented as Adjusted Ratios)
PERFLUOROALKYLS 416

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFOS

Epidemiology Studies. In a general population study conducted by Su et al. (2016), an increased risk of 

diabetes was noted, as well as associations between serum PFOS levels and fasting blood glucose, 

response to glucose tolerance test, and glycated hemoglobin levels. Two other general population studies 

did not find increased risks of diabetes (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; Nelson et al. 2010). Lin et al. (2009) found associations 

between serum PFOS and insulin and HOMA-IR in a study of NHANES adult participants; these 

associations were not found in adolescent participants. No alterations in the risk of gestational diabetes 

were observed in two general population studies (Shapiro et al. 2016; Zhang et al. 2015a); the Shapiro et 

al. (2016) study also found no association between serum PFOS and glucose tolerance. The ORs for the 

risk of diabetes and gestational diabetes are graphically presented in Figure 2-38.

PFHxS

Epidemiology Studies. Five general population studies have examined diabetes-related outcomes and 

have not found associations between serum PFHxS levels and diabetes risk (Lind et al. 2014), gestational 

diabetes (Shapiro et al. 2016) or insulin, blood glucose, or HOMA-IR levels (Fisher et al. 2013; Lin et al. 

2009; Lind et al. 2014; Nelson et al. 2010).

PFNA

Epidemiology Studies. An inverse association between serum PFNA levels and the risk of diabetes was 

observed in a general population study (Su et al. 2016). Two other studies did not find associations for 

diabetes (Lind et al. 2014) or gestational diabetes (Zhang et al. 2015a). The Su et al. (2016) study also 

reported an inverse association between PFNA levels and response on a glucose tolerance test. A study of 

adolescent NHANES participants found decreasing levels of insulin with increasing serum PFNA levels 

(Lin et al. 2009); this association was not found in adult NHANES participants (Lin et al. 2009). Several 

studies did not find associations between serum PFNA levels and HOMA-IR (Lin et al. 2009; Lind et al. 

2014; Nelson et al. 2010).

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).
PERFLUOROALKYLS 417

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Figure 2-38. Diabetes Risk Relative to Serum PFOS Levels (Presented as Adjusted Odds Ratios)
PERFLUOROALKYLS 418

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFDeA

Epidemiology Studies. In the only study identified, Zhang et al. (2015a) did not find an association 

between serum PFDeA levels and the risk of gestational diabetes.

PFUA

Epidemiology Studies. The two epidemiology studies evaluating associations between PFUA and 

diabetes-related outcomes have found conflicting results. Su et al. (2016) found inverse associations 

between serum PFUA levels and diabetes risk, fasting blood glucose levels, and glucose tolerance test 

results, whereas Lind et al. (2014) found no alterations in the risk of diabetes or HOMA.

PFHpA

Epidemiology Studies. Lind et al. (2014) did not find associations between serum PFHpA levels and the 

risk of diabetes or HOMA alterations.

PFOSA

Epidemiology Studies. In the one epidemiology study identified, no associations between serum PFOSA 

levels and the risk of diabetes or HOMA were found (Lind et al. 2014).

Me-PFOSA-AcOH

Epidemiology Studies. In a case-control study, Zhang et al. (2015a) did not find alterations in the risk of 

gestational diabetes associated with serum Me-PFOSA-AcOH levels.

2.19 CANCER

Overview. A number of occupational exposure, community, and general population studies have 

examined possible associations between perfluoroalkyls and cancer risk; these studies are summarized in 

Table 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 kidney 

cancer associated with PFOA. No consistent epidemiologic evidence for other cancer types were found 
PERFLUOROALKYLS 419

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-27. Summary of Cancer Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOA

Gilliland and Mandel 1993

Occupational (n=389 deaths)

Reference population: Minnesota general 

population

NR All cancer deaths SMR 0.86 (0.72–1.01), males

SMR 0.75 (0.56–0.99), females

Prostate cancer SMR 2.03 (0.55–4.59) 

RR 1.13 (1.01–1.27) for a 1-year 

increase in employment length

RR 3.3 (1.02–10.6)* for a 10-year 

employment length

Leonard 2006; Leonard et al. 2008

Occupational (n=6,027)

Reference population: DuPont workers at 

other regional facilities

5–9,550 ng/mL (estimated 

range of PFOA)

All cancer deaths SMR 100 (88–114), males

SMR 149 (77–260), females 

Kidney cancer deaths SMR 185 (95–323), males

Biliary passages and 

liver cancer deaths

SMR 133 (53–274)

Pancreatic cancer 

deaths

SMR 100 (50–180)

Bladder or other urinary 

organ cancer deaths 

SMR 131 (53–269)

Prostate cancer deaths SMR 65 (34–114)

Bronchus, trachea, lung 

cancer deaths

SMR 81 (63–104)

Lundin et al. 2009

Occupational (n=3,993)

Reference population: Minnesota general 

population; for HR analysis comparisons with 

workers with low exposure or <1 year of 

exposure

2,600–5,200 and 300–

1,500 ng/mL (range of PFOA in 

subset of current workers with 

definite exposure jobs and 

probable exposure jobs) 

All cancer deaths SMR 0.9 (0.5–1.4), definite exposure 

SMR 0.9 (0.8–1.1), probable exposure 

Pancreas cancer 

deaths

SMR 0.9 (0.0–4.7), definite exposure 

SMR 1.0 (0.4–2.1), probable exposure 

Trachea, bronchus, and 

lung cancer deaths

SMR 1.2 (0.5–2.3), definite exposure 

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 exposure 

for ≥5 years
PERFLUOROALKYLS 420

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-27. Summary of Cancer Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Raleigh et al. 2014

Occupational (n=9,207)

Reference population: Minnesota general 

population

>7.9x10-4 μg/m3 (cumulative 

exposure, 4th PFOA quartile)

All cancer deaths SMR 0.87 (0.78–0.97)

Pancreatic cancer 

deaths

SMR 0.85 (0.50–1.34)

Prostate cancer deaths SMR 0.83 (0.53–1.23)

Kidney cancer deaths SMR 0.53 (0.20–1.16)

Liver cancer deaths SMR 0.81 (0.35–1.59)

Breast cancer deaths SMR 0.82 (0.41–1.47)

Bladder cancer deaths SMR 0.89 (0.38–1.76)

Raleigh et al. 2014

Occupational (n=9,207)

Reference population: non-APFO exposed 

workers at a St. Paul facility

≤7.9x10-4 and >7.9x10-4 μg/m3

(cumulative exposure,3rd and 

4th PFOA quartile)

Pancreatic cancer 

deaths

HR 1.23 (0.50–3.00), 3rd and 4th

quartiles combined

Pancreatic cancer HR 1.36 (0.59–3.11), 3rd and 4th

quartiles 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 4th

quartiles combined

Kidney cancer HR 0.73 (0.21–2.48), 4th quartile

Liver cancer deaths HR 0.67 (0.14–3.27), 3rd and 4th

quartiles combined

Breast cancer deaths HR 0.54 (0.15–1.94), 3rd and 4th

quartiles combined

Breast cancer HR 1.27 (0.70–2.31), 4th quartile

Bladder cancer deaths HR 1.96 (0.63–6.15), 3rd and 4th

quartiles combined

Bladder cancer HR 1.66 (0.86–3.18), 4th quartile 

Steenland et al. 2015

Occupational (n=3,713)

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 with 

no lag
PERFLUOROALKYLS 421

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-27. Summary of Cancer Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Colorectal cancer NS (p=0.91 and 0.86 for trend), with no 

lag or 10-year lag

Prostate cancer NS (p=0.83 and 0.91 for trend), no lag 

or 10-year lag),

Melanoma NS (p=0.16 and 0.55 for trend), no lag 

or 10-year lag)

Steenland and Woskie 2012

Occupational (n=1,084 deceased workers)

Reference population: DuPont workers at other 

regional facilities 

≥2,700,000 ng/mL-years 

(cumulative 4th PFOA quartile)

All cancer deaths SMR 0.94 (0.76–1.16), 4th quartile 

Pancreatic cancer 

deaths 

SMR 0.92 (0.30–2.16), 4th quartile

Lung cancer deaths SMR 0.75 (0.48–1.11), 4th quartile

Prostate cancer deaths SMR 0.57 (0.16–1.46), 4th quartile

Bladder cancer deaths SMR 0.36 (0.10–2.01), 4th quartile

Kidney cancer deaths 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

Barry et al. 2013

Community and occupational (n=32,254)

Cumulative exposure

24.2 and 112.7 ng/mL (median 

PFOA) 

Testicular cancer HR 1.34 (1.00–1.79, p=0.05)* no lag

HR 1.28 (0.95–1.73, p=0.10) 10-year 

lag

HR 3.17 (0.75–13.45, p=0.04 for 

trend)*, 4th quartile

Kidney cancer 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

Breast cancer HR 0.94 (0.89–1.00, p=0.05)*, no lag

HR 0.93 (0.88–0.99, p=0.03)*, 10-year 

lag

Colorectal cancer HR 0.99 (0.92–1.07, p=0.84), no lag
PERFLUOROALKYLS 422

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-27. Summary of Cancer Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Ducatman et al. 2015a, 2015b

Community (C8) (n=25,412 men)

86.6 ng/mL (mean PFOA) Prostate specific 

antigen

NS (p<0.05)

Innes et al. 2014

Community (n=208 cases of colorectal cancer 

and 47,359 cancer-free adults) 

13.5–27.8 ng/mL (2nd PFOA 

quartile)

Colorectal cancer OR 0.47 (0.31–0.74)*, 2nd quartile

Vieira et al. 2013

Community (n=25,107)

30.8–109 and 110–655 ng/mL 

(estimated PFOA in high and 

very high exposure groups) 

Kidney cancer AOR 2.0 (1.3–3.2)*, high exposure 

group

AOR 2.0 (1.0–3.9), very high exposure 

group 

Testes cancer AOR 2.8 (0.8–9.2), very high exposure 

group

Prostate cancer AOR 1.5 (0.9–2.5), very high exposure 

group

Breast cancer AOR 1.4 0.9–2.3) very high exposure 

group, females only

Bonefeld-Jorgensen et al. 2011

General population (n=31 breast cancer cases 

and115 matched controls)

2.5 and 1.6 ng/mL (median 

PFOA in cases and controls) 

Breast cancer AOR 1.20 (0.77–1.88, p=0.43)

Bonefeld-Jorgensen et al. 2014

General population (n=250 breast cancer cases 

and 233 matched controls) 

5.2 ng/mL (mean PFOA) Breast cancer RR 1.00 (0.90–1.11).

Eriksen et al. 2009

General population (n=713 for prostate cancer, 

n=332 for bladder cancer, n=128 for pancreatic 

cancer, n=67 for liver cancer, and 

n=772 controls) 

6.8 and 6.0 ng/mL (median 

PFOA in male and female 

cancer patients)

6.9 and 5.4 ng/mL (median 

PFOA in male and female 

controls)

Prostate cancer IRR 1.18 (0.84–1.65) 

Bladder cancer IRR 0.81 (0.53–1.24)

Pancreas cancer IRR 1.55 (0.85–2.80)

Liver cancer IRR 0.60 (0.26–1.37)
PERFLUOROALKYLS 423

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-27. Summary of Cancer Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Hardell et al. 2014

General population (n=201 cases and 

186 controls)

2.3 and 1.9 ng/mL (mean 

PFOA in cases and controls) 

Prostate 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

PFOS

Alexander et al. 2003

Occupational (n=2,083; 145 deaths) 

Reference population: Alabama general 

population 

NR All cancer deaths SMR 0.84 (0.50–1.32), high potential 

exposure group

Bladder and other 

urinary organs cancer

SMR 12.77 (2.63–37.35)*, high 

potential exposure group

SMR 16.12 (3.32–47.14)*, high 

exposure group ≥1 year exposure

Alexander and Olsen 2007

Occupational (n=1,895; 1,488 deaths) 

Reference population: NIOSH SEER referent 

data

NR Bladder cancer SIR 1.74 (0.64–3.79), high potential 

exposure group

SIR 1.43 (0.16–5.15) ≥10-year 

exposure group

Grice et al. 2007

Occupational (n=1,400 current, retired, or 

former workers)

1,300–1,970 ng/mL (PFOS 

levels in high potential 

exposure group)

Colon cancer OR 1.69 (0.68–4.17)

Melanoma OR 1.01 (0.25–4.11)

Prostate cancer OR 1.08 (0.44–2.69)

Olsen et al. 2004a

Occupational (current and retired workers)

NR Malignant melanoma of 

the skin

RREpC 12 (1.0–>100) 

RREpC 10 (0.7–>100), >10 years 

employment

Malignant neoplasm of 

the colon 

RREpC 5.4 (0.5–>100) 

RREpC 12 (0.8–>100), >10 years 

employment

Ducatman et al. 2015a, 2015b

Community (C8) (n=25,412 men)

22.18 ng/mL (mean PFOS) Prostate specific 

antigen

NS (p<0.05)

Innes et al. 2014

Community (n=208 cases of colorectal cancer 

and 47,359 cancer-free adults) 

13.6–20.1 ng/mL (2nd PFOS 

quartile)

Colorectal cancer OR 0.35 (0.24–0.53)*
PERFLUOROALKYLS 424

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-27. Summary of Cancer Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

Bonefeld-Jorgensen et al. 2011

General population (n=31 breast cancer cases 

and 115 matched controls)

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)*

Bonefeld-Jorgensen et al. 2014

General population (n=250 breast cancer cases 

and 115 matched controls) 

30.6 ng/mL (mean PFOS) Breast cancer RR 0.99 (0.98–1.01)

Eriksen et al. 2009

General population (n=713 for prostate cancer, 

n=332 for bladder cancer, n=128 for pancreatic 

cancer, n=67 for liver cancer, and 

n=772 controls)

35.1 and 32.1 ng/mL and 

35.0 and 29.3 ng/mL (median 

PFOS in male and female 

cancer patients and males and 

females in the comparison 

group)

Prostate cancer IRR 1.05 (0.97–1.14)

Bladder cancer IRR 0.93 (0.83–1.03)

Pancreas cancer IRR 0.99 (0.86–1.14)

Liver cancer IRR 0.59 (0.27–1.27)

Hardell et al. 2014

General population (n=201 cases of prostate 

cancer and 186 controls)

11 and 10 ng/mL (mean PFOS 

in cases and controls)

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 median

PFHxS

Ducatman et al. 2015a, 2015b

Community (C8) (n=25,412 men)

3.58 ng/mL (mean PFHxS) Prostate specific 

antigen

NS (p<0.05)

Bonefeld-Jorgensen et al. 2014

General population (n=250 breast cancer cases 

and 115 matched controls)

1.2 ng/mL (mean PFHxS) Breast cancer RR 0.66 (0.47–0.94)*

Hardell et al. 2014

General population (n=201 cases of prostate 

cancer and 186 controls)

1.1 and 0.940 ng/mL (mean 

PFHxS in cases and controls)

Prostate 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
PERFLUOROALKYLS 425

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-27. Summary of Cancer Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFNA

Ducatman et al. 2015a, 2015b

Community (C8) (n=25,412 men)

1.47 ng/mL (mean PFNA) Prostate specific 

antigen

NS (p<0.05)

Bonefeld-Jorgensen et al. 2014

General population (n=250 breast cancer cases 

and 115 matched controls)

0.5 ng/mL (mean PFNA) Breast cancer RR 0.76 (0.30–1.94)

Hardell et al. 2014

General population (n=201 cases of prostate 

cancer and 186 controls)

0.679 and 0.631 ng/mL (mean 

PFNA in cases and controls)

Prostate cancer OR 1.2 (0.8–1.8)

OR 2.1 (0.9–4.8), among subjects with 

a heredity risk and serum PFNA above 

the median

PFDeA

Hardell et al. 2014

General population (n=201 cases of prostate 

cancer and 186 controls)

0.338 and 0.291 ng/mL (mean 

PFDeA in cases and controls)

Prostate cancer OR 1.4 (0.9–2.1)

OR 2.6 (1.1–6.1)*, among subjects 

with a heredity risk and serum 

PFDeA above the median

PFUA

Hardell et al. 2014

General population (n=201 cases of prostate 

cancer and 186 controls)

0.308 and 0.285 ng/mL (mean 

PFUA in cases and controls)

Prostate cancer OR 1.2 (0.8–1.9)

OR 2.6 (1.1–5.9)*, among subjects 

with a heredity risk and serum 

PFUA above the median
PERFLUOROALKYLS 426

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-27. Summary of Cancer Outcomes in Humansa

Reference and study populationb Serum perfluoroalkyl level Outcome evaluated Resultc

PFOSA

Bonefeld-Jorgensen et al. 2014

General population (n=250 breast cancer cases 

and 115 matched controls)

3.5 ng/mL (mean PFOSA) Breast cancer RR 1.89 (1.01–3.54)*, among women 

with serum PFOSA >5.75 ng/mL

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 compound; unless otherwise specified, values in parenthesis are 95% confidence intervals. 

AOR = adjusted odds ratio; CI = confidence interval; HR = hazard ratio; IRR = incidence rate ratio; NIOSH = National Institute for Occupational Safety and Health; 

NR = not reported; NS = not significant; OR = odds ratio; PFDeA = perfluorodecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic 

acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; PFUA = 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 427

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

for PFOA. For PFOS, one occupational exposure study reported an increase in bladder cancer, but this 

was not supported by subsequent occupational studies. General population studies have not consistently 

reported increases in malignant tumors for PFOS. Epidemiology studies examining other perfluoroalkyl 

compounds consisted of two case-control studies. No increases in breast cancer risk were observed for 

PFHxS or PFNA; an increased breast cancer risk was observed for PFOSA. Another case-control study 

did not find increases in prostate cancer for PFOA, PFOS, PFHxS, PFNA, PFDeA, or PFUA. However, 

among men with a first-degree relative with prostate cancer, associations were found for PFOA, PFOS, 

PFHxS, PFDeA, and PFUA, but not for PFNA. 

Laboratory animal studies have evaluated the carcinogenicity of PFOA and PFOS; the results of these 

studies are summarized in Tables 2-3 and 2-4. In laboratory animals, there is some evidence for increases 

in Leydig cell adenomas and pancreatic acinar cell 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 1 year and allowed to recover 

for an additional year. 

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

Epidemiology 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 the 

community 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 and 

Mandel 1993; Leonard 2006; Leonard et al. 2008; Lundin et al. 2009; Raleigh et al. 2014; Steenland and 

Woskie 2012). The occupational exposure studies have consistently found no increases in the risk of 
PERFLUOROALKYLS 428

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

pancreatic, 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 and 

risk of breast cancer (Bonefeld-Jorgensen et al. 2011, 2014). Steenland et al. (2015) found an inverse 

association between 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, and 

testicular 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); no increase in prostate cancer risk 

was observed when all workers in the Chemical Division were analyzed. The investigators noted that the 

prostate cancer findings are based on a small number of cases and 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 in workers 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 low-exposure 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 of potential exposure and the fact 

that workers in the low exposure categories were likely research-and-development 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 to workers at another facility and did 

not find an increase in the incidence of prostate cancer when the workers 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 Woskie 2012) 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 relative with 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 and serum PFOA levels in men 20–49 or 50–

69 years of age. 
PERFLUOROALKYLS 429

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

In the earliest cancer assessment of workers at the Washington Works facility (Leonard 2006; Leonard et 

al. 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 with 

no 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 and 

Woskie (2012) noted that tetrafluoroethylene, a rodent kidney carcinogen, is used in the manufacture of a 

variety of fluoropolymers and noted that the tetrafluoroethylene is well controlled due to its volatile and 

explosive 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 

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, and 

thus, it was difficult for the investigators to evaluate separate associations for each compound. It is noted 

that 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 these 

studies also included workers at the facility. Barry et al. (2013) reported an increased risk of testicular 

cancer that was associated with 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 the participants 

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 or very high 

exposure to PFOA; Barry et al. (2013) also concluded that there was an association between 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 epidemiology data, IARC (2017) concluded that the evidence for testicular 

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 
PERFLUOROALKYLS 430

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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), 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 of hepatocellular carcinoma was 

not significantly increased. The investigators noted that the incidence of fibroadenoma 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 the 3M (1983) 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 statistically significant 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 SpragueDawley 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; a pancreatic 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 no increase in cell proliferation. In Leydig cells, neither 

peroxisome proliferation nor cell proliferation were increased.

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 et 

al. 1991, 2004). PFOA induced a marked increase in acylCoA oxidase activity and only a slight increase 

in 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 that 

PFOA did not require extensive DNA damage for its promoting activity (Abdellatif et al. 2004). PFOA 
PERFLUOROALKYLS 431

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 carcinogenicity 

of PFOA.

PFOS

Epidemiology Studies. Four studies have evaluated the carcinogenic potential in workers at a Decatur, 

Alabama perfluorooctanesulphonyl fluoride (PFOSF) based fluorochemical production facility. In the 

earliest 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

cases in the high exposure group. In a reanalysis of workers at this facility conducted by Alexander and 

Olsen (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 exposure 

group were elevated, but the CIs included unity. When compared with workers with <1 year of high 

exposure, 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, as 

compared to 56% reported in the noncases. An additional limitation of the study is inclusion of four cases 

of 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 in 

another division, but the CIs included unity. No increases in the risk ratio episodes of care were found for 

liver, 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 for 

analyses that included all self-reported or only validated cancers. 
PERFLUOROALKYLS 432

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 by 

Bonefeld-Jorgensen et al. (2011) found a slight increase in breast cancer risk, a finding not replicated in 

another larger study of a different population (Bonefeld-Jorgensen et al. 2014). Eriksen et al. (2009) and 

Hardell et al. (2014) did not find increases 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.

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 to 

1.17 mg/kg/day for 1 year and allowed to recover for the second year. High-dose males from the 

recovery 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 a 

significant positive trend for incidences of hepatocellular adenoma, which was associated with a 

significant 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

Epidemiology Studies. Two case-control studies have examined the possible association between serum 

PFHxS and cancer. Bonefeld-Jorgensen et al. (2014) found in inverse association between PFHxS levels 

and breast cancer risk. No association between PFHxS and prostate cancer was observed (Hardell et al. 

2014), with the exception of increased risk in men with a first-degree relative with prostate cancer and 

above-median serum PFHxS levels. No associations between serum PFHxS and PSA levels were 

observed in men 20–49 or 50–69 years of age participating in the C8 Health Studies (Ducatman et al. 

2015b).
PERFLUOROALKYLS 433

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

PFNA

Epidemiology Studies. The carcinogenic potential of PFNA has been examined in two case-control 

studies. No associations between serum PFNA levels and breast cancer (Bonefeld-Jorgensen et al. 2014) 

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).

PFDeA

Epidemiology Studies. Hardell et al. (2014) examined the possible association between the serum 

PFDeA level and risk of prostate cancer and only found an association in men with a heredity risk factor 

and PFDeA levels above the median.

PFUA

Epidemiology Studies. An increased risk of prostate cancer was found in men with first-degree relatives 

with prostate cancer and serum PFUA levels above the median (Hardell et al. 2014).

PFOSA

Epidemiology Studies. Bonefeld-Jorgensen et al. (2014) reported an increased risk of breast cancer 

among women with serum PFOSA levels >5.75 ng/mL.

2.20 MECHANISM OF TOXICITY

The primary effects observed in laboratory animals exposed to perfluoroalkyl compounds 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 data indicate that perfluoroalkyl compounds produce a number of adverse effects 

through activation of the PPARα, a member of the nuclear receptor superfamily that mediates a broad 

range of biological responses (Issemann and Green 1990). However, some adverse effects of 

perfluoroalkyl compounds occur through PPARα-independent mechanisms, which may include activation 

of other nuclear receptors, increased oxidative stress, dysregulation of mitochondrial function, and 

inhibition of gap junction intercellular communication (GJIC). In the sections below, cellular 
PERFLUOROALKYLS 434

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

mechanisms of action that are mediated by PPARα and independent of PPARα are discussed, followed by 

discussions of mechanisms specific to the hepatic, developmental, immunotoxic, and hormone effects of 

perfluoroalkyl compounds.

2.20.1 Cellular Mechanisms of Toxicity

PPARα-Dependent Mechanisms 

Activation of the PPARα receptor in rodents initiates a characteristic sequence of morphological and 

biochemical 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 in 

peroxisomal fatty acid β oxidation, increased cytochrome 450-mediated ω hydroxylation of lauric acid, 

and alterations in lipid metabolism. Proliferation of peroxisomes in laboratory animals exposed to 

perfluoroalkyl compounds 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 PFDeA. 

Many, but not all, of the adverse effects induced by perfluoroalkyl compounds are mediated through 

activation of the PPARα. Ligands, including perfluoroalkyl compounds, 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 to 

recruitment of co-activators that acetylate histones and remodel chromatin, enabling RNA polymerase to 

transcribe the target gene(s). PPARα regulates lipid homeostasis by modulating the expression of genes 

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 tissues, 

competition among receptors for endogenous and exogenous ligands and for binding sites on chromatin, 

and availability and abundance of co-activators and/or co-repressors (Corton et al. 2014). 

PPARα Receptor Activation. Many perfluoroalkyl compounds, including PFOA, PFOS, PFUA, PFHpA, 

PFDoA, and perfluoropentanoic acid 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, 
PERFLUOROALKYLS 435

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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. Perfluoroalkyl compounds have been shown to induce 

changes in the expression of genes under the regulation of PPARα. The expression of PPARα target 

genes involved in fatty acid metabolism, cell cycle control, peroxisome biogenesis, and proteasome 

structure and organization were upregulated, while inflammatory response genes 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 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 the hepatic effects of 

perfluoroalkyl compounds, and the diminished expression of inflammatory response genes may be 

involved in immunosuppression induced by perfluoroalkyl compounds.

Gene expression changes induced by perfluoroalkyl compounds 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 to perfluoroalkyl compounds, demonstrate the following:

• A majority of the gene expression changes induced in rodents by perfluoroalkyl compounds 

tested to date, especially PFOA and PFNA, are dependent on activation of PPARα.

• Perfluoroalkyl compounds 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.

• PPARα-independent gene expression changes induced by perfluoroalkyl compounds are similar 

to those induced by compounds that activate PPARγ, constitutive androstane receptor (CAR), and 

estrogen receptor alpha (ERα) (discussed further under PPARα-independent mechanisms).
PERFLUOROALKYLS 436

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Species Differences in PPARα Activation. Species differences in response to PPARα activators have 

been reviewed by Corton et al. (2014). Studies of PPARα activation by structurally diverse ligands in 

various 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: PPARα 

cDNA from humans is indistinguishable from the rodent PPARα. Species differences in response to 

exogenous PPARα activators may stem from any or all of the following: (1) differences in the expression 

of PPARα in a given tissue; (2) differences in the gene product structure; and (3) differences in the 

ligand-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 the 

activity of the full-length receptor, possibly via sequestering critical co-activators. Other, non-truncated 

variants 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 perfluoroalkyl compounds 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 

perfluoroalkyl compounds in transfected COS-1 cells, Wolf et al. (2008b, 2012; see Table 2-28) found 

that some perfluoroalkyls exhibited marked species differences in transactivation potency (for example, 

PFUA, PFDeA, PFDoA), while other compounds showed similar transactivation potency for both human 

and mouse PPARα (for example, PFNA, PFOA, perfluoropentanoic acid [PFPeA]). 

Table 2-28. Transactivation of Human and Mouse PPARα in Transfected Cos-1 

Cells Exposed to Perfluoroalkyl Compounds (In Order of Decreasing C20max 

in the Mouse)

Perfluoroalkyl

Carbon 

number

Human Mouse C20max (μM)a

NOEC 

(μM) LOEC (μM)

NOEC 

(μM)

LOEC 

(μM) Human Mouse

PFNA 9 1 5 1 5 11 5

PFOAb 8 5, 0.5 10,1 0.5, 1 1, 3 7 6
PERFLUOROALKYLS 437

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-28. Transactivation of Human and Mouse PPARα in Transfected Cos-1 

Cells Exposed to Perfluoroalkyl Compounds (In Order of Decreasing C20max 

in the Mouse)

Perfluoroalkyl

Carbon 

number

Human Mouse C20max (μM)a

NOEC 

(μM) LOEC (μM)

NOEC 

(μM)

LOEC 

(μM) Human Mouse

PFUA 11 50 75 5 10 86 8

PFHpA 7 <0.5 0.5 3 5 15 11

PFDeA 10 100 >100c <5 5 – 20

PFDoA 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

PFBuS 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-effect 

concentration; PFBA = perfluorobutyric acid; PFBuS = perfluorobutane sulfonic acid; PFDeA = perfluorodecanoic 

acid; PFDeA = perfluorodecanoic acid; PFDoA = 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; 

PFUA = 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 hypolipidemic 

changes 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, while 

some (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 for 

the species difference in response to exogenous PPARα ligands include variations in the structure of the 

PPRE that alter the response of the human genes compared with rodents; differences between humans and 
PERFLUOROALKYLS 438

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

rodents 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 perfluoroalkyl compounds exert some 

adverse effects, including developmental and hepatic effects, through mechanisms other than activation of 

PPARα. These may 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 by 

perfluoroalkyl compounds may be mediated by activation of other nuclear receptors, especially PPARγ, 

CAR, and ERα. In a series of experiments, Rosen et al. (2008b, 2010, 2017) compared the gene 

expression changes induced by perfluoroalkyl compounds 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 in Table 2-29, show that between 10 and 24% of gene 

expression changes induced by perfluoroalkyl compounds are independent of PPARα. All four 

compounds tested (PFOA, PFOS, PFNA, and PFHxS) were shown to alter the expression of PPARγ- and 

CAR-regulated genes in PPARα-null mice, and PFNA and PFHxS also altered the expression of ERαregulated genes in the knock-out mice. In contrast, none of the compounds altered the expression of 

genes commonly affected by an agonist of LXR in either wild-type or null mice. 
PERFLUOROALKYLS 439

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

Table 2-29. Gene Expression Changes Induced by Perfluoroalkyl Compounds

Dose 

(mg/kg/day

for 7 days)

% PPARαindependent 

gene 

changes

Gene expression changes similar to those induced by 

prototypical agonist

PPARγ CAR ERα LXR 

WT

PPARαnull WTPPARαnull WTPPARαnull WTPPARαnull

PFOA 3 ~14 + + + + + – – –

PFOS 10 ~16 + + + + + – – –

PFNA 

1 ~10 + +/– + – + – – –

3 ~17 + + + + + + – –

PFHxS 3 24 + – + – + + – –

10 22 + + + + + + – –

WY14,643 0.1% in diet 2 + – – – + – – –

+ = significant (p<0.0001) similarity to gene expression changes induced by prototypical receptor agonist as 

assessed by running Fisher test; 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 activated receptor; 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 perfluoroalkyl compounds induce gene expression changes through activation of 

other nuclear 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 perfluoroalkyl 

compounds. Both PFOA 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 this system (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. 

Oxidative Stress. Perfluoroalkyl compounds increase oxidative stress in the liver, kidney, and brain. 

Increases in oxidative stress may be mediated in part via PPARα activation, but may also result from 

activation of the Nrf2 receptor (Xu et al. 2016). 
PERFLUOROALKYLS 440

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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 stress 

can have diverse physiological effects. Evidence that perfluoroalkyl compounds increase oxidative stress 

is available from in vivo and in vitro studies. For example, oxidative DNA damage (measured as 8-OHdG 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 

in ROS (measured as 2’7’-dichlorofluorescein diacetate fluorescence) were observed, 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 was 

decreased 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 and 

21, and in the liver of females treated on PND 14. Thus, these data demonstrated increased sensitivity of 

younger male mouse pups, compared with older pups or female pups, to oxidative damage by PFOS. 

Increases in oxidative stress can lead to NFκB activation (Corton et al. 2014). NFκB activation plays a 

role in tumorigenesis, and NFκB transcription factors coordinate immune responses. Few studies have 

examined NFκB activation after exposure to perfluoroalkyls. An increase in NFκB mRNA level was seen 

in 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. Perfluoroalkyl compounds also have 

been shown to inhibit GJIC both in vivo and in vitro (Corton et al. 2014). GJIC plays an important role in 

maintenance of tissue homeostasis, intercellular transmission of regulatory signals, and metabolic 

cooperation. Disruption of GJIC is thought to be involved in neurological, reproductive, and endocrine 

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 and 

PFOS inhibited GJIC in the livers of rats exposed via diet for 1 week or 3 or 21 days, respectively (Hu et 
PERFLUOROALKYLS 441

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

al. 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-specific 

phospholipase C partially mitigated the GJIC inhibition, suggesting that PFOA-induced activation of this 

enzyme 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 et 

al. 2002; Wan et al. 2014a). In Sertoli cells, GJIC plays an important role in maintenance of the 

blood: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 perfluoroalkyl compounds. 

Available data suggest 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 

PFBuS and PFHxA) (Wallace et al. 2013).

2.20.2 Hepatic Toxicity Mechanisms

Hepatic effects of perfluoroalkyl compounds in rodents likely result from a combination of PPARαdependent and independent changes; see Table 2-30. For example, increased liver weight has been 

observed in both wild-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 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, and 
PERFLUOROALKYLS 442

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

decreased 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 a 

higher 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 Perfluoroalkyl Compounds in Wild-Type and 

PPARα-Null Mice Exposed Orally

Dose 

(mg/kg/day)

↑ Relative liver 

weight

↑ % Lipid by 

cell area

↑ Hepatic 

triglycerides

↑ Hepatocyte 

cell size

↓ Hepatic DNA 

content

WT

PPARαnull WTPPARαnull WTPPARαnull WTPPARαnull WTPPARαnull

PFOA 3 +++ +++ +++ - +++ - +++ +++ + +

PFOS 10 ++ ++ ND

PFNA 

1 ++ + ND 3 +++ ++

10 +++ +++ +++ +++ +++ +++ +++ ++ + +

PFHxS 3 + + ND

10 +++ +++ +++ +++ +++ – +++ +++ + +

WY-14,643 50 +++ – +++ – – – +++ – + –

+ = 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 perfluoroalkyl compounds affect both sides of this balance, 

but a growing body of evidence indicates that fatty acid accumulation induced by perfluoroalkyl 

compounds tips the balance in favor of hepatic steatosis (Das et al. 2017). As discussed above, 

perfluoroalkyl compounds 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 perfluoroalkyl compounds 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 perfluoroalkyl compounds (Das et al. 2017; Minata et al. 2010; 

Nakagawa et al. 2012), but not in those exposed to 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 443

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

perfluoroalkyl compounds (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 mediated 

by 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 upregulation 

of genes involved in fatty acid and triglyceride synthesis in both wild-type and PPARα-null mice. In 

contrast, in vitro experiments demonstrated that these perfluoroalkyl compounds did not affect 

mitochondrial fatty acid oxidation in isolated rat liver mitochondria, and neither PFOA nor PFOS altered 

fatty acid oxidation in HepG2/C3A human liver cells. The authors suggested that perfluoroalkyl 

compounds induce hepatic steatosis by perturbing lipid homeostasis in favor of the accumulation of fatty 

acids and triglycerides in the liver. 

2.20.3 Developmental Toxicity Mechanisms

Developmental effects observed in laboratory rodents exposed to perfluoroalkyl compounds include 

prenatal loss, reduced neonate weight and viability, neurodevelopment toxicity, and delays in mammary 

gland differentiation, 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 to levels in adult tissues (Abbott et al. 2010). PPARα activation also appears to be involved in 

some, but not all, of the developmental effects of perfluoroalkyl compounds in mice, and the role of 

PPARα in mediating developmental toxicity differs among the various compounds. For example, a 

gestational exposure study of 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 and PPARα-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 wildtype, and not in PPARα-null mice; however, maternal pregnancy rate was affected only in the null mice 

(Wolf et al. 2010). 
PERFLUOROALKYLS 444

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

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, in 

part, 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) showed 

that 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 was 

consistent with immaturity. However, treatment of neonates with rescue agents that hasten lung 

maturation 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) to 

conclude that neonatal mortality in neonatal rats exposed to PFOS was not due to immaturity. Other 

hypotheses pertaining to the mechanisms of developmental toxicity of perfluoroalkyl compounds were 

not located. However, other molecular- and cellular-level effects of perfluoroalkyl compounds, including 

increased oxidative stress, dysregulation of mitochondrial function, and receptor-mediated events, may be 

involved in the observed 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 both 

compounds 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 natural 

killer 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 showed 

that 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 cell 

function 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 perfluoroalkyl compounds may modulate cell-signaling responses critical to antibody production, 

including c-Jun, NF-κB, and IL-6. 
PERFLUOROALKYLS 445

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

2.20.5 Endocrine Mechanisms

Perfluoroalkyl compounds 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 human epidemiological studies (see Section 2.13). Few data examining mechanisms of thyroid 

hormone disruption are available, but suggest that effects of perfluoroalkyl compounds on thyroid 

function may be mediated by binding to the thyroid hormone receptor, and/or by altering expression of 

genes involved in thyroid function or thyroid hormone regulation. Several perfluoroalkyl compounds 

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 (Ren et al. 2015). Among the tested compounds, PFOS exhibited 

the strongest agonist activity (Ren et al. 2015). Alterations in the mRNA or protein levels of thyroidregulating genes have been observed after oral exposure of male Sprague-Dawley rats to PFOS. PFOS 

exposure for 5 or 90 days resulted in decreased hepatic levels of mRNA type 1 deiodinase (DIO1, which 

bioactivates T3 by deiodination of T4) (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 in thyroid 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 perfluoroalkyl compounds may interact with 

the estrogen and androgen receptors. PFOA, PFOS, PFHxS, PFNA, and PFDeA were all shown to be 

antagonists 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 data 

from the livers of wild-type and PPARα-null mice exposed to PFOA, PFOS, PFHxS, and PFNA by 

gavage 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 in 

uterine 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. 
PERFLUOROALKYLS 446

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

2.20.6 Cancer Mechanisms

Like many other PPARα agonists, PFOA induced hepatocellular adenomas, Leydig cell adenomas, and 

pancreatic acinar cell adenomas in rats (Biegel et al. 2001). Liver tumors induced by PFOA are believed 

to be mediated largely through PPARα 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 from academia, 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 mode of 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).

Studies conducted in rainbow trout, an animal model that is similar to humans in terms of insensitivity to 

peroxisome 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, PFDeA, and PFUA were potent inducers of vitellogenin, an estrogen-responsive 

biomarker protein. In vitro, PFOA, PFOS, PFNA, and PFDeA 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 PFDeA enhanced liver carcinogenesis 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 

perfluoroalkyl compounds, the mode of action by which these tumors are induced, and thus their 

relevance to humans, 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 in wild-type mice exposed to PFOA (Li et al. 2011). Evidence of decreased serum 

testosterone and increased serum estradiol was seen in studies of male rats exposed orally to PFOA for 
PERFLUOROALKYLS 447

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

14 days (Biegel et al. 1995; Cook et al. 1992; Liu et al. 1996). Reduced testosterone levels may occur 

through the conversion 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 of Leydig cell tumors induced by PFOA to human risk assessment is uncertain. For example, 

an intermediate-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 the 

average 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 on 

aromatase activity or testosterone biosynthesis, both of which may be related to PPARα activation (EPA 

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 has not been 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). Effects on bile acid 

composition 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 and 

Klassen 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 mode 

of action for PFOA-induced pancreatic tumors (EPA 2016e). 

2.21 GENOTOXICITY

No studies of genotoxicity in humans exposed to perfluoroalkyl compounds were located.

Administration of a single intraperitoneal injection of 100 mg/kg PFOA to male Fischer-344 rats resulted 

in a significant increase in the levels of 8-hydroxydeoxyguanosine (a marker of oxidative DNA damage) 
PERFLUOROALKYLS 448

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

in liver DNA, but not in kidney DNA; the same dose of PFBA had no effect on liver or kidney DNA 

(Takagi et al. 1991). Oral administration of approximately 20 mg/kg/day PFOA or 10 mg/kg/day PFDeA 

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). These findings led 

the authors to conclude that induction of peroxisome proliferation also leads to organ-specific oxidative 

DNA damage. Unpublished studies summarized by Butenhoff et al. (2014) and Kennedy et al. (2004) did 

not find increases in the occurrence of polychromatic erythrocytes in the bone marrow of mice orally 

exposed to PFOA. PFOS induced micronuclei frequency and decreased the ratio of polychromatic 

erythrocytes to normochromatic erythrocytes in bone marrow of rats following oral exposure to 0.6–

2.5 mg/kg for 30 days (Celik et al. 2013; Eke and Celik 2016).

In vitro studies provide evidence that PFOA and PFOS are not mutagenic at noncytotoxic concentrations. 

Butenhoff et al. (2014) and Kennedy et al. (2004) summarized the results of various unpublished 

mutagenicity studies with PFOA. Negative results were found in reverse mutation assays using 

Salmonella typhimurium (strains TA98, TA100, TA1535, TA1537, and TA1538), Saccharomyces 

cerevisiae, and Escherichia coli (WP2uvrA strain) with or without metabolic activation. 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 cell transformation in C3H 

10T1/2 cells. Similarly, two in vivo assays found no alterations in the occurrence of micronuclei in mice. 

PFOA also was not mutagenic in S. 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).

Incubation of 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 reactive oxygen species (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/C3a hepatoma 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 were very 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 
PERFLUOROALKYLS 449

2. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT***

(Zhao et al. 2011). Concurrent treatment with a ROS inhibitor significantly decreased the mutagenic 

potential, indicating that ROS may play an important role in mediating the genotoxic effects of PFOA. 

PFOA induced DNA damage in Paramecium caudatum following exposure to 100 μM for 12 and 

24 hours (Kawamoto et al. 2010). Intracellular ROS was significantly increased and DNA damage was 

not reversed by the application of glutathione, a ROS-inhibitor, indicating that intracellular ROS may not 

be the cause of PFOA-induced DNA damage. PFOS did not induce DNA damage in this study. In 

contrast, no increases in DNA damage or micronuclei formation were found in human hepatoma HepG2 

cells following a 24-hour exposure to PFOA concentrations as high as 800 μM (Florentin et al. 2011); 

cytotoxicity was observed at ≥200 μM. Eriksen et al. (2010) also found no evidence of DNA damage in 

HepG2 cells incubated with 100 or 400 μM PFOA for 24 hours.

OECD (2002) summarized unpublished mutagenicity studies conducted with PFOS. PFOS was negative 

in all tested assays. It 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). 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. In addition, PFOS did not induce micronuclei in the 

bone marrow of CD-1 mice in an in vivo assay. 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 micronuclei formation in human hepatoma HepG2 cells following 

a 24-hour exposure to PFOA 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).

Limited in vitro data on the genotoxicity of other perfluoroalkyls were located. No DNA damage was 

found in HepG2 cells incubated with 100 or 400 μM PFHxS or PFBuS for 24 hours (Eriksen et al. 2010). 

A “modest” increase in DNA damage was observed at 400 μM PFNA, a cytotoxic concentration (Eriksen 

et al. 2010).
PERFLUOROALKYLS 450

***DRAFT FOR PUBLIC COMMENT***

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, 

BIOMARKERS, CHEMICAL INTERACTIONS

3.1 TOXICOKINETICS 

Toxicokinetic data on perfluoroalkyls examined in this profile are available from studies in humans and 

animals. 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 in 

animals range from >50% for PFHxS to >95% for PFOA, PFBA, PFNA, PFDeA, PFUA, and 

PFDoA. 

- 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 the 

liver, 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 route of absorption has no substantial effect on rates of elimination of absorbed 

perfluoroalkyls.

- Perfluoroalkyls are primarily eliminated in the urine, with smaller amounts eliminated in 

feces and breast milk.
PERFLUOROALKYLS 451

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

- 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 with 

increased 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 in 

rats. Menstruation may contribute to faster elimination of PFOS in younger women 

(≤50 years) women 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 reflects a predominant contribution from 

inhaled 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 (mass 

median 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) in 

females (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 of 

approximately 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).
PERFLUOROALKYLS 452

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 of 

absorption 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 perfluoroalkyl 

compounds was provided in studies that found associations between environmental levels (e.g., drinking 

water) and perfluoroalkyl 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, and PFHxS, PFHpA, PFNA, PFDeA, PFUA, and PFDoA, with estimates ranging from 

>50% for PFHxS to >95% for PFOA, PFBA, PFNA, PFDeA, PFUA, and PFDoA. 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 was 

absorbed for PFOA (females), PFNA (males and female), PFDeA (males and females), PFUA (males and 

females), and PFDoA (males and female); however, absorption of PFOA in males was 80%, compared to 

100% in females (Fujii et al. 2015a, 2015b). 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. 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 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 and secreted 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 
PERFLUOROALKYLS 453

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 estimated absorption fraction of PFBA 

(administered as 30 mg/kg oral dose of PFBA) was >95% in rats (Chang et al. 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; and 65–69% in urine, and 5–7% in 

feces in female mice (Chang et al. 2008a).

Studies examining the rate of absorption of PFOA, PFBA, and PFBuS show rapid absorption from the 

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 be 

calculated from these observations (Equations 3-1 and 3-2): 

 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) in 

female rats and 10 hours (range 7–15 hours) in male rats 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 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 

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–

)(

1 max ln

eae

a

kkk

k

t − ⋅=

ke

t )2ln(

2/1 =
PERFLUOROALKYLS 454

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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). Similar results 

for were reported by Olsen et al. (2009) based on estimated compartmental pharmacokinetic parameters 

for PFBuS in serum of male and female rats following a single intravenous or gavage dose of 30 mg 

potassium PFBuS. Plasma concentration-time profiles were fit to a two-compartment elimination model. 

The absorption t1/2 can be approximated from these 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 yield similar values for the absorption t1/2

(0.12–0.16 hours). The estimated tmax values following the gavage 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) yielded values 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 of 

dermal absorption in humans or animals have not been reported. PFOA was detected in serum of mice 

following 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 in 

content of total organic fluoride compared to controls, indicating that dermal absorption was not 

detectable 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 

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 full 

thickness human skin in 24 hours and 45% of the dose was retained in skin (Franko et al. 2012); it is 

noted 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 
PERFLUOROALKYLS 455

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

(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 is 

greater than that of the dissociated anion. Lower permeability of ionized PFOA is also suggested by 

relatively 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 across 

rat epidermis in 40 hours. The estimated dermal penetration coefficients were 9.49x10-7 cm/hour in the 

isolated human epidermis and 3.25x10-5 cm/hour in the isolated rat epidermis. 

3.1.2 Distribution 

Available information on the distribution of perfluoroalkyls is obtained from oral exposure studies in 

laboratory 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 perfluoroalkyl workers, serum:plasma ratios for PFHxS, PFOS, and 

PFOA were 1:1, and this 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 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 to 

serum albumin is approximately 0.4 mM (0.38 mM, ±0.04 standard deviation [SD] for human serum 

albumin; 0.36 nM, ±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 456

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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, PFDeA) (Ohmori et al. 2003; Kerstner-Wood et al. 2003). 

Comparison of dissociation constants for binding of PFOA and PFOS to human serum albumin indicates 

that PFOS (KD: 8x10-8) has a higher binding affinity than PFOA (KD: 1x10-4) for albumin, consistent with 

the longer t1/2 of PFOS versus PFOA in humans (Beesoon and Martin 2015; see section 3.1.4 for 

additional information). PFOS has also been shown to bind to human hemoglobin in vitro (Wang et al. 

2016). PFBuS was found to bind only to albumin, whereas PFOS, PFOA, and PFHxS were found to have 

the 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 human 

cadavers attempted to quantify PFOA, PFOS, PFOSA, 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 not 

different 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, PFOSA, and PFHxA were below the limit of 

quantification; these limits were <17.9–<35.9 ng/mL for PFOA, <7.5–<19.6 ng/g for PFOSA, and <3.4–

<18.5 ng/mL for PFHxA.

Studies 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 as 

well 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 consistent 

finding 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 investigations 

of tissue distribution have been conducted in rodents. 
PERFLUOROALKYLS 457

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 dose 

groups. In low-dose animals after 5 days of treatment, the highest tissue concentrations (excluding the 

gastrointestinal 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, the 

highest 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) to 

male 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, the 

highest 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 and 

0, 0.15, 1.43, 3.73, and 7.58 mg/kg/day in males and females, respectively) for 28 days, PFOS levels were 

highest in liver, followed by spleen, heart, and serum. Liver:serum ratios for the 2, 20, 50, and 

100 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, the 

liver: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.

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 (as 

ammonium 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 concentrations 

of 14C were observed in blood, liver, and kidney (Figure 3-1). Liver, blood, and kidney accounted for 

approximately 22, 22, and 2% of the administered dose of 1 mg/kg in male rats; and 6, 7, and, 3% in 

female 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, in 

female rats, a disproportionately higher concentration in kidney was observed following the 25 mg/kg dose 
PERFLUOROALKYLS 458

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

(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, with 

little 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 (see 

Section 3.1.4). 

Figure 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*

0

20

40

60

80

100

120

140

160

180

0 5 10 15 20 25 30

Dose (mg/kg)

Tissue (ug/g)

Blood, M

Liver, M

Kidney, M

Blood, F

Liver, F

Kidney, F

*Tissue levels are measured at time of maximum concentration in each tissue.

Source: Kemper 2003
PERFLUOROALKYLS 459

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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

Source: Ylinen et al. 1990

0

2

4

6

8

10

12

14

16

0 5 10 15 20 25 30 35

Dose (mg/kg/day)

Tissue (ug/g)

Serum

Liver

Kidney

Female rat

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35

Dose (mg/kg/day)

Tissue (ug/g)

Serum

Liver

Kidney

Male rat
PERFLUOROALKYLS 460

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

A comparison of PFOA disposition in rats, mice, hamsters, and rabbits showed pronounced species and 

sex differences (Hundley et al. 2006; Table 3-1). In this study, rats, mice, hamsters, or rabbits received an 

oral 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 and 

kidney, 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 were 

similar 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 and 

rabbits, with males having lower tissue levels than females, although, in common with rats and mice, 

blood, liver and kidney had the highest concentrations. Male rats that received a single oral dose of 5 mg 

PFOSA/kg had liver PFOSA 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 to 

perfluoroalkyls 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 (one 

male) or 50 μg/g (one female) at the low dose and 45 μg/g (one male) and 72 μg/g (one female) at the 

higher 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 

that liver levels did not increase proportionately with increasing dose. A similar observation was made in 

a 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 from 

11 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, an 

analysis 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 that 

received daily oral doses of PFOS (0, 0.03, 0.15, or 0.75 mg PFOS/kg/day) for 26 weeks, liver 

concentrations 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). 
PERFLUOROALKYLS 461

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 Rabbit

Sample Male Female Male Female Male Female Male Female

Blood 23.5 <0.1 13.8 10.1 0.1 8.8 <0.1 0.1

Liver 40.0 <0.1 43.2 45.3 0.3 7.3 0.1 1.5

Kidneys 24.0 <0.1 2.9c 2.2c 0.2 7.1 0.1 0.4

Lungs 8.7 <0.1 1.4c 1.3c <0.1 3.8 <0.1 0.1

Heart 6.4 <0.1 1.2c 0.6c <0.1 2.9 <0.1 <0.1

Skin 4.8 <0.01 3.5 0.2 <0.1 3.4 <0.1 <0.1

Testes 3.2 – 0.9c – <0.1 – <0.1 –

Muscle 1.9 <0.1 1.1 0.5 <0.1 0.9 <0.1 <0.1

Fat 1.7 <0.1 1.6 1.3 <0.1 1.5 <0.1 <0.1

Brain 0.6 <0.1 0.2c 0.8c <0.1 0.3 <0.1 <0.1

Percent of dose

Tissues 59.6 0.6 73.6 50.0 0.7 26.5 <0.1 0.3

Urine 25.6 73.9 3.4 6.7 90.3 45.3 76.8 87.9

Feces 9.2 27.8 8.3 5.4 8.2 9.3 4.2 4.6

Expiration 3.6 1.5 5.2 4.4 1.3 2.9 No data No data

Cage wash 0.6 0.8 4.9 4.9 0.6 2.1 0.5 4.8

Percent recovered 98.5 104.6 95.4 71.4 101.1 86.1 81.6 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

Bogdanska et al. (2014) examined distribution of 35S in 20 tissues following dietary exposure of adult 

male C57/BL6 mice to PFBuS (16 mg/kg/day) for 1–5 days. 35S was detected in all tissues and 

concentrations 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.

Subcellular Distribution. The subcellular distribution of perfluoroalkyls has been examined in rats (Han 

et 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 in 
PERFLUOROALKYLS 462

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

liver; 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

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 to 

proteins (>6,000 Da) in both males and females, whereas in kidney, 42% of the cytosolic fraction was 

bound 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 the 

liver 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 and 

PFDeA appeared to be bound covalently to protein. Following an intraperitoneal dose of 9.4 μmol/kg 

[

14C]PFDeA 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 et 

al. 1992b). Covalent binding was detected when cytosolic or microsomal fractions of rat liver were 

incubated in vitro with [14C]PFDeA (Vanden Heuvel et al. 1992b).

PFOA binds to rat kidney and urine α2u-globulin; dissociation constants were estimated to be 

approximately 1.5 and >2 mM (for a single binding site) for the proteins isolated from rat kidney and

urine, respectively. These values suggest relatively low affinity for the protein, compared to other ligands 

that 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; 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, Lee et 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 found relatively 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 et al. 2011; Needham 

et al. 2011). PFOS was detected in amniotic fluid obtained from amniocentesis (Jensen et al. 2012). The 
PERFLUOROALKYLS 463

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

median concentration in amniotic fluid samples from 300 pregnancies (from the Danish amniotic fluid 

sample back) was 1.1 ng/mL.

Table 3-2. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant 

Pairs

Study

PerfluoroalkylPerfluoroalkyl 

chain length N

Maternal 

(ng/mL)

Cord 

(ng/mL) Ratioa r

Glynn et al. 2012 PFOA 7 413 4 1 NR 0.89

PFOS 8 413 29 5 NR 0.86

PFNA 8 413 0.6 0.1 NR 0.53

Cariou et al. 2015 PFHxS 6 59 0.62 0.34 0.56 0.99

PFOA 7 89 1.05 0.86 0.78 0.83

PFOS 8 94 3.07 1.11 0.38 0.88

PFNA 8 22 0.43 0.27 0.51 0.92

Fisher et al. 2016 PFHxS 6 315 NR NR 0.23 NR

PFOA 7 865 NR NR 0.28 NR

PFOS 8 648 NR NR 0.14 NR

Fromme et al. 2010 PFHxS 6 53 0.60 0.30 0.50 0.89

PFOA 7 53 2.60 1.70 0.65 0.94

PFOS 8 53 3.50 1.10 0.31 0.89

PFNA 8 53 0.60 <0.4 ND ND

Gützkow et al. 2012 PFHxS 6 123 0.34 0.23 0.68 0.70

PFOA 7 123 1.25 1.03 0.82 0.82

PFOS 8 123 5.37 1.78 0.33 0.74

PFNA 8 123 0.40 0.16 0.40 0.64

PFDeA 9 123 0.10 0.04 ND ND

PFUA 10 123 0.19 0.06 0.32 0.67

Hanssen et al. 2013 PFHxS 6 7 0.26 0.17 0.65 ND

PFOA 7 7 1.50 1.26 0.84 ND

PFOS 8 7 10.70 3.93 0.37 ND

PFNA 8 7 0.89 0.50 0.56 ND

PFOSA 8 7 0.41 0.45 1.10 ND

PFUA 10 7 0.33 0.16 0.48 ND

Inoue et al. 2004 PFOA 7 15 8.90 2.90 0.32 0.94

Kim et al. 2011 PFHxS 6 20 0.89 0.58 0.65 ND

PFOA 7 20 1.60 1.10 0.69 ND

PFOS 8 20 5.60 2.00 0.36 ND

PFNA 8 20 0.79 0.37 0.47 ND

PFDeA 9 20 0.36 0.01 0.03 ND

PFUA 10 20 1.60 0.46 0.29 ND
PERFLUOROALKYLS 464

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-2. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant 

Pairs

Study

PerfluoroalkylPerfluoroalkyl 

chain length N

Maternal 

(ng/mL)

Cord 

(ng/mL) Ratioa r

Kato et al. 2014 PFHxS 6 78 1.20 0.60 0.50 0.89

PFOA 7 78 3.30 3.10 0.89 0.88

PFOS 8 78 8.50 3.50 0.31 0.82

MePFOSAAcOH8 78 0.20 0.30 1.50 0.92

PFNA 8 78 0.66 0.41 0.62 0.79

PFDeA 9 78 0.20 ND ND ND

Lee et al. 2013 PFHS 6 70 1.35 0.67 0.57 ND

PFOA 7 70 2.73 2.09 0.84 ND

PFOS 8 70 10.77 3.44 0.35 ND

Liu et al. 2011 PFHxS 6 50 0.08 0.06 0.79 0.59

PFOA 7 50 1.66 1.50 0.91 0.91

PFOS 8 50 3.18 1.69 0.53 0.75

PFNA 8 50 0.55 0.33 0.61 0.82

PFDeA 9 50 0.58 0.24 0.41 0.82

PFUA 10 50 0.56 0.30 0.53 0.70

PFDoA 11 50 0.08 ND ND ND

Manzano-Salgado et 

al. 2015

PFHxS 6 66 0.84 0.40 0.446 NR

PFOA 7 66 2.97 1.90 0.746 NR

PFOS 8 66 6.99 1.86 0.299 NR

PFNA 8 66 0.85 0.32 0.4 NR

Midasch et al. 2007 PFOA 7 11 2.70 3.40 1.30 0.42

PFOS 8 11 12.10 7.20 0.60 0.72

Monroy et al. 2008 PFHxS 6 101 4.05 5.05 1.25 ND

PFOA 7 101 2.24 1.94 0.87 0.94

PFOS 8 101 16.19 7.19 0.44 0.91

PFNA 8 101 0.80 0.94 1.18 ND

Needham et al. 2011 PFHxS 6 12 12.30 9.10 0.74 0.05

PFOA 7 12 4.20 3.10 0.72 0.91

PFOS 8 12 19.70 6.60 0.34 0.82

PFNA 8 12 0.76 0.37 0.50 0.84

PFDeA 9 12 0.34 0.10 0.29 0.91

Ode et al. 2013 PFOA 7 263 2.30 2.80 1.30 0.74

PFOS 8 263 17.00 7.40 0.45 0.76

PFNA 8 263 0.31 0.26 0.93 0.51

Porpora et al. 2013 PFOA 7 38 2.90 1.60 0.55 0.70

PFOS 8 38 3.20 1.40 0.44 0.72
PERFLUOROALKYLS 465

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-2. Serum (or Plasma) Concentrations in Matched Human Maternal-Infant 

Pairs

Study

PerfluoroalkylPerfluoroalkyl 

chain length N

Maternal 

(ng/mL)

Cord 

(ng/mL) Ratioa r

Yang et al. 2016a PFHxS 6 50 0.064 0.033 0.52 0.80

PFOA 7 50 1.24 1.03 0.83 0.93

PFOS 8 50 2.98 1.23 0.41 0.88

PFNA 8 50 0.55 0.35 0.64 0.89

PFDeA 9 50 0.56 0.22 0.39 0.92

PFUA 10 50 0.55 0.23 0.42 0.88

PFDoA 11 50 0.085 0.058 0.68 0.76

Yang et al. 2016b PFHxS 6 157 0.53 0.26 0.43 0.68

PFOA 7 157 1.74 1.32 0.71 0.81

PFOS 8 157 4.23 1.52 0.36 0.63

PFNA 8 157 0.46 0.23 0.49 0.70

PFDeA 9 157 0.37 0.13 0.35 0.65

PFUA 10 157 0.38 0.14 0.36 0.63

PFDoA 11 157 0.040 0.026 0.61 0.52

aRatio of cord:maternal perfluoroalkyl level

ND = no data (detected but below limit of quantification); NR = not reported; PFDeA = perfluorodecanoic acid; 

PFDoA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; 

PFTrDA = perfluorotridecanoic acid; PFUA = 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 et 

al. 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) to 

potassium 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 

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).
PERFLUOROALKYLS 466

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 10 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 were 

approximately 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 was 

detected 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; Liu 

et al. 2011; Tao et al. 2008a, 2008b). Studies that measured perfluoroalkyls in maternal serum (or 

plasma) 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 their 

infants 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 with 

breastfeeding duration (Tao et al. 2008b; Thomsen et al. 2010). Numerous perfluoroalkyl compounds 

(including PFOS, PFOA, PFBuS, PFHxS, PFNA, PFDeA, PFDoA, PFUA, and PFOSA) have been 

detected in breast milk samples in women in China, Korea, Japan, Malaysia, Cambodia, India, Korea, 

Vietnam, Indonesia, 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 
PERFLUOROALKYLS 467

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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, PFDeA, PFUA, PFDoA, and PFBuS 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 (Fromme et al. 2010; Mondal et al. 2014; Post et al. 

2012). 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 

Humans

Study Perfluoroalkyl

Perfluoroalkyl 

chain length N

Serum 

(ng/mL) 

Milk 

(ng/mL) Ratioa r

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 ND

PFOA 7 12 3.8 0.49 0.120 0.88

PFOS 8 12 20.7 0.20 0.010 0.83

PFOSA 8 12 0.24 0.013 0.070 ND

PFNA 8 12 0.80 0.017 0.010 ND

Kim et al. 2011 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 0.60

PFNA 8 20 0.79 <0.0088 ND ND

PFDeA 9 20 0.36 <0.018 ND ND

PFUA 10 20 1.60 <0.024 ND ND

Liu et al. 2011 PFHxS 6 50 0.08 ND ND ND

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

PFDeA 9 50 0.58 0.02 0.034 0.54

PFUA 10 50 0.56 0.026 0.046 0.44

PFDoA 11 50 0.08 ND ND ND

PFTrDA 12 50 0.08 ND ND ND

aMilk to serum ratio

ND = no data (detected but below limit of quantification); NS = not significantly correlated; 

PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHxS = perfluorohexane sulfonic acid; 

PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; 

PFOSA = perfluorooctane sulfonamide; PFTrDA = perfluorotridecanoic acid; PFUA = perfluoroundecanoic acid;
PERFLUOROALKYLS 468

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 10 mg/kg/day, administered daily beginning on GD 4). Milk concentrations of PFOA 

measured on postpartum days 3, 7, 14, or 21 in rats were approximately 0.1 of maternal plasma 

concentration. In dams exposed to 0.1, 1, or 5 mg/kg PFOA by gavage on GD 17, a dose-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 maternal-infant transfer of PFOS in rats and mice 

(see Section 2.17).

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. 2012c; 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 et 

al. 1992b; Wu et al. 2009; Ylinen and Auriola 1990; Zhang et al. 2009). The dissociation constant for 

albumin-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). Noncovalent 

binding 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 extravascular 

concentrations 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, which 
PERFLUOROALKYLS 469

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

facilitates 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 in 

rats (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 proteins 

that 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 this 

profile are not metabolized and do not undergo chemical reactions in the body. Studies conducted in male 

and female rats did not detect fluorine metabolites in the urine, plasma, or liver following a single 

injection of 4–150 mg/kg PFOA or 5–50 mg/kg PFDeA (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 urine and bile (Vanden Heuvel et al. 1991c). 

PFOA was not metabolized when incubated with microsomal fractions of human or rat intestine, kidney, 

or liver homogenates (Kemper and Nabb 2005). Although no studies examining metabolism of 

perfluoroalkyls 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. 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 

and breast milk (see Section 3.1.2; Distribution, Maternal-fetal Transfer). 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 
PERFLUOROALKYLS 470

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

by exercise or sauna does not alter clearance of PFOA, PFOA, PFHxA, or PFNA (Genuis et al. 2013). 

Perfluoroalkyls are eliminated in menstrual fluid, which appears to contribute to sex differences in serum 

elimination rates (Wong et al. 2014, 2015; Zhang et al. 2013). 

In humans, absorbed perfluoroalkyls are excreted in urine. Estimates of renal clearance of PFOA and 

PFOS 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 were 

excreted 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

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 and 

23 years, respectively). Mean renal clearances for PFOS were 0.66 mL/day (±0.48 SD, n=5) in males and 

0.91 (±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), PFDeA (0.015±0.01), PFUA (0.005±0.00), and PFDoA (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 be 

differences in renal clearance for PFOA; clearance rates were 0.30 mL/day/kg (95% CI 0.11–0.49) in 

young 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 than 

in nonpregnant female adults (n=25). In addition, urinary excretion of PFOS was inversely correlated 

with 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 are 

presented in Table 3-4 (Harada et al. 2007). Biliary clearances of PFOA and PFOS were 1.06 and 

2.98 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 been 
PERFLUOROALKYLS 471

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

reabsorbed from the gastrointestinal tract. Fujii et al. (2015a) also reported that biliary clearances of

several perfluoroalkyls (PFOA, PFNA, PFDeA, PFUA, PFDoA) were much higher than total body 

clearance 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 t1/2a day 1,387 1,971

Total clearanceb mL/kg/day 0.150 0.106

Urinary clearancec mL/kg/day 0.030 0.150

Biliary clearanced mL/kg/day 1.06 2.98

Reabsorbed from bilee % 89 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 major 

route 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. 2009; 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 PFDeA, 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 PFBuS are excreted in feces following intravenous dosing of rats, suggesting that 

these perfluoroalkyls 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 PFBuS. 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 in female 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 bound to 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 
PERFLUOROALKYLS 472

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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). 

Rates of elimination of perfluoroalkyls vary substantially across chemical species and animal species, and 

show sex differences and age-dependencies within certain species. Table 3-5 summarizes estimates of the 

elimination t1/2 for perfluoroalkyls in humans and experimental animals. In compiling the estimates 

presented 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 the 

perfluoroalkyl 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 to 

estimate 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 of 

several weeks. Direct comparisons of t1/2 values should be made with consideration of whether or not the 

observation periods were comparable. Differences in estimation methodology can also contribute to 

differences 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 the 

systemic clearance (ClS), typically estimated from the absorbed dose (AD) and the area under the serum 

concentration curve (AUCS):

S

S AUC

AD Cl = 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 
PERFLUOROALKYLS 473

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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. 

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls 

Estimated in Humans and Experimental Animals

Species, age, and 

sex Route Dose

Exposure 

durationa 

Elimination halflifeb Reference

PFOA—Human

Human (n=26), adult, 

M (24) F (2)

NA NA NA 3.8 years (95% CI 

3.1–4.4, GM 3.5)

Olsen et al. 2007a

Human (n=20) 15–

50 years M

NA NA NA 2.8 years (95 %CI 

2.4–3.4)

Li et al. 2018

Human (n=30) 15–

50 years F

NA NA NA 2.4 years (95% CI 

2.0–3.0)

Li et al. 2018

Human (n=66), 

>50 years, M, F

NA NA NA 2.6 years (SE 0.4, 

GM 1.2)

Zhang et al. 2013

Human (n=20), 

≤50 years, F

NA NA NA 2.1 years (SE 0.3, 

GM 1.5)

Zhang et al. 2013

Human (n=45) M, F NA NA NA 3.9 years Worley et al. 2017a

Human (n=5), 

22±0.9, M

NA NA NA 2.3 years Harada et al. 2005a

Human (n=5), 68±5, 

M

NA NA NA 2.6 years Harada et al. 2005a

Human (n=5), 23±3, 

F

NA NA NA 3.5 years Harada et al. 2005a

Human (n=5), 69±5, 

F

NA NA NA 2.9 years Harada et al. 2005a

Human (n=200)

54±15, M, F

Oral NA NA 2.3 years (95% CI 

2.1–2.4)

Bartell et al. 2010

Human (n=643)

Adults, M, F

Oral NA NA 2.9 years 

(<4 years)

(95% CI 2.3–3.8)

10.1 years 

(>4 years)

Seals et al. 2011

Human (n=1,029)

Adults, M, F

Oral NA NA 8.5 years 

(<9 years)

(95% CI 7.1–10.1)

Seals et al. 2011

Humans (n=17) 

Adults, M, F

Oral NA NA 5.1 years (SD 1.7, 

GM 4.8)

Costa et al. 2009

PFOS—Human

Human (n=26), adult, 

M (24) F (2)

NA NA NA 5.4 years (95% CI 

3.9–6.9, GM 4.8)

Olsen et al. 2007a

Human (n≅1,000), 

>12–>80 years, M

NA NA NA 4.7 years Wong et al. 2014

Human (n≅1,000), 

>12–>80 years, F

NA NA NA 4.3 years (95% CI 

4.1–4.5)

Wong et al. 2015
PERFLUOROALKYLS 474

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls 

Estimated in Humans and Experimental Animals

Species, age, and 

sex Route Dose

Exposure 

durationa 

Elimination halflifeb Reference

Human (n=66), 

>50 years, M, F

NA NA NA 27 years (SE 3.1, 

GM 18)

Zhang et al. 2013

Human (n=20), 

≤50 years, F

NA NA NA 6.2 years (SE 0.5, 

GM 5.8)

Zhang et al. 2013

Human (n=45) M, F NA NA NA 3.3 years Worley et al. 2017a

Human (n=20) 15–

50 years M

NA NA NA 4.6 years (95% CI 

3.7–6.1)

Li et al. 2018

Human (n=30) 15–

50 years F

NA NA NA 3.1 years (95% CI 

2.7–3.7)

Li et al. 2018

Human (n=5), 

22±0.9, M

NA NA NA 4.9 years Harada et al. 2005a

Human (n=5), 68±5, 

M

NA NA NA 7.4 years Harada et al. 2005a

Human (n=5), 23±3, 

F

NA NA NA 4.5 years Harada et al. 2005a

Human (n=5), 69±5, 

F

NA NA NA 4.6 years Harada et al. 2005a

PFHxS—Human

Human (n=26), adult, 

M (24), F (2)

NA NA NA 8.5 years (95% CI 

6.4–10.6, GM 7.3)

Olsen et al. 2007a

Human (n=20), 

≤50 years, F

NA NA NA 7.7 years (SE 0.6, 

GM 7.1)

Zhang et al. 2013

Human (n=20) 15–

50 years M

NA NA NA 7.4 years (95% CI 

6.0–9.7)

Li et al. 2018

Human (n=30) 15–

50 years F

NA NA NA 4.7 years (95% CI 

3.9–5.9)

Li et al. 2018

Human (n=45) M, F NA NA NA 15.5 years Worley et al. 2017a

Human (n=66), 

>50 years, M, F

NA NA NA 35 years (SE 3.9, 

GM 25)

Zhang et al. 2013

PFBA—Human

Human (n=3), adult, 

M

NA NA NA 81 hours (SD 41) Chang et al. 2008b

Human (n=9), adult, 

M (7), F (2)

NA NA NA 72 hours (SD 38) Chang et al. 2008b

PFBuS—Human

Human (n=6), adult 

M (5), F(1)

665 hours (SD 

266)

Olsen et al. 2009

PFNA—Human 

Human (n=66), 

>50 years, M, F

NA NA NA 4.3 years (SE 0.5, 

GM 3.2)

Zhang et al. 2013

Human (n=20), 

≤50 years, F

NA NA NA 2.5 years (SE 0.6, 

GM 1.7)

Zhang et al. 2013
PERFLUOROALKYLS 475

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls 

Estimated in Humans and Experimental Animals

Species, age, and 

sex Route Dose

Exposure 

durationa 

Elimination halflifeb Reference

PFDeA—Human 

Human (n=66), 

>50 years, M, F

NA NA NA 12 years (SE 1.5, 

GM 7.1)

Zhang et al. 2013

Human (n=20), 

≤50 years, F

NA NA NA 4.5 years (SE 0.4, 

GM 4.0)

Zhang et al. 2013

PFUA—Human 

Human (n=66), 

>50 years, M, F

NA NA NA 12 years (SE 2.0, 

GM 7.4)

Zhang et al. 2013

Human (n=20), 

≤50 years, F

NA NA NA 4.5 years (SE 0.5, 

GM 4.0)

Zhang et al. 2013

PFHpA—Human 

Human (n=66), 

>50 years, M, F

NA NA NA 1.2 years (SE 0.2, 

GM 0.82)

Zhang et al. 2013

Human (n=20), 

≤50 years, F

NA NA NA 1.5 years (SE 0.3, 

GM 1.0)

Zhang et al. 2013

PFOA—Nonhuman primate

Cynomolgus 

monkey, adult, M

Oral 10 mg/kg/day 6 months 20.1 days Butenhoff et al. 2004c

Cynomolgus 

monkey, adult, M

IV 10 mg/kg 1 day 20.9 days (SD 

12.5)

Butenhoff et al. 2004c

Cynomolgus 

monkey, adult, F

IV 10 mg/kg 1 day 32.6 days (SD 8.0) Butenhoff et al. 2004c

PFOS—Nonhuman primate

Cynomolgus 

monkey, adult, M

Oral 0.15 mg/kg/day 6 months 170 days Seacat et al. 2002

Cynomolgus 

monkey, adult, M

Oral 0.75 mg/kg/day 6 months 170 days Seacat et al. 2002

Cynomolgus 

monkey, adult, F

Oral 0.15 mg/kg/day 6 months 170 days Seacat et al. 2002

Cynomolgus 

monkey, adult, F

Oral 0.75 mg/kg/day 6 months 170 days Seacat et al. 2002

Cynomolgus 

monkey, adult, M

IV 2 mg/kg 1 day 132 days (SE 7) Chang et al. 2012

Cynomolgus 

monkey, adult, F

IV 2 mg/kg 1 day 110 days (SE 15) Chang et al. 2012

PFHxA—Nonhuman primate

Cynomolgus 

monkey, adult, M

IV 10 mg/kg 1 day 5.3 days (SD 2.5) Chengelis et al. 2009

Cynomolgus 

monkey, adult, F

IV 10 mg/kg 1 day 2.4 days (SD 1.7) Chengelis et al. 2009
PERFLUOROALKYLS 476

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls 

Estimated in Humans and Experimental Animals

Species, age, and 

sex Route Dose

Exposure 

durationa 

Elimination halflifeb Reference

PFHxS—Nonhuman primate

Cynomolgus 

monkey, adult, M

IV 10 mg/kg 1 day 141 days (SE 30.) Sundström et al. 2012

Cynomolgus 

monkey, adult, F

IV 10 mg/kg 1 day 87 days (SE 27) Sundström et al. 2012

PFBA—Nonhuman primate

Cynomolgus 

monkey, adult, M

IV 10 mg/kg 1 day 40.3 hours (SD 

2.4)

Chang et al. 2008b

Cynomolgus 

monkey, adult, F

IV 10 mg/kg 1 day 41.0 hours (SD 

4.7)

Chang et al. 2008b

PFBuS—Nonhuman primate 

Cynomolgus 

monkey, adult, M

IV 10 mg/kg 1 day 15.0 hours (SD 

9.8)

Chengelis et al. 2009

Cynomolgus 

monkey, adult, F

IV 10 mg/kg 1 day 8.0 hours (SD 2.0) Chengelis et al. 2009

Cynomolgus 

monkey, adult, M

IV 10 mg/kg 1 day 95.2 hours 

(SE 27.1)

Olsen et al. 2009

Cynomolgus 

monkey, adult, F

IV 10 mg/kg 1 day 83.2 hours 

(SE 41.9)

Olsen et al. 2009

PFOA—Rat

Rat (CR), adult, M Oral 11.4 mg/kg 1 day 115 hours Johnson and Ober 

1980

Rat (SpragueDawley), adult, MOral 0.1 mg/kg 1 day 202 hours (SD 38) Kemper 2003

Rat (SpragueDawley), adult, MOral 1 mg/kg 1 day 138 hours (SD 32) Kemper 2003

Rat (SpragueDawley), adult, MOral 1 mg/kg 1 day 44 hours Kim et al. 2016b

Rat (SpragueDawley), adult, MOral 5 mg/kg 1 day 174 hours (SD 29) Kemper 2003

Rat (SpragueDawley), adult, MOral 25 mg/kg 1 day 157 hours (SD 38) Kemper 2003

Rat (SpragueDawley), adult, MIV 1 mg/kg 1 day 185 hours (SD 19) Kemper 2003

Rat (SpragueDawley), adult, MIV 1 mg/kg 1 day 39 hours Kim et al. 2016b

Rat (SpragueDawley), adult, MOral 0,4 mg/kg 1 day 322 hours (SD 38) Benskin et al. 2009

Rat (SpragueDawley), adult, MOral 0.022 mg/kg/day 12 weeks 218 hours (95% CL 

127–792)

De Silva et al. 2009

Rat (Wistar), adult, M IV 21.5 mg/kg 1 day 136 hours (SD 24) Kudo et al. 2002

Rat (Wistar), adult, M IV 20.1 mg/kg 1 day 135 hours (SD 29) Ohmori et al. 2003
PERFLUOROALKYLS 477

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls 

Estimated in Humans and Experimental Animals

Species, age, and 

sex Route Dose

Exposure 

durationa 

Elimination halflifeb Reference

Rat (SpragueDawley), adult, MIP 3.9 mg/kg 1 day 216 hours (SE 

30.9)

Vanden Heuvel et al. 

1991c

Rat (Wistar), adult, M IP 50 mg/kg 1 day 105 hours Ylinen et al. 1990

Rat (SpragueDawley), adult, FOral 0.1 mg/kg 1 day 3.2 hours (SD 0.9) Kemper 2003

Rat (SpragueDawley), adult, FOral 1 mg/kg 1 day 3.5 hours (SD 1.1) Kemper 2003

Rat (SpragueDawley), adult, FOral 1 mg/kg 1 day 3.6 hours Kim et al. 2016b

Rat (SpragueDawley), adult, FOral 5 mg/kg 1 day 4.6 hours (SD 0.6) Kemper 2003

Rat (SpragueDawley), adult, FOral 25 mg/kg 1 day 16.2 hours (SD 

9.9)

Kemper 2003

Rat (SpragueDawley), adult, FIV 1 mg/kg 1 day 2.8 hours (SD 0.5) Kemper 2003

Rat (SpragueDawley), adult, FIV 1 mg/kg 1 day 4.6 hours Kim et al. 2016b

Rat (Wistar), adult, F IV 21.5 mg/kg 1 day 1.9 hours (SD 0.7) Kudo et al. 2002

Rat (Wistar), adult, F IV 20.1 mg/kg 1 day 1.9 hours (SD 0.7) Ohmori et al. 2003

Rat (SpragueDawley), adult, FIP 3.9 mg/kg 1 day 2.9 hours (SE 0.2) Vanden Heuvel et al. 

1991c

Rat (Wistar), adult, F IP 50 mg/kg 1 day 24 hours Ylinen et al. 1990

PFOS—Rat

Rat (SpragueDawley), adult, MOral 4.2 mg/kg 1 day 179 hours Johnson and Ober 

1979

Rat (SpragueDawley), adult, MOral 0.27 mg/kg 1 day 809 hours Benskin et al. 2009

Rat (SpragueDawley), adult, MOral 0.023 mg/kg/day 12 weeks 1,968 hours (95% 

CL 1.584–2.568)

De Silva et al. 2009

Rat (SpragueDawley), adult, MOral 2 mg/kg 1 day 1,495 hours (SE 

50)

Chang et al. 2012

Rat (SpragueDawley), adult, MOral 2 mg/kg 1 day 635 hours Kim et al. 2016b

Rat (SpragueDawley), adult, MOral 15 mg/kg 1 day 1,707 hours 

(SE 270)

Chang et al. 2012

Rat (SpragueDawley), adult, FOral 0.023 mg/kg/day 12 weeks 1,992 hours (95% 

CL 1,752–2,280)

De Silva et al. 2009

Rat (SpragueDawley), adult, FOral 2 mg/kg 1 day 919 hours (SE 56) Chang et al. 2012

Rat (SpragueDawley), adult, FOral 2 mg/kg 1 day 564 hours Kim et al. 2016b

Rat (SpragueDawley), adult, FOral 15 mg/kg 1 day 989 hours (SE 48) Chang et al. 2012
PERFLUOROALKYLS 478

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls 

Estimated in Humans and Experimental Animals

Species, age, and 

sex Route Dose

Exposure 

durationa 

Elimination halflifeb Reference

Rat (SpragueDawley), adult, MIV 2 mg/kg 1 day 689 hours Kim et al. 2016b

Rat (SpragueDawley), adult, FIV 2 mg/kg 1 day 595 hours Kim et al. 2016b

PFOSA—Rat

Rat (SpragueDawley), adult, MOral 5.0 mg/kg 1 day 125 hours Seacat and Luebker 

2000

PFDeA—Rat

Rat (SpragueDawley), adult, MIP 4.8 mg/kg 1 day 1,008 hours Vanden Heuvel et al. 

1991b

Rat (Wistar), adult, M IV 25 mg/kg 1 day 958 hours (SD 

207)

Ohmori et al. 2003

Rat (Wistar), adult, F IV 25 mg/kg 1 day 1,406 hours 

(SD 140)

Ohmori et al. 2003

Rat (SpragueDawley), adult, FIP 4.8 mg/kg 1 day 552 hours Vanden Heuvel et al. 

1991b

PFNA—Rat

Rat (SpragueDawley), adult, MOral 0.2 mg/kg 1 day 974 hours Benskin et al. 2009

Rat (SpragueDawley), adult, MOral 0.029 mg/kg/day 12 weeks 1,128 hours (95% 

CL 935–1,416)

De Silva et al. 2009

Rat (SpragueDawley), adult MOral 1, 3, or 10 mg/kg 1 day 734.4 hours Tatum-Gibbs et al. 

2011

Rat (Wistar), adult, M IV 22.6 mg/kg 1 day 710 hours (SD 55) Ohmori et al. 2003

Rat (SpragueDawley), adult FOral 1, 3, or 10 mg/kg 1 day 33.6 hours Tatum-Gibbs et al. 

2011

Rat (Wistar), adult, F IV 22.6 mg/kg 1 day 58.6 hours (SD 

9.8)

Ohmori et al. 2003

PFHpA—Rat

Rat (Wistar), adult, M IV 17.7 mg/kg 1 day 2.4 hours (SD 1.2) Ohmori et al. 2003

Rat (Wistar), adult, F IV 17.7 mg/kg 1 day 1.2 hours (SD 0.2) Ohmori et al. 2003

PFHxA—Rat

Rat (SpragueDawley), adult, M IV 10 mg/kg 1 day 1.0 hour Chengelis et al. 2009

Rat (SpragueDawley), adult, M Oral 50 mg/kg 1 day 2.2 hours Chengelis et al. 2009

Rat (SpragueDawley), adult, M Oral 150 mg/kg 1 day 2.4 hours Chengelis et al. 2009

Rat (SpragueDawley), adult, M Oral 300 mg/kg 1 day 2.5 hours Chengelis et al. 2009

Rat (SpragueDawley), adult, F IV 10 mg/kg 1 day 0.42 hour Chengelis et al. 2009
PERFLUOROALKYLS 479

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls 

Estimated in Humans and Experimental Animals

Species, age, and 

sex Route Dose

Exposure 

durationa

Elimination halflifeb Reference

Rat (SpragueDawley), adult, F Oral 50 mg/kg 1 day 2.6 hours Chengelis et al. 2009

Rat (SpragueDawley), adult, F Oral 150 mg/kg 1 day 2.2 hours Chengelis et al. 2009

Rat (SpragueDawley), adult, F Oral 300 mg/kg 1 day 2.1 hours Chengelis et al. 2009

PFHxS—Rat

Rat (SpragueDawley), adult, M Oral 0.030 mg/kg 1 day 382 hours Benskin et al. 2009

Rat (SpragueDawley), adult, MOral 4 mg/kg 1 day 645.6 hours Kim et al. 2016b

Rat (SpragueDawley), adult, FOral 4 mg/kg 1 day 41.28 hours Kim et al. 2016b

Rat (SpragueDawley), adult, MIV 4 mg/kg 1 day 496.8 hours Kim et al. 2016b

Rat (SpragueDawley), adult, M IV 10 mg/kg 1 day 688 hours (SE 

14.4)

Sundström et al. 2012

Rat (SpragueDawley), adult, FIV 4 mg/kg 1 day 21.12 hours Kim et al. 2016b

Rat (SpragueDawley), adult, F IV 10 mg/kg 1 day 39 hours (SE 1.9) Sundström et al. 2012

PFBA—Rat

Rat (SpragueDawley), adult, MOral 30 mg/kg 1 day 9.22 hours 

(SE 0.75)

Chang et al. 2008b

Rat (SpragueDawley), adult, MIV 30 mg/kg 1 day 6.38 hours 

(SE 0.53)

Chang et al. 2008b

Rat (SpragueDawley), adult, FOral 30 mg/kg 1 day 1.76 hours 

(SE 0.26)

Chang et al. 2008b

Rat (SpragueDawley), adult, FIV 30 mg/kg 1 day 1.03 hours 

(SE 0.03)

Chang et al. 2008b

PFBuS—Rat

Rat (SpragueDawley), adult, MIV 10 mg/kg 1 day 2.1 hours Chengelis et al. 2009

Rat (SpragueDawley), Rat (SD), 

adult, M

IV 30 mg/kg 1 day 4.51 hours 

(SE 2,22)

Olsen et al. 2009 

Rat (SpragueDawley), adult, MOral 30 mg/kg 1 day 4.68 hours 

(SE 0.07)

Olsen et al. 2009 

Rat (SpragueDawley), adult, FIV 10 mg/kg 1 day 0.64 hours Chengelis et al. 2009

Rat (SpragueDawley), adult, FIV 30 mg/kg 1 day 3.96 hours 

(SE 0.21)

Olsen et al. 2009 
PERFLUOROALKYLS 480

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls 

Estimated in Humans and Experimental Animals

Species, age, and 

sex Route Dose

Exposure 

durationa

Elimination halflifeb Reference

Rat (SpragueDawley), adult, FOral 30 mg/kg 1 day 7.42 hours 

(SE 0.79)

Olsen et al. 2009 

PFOS—Mouse

Mouse (CD), adult, M Oral 1 mg/kg 1 day 1,027 hours Chang et al. 2012

Mouse (CD), adult, M Oral 20 mg/kg 1 day 874 hours Chang et al. 2012

Mouse (CD), adult, F Oral 1 mg/kg 1 day 907 hours Chang et al. 2012

Mouse (CD), adult, F Oral 20 mg/kg 1 day 731 hours Chang et al. 2012

PFHxS—Mouse

Mouse (CD), adult, M Oral 1 mg/kg 1 day 732 hours Sundström et al. 2012

Mouse (CD), adult, M Oral 20 mg/kg 1 day 671 hours Sundström et al. 2012

Mouse (CD), adult, F Oral 1 mg/kg 1 day 597 hours Sundström et al. 2012

Mouse (CD), adult, F Oral 20 mg/kg 1 day 643 hours Sundström et al. 2012

PFNA—Mouse 

Mouse (CD-1), adult 

M

Oral 1 or 10 mg/kg 1 day 823.2–

1,653.6 hours

Tatum-Gibbs et al. 

2011

Mouse (CD-1), adult 

F

Oral 1 or 10 mg/kg 1 day 619.2–

1,641.6 hours

Tatum-Gibbs et al. 

2011

PFBA—Mouse

Mouse (CD1), adult, 

M

Oral 10 mg/kg 1 day 13.34 hours 

(SE 4.55)

Chang et al. 2008b

Mouse (CD1), adult, 

M

Oral 30 mg/kg 1 day 16.3 hours (SE 7.2) Chang et al. 2008b

Mouse (CD1), adult, 

M

Oral 100 mg/kg 1 day 5.22 hours 

(SE 2.27)

Chang et al. 2008b

Mouse (CD1), adult, 

F

Oral 10 mg/kg 1 day 2.87 hours 

(SE 0.30)

Chang et al. 2008b

Mouse (CD1), adult, 

F

Oral 30 mg/kg 1 day 3.08 hours 

(SE 0.26)

Chang et al. 2008b

Mouse (CD1), adult, 

F

Oral 100 mg/kg 1 day 2.79 hours (SE 0.3) Chang et al. 2008b
PERFLUOROALKYLS 481

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-5. Summary Elimination Half-Lives for Perfluoroalkyls 

Estimated in Humans and Experimental Animals

Species, age, and 

sex Route Dose

Exposure 

durationa

Elimination halflifeb Reference

PFOS—Rabbit

Rabbit (New 

Zealand), adult, F

Oral 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 were 

observed.

CI = confidence interval; CL = confidence limit; F = female; GM = geometric mean; IP = intraperitoneal; 

IV = intravenous; M = male; NA = not applicable; PFBA = perfluorobutyric acid; PFDeA = perfluorodecanoic acid; 

PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; 

SD = standard deviation; SE = standard error

Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated in 

Experimental Animals

Species, age, and sex Route

Dose

(mg/kg)

Exposure 

duration

Systemic clearance

(mL/day/kg)a Reference

PFOA—Nonhuman primate

Cynomolgus monkey, 

adult, M

IV 10 1 day 12.4 (SD 7.4) Butenhoff et al. 2004c

Cynomolgus monkey, 

adult, F

IV 10 1 day 5.3 (SD 3.3) Butenhoff et al. 2004c

PFOS—Nonhuman primate

Cynomolgus monkey, 

adult, M

IV 2 1 day 1.10 (SE 0.06) Chang et al. 2012

 Cynomolgus

 monkey, adult, F

IV 2 1 day 1.65 (SE 0.04) Chang et al. 2012

PFHxA—Nonhuman primate

 Cynomolgus

 monkey, adult, M

IV 10 1 day 569 Chengelis et al. 2009

 Cynomolgus

 monkey, adult, F

IV 10 1 day 535 Chengelis et al. 2009

PFHxS—Nonhuman primate

Cynomolgus monkey, 

adult, M

IV 10 1 day 1.3 (SE 0.1) Sundström et al. 2012

Cynomolgus monkey, 

adult, F

IV 10 1 day 1.9 (SE 0.4) Sundström et al. 2012
PERFLUOROALKYLS 482

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated in 

Experimental Animals

Species, age, and sex Route

Dose

(mg/kg)

Exposure 

duration

Systemic clearance

(mL/day/kg)a Reference

PFBA—Nonhuman primate

Cynomolgus monkey, 

adult, M

IV 10 1 day 2,371 (SE 293) Chang et al. 2008a

Cynomolgus monkey, 

adult, F

IV 10 1 day 1,075 (SE 91) Chang et al. 2008a

PFBuS—Nonhuman primate 

Cynomolgus monkey, 

adult, M

IV 10 1 day 159 Chengelis et al. 2009

Cynomolgus monkey, 

adult, F

IV 10 1 day 238 Chengelis et al. 2009

Cynomolgus monkey, 

adult, M

IV 10 1 day 12,264 (SE 3384) Olsen et al. 2009

Cynomolgus monkey, 

adult, F

IV 10 1 day 8,832 (SE 2880) Olsen et al. 2009

PFOA—Rat

Rat (Sprague-Dawley), 

adult, M

Oral 0.1 1 day 23.1 (SD 5.8) Kemper 2003

Rat (Sprague-Dawley), 

adult, M

Oral 1 1 day 20.9 (SD 3.8) Kemper 2003

Rat (Sprague-Dawley), 

adult, M

Oral 1 1 day 40.40 (SD 2.29) Kim et al. 2016b

Rat (Sprague-Dawley), 

adult, M

Oral 5 1 day 20.4 (SD 5.0) Kemper 2003

Rat (Sprague-Dawley), 

adult, M

Oral 25 1 day 27.1 (SD 7.4) Kemper 2003

Rat (Sprague-Dawley), 

adult, M

IV 1 1 day 21.5 (SD 2.0) Kemper 2003

Rat (Sprague-Dawley), 

adult, M

IV 1 1 day 47.39 (SD 3.40) Kim et al. 2016b

Rat (Sprague-Dawley), 

adult, F

Oral 0.1 1 day 778 (SD 144) Kemper 2003

Rat (Sprague-Dawley), 

adult, F

Oral 1 1 day 655 (SD 173) Kemper 2003

Rat (Sprague-Dawley), 

adult, F

Oral 1 1 day 645.12 (SD 43.44) Kim et al. 2016b

Rat (Sprague-Dawley), 

adult, F

Oral 5 1 day 1,164 (SD 118) Kemper 2003

Rat (Sprague-Dawley), 

adult, F

Oral 25 1 day 842 (SD 166) Kemper 2003

Rat (Sprague-Dawley), 

adult, F

IV 1 1 day 816 (SD 221) Kemper 2003

Rat (Sprague-Dawley), 

adult, F

IV 1 1 day 612.84 (SD 32.54) Kim et al. 2016b
PERFLUOROALKYLS 483

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated in 

Experimental Animals

Species, age, and sex Route

Dose

(mg/kg)

Exposure 

duration

Systemic clearance

(mL/day/kg)a Reference

Rat (Wistar), adult, M 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

PFOS—Rat

Rat (Sprague-Dawley), 

adult, M

Oral 2 1 day 7.33 (SD 0.55) Kim et al. 2016b

Rat (Sprague-Dawley), 

adult, M

Oral 2 1 day 11.3 (SE 0.56) Chang et al. 2012

Rat (Sprague-Dawley), 

adult, M

Oral 15 1 day 4.9 (SE 0.52) Chang et al. 2012

Rat (Sprague-Dawley), 

adult, M

IV 2 1 day 9.24 (SD 0.37) Kim et al. 2016b

Rat (Sprague-Dawley), 

adult, F

Oral 2 1 day 8.52 (SD 0.37) Kim et al. 2016b

Rat (Sprague-Dawley), 

adult, F

Oral 2 1 day 22.2 (SE 0.28) Chang et al. 2012

Rat (Sprague-Dawley), 

adult, F

Oral 15 1 day 5.4 (SE 20) Chang et al. 2012

Rat (Sprague-Dawley), 

adult, F

IV 2 1 day 9.82 (SD 0.21) Kim et al. 2016b

PFDeA—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

PFHxA—Rat

Rat (Sprague-Dawley), 

adult, M 

IV 10 1 day 2,784 Chengelis et al. 2009

Rat (Sprague-Dawley), 

adult, F 

IV 10 1 day 18,600 Chengelis et al. 2009

PFHxS—Rat

Rat (Sprague-Dawley), 

adult, M

Oral 4 1 day 7.15 (SD 0.06) Kim et al. 2016b

Rat (Sprague-Dawley), 

adult, M

IV 4 1 day 9.01 (SD 0.05) Kim et al. 2016b
PERFLUOROALKYLS 484

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated in 

Experimental Animals

Species, age, and sex Route

Dose

(mg/kg)

Exposure 

duration

Systemic clearance

(mL/day/kg)a Reference

Rat (Sprague-Dawley), 

adult, M 

IV 10 1 day 6.7 (SE 0.06) Sundström et al. 2012

Rat (Sprague-Dawley), 

adult, F

Oral 4 1 day 124.83 (SD 3.40) Kim et al. 2016b

Rat (Sprague-Dawley), 

adult, F

IV 4 1 day 227.93 (SD 6.73) Kim et al. 2016b

Rat (Sprague-Dawley), 

adult, F 

IV 10 1 day 53.4 (SE 4.38) Sundström et al. 2012

PFBA—Rat

Rat (Sprague-Dawley), 

adult, M

IV 30 1 day 851 (SE 61) Chang et al. 2008a

Rat (Sprague-Dawley), 

adult, F

IV 30 1 day 2,949 (SE 59) Chang et al. 2008a

Rat (Sprague-Dawley), 

adult, M

Oral 30 1 day 494 (SE 29) Chang et al. 2008a

Rat (Sprague-Dawley), 

adult, F

Oral 30 1 day 1,527 (SE 145) Chang et al. 2008a

PFBuS—Rat

Rat (Sprague-Dawley), 

adult, M

IV 10 1 day 946 Chengelis et al. 2009

Rat (Sprague-Dawley), 

adult, F

IV 10 1 day 7,464 Chengelis et al. 2009

Rat (Sprague-Dawley), 

adult, M

IV 30 1 day 2,856 (SE 816) Olsen et al. 2009 

Rat (Sprague-Dawley), 

adult, F

IV 30 1 day 11,265 (SE 960) Olsen et al. 2009 

PFOA—Mouse

Mouse (FVB/NJcl),

adult, M

IV 0.13 1 day 14.2 (SD 8.4) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

IV 0.13 1 day 11.8 (SD 6.1) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, M

Oral 1.3 1 day 13.1 (SD 7.4) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

Oral 1.3 1 day 9.0 (SD 1.9) Fujii et al. 2015a, 

2015b

PFOS—Mouse

Mouse (CD), adult, M Oral 1 1 day 4.7 Chang et al. 2012

Mouse (CD), adult, M Oral 20 1 day 4.7 Chang et al. 2012

Mouse (CD), adult, F Oral 1 1 day 5.0 Chang et al. 2012

Mouse (CD), adult, F Oral 20 1 day 6.0 Chang et al. 2012

PFHxS—Mouse

Mouse (CD), adult, M Oral 1 1 day 2.9 Sundström et al. 2012
PERFLUOROALKYLS 485

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated in 

Experimental Animals

Species, age, and sex Route

Dose

(mg/kg)

Exposure 

duration

Systemic clearance

(mL/day/kg)a Reference

Mouse (CD), adult, M Oral 20 1 day 4.8 Sundström et al. 2012

Mouse (CD), adult, F Oral 1 1 day 2.7 Sundström et al. 2012

Mouse (CD), adult, F Oral 20 1 day 3.8 Sundström et al. 2012

PFNA—Mouse

Mouse (FVB/NJcl),

adult, M

IV 0.14 1 day 3.9 (SD 1.9) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

IV 0.14 1 day 5.1 (SD 2.3) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, M

Oral 1.4 1 day 4.0 (SD 1.7) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

Oral 1.4 1 day 2.4 (SD 1.0) Fujii et al. 2015a, 

2015b

PFDeA—Mouse

Mouse (FVB/NJcl),

adult, M

IV 0.16 1 day 2.2 (SD 0.9) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

IV 0.16 1 day 2.8 (SD 1.2) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, M

Oral 1.6 1 day 3.9 (SD 1.8) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

Oral 1.6 1 day 2.2 (SD 1.1) Fujii et al. 2015a, 

2015b

PFUA—Mouse

Mouse (FVB/NJcl),

adult, M

IV 0.17 1 day 2.8 (SD 1.0) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

IV 0.17 1 day 3.4 (SD 1.5) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, M

Oral 1.7 1 day 5.7 (SD 2.6) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

Oral 1.7 1 day 3.1 (SD 1.7) Fujii et al. 2015a, 

2015b

PFDoA—Mouse

Mouse (FVB/NJcl),

adult, M

IV 0.19 1 day 4.4 (SD 1.6) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

IV 0.19 1 day 4.8 (SD 2.4) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, M

Oral 1.9 1 day 9.4 (SD 4.1) Fujii et al. 2015a, 

2015b

Mouse (FVB/NJcl),

adult, F

Oral 1.9 1 day 5.2 (SD 3.2) Fujii et al. 2015a, 

2015b
PERFLUOROALKYLS 486

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-6. Summary Systemic Clearance for Perfluoroalkyls Estimated in 

Experimental Animals

Species, age, and sex Route

Dose

(mg/kg)

Exposure 

duration

Systemic clearance

(mL/day/kg)a Reference

PFBA—Mouse

Mouse (CD1), adult, M 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

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 = perfluorobutyric acid; 

PFBuS = perfluorobutane sulfonic acid; PFDeA = 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 PFBuS 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 

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): 

V

Cl ke = Eq. (3-4) 

e k

t )2ln(

2/1 = Eq. (3-5) 

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; Harada 

et 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 the 
PERFLUOROALKYLS 487

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

detection of slower elimination phases of multiphasic elimination kinetics (Seals et al. 2011). 

Perfluoroalkyl sulfonates are eliminated more slowly in humans than corresponding carboxylates of the 

same 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 the 

elimination 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 contaminated 

drinking water. The estimated t1/2 for PFOS were 4.6 years in males and 3.1 years in females. Zhang et 

al. (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 to 

males and older females (t1/2 =27 years±3.1 SE, n=20). Zhang et al. (2013) attributed the difference in 

serum 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 

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 populations 

of 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 a 

second 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 in 
PERFLUOROALKYLS 488

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

males (27%) compared to females (18%) for the first 4 years post-exposure; however, no difference was 

evident 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 of 

elimination 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-life 

of 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 from 

37 to 3,490 ng/mL (Olsen et al. 2007a). Estimates for the two females in the same study were 4.9 and 

6.8 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 

ranged from 4 to 49 ng/mL (Harada et al. 2005a). Estimates in males (7.4, 2.9 years) were similar to 

females (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 to 

various PFBA precursors (Chang et al. 2008a). In three male workers, the estimated mean t1/2 based on 

serum PFBA kinetics was 81 hours (±41 SD). In a larger study of nine workers (seven males, two 

females), the mean t1/2 was 72 hours (±38 SD). Estimates for the two female subjects were 56 and 

118 hours. The combined mean value for the 12 estimates was 75 hours (±38 SD). Olsen et al. (2009) 
PERFLUOROALKYLS 489

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

estimated serum t1/2 of PFBuS 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 and 

PFBuS are eliminated substantially faster in humans than perfluoroalkyls having longer carbon chain 

lengths (e.g., PFHxS, PFOA, PFOS).

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 of 

pregnant 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 clearances 

for PFOA, PFOS, PFHxA, PFHxS, PFBA, and PFBuS have been estimated in Cynomolgus monkeys 

(Buttenoff et al. 2004c; Chang et al. 2012; Chengelis et al. 2009; 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 PFBuS. Elimination of 

perfluoroalkyls in monkeys is multiphasic and, as a result, estimates of the terminal t1/2 can vary with the 

duration of the observation period and assumptions made in modeling elimination kinetics (Chang et al. 

2012; Chengelis et al. 2009; Olsen et al. 2009; Sundström et al. 2012). For example, the t1/2 values for 

PFBuS 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. 2009), whereas the t1/2 values were 

95 and 83 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 

in monkeys 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, and 

PFBuS 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, PFOSA, PFDeA, PFNA, PFHpA, PFHxA, PFHxS, PFBA, and PFBuS have been estimated in rats 

(Benskin et al. 2009; Chang et al. 2008b, 2012; Chengelis et al. 2009; De Silva et al. 2009; Johnson and 
PERFLUOROALKYLS 490

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Ober 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, 

PFBuS) 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 in 

females than in males (Benskin et al. 2009; Chang et al. 2008b; Chengelis et al. 2009; 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 PFBuS 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 

female rats, daily periodic oscillations of plasma concentrations from peak to below detection occurred on 

each day of exposure. Steady-state plasma concentrations in male rats were approximately 10 times that 

of 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 dose 

of 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 (Kemper 

2003). 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 in 

elimination 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 and 
PERFLUOROALKYLS 491

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

involvement 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 (Chang 

et 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 the 

apparent 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 were 

similar 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 

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 high 

molecular 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 other 

perfluoroalkyls shows pronounced sex differences in rats, with slower elimination in males for PFOA, 

PFOS, PFNA, PFHxA, PFHxS, PFBA, and PFBuS (Chang et al. 2008a, 2012; Chengelis et al. 2009; 

Kemper 2003; Kudo et al. 2002; Ohmori et al. 2003; Sundström et al. 2012). The sex difference in PFOA 
PERFLUOROALKYLS 492

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 to 

female 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 the 

tubular 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. Affinities of OATP1a1 (rat), 

OAT4 (human), and URAT1 (human) are highest for C7–C10 perfluoroalkyl carboxylates (Weaver et al. 

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 of 

perfluoroalkyls; 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 to 

faster 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 in 

younger (≤50 years) women compared to men and older women (Zhang et al. 2013). Two studies have 

found 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 and 

older 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 
PERFLUOROALKYLS 493

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

metric than serum t1/2 for evaluating sex differences in elimination for this would be systemic or renal 

clearance of the perfluoroalkyl compound. Harada et al. (2005a) measured renal clearance in a small 

sample of young adults (five males and five females, age 22–23 years) and found that renal clearance was 

not different 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 PFDeA, PFNA, PFOA, PFOS, and PFHxA are secreted in bile 

and 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 to 

kidney; the latter is approximately 7–8 times higher in adult female rats compared to male rats (Kudo et 

al. 2002).

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

PBPK models use mathematical descriptions of the uptake and disposition of chemical substances to 

quantitatively 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 in 

risk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical that 

will 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 relationship 

between 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 and 

PFOS 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 in 

rats and mice also have been reported (Loccisano et al. 2012a, 2012b; Rodriguez et al. 2009). Various 
PERFLUOROALKYLS 494

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 dose 

corresponding 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 to 

in vivo extrapolation. PBPK models were not identified for other perfluoroalkyls examined in this profile. 

Given the toxicokinetic differences between compounds, the PFOA and PFOS PBPK models may not be 

appropriate for other 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 and 

female 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 

for parameter values and evaluations of model predictions in comparison to observations are described in 

Loccisano et al. (2012a, 2012b).

The basic (i.e., adult nonpregnant rat) model includes compartments representing plasma (including a 

bound 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 to 

simulate 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 and 

fecal excretion of unabsorbed chemical. Absorbed PFOA and PFOS are assumed to be delivered to the 

liver 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 to 

plasma proteins has been demonstrated in various animal species including rats (see Section 3.1.2). For 
PERFLUOROALKYLS 495

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Figure 3-3. Structure of PBPK Model of PFOA and PFOS in the Rat

Bmax = liver binding capacity; kabs = first-order absorption rate constant; Kb = liver binding affinity 

constant; kbile = biliary excretion rate constant; Koff = liver binding dissocation 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 of 

liver; 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 a 

government report via Copyright Clearance Center; Reproductive Toxicology by Reproductive Toxicology 

Center; Washington, DC)

Oral,

diet

Liver

Bmax, Kb, koff

kabs

storage

Plasma

Free 

fraction

Gut Intravenous

QLiv

Rest of body

Kidney

Filtrate

QTis

QKid

QFil

urine

storage feces

kunabs

kbile

Tm,Kt
PERFLUOROALKYLS 496

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Figure 3-4. PBPK Model Structure for Simulating PFOA and PFOS Exposure 

During Gestation in the Rat (Dam, Left; Fetus, Right)

kabs = 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 in 

and out of liver; QMam = blood flow in and out of mammary tissue; QPla = blood flow in and out of 

placenta; 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 a 

government report via Copyright Clearance Center; Reproductive Toxicology by Reproductive Toxicology 

Center; Washington, DC)

Plasma

free 

fraction

QLiv

storage

Mammary

Rest of body

kunabs

Tm,Kt

Liver

Kidney

Fat

Filtrate

QKid

QFil

QMam

QFat

QTis

Gut

storage feces

Amniotic

fluid

Rest of fetal

tissues/body

Fetal

plasma

QFTis

Fetal structure for PFOS

Fetal brain

QFBrn

Fetal

plasma

kabs

kbile

Placenta

ktrans2

ktrans1

ktrans4 ktrans3

Fetal liver

QFLiv

Rest of fetal

tissues/body

QFTis

urine

Oral dose

QPla
PERFLUOROALKYLS 497

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Figure 3-5. PBPK Model Structure for Simulating PFOA/PFOS Exposure During 

Lactation in the Rat (Dam, Left; Pup, Right)

kabs = 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 = blood 

flow 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 out 

of 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 a 

government report via Copyright Clearance Center; Reproductive Toxicology by Reproductive Toxicology 

Center; Washington, DC)

Oral dose

Plasma

Free 

fraction

QTis

storage

Fat

Filtrate

klac

urine

Tm,Kt

Rest of body

Mammary 

tissue

Kidney

Liver

QMam

QLiv

QFat

QKid

QFil

Gut

storage

feces

Milk Pup gut

Pup liver

Pup kidney

Pup filtrate

Rest of body

Pup

plasma

QPLiv

QPKid

QPTis

QPFil

Pup urine TmP,KtP

Transfer of PFOS to milk

Pup gut

klac Milk

QMam

Plasma

Free 

fraction

kabs

PAMilk

kabsP

Pup feces

kbile
PERFLUOROALKYLS 498

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 no 

effect on longer-term kinetics or steady state. Although the time-dependence of the free fraction in 

plasma was needed to simulate short-term plasma PFOS kinetics in rats, the physiological mechanism for 

a 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 and 

renal tubular reabsorption, which removes PFOA and PFOS 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/kg body weight), 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 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 to 

female rats (Tm/KT=0.045), and correspondingly lower urinary clearance of PFOA from plasma in male 

rats. Reabsorption parameters for PFOS are the same in both sexes and result in reabsorptive clearances 

that 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 with as a constant fraction for PFOA and PFOS (i.e., no dependence on time as 

in the adult). 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 
PERFLUOROALKYLS 499

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 and 

PFOS 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 of 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 with 

flow-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 in 

mammary tissue of rodents were not available to establish parameters for a mammary tissue 

compartment; 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 to 

be 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 

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 the 

male rat values). Reabsorptive transport parameters for PFOS are allometrically scaled from the lactating 

dam. 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 or 

allometrically 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 the 

gestation 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).
PERFLUOROALKYLS 500

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 for 

predicting plasma urinary and liver PFOA and PFOS following single intravenous or single and repeated 

oral 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, and 

differences 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 with 

observations, 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 concentrations 

of PFOA in nursing pups were approximately 10–50% lower than maternal concentrations, whereas 

maternal 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 data 

from 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 

Harris and Barton (2008) model is very different from the Loccisano et al. (2012a) model, these results 

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 to 

include simulations of pregnancy and lactation (Loccisano et al. 2013). The monkey model was based, in 

part, 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 for 

biliary transfer. Complete lists of parameters and parameter values and the bases for parameter values 
PERFLUOROALKYLS 501

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Figure 3-6. Structure of PBPK Model for PFOA and PFOS in Monkeys and 

Humans

Kt = half-saturation constant; kurine = urinary elmination 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 out 

of kidney; QLiv = blood flow in and out of liver; QR = blood flow in and out of rest of body; QSkin = blood flow in and 

out 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 of 

Regulatory Toxicology and Pharmacology)

Oral dose,

drinking water

Plasma

Free 

fraction

Intravenous

QGut

storage

Rest of body

Filtrate

kurine

Urine

Tm,Kt

Gut

Liver

Skin

Kidney

Fat

QLiv

QFat

QSkin

QR

QKid

QFil
PERFLUOROALKYLS 502

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 fraction 

in 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 for 

a 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 to 

plasma 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 derive 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 and PFOS 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 the monkey and human 

models.

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, these 

data 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 in 

serum 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 
PERFLUOROALKYLS 503

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 rat pregnancy model (Loccisano et al. 2012b, Figure 3-4). Rate constants for 

placental 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 et 

al. 2007; Midasch et al. 2007; Washino et al. 2009). Transfers from amniotic fluid to fetus were the same 

as 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 the 

infant. 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 obviated 

the 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; Inoue 

et al. 2004; Kim et al. 2011; Midasch et al. 2007; Monroy et al. 2008; Tittlemier et al. 2004). The 

lactation model was evaluated by comparing predicted maternal plasma/milk ratios for PFOA and PFOS 

with observations from various human monitoring studies (Fromme et al. 2009; Kärrman et al. 2007; Liu 

et 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 skin 

compartment 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 human 

populations (e.g., 2.3 or 3.8 years for PFOA, 5.4 years for PFOS). As a result, comparisons made 

between observed and predicted serum concentrations evaluate whether or not the populations actually 

exhibit 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 human 

model can accurately predict doses to liver or any other tissues. Fábrega et al. (2014) applied the human 
PERFLUOROALKYLS 504

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

adult 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 water 

supply concentrations in the local area where the subjects had resided (Catalonia, Spain) and 

concentrations in local market basket foods (Domingo et al. 2012a, 2012b). The human model predicted 

levels of PFOA in plasma and liver that were approximately 10- and 5-fold higher, respectively, than 

observed. Predicted plasma levels of PFOS were approximately 2-fold higher than observed and 

predicted levels of PFOS in kidney were approximately 25% of observed. Fábrega et al. (2014) explored 

alternative 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 male 

and 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 and 

PFOS 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 

model, the target plasma elimination t1/2 was achieved solely by adjusting Tm. Thus, despite the 

complexity 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 predicted 

empirically 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 of 

parameters 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 
PERFLUOROALKYLS 505

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Figure 3-7. Renal Resorption Pharmacokinetic Model of Gestation and Lactation 

used in the Analysis of CD-1 Mice

Ccon = concentration in concepti; Cdam = concentration in dam; Cmilk = concentration in milk; Cpup = concentration 

in 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 pup

Source: 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, 

DC)

Concepti

Vcon Ccon

Pups

Cpup Vpup

Qcon

Pup excreta

recirculation

(from birth to 

postnatal day 4)

Urine

Lactation days 19

–39

Dam

Cdam Vdam

Milk

Cmilk Vm

Qur

klac

klac

Oral dose 

(mg/kg)

Qcon

kep

Urine

kad

Gestation days 1

–18

free

QGF

Qr-QGF

Filtrate

Renal

plasma

Qr-Qur

Kidney

Tm; Kt
PERFLUOROALKYLS 506

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

systems are simulated as single well-mixed compartments. Absorption from the gastrointestinal tract is 

simulated 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 the 

fetus 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 a 

lactation transfer rate constant. Elimination of PFOA from the pup is first-order to urine. Data sets 

utilized 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 the 

maternal 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 the 

modeling effort), it does not allow for simulation of tissue levels of PFOA in the maternal system, fetus, 

or pup.

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-compartmental

monkey 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 a 

central 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 all 

other 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 the 

glomerular filtrate is first order and governed by the glomerular filtration rate (Qfilc, L/hour). Transfer for 
PERFLUOROALKYLS 507

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 filtrate 

compartments, respectively; Vc, Vt, and Vfil are the volumes of distribution of the central, second, and filtrate 

compartments; 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 is 

modeled with Michaelis-Menten kinetics, with a maximum rate Tmaximum and a half-maximum concentration KT.

Reprinted from Wambaugh et al. (2013) by permission of Oxford University Press
PERFLUOROALKYLS 508

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Table 3-7. Estimated and Assumed Pharmacokinetic Parameters for the Modified Andersen et al. (2006) Model 

for PFOA and PFOS

Reference Species

Parameter (units)

BW (kg)

Cardiac outputa

(L/hour/kg0.74) Ka (hour

-1) Vcc (L/kg) k12 (hour-1)

RV2:V1

(unitless)

Tmaxc

(μmole/hour) KT (μM)

Free 

(unitless) Qfilc (L/hour) Vfilc (L/kg)

PFOAb

Lou et al. 

(2009)

Mouse: CD1 

(F)

0.02 8.68 290 (0.6–

73,000)

0.18 (0.16–

2.0)

0.021 

(3.1x10-10 to 

3.8x104)

1.07 (0.26–

5.84)

4.91 (1.75–

2.96)

0.037 

(0.0057–0.17)

0.011 

(0.0026–

0.051

0.077 (0.015–

0.58)

9.7x10-4

(3.34x10-9–

7.21)

Dewitt et al. 

(unpublished)

Mouse: 

C57Bl/6 (F)

0.02 8.68 340 (0.53–

69,000)

0.17 (0.13–

2.3)

0.35 (0.058–

52)

53 (11–97) 2.7 (0.95–22) 0.12 (0.033–

0.24)

0.034 (0.014–

0.17)

0.017 (0.010–

0.081)

7.6x10-5

(2.7x10-10–

6.4)

Kemper (2003) Rat: 

SpragueDawley (F)

0.20 

(0.16–

0.23)c

12.39 1.7 (1.1–3.1) 0.14 (0.11–

0.17)

0.098 (0.039–

0.27)

9.2 (3.4–28) 1.1 (0.25–9.6) 1.1 (0.27–4.5) 0.086 (0.031–

0.23)

0.039 (0.014–

0.13)

2.6x10-5

(2.9x10-10–28)

Kemper (2003) Rat: 

SpragueDawley (M)

0.24 

(0.21–

0.28)c

12.39 1.1 (0.83–1.3) 0.15 (0.13–

0.16)

0.028 

(0.0096–0.08)

8.4 (3.1–23) 190 (5.5–

50,000)

0.092 

(3.4x10-4–1.6)

0.08 (0.03–

0.22)

0.22 (0.011–

58)

0.0082 

(1.3x10-8–7.6)

Butenhoff et al. 

(2004b)

Monkey: 

Cynomolgus 

(M/F)

7 (m), 

4.5 (f)

19.8 230 (0.27–

73,000)

0.4 (0.29–

0.55)

0.0011 

(2.4x10-10 to 

3.5x104)

0.98 (0.25–

3.8)

3.9 (0.65–

9,700)

0.043 

(4.3x10-5–

0.29

0.01 (0.0026–

0.038)

0.15 (0.02–

24)

0.0021 

(3.3x10-9–6.9)

Reference Species

Parameter (units)

BWd (kg)

Cardiac outpute

(L/hour/kg0.74) Ka (hour

-1) Vcc (L/kg) k12 (hour-1)

RV2:V1

(unitless)

Tmaxc

(μmol/hour) KT (μM)

Free 

(unitless) Qfilc (L/hour) Vfilc (L/kg)

PFOS

Chang et al. 

(2012)

Mouse: CD1 

(F)

0.02 8.68 1.16 (0.617–

42,400)

0.264 (0.24–

0.286)

0.0093 

(2.63e-10–

38,900)

1.01 (0.251–

4.06)

57.9 (0.671–

32,000)

0.0109 

(1.44x10-5–

1.45)

0.00963 

(0.00238–

0.0372)

0.439 

(0.0125–307)

0.00142 

(4.4x10-10–

6.2)

Chang et al. 

(2012)

Mouse: CD1 

(M) 

0.02 8.68 433.4 (0.51–

803.8

0.292 (0.268–

0.317

2,976 (2.8e10–4.2e4)1.29 (0.24–

4.09)

1.1e4 (2.1–

7.9e4)

381 

(2.6x10-5–

2,900)

0.012 

(0.0024–

0.038)

27.59 (0.012–

283)

0.51 

(3.5x10-10–

6.09)

Chang et al. 

(2012)

Rat: 

SpragueDawley (F)

0.203 12.39 4.65 (3.02–

1,980)

0.535 (0.49–

0.581)

0.0124 (3.1e10–46 800)0.957 (0.238–

3.62)

1,930 (4.11–

83,400)

9.49 

(0.00626–

11,100)

0.00807 

(0.00203–

0.0291)

0.0666 

(0.0107–8.95)

0.0185 

(8.2x10-7–

7.34)

Chang et al. 

(2012)

Rat: 

SpragueDawley (M)

0.222 12.39 0.836 (0.522–

1.51)

0.637 (0.593–

0.68)

0.00524 

(2.86e-10–

43,200)

1.04 (0.256–

4.01)

1.34e-06 

(1.65e-10–44)

2.45 

(4.88x10-10–

60 300)

0.00193 

(0.000954–

0.00249)

0.0122 

(0.0101–

0.025)

0.000194 

(1.48x10-9–

5.51)

Seacat et al. 

(2002) and 

Chang et al. 

(2012)

Monkey: 

Cynomolgus 

(M/F)

3.42 19.8 132 (0.225–

72,100)

0.303 (0.289–

0.314)

0.00292 

(2.59e-10–

34,500)

1.03 (0.256–

4.05)

15.5 (0.764–

4,680)

0.00594 (2.34

x10-5–0.0941)

0.0101 

(0.00265–

0.04)

0.198 (0.012–

50.5)

0.0534 

(1.1x10-7–

8.52)

aCardiac outputs obtained from Davies and Morris (1993). bMeans and posterior distributions from the Bayesian Markov Chain Monte Carlo (MCMC) analysis (95% credible interval in parentheses) are reported. c

Estimated average body weight (BW) for species used except with Kemper (2003) study where individual rat weights were available and assumed to be constant. d

Average BW for species: individual-specific BWs. e

Cardiac outputs obtained from Davies and Morris (1993).

Source: Wambaugh et al. (2013)

1 
PERFLUOROALKYLS 509

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 parameter 

values 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 the 

model 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 then 

extrapolated to equivalent steady-state concentrations in humans using a model of first-order elimination 

of PFOA and PFOS from plasma. The same approach was used to derive MRLs for PFOA and PFOS 

(see Appendix A).

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 and 

the bases for parameter values and evaluations of model predictions in comparison to observations are 

reported 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 all 
PERFLUOROALKYLS 510

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Figure 3-9. Conceptual Representation of a Physiologically Based 

Pharmacokinetic Model for PFOS Exposure in Rats

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 a 

government report via Copyright Clearance Center; Toxicology Letters by European Societies of Toxicology)

P + A ↔ P:A Plasma

Red blood cells

Lower

gastrointestinal

tract

QPlas

QR

QL

feces

intravenous

urine

Rest of body plasma

Rest of body tissue

Liver plasma

Liver tissue

Upper

gastrointestinal

tract

oral

kal

kau

ktl

kb
PERFLUOROALKYLS 511

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

other 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 binding 

on 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-order 

process acting on the total amount of PFOS in liver. PFOA is transferred to urine from the free fraction of 

plasma at a rate governed by a urinary clearance parameter, which is assigned 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 by 

having 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. 

Applications 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 from 

other PBPK models of perfluoroalkyls. The Harris and Barton (2008) model includes a red cell 

compartment 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 other 

perfluoroalkyls) 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 be 

significant 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 
PERFLUOROALKYLS 512

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

understanding of the time-dependent changes in PFOS kinetics will be important for applications of these 

models 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 specific 

transporters thought to be involved in proximal tubular transport of PFOA in the parametrization of the 

model. 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 the 

tubule 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) and 

OAT1 and OAT3 (basolateral) (Nakagawa et al. 2008; Weaver et al. 2010; Yamada et al. 2007). These 

estimates were scaled to kidney proximal tubule cell mass (Hsu et al. 2014) and the mass-scaled estimates 

of Vmax were adjusted with relative activity factors, which were calibrated to in vivo observations of 

plasma PFOA elimination kinetics in rats (Kemper 2003). Values for kefflux (proximal tubule cell to 

kidney plasma) and kdif (diffusion between kidney plasma and the tubule cell) were also calibrated with 

in 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 in 

females compared to males. This resulted in the model predicting lower rates of reabsorptive transfer of 

filtered 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 in 

clearance 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).
PERFLUOROALKYLS 513

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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 were 

allometrically 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 to 

kidney proximal tubule cell mass (Hsu et al. 2014) and the mass-scaled estimates of Vmax were adjusted 

with relative activity factors. Parameters that control apical and basolateral transfers of PFOA in the 

proximal 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 the 

model identified that following biokinetic parameters that had standardized sensitivity coefficients >0.1: 

parameters controlling proximal tubule transport and urinary excretion, plasma-liver partition coefficient,

biliary excretion and protein binding. These parameters, along with drinking water consumption, were 

assigned 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 et 

al. 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 and 

PFOS 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) in 

place 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) 
PERFLUOROALKYLS 514

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

and lung (1.27). For PFOS, the major differences in the partition coefficients were lower values for liver 

in 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 from 

glomerular 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 based 

on cadaver data. Fàbrega et al. (2016) performed a quantitative uncertainty analysis of predictions of 

tissue PFOA and PFOS concentrations by assigning lognormal probability distributions to renal transport 

parameters, 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. 

3.1.6 Animal-to-Human Extrapolations 

Interspecies differences in the toxicokinetics of perfluoroalkyls and possible differences in the 

mechanisms 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 these 

compounds 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; Kemper 

2003), and 1 day in female rats (t1/2=0.2 days; Kemper 2003). Using an internal dose metric such as 

serum perfluoroalkyl concentration and PBPK models that can account for these differences in 

elimination rates can decrease the uncertainty in extrapolating from animals to humans. 
PERFLUOROALKYLS 515

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Many perfluoroalkyl-induced effects in rats and mice are mediated through the PPARα and 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 some immunological effects (Yang et al. 2002b), other effects such as 

hepatomegaly and antigen-specific antibody response (DeWitt et al. 2016) were reported to be PPARαindependent (Yang et al. 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. 

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

This section discusses potential health effects from exposures during the period from conception to 

maturity 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 health 

effects 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 these 

chemicals 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 a 

number of health effects including alterations in serum lipid levels, adverse renal outcomes, 

neurodevelopmental alterations, and reproductive development. Immunotoxicity has been examined in 

children in several general population studies. Additionally, a large number of studies have examined the 

possible association of elevated serum perfluoroalkyl levels and adverse birth outcomes.
PERFLUOROALKYLS 516

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

Similar to adults, associations between serum PFOA and PFOS and serum cholesterol levels were 

observed 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) 

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 in 

children 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 s 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, 

PFDeA, PFHxS, and PFOSA 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 significance 

of 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 PFDeA (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 was also found for PFOS, PFHxS, PFNA, PFDeA, PFBuS, and PFDoA (Dong 

et al. 2013; Zhu et al. 2016), although some studies found no associations 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 were 

also observed in the mice exposed to 0.01 and 0.1 mg/kg/day. The study also compared body weight and 

body 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 in 

significantly higher body weight, brown fat weight, and white fat weight; this was not observed in mice 
PERFLUOROALKYLS 517

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

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. 

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 birth 

weight have been found to be associated with higher PFOA (Fei et al. 2007; Lee et al. 2013; Maisonet et 

al. 2012; Savitz et al. 2012b) or PFOS levels (Maisonet et al. 2012), but not with lower levels of 

perfluoroalkyls (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 and not 

likely biological relevant. 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 mouse 

studies. The observed effects include PFOA- and PFOS-induced increases in prenatal losses and 

decreases 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; Wolf 

et al. 2007; Xia et al. 2011; Yahia et al. 2008, 2010). Additionally, delays in mammary gland 

development 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 

PFDeA, PFHxS, or PFBA (Butenhoff et al. 2009a; Das et al. 2008; Harris and Birnbaum 1989; Hoberman 

and York 2003; Johansson et al. 2008; Viberg et al. 2013). A more in-depth discussion of the 

developmental toxicity of perfluoroalkyls in animals is included in Section 2.17. 

PFOA and PFOS, as well as other perfluoroalkyl compounds, are valid biomarkers of exposure to these 

compounds in children, as they are in adults. No relevant studies were located regarding interactions of 

perfluoroalkyl compounds with other chemicals in children or adults. No information was located 

regarding pediatric-specific methods for reducing peak absorption following exposure to perfluoroalkyl 

compounds, reducing body burden, or interfering with the mechanism of action for toxic effects. 
PERFLUOROALKYLS 518

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

No studies examining increased susceptibility to the toxicity of perfluoroalkyls were identified. The 

available epidemiology data identify several potential targets of toxicity of perfluoroalkyls, and 

individuals 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 levels 

of cholesterol or with other existing cardiovascular risk factors. Similarly, increases in uric levels have 

been observed in individuals with higher perfluoroalkyl levels; increased uric acid may be associated with 

an increased risk of high blood pressure and individuals with hypertension may be at greater risk. 

Additionally, associations have been found between PFOA 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 indication that it is also a target in humans. Therefore, 

individuals with compromised liver function may represent a susceptible 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 have 

been 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 compartment 

of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance 

itself, 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 health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 
PERFLUOROALKYLS 519

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

tissue 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 lung 

capacity. 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 caused 

by 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 or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

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. Perfluoroalkyl compounds 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 14 perfluoroalkyls examined in this toxicological profile, blood concentrations of 7 compounds 

(PFOA, PFOS, PFDeA, PFHxS, PFNA, Me-PFOSA-AcOH, and PFUA) 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 much higher 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; Hölzer et al. 2008; Steenland et al. 2009a), suggesting that

serum levels are a good biomarker of exposure. Due to the long half-life of some perfluoroalkyl 

compounds, particularly PFOA and PFOS, elevated serum 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 other perfluoroalkyl compounds. For example, 

PFOS can be derived from metabolism of Et-PFOSA-AcOH, Me-PFOSA-AcOH, or PFOSA (Olsen et al. 

2005; Seacat and 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). Because Et-PFOSAAcOH and Me-PFOSA-AcOH are metabolized fairly rapidly and have a relatively short serum t1/2, their 
PERFLUOROALKYLS 520

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

***DRAFT FOR PUBLIC COMMENT***

presence in serum should indicate only recent non-occupational exposure in the general population (Olsen 

et al. 2005). 

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, PFBuS, 

and PFHxS 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 

not allow for an assessment of whether it is a viable biomarker of exposure. 

3.3.2 Biomarkers of Effect

There are no specific biomarkers of effect caused by perfluoroalkyl compounds. 

3.4 INTERACTIONS WITH OTHER CHEMICALS 

There are limited data on the interactions of perfluoroalkyls with other chemicals. Particularly absent are 

studies examining toxicological and toxicokinetic interactions of a perfluoroalkyl compound with other 

perfluoroalkyl compounds. 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 perfluoroalkyl compounds and other chemicals. Both PFOA and 

PFOS (and many other diverse 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 the receptor level might occur; however, there are no experimental data to 

support or rule out this presumption. Given that the PPARα receptor is much less responsive in humans 

than it is in rodents, it is unclear if this type of possible interaction would be relevant to humans. 
PERFLUOROALKYLS 521

***DRAFT FOR PUBLIC COMMENT***

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. 

Perfluoroalkyl compounds are very stable, owing to the strength of the carbon-fluorine bonds, the 

presence of the three 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 are resistant 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 to 

decompose 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 and 

oleophobic 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 in 

surface 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 and 

water. Conversely, charged species, salts, and ionized species at relevant pH (i.e., PFOS, PFOA, PFHpA, 

PFNA) and short-chain species (i.e., PFBA, PFBuS) have relatively good solubility in water and alcohol. 
PERFLUOROALKYLS 522

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-1. Chemical Identity of Perfluoroalkyls

Characteristic Information

Chemical name Perfluorooctanoic acid Ammonium perfluorooctanoate Perfluorobutyric acid

Synonym(s) PFOA; pentadecafluoro-1-octanoic 

acid; pentadecafluoro-n-octanoic acid; 

pentadecafluoroctanoic acid; 

perfluorocaprylic acid; perfluoroctanoic 

acid; perfluoroheptanecarboxylic acid; 

octanoic acid, 

2,2,3,3,4,4,5,5,6,6,7,7,8,8, 

8-pentadecafluoroAPFO; ammonium 

pentadecafluorooctanoate; octanoic 

acid, 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-

pentadecafluoro-ammonium salt (1:1)

PFBA; heptafluoro-1-butanoic acid; 

heptafluorobutanoic acid; 

heptafluorobutyric acid; 

perfluorobutanoic acid; 

perfluorobutyric acid; 

perfluoropropanecarboxylic acid; 

2,2,3,3,4,4,4-heptafluorobutanoic 

acid

Registered trade name(s) No data No data No data

Chemical formula C8HF15O2 C8H4F15NO2 C4HF7O2

Chemical structure

F

F

F

F

F

F

F

F

F

F

F

F

F F

OH

O

F

F

F

F

F

F

F

OH

O

F

CAS Registry Number 335-67-1 3825-26-1 375-22-4

F F

F

F

F

F

F

F

F

F

F

F

F

F

F

O

O
PERFLUOROALKYLS 523

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-1. Chemical Identity of Perfluoroalkyls

Characteristic Information

Chemical name Perfluorohexanoic acid Perfluoroheptanoic acid Perfluorononanoic acid

Synonym(s) PFHxA; undecafluoro-1-hexanoic acid; 

hexanoic acid, 

2,2,3,3,4,4,5,5,6,6,6-undecafluoroPFHpA; perfluoro-n-heptanoic acid; 

tridecafluoro-1-heptanoic acid; 

heptanoic acid, 2,2,3,3,4,4,5,5,6,6,7,7, 

7-tridecafluoroPFNA; 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-heptadecafluoroRegistered trade name(s) No data No data No data

Chemical formula C6HF11O2 C7HF13O2 C9HF17O2

Chemical structure

 

F F

F

F

F

F

F

F

F

F

F

F

F

OH

O

F

F

F

F

F

F

F

F

F

F

F

F

F

OH

O

F

F F

F

CAS Registry Number 307-24-4 375-85-9 375-95-1

F F

F

F

F

F

F

F

F

F OH

O

F
PERFLUOROALKYLS 524

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-1. Chemical Identity of Perfluoroalkyls

Characteristic Information

Chemical name Perfluorodecanoic acid Perfluoroundecanoic acid Perfluorododecanoic acid

Synonym(s) 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-nonadecafluoroPFUA; perfluoro-n-undecanoic acid; 

henicosafluoroundecanoic acid; 

2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,

11,11-heneicosafluoroundecanoic acid

PFDoA; tricosafluorododecanoic 

acid; dodecanoic acid, 

2,2,3,3,4,4,5,5,6,6,7,7,8,

8,9,9,10,10,11,11,12,12,

12-tricosafluoroRegistered trade name(s) No data No data No data

Chemical formula C10HF19O2 C11HF21O2 C12HF23O2

Chemical structure

F

F

F

F

F

F

F

F

F

F

F

F

F

OH

O

F

F

F

F

F

F

F

F

F

F

F

F

F

F

F

F

F

F

F

OH

O

F

F

F F

F F F

F F

F

F

F

F

F

F

F

F

F

F

F

F

OH

O

F

F

F F

F F

F

F F

F

CAS Registry Number 335-76-2 2058-94-8 307-55-1
PERFLUOROALKYLS 525

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-1. Chemical Identity of Perfluoroalkyls

Characteristic Information

Chemical name Perfluorooctane sulfonic acid Perfluorohexane sulfonic acid Perfluorobutane sulfonic acid

Synonym(s) PFOS; 1-perfluorooctanesulfonic acid; 

heptadecafluoro-1-octanesulfonic acid; 

heptadecafluorooctan-1-sulphonic 

acid; perfluorooctane sulfonate; 

perfluorooctylsulfonic acid; 1-octanesulfonic acid, 

1,1,2,2,3,3,4,4,5,5,6,6,7,7,

8,8,8-heptadecafluoroPFHxS; 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-sulfonic

PFBuS; 1-perfluorobutanesulfonic 

acid; nonafluoro-1-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-nonafluorobutane1-sulphonic acid; 1-butanesulfonic 

acid, nonafluoro- (6Cl,7Cl,8Cl)

Registered trade name(s) No data No data No data

Chemical formula C8HF17O3S C6HF13O3S C4HF9O3S

Chemical structure

F

F

F

F

F

F

F

F

F

F

F

F

F

F

S

O

O

OH

F

F

F F

F

F

F

F

F

F

F

F

F

F

F S

O

O

OH

F F

F

F

F

F

F

F

F S

O

O

OH

F

CAS Registry Number 1763-23-1 355-46-4 375-73-5
PERFLUOROALKYLS 526

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-1. Chemical Identity of Perfluoroalkyls

Characteristic Information

Chemical name Perflurorooctanesulfonamide 2-(N-methyl-perfluorooctane 

sulfonamide) acetic acid

2-(N-ethyl-perfluorooctane 

sulfonamide) acetic acid

Synonym(s) PFOSA; perfluoroctylsulfonamide; 

perfluorooctanesulfonic acid amide; 

heptadecafluorooctanesulphonamide; 

1-octanesulfonamide, 1,1,2,2,3,3,4,4,

5,5,6,6,7,7,8,8,8-heptadecafluoroMe-PFOSA-AcOH Et-PFOSA-AcOH

Registered trade name(s) No data No data No data

Chemical formula C8H2F17NO2S C11H6F17NO4S C12H8F17NO4S

Chemical structure

F

F

F

F

F

F

F

F

F

F

F

F

F

F

S

O

O

NH2

F

F

F

F

F

F

F

F

F

F

F

F

F

F

F

F

F

S

O

O

N

F

F

F

CH3

OH

O

F

F

F

F

F

F

F

F

F

F

F

F

F

F

S

O

O

N

F

F

F

OH

H3C O

CAS Registry Number 754-91-6 2355-31-9 2991-50-6

CAS = Chemical Abstracts Services 

Sources: Calafat et al. 2007a, 2007b; CAS 2008; ChemIDplus 2008, 2017; RTECS 2008

1
PERFLUOROALKYLS 527

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls

Property PFOA APFO PFBA PFHxA

Molecular weight 414.069a 431.1b 214.039a 314.06c

Color No data No data No data No data

Physical state Solidd Solidb Liquida No data

Melting point 54.3°Ca Decomposition starts 

above 105°Cb

-17.5°Ca No data

Boiling point 188°Ca No data 121°Ca 168°C at 742 mm 

Hge

Density at 20°C 1.8 g/cm3f No data 1.651 g/cm3a 1.789e

Odor No data No data No data No data

Odor threshold:

Water No data No data No data No data

Air No data No data No data No data

Solubility:

Water 9.5x103 mg/L at 

25°Cg

>500 g/Lb 2.14x105 mg/L at 

25°Ch

15,700 mg/Li

Organic solvents No data No data Soluble in ethanol 

and toluene; 

insoluble in 

petroleum ethera

No data

Partition coefficients:

Log Kow Not applicablej No data Not applicablej Not applicablej

Koc 17–230k No data No data No data

pKa 3.8l No data 0.08 (estimated)m -0.16i

Vapor pressure 0.017 mm Hg at 

20°C (extrapolated); 

0.962 mm Hg at 

59.25°C (measured)n

0.0081 Pa at 20°Cb 44 mm Hg at 56°Cg No data

Henry's law constant 0.362 Pa-m3/molh No data 1.24Pa-m3/molh No data

Autoignition 

temperature

Not applicableo No data Not applicableo Not applicableo

Flashpoint Not applicableo No data Not applicableo Not applicableo

Flammability limits Not applicableo No data Not applicableo Not applicableo

Conversion factors 1 ppm=17.21 mg/m3

; 

1 mg/m3=0.058 ppmp

1 ppm=17.63 mg/m3; 

1 mg/m3=0.06 ppmp

1 ppm=8.90 mg/m3; 

1 mg/m3=0.11 ppmp

1 ppm=12.84 mg/m3; 

1 mg/m3=0.08 ppmp

Explosive limits Not applicableo Not applicableo Not applicableo Not applicableo
PERFLUOROALKYLS 528

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls

Property PFHpA PFNA PFDeA PFUA

Molecular weight 364.06c 464.08c 514.084a 564.085q

Color No data No data No data No data

Physical state No data No data No data No data

Melting point 24–30°Cr No data No data 97.9–100.3°Cr

Boiling point 175°C at 742 mm 

Hgg

No data 219°C No data

Density at 20°C No data No data No data No data

Odor No data No data No data No data

Odor threshold:

Water No data No data No data No data

Air No data No data No data No data

Solubility:

Water 4.37x105 mg/L at 

25°Ch

No data No data No data

Organic solvents No data No data No data No data

Partition coefficients:

Log Kow Not applicablej Not applicablej Not applicablej Not applicablej

Koc No data No data No data No data

pKa -0.15 (estimated)m -0.17 (estimated)m -0.17 (estimated)m -0.17 (estimated)m

Vapor pressure 4.6 mm Hg at 25 °Ch 4.83x10-3 mm Hg at 

20°C (extrapolated); 

8.4 mm Hg at 

99.63°C (measured)n

7.62x10-4 mm Hg at 

20°C (extrapolated); 

23.5 mm Hg at 

129.56°C 

(measured)s

3.44x10-4 mm Hg at 

20°C (extrapolated); 

4.62 mm Hg at 

112.04°C 

(measured)s

Henry's law constant 

at 25°C

0.573 Pa-m3/molh No data No data No data

Autoignition 

temperature

Not applicableo Not applicableo Not applicableo Not applicableo

Flashpoint Not applicableo Not applicableo Not applicableo Not applicableo

Flammability limits Not applicableo Not applicableo Not applicableo Not applicableo

Conversion factors 1 ppm=15.14 mg/m3

; 

1 mg/m3=0.07 ppmp

1 ppm=19.29 mg/m3; 

1 mg/m3=0.05 ppmp

1 ppm=21.37 mg/m3; 

1 mg/m3=0.05 ppmp

1 ppm=23.45 mg/m3; 

1 mg/m3=0.04 ppmp

Explosive limits Not applicableo Not applicableo Not applicableo Not applicableo
PERFLUOROALKYLS 529

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls

Property PFDoA PFOS PFHxS PFBuS

Molecular weight 614.1c 500.03c 400.12c 300.1c

Color No data No data No data No data

Physical state No data No data No data No data

Melting point No data ≥400°C (potassium 

salt)s

No data No data

Boiling point No data No data No data No data

Density at 20°C No data No data No data No data

Odor No data No data No data No data

Odor threshold:

Water No data No data No data No data

Air No data No data No data No data

Solubility:

Water No data 570 mg/L (potassium 

salt in pure water)s

No data No data

Organic solvents No data No data No data No data

Partition coefficients:

Log Kow Not applicablej Not applicablej Not applicablej Not applicablej

Koc No data No data No data No data

pKa -0.17 (estimated)m 0.14 (estimated)m 0.14 (estimated)m 0.14 (estimated)m

Vapor pressure 5.11x10-60 mm Hg at 

20°C (extrapolated)s

2.48x10-6 mm Hg at 

20°C (potassium 

salt)d

No data No data

Henry's law constant 

at 25°C

No data No data No data No data

Autoignition 

temperature

Not applicableo Not applicableo Not applicableo Not applicableo

Flashpoint Not applicableo Not applicableo Not applicableo Not applicableo

Flammability limits Not applicableo Not applicableo Not applicableo Not applicableo

Conversion factors 1 ppm=25.53 mg/m3

; 

1 mg/m3=0.04 ppmp

1 ppm=20.79 mg/m3; 

1 mg/m3=0.05 ppmp

1 ppm=16.63 mg/m3; 

1 mg/m3=0.06 ppmp

1 ppm=12.48 mg/m3; 

1 mg/m3=0.08 ppmp

Explosive limits Not applicableo Not applicableo Not applicableo Not applicableo
PERFLUOROALKYLS 530

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls

Property PFOSA Me-PFOSA-AcOH Et-PFOSA-AcOH

Molecular weight 499.15c 571.21 (from structure) 585.24c

Color No data No data No data

Physical state No data No data No data

Melting point No data No data No data

Boiling point No data No data No data

Density at 20°C No data No data No data

Odor No data No data No data

Odor threshold:

Water No data No data No data

Air No data No data No data

Solubility:

Water No data No data No data

Organic solvents No data No data No data

Partition coefficients:

Log Kow Not applicablej Not applicablej Not applicablej

Koc No data No data No data

pKa 6.24 (estimated)m 3.92 (estimated)m 3.92 (estimated)m

Vapor pressure No data No data No data

Henry's law constant No data No data No data

Autoignition 

temperature

Not applicableo Not applicableo Not applicableo

Flashpoint Not applicableo Not applicableo Not applicableo

Flammability limits Not applicableo Not applicableo Not applicableo
PERFLUOROALKYLS 531

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls

Property PFOSA Me-PFOSA-AcOH Et-PFOSA-AcOH

Conversion factors 1 ppm=20.75 mg/m3

; 

1 mg/m3=0.05 ppmp

1 ppm=23.75 mg/m3; 

1 mg/m3=0.04 ppmp

1 ppm=24.33 mg/m3; 

1 mg/m3=0.04 ppmp

Explosive limits Not applicableo Not applicableo Not applicableo

aLide 2005.

bEPA 2014. cEPA 2008c. d3M 2008c. eSavu 1994a. f

Kroschwitz and Howe-Grant 1994.

gKauck and Diesslin 1951. hKwan 2001. i

Zhao et al. 2014. j

The log Kow is not measureable since these substances are expected to form multiple layers in an octanol-water 

mixture (3M 1999, 2008c; EPA 2005a).

kPrevedouros et al. 2006. l

Burns et al. 2008. mSPARC 2008. nKaiser et al. 2005. oPerfluorocarboxylates 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).

pCalculated using molecular weight. qChemID Plus 2008. r

Kunleda and Shinoda 1976.

s

3M 2000.

Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; Me-PFOSA-AcOH = 2-(N-methylperfluorooctane sulfonamide) acetic acid; PFBA = perfluorobutyric acid; PFBuS = perfluorobutane sulfonic acid; 

PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; 

PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; 

PFUA = perfluoroundecanoic acid
PERFLUOROALKYLS 532

4. CHEMICAL AND PHYSICAL INFORMATION

***DRAFT FOR PUBLIC COMMENT***

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).

With the exception of PFOSA, estimated pKa values for the perfluoroalkyls listed in Table 4-2 range 

from -0.17 to 3.92 (SPARC 2008). This pKa range indicates that these substances will exist in anion 

form when in contact with water at environmental and physiologically relevant pHs. An estimated pKa of 

6.24 indicates that PFOSA 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 the formation of micelles.

Vapor pressures at 25°C were extrapolated for PFOA, PFNA, PFDeA, PFUA, and PFDoA 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 PFDeA; 

4.62–750 mm Hg (112.04–237.65°C) for PFUA; and 6.42–750 mm Hg (127.58–247.36°C) for PFDoA 

(Kaiser et al. 2005).
PERFLUOROALKYLS 533

***DRAFT FOR PUBLIC COMMENT***

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE 

5.1 OVERVIEW 

Perfluoroalkyls has 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 in which substance perfluoroalkyls has been evaluated is not known. The number of sites in each 

state is shown in Figure 5-1. Of these sites, 4 are located within the United States. 

Figure 5-1. Number of NPL Sites with Perfluoroalkyls Contamination

• 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 these 

substances.

• 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. 

Perfluoroalkyls have been released to air, water, and soil in and around fluorochemical facilities located 

within the United States (3M 2007b, 2008a, 2008b; Barton et al. 2007; Davis et al. 2007; DuPont 2008; 

EPA 2008a). Since the early 2000s, companies in the fluorochemical industry have been working in 

concert with the EPA to phase out the production and use of long-chain perfluoroalkyl compounds and 

their precursors (3M 2008a; DuPont 2008; EPA 2007a, 2008a, 2016a). Perfluorocarboxylic acids 
PERFLUOROALKYLS 534

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

containing seven or more perfluorinated carbon groups and perfluoroalkyl sulfonic acids containing six or 

more perfluorinated carbon units are considered long-chain substances. Perfluorinated carboxylic acids 

and sulfonic acids containing less than seven and six perfluorinated carbons, respectively, are considered 

short-chain substances. The short-chain substances are not as bioaccumulative as the longer-chain 

substances such as PFOA and PFOS. PFOA, PFOA precursors, and higher homologues have been 

phased out by the eight corporations in the perfluorotelomer/fluorotelomer industry (Arkema, Asahi, 

BASF [successor to Ciba], 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 been totally eliminated based on company reports 

submitted to EPA (EPA 2008a, 2016a). 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 have 

been 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 the 

ground 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 indicate 

that perfluoroalkyls will be persistent in water and soil (3M 2000; Prevedouros et al. 2006). Soil 

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 other 

remote locations such as open ocean waters (Barber et al. 2007; 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 535

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

perfluoroalkyls via oceanic currents, and transport of perfluoroalkyls in the form of marine aerosols 

(Armitage et al. 2006; Barber et al. 2007; 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, which 

indicates 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, and 

eggs 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 the 

phase out of these substances in the United States. The geometric mean serum levels of PFOS have 

declined over 80% from NHANES survey years 1999–2000 (30.4 ng/mL) to 2013–2014 (4.99 ng/mL) 

and the geometric mean serum levels of PFOA have declined almost 70% over the same temporal period, 

decreasing from 5.2 ng/mL in years 1999–2000 to 1.94 ng/mL for 2013–2014 (CDC 2018).

Mean concentrations of PFHpA, PFNA, PFDeA, PFUA, PFDoA, PFBuS, PFBA, PFOSA, Me-PFOSAAcOH, and Et-PFOSA-AcOH 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-mouth transfer 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 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 et al. 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 
PERFLUOROALKYLS 536

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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). 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 to 

greater 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 a 

minor contribution to the total exposure, under certain scenarios, it was estimated that up to 80% of the 

intake could be attributable to exposure to precursor substances followed by subsequent metabolism to 

PFOS or PFOA.

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 perfluoroalkyl compounds 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, such 

as individuals who install and treat carpets or firefighters, are expected to have occupational exposure to 

these 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 near 

fluorochemical facilities indicate that drinking water is the major exposure pathway (Emmett et al. 2006a; 

Hölzer et al. 2008; Wilhelm et al. 2009). 3M conducted an exposure assessment to estimate the 

cumulative 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 the 

West Morgan/East Lawrence (WM/EL) public drinking water supply (3M 2008c).
PERFLUOROALKYLS 537

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

5.2.1 Production

Perfluoroalkyls been manufactured industrially by electrochemical fluorination (ECF), fluorotelomer 

iodide oxidation, fluorotelomer olefin oxidation, and fluorotelomer iodide carboxylation (Prevedouros et 

al. 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 the 

molecule with fluorines. Perfluoroacyl fluorides produced by ECF are hydrolyzed to form the 

perfluorocarboxylic 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 et 

al. 2003). 

RhCOF + HF → RfCOF + H2 + byproducts 

RfCOF + H2O → RfCOOH + HF

Perfluoroalkanesulfonyl fluorides produced by ECF are hydrolyzed under alkaline conditions to form the 

corresponding salt (Savu 1994b; Siegemund et al. 2005). Acidification followed by distillation yields the 

anhydrous perfluoroalkanesulfonic acid.

RhSO2F + HF → RfSO2F + H2

RfSO2F + KOH → RfSO3K + HF

RfSO3K + H2SO4 → RfSO3H + KHSO4 

Perfluorosulfonamido compounds, such as PFOSA, can be formed by reacting the perfluoroalkanesulfonyl fluoride with a primary or secondary amine (3M 1999; Hekster et al. 2003; Siegemund et al. 

2005). 

The fluorotelomer iodide oxidation process was developed by DuPont and has served as the basis for their 

fluoropolymer 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. Tetrafluoroethene 

is then added to this product at a molar ratio that gives a product of desired chain length. Finally, the 
PERFLUOROALKYLS 538

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

product is oxidized to form the carboxylic acid. The process produces linear perfluorocarboxylic acids of 

even carbon numbers as illustrated below. 

5C2F4 + IF5 + 2I2 catalyst  → 5C2F5I 

C2F5I + nC2F4 → C2F5(C2F4)nI 

C2F5(C2F4)nI SO→ 3 C2F5(C2F4)n-1CF2COOH

Fluorotelomer 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 the 

Emergency Planning and Community Right-to-Know Act (Title III of the Superfund Amendments and 

Reauthorization 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 with 

information 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 their 

use 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 perfluoroalkyl 

compounds 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. 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. 
PERFLUOROALKYLS 539

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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.
PERFLUOROALKYLS 540

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

The 3M Company was the principal worldwide manufacturer of PFOS and related chemicals. As a result 

of 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 within 

approximately 2 years of the phase-out announcement, and ceased all manufacturing and the last 

significant use of this chemistry by the end of 2008 (3M 2008a; EPA 2007a). In 2000, EPA finalized the 

significant new use rule (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 time for evaluation (EPA 2002, 2007a, 2008a). The purpose of this rule 

was to limit future manufacturing and importation 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, PFOSA, and Et-PFOSA-AcOH. 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 new use if there are no current ongoing uses, or for uses that were scheduled to end 

December 31, 2015 (EPA 2015). 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 toward 

elimination of these substances in products by 2015. Progress reports have been submitted annually 

beginning in 2007 and are available from the EPA PFOA Stewardship Program website. Data from these 

reports 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 
PERFLUOROALKYLS 541

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 the 

ammonium salt of 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, also known as GenX (Wang et 

al. 2013b). Similarly, 3M and other manufacturers are using various perfluoropolyethers 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.

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

Content

Percent 

reductiona Content

Percent 

reductiona Content

Percent 

reductiona

2006 (EPA 2008a)

Arkema, Inc. PFOA and 

higher 

homologues

>500–

1,000

0% >70–150 30 Not 

applicable

Not 

applicable

Precursors Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Asahi Glass 

Company

PFOA, PFOA 

salts, and higher 

homologues

500–1,570 12% 0.12 Not 

applicable

Not 

applicable

Not 

applicable

Precursors Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Ciba Specialty 

Chemicals 

Corporation

PFOA 0.05 kg >99% 0.05 kg >99% 0.05 kg >99%

Higher 

homologues

0.05 kg >99% 0.05 kg >99% 0.05 kg >99%

Precursors 0 >99% 0 >99% 0 >99%

Clariant International Ltd.Not applicable Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable
PERFLUOROALKYLS 542

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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

Content

Percent 

reductiona Content

Percent 

reductiona Content

Percent 

reductiona

Daikin 

America, Inc.

PFOA 280 34% 2; 300 0% 0.28 72%

Precursors and 

higher 

homologues

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

2,500 78%

E.I. DuPont 

de Nemours 

and Company

PFOA, PFOA 

salts

547 44% 69 80% 246 kg 50%

Direct 

precursors

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

57 kg 14%

3M/Dyneon PFOA 0 100% Not 

reported

Not 

reported

Not 

applicable

Not 

applicable

Solvay 

Solexis

PFOA and 

PFOA salts

600–700 59% Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Higher 

homologues

Not 

applicable

Not 

applicable

170–200 0% Not 

applicable

Not 

applicable

Precursors 0 Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

2013 (EPA 2016a)

Arkema, Inc. PFOA and 

higher 

homologues

Not 

applicable

100% >25–75 96% Not 

applicable

Not 

applicable

Precursors Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Asahi Glass 

Company

PFOA, PFOA 

salts, and higher 

homologues

0 100% 18 100% Negligible Not 

applicable

Precursors Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

BASF (Ciba 

Specialty 

Chemicals 

Corporation)

PFOA and 

higher 

homologues

Not 

applicable

100% Not 

applicable

100% Not 

applicable

100%

Precursors Not 

applicable

100% Not 

applicable

100% Not 

applicable

100%

Clariant International Ltd.PFOA, PFOA 

salts, and higher 

homologues

None 

reported

Not 

applicable

None 

reported

Not 

applicable

<1 kg Not 

applicable

Precursors None 

reported

Not 

applicable

None 

reported

Not 

applicable

<7 kg Not 

applicable
PERFLUOROALKYLS 543

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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

Content

Percent 

reductiona Content

Percent 

reductiona Content

Percent 

reductiona

Daikin 

America, Inc.

PFOA None 

reported

100% None 

reported

100% None 

reported

100%

Precursors and 

higher 

homologues

None 

reported

Not 

applicable

None 

reported

Not 

applicable

None 

reported

>99%

E.I. DuPont 

de Nemours 

and Company

PFOA and 

PFOA salts

1 99% 0 99% 9 kg >99%

Higher 

homologues

1 99% 0 99% None 

reported

99%

Precursors None 

reported

None 

reported

None 

reported

None 

reported

None 

reported

98%

3M/Dyneon PFOA, PFOA 

salts, and higher 

homologues

0 100% 0 Not 

applicable

0 No 

telomere 

production

Precursors No 

precursor 

production

No 

precursor 

production

No 

precursor 

production

No 

precursor 

production

No 

precursor 

production

No 

precursor 

production

Solvay 

Solexis

PFOA, PFOA 

salts, and higher 

homologues

Not 

applicable

>99.999% Not 

applicable

>99.999% Not 

applicable

>99.999%

Precursors Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

Not 

applicable

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.

PFOA precursors include: Octane, 1,l,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 
PERFLUOROALKYLS 544

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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, and 

2006, 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 from 

the 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)/best 

environmental practice (BEP) analysis with the ultimate goal of completely phasing out the production 

and use of PFOS and potential precursors (HAES 2017).

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 the 

ammonium 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 perfluoroalkyl compounds were listed in EPA’s 

IUR database. Current U.S. production volume data for perfluoroalkyl compounds are limited. The IUR 

database has been superseded by the Chemical Data Reporting (CDR) database. Data for 2012 indicated 

that PFOA was not imported 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.
PERFLUOROALKYLS 545

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-2. U.S. Production Volume Ranges for Perfluoroalkyls (1986–2002) 

Reported under the EPA Inventory Update Rule

Perfluoroalkyl

Reporting year production volume range (pounds)

1986 1990 1994 1998 2002

PFOA 10,000–500,000 Not reported 10,000–500,000 10,000–500,000 10,000–500,000

APFO 10,000–500,000 10,000–500,000 10,000–500,000 10,000–500,000 500,000–1,000,000

PFBA 10,000–500,000 Not reported Not reported Not reported Not reported

PFOS Not reported Not reported 10,000–500,000 Not reported 10,000–500,000

APFO = ammonium perfluorooctanoate; EPA = Environmental Protection Agency; PFBA = perfluorobutyric 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 as 

confidential 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 both production 

volume and import volumes as confidential business information (EPA 2016d).

5.2.3 Use

Applications of perfluoroalkyl compounds have made use of their unique surfactant properties (Schultz et 

al. 2003). The alkyl tails of perfluoroalkyls make these substances both hydrophobic (water-repelling) 

and oleophobic (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, personal 
PERFLUOROALKYLS 546

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

care 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 then 

disposed of in an approved industrial solid waste landfill or incinerated, while the liquid waste is 

discharged 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 Europe 

2012). 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 which 

carpet samples were incinerated using a rotary kiln incinerator indicated that most perfluoroalkyls were 

effectively 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.

5.3 RELEASES TO THE ENVIRONMENT 

There is no information listed in EPA’s Toxic Release Inventory (TRI) on releases of perfluoroalkyls to 

the 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 the 

general population (Calafat et al. 2006b, 2007a, 2007b; CDC 2018; De Silva and Mabury 2006; 

Kuklenyik et al. 2004; Olsen et al. 2003b, 2003c, 2004b, 2004c, 2005, 2007a; Prevedouros et al. 2006).
PERFLUOROALKYLS 547

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

In 2006, the eight major companies of the perfluoropolymer/perfluorotelomer industry agreed to 

participate in EPA's PFOA Stewardship Program (EPA 2008a). This 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 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 Chemicals

Releases to all media from fluorotelomer and telomer manufacturing

Percent reduction 

in emissionsa kg

kg of release/100 kg of 

product produced

2006 Data (EPA 2008a)

Arkema, Inc. PFOA and higher 

homologues

>1,000–10,000 For fluorotelomer 

production: >0.1–1

22%

Precursors Not applicable Not applicable Not applicable

Asahi Glass 

Company

PFOA, PFOA salts, 

and higher 

homologues

4,922 For fluorotelomer 

production: <1

6%

Precursors Not applicable Not applicable Not applicable

BASF (Ciba 

Specialty 

Chemicals 

Corporation)

PFOA 0.05b >99%

Higher homologues 0.05b >99%

Precursors 0b >99%

Clariant 

International Ltd.

Not applicable Not applicable Not applicable Not applicable

Daikin America, 

Inc.

PFOA Confidential 

business 

information

For fluorotelomer 

production: 8.0x10-3; for 

telomer production: 

6.4x10-7

94% for FP 

production; 92% for 

telomer production

Precursors and 

higher homologues

Confidential 

business 

information

For production: 6.4x10-7 22% for telomer 

production

E.I. DuPont de 

Nemours and 

Company

PFOA, PFOA salts 1,100 Not reported 98%

Direct precursors Confidential 

business 

information

Not reported Confidential 

business 

information
PERFLUOROALKYLS 548

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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

Releases to all media from fluorotelomer and telomer manufacturing

Percent reduction 

in emissionsa kg

kg of release/100 kg of 

product produced

3M/Dyneon PFOA 0 0 100%

Solvay Solexis PFOA and PFOA 

salts

Not applicable Not applicable Not applicable

Higher homologues >1,000–10,000 For fluorotelomer 

production: 0.161

28%

Precursors Not applicable Not applicable Not applicable

2013 data (EPA 2016a)

Arkema, Inc. PFOA and higher 

homologues

>500–2,000 >0.001–0.005 91%

Precursors Not applicable Not applicable Not applicable

Asahi Glass 

Company

PFOA, PFOA salts, 

and higher 

homologues

0 Not applicable 100%

Precursors Not applicable Not applicable Not applicable

BASF (Ciba 

Specialty 

Chemicals 

Corporation)

PFOA Not applicable Not applicable 100%

Precursors Not applicable Not applicable 100%

Clariant 

International Ltd.

PFOA, PFOA salts Not applicable Not applicable Not applicable

Precursors Not applicable Not applicable Not applicable

Daikin America, 

Inc.

PFOA 0 0 100%

E.I. DuPont de 

Nemours and 

Company

Precursors and 

higher homologues

0 0 100%

PFOA, PFOA salts 90 None reported 99.8%

Higher homologues None reported None reported None reported

Precursors Confidential 

business 

information

None reported Confidential 

business 

information

3M/Dyneon PFOA, PFOA salts, 

and higher 

homologues

0 0 100%

Precursors 0 0 Not applicable
PERFLUOROALKYLS 549

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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

Releases to all media from fluorotelomer and telomer manufacturing

Percent reduction 

in emissionsa kg

kg of release/100 kg of 

product produced

Solvay Solexis PFOA, PFOA salts, 

and higher 

homologues

0 0 >99.999%

Precursors 0 0 Not applicable

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 the 

environment 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.

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 

from industrial processes such as the manufacture of perfluoroalkyl carboxylates (470–900 metric tons),
PERFLUOROALKYLS 550

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-4. Global Historical PFCA Production and Emissions Estimates from 

1951 to 2004a

Environmental input source 

Historical time 

period (years) 

Estimated total global 

historical PFCA emissions 

(tonnes) 

Direct PFCA sources 

PFCA manufacture 

PFO/APFO 1951–2004 400–700 

PFN/APFN 1975–2004 70–200

Total manufactured 470–900

Industrial and consumer uses 

Fluoropolymer manufacture (APFO) 1951–2004 2,000–4,000

Fluoropolymer dispersion processing (APFO) 1951–2004 200–300

Fluoropolymer manufacture (APFN) 1975–2004 400–1,400

Fluoropolymer processing (APFN) 1975–2004 10–20

Aqueous firefighting foams (AFFF) 1965–1974 50–100

Consumer and industrial products 1960–2000 40–200 

Total direct 3,200–6,900

Indirect PFCA sources 

POSF-based products 

PFCA residual impuritiesb 1960–2002 20–130

POSF-based precursor degradation 1960–2002 1–30

POSF-based AFFF 1970–2002 3–30

Fluorotelomer-based products

PFCA residual impuritiesb 1974–2004 0.3–30

Fluorotelomer-based precursor degradation 1974–2004 6–130

Fluorotelomer-based AFFF 1975–2004 <1

Total indirect 30–350

Total source emissions (direct and indirect) 3,200–7,300 

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
PERFLUOROALKYLS 551

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

fluoropolymer manufacture (2,400–5,400 metric tons), and fluoropolymer processing (210–320 metric 

tons). 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 and projecting 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 et al. (2006) and Wang et al. (2014) contain a great degree of uncertainty as demonstrated 

by the wide range of 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 

qualitative description of the accuracy of the estimates that ranged from 0–1 (low uncertainty) to 2–3 

(high uncertainty where estimates were based on crude assumptions or extrapolations).

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 to 

be 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 

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

.

The presence of perfluoroalkyl compounds 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 et al. 2007b; Kubwabo et al. 2005; Moriwaki et al. 2003; Prevedouros et al. 2006; Shoeib et al. 
PERFLUOROALKYLS 552

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

2004; Strynar and Lindstrom 2008). Perfluoroalkyl compounds 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) proposed that 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 atmospheric 

photooxidation 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 et 

al. 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 to 

be 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 contaminated 

biosolids (3M 2008b; Clara et al. 2009; Davis et al. 2007; Eggen et al. 2010; EPA 2009a; Kelly and 

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 from 

3.65 to 377 μg/L (EPA 2008d). Reported concentrations of APFO and PFOA measured in surface water 

from 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 perfluoroalkyl compounds was discharged to the Mississippi River. 
PERFLUOROALKYLS 553

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Discharge into Bakers Creek from the waste water treatment plant at the 3M Decatur facility was a 

principal source of 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 a 

military 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 water 

phase of leachates, which could eventually contaminate ground water (Eggen et al. 2010).

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 perfluoroalkyl compounds; detectable concentrations of perfluoroalkyl compounds 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 to control 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 plants located in New York at levels of 0.058–1.05 and 

0.003–0.068 μg/L, respectively (Sinclair and Kannan 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 PFOSA, in 

the effluent, as compared to the influent (Loganathan et al. 2007; Schultz et al. 2006b). For others, such 

as PFHxS and PFDeA, waste water treatment resulted in lower concentrations or no change in the 
PERFLUOROALKYLS 554

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

concentrations. Increases in perfluoroalkyl concentrations are likely due to the breakdown of 

perfluoroalkyl precursors such as polyfluoroalkyl phosphoric acids or fluorotelomer alcohols (D’eon et al. 

2009; Gauthier and Mabury 2005; Wang et al. 2005a, 2005b). 

Land application of biosolids (treated sewage sludge) can also result in the release of perfluoroalkyls to 

surface and groundwater (Clark and Smith 2011; Lindstrom et al. 2011; Sepulvado et al. 2011). There 

appears to be some differences in the distribution of PFOA and PFOS in waste water effluent and 

biosolids, 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 to 

be reported (EPA 2005b, 2016g).

Perfluoroalkyls can be inadvertently released to soils through the use of biosolids applied as fertilizer to 

help maintain productive agricultural soils and stimulate plant growth. PFOA and PFOS were detected in 

both 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, Me-PFOSA, 

Et-PFOSA, and PFOA of 80–219, 63–143, 42–72, 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 of 

fluorotelomer 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).
PERFLUOROALKYLS 555

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

5.4 ENVIRONMENTAL FATE 

5.4.1 Transport and Partitioning 

Air. 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 in 

raindrops 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 atmospheric 

particles (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, low 

concentrations (<0.12–3.16 pg/m3

) of vapor-phase perfluoroalkyl compounds measured by Kim and 

Kannan (2007) in urban air provide evidence of a partitioning equilibrium. Wet and dry deposition are 

expected to be the principal 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 and 

perfluoroalkyl sulfonamides followed by the atmospheric photooxidation of these substances to form 

perfluoroalkyl carboxylic acids and perfluoroalkyl sulfonic acids resulted in PFOA and PFOS 

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 and 

perfluoroalkyl 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 the 

conversion of these substances to perfluoroalkyl carboxylic acids and sulfonates. According to Young et 

al. (2007), the presence of perfluorodecanoic acid and perfluoroundecanoic acid in an Arctic ice cap 

indicates atmospheric oxidation as a source.

Water. With the exception of PFOSA, estimated pKa values for the perfluoroalkyls discussed in this 

profile range from -0.17 to 3.92 (SPARC 2008). This pKa range indicates that these substances will exist 

primarily as the dissociated 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 
PERFLUOROALKYLS 556

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 of these 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 especially relevant since surfactants have been shown to accumulate in upper sea layers and at 

water surfaces (Prevedouros et al. 2006).

Perfluoroalkyl compounds have been measured in invertebrates, fish, amphibians, reptiles, birds, bird 

eggs, and mammals located around the world (Dai et al. 2006; Giesy and Kannan 2001; Houde et 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 and 

PFOS in animals are measured in apex predators, such as polar bears, which indicates that these 

substances biomagnify in food webs (de Vos et al. 2008; Houde et al. 2006b; Kannan et al. 2005; Kelly et 

al. 2007). Table 5-5 shows levels of PFOA and PFOS measured in Arctic organisms. The 

bioaccumulation potential of perfluoroalkyls increases with increasing chain length from 4 to 8 carbon 

units and then declines with further increases in chain length (Conder et al. 2008; de Vos et al. 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). 

Table 5-5. Biological Monitoring of PFOA and PFOS in the Arctic

Location and organism

Concentration (ng/g)

PFOA PFOS Reference

Northeastern Canada, 1996–2002; wet weighta Tomy et al. 2004

Zooplankton (n=5) 2.6 1.8

Clams (n=5) ND 0.28

Shrimp (n=7) 0.17 0.35

Arctic cod (n=6) 0.16 1.3

Redfish (n=7) 1.2 1.4

Walrus (n=5) 0.34 2.4

Narwhal (n=5) 0.9 10.9

Beluga (n=5) 1.6 12.6

Black-legged kittiwake (n=4) ND 10.0

Glaucous gulls (n=5) 0.14 20.2
PERFLUOROALKYLS 557

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-5. Biological Monitoring of PFOA and PFOS in the Arctic

Location and organism

Concentration (ng/g)

PFOA PFOS Reference

Northern Canada, 1992–2002a Martin et al. 2004a

Polar bear (n=7) 8.6 3,100

Arctic fox (n=10) <2 250

Ringed seal (n=9) <2 16

Mink (n=10) <2 8.7

Common loon (n=5) <2 20

Northern fulmar (n=5) <2 1.3

Black guillemot (n=5) <2 ND

White sucker (n=3) <2 7.6

Brook trout (n=2) <2 39

Lake whitefish (n=2) <2 12

Lake trout (n=1) <2 31

Northern pike (n=1) <2 5.7

Arctic sculpin (n=1) <2 12

Northwestern Canada, 2004 Powley et al. 2008

Zooplankton (n=3) ND ND–0.2

Arctic cod (n=5) ND 0.3–0.7

Ringed seal (n=5) 2.5–8.6

Bearded seal (n=1) ND 1.3

Northern Norway; ng/g wet weighta Verreault et al. 2005, 2007

Herring gull eggs <0.091–0.652 21.4–42.2

Glaucous gulls

Eggs (n=10) <0.70 104

Plasma (n=20) <0.70–0.74 134

Nanavut, Canada Butt et al. 2007a, 2007b

Thick-billed murres <MDLb–0.16 <0.40–0.76

Northern fulmars <MDLb–0.09 <0.40–0.60

Ringed seals <0.85–6.2 2–20

Northern Canada, 2002–2005 Butt et al. 2008

Ringed seal livers (n=110) <0.7–13.9 0.89–189

Greenland Bossi et al. 2005

Ringed seals <1.2 12.5–95.6

North American and European Arctic, 1999–2002 Smithwick et al. 2005a

Polar bears (n>72) <2.3–57.1 263–6,340

Greenland, 1999–2001 Smithwick et al. 2005b

Polar bears (n=29)a 10 2,470
PERFLUOROALKYLS 558

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-5. Biological Monitoring of PFOA and PFOS in the Arctic

Location and organism

Concentration (ng/g)

PFOA PFOS Reference

Greenland, 1972–2002 Smithwick et al. 2006

Polar bears 1.6–4.4 120–1,400

aReported as mean values bMinimum detection limits for study analytes ranged from 0.03 to 2.3 ng/g. To calculate means, concentrations less 

than 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 sulfonic 

acid

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). This is supported by the presence of 

PFOA in groundwater at the Decatur, Cottage Grove, and Washington Works fluorochemical industrial 

facilities (3M 2007b, 2008b; Davis et al. 2007). In addition to migration to groundwater from plumes 

near industrial facilities, other sources of perfluoroalkyls that may contaminate nearby groundwater 

include air emissions followed by atmospheric deposition to soils and subsequent leaching (Davis et al. 

2007). Low volatility, high water solubility (9,500 mg/L at 25°C), and low sorption to solids indicate that 

the perfluorooctanoate anion will accumulate in surface waters, especially oceans (Armitage et al. 2006; 

Kauck and Diesslin 1951; Prevedouros et al. 2006; Wania 2007).

Perfluoroalkyl compounds can be taken up by plants in contaminated soils. Laboratory studies have 

suggested that short-chain perfluoroalkyls such as PFBA are more concentrated in edible portions of 

plants when compared 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 and calculated the grass-soil accumulation factor (GSAF), which is the concentration of 

perfluoroalkyl in grass 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 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, PFDeA, PFUA, and PFDoA, 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 
PERFLUOROALKYLS 559

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

carbon chain length. Concentrations in the shoots of the wheat plants increased in the following order: 

PFBA > PFHpA > PFOA > PFDoA.

Other Media. Data are not available regarding the transport and partitioning of perfluoroalkyl 

compounds in other media.

5.4.2 Transformation and Degradation 

Perfluoroalkyl compounds 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 the shielding effect of the fluorine atoms; furthermore, environmental degradation processes generally 

do not possess the energy needed to break apart the strong fluorine-carbon bonds (3M 2000; Hekster et al. 

2003; Schultz et al. 2003). Perfluoroalkyl compounds are resistant to biodegradation, direct photolysis, 

atmospheric photooxidation, and hydrolysis (OECD 2002, 2007; Prevedouros et al. 2006).

Air. Although transport and partitioning information indicates that air will not be a sink for 

perfluoroalkyl compounds 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 et al. 2007; Kim and Kannan 2007). Available information indicates that 

photodegradation will not compete 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 the 

test conditions (OECD 2002). Based on these test results for PFOS, perfluoroalkyl sulfonic acids are not 

expected to undergo direct photolysis in the atmosphere. Direct photolysis data were not located for 

perfluoroalkyl sulfonic acids. 
PERFLUOROALKYLS 560

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

A measured photooxidation rate constant is not available for PFOA. Hurley et al. (2004) measured the 

reaction 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 followed 

by the removal of the carboxyl group and generation of a perfluoroalkyl radical. Finally, the 

perfluoroalkyl chain is broken down one carbon atom at a time through an unzipping sequence. The same 

rate constant, 1.69x10-13 cm3

/molecule-second, was measured for the photooxidation of the C2, C3, and 

C4 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 is 

predicted to occur on a time scale of the order of 10 days.

Atmospheric photooxidation data are not available for perfluoroalkyl sulfonic acids. Atmospheric 

photooxidation studies involving n-methyl perfluorobutane sulfonamidoethanol (Me-FBSE) and n-ethyl 

perfluorobutanesulfonamide (Et-FBSA) indicate possible mechanisms for the reaction of these substances 

with atmospheric hydroxyl radicals (D'eon et al. 2006; Martin et al. 2006). Products observed from the 

photooxidation 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 the 

sulfonamido group (cleavage of the S-C bond) (D'eon et al. 2006; Martin et al. 2006). Each of these 

pathways would be applicable to the photooxidation of Me- and Et-PFOSA-AcOH. The last two 

pathways indicate that PFOSA 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 

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 days 

for Et-FBSA.

Water. PFOS and PFOA are expected to be stable to hydrolysis in the environment based on half-lives 

of 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 
PERFLUOROALKYLS 561

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 perfluoroalkyl compounds 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 the theoretical 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 other 

substances such as PFOA and PFOS in water and can be considered a source of these substances in the 

environment (Liu et al. 2007).

Sediment and Soil. Data are not available regarding the transformation and degradation of 

perfluoroalkyl compounds in sediment and soil. Based on the chemical stability of these substances and 

their resistance to biodegradation in screening tests, environmental degradation processes are not 

expected to be important removal mechanisms for perfluoroalkyl compounds 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 other 

substances such as PFOA and PFOS in soil and sediment and can be considered a source of these 

substances in the environment (Liu et al. 2007; Washington and Jenkins 2015; Washington et al. 2015).

Other Media. Data are not available regarding the transformation and degradation of perfluoroalkyl 

compounds in other media.

5.5 LEVELS IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to perfluoroalkyls depends, in part, on the 

reliability 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 
PERFLUOROALKYLS 562

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 in 

Table 5-7.

Table 5-6. Lowest Limit of Detection Based on Standardsa

Media Detection limit Reference

Air 0.1 pg/m3 Harada et al. 2006

Drinking water 0.5–6.5 ng/L EPA 2009c (Method 537)

Surface water and 

groundwater

No data

Soil 0.11–0.75 μg/kg (median reporting limits) Anderson et al. 2016

Sediment 0.21–1.2 μg/kg (median reporting limits) Anderson et al. 2016

Whole blood

Serum

0.1–2 ng/mL

0.082–0.2 ng/mL

Kärrman et al. 2005

CDC 2015

aDetection limits based on using appropriate preparation and analytics. These limits may not be possible in all 

situations.

Table 5-7. Summary of Environmental Levels of Perfluoroalkylsa

Media Low Highb For more information

Outdoor air (pg/m3) <1 900,000 Table 5-9

Indoor air (pg/m3) <5 12,100 Table 5-10

Dust (ng/g) <2.6 43,765 Table 5-11

Surface water (ppb) <1 67,000 Tables 5-12, 5-13, 5-14, 5-17

Groundwater (ppb) <0.1 619 Tables 5-14, 5-17

Drinking water (ppb) <0.0023 ~100 EPA 2010

Ocean water (pg/L) <0.2 192,000 Table 5-15

Food (ppb) <1 118.29 Fromme et al. 2007b

Soil (ppb) <0.17 104,000 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.
PERFLUOROALKYLS 563

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Detections of perfluoroalkyls in air, water, and soil at NPL sites are summarized in Table 5-8. 

Table 5-8. Perfluoroalkyls Levels in Water, Soil, and Air of National Priorities List 

(NPL) Sites

Medium Mediana

Geometric 

meana

Geometric 

standard 

deviationa

Number of 

quantitative 

measurements NPL sites

PFOA

Water (ppb) 0.35 0.25 6,064 5 4

Soil (ppb) 18,050 18,050 1,000 2 2

Air (ppbv) No data

PFOS

Water (ppb) 0.91 0.35 9,089 4 3

Soil (ppb) 108,000 108,000 1,000 2 2

Air (ppbv) No data

PFBA

Water (ppb) 2.15 1.03 28,192 3 3

Soil (ppb) 1,600 1,600 1,000 2 2

Air (ppbv) No data

PFBuS

Water (ppb) 0.05 0.02 6,770 2 2

Soil (ppb) 224 224 1,000 2 2

Air (ppbv) No data

PFHpA

Water (ppb) 0.07 0.04 3,169 3 2

Soil (ppb) 1,275 1,275 1,000 2 2

Air (ppbv) No data

PFHxA

Water (ppb) 0.25 0.10 8,444 2 2

Soil (ppb) 1,175 1,175 1,000 2 2

Air (ppbv) No data

PFHxS

Water (ppb) 0.26 1.12 52,496 4 3

Soil (ppb) 5,585 5,585 1,000 2 2

Air (ppbv) No data

PFNA

Water (ppb) No data

Soil (ppb) 27.2 27.2 1,000 2 2

Air (ppbv) No data
PERFLUOROALKYLS 564

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-8. Perfluoroalkyls Levels in Water, Soil, and Air of National Priorities List 

(NPL) Sites

Medium Mediana

Geometric 

meana

Geometric 

standard 

deviationa

Number of 

quantitative 

measurements NPL sites

PFPeA

Water (ppb) 0.18 0.11 3,465 3 3

Soil (ppb) 178 178 1,000 2 2

Air (ppbv) No data

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 not 

necessarily involve exposure or levels of concern.

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 and 

Kannan 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 the 

urban locations in Oyamazaki, Japan and Manchester, United Kingdom, and semirural locations in 

Hazelrigg, 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 semirural 

community.

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).
PERFLUOROALKYLS 565

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-9. Concentrations of Perfluoroalkyl in Outdoor Air

Location

Mean (range) concentration (pg/m3)

PFOA PFHpA PFNA Reference

Urban

Albany, New York 

Gas phase (n=8) 3.16 (1.89–6.53) 0.26 (0.13–0.42) 0.21 (0.16–0.31) Kim and 

Kannan 2007

Particulate phase (n=8) 2.03 (0.76–4.19) 0.37 (<0.12–0.81) 0.13 (<0.12–0.40) Kim and 

Kannan 2007

Oyamazaki, Japan (n=12) 262.7 (72–919); 

3,412.8 ng/g in 

dust

— — Harada et al. 

2005b

Fukuchiyama, Japan 15.2; 314 ng/g in 

dust

— — Harada et al. 

2006

Morioka, Japan (n=8) 2.0 (1.59–2.58) — — Harada et al. 

2005b

Manchester, United 

Kingdom (n=2,1)a

341, 15.7 8.2, 0.2 <26.6, 0.8 Barber et al. 

2007

Rural

Kjeller, Norway (n=2) 1.54 0.87 0.12 Barber et al. 

2007

Mace Head, Ireland (n=4) 8.9 <0.001 <3.3 Barber et al. 

2007

Hazelrigg, United Kingdom 

(semi-rural) (n=10)

101, 552b,c 1.6, 14.4b 0.9 Barber et al. 

2007

Marine air

Near Europe (northwest) 

(n=3)

1.22 (0.5–2.0) <0.6 (ND–<0.6) 0.3 (ND–0.5) Jahnke et al. 

2007a

Near Africa (east coast) 

(n=5)

<0.5 (ND–0.7) ND <0.2 (ND–0.3) Jahnke et al. 

2007a

Source dominated

DuPont Washington Works 

Facility; Parkersburg, West 

Virginia (n=28)

430,000 (75,000–

900,000)d

— — Barton et al. 

2006

DuPont Washington Works 

Facility; Parkersburg, West 

Virginia (n=90)

5,500 (10–75,900) — — EPA 2007b

Location

Mean (range) concentration (pg/m3)

PFDeA PFUA PFDoA Reference

Urban

Albany, New York 

Gas phase (n=8) 0.63 (0.24–1.56) <0.12 (ND–0.16) 0.27 (0.14–0.43) Kim and 

Kannan 2007

Particulate phase (n=8) 0.27 (0.13–0.49) ND 0.12 (<0.12–0.38) Kim and 

Kannan 2007
PERFLUOROALKYLS 566

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-9. Concentrations of Perfluoroalkyl in Outdoor Air

Oyamazaki, Japan (n=12) — — — Harada et al. 

2005b

Fukuchiyama, Japan — — — Harada et al. 

2006

Morioka, Japan (n=8) — — — Harada et al. 

2005b

Manchester, United 

Kingdom (n=2,1)a

5.4, <0.8 <0.01, <0.4 <0.01, <0.01 Barber et al. 

2007

Rural

Kjeller, Norway (n=2) <0.15 <0.12 <0.12 Barber et al. 

2007

Mace Head, Ireland (n=4) <2.8 <0.002 <0.003 Barber et al. 

2007

Hazelrigg, United Kingdom 

(semi-rural) (n=10)

1.0, 8.3b 0.7 <0.01 Barber et al. 

2007

Marine air

Near Europe (northwest) 

(n=3)

<0.6 (ND–0.6) ND <0.14 (ND–0.17) Jahnke et al. 

2007a

Near Africa (east coast) 

(n=5)

ND 0.03 (ND–0.2) ND Jahnke et al. 

2007a

Source dominated

DuPont Washington Works 

Facility; Parkersburg, West 

Virginia (n=28)

— — — Barton et al. 

2006

DuPont Washington Works 

Facility; Parkersburg, West 

Virginia (n=90)

— — — EPA 2007b

Location

Mean (range) concentration (pg/m3)

PFOS PFBuS PFHxS PFOSA Reference

Urban

Albany, New York 

Gas phase (n=8) 1.70 (0.94–3.0) — 0.31 (0.13–

0.44)

0.67 (0.22–

2.26)

Kim and 

Kannan 2007

Particulate phase (n=8) 0.64 (0.35–1.16) — <0.12 0.29 (<0.12–

0.79)

Kim and 

Kannan 2007

Oyamazaki, Japan (n=12) 5.2 (2.51–-9.80); 

72.2 ng/g in dust

— — — Harada et al. 

2005b

Fukuchiyama, Japan 2.2; 46.0 ng/g in 

dust

— — — Harada et al. 

2006

Morioka, Japan (n=8) 0.7 (0.46–1.19) — — — Harada et al. 

2005b

Manchester, United 

Kingdom (n=2,1)a

46, 7.1 2.2, <1.6 1.0, 0.1 <1.6, <0.2 Barber et al. 

2007
PERFLUOROALKYLS 567

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-9. Concentrations of Perfluoroalkyl in Outdoor Air

Rural

Kjeller, Norway (n=2) 1.0 <0.09 0.05 0.78 Barber et al. 

2007

Mace Head, Ireland (n=4) <1.8 <1.0 0.07 <0.56 Barber et al. 

2007

Hazelrigg, United Kingdom 

(semi-rural) (n=10)

1.6 2.6 0.04 0.2 Barber et al. 

2007

Marine air

Near Europe (north west) 

(n=3)

1.36 (0.4–2.5) ND 0.12 (0.02–

0.3)

ND Jahnke et al. 

2007a

Near Africa (east coast) 

(n=5)

0.544 (0.05–1.9) ND 0.013 (ND–

0.05)

ND Jahnke et al. 

2007a

Source dominated

DuPont Washington Works 

Facility; Parkersburg, West 

Virginia (n=28)

— — — — Barton et al. 

2006

DuPont Washington Works 

Facility; Parkersburg, West 

Virginia (n=90)

— — — — 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; ND = not detected; PFBuS = perfluorobutane sulfonic acid; PFDeA = 

perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; PFHxS = 

perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = 

perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; PFUA = 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

.

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, PFDeA, PFUA, PFDoA, PFBuS, 

PFHxS, and PFOSA) 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.
PERFLUOROALKYLS 568

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 indicate that 

these substances may be generated 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 PFDeA, and <6–27 pg/L for PFUA.

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, PFDeA, PFUA, and PFDoA 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 (Table 5-10). The reported 

mean concentrations of perfluoroalkyls measured in four indoor air samples collected from Tromso, 

Norway were 0.2 pg/m3 for PFOSA, <0.5 pg/m3 for PFBuS, <4.1 pg/m3 for PFHxS, <47.4 pg/m3 for 

PFOS, 0.8 pg/m3 for PFHpA, 4.4 pg/m3 for PFOA, 2.7 pg/m3 for PFNA, 3.4 pg/m3 in PFDeA, <1.3 pg/m3

for PFUA, and 1.2 pg/m3 for PFDoA (Barber et al. 2007).

Table 5-10. Concentrations of Perfluoroalkyl in Indoor Air

Location

Concentration: mean (range); median (pg/m3)

PFOA PFHpA PFNA Reference

Indoor air (pg/m3)

Tromso, Norway (n=4) 4.4 0.8 2.7 Barber et al. 2007

Indoor dust (ng/g)

Ottawa, Canada (n=67) 106.00 (<2.29–

1,234); 19.72a

— — Kubwabo et al. 2005

Japan (n=16) 380 (70–3,700); 165 — — Moriwaki et al. 2003

North Carolina and Ohio 

(n=112)

296 (<10.2–1,960); 

142b

109 (<12.5–

1,150); 50.2b

22.1 (<11.3–

263); 7.99b

Strynar and 

Lindstrom 2008
PERFLUOROALKYLS 569

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-10. Concentrations of Perfluoroalkyl in Indoor Air

Location

Concentration: mean (range) median (pg/m3)

PFDeA PFUA PFDoA Reference

Indoor air (pg/m3)

Tromso, Norway (n=4) 3.4 <1.3 1.2 Barber et al. 2007

Indoor dust (ng/g)

Ottawa, Canada (n=67) — — — Kubwabo et al. 2005

Japan (n=16) — — — Moriwaki et al. 2003

North Carolina and Ohio 

(n=112)

15.5 (<9.40–267); 

6.65b

30.4 (<10.7–

588); 7.57b

18.0 (<11.0–

520); 7.78b

Strynar and 

Lindstrom 2008

Location

Concentration: mean (range); median (pg/m3)

PFOS PFBuS PFHxS PFOSA Reference

Indoor air (pg/m3)

Tromso, Norway (n=4) <47.4 <0.5 <4.1 2.8 Barber et al. 2007

Indoor dust (ng/g)

Ottawa, Canada (n=67) 443.68 (<4.56–

5,065); 37.8a

NDa 391.96 

(<4.56–

4,305); 23.1a

<0.99a Kubwabo et al. 2005

Japan (n=16) 200 (11–

2,500); 24.5

— — — Moriwaki et al. 2003

North Carolina and Ohio 

(n=112)

761 (<8.93–

12,100); 201b

41.7 (<12.5–

1,150); 9.11b

874 (<12.9–

35,700); 45.5b

— Strynar and 

Lindstrom 2008

aMethod detection limits (MDL) and percent below MDL are as follows: PFOA (2.29 ng/g, 37%), PFOS (4.56 ng/g, 

33%), PFBuS (1.38 ng/g, 100%), PFHxS (4.56, 15%), and PFOSA (0.99 ng/g, 90%). bLimit of quantitation (LOQ) and percent above LOQ are as follows: PFHpA (12.5 ng/g, 74.1%), PFOA (10.2 ng/g, 

96.4%), PFNA (11.3 ng/g, 42.9%), PFDeA (9.40 ng/g, 30.4%), PFUA (10.7 ng/g, 36.6%), PFDoA (11.0 ng/g, 

18.7%), PFOS (8.93 ng/g, 94.6%), PFHxS (12.9 ng/g, 77.7%), PFBuS (12.5 ng/g, 33.0%). Values below the LOQ 

were assigned a value of LOQ/1.412 when calculating the median and mean.

“—“ indicates no available data; ND = not detected; PFBuS = perfluorobutane sulfonic acid; PFDeA = 

perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; PFHxS = 

perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; PFOS = 

perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide

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). Mean, median, and range of 

concentrations in these samples were 106, 19.72, and 1.15–1,234 ng/g, respectively, for PFOA; 443.68, 

37.8, and 2.28–5,065 ng/g, respectively, for PFOS; and 391.96, 23.1, and 2.28–4,305 ng/g, respectively, 

for PFHxS. Concentrations were not reported for PFOSA, which was detected above 0.99 ng/g in 10% of 

the samples. PFBuS 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, 
PERFLUOROALKYLS 570

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

respectively, in 15 of the 16 samples. One of the samples contained 2,500 ng/g PFOS and 3,700 ng/g 

PFOA.

Strynar and Lindstrom (2008) measured perfluoroalkyl levels in 112 indoor dust samples collected from 

homes and daycare centers in North Carolina and Ohio. These authors detected PFHpA, PFOA, PFNA, 

PFDeA, PFUA, PFDoA, PFOS, PFHxS, and PFBuS. Mean values ranged from 15.5 to 874 ng/g. 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). These data are summarized in Table 5-11.

Table 5-11. Concentration (ng/g) of Perfluoroalkyls in 39 Dust Samplesa

Analyte 25th percentile 50th percentile 75th percentile Maximum

Frequency of 

detection (%)

PFBuS 86.3 359.0 782.1 7,718 92.3

PFHxS 47.7 185.5 632.2 43,765 79.5

PFOS 31.7 479.6 1,456.6 18,071 74.4

PFHpA 33.9 97.3 532.5 5,195 61.2

PFOA <LOQ 96.5 667.7 9,818 64.1

PFNA <LOQ <LOQ 26.2 832 25.6

PFDeA <LOQ <LOQ 61.0 1,965 38.5

PFUA <LOQ <LOQ <LOQ 732 20.5

PFDoA <LOQ <LOQ 37.6 1,048 43.6

PFOSA <LOQ <LOQ 16.1 184 23.1

Me-PFOSA-AcOH <LOQ <LOQ 110.3 4,520 33.3

Et-PFOSA-AcOH 92.4 243.5 417.9 3,795 87.2

aThe LOQs are 2.6 ng/g except for PFHpA, which is 4.0 ng/g.

Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; LOQ = limit of quantification; Me-PFOSAAcOH = 2-(N-methyl-perfluorooctane sulfonamide) acetic acid; PFBuS = perfluorobutane sulfonic acid; 

PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; 

PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; 

PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid

Source: Kato et al. 2009a

Median levels of PFOS in dust samples collected in homes, apartments, daycare centers, offices, and cars 

in Sweden were 39, 85, 31, 110, and 12 ng/g, respectively (Björklund et al. 2009). Median PFOA levels 

in dust samples from the same study were 54, 93, 41, 70, and 33 ng/g in homes, apartments, daycare 

centers, offices, and cars, respectively. The authors concluded that while dietary intake was the major 
PERFLUOROALKYLS 571

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

PFOA/PFOS exposure pathway for adults and toddlers in the general population, dust ingestion could 

become an important pathway under a worst-case scenario (high dust ingestion and maximum dust 

levels). 

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 and 

Kannan 2007; Nakayama et al. 2007; Simcik and Dorweiler 2005; Sinclair et al. 2004, 2006). Levels of 

these 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 14 perfluoroalkyls in 2014 at 37 sites across the 

northeastern United States. Although PFOA and PFOS were detected in 100 and 95% of the samples 

collected, respectively, the levels were lower when compared to measurements of U.S. surface waters 

from other regions of the country from 2000 to 2009. The maximum concentration of PFOA was 56 ng/L 

measured in the Passaic River, New Jersey and the maximum PFOS concentration was 27.5 ng/L 

measured in the Woonasquatucket River, Rhode Island (Zhang et al. 2016).

Less data are available regarding the concentrations of other perfluoroalkyl compounds 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 other 

perfluoroalkyls are summarized in Table 5-13. Maximum concentrations of PFOS, PFOA, PFHpA, 

PFNA, PFDeA, PFUA, PFDoA, PFBuS, 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.
PERFLUOROALKYLS 572

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-12. Concentrations of PFOA and PFOS in Surface Water (ng/L)

Location

Concentration

PFOA PFOS Reference

Great Lakes Boulanger et al. 2004

Lake Ontario (n=8) 15–70 6–121

Lake Erie (n=8) 21–47 11–39

New York State waters Sinclair et al. 2006

Lake Ontario (n=13) 18–34 2.9–30

Niagara River (n=3) 18–22 3.3–6.7

Lake Erie (n=3) 13–27 2.8–5.5

Finger Lakes (n=13) 11–20 1.3–2.6

Onondaga Lake (n=3) 39–64 198–1,090

(median=756)

Oneida Lake (n=1) 19 3.5

Erie Canal (n=3) 25–59 5.7–13

Hudson River (n=8) 22–173

(median=35)

1.5–3.4

Lake Champlain (n=4) 10–46 0.8–7.7

Albany, New York Kim and Kannan 2007

Lake water (n=11) 3.27–15.8

(median=7.20)

ND–9.30

(median=2.88)

Surface water runoff (n=14) 0.51–29.3

(median=3.80)

<0.25–14.6

(median=0.81)

New York/New Jersey/Rhode Island 

metropolitan region

56 (maximum)

3.5 (median)

27.5 (maximum)

0.96 (median)

Zhang et al. 2016

Michigan water regions Sinclair et al. 2004

Detroit (n=10) <8–16.14 <0.08–6.13

Flint (n=4) <8–23.01 1.50–12.31

Saginaw Bay (n=5) <8–24.08 3.10–12.69

Northeastern Michigan (n=2) <8 0.87–6.34

Upper Peninsula (n=7) <8–13.77 <0.8–3.09

Northwestern Michigan (n=2) 11.96 <0.8–4.48

Western Michigan (n=6) <8–15.17 <0.8–5.32

Southwestern Michigan (n=5) 8.74–35.86 7.22–29.26

Lansing (n=3) <8–13.37 1.04–4.96
PERFLUOROALKYLS 573

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-12. Concentrations of PFOA and PFOS in Surface Water (ng/L)

Location

Concentration

PFOA PFOS Reference

Minnesota Waters and Lake Michigan Simcik and Dorweiler 

2005

Remote (n=4)

Loiten 0.7 ND

Little Trout 0.3 1.2

Nipisiquit 0.1 ND

Tettegouche 0.5 0.2

Urban (n=4)

Calhoun 20 47

Lake Harriet 3.5 21

Lake of the Isles 0.5 2.4

Minnesota River 1.2 9

Lake Michigan (n=4) <0.6–0.5 1–3.2

Cape Fear Basin, North Carolina Nakayama et al. 2007

80 Sites (n=100)

Mean 43.4 31.2

Median 12.6 28.9

Minimum ND <1

Maximum 287 132

Percent not detecteda 7.6 0

Raisin and St. Clair Rivers, Michigan Kannan et al. 2005

Raisin River 14.7 3.5

St. Clair River (n=3) 4.0–5.0 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) DRBC 2013

2007 3.54–75.40 2.70–8.42

2008 3,99–48 3.53–11.7

2009 3.29–27.7 2.86–7.97

Several rivers in Japan 0.1–67,000 0.3–59 Harada and Koizumi 

2009

Lake Victoria Gulf, Kenya 0.4–96.4 (rivers) <0.4–13.23 (rivers); Orata et al. 2009

0.4–11.6 (lakes) <0.4–2.53 (lakes)

River Po, Italy 1–1,270 1–25 Loos et al. 2008

aDetection limit is 0.05 ng/L

ND = not detected; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid
PERFLUOROALKYLS 574

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-13. Concentrations of Other Perfluoroalkyls in Surface Water

Location 

(reference)a

Concentration (ng/L)

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

EtPFOSA

-AcOH

Great Lakes (Boulanger et al. 2004)

Lake Ontario 

(n=8)

— — — — — — — — <0.3–10

Lake Erie 

(n=8)

— — — — — — — — 3–11

New York State waters (Sinclair et al. 2006)

Onondaga 

Lake (n=3)

— — — — — — 4.2–8.5 — —

Erie Canal 

(n=3)

— — — — — — 2.5–5.6 — —

Other lakes 

and rivers

— — — — — — 0.5–2.8 — —

Albany, New York (Kim and Kannan 2007)

Lake water 

(n=11)

1.15–

12.7

ND–3.51 0.25–

3.58

ND–1.45 ND–

<0.25

— <0.25–

4.05

ND–

0.47

—

Surface 

water runoff 

(n=14)

<0.25–

6.44

<0.25–

5.90

ND–8.39 ND–1.99 ND–1.60 — ND–13.5 ND–

2.14

—

New York/New Jersey/Rhode Island metropolitan region (Zhang et al. 2016)

48.2 

(max); 

0.9 

(median)

14 

(max); 

0.4 

(median)

5.8 

(max); 

0.2

(median)

1.9 

(max); 

0.1 

(median)

2.6 

(max); 

0.0 

(median)

6.2 

(max); 

0.4 

(median)

43 

(max); 

0.7 

(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 

Isles

0.4 ND ND — — — — — —

Minnesota 

River

0.7 1.9 ND — — — — — —

Lake 

Michigan 

(n=4)

<0.6–4.1 <0.6–3.1 ND — — — — — —
PERFLUOROALKYLS 575

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-13. Concentrations of Other Perfluoroalkyls in Surface Water

Location 

(reference)a

Concentration (ng/L)

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

EtPFOSA

-AcOH

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 

detectedb

32.9 10.1 15.2 17.7 53.2 38.0 45.6 — —

Raisin and St. Clair Rivers, Michigan (Kannan et al. 2005)

Raisin River — — — — — — <1 <10 —

St. Clair 

River (n=3)

— — — — — — <1 <10 —

Delaware River (6 locations) (DRBC 2013)

2007 ND24.301.71-976 ND-9.97 ND-26 ND — ND-4.48 ND —

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-8.3 ND — 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; Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; ND = not 

detected; PFBuS = perfluorobutane sulfonic acid; PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic 

acid; PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid

Higher levels perfluoroalkyl compounds are expected in surface water and groundwater surrounding 

perfluorochemical industrial facilities. Paustenbach et al. (2007) estimated PFOA concentrations in 

environmental media for communities located near the DuPont Washington Works chemical 

manufacturing facility. From this analysis, the authors concluded that much of the PFOA detected in 

groundwater near the facility was attributed to deposition to soil surfaces following atmospheric 

emissions from the plant followed by subsequent leaching into groundwater. DuPont entered into an 

agreement 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 
PERFLUOROALKYLS 576

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

concentration measured in 2011 was 200 ng/L and was obtained from a monitoring location adjacent to 

the site.

Xiao et al. (2015) summarized soil and groundwater monitoring data of select perfluoroalkyls near the 3M 

Cottage Grove facility in Minnesota. 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, even though 3M had stopped producing perfluoroalkyls at this facility 

in 2002. Levels in groundwater were shown 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 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 Groundwater 

at Fluorochemical Industrial Facilities

Location

Percent detection and concentration (μg/L)

PFOA PFBA PFOS PFHxS PFBuS Reference

DuPont Washington Works Facility, West Virginia

Groundwater

Borings (n=18) Davis et al. 2007

Percent detected 89%a — — — —

Minimum 0.0912a — — — —

Maximum 78a — — — —

Wells (n=14) — — — Davis et al. 2007

Percent detected 100%a — — — —

Minimum 0.081a — — — —

Maximum 37.1a — — — —

Wells (n=3) — — — EPA 2008d

Percent detected 100% — — — —

Minimum 2.8 — — — —

Maximum 100 — — — —

Surface water

Outlets (n=4) EPA 2008d

Percent detected 100% — — — —

Minimum 2.3 — — — —

Maximum 61 — — — —
PERFLUOROALKYLS 577

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-14. Concentrations of Perfluoroalkyls in Surface Water and Groundwater 

at Fluorochemical Industrial Facilities

Location

Percent detection and concentration (μg/L)

PFOA PFBA PFOS PFHxS PFBuS Reference

3M Cottage Grove Facility, Minnesota

Groundwater

Wells (n=1–7) 3M 2007b 

Percent detected 100% 100% 100% 100% 100%

Minimum 24.6 23.3 26.0 6.47 2.11

Maximum 619 318 26.0 40.0 26.1

Surface water

East and West Cove (n=3–9) 3M 2007b

Percent detected 100% 100% 100% 100% 78%

Minimum 0.172 0.803 0.227 0.0936 0.304

Maximum 2.79 1.01 3.12 4.58 9.69

Mississippi River Shoreline (n=52–80) 3M 2007b

Percent detected 60% 52% 43% 28% 56%

Maximum 0.760 6.92 0.539 1.04 3.05

Mississippi River Transect (n=34–44) 3M 2007b

Percent detected 14% 12% 0% 0% 0%

Maximum 0.0501 0.0530 ND ND ND

3M Decatur Facility, Alabama

Groundwater

Off-site groundwater (n=18) 3M 2008c 

Percent detected 94% — — — —

Mean 1.87 — — — —

Range 0.083–19.8 — — — —

Off-site groundwater 3M 2010

Range 0.0404–

2.41

0.0396–

0.622

0.0615–

0.480

Groundwater range (n=51) 0.149–6.41 0.0104–

1.26

0.012–

0.151

0.0127–

0.0875

0.0101–

0.0766

Lindstrom et al. 

2011

Surface water

On-site surface water (n=7) 3M 2008c 

Percent detected 100% — — — —

Median 2.66 — — — —

Range 0.32–127 — — — —

Off-site surface water (n=60) 3M 2008c 

Percent detected 98% — — — —

Range 0.026–27.7 — — — —
PERFLUOROALKYLS 578

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-14. Concentrations of Perfluoroalkyls in Surface Water and Groundwater 

at Fluorochemical Industrial Facilities

Location

Percent detection and concentration (μg/L)

PFOA PFBA PFOS PFHxS PFBuS Reference

Tennessee River Hansen et al. 

2002 Upstream of facility (n=19)

Percent detected 0% — 100% — —

Range <25 — 16.8–52.6 — —

Downstream of facility (n=21) — —

Percent detected 0% — 100% — —

Median 355 — 107 — —

Range <25–598 — 30.3–144 — —

aAnalyte was reported as APFO.

“—“ indicates no available data; APFO = ammonium perfluorooctanoate; ND = not detected; PFBA = perfluorobutyric 

acid; PFBuS = perfluorobutane sulfonic acid; PFHxS = perfluorohexane sulfonic acid; PFOA = perfluorooctanoic 

acid; PFOS = perfluorooctane sulfonic acid

Yamashita et al. (2005) measured PFOA, PFOS, PFNA, and PFHxS concentrations in ocean water 

collected 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 and 

PFOA 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, PFBuS, PFDoA, 

PFDeA, PFNA, PFHpA) were generally below detection in most samples, with the exceptions being in 

samples collected near Shanghai, the Philippines, and Indonesia. Maximum concentrations of these 

perfluoroalkyls 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 Water

Location

Concentration (pg/L)

PFOA PFOS PFNA PFHxS

North Atlantic (n=9) 160–338 8.6–36 15–36 4.1–6.1

Mid Atlantic (n=7) 100–439 37–73 — 2.6–12

Central to Eastern Pacific (n=14) 15–62 1.1–20 1.0–16 0.1–1.6
PERFLUOROALKYLS 579

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-15. Concentrations of PFOA and PFOS in Ocean Water

Location

Concentration (pg/L)

PFOA PFOS PFNA PFHxS

Western Pacific (n=2) 136–142 54–78 — 2.2–2.8

Tokyo Bay (n=8) 1,800–192,000 338–57,700 163–71,000 17–5,600

Offshore Japan (n=4) 137–1,060 40–75 — 3.0–6.1

Coastal Hong Kong (n=12) 673–5,450 70–2,600 22–207 <5–311

Coastal China (n=14) 243–15,300 23–9,680 2.0–692 <5–1,360

Coastal Korea (n=10) 239–11,350 39–2,530 15–518 <5–1,390

Sulu Sea (n=5) 88–510 <17–109 — <0.2

South China Sea (n=2) 160–420 8–113 — <0.2

“—“ indicates no available data; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = 

perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

Source: Yamashita et al. 2005

The presence of PFOA and PFOS in surface water in the United States indicates that drinking water taken 

from 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 was 

detected 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).

Hu et al. (2016) presented geospatial monitoring data for six perfluoroalkyls (PFBuS, 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 and 

concentrations in drinking water was correlated with proximity to industrial facilities using 

perfluoroalkyls, military fire training areas, and the number of waste water treatment plants. Under the 

UCMR 3, the final data indicate that 63 out of 4,920 public water systems (PWSs) reported PFOA and 

PFOS at concentrations that exceed the EPA Health Advisory of 0.07 μg/L (final UCMR 3 data posted 

January 2017). These systems represent 1.3% of all of the PWSs that monitored under UCMR 3. 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. In addition, the results showed that one or more of the other four perfluoroalkyls 
PERFLUOROALKYLS 580

5. POTENTIAL FOR HUMAN EXPOSURE

monitored under UCMR 3 were detected above their respective minimum reporting levels at 118 out of 

4,920 public water systems (EPA 2017).

It was also 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. The 

dataset used by Hu et al. (2016) has since been updated by the EPA (EPA 2016c). UCMR 3 data are 

added, removed, or updated following additional reviews by the analytical laboratory conducting the 

testing, the individual states, and EPA staff. The most recent report dated July 2016 showed that the six 

perfluoroalkyls were detected above their respective minimal reporting level in 365 out of 4,905 public 

water systems and that PFOA and PFOS were identified above the health advisory level of 0.07 μg/L in 

59 out of the 4,905 public water supplies (EPA 2016c). 

Based on a memorandum of understanding with the EPA, DuPont began collecting water monitoring data 

of both public and private wells near the Washington Works chemical plant. The quarterly reports and 

monitoring 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 to 

2009 in West Virginia and Ohio, PFOA levels ranged from below the detection limit (0.0023 μg/L) to 

nearly 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) have reviewed the presence of PFOS and PFOA in drinking waters worldwide and

discussed treatment methods for removing these substances from public water supplies. Conventional 

waste water treatment does not always efficiently remove perfluoroalkyls, and effluent may contain

higher levels of some perfluoroalkyls than influent due to degradation of precursor substances during the 

treatment 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 of

perfluoroalkyls when compared to water systems that were not highly impacted by waste water treatment

***DRAFT FOR PUBLIC COMMENT***
PERFLUOROALKYLS 581

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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, PFDeA PFUA, 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 were 

commonly detected in the influent and effluent of 10 waste water treatment plants across the United 

States (Schultz et al. 2006a). PFBuS 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 were 

detected in 80% of the influent and effluent samples at the 10 plants. In a national study of 

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 were 

detected 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, PFBuS, 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 in 

treated water than raw water at all sampling points of the first plant, but were slightly lower in the treated 

water of the second drinking water plant even though both systems used simple chlorination to treat the 

water.

According to ATSDR (2008), PFOA, PFOS, PFBA, PFHxS, and PFBuS have been detected in the 

municipal drinking water of communities located near the 3M Cottage Grove fluorochemical facility. 

According to Chang et al. (2008a), concentrations of PFBA in precipitation, surface waters, and water 

treatment effluents were measured in the low ng/L range in effluent at these locations, but could be in the 

μg/L range in public and private wells.
PERFLUOROALKYLS 582

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 water 

collected 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 exception 

of certain location of India where PFOS or PFOA may not have been present or were present at low 

levels.

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 observed 

in tap water at 0.0427 μg/L. The maximum concentration of individual perfluoroalkyls occurring in 

bottled water, spring water, untreated water, and tap water were observed for PFBuS (0.0133 μg/L), 

PFOA (0.0074 μg/L), PFBuS (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 (PFOSA) 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.

5.5.3 Sediment and Soil 

Concentrations of perfluoroalkyls in soils are expected to be greater in the vicinity of fluorochemical 

plants that produced or used these substances as processing aids in the manufacture of fluoropolymers 

than in the environment at large. Levels of some perfluoroalkyl compounds measured in soil and 

sediment surrounding perfluorochemical industrial facilities are listed in Table 5-16. PFOA was detected 

in most soil and sediment samples collected on- and off-site at the 3M Decatur facility in Alabama in 
PERFLUOROALKYLS 583

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

monitoring studies conducted between October 2004 and December 2006. Maximum soil concentrations 

were as high 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 

this location, six on-site soil samples were analyzed in December 2012 for the presence of PFOA, PFOS, 

PFBuS, and PFHxS. Average levels were 3.86–3,890 ng/g (PFOS), 3.56–270 ng/g (PFHxS), 0.423–

64.8 ng/g (PFBuS), 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 PFBuS Reference

DuPont Washington Works Facility, West Virginia

Soil

Boring samples (n=22) Davis et al. 

2007

Percent detected 36%a — — — —

Minimum <0.17a — — — —

Maximum 170a — — — —

3M Cottage Grove Facility, Minnesota

Soil

Boring samples (n=50–108) 3M 2007b

Percent detected 100% — 95% 90% 60%

Maximum 21,800 — 104,000 3,470 139

Fire training area (n=8–11) 3M 2007b

Percent detected 91% 82% 100% 100% 73%

Maximum 262 11.5 2,948 62.2 24.6

Sediment

East and West Cove (n=21–28) 3M 2007b

Percent detected 100% 93% 100% 96% 65%

Minimum 0.764 ND 40.0 ND ND

Maximum 1,845 94.6 65,450 126 9.14

Mississippi River shoreline (n=84–92) 3M 2007b

Percent detected 70% 44% 80% 28% 29%

Maximum 341 124 79.0 11.5 29.4

Mississippi River transect (n=38–40) 3M 2007b

Percent detected 18% 0% 82% 0% 0%

Maximum 1.09 ND 3.16 ND ND
PERFLUOROALKYLS 584

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 PFBuS Reference

3M Decatur Facility, Alabama

Soil

On-site former sludge incorporation area (n=357) 3M 2008c 

Percent detected 99% — — — —

Mean 885–929

Range 2.91–14,750 — — — —

On-site background (n=18) 3M 2008c 

Percent detected 100% — — — —

Mean 3.53–4.1

Range 1.61–6.03 — — — —

Off-site soil (n=23) 3M 2008c 

Percent detected 100% — — — —

Mean 3.68–4.6

Range 0.72–7.85 — — — —

Sediment

On-site sediment (n=8) 3M 2008c 

Percent detected 88% — — — —

Median 16.8

Range 1.64–347 — — — —

Off-site sediment (n=30) 3M 2008c 

Percent detected 93% — — — —

Range 0.39–2,385 — — — —

3M Decatur Facility, Alabama December 2012 

On-site former sludge 

incorporation area (n=6)

3M 2012

Percent detected 100% — 100% 86% 86%

Mean 17.0–1,410 — 3.86–

3,890

3.56–

270

0.423–

64.8
PERFLUOROALKYLS 585

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 PFBuS Reference

3M Cottage Grove Facility, Minnesota

Surface soil along U.S. 

Highway 10 near facility

Xiao et al. 2015

Percent detected 100% — 100% — —

Median 8.0 12.2

Range 5.5–125.7 0.2–28.2

aAnalyte was reported as APFO.

“—“ indicates no available data; APFO = ammonium perfluorooctanoate; ND = not detected; PFBA = perfluorobutyric 

acid; PFBuS = perfluorobutane sulfonic acid; PFHxS = perfluorohexane sulfonic acid; PFOA = perfluorooctanoic 

acid; PFOS = perfluorooctane sulfonic acid

PFOA, 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 (3M 

2007b). PFBuS was detected in 60–73% of these samples. Maximum concentrations for these substances 

were 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 that 

in 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. Levels 

of 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 PFBuS were 341, 124, 79.0, 11.5, and 29.4 ng/g, respectively. PFHxS, PFBuS, 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 
PERFLUOROALKYLS 586

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 in 

widespread contamination of perfluoroalkyl compounds in the soil and groundwater at these facilities. 

Monitoring data 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 

in Table 5-17.

Table 5-17. Summary of Perfluoroalkyl Compounds Detected in Soil, Sediment, 

Surface Water, and Groundwater at 10 Military Installationsa

Compound Parameter

Surface soil 

(μg/kg)

Subsurface 

soil (μg/kg)

Sediment 

(μg/kg)

Surface water 

(μg/L)

Groundwater 

(μg/L)

PFBA DF 38.46 29.81 24.24 84.00 85.51

Median 1.00 0.960 1.70 0.076 0.180

Maximum 31.0 14.0 140 110 64.0

PFBuS DF 35.16 34.62 39.39 80.00 78.26

Median 0.775 1.30 0.710 0.106 0.200

Maximum 52.0 79.0 340 317 110

PFHxA DF 70.33 65.38 63.64 96.00 94.20

Median 1.75 1.04 1.70 0.320 0.820

Maximum 51.0 140 710 292 120

PFHxS DF 76.92 59.62 72.73 88.00 94.93

Median 5.70 4.40 9.10 0.710 0.870

Maximum 1,300 520 2,700 815 290

PFHpA DF 59.34 45.19 48.48 84.00 85.51

Median 0.705 0.660 1.07 0.099 0.235

Maximum 11.4 17.0 130 57.0 75.0

PFOA DF 79.12 48.08 66.67 88.00 89.86

Median 1.45 1.55 2.45 0.382 0.405

Maximum 58.0 140 950 210 250

PFOSA DF 64.84 29.81 75.76 52.00 48.55

Median 1.20 0.470 1.30 0.014 0.032

Maximum 620 160 380 15.0 12.0

PFOS DF 98.90 78.85 93.94 96.00 84.06

Median 52.5 11.5 31.0 2.17 4.22

Maximum 9,700 1,700 190,000 8,970 4,300

PFNA DF 71.43 14.42 12.12 36.00 46.38

Median 1.30 1.50 1.10 0.096 0.105

Maximum 23.0 6.49 59.0 10.0 3.00
PERFLUOROALKYLS 587

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-17. Summary of Perfluoroalkyl Compounds Detected in Soil, Sediment, 

Surface Water, and Groundwater at 10 Military Installationsa

Compound Parameter

Surface soil 

(μg/kg)

Subsurface 

soil (μg/kg)

Sediment 

(μg/kg)

Surface water 

(μg/L)

Groundwater 

(μg/L)

PFDeA DF 67.03 12.50 48.48 52.00 34.78

Median 0.980 1.40 1.90 0.067 0.023

Maximum 15.0 9.40 59.0 3.20 1.80

PFUA DF 45.05 9.62 24.24 20.00 8.70

Median 0.798 1.15 160 0.021 0.025

Maximum 10.0 2.00 14.0 0.210 0.086

PFDoA DF 21.98 6.73 45.45 20.00 4.35

Median 1.95 2.40 2.80 0.058 0.022

Maximum 18.0 5.10 84.0 0.071 0.062

aWater concentrations are ppb (μg/L); soil and sediment levels are ppb (μg/kg).

DF = detection frequency as a percentage; PFBA = perfluorobutyric acid; PFBuS = perfluorobutane sulfonic acid; 

PFDoA = perfluorododecanoic acid; PFDeA = perfluoro-n-decanoic acid; PFHpA = perfluoroheptanoic acid; 

PFHxA = perfluorohexanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; 

PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; PFUA = 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 predominant 

compound with levels ranging from 5.5 to 483 ng/g, depending upon the loading rate.

5.5.4 Other Media 

Levels of PFOS, PFOA, PFBuS, PFHxS, PFHxA, PFHpA, PFDeA, PFNA, and PFDoA 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 in olive oil. PFOS, PFHxA, PFHpA, PFNA, PFDeA, and PFDoA were 

not detected in any samples. PFBuS and PFHxS were detected in cod at 0.12 and 0.07 ng/g, respectively. 

The data for PFOA are summarized in 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.
PERFLUOROALKYLS 588

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-18. Detections of PFOA in 31 U.S. Food Items

Food PFOA concentration in ng/g (LOD for non-detects)

Hamburger 0.15

Bacon 0.24

Sliced turkey ND (0.02)

Sausage 0.09

Ham 0.02

Sliced chicken breast 0.02

Roast beef ND (0.02)

Canned chili 0.02

Salmon 0.23

Canned tuna ND (0.05)

Fresh catfish fillet 0.30

Tilapia 0.10

Cod 0.10

Canned sardines 0.19

Frozen fish sticks 0.21

Butter 1.07

American cheese ND (0.04)

Other cheese ND (0.04)

Whole milk ND (0.02)

Ice cream ND (0.03)

Frozen yogurt ND (0.02)

Whole milk yogurt ND (0.02)

Cream cheese ND (0.03)

Eggs ND (0.04)

Olive oil 1.80

Canola oil ND (0.05)

Margarine 0.19

Cereals ND (0.04)

Apples ND (0.02)

Potatoes 0.07

Peanut butter 0.10

LOD = limit of detection; ND = not detected; PFOA = perfluorooctanoic acid

Source: Schecter et al. 2010
PERFLUOROALKYLS 589

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-19. Detections of Perfluoroalkyls in Fish from U.S. Lakes and Rivers

Type of seafood

(location)

Perfluoroalkyl concentration in ng/g

PFOA PFOS PFHxS PFNA PFDeA PFUA PFHpA PFBuS PFDoA PFOSA Reference

Lake trout 

(Lake Superior)

1.1 4.8 <0.01–

0.43

1.0 0.72 0.90 <0.02–

0.87

0.37 0.25 Furdui et al. 2007

Lake trout (Lake 

Superior)

<0.42 2.3 <0.10 0.70 0.39 1.1 0.97 DeSilva et al. 2011

Lake trout 

(Lake Michigan)

4.4 16 <0.01–

0.87

0.57 0.76 0.74 <0.02–

0.97

0.41 0.99 Furdui et al. 2007

Lake trout 

(Lake Huron)

1.6 39 <0.01–

6.2

2.8 2.2 2.7 <0.02–

1.43

0.88 1.6 Furdui et al. 2007

Lake trout 

(Lake Huron)

<0.42 17 <0.10 1.4 1.3 1.8 0.74 DeSilva et al. 2011

Lake trout 

(Lake Erie)

1.6 121 <0.01–

1.2

2.9 4.9 3.5 <0.02–

0.71

0.97 2.1 Furdui et al. 2007

Lake trout 

(Eastern Lake Erie)

<0.42 96 1.4 2.6 6.1 5.7 2.0 DeSilva et al. 2011

Walleye

(Western Lake 

Erie)

0.50 1.1 <0.10 1.2 3.6 3.1 1.1 DeSilva et al. 2011

Lake trout 

(Lake Ontario)

1.5 46 0.65 1.1 1.8 1.6 <0.02–

1.39

0.70 0.82 Furdui et al. 2007

Lake trout 

(Lake Ontario)

0.88 2.5 0.70 0.90 1.4 2. 0.64 0.32 DeSilva et al. 2011

Mixture of whole 

fish

(Missouri River)

<1.00 84.7 1.89 0.43 0.25 <1.00 1.53 <0.40 0.49 Ye et al. 2008

Mixture of whole 

fish

(Mississippi River)

<0.20 83.1 0.42 0.78 1.24 3.38 0.27 <0.20 <0.40 Ye et al. 2008

Mixture of whole 

fish

(Ohio River)

<1.00 147 0.52 1.03 3.88 6.57 <4.00 <0.40 1.72 Ye et al. 2008
PERFLUOROALKYLS 590

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-19. Detections of Perfluoroalkyls in Fish from U.S. Lakes and Rivers

Type of seafood

(location)

Perfluoroalkyl concentration in ng/g

PFOA PFOS PFHxS PFNA PFDeA PFUA PFHpA PFBuS PFDoA PFOSA Reference

Smallmouth bass 

(Raisin River)

<2 2.0–41.3 <1 <1–4.1 Kannan e al. 2005

Smallmouth bass 

(St Clair River)

<2 <2–2.7 <1 1.1–6.3 Kannan e al. 2005

Smallmouth bass 

(Calumet River)

<2 2.5–7.6 <1 <1 Kannan e al. 2005

Carpa

(Saginaw Bay)

<36 124 <34 <19 Kannan e al. 2005

Carpa

(Saginaw Bay)

120 Giesy and Kannan 

2001

Lake whitefisha

(Michigan waters)

130 Giesy and Kannan 

2001

Chinook salmona

(Michigan waters)

110 Giesy and Kannan 

2001

Brown trouta

(Michigan waters)

<6–46 Giesy and Kannan 

2001

Bluegill

(St Croix River, 

Minnesota)

2.87 <LOQ <LOQ <LOQ Delinsky et al. 

2009

Bluegill

(Lake Calhoun, 

Minnesota)

272 5.82 4.18 4.72 Delinsky et al. 

2009

Bluegill

(Haw River, North 

Carolina)

29.8 10.3 26.9 7.25 Delinsky et al. 

2009

Mixture of fish fillet

(Zumbrol Lake, 

Minnesota)

52.4 3.24 Delinsky et al. 

2010

Mixture of fish fillet

(McCarrons Lake, 

Minnesota)

47.3 1.97 Delinsky et al. 

2010
PERFLUOROALKYLS 591

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-19. Detections of Perfluoroalkyls in Fish from U.S. Lakes and Rivers

Type of seafood

(location)

Perfluoroalkyl concentration in ng/g

PFOA PFOS PFHxS PFNA PFDeA PFUA PFHpA PFBuS PFDoA PFOSA Reference

Mixture of fish fillet

(Pickerel Lake, 

Minnesota)

10.0 1.23 Delinsky et al. 

2010

Mixture of fish fillet

(Carlos Lake, 

Minnesota)

12.3 Delinsky et al. 

2010

Mixture of fish fillet

(other Minnesota 

lakes)

1.08–

5.13

Delinsky et al. 

2010

Mixture of fish fillet

(Mississippi River 

sites, Minnesota)

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.

LOQ = limit of quantitation; PFBuS = perfluorobutane sulfonic acid; PFDoA = perfluorododecanoic acid; PFDeA = perfluorodecanoic acid; 

PFHpA = perfluoroheptanoic acid; PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOS = perfluorooctane sulfonic acid; 

PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid
PERFLUOROALKYLS 592

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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. PFDeA, PFUA, and PFDoA were 

analyzed 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, meat 

products, 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, and 

PFHxS 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 were 

0.11 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 were 

studied 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 decrease 

in 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 were 

generally 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 a 

concentration of 2,300 ng/g. Maximum levels of PFOS in smallmouth bass, largemouth bass, and 
PERFLUOROALKYLS 593

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 a 

concentration 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, PFDeA, PFUA, and PFDoA were detected

in one of the bags at 0.4–3.2 ng/cm2

 uncooked and 0.5–4.3 ng/cm2 cooked; however, these 

perfluoroalkyls 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 food 

restaurants 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 that

can degrade or metabolize to perfluoroalkyl carboxylic acids such as PFOA continue to be detected in

food 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 and 

25 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, all 

fluorotelomer 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 

***DRAFT FOR PUBLIC COMMENT***
PERFLUOROALKYLS 594

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 80 485

8:2 FTOH 4,810 1.36

10:2 FTOH 6,700 0.73

12:2 FTOH 5,650 0.55

14:2 FTOH 384 0.12

16:2 FTOH 61 <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 was 

detected 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 and 

wax 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 in 

treated 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 used 

indoors, 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 PFBuS, 

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, 
PERFLUOROALKYLS 595

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 nondetectable 

or 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 food 

contact materials. Cleaning agents, nanosprays, and impregnation sprays tended to have the highest level

of 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 acids levels ranged from below the detection limit (1.5 ng/g) to 47,100 ng/g, with 

levels 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 sealant 

tape. 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 and 

curing step of nonstick cookware coatings in a high temperature oven; however, residual PFOA could be 

found 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, and 

1,800 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 the 

detection 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 

***DRAFT FOR PUBLIC COMMENT***
PERFLUOROALKYLS 596

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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).

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 

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).

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. 

Perfluoroalkyl compounds, 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 

As a group of compounds, perfluoroalkyls appear to be ubiquitous in human blood based on the 

widespread detection of these substances in human serum samples (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 perfluoroalkyl compounds measured in serum 

samples collected from the general population in the United States. There is a clear trend in decreasing 

serum levels of both PFOS and PFOA in the general population of the United States since 2000 as these 

substances were phased out.
PERFLUOROALKYLS 597

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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) Calafat et al. 2007a

Percent >LOD 100% 100%

LOD 0.1 0.2

Geometric mean 5.2 30.4

95th percentile 11.9 75.6

2003–2004 (n=2,094) Calafat et al. 2007b

Percent >LOD 99.7% 99.9%

LOD 0.1 0.4

Geometric mean 3.95 20.7

95th percentile 9.80 54.6

2005–2006 (n=2,120)

Percent >LOD NR NR CDC 2018

LOD 0.1 0.2

Geometric mean 3.92 17.1

95th percentile 11.3 47.5

2007–2008 (n=2,100) CDC 2018

Percent >LOD NR NR

LOD 0.1 0.2

Geometric mean 4.12 13.2

95th percentile 9.60 40.5

2009–2010 (n=2,233) CDC 2018

Percent >LOD NR NR

LOD 0.1 0.2

Geometric mean 3.07 9.32

95th percentile 7.50 32.0

2011–2012 (n=1,904) CDC 2018

Percent >LOD NR NR

LOD 0.1 0.2

Geometric mean 2.08 6.31

95th percentile 5.68 21.7

2013–2014 (n=2,165) CDC 2018

Percent >LOD NR NR

LOD 0.1 0.2

Geometric mean 1.94 4.99

95th percentile 5.57 18.5
PERFLUOROALKYLS 598

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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

1990–2002 (n=23 pooled 

samples)

Calafat et al. 2006b

Percent >LOD 100% 100%

LOD 0.2 0.4

Geometric mean 9.6 30.0

95th percentile 23.0 52.3

U.S. blood donors

2000–2001 (n=645) Olsen et al. 2003b

Percent >LLOQb 92% 99.8%

Geometric mean 4.6 34.9

95th percentilec 12.1 88.5

Maximum 52.3 1,656.0

2006 (n=600) Olsen et al. 2017b

Geometric mean 3.44 14.5

95th percentile 7.9 31.5

2010 (n=600) Olsen et al. 2017b

Geometric mean 2.44 8.3

95th percentile 5.6 21.8

2015 (n=616) Olsen et al. 2017b

Geometric mean 1.09 4.3

95th percentile 3.2 8.6

U.S. residents

(n=24) Olsen et al. 2003c

Percent >LLOQd NR 98%

Geometric mean 2.5 14.7

Minimum <3.0 <6.1

Maximum 7.0 58.3

Midwestern United States

2004–2005 (n=16) De Silva and Mabury 2006

Percent detectedd 100% Not detected

Mean 4.4

Maximum 8.6
PERFLUOROALKYLS 599

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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

Minneapolis-St. Paul blood donors (plasma)

2005 (n=40) Olsen et al. 2007b

Percent >LLOQ 95% 100%

LLOQ NR 3.4

Geometric mean 2.2 15.1

75th percentile 3.5 20.2

Maximum 4.7 36.9

Atlanta, Georgia

2003 (n=20) Kuklenyik et al. 2004

Percent >LOD 100% 100%

LOD 0.1 0.4

Mean 4.9 55.8

Minimum 0.2 3.6

Maximum 10.4 164.0

Seattle, Washington elderly individuals

(n=238) Olsen et al. 2004c

Percent >LLOQb 99.2% 99.5%

Geometric mean 4.2 31.0

95th percentileb 9.7 84.1

Maximum 16.7 175.0

Washington County, Maryland

1974 (n=178) Olsen et al. 2005

Percent >LLOQ 71% 100%

LLOQ 1.9 3.9

Geometric mean 2.1 30.1

75th percentile 3.0 40.2

1989 (n=178) Olsen et al. 2005

Percent >LLOQ 99%o 100%p

Geometric mean 5.5 33.3

LLOQ 1.9 3.9

75th percentile 6.7 44.0
PERFLUOROALKYLS 600

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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

Boston, Massachusetts; Charlotte, North Carolina; Hagerstown, Maryland; Los Angeles, California; 

Minneapolis-St. Paul, Minnesota; Portland, Oregon 

2006 (n=600) Olsen et al. 2008

Percent >LLOQ 99% 99%

Geometric mean 3.4 14.5

LLOQ 1.0 <2.5

95th percentile CI 

geometric mean

3.3–3.6 13.9–15.2

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 the 

LOD 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; NR = not reported; 

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid

Table 5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collected 

in the United States

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSA

-AcOH

EtPFOSA

-AcOH

U.S. residents NHANES

1999–2000 (n=1,562) (Calafat et al. 2007a)

Percent >LOD 10% 95% 25% 12% <1% — 100% 100% 96% 91%

LOD 0.4 0.1 0.2 0.2 0.2 — 0.1 0.05 0.2 0.2

Geometric 

mean

<0.4 0.5 <0.2 <0.2 <0.2 2.1 0.4 1.0 0.6

95th percentile NR 1.7 0.5 NR NR 8.7 1.4 3.2 2.2

2003–2004 (n=2,094) (Calafat et al. 2007b)

Percent >LOD 6.2% 98.8% 31.3% 9.7% <0.1% <0.4% 98.3% 22.2% 27.5% 3.4%

LOD 0.3 0.1 0.3 0.3 1.0 0.4 0.3 0.2 0.6 0.4

Geometric 

mean

<0.3 1.0 <0.3 <0.3 <1.0 <0.4 1.9 <0.2 <0.6 <0.4

95th percentile 0.4 3.2 0.8 0.6 <1.0 <0.4 8.3 0.2 1.3 <0.4
PERFLUOROALKYLS 601

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collected 

in the United States

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSA

-AcOH

EtPFOSA

-AcOH

2005–2006 (n=2,120) (CDC 2018)

Percent >LOD NR NR NR NR NR NR NR NR NR NR

LOD 0.4 0.1 0.2 0.2 0.2 0.1 0.1 0.1 0.174 0.2

Geometric 

mean

— 1.09 0.355 — — — 1.67 — 0.410 —

95th percentile 0.700 3.60 1.50 0.700 <LOD 0.1 8.30 0.300 1.57 0.300

2007–2008 (n=2,100) (CDC 2018)

Percent >LOD NR NR NR NR NR NR NR NR NR NR

LOD 0.4 0.082 0.2 0.2 0.2 0.1 0.1 0.1 0.174 0.2

Geometric 

mean

— 1.22 0.286 — — — 1.95 — 0.303 —

95th percentile 0.500 3.28 0.900 0.600 <LOD <LOD 9.80 <LOD 1.30 <LOD

2009–2010 (n=2,233) (CDC 2018)

Percent >LOD NR NR NR NR NR NR NR NR NR NR

LOD 0.1 0.082 0.1 0.1 0.1 0.1 0.1 0.1 0.087 0.1

Geometric 

mean

— 1.26 0.279 0.172 — — 1.66 — 0.198 —

95th percentile 0.200 3.77 0.900 0.900 <LOD <LOD 6.90 <LOD 1.00 0.100

2011–2012 (n=1,904) (CDC 2018)

Percent >LOD NR NR NR NR NR NR NR NR NR NR

LOD 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1

Geometric 

mean

— 0.881 0.199 — — — 1.28 — — —

95th percentile 0.220 2.54 0.690 0.620 0.140 <LOD 5.44 <LOD 0.690 0.110

2013–2014(n=2,168) (CDC 2018)

Percent >LOD NR NR NR NR NR NR NR NR NR NR

LOD 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1

Geometric 

mean

— 0.675 0.185 — — — 1.35 NR — NR

95th percentile 0.200 2.00 0.700 0.500 0.200 <LOD 5.60 NR 0.600 NR
PERFLUOROALKYLS 602

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collected 

in the United States

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSA

-AcOH

EtPFOSA

-AcOH

U.S. residents (Calafat et al. 2006b)

1990–2002 (n=23 

pooled samples)

Percent >LOD 0% 8.7% 0% 13% 0% — 91.3% 26.1% 13% 56.5%

LOD 0.3 0.1 0.3 0.3 1 0.3 0.2 0.6 0.4

Geometric 

mean

NA <0.3 NA <0.3 NA 1.6 <0.4 <0.6 <0.4

95th percentile NA 0.3 NA 1.3 NA 2.7 0.7 1.9 2.5

U.S. blood donors (Olsen et al. 2003b)

2000–2001 (n=645)

Percent 

>LLOQc

— — — — — — 52% 2% 40% 42%

Geometric 

mean

1.9 NR 1.3 2.0

95th percentileb 9.5 NR 5.0 7.6

Maximum 66.3 NR 16.4 60.1

U.S. blood donors (Olsen et al. 2017a, 2017b)

2006 (n=600)

Percent>LLOQ 62% 100% 99.8% 99.8% 68% 1.2% 95.7% 62.4% 1.7%

LLOQd <0.5 NR <0.05 <0.05 <0.05 <0.5 <0.5 <1.3 <1.0

Geometric 

mean

0.09 0.97 0.34 0.18 0.04 LLOQ 1.52 0.60 LLOQ

95th percentile 0.4 2.2 0.8 0.5 0.07 LLOQ 5.7 1.8 LLOQ

2010 (n=600)

Percent>LLOQ 79.7% 100% 100% 99.8% 46.2% 22.5% 95.5%

LLOQd <0.05 NR NR <0.025 <0.025 <1.0 <0.05

Geometric 

mean

0.05 0.83 0.27 0.14 0.03 LLOQ 1.34

95th percentile 0.2 2.3 0.8 0.5 0.06 0.3 5.3

2015 (n=616)

Percent>LLOQ 3.3% 100% 96.9% 47.9% 0.6% 8.4% 99.7% 0% 63.1% 8.2%

LLOQd <0.09 <0.093 <0.093 <0.466 <0.932 <0.047 <0.04 <0.093 <0.09 <0.23

Geometric 

mean

0.43 0.15 LLOQ 0.87 LLOQ 0.09 LLOQ

95th percentile 0.16 1.1 0.49 0.25 LLOQ 0.02 3.5 LLOQ 0.43 0.05
PERFLUOROALKYLS 603

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collected 

in the United States

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSA

-AcOH

EtPFOSA

-AcOH

U.S. residents (Olsen et al. 2003c)

(n=24)

Geometrice

mean

— — — — — — 1.8 3.0 — —

Minimum <1.2 <1.3

Maximum 5.9 22.1

Midwestern United States (De Silva and Mabury 2006)

2004–2005 

(n=16)

Percent 

detectede

— 100% 100% 13% 0% — — — — —

Mean 0.77 0.17 NR NA

Maximum 1.2 0.25 0.067 NA

Atlanta, Georgia (Kuklenyik et al. 2004)

2003 (n=20)

Percent >LOD 10% 100% 75% 85% 10% — 100% 75% 100% 90%

LOD 0.2 0.6 0.4

Meanb <0.3 2.6 0.7 0.8 <1 3.9 0.34 1.7 0.9

Maximum 8.5 3.9 1.2 1.4 1.6 11.2 0.7 5.2 1.4

Seattle, Washington (Olsen et al. 2004c)

(n=238)

Percent 

>LLOQc

— — — — — — 76% "Few" 65% 52%

Geometric 

mean

2.2 NR 1.2 <1.6

95th percentileb 8.3 NR 3.8 7.8

Maximum 40.3 NR 6.6 21.1

Washington County, Maryland (Olsen et al. 2005)

1974 (n=178)

Percent >LLOQ — — — — — — 63% 0% 4% 33%

LLOQ 1.4 1.0 1.6

Geometric 

mean

1.5 NA 0.5 1.2

75th percentile 2.5 NA <1.0 1.8
PERFLUOROALKYLS 604

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-22. Concentrations of Other Perfluoroalkyls in Human Serum Collected 

in the United States

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSA

-AcOH

EtPFOSA

-AcOH

1989 (n=178)

Percent >LLOQ — — — — — — 82% 0% 38% 93%

LLOQ 1.4 1.0 1.6

Geometric 

mean

2.5 NA 0.8 3.6

75th percentile 1.6 NA 1.3 4.7

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.

“—“ indicates no available data; Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; 

LLOQ = lower limit of quantification; LOD = limit of detection; Me-PFOSA-AcOH = 2-(N-methyl-perfluorooctane 

sulfonamide) acetic acid; NA = not applicable; NR = not reported; PFBuS = perfluorobutane sulfonic acid; 

PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; 

PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOSA = perfluorooctane sulfonamide; 

PFUA = perfluoroundecanoic acid

Calafat et al. (2007a, 2007b) analyzed serum levels of different subsamples of the general population 

during the 1999–2000 and 2003–2004 periods of the NHANES. The numbers of individuals included in 

the analyses for each survey period were 1,562 and 2,094, respectively. PFOA, PFOS, PFNA, and 

PFHxS were detected in 95–100% of serum samples collected during both survey periods. In an analysis 

of NHANES data from 1999 to 2008, Kato et al. (2011) found that males had significantly higher levels 

of PFOA, PFOS, and PFNA than females and that PFOS levels increased with age, especially in females. 

An upward trend of PFNA levels and a downward trend for PFHxS levels were also noted. Mean 

concentrations for PFOA, PFOS, and PFHxS declined by 10–30% in the 2003–2004 survey, while PFNA 

values doubled from 0.5 to 1.0 ng/mL. NHANES survey data from 2005–2006, 2007–2008, 2009–2010, 

2011–2012, and 2013–2014 have generally continued to show declining levels of PFOA and PFOS in 

human serum samples (CDC 2015, 2018). A dramatic difference in detection frequency was observed for 

PFOSA, Me-PFOSA-AcOH, and Et-PFOSA-AcOH, which were widely detected (91–100%) during the 

1999–2000 survey period but were present in only 3.4–27.5% of samples collected during the 2003–2004 

survey period. PFDoA and PFBuS were detected in <1% of the NHANES samples. The geometric mean 

serum concentration of PFOS has declined nearly 80% from NHANES survey years 1999–2000 to 2013–
PERFLUOROALKYLS 605

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

2014 and the geometric mean serum levels of PFOA have declined nearly 70% over the same temporal 

period. Olsen et al. (2008) reported a nearly 60% decline in PFOS blood levels when comparing data 

from 2001 to 2006 American Red Cross surveys of participants.

Levels of perfluoroalkyl compounds have been measured in indoor air, outdoor air, dust, food, surface 

water, and various consumer products. Possible exposure pathways have been proposed; however, the 

relative importance of these pathways, including their association with the accumulation of 

perfluoroalkyls in blood, 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, the primary route of exposure is expected to be ingestion of contaminated drinking water. 

Using a stratified random sample of residents in the Little Hocking Water district in Ohio between July 

2004 and February 2005, Emmett et al. (2006a) reported median serum PFOA levels of 329 ng/mL in 

residents of households with a median drinking water concentration of 3.55 ng/mL. 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 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).

A study conducted by the Minnesota Department of Health reported higher PFOA, PFHxS, and PFOS 

serum levels in residents of two communities with contaminated water supplies as compared to the 

general population (MDH 2009). Similar findings have been reported by Steenland et al. (2009a) in a 

study of residents in six water districts in the mid-Ohio Valley located near the DuPont Washington 

Works facility in Washington, West Virginia. The Minnesota Department of Health instituted a program 

to reduce levels of perfluoroalkyls in drinking water that included using granulated activated carbon 

(GAC) filters for home use in areas where private wells showed high levels of contamination and large 

GAC filters for the municipal water supplies (MDH 2009). In two Mid-Ohio Valley locations with 

PFOA-contaminated drinking water, blood serum levels of PFOA in residents declined significantly 

following the implementation of GAC filtration of the public water supply (Bartell et al. 2010). The 

Lubeck, West Virginia and Little Hocking, Ohio public water systems, which were contaminated with 

PFOA from the DuPont Washington Works facility, began GAC treatment to remove PFOA from the 
PERFLUOROALKYLS 606

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

potable water supply in 2007. The average decrease in serum PFOA levels for Lubeck, West Virginia 

residents primarily consuming public water at home (n=130) was 26% a 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 (Bartell et al. 2010).

Trudel et al. (2008) provide a thorough analysis of general population exposure to PFOS and PFOA based 

on the available information and have proposed the following possible exposure pathways: food and 

water 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 of 

impregnation spray aerosols. Other pathways proposed to be less significant included oral exposure from 

hand-to-mouth contact with clothes and upholstery, migration into food prepared with PTFE-coated 

cookware, dermal exposure from wearing treated clothes, deposition of spray droplets on skin while 

impregnating, 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 

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 from 

mill-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, inhalation 

from impregnated clothes, and dust ingestion. Relative contributions of these pathways to the total uptake 

of 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 be 

through food and drinking water (PFOA and PFOS) and ingestion of house dust (PFOA only).

Based on these 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 and 
PERFLUOROALKYLS 607

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

approximately 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.

Fromme et al. (2009) assessed human exposure to perfluoroalkyls for adults in the general population of 

western countries. Based on measured in indoor and outdoor air, house dust, drinking water, and dietary 

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 to 

perfluoroalkyls (Fromme et al. 2007a, 2007b, 2009). The geometric mean adult daily intakes for PFOA 

and PFOS were estimated as 92.6 and 83.3 ng/day, respectively, for residents in Kansai, Japan and 

53.7 and 63.8 ng/day, respectively, for residents in Tohoku, Japan (Harada and Koizumi 2009). The most 

important exposure pathway for both compounds was food ingestion.

Limited monitoring data are available for PFBA. Monitoring efforts conducted in Washington County, 

Minnesota near the 3M Cottage Grove Facility revealed widespread contamination of this substance in the 

groundwater of that area in 2006. This compound has since also been detected along with PFOA, PFOS, 

PFHxS, and PFBuS in municipal drinking water in Washington County (ATSDR 2008). 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. Landsteiner et al. (2014) conducted a 

biomonitoring study of 196 residents of Washington County, Minnesota for the presence of 

perfluoroalkyls. The residents of this area were suspected to have been exposed to perfluoroalkyls from 

drinking water sources. PFOA, PFOS, and PFHxS were detected in all serum samples collected from the 

196 residents, while PFBA and PFBuS were detected in 28 and 23% of the samples, respectively. The 

geometric mean serum concentrations of PFOA, PFOS, and PFHxS were 15.4, 35.9, and 8.4 ng/mL, 

respectively, which are several times greater than the levels of the U.S. general population when 

compared to NHANES survey results shown in Tables 5-21 and 5-22. The authors also 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. 
PERFLUOROALKYLS 608

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Another possible source for perfluoroalkyls in human blood is through uptake of precursor compounds 

and then conversion of these within the human body (Trudel et al. 2008). For example, Me-PFOSAAcOH and Et-PFOSA-AcOH are the oxidation products of 2-(N-methyl-perfluorooctane sulfonamido) 

ethanol and 2-(N-ethyl-perfluorooctane sulfonamido) ethanol, which were used in surface treatment 

applications (Calafat et al. 2006a). Concentrations of Me- and Et-PFOSA-AcOH measured in human 

serum may have resulted from exposure of individuals to these perfluoroalkyl sulfonamido ethanols and 

then conversion of the ethanols to the perfluoroalkyl sulfonamido acetates within the body.

Levels of perfluoroalkyl compounds measured in the blood of occupationally exposed individuals are 

listed in Table 5-23. 3M estimated doses for various on-site exposure scenarios based on monitoring 

information collected at the Decatur Facility in Alabama (3M 2008c). Occupational exposure scenarios 

included groundskeeper/maintenance worker and construction/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 estimated exposure corresponding to construction/utility 

workers engaged in projects involving contact with soil from an on-site field. Individuals who performed 

jobs that require frequent contact with perfluoroalkyl containing products, such as firefighters, waste 

handlers, and individuals who install and treat carpets, were also expected to have occupational exposure 

to these substances (Emmett et al. 2006a). However, Emmett et al. (2006a) determined that levels of 

PFOA in the serum of these types of individuals were only slightly higher than the non-occupational 

exposure group (388 ng/mL compared to 329 ng/mL, respectively) while serum levels in workers at a 

fluoropolymer manufacturing facility were much higher (775 ng/mL).

Table 5-23. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for 

Occupationally Exposed Individuals

Location

Mean concentration (μg/mL [ppm])

PFOA PFOS PFHxS Reference

Decatur, Alabama

1993 (n=111) 0.00–80.00 (range) — — Olsen et al. 1998b

1995 (n=80) 0.00–114.10 (range) — — Olsen et al. 1998b

1995 (n=90) — 2.44 — Olsen et al. 1999

1997 (n=84) — 1.96 — Olsen et al. 1999

2000 (n=215) 11.90 1.40 — Olsen et al. 2003a

1999–2004 (n=26)a Olsen et al. 2007a

Initial 0.691 0.799 0.290 

Final 0.262 0.403 1.85
PERFLUOROALKYLS 609

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-23. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for 

Occupationally Exposed Individuals

Location

Mean concentration (μg/mL [ppm])

PFOA PFOS PFHxS Reference

Cottage Grove, Minnesota

1993 (n=111) 5.0 — — Olsen et al. 2000

1995 (n=80) 6.8 — — Olsen et al. 2000

1997 (n=74) 6.4 — — Olsen et al. 2000

2000 (n=122) 4.63 0.86 — Olsen and Zobel 

2007

Washington Works, Little Hocking, Ohio

2004–2005 Emmett et al. 2006a

Substantial occupational 

exposure (n=18)

0.824 — —

Antwerp, Belgium

1995 (n=88) — 1.93 — Olsen et al. 1999

1997 (n=65) — 1.48 — Olsen et al. 1999

2000 (n=206) 1.03 0.96 — Olsen et al. 2003a

Miteni, Trissino, Italy

2007

Current occupational exposure 

(n=39)

5.71c (0.20–47.04) — — Costa et al. 2009

Former occupational exposure 

(n=11)

4.43c (0.53–18.66) — — Costa et al. 2009

2000 (n=25) 18.8 — — Costa et al. 2009

2001 (n=42) 19.7 — — Costa et al. 2009

2002 (n=46) 19.3 — — Costa et al. 2009

2003 (n=41) 13.7 — — Costa et al. 2009

2004 (n=34) 11.4 — — Costa et al. 2009

2006 (n=49) 10.8 — — Costa et al. 2009

2007 (n=50) 11.6 — — Costa et al. 2009
PERFLUOROALKYLS 610

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-23. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for 

Occupationally Exposed Individuals

Location

Mean concentration (μg/mL [ppm])

PFOA PFOS PFHxS Reference

Washington Works

2004

Current occupational exposure 

(n=259)

0.494 (median) — — Sakr et al. 2007b

Intermittent current 

occupational exposure (n=160)

0.176 (median) — — Sakr et al. 2007b

Past occupational exposure 

(n=264)

0.195 (median) — — Sakr et al. 2007b

No occupational exposure 

(n=342)

0.114 (median) — — Sakr et al. 2007b

aData include results from three retirees from the 3M plant in Cottage Grove, Minnesota.

“—“ indicates no available data; PFHxS = perfluorohexane sulfonic acid; PFOA = perfluorooctanoic acid; PFOS = 

perfluorooctane sulfonic acid

Fu et al. (2014b) analyzed the effects of sex and age on levels of perfluoroalkyl compounds in a study of 

133 (79 male, 54 female) participants. In general, higher levels of PFOA, PFOS, PFNA, and PFDeA 

were observed in male subjects; however, differences were only statistically significant for PFOA and 

PFDeA. Sex differences in other perfluoroalkyl compounds were not observed. For both male and 

female subjects, increasing levels of PFOA, PFNA, and PFOS were positively correlated with increasing 

age. Data from the 2005–2012 NHANES survey were used to derive a regression-based model to 

estimate serum levels of total perfluoroalkyl residues in the human population using only age, sex, and 

PFOA and PFOS levels (Jain 2015). Although the data used in the regression-based model were derived 

from the U.S. population, the author expected that the data could be used to estimate exposures to 

populations elsewhere in the world as well.

Christensen et al. (2016) conducted a biomonitoring study of perfluoroalkyls on male fishermen from 

Wisconsin ≥50 years old with a history of sport fish consumption. Increasing age and lower BMI were 

generally associated with higher levels of the perfluoroalkyls; however, there were only weak correlations 

observed between amounts of fish consumption and perfluoroalkyl levels, with the exception of PFDeA. 

Levels of PFOA, PFNA, and PFHxS 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 PFDeA were approximately 2 times greater in the anglers as compared to the NHANES survey 

subgroup. The median and 95th percentile concentrations of PFOS in the anglers were 19.00 and 
PERFLUOROALKYLS 611

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 PFDeA 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.

Perfluoroalkyl compounds have been detected in childhood serum samples, human breast milk, and 

umbilical cord blood; reported concentrations are listed in Tables 5-24 and 5-25. Measurements of 

perfluoroalkyl compounds in amniotic fluid, meconium, neonatal blood, or other tissues have not been 

located.

Table 5-24. Percent Detection and Levels of PFOA and PFOS in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Location

Detection and concentration (ng/mL 

[ppb])a

PFOA PFOS Reference

Serum

U.S. adolescents—NHANES (ages 12–19)

1999–2000 (n=543) Calafat et al. 2007a

Percent >LOD 100% 100%

LOD 0.1 0.2

Geometric mean 5.5 29.1

95th percentile 11.2 56.8

2003–2004 (n=640) Calafat et al. 2007b

Percent >LOD 99.7%b 99.9%b

LOD 0.1 0.4

Geometric mean 3.9 19.3

95th percentile 8.6 42.2

2005–2006 (n=640) CDC 2018

Percent >LOD NR NR

LOD 0.1 0.2

Geometric mean 3.59 15.0

95th percentile 8.40 38.5

2007–2009 (n=357) CDC 2018

Percent >LOD NR NR

LOD 0.1 0.2

Geometric mean 3.91 11.3

95th percentile 7.30 28.0
PERFLUOROALKYLS 612

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-24. Percent Detection and Levels of PFOA and PFOS in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Location

Detection and concentration (ng/mL 

[ppb])a

PFOA PFOS Reference

2009–2010 (n=364) CDC 2013

Percent >LOD NR NR

LOD 0.1 0.2

Geometric mean 2.74 6.84

95th percentile 5.00 18.1

2011–2012 (n=344) CDC 2018

Percent >LOD NR NR

LOD 0.1 0.2

Geometric mean 1.80 4.16

95th percentile 3.59 10.8

2013–2014 (n=401) CDC 2018

Percent >LOD NR NR

LOD 0.1 0.2

Geometric mean 1.66 3.54

95th percentile 3.47 9.30

U.S. children—NHANES 2013-2014

Ages 3-5 (n=181)

Percent >LOD 100% 100% Ye et al. 2018a; CDC 

2018 LOD 0.1 0.1

Geometric mean 2.00 3.38

95th percentile 5.58 8.82

Ages 6-11 (n=458)

Percent >LOD 100% 100% Ye et al. 2018a; CDC 

2018 LOD 0.1 0.1

Geometric mean 1.89 4.15

95th percentile 3.84 12.4

U.S. girls (ages 6–8) 

Cincinnati, Ohio (n=353)

Percent >LODc 99.7% 99.7% Pinney et al. 2014

Geometric mean 7.8 13.2

Median 7.3 13.6

U.S. girls (ages 6–8)

San Francisco, California (n=351)

Percent >LODc 100% 100% Pinney et al. 2014

Geometric mean 5.7 13.2

Median 5.8 12.5
PERFLUOROALKYLS 613

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-24. Percent Detection and Levels of PFOA and PFOS in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Location

Detection and concentration (ng/mL 

[ppb])a

PFOA PFOS Reference

U.S. children (ages 2–12)

1994–1995 (n=598) Olsen et al. 2004b 

Percent >LLOQc 96% 100%

Geometric mean 4.9 37.5

95th percentiled 10 89

U.S. children (West Virginia

and Ohio; ages 1–19)

Mondal et al. 2012

2005–2006 (n=4,943)

Geometric mean 31.2 19.2

90th percentile 201 36.8

U.S. children NHANES 2001–

2002 (ages 6–11)

Kato et al. 2009b

2001–2002 (n=936)

Least square mean 6.1–7.6 30.45–42.45

Umbilical cord blood

San Francisco, California Morello-Frosch et al. 

2016

Percent >LODc 56% 100%

Geometric mean – 2.27

95th percentile 1.68 4.35

Baltimore THREE Study Apelberg et al. 

2007a, 2007b

Cord serum (n=299)

Percent >LOD 100% 99%

LOD 0.1–0.2 0.2

Geometric mean 1.6 4.9

Minimum 0.3 <0.2

Maximum 7.1 34.8

Maternal serum (n=293)

Median 1.4–1.6 4.1–5.0

Germany Midasch et al. 2007

Cord plasma (n=11)

Percent detected 100% 100%

LOQ 0.5 0.5

Median 3.4 7.3
PERFLUOROALKYLS 614

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-24. Percent Detection and Levels of PFOA and PFOS in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Location

Detection and concentration (ng/mL 

[ppb])a

PFOA PFOS Reference

Maternal plasma (n=11)

Percent detected 100% 100%

LOQ 0.5 0.5

Median 2.6 13.0

Danish National Birth Cohort Fei et al. 2007

Cord blood (n=50)

Percent >LLOQ 98% 100%

LLOQ 1.0 1.0

Mean 3.7 11.0

Maternal blood (n=200)

Percent >LLOQ 98% 100%

LLOQ 1.0 1.0

Mean 4.5 29.9

Japan Inoue et al. 2004

Cord serum (n=15)

Percent >LOD 0% 100%

LOD 0.5 0.5

Range 1.6–5.3

Maternal serum (n=15)

Percent >LOD 20% 100%

LOD 0.5 0.5

Range 0.5–2.3 4.9–17.6

Breast milk

Massachusetts (n=45) Tao et al. 2008

Milk

Percent >LOQc 89% 96%

Median 0.0361 0.106

Minimum <0.0301 <0.032

Maximum 0.161 0.617

Sweden (n=12) Kärrman et al. 2007

Milk

Percent >LOD 8%d 100%

LOD 0.01 0.005

Mean – 0.201

Range <0.209–0.492 0.060–0.470
PERFLUOROALKYLS 615

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-24. Percent Detection and Levels of PFOA and PFOS in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Location

Detection and concentration (ng/mL 

[ppb])a

PFOA PFOS Reference

Maternal serum

Percent >LOD 100% 100%

LOD 0.01 0.005

Mean 3.8 20.7

Range 2.4–5.3 8.2–48.0

China (n=19) So et al. 2006b

Percent >LOD 100% 100%

LOD 0.021–0.027 0.001–0.0036

Range 0.047–0.210 0.045–0.360

Germany/Hungary (n=70) Völkel et al. 2008

Percent >LOQ 16% 100%

Minimum <0.200 0.028

Maximum 0.460 0.639

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 the 2003–2004 NHANES samples. 

Percentages listed here are for the total sample population.

cLOD or LLOQ not reported. dReported as bias-corrected estimates.

“—“ indicates no available data; LLOQ = lower limit of quantification; LOD = limit of detection; LOQ = limit of 

quantification; NR = not reported; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid
PERFLUOROALKYLS 616

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-25. Percent Detection and Levels of Other Perfluoroalkyls in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSAAcOHEtPFOSAAcOH

Serum

U.S. NHANES (ages 12–19)

1999–2000 (n=543) (Calafat et al. 2007a)

Percent 

>LOD

10%b 96% 15% 12%b <1%b — 100% 100% 100% 98%

Geometric 

mean

— 0.5 <0.2 — — — 2.7 0.4 1.3 0.8

95th 

percentile

— 1.1 0.5 — — — 12.9 1.5 3.7 2.4

2003–2004 (n=640) (Calafat et al. 2007b)

Percent 

>LOD

6.2%b 98.8%b 31.3%b 9.7%b <0.1%b <0.4%b 98.3%a 22.2%b 27.5%b 3.4%b

Geometric 

mean

<0.3 0.9 <0.3 <0.3 <1.0 <0.4 2.4 <0.2 <0.6 <0.4

95th 

percentile

0.5 2.7 0.7 <0.3 <1.0 <0.4 13.1 0.3 1.4 <0.4

2005–2006 (n=640) (CDC 2018)

Percent 

>LOD

NR NR NR NR NR NR NR NR NR NR

Geometric 

mean

— 0.929 0.295 — — — 2.09 — 0.432 —

95th 

percentile

1.10 2.70 0.800 0.500 <LOD 0.100 14.1 0.300 1.48 0.200

2007–2008 (n=357) (CDC 2018)

Percent 

>LOD

NR NR NR NR NR NR NR NR NR NR

Geometric 

mean

— 1.16 0.231 — — — 2.40 — 0.340 —

95th 

percentile

0.600 2.54 0.800 0.300 <LOD <LOD 15.9 0.300 1.60 <LOD

2009–2010 (n=364) (CDC 2018)

Percent 

>LOD

NR NR NR NR NR NR NR NR NR NR

Geometric 

mean

— 1.10 0.220 — — — 2.03 — 0.235 —

95th 

percentile

0.400 2.62 0.600 0.400 <LOD <LOD 12.3 <LOD 0.900 <LOD

2011–2012 (n=344) (CDC 2018)

Percent 

>LOD

NR NR NR NR NR NR NR NR NR NR

Geometric 

mean

— 0.741 0.146 — — — 1.28 — 0.134 —
PERFLUOROALKYLS 617

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-25. Percent Detection and Levels of Other Perfluoroalkyls in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSAAcOHEtPFOSAAcOH

95th 

percentile

0.190 2.06 0.360 0.250 <LOD <LOD 6.45 <LOD 0.510 <LOD

2013–2014 (n=402) (CDC 2018)

Percent 

>LOD

NR NR NR NR NR NR NR NR NR NR

Geometric 

mean

— 0.599 0.136 — — — 1.27 — — NR

95th 

percentile

0.200 2.00 0.400 0.200 0.200 <LOD 6.30 <LOD 0.600 NR

2013-2014 

Ages 3–5 (n=181) (Ye et al. 2018a, 2018b; CDC 2018)

Percent 

>LOD

27% 100% 50% 27% 0% 1% 100% 7% 51% 4%

LOD 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1

Geometric 

mean

<LOD 0.764 <LOD <LOD <LOD <LOD 0.715 <LOD <LOD <LOD

95th 

percentile

0.310 3.49 0.370 0.370 <LOD <LOD 1.62 0.110 1.02 <LOD

Ages 6–11 (n=458) (Ye et al. 2018a, 2018b; CDC 2018)

Percent 

>LOD

15% 100% 46% 28% 0% 7% 100% 2% 54% 3%

LOD 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1

Geometric 

mean

<LOD 0.809 <LOD <LOD <LOD <LOD 0.913 <LOD <LOD <LOD

95th 

percentile

0.170 3.19 0.350 0.250 <LOD 0.130 4.14 <LOD 0.940 <LOD
PERFLUOROALKYLS 618

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-25. Percent Detection and Levels of Other Perfluoroalkyls in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSAAcOHEtPFOSAAcOH

U.S. children (ages 2–12)

1994–1995 (n=598) (Olsen et al. 2004b)

Percent 

>LLOQ

— — — — — — 78% 14% 67% 81%

LLOQ NR 1.0 NR NR

Geometric 

mean

— — — — — — 4.5 <2.0 1.9 3.3

95th 

percentileb

— — — — — — 65 <2.0 12 10

U.S. girls (ages 6–8)

Cincinnati, Ohio (Pinney et al. 2014)

Percent

>LODc

— 99.9 75.8 — — — 99.7 19 94.9 14.4%

Geometric 

mean

— 1.4 0.3 — — — 5.1 <LOD 0.7 <LOD

Median — 1.4 0.3 — — — 5.2 <LOD 0.7 <LOD

U.S. girls (ages 6–8)

San Francisco, California (Pinney et al. 2014)

Percent 

>LODc

— 100 78.7 — — — 100 10 96.3 14.8

Geometric 

mean

— 1.7 0.3 — — — 3.0 <LOD 0.7 <LOD

Median — 1.6 0.3 — — — 2.3 <LOD 0.6 <LOD

Umbilical cord 

blood

San Francisco, California (Morello-Frosch et al. 2016) (n=65) 

Percent 

>LODc

56% 97% 9% 84% 0% 25% — 91% 95% 63%

Geometric 

mean

— 0.29 — 0.03 — — — 0.02 0.07 0.02

95th 

percentile

0.23 0.93 0.49 0.16 — 0.03 — 0.10 0.38 0.05

Baltimore THREE Study (Apelberg et al. 2007a, 2007b)

Cord serum (n=299)

Percent 

>LOD

2% — 24% 34% 5% 3% — 26% 40% 1%

LOD 0.4 0.2 0.2 0.2 0.1 0.05 0.2 0.2

Minimum <0.4 — <0.2 <0.2 <0.2 <0.1 — <0.05 <0.2 <0.2

Maximum 2.6 — 1.1 1.9 1.7 0.2 — 0.8 1.8 0.5
PERFLUOROALKYLS 619

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-25. Percent Detection and Levels of Other Perfluoroalkyls in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSAAcOHEtPFOSAAcOH

Japan (Inoue et al. 2004)

Cord serum (n=15)

Percent 

>LOD 

— — — — — — — 0% — —

LOD 1.0 

Maternal serum 

(n=15)

Percent 

>LOD

— — — — — — — 0% — —

LOD 1.0

Breast milk

Massachusetts (n=45) (Tao et al. 2008b)

Milk

Percent 

>LOQc

<1% 64% <1% <1% <1% <1% 51% — — —

Minimum <0.010 <0.0052 <0.00772 <0.00499 <0.00440 <0.0100 <0.0120 — — —

Maximum 0.0234 0.0184 0.0111 0.00884 0.00974 0.0198 63.8 — — —

Sweden (n=12) (Kärrman et al. 2007a)

Milk

Percent 

>LOD

— 17% 0% 0% — — 100% 67% — —

LOD 0.005 0.008 0.005 0.01 0.007

Mean — 0.017 — — 0.085 0.013 — —

Range — <0.005–

0.020

— — 0.031–

0.172

<0.007–

0.030

— —

Maternal 

serum

Percent 

>LOD

— 100% 100% 100% — — 100% 75% — —

LOD 0.005 0.008 0.005 0.01 0.007 — —

Mean 0.80 0.53 0.40 4.7 0.24

Range — 0.43–

2.5

0.27–1.8 0.20–1.5 — — 1.8–

11.8

0.16–

0.19

— —
PERFLUOROALKYLS 620

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Table 5-25. Percent Detection and Levels of Other Perfluoroalkyls in Children’s 

Serum, Umbilical Cord Blood, and Breast Milk

Sample 

population

Detection and concentration (ng/mL [ppb])a

PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA

MePFOSAAcOHEtPFOSAAcOH

China (n=19) (So et al. 2006b)

Percent 

>LOD

37% 100% 100% 100% — 11% 100% — — —

LOD 0.005–

0.010

0.001–

0.010

0.0011–

0.0025

0.0022–

0.0050

0.001–

0.005

0.001–

0.010

Range <0.005–

0.0067

0.01–

0.062

0.0038–

0.011

0.0091–

0.056

— <0.001–

0.0025

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.

bPercent detection for the adolescent age group was not specified for these samples. Percentages listed here are 

for the total sample population.

cLOD or LLOQ not reported.

“—“ indicates no available data; Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; 

LLOQ = lower limit of quantification; LOD = limit of detection; Me-PFOSA-AcOH = 2-(N-methyl-perfluorooctane 

sulfonamide) acetic acid; ND = no data; NR = not reported; PFBuS = perfluorobutane sulfonic acid; 

PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; 

PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOSA = perfluorooctane sulfonamide; 

PFUA = perfluoroundecanoic acid

A few studies are available that reported serum levels of perfluoroalkyls measured in children. Calafat et 

al. (2007a, 2007b) reported perfluoroalkyl serum concentrations measured in 543–640 adolescents who 

made up the 12–19-year-old age subpopulation in the 1999–2000 and 2003–2004 NHANES surveys. 

Olsen et al. (2003a) measured PFOA, PFOS, PFHxS, PFOSA, Me-PFOSA-AcOH, and Et-PFOSA-AcOH 

in the serum of 598 children of ages 2–12 years from various locations in the United States who were 

diagnosed with group A streptococcal infections. Mean serum concentrations of perfluoroalkyl 

compounds measured in children from these studies are similar to mean concentrations reported for adults 

(Calafat et al. 2007a, 2007b; Olsen et al. 2003a). For example, geometric mean concentrations of PFOA 

and PFOS measured during the NHANES surveys were 3.9–5.5 and 19.3–29.1 ng/mL, respectively, in 

adolescent serum and 3.9–5.2 and 20.7–30.4 ng/mL, respectively, in serum of the total population. 

Emmett et al. (2006a) found that 2–5-year-old children had a higher serum PFOA (median 600 ng/mL) in 

the Little Hocking Water Association district 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 
PERFLUOROALKYLS 621

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

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 transplacental and breast milk exposures could also contribute to levels in children.

Kato et al. (2009b) reported serum levels in children aged 3–5 and 6–11 years from the 2001–2002 

NHANES survey for PFNA, PFOA, PFOS, and PFOSA. The highest levels were typically observed for 

PFOS. The least square mean (LSM is equivalent to arithmetic mean) serum concentrations for PFOS 

ranged from 30.45 ng/mL for Mexican Americans to 42.45 ng/mL for non-Hispanic whites aged 6–

11 years (Kato et al. 2009b). The LSM for PFOA ranged from 6.1 ng/mL for Mexican Americans to 

7.6 ng/mL for non-Hispanic whites aged 6–11 years. Among 3–5 year olds, specific data from pooled 

samples were only presented for PFNA. The LSM serum PFNA serum concentrations for this age group 

were 0.9, 1.2, and 0.6 ng/mL for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans, 

respectively (Kato et al. 2009b).

Blood serum levels of PFOA, PFOS, and PFHxS obtained in 2006–2007 from children residing in 

Australia were reported by Toms et al. (2009). The highest levels tended to occur for PFOS. Mean PFOS 

serum levels (combined male and female) ranged from 7.0 ng/mL for infants 0–0.5 years of age to 

18.3 ng/mL for 6–9 year olds, while mean PFOA serum levels ranged from 4.5 ng/mL for infants 0–

0.5 years of age to 8.2 ng/mL for 6–9 year olds. Mean serum PFHxS levels ranged from 0.9 ng/mL for 

infants 0–0.5 years of age to 5.8 ng/mL for 6–9 year olds (Toms et al. 2009).

Although mean serum concentrations of perfluoroalkyl compounds are reported to be similar for older 

children (12–19 years of age) and adults, estimated 95th percentile values of PFHxS measured in 

childhood serum were noted to be higher than values estimated for adults. Olsen et al. (2003a) 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 645 U.S. adult blood donors and 238 elderly individuals from the Seattle, 

Washington area, respectively (Olsen et al. 2003b, 2004b, 2004c). 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. Olsen et al. (2004b) also noted statistically 

higher levels of Me-PFOSA-AcOH measured in children citing estimated 95th percentile values of 12.0, 

5.0, and 3.8 ng/mL for serum concentrations of this substance measured in children, adult donors, and 

elderly individuals, respectively (Olsen et al. 2003b, 2004b, 2004c).
PERFLUOROALKYLS 622

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

Reasons for the observed differences of PFHxS and Me-PFOSA-AcOH levels in childhood serum 

samples compared to adult samples have not been determined. Olsen et al. (2004b) stated that different 

exposure and activity patters 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).

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-mouth 

transfer 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 food 

consumption 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 body 

weight/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) were 

approximately the same as for adults.

Tao et al. (2008b) measured perfluoroalkyl concentrations in 45 human breast milk samples collected 

from Massachusetts. PFOS, PFOA, PFHxS, and PFNA were each detected in 96, 89, 51, and 64% of the 

samples, respectively, with median concentrations of 106, 36.1, 12.1, and 6.97 pg/mL, respectively. 

PFHpA, PFDeA, PFUA, PFDoA, and PFBuS 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 concentrations 

of 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, PFDeA, PFUA, PFBuS, 

PFHxS, and PFOSA. Maximum concentrations of these compounds were reported to be <0.18 ng/mL

(Kärrman et al. 2007).
PERFLUOROALKYLS 623

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

The presence of perfluoroalkyl compounds in umbilical cord blood indicates that these substances can 

cross the placental 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 

in 99–100% of umbilical cord blood samples with reported concentrations were 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; 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 three mothers. Apelberg 

et al. (2007a) also reported concentrations of other perfluoroalkyl compounds measured in 299 cord 

serum samples collected during the Baltimore THREE Study. Of these compounds, PFDeA, PFUA, 

PFOSA, and Me-PFOSA-AcOH were detected most frequently (24, 34, 26, and 40%, respectively). 

Maximum concentrations in these samples ranged from 1.1 to 1.9 ng/mL. PFHpA, PFDoA, PFBuS, and 

Et-PFOSA-AcOH 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 presence of perfluoroalkyls. A positive correlation was found 

between maternal plasma and maternal serum with cord 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, in maternal 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 levels of 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 PFDeA 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 the levels 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.

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. These populations 
PERFLUOROALKYLS 624

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

may have higher exposure to perfluoroalkyl compounds than the general population based on elevated 

concentrations of these substances measured in air, soil, sediment, surface water, groundwater, and 

vegetation surrounding these facilities (3M 2007b, 2008b, 2008c; Barton et al. 2006; Davis et al. 2007; 

Olsen 2015). 

A number of studies have evaluated serum perfluoroalkyl levels in former workers at 3M and DuPont 

PFOA and/or PFOS facilities in the United States. At the 3M Cottage Grove facility, the geometric mean 

serum PFOA level was 5,200 ng/mL in PFOA production workers and the PFOS level was 1,760 ng/mL 

in PFOS production workers in 2000 (Olsen 2015). At another 3M facility in Decatur, geometric mean 

serum PFOA, PFOS, and PFHxS levels were 910, 1,130, and 180 ng/mL, respectively (Olsen 2015). The 

estimated mean serum PFOA level at DuPont’s Washington Works facility was 2,050 ng/mL for all 

workers (Woskie et al. 2012)

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, PFBuS, PFNA, and PFHxS have been detected in the municipal 

drinking water and private 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 

exposure for individuals living in the Little Hocking community (near DuPont's Washington Works 

facility) and concluded 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. In residents with residential drinking water but without occupational 

exposure, the model of best-fit for serum PFOA also varied significantly by age (highest in children 

≤5 years old and adults >60 years old), use of carbon home water filters (negative effect), number of 

servings of home-grown fruits and vegetables (positive effect), and number of tap water-based drinks per 

day (positive effect). 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 median concentration ranged from 10.5 to 33.7 ng/mL for residents who previously worked or 

resided in these districts (Steenland et al. 2009a). PFOA serum levels tended to be highest for children 

aged 0–9 years and persons >50 years old. These authors also reported that 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). The serum levels of the 69,030 residents participating in this 
PERFLUOROALKYLS 625

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

study categorized by age are provided in Table 5-26. 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 are available from the EPA docket on PFOA and 

related perfluoroalkyls (EPA-HQ-OPPT-2003-0012) (Bilott 2004, 2005a, 2005b, 2007).

Table 5-26. 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 4,915 (7.1) 32.8

10–19 9,658 (14.0) 26.6

20–29 10,073 (14.6) 21.0

30–39 10,547 (15.3) 22.7

40–49 12,113 (17.6) 28.0

50–59 10,515 (15.2) 33.6

60–69 6,881 (10) 42.9

≥70 4,328 (6.3) 40.1

Source: Steenland et al. 2009a

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 of five of the 

substances were lower or similar to levels of the general population when compared to the NHANES 

results. Residents who used the West Morgan/East Lawrence public water supply had significantly 

higher geometric mean serum levels of two substances (PFOA and PFHxS) as compared to the geometric 

mean for a similar demographic group from the NHANES survey. Serum levels in the residents for all 

eight compounds were shown to be much lower than levels found in occupationally exposed individuals 

who regularly worked with these substances (ATSDR 2013). 

Residents of Arnsberg, Germany who were exposed to perfluoroalkyls from contaminated drinking water 

had serum PFOA levels that were 4.5–8.3 times greater than those from a non-exposed reference 

population depending upon the age and sex of the groups (Hölzer et al. 2008).

Shin et al. (2011) provided PFOA exposure data on 45,276 non-occupationally exposed individuals 

residing in eastern Ohio and West Virginia who were exposed to PFOA via drinking water. The median 

serum concentration for all subjects was 24.3 ng/mL (ppb) measured in 2005–2006. This was about 
PERFLUOROALKYLS 626

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

6 times greater than the median concentration (3.20 ng/mL) of 2,120 residents of the general population 

taken from the NHANES data for 2005–2006 (CDC 2018).

Individuals involved in activities with prolonged use of perfluoroalkyl-containing products, such as the 

application of protective coatings for fabrics and carpet and the use of paper coatings or ski wax, may 

have higher levels of exposure to perfluoroalkyl compounds than the general population (Calafat et al. 

2006a; Olsen 2015). Elevated serum levels of PFOA, PFNA, PFHxA, PFHpA, PFDeA, and PFUA have 

been found in professional ski waxers using products containing fluorotelomers; the perfluoroalkyls were 

likely formed via fluorotelomer metabolism (Olsen 2015). Some firefighting foams contain 

perfluoroalkyls, and firefighters who use these products have been shown 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, PFDeA 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 the geometric mean (0.90 ng/mL compared to 

0.30 ng/mL). In a small-scale study of 37 firefighters participating 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 male participants with other jobs (Jin et al. 2011). 

Geometric mean PFOA and PFHxS levels were 37.59 and 4.77 ng/mL, respectively, in the firefighters 

and 31.59 and 3.62 ng/mL, respectively, in the other 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 of Australia and Canada, while PFOS levels in the firefighters were 

approximately 6–10 times greater than the general population of these nations.

3M estimated doses for various off-site exposure scenarios based on monitoring information collected at 

the Decatur Facility in Alabama (3M 2008c). Exposure scenarios include local children and adult 

residents 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 
PERFLUOROALKYLS 627

5. POTENTIAL FOR HUMAN EXPOSURE

***DRAFT FOR PUBLIC COMMENT***

corresponding to children whose source of drinking water was groundwater adjacent to the southern side 

of the facility.
PERFLUOROALKYLS 628

***DRAFT FOR PUBLIC COMMENT***

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 of 

research designed to determine the adverse health effects (and techniques for developing methods to 

determine such health effects) of perfluoroalkyls.

Data needs are defined as substance-specific informational needs that, if met, would reduce the 

uncertainties of human health risk assessment. This definition should not be interpreted to mean that all 

data 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 the 

health effects of perfluoroalkyls. The number of human and animal studies examining each endpoint is 

indicated 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 other 

perfluoroalkyls come from epidemiology studies in humans; oral exposure is the assumed route of 

exposure for the epidemiology studies. The epidemiology database consists of health evaluations of 

subjects 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

examined in the epidemiology studies were developmental, hepatic, reproductive, and immunological 

effects. 
PERFLUOROALKYLS 629

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

Figure 6-1. Summary of Existing Health Effects Studies on PFOA By Route and 

Endpoint*

Potential body weight, hepatic, and developmental effects were the most studied 

endpoints

The majority of the studies examined oral exposure in humans (versus animals) 

*In this figure, the number of human studies is referring to the number of publications; a “—“ indicates that no studies 

are available.
PERFLUOROALKYLS 630

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

Figure 6-2. Summary of Existing Health Effects Studies on PFOS By Route and 

Endpoint*

Potential developmental, hepatic, reproductive, and body weight effects were the most 

studied endpoints

The studies examined oral exposure in humans (versus animals) 

*Oral exposure was the presumed route of exposure for epidemiology studies; in this figure, the number of human 

studies is referring to the number of publications. 
PERFLUOROALKYLS 631

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

Figure 6-3. Summary of Existing Health Effects Studies on Other Perfluoroalkyls 

By Route and Endpoint* 

Potential body weight, hepatic, and developmental effects were the most studied 

endpoints

The majority of the studies examined oral exposure in humans (versus animals)

*In this figure, the number of human studies is referring to the number of publications; a “—“ indicates that no studies 

are available. Includes data for PFBA, PFHxA, PFHpA, PFNA, PFDeA, PFUA, PFBuS, PFHxS, PFDoA, PFOSA, MePFOSA-AcOH, and Et-PFOSA-AcOH.
PERFLUOROALKYLS 632

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

Studies in laboratory animals have primarily been conducted using oral exposure. Most of the 

information regarding the effects of perfluoroalkyl compounds 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 other 

perfluoroalkyls covered in this profile is limited to acute-duration oral studies with PFNA, PFDeA, 

PFBA, PFDoA, and PFOSA; intermediate-duration oral studies with PFHxS, PFNA, PFUA, PFBuS, 

PFBA, PFDoA, and PFHxA; and a chronic-duration oral study with PFHxA. An acute-durationinhalation 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 and 

the lack of PBPK model parameters that could be used to predict serum levels. The inhalation database 

for 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 other 

perfluoroalkyl compounds. 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 evaluated potential sensitive targets of acute toxicity for PFNA and PFDeA. However, 

toxicokinetic differences between humans and laboratory animals, particularly the relative short half-life 

in rodents compared to humans, preclude derivation of an acute MRL for these compounds. For other 

perfluoroalkyls (PFHxS, PFBA, PFDoA, PFOSA), the available studies were not considered adequate for 

identification of critical targets; did not examine sensitive targets that were identified for other 

perfluoroalkyl compounds, such as developmental and immunological endpoints; or involved a single 

exposure. No acute oral data were identified for PFUA, PFHpA, or PFBuS. Research is needed to 

develop a PBPK model that would allow for extrapolation from rodents to humans. Additionally, toxicity 
PERFLUOROALKYLS 633

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

studies are needed for most perfluoroalkyl compounds to identify critical targets of toxicity and/or 

establish dose-response relationships. These studies should examine developmental and reproductive 

endpoints that have been established as the most sensitive targets of toxicity for PFOA and PFOS.

Intermediate-Duration MRLs. No intermediate-duration inhalation studies were identified for 

perfluoroalkyl compounds. 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 

perfluoroalkyl compounds 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. The 

intermediate-duration oral databases were considered adequate for derivation of provisional MRLs for 

PFOA and PFOS. A modifying factor was used for PFOS due to the lack of PBPK modeling parameters 

that would allow for predicting steady-state serum PFOS levels for immunotoxicity studies in laboratory 

animals. Provisional 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 PFUA, PFBuS, PFBA, or PFDoA due 

to the lack of studies examining potential sensitive targets (developmental and/or immune effects). No 

intermediate-duration oral studies are available for PFDeA, PFHpA, or PFOSA. Intermediate-duration 

oral studies are needed for these 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 human equivalent doses (HEDs). 

Chronic-Duration MRLs. The lack of chronic-duration inhalation studies for perfluoroalkyl 

compounds precluded derivation of chronic MRLs. Chronic toxicity studies examining a wide range of 

endpoints are needed 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 suitable for 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 perfluoroalkyl compounds; 

epidemiology studies account for over 400 of the toxicity studies. Evidence from epidemiology studies 

suggest links between perfluoroalkyl exposure and several health outcomes including liver damage, 

increases in serum lipids, thyroid disease, immune effects, reproductive toxicity, and developmental 
PERFLUOROALKYLS 634

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

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 of 

serum perfluoroalkyl levels, as this would provide valuable information for comparing effects observed in 

laboratory animals to effects observed in humans. 

Hepatic Effects. Evidence from acute, intermediate, and/or chronic oral studies in rats, mice, and 

monkeys indicates that the liver is a sensitive target of PFOA, PFOS, PFHxS, PFNA, PFDeA, PFUA, 

PFBA, PFBuS, PFDoA, and PFHpA toxicity. The effects observed in rodents differ from those 

observed in humans. In humans, exposure to PFOA, PFOS, PFNA, and PFDeA appear to result in 

increases in serum lipid levels, particularly total cholesterol levels. However, animal studies have 

found decreases in serum lipid levels associated with exposure to most perfluoroalkyls. It is not 

known if the species differences are due to different mechanisms of toxicity or differences in 

exposure levels (serum levels observed in animal studies are orders of magnitude higher than those in 

human studies). 

Immune Effects: Epidemiology data suggest a link between PFOA, PFOS, PFHxS, and PFDeA 

and decreased antibody response to vaccines. This is supported by acute- and intermediate-duration 

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 perfluoroalkyl compounds. 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 in 

several 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 affect 

lactation. Additional studies are needed to evaluate the adversity of these alterations. This endpoint 

has not been evaluated for other perfluoroalkyl compounds and studies are needed to determine 

whether it is also a sensitive effect for these compounds.

Developmental Effects. Based on the results of laboratory animal studies, developmental 

endpoints are targets of PFOA, PFOS, PFHxS, PFNA, PFDeA, PFUA, and PFBA toxicity following 

acute- and/or intermediate-duration oral exposure. Studies are needed to evaluate potential 
PERFLUOROALKYLS 635

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

developmental effects for PFHxS following intermediate-duration oral exposure. Epidemiology 

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 epidemiology 

data is co-exposure to multiple perfluoroalkyl compounds. There are limited data on possible 

interactions between perfluoroalkyl compounds and possible effects on toxicity and toxicokinetics. 

Animal studies examining the possible interactions between perfluoroalkyl compounds would be 

useful for interpreting the epidemiology study results; this is especially important since humans are 

typically exposed to multiple perfluoroalkyls and many of them are likely to have similar mechanisms 

of action. 

Mechanisms of Toxicity. 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 PPARα agonists than rats and mice. However, the results of studies in PPARα-null 

mice suggest that PPARα-independent mechanisms also play a role in the liver, immunological, and 

developmental toxicity. Additional studies are needed on the mechanisms of toxicity to assess 

whether the effects observed in laboratory animal are relevant to humans.

Epidemiology and Human Dosimetry Studies. As previously mentioned, information is available 

regarding the effects of exposure to perfluoroalkyl compounds 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 

statistically significant associations between serum perfluoroalkyl levels and the occurrence of an adverse 

health effect, the findings were not consistent across studies. Interpretation of the human data is limited 

by the reliance 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 and 

flattens 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 also 

needed. Longitudinal studies examining a wide range of endpoints would be useful for identifying critical 

targets of toxicity in humans exposed to perfluoroalkyls. The available human studies have identified 
PERFLUOROALKYLS 636

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

some potential targets of toxicity; however, cause-and-effect relationships have not been established for 

any 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 of 

different race/ethnicity and age to determine potential race/ethnicity- and age-based susceptibilities. 

Another limitation of the epidemiology studies is co-exposure to other perfluoroalkyl compounds; studies 

that statistically controlled for co-exposure to other pollutants would decrease this uncertainty. As noted 

previously, there is a need for studies evaluating potential interactions between perfluoroalkyl 

compounds. 

Biomarkers of Exposure and Effect. Data are available regarding levels of perfluoroalkyl 

compounds in serum from the general population, highly exposed residents, and perfluoroalkyl workers. 

Information is needed regarding the toxicokinetics (see also below) of perfluoroalkyl compounds in 

humans to be able to relate levels of 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 and liver concentrations of perfluoroalkyl compounds in humans. 

Absorption, Distribution, Metabolism, and Excretion. Several epidemiology studies have 

examined 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 PFBuS. 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 of 

perfluoroalkyls in humans are not available and could serve to improve predictions of internal dosimetry 

associated with exposures to perfluoroalkyls (bioavailability, kinetics of tissue distribution and 

elimination, binding in tissues, external-internal dose relationships, all aspects of toxicokinetics in 

children and aging populations). 

Toxicokinetics of perfluoroalkyls have been studied much more extensively in rodents (rats and mice) and 

less 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 perfluoroalkyl compounds and for other exposure routes. Studies elucidating 

the mechanisms 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 
PERFLUOROALKYLS 637

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

sulfonate), carbon chain length, and carbon chain branching. These structural features affect 

plasma and tissue protein binding, renal and biliary clearances, tissue levels, maternal-fetal 

transfer, and lactational transfer of perfluoroalkyls. Studies examining differences between 

perfluoroalkyl compounds would be useful for extrapolating health effects and toxicokinetic data 

across compounds. 

• Toxicokinetic studies have found sex- and dose-dependent subcellular distribution of PFOA in 

rats. Further studies on the mechanisms for dose-dependency, characterization of subcellular

binding proteins, and mechanistic linkages between subcellular distribution and toxicity of 

perfluoroalkyls 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 data 

suggest that binding to plasma proteins, as well as the volume of distribution, may be sex- and 

species-specific. Interactions with albumin have been partially characterized to the extent that 

binding capacity and affinity constants have been estimated, but the rates of association and 

dissociation have not been reported. 

• 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 and 

Barton 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 as 

well 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 the 

sexually mature male rat (see Section 3.5.1, Excretion). 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. 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 were

conducted 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 estrogen 

levels (in postmenopausal women) and reduced testosterone levels (in older males) in occupational and/or 

site-related epidemiology studies may also account for the lack of finding of sex-related differences.
PERFLUOROALKYLS 638

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental 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 perfluoroalkyl compounds because there are no studies that specifically addressed this 

question. Several studies have examined the possible associations between perfluoroalkyl exposure and 

health outcome 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 for 

establishing causality. Follow-up studies of the C8 population could allow for a longitudinal assessment 

of health effects in children and would be useful in determining whether the observed effects are due to 

perfluoroalkyl 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 

studies that have examined whether young animals are more or less susceptible than adults to 

perfluoroalkyls toxicity. Additional information on this issue would be useful. 

Physical and Chemical Properties. Perfluoroalkyl compounds have unique and complex physical 

and chemical 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 are still 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, a thorough 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 in 

the 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 perfluoroalkyl compounds 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 
PERFLUOROALKYLS 639

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

fluorinated substances in their production processes. Information regarding the production, import, and 

export volumes of these substances is needed.

Recommended methods for the disposal of perfluoroalkyl compounds 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 that 

avoid 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. 

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 et 

al. 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). Wang 

et al. (2013b) identified several of the fluorinated compounds that are currently being used by major 

manufacturers as alternatives to PFOA and PFOS. A data need exists to determine the fate properties of 

these replacement substances.

Bioavailability from Environmental Media. Perfluoroalkyls are widely detected in humans and 

animals, 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, and 

eggs and do not accumulate in fat tissue (de Vos et al. 2008; Kissa 2001). The mechanism of 

perfluoroalkyl 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 to 
PERFLUOROALKYLS 640

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

determine the bioavailability of the replacement substances identified in Wang et al. (2013b) used in place 

of PFOA and PFOS.

Food Chain Bioaccumulation. High levels of certain perfluoroalkyls in animals have been 

measured in apex predators, such as polar bears, which indicates that some perfluoroalkyls possess the 

ability 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 to 

bioaccumulate less than PFOS. Ongoing monitoring of perfluoroalkyl levels in animals may help to 

determine 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 in 

place of PFOA and PFOS.

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of 

perfluoroalkyls 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 body 

burden of perfluoroalkyls to assess the potential risk of adverse health effects in populations living in the 

vicinity of hazardous waste sites.

Concentrations of perfluoroalkyls have been measured in surface water from several locations across the 

United 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 in 

surface 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 in 

air, water, soil, and sediment near fluorochemical industrial facilities (3M 2007b, 2008b, 2008c; Barton et 

al. 2006; Davis et al. 2007; Hansen et al. 2002). Continued monitoring for perfluoroalkyls in these 

matrices are needed to assess exposure of individuals working at these locations 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 and PFOS, particularly near 

manufacturing locations.
PERFLUOROALKYLS 641

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

Exposure Levels in Humans. Trudel et al. (2008) provided a thorough assessment of the exposure 

of the general population to PFOS and PFOA. 3M (2008b) provided an assessment of exposure of 

individuals 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 of 

human 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 the 

phasing out of perfluoroalkyl compounds by companies of the fluorochemical industry. Levels of 

perfluoroalkyl compounds in human 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 have been documented (Emmett et al. 2006a, 2009). Continued 

biomonitoring of legacy compounds such as PFOA and PFOS as well as replacement substances 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 of 

children 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 of 

perfluoroalkyls 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 et 

al. 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.
PERFLUOROALKYLS 642

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

6.3 Ongoing Studies 

A number of ongoing studies were identified in NIH Reporter (2017), these studies are summarized in 

Table 6-1. 

Table 6-1. Ongoing Studies on Perfluoroalkyls

Investigator Affiliation Research description Sponsor

Bruan J Brown University Early life exposure to PFOA, PFOS, PFNA, and 

PFHxS on obesity mechanisms and phenotyping

NIEHS

Chen, A University of 

Cincinnati

Longitudinal study of exposure to PBDEs and PFCs 

and child neurobehavior

NIEHS

Fenton S NIEHS Examination of the mammary gland as a sensitive 

endpoint to effects of endocrine disruptors 

NIEHS

Frisbee S West Virginia 

University

Study of the effects of perfluoroalkyl chemicals on 

stroke incidence, mortality and morbidity in humans

NIGMS

Hijtmancik M Battelle Centers Chronic toxicity and carcinogenicity study of PFOA in 

rats

NIEHS

Hocevar B Indiana University, 

Bloomington

Study of the promotion of pancreatic cancer by PFOA NIEHS

Kissling G NIEHS PFOA-induced liver toxicity in wild and PPARα-null 

rats and mice

NIEHS

Sagiv S University of 

California, Berkeley

Prenatal exposure to perfluoroalkyls (PFOA, PFOS, 

PFHxS, PFNA) effect on growth and development in 

children

NIEHS

Shankar A West Virginia 

University

Perfluoroalkyls (PFOA, PFOS, PFHxS, PFNA, 

PFHpA, PFDeA, PFUA, PFDoA, PFOSA, Et-PFOSAAcOH, Me-PFOSA-AcOH) and the risk of developing 

clinical and subclinical cardiovascular disease in 

humans

NIEHS

Stein C Icahn School of 

Medicine at Mount 

Sinai

Examination of possible associations between 

environmental toxicants (PFOA and other 

perfluoroalkyls) and child neurobehavioral 

development

NIEHS

Sun Q Harvard School of 

Public Health

Examination of the relationship between 

perfluoroalkyls and other pollutants and the risk of 

diabetes in the Nurses’ Health Study

NIEHS

Sun Q Harvard School of 

Public Health

Perspective study of possible effects of 

perfluoroalkyls and other pollutants on body weight 

regulation 

NIEHS
PERFLUOROALKYLS 643

6. ADEQUACY OF THE DATABASE

***DRAFT FOR PUBLIC COMMENT***

Table 6-1. Ongoing Studies on Perfluoroalkyls

Investigator Affiliation Research description Sponsor

Taylor L Battelle Centers Toxicity study of perfluorinated compounds using 

microarray analysis of rat liver samples

NIEHS

Source: NIH Reporter 2017

Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; Me-PFOSA-AcOH = 2-(N-methylperfluorooctane sulfonamide) acetic acid; NIEHS = National Institute of Environmental Health Sciences; 

NIGMS = National Institute of General Medical Sciences; PBDE = polybrominated diphenyl ether; PFC = perfluoro 

compound; PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFHpA = perfluoroheptanoic acid; 

PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; 

PFOS = perfluorooctane sulfonic acid; PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid
PERFLUOROALKYLS 644

***DRAFT FOR PUBLIC COMMENT***

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 provisional MRLs for perfluoroalkyls.

Table 7-1. Regulations and Guidelines Applicable to Perfluoroalkyls

Agency Description Information Reference

Air

EPA RfC No data IRIS 2017

WHO Air quality guidelines No data WHO 2010

Water & Food

EPA Drinking water standards and health advisories 

Lifetime Health Advisory 

PFOA 0.07 μg/L EPA 2016e

PFOS 0.07 μg/L EPA 2016f

National primary drinking water regulations No data EPA 2009d

RfD No data IRIS 2017

PFOA 2x10-5 mg/kg/day EPA 2016e

PFOS 2x10-5 mg/kg/day EPA 2016f

WHO Drinking water quality guidelines No data WHO 2017

FDA EAFUS No dataa FDA 2013

Cancer

ACGIH Carcinogenicity classification No data ACGIH 2016

HHS Carcinogenicity classification No data NTP 2016a

EPA Carcinogenicity classification No data IRIS 2017

IARC Carcinogenicity classification IARC 2017

PFOA Group 2Bb

Occupational

ACGIH TLV No data ACGIH 2016

OSHA PEL (8-hour TWA) for general industry, 

shipyards and construction

No data OSHA 2013

29 CFR 1910.1000, 

Table Z-1
PERFLUOROALKYLS 645

7. REGULATIONS AND GUIDELINES

***DRAFT FOR PUBLIC COMMENT***

Table 7-1. Regulations and Guidelines Applicable to Perfluoroalkyls

Agency Description Information Reference

PEL (8-hour TWA) for shipyards and 

construction

No data OSHA 2014b

29 CFR 1915.1000,

Table Z

PEL (8-hour TWA) for construction No data OSHA 2014a

29 CFR 1926.55,

Appendix A

NIOSH REL (up to 10-hour TWA) No data NIOSH 2016

Emergency Criteria

EPA AEGLs-air No data EPA 2016b

AIHA ERPGs No data AIHA 2015

DOE PACs-air DOE 2016a

PFOA

PAC-1c 1.1 mg/m3

PAC-2c 12 mg/m3

PAC-3c 75 mg/m3

PFBA

PAC-1c 0.5 mg/m3

PAC-2c 5.5 mg/m3

PAC-3c 33 mg/m3

aThe EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food 

additives or listed or affirmed as GRAS. bGroup 2B: possibly carcinogenic to humans.

cDefinitions of PAC terminology are available from DOE (2016b).

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline level; 

AIHA = American Industrial Hygiene Association; CFR = Code of Federal Regulations; DOE = Department of 

Energy; EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency; 

ERPG = emergency response planning guidelines; FDA = Food and Drug Administration; GRAS = generally 

recognized as safe; HHS = Department of Health and Human Services; IARC = International Agency for Research 

on Cancer; IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and

Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; 

PAC = Protective Action Criteria; PEL = permissible exposure limit; 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
PERFLUOROALKYLS 646

7. REGULATIONS AND GUIDELINES

***DRAFT FOR PUBLIC COMMENT***

Table 7-2. Select State Drinking Water and Daily Intake Levels for Perfluoroalkyls

Value type

Value (ppb or μg/L)

PFOA PFOS PFBuS PFBA PFNA PFHxS Reference

Maine

Maximum exposure guideline for 

drinking water

0.07a 0.07a ND ND ND ND MECDC 

2016

Michigan

Human noncancer drinking water 

value

0.42 0.011 ND ND ND ND Michigan 

DEQ 2016

Minnesota

Health risk limit MDH 

2017a, 

2017b

Short-term ND ND ND 7 ND ND

Subchronic ND ND 9 7 ND ND

Chronic 0.3 0.3 7 7 ND ND

Health-based value

Short-term, subchronic or chronic 0.035 0.027 ND 7 ND 0.027b

Nevada

Basic comparison level 0.667 0.667 667 ND ND ND NDEP 2017

New Jersey

Health-based chronic maximum 

contaminant level

0.014 0.013 

(draft)

ND ND 0.013 ND DWQI 

2015, 

2017a, 

2017b

North Carolina

Interim maximum allowable 

concentration in groundwater

1.1–1.6 ND ND ND ND ND NCDENR 

2012, NC 

DEQ 2013

Vermont

Drinking water health advisory 0.02c 0.02c ND ND ND ND Vermont 

DOH 2017

aMECDC notes that according to the U.S. EPA lifetime health advisory for PFOA and PFOS, when both PFOS and 

PFOA are present in drinking water combined levels are not to exceed 0.07 ppb (EPA 2016j). bMDH recommends using the health based value for PFOS (0.027 ppb) as a surrogate for PFHxS until more 

toxicological research on PFHxS is available (MDH 2017b). cSum of PFOS and PFOA not to exceed 0.02 μg/L.

DEC = Department of Environmental Conservation; DEQ = Department of Environmental Quality; 

DOH = Department of Health; DTSC = Department of Toxic Substances Control; DWQI = Drinking Water Quality 

Institute; MECDC = Maine Center for Disease Control & Prevention; MDH = Minnesota Department of Health; 

NCDENR = North Carolina Department of Environment and Natural Resources; ND = no data; NDEP = Nevada 

Division of Environmental Protection
PERFLUOROALKYLS 647

***DRAFT FOR PUBLIC COMMENT***

CHAPTER 8. REFERENCES 

+3M. 1983. Two year oral (diet) toxicity/carcinogenicity study of fluorochemical FC-143 in rats. 

Washington, DC: U.S. Environmental Protection Agency. Submitted to the U.S. Environmental 

Protection Agency under TSCA Section 8E. OTS0204926-1. 

3M. 1999. The science of organic fluorochemistry. U.S. Environmental Protection Agency. OPPT2002-0043-0006. http://www.fluoridealert.org/pesticides/pfos.fr.final.docket.0006.pdf. July 08, 

2008. 

3M. 2000. Sulfonated perfluorochemicals in the environment: Sources; dispersion, fate and effects. 3M 

Company submission to the U.S. Environmental Protection Agency's Administrative Record. 

OPPT-2002-0043-0005. 

+3M. 2001. A 28-day oral (gavage) toxicity study of T-7485 in Sprague-Dawley rats. St Paul, MN: 3M 

Corporate Toxicology. 

+3M. 2007a. A 5-day repeat dose oral toxicity screening study in rats with a 7-day recovery period with 

MTDID. St. Paul, MN: 3M Corporate Toxicology.

3M. 2007b. Remedial investigation report. Phase 2. Fluorochemical (FC) data assessment report for the 

Cottage Grove, MN site. St. Paul, MN: 3M Corporate Toxicology. 

3M. 2008a. Information about PFOS and PFOA. 3M Company. 

http://solutions.3m.com/wps/portal/3M/en_US/PFOS/PFOA/. April 01, 2008. 

3M. 2008b. Data assessment report. 3M Decatur, Alabama facility PFOA site-related environmental 

monitoring program. St. Paul, MN: 3M Company. 

3M. 2008c. Screening level human exposure assessment report. 3M Decatur, Alabama facility PFOA 

site-related environmental monitoring program. St. Paul, MN: 3M Company. 

3M. 2010. GLP10-01-01, Interim report 10: Analysis of PFBS, PFHS, and PFOS in groundwater 

samples collected at off-site wells located in Decatur, AL in October 2010. In: Docket EPA-HQ2004-0112-0155. Letter to USEPA, Docket Center, from Gary A. Hohenstein, Manager of 

Environmental and Regulatory Affairs, 3M Company. 3M. 

https://www.regulations.gov/contentStreamer?documentId=EPA-HQ-OPPT-2004-0112-

0155&attachmentNumber=9&contentType=pdf February 28, 2017. 

3M. 2012. E12-0849 Revised final report- Decatur soils- December 2012. 

https://www.regulations.gov/contentStreamer?documentId=EPA-HQ-OPPT-2004-0112-

0155&attachmentNumber=36&contentType=pdf February 28, 2017. 

Abbott BD. 2009. Review of the expression of peroxisome proliferator-activated receptors alpha 

(PPARα), beta (PPARβa), and gamma (PPARγ) in rodent and human development. Reprod Toxicol 

27(3-4, Sp. Iss. SI):246-257. 10.1016/j.reprotox.2008.10.001. 

+Abbott BD, Wolf CJ, Das KP, et al. 2009. Developmental toxicity of perfluorooctane sulfonate (PFOS) 

is not dependent on expression of peroxisome proliferator activated receptor-alpha (PPARα) in the 

mouse. Reprod Toxicol 27(3-4):258-265. 

+Abbott BD, Wolf CJ, Schmid JE, et al. 2007. Perfluorooctanoic acid (PFOA)-induced developmental 

toxicity in the mouse is dependent on expression of peroxisome proliferator activated receptor-alpha. 

Toxicol Sci 98(2):571-581. 

Abbott BD, Wood CR, Watkins AM, et al. 2010. Peroxisome proliferator-activated receptors alpha, beta, 

and gamma mRNA and protein expression in human fetal tissues. PPAR Res 10.1155/2010/690907. 

Abbott BD, Wood CR, Watkins AM, et al. 2012. Effects of perfluorooctanoic acid (PFOA) on 

expression of peroxisome proliferator-activated receptors (PPAR) and nuclear receptor-regulated 

genes in fetal and postnatal CD-1 mouse tissues. Reprod Toxicol 33(4):491-505. 

_______________________ 

+ Cited in supplemental document 
PERFLUOROALKYLS 648

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Abdellatif A, Al-Tonsy AH, Awad ME, et al. 2004. Peroxisomal enzymes and 

δ-hydroxydeoxyguanosine in rat liver treated with perfluorooctanoic acid. Dis Markers 19(1):19-25. 

Abdellatif AG, Preat V, Taper HS, et al. 1991. The modulation of rat liver carcinogenesis by 

perfluorooctanoic acid, a peroxisome proliferator. Toxicol Appl Pharmacol 111:530-537. 

ACGIH. 2016. CAS Number index. TLVs and BEIs based on the documentation of the threshold limit 

values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH: 

American Conference of Governmental Industrial Hygienists, 233-250. 

Ahmed DY, Abd Ellah MR. 2012. Effect of exposure to perfluorooctanoic acid on hepatic antioxidants 

in mice. Comp Clin Pathol 21(6):1643-1645. 

AIHA. 2015. Current ERPG Values (2015). Fairfax, VA: American Industrial Hygiene Association. 

https://www.aiha.org/getinvolved/AIHAGuidelineFoundation/EmergencyResponsePlanningGuidelines/Documents/2015%20

ERPG%20Levels.pdf. March 22, 2016. 

+Albrecht PP, Torsell NE, Krishnan P, et al. 2013. A species difference in the peroxisome proliferatoractivated receptor α-dependent response to the developmental effects of perfluorooctanoic acid. 

Toxicol Sci 131(2):568-582. 

Alexander BH, Olsen GW. 2007. Bladder cancer in perfluorooctanesulfonyl fluoride manufacturing 

workers. Ann Epidemiol 17(6):471-478. 

Alexander BH, Olsen GW, Burris JM, et al. 2003. Mortality of employees of a perfluorooctanesulphonyl 

fluoride manufacturing facility. Occup Environ Med 60:722-729. 

Allen BC, Covington TR, Clewell HJ. 1996. Investigation of the impact of pharmacokinetic variability 

and uncertainty on risks predicted with a pharmacokinetic model for chloroform. Toxicology 111(1-

3):289-303. 

Alves A, Jacobs G, Vanermen G, et al. 2015. New approach for assessing human perfluoroalkyl 

exposure via hair. Talanta 144:574-583. 10.1016/j.talanta.2015.07.009. 

Andersen CS, Fei C, Gamborg M, et al. 2010. Prenatal exposures to perfluorinated chemicals and 

anthropometric measures in infancy. Am J Epidemiol 172(11):1230-1237. 

Andersen CS, Fei C, Gamborg M, et al. 2013. Prenatal exposures to perfluorinated chemicals and 

anthropometry at 7 years of age. Am J Epidemiol 178(6):921-927. 

Andersen ME, Butenhoff JL, Chang SC, et al. 2008. Perfluoroalkyl acids and related chemistriestoxicokinetics and modes of action. Toxicol Sci 102(1):3-14. 

Andersen ME, Clewell HJ, Tan YM, et al. 2006. Pharmacokinetic modeling of saturable, renal 

resorption of perfluoroalkylacids in monkeys - probing the determinants of long plasma half-lives. 

Toxicology 227(1-2):156-164. 

Anderson RH, Long GC, Porter RC, et al. 2016. Occurrence of select perfluoroalkyl substances at U.S. 

Air Force aqueous film-forming foam release sites other than fire-training areas: Field-validation of 

critical fate and transport properties. Chemosphere 150:678-685. 

10.1016/j.chemosphere.2016.01.014. 

Anderson-Mahoney P, Kotlerman J, Takhar H, et al. 2008. Self-reported health effects among 

community residents exposed to perfluorooctanoate. New Solut 18(2):129-143. 

Apelberg BJ, Goldman LR, Calafat AM, et al. 2007a. Determinants of fetal exposure to polyfluoroalkyl 

compounds in Baltimore, Maryland. Environ Sci Technol 41:3891-3897. 

Apelberg FJ, Witter FR, Herbstman JB, et al. 2007b. Cord serum concentrations of perfluorooctane 

sulfonate (PFOS) and perfluorooctanoate (PFOA) in relation to weight and size at birth. Environ 

Health Perspect 115:1670-1676. 

Armitage J, Cousins I, Buck RC, et al. 2006. Modeling global-scale fate and transport of 

perfluorooctanoate emitted from direct sources. Environ Sci Technol 40:6969-6975. 

Ashley-Martin J, Dodds L, Arbuckle TE, et al. 2016. Maternal and neonatal levels of perfluoroalkyl 

substances in relation to gestational weight gain. Int J Environ Res Public Health 13(1):146. 

10.3390/ijerph13010146. 
PERFLUOROALKYLS 649

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Ashley-Martin J, Dodds L, Levy AR. 2015. Prenatal exposure to phthalates, bisphenol A and 

perfluoroalkyl substances and cord blood levels of IgE, TSLP and IL-33. Environ Res 140:360-368. 

ATSDR. 1989. Decision guide for identifying substance-specific data needs related to toxicological 

profiles; Notice. Agency for Toxic Substances and Disease Registry, Division of Toxicology. Fed 

Regist 54(174):37618-37634.

ATSDR. 2003. Guidance for the preparation of toxicological profiles. Agency for Toxic Substances and 

Disease Registry. https://www.atsdr.cdc.gov/toxprofiles/index.asp#profiledevelopment. July 6, 

2017.

ATSDR. 2005. Health consultation. 3M chemolite. Perfluorochemical releases at the 3M-Cottage 

Grove facility. Atlanta, GA: Agency for Toxic Substances and Disease Registry. 

http://www.atsdr.cdc.gov/HAC/pha/3M-CGF021805-MN/3M-CGF021805-MN_pt1.pdf. June 27, 

2008.

ATSDR. 2008. Public health Assessment for perfluorochemical contamination in Lake Elmo and 

Oakdale, Washington County, Minnesota. EPA facility ID: MND980704738 and MND980609515 

August 29, 2008. Agency for Toxic Substances and Disease Registry. 

http://www.health.state.mn.us/divs/eh/hazardous/sites/washington/lakeelmo/phaelmooakdale.pdf. 

November 13, 2008.

ATSDR. 2013. Health consultation. Exposure investigation report. Perfluorochemical serum sampling 

in the vicinity of Decatur, Alabama, Morgan, Lawrence, and Limestone counties. Atlanta, GA: 

Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human 

Services. 

ATSDR. 2017. Perfluoroalkyls. Full SPL data. Substance priority list (SPL) resource page. Agency for 

Toxic Substances and Disease Registry, Centers for Disease Control and Prevention. 

http://www.atsdr.cdc.gov/SPL/resources/index.html. October 6, 2017.

Bach CC, Bech BH, Nohr EA, et al. 2016. Perfluoroalkyl acids in maternal serum and indices of fetal 

growth: The Aarhus Birth Cohort. Environ Health Perspect 10.1289/ehp.1510046. 

Bach CC, Bech BH, Nohr EA, et al. 2015a. Serum perfluoroalkyl acids and time to pregnancy in 

nulliparous women. Environ Res 142:535-541. 10.1016/j.envres.2015.08.007.

Bach CC, Liew Z, Bech BH, et al. 2015b. Perfluoroalkyl acids and time to pregnancy revisited: An 

update from the Danish National Birth Cohort. Environ Health 14:59. 10.1186/s12940-015-0040-9. 

Bach CC, Liew Z, Bech BH, et al. 2015c. Additional file to perfluoroalkyl acids and time to pregnancy 

revisited: An update from the Danish National Birth Cohort [Environ Health 14:59]. Environ 

Health 10.1186/s12940-015-0040-9. 

Bae J, Kim S, Schisterman EF, et al. 2015. Maternal and paternal serum concentrations of perfluoroalkyl 

and polyfluoroalkyl substances and the secondary sex ratio. Chemosphere 133:31-40. 

10.1016/j.chemosphere.2015.03.015. 

Barbarossa A, Masetti R, Gazzotti T, et al. 2013. Perfluoroalkyl substances in human milk: A first 

survey in Italy. Environ Int 51:27-30.

Barber JL, Berger U, Chaemfa C, et al. 2007. Analysis of per- and polyfluorinated alkyl substances in air 

samples from Northwest Europe. J Environ Monit 9:530-541.

Barnes DG, Dourson M. 1988. Reference dose (RfD): Description and use in health risk assessments. 

Regul Toxicol Pharmacol 8(4):471-486.

Barrett ES, Chen C, Thurston SW, et al. 2015. Perfluoroalkyl substances and ovarian hormone 

concentrations in naturally cycling women. Fertil Steril 103(5):1261-1270 e1263. 

10.1016/j.fertnstert.2015.02.001.

Barry V, Darrow LA, Klein M, et al. 2014. Early life perfluorooctanoic acid (PFOA) exposure and 

overweight and obestity risk in adulthood in a community with elevated exposure. Environ Res 

132:62-69.

Barry V, Winquist A, Steenland K. 2013. Perfluorooctanoic acid (PFOA) exposures and incident cancers 

among adults living near a chemical plant. Environ Health Perspect 121(11-12):1313-1318.
PERFLUOROALKYLS 650

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Bartell SM, Calafat AM, Lyu C, et al. 2010. Rate of decline in serum PFOA concentrations after 

granular activated carbon filtration at two public water systems in Ohio and West Virginia. Environ 

Health Perspect 118(2):222-228.

Barton CA, Butler LE, Zarzecki CJ, et al. 2006. Characterizing perfluorooctanoate in ambient air near 

the fence line of a manufacturing facility: Comparing modeled and monitored values. J Air Waste 

Manag Assoc 56:48-55.

Barton CA, Kaiser MA, Russell MH. 2007. Partitioning and removal of perfluorooctanoate during rain 

events: The importance of physical-chemical properties. J Environ Monit 9:839-846.

Beesoon S, Martin JW. 2015. Isomer-specific binding affinity of perfluorooctanesulfonate (PFOS) and 

perfluorooctanoate (PFOA) to serum proteins. Environ Sci Technol 49(9):5722-5731. 

Begley TH, White K, Honigfort P, et al. 2005. Perfluorochemicals: Potential sources of and migration 

from food packaging. Food Addit Contam 22(10):1023-1031.

Benninghoff AD, Bisson WH, Koch DC, et al. 2011. Estrogen-like activity of perfluoroalky acids in 

vivo and interaction with human and rainbow trout estrogen receptors in vitro. Toxicol Sci 

120(1):42-58. 

Benninghoff AD, Orner GA, Buchner CH, et al. 2012. Promotion of hepatocarcinogenesis by 

perfluoroalkyl acids in rainbow trout. Toxicol Sci 125(1):69-78. 10.1093/toxsci/kfr267. 

Benskin JP, De Silva AO, Martin LJ, et al. 2009. Disposition of perfluorinated acid isomers in SpragueDawley rats: Part 1: Single dose. Environ Toxicol Chem 28(3):542-554.

Berg V, Nost TH, Hansen S, et al. 2015. Assessing the relationship between perfluoroalkyl substances, 

thyroid hormones and binding proteins in pregnant women; a longitudinal mixed effects approach. 

Environ Int 77:63-69. 10.1016/j.envint.2015.01.007. 

+Biegel LB, Hurtt ME, Frame SR, et al. 2001. Mechanisms of extrahepatic tumor induction by 

peroxisome proliferators in male CD rats. Toxicol Sci 60(1):44-55.

+Biegel LB, Liu RC, Hurtt ME, et al. 1995. Effects of ammonium perfluorooctanoate on Leydig cell 

function: In vitro, in vivo, and ex vivo studies. Toxicol Appl Pharmacol 134(1):18-25.

+Bijland S, Rensen PC, Pieterman EJ, et al. 2011. Perfluoroalkyl sulfonates cause alkyl chain lengthdependent hepatic steatosis and hypolipidemia mainly by impairing lipoprotein production in 

APOE*3-Leiden CETP mice. Toxicol Sci 123(1):290-303. 10.1093/toxsci/kfr142. 

Bilott RA. 2004. PFOA-exposed community blood sample results (for AR-226 and OPPT-2003-0012). 

Submitted to the U.S. Environmental Protection Agency under TSCA Section FYI. 

http://www.epa.gov/oppt/tsca8e/pubs/8ehq/2004/oct04/fyi_1004_01480a.pdf. May 5, 2014.

Bilott RA. 2005a. Perfluorochemical residential exposure data for Washington County, Minnesota. 

Submitted to the U.S. Environmental Protection Agency.

Bilott RA. 2005b. Perfluorochemical residential exposure data for Washington County, Minnesota. 

Submitted to the U.S. Environmental Protection Agency. 

http://yosemite.epa.gov/sab/sabproduct.nsf/1BF9ABCD791BDDE38525711F000156BE/$File/pfoa_

sab_lett-bilott_05-20-05.pdf. May 5, 2014.

Bilott RA. 2007. Perfluorochemical residential exposure data for Washington County, Minnesota. EPAHQ-OPPT-2003-0012-1230. https://www.regulations.gov/document?D=EPA-HQ-OPPT-2003-

0012-1230. February 28, 2017.

Bischel HN, MacManus-Spencer LA, Zhang C, et al. 2011. Strong associations of short-chain 

perfluoroalkyl acids with serum albumin and investigation of binding mechanisms. Environ Toxicol 

Chem 30(11):2423-2430.

Bjermo H, Darnerud PO, Pearson M, et al. 2013. Serum concentrations of perfluorinated alkyl acids and 

their associations with diet and personal characteristics among Swedish adults. Mol Nutr Food Res 

57(12):2206-2215.

Bjerregaard-Olesen C, Bach CC, Long M, et al. 2016. Time trends of perfluorinated alkyl acids in serum 

from Danish pregnant women 2008-2013. Environ Int 91:14-21. 10.1016/j.envint.2016.02.010.
PERFLUOROALKYLS 651

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Bjork JA, Wallace KB. 2009. Structure-activity relationships and human relevance for perfluoroalkyl 

acid-induced transcriptional activation of peroxisome proliferation in liver cell cultures. Toxicol Sci 

111(1):89-99.

Bjork JA, Butenhoff JL, Wallace KB. 2011. Multiplicity of nuclear receptor activation by PFOA and 

PFOS in primary human and rodent hepatocytes. Toxicology 288(1-3):8-17. 

10.1016/j.tox.2011.06.012. 

Björklund JA, Thuresson K, de Wit CA. 2009. Perfluoroalkyl compounds (PFCs) in indoor dust: 

Concentrations, human exposure estimates, and sources. Environ Sci Technol 43(7):2276-2281.

Blaine AC, Rich CD, Hundal LS, et al. 2013. Uptake of perfluoroalkyl acids into edible crops via land 

applied biosolids: Field and greenhouse studies. Environ Sci Technol 47:14062-14069. 

Blaine AC, Rich CD, Sedlacko EM, et al. 2014a. Perfluoroalkyl acid distribution in various plant 

compartments of edible crops grown in biosolids-amended soils. Environ Sci Technol 48(14):7858-

7865. 10.1021/es500016s. 

Blaine AC, Rich CD, Sedlacko EM, et al. 2014b. Perfluoroalkyl acid uptake in lettuce (Lactuca sativa) 

and strawberry (Fragaria ananassa) irrigated with reclaimed water. Environ Sci Technol 48:14361-

14368. 

Bloom MS, Kannan K, Spliethoff HM, et al. 2010. Exploratory assessment of perfluorinated compounds 

and human thyroid function. Physiol Behav 99(2):240-245.

Bogdanska J, Borg D, Sundstrom M, et al. 2011. Tissue distribution of 35S-labelled perfluorooctane 

sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high 

experimental dose. Toxicology 284(1-3):54-62.

Bogdanska J, Sundstrom M, Bergstrom U, et al. 2014. Tissue distribution of 35S-labelled 

perfluorobutanesulfonic acid in adult mice following dietary exposure for 1-5 days. Chemosphere 

98:28-36. 

Boiteux V, Dauchy X, Rosin C, et al. 2012. National screening study on 10 perfluorinated compounds in 

raw and treated tap water in France. Arch Environ Contam Toxicol 63(1):1-12. 10.1007/s00244-

012-9754-7. 

Bonefeld-Jorgensen EC, Long M, Bossi R, et al. 2011. Perfluorinated compounds are related to breast 

cancer risk in Greenlandic Inuit: A case control study. Environ Health 10:88. 10.1186/1476-069X10-88.

Bonefeld-Jorgensen EC, Long M, Fredslund SO, et al. 2014. Breast cancer risk after exposure to 

perfluorinated compounds in Danish women: A case-control study nested in the Danish National 

Birth Cohort. Cancer Causes Control 25(11):1439-1448. 10.1007/s10552-014-0446-7.

Borg D, Bogdanska J, Sundstrom M, et al. 2010. Tissue distribution of 35S-labelled perfluorooctane 

sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure. Reprod Toxicol 30(4):558-

565.

Bossi R, Riget FF, Dietz R. 2005. Temporal and spatial trends of perfluorinated compounds in ringed 

seal (Phoca hispida) from Greenland. Environ Sci Technol 39:7416-7422.

Boulanger B, Peck AM, Schnoor JL, et al. 2005. Mass budget of perfluorooctane surfactants in Lake 

Ontario. Environ Sci Technol 39:74-79.

Boulanger B, Vargo J, Schnoor JL, et al. 2004. Detection of perfluorooctane surfactants in Great Lakes 

water. Environ Sci Technol 38:4064-4070.

Brantsaeter AL, Whitworth KW, Ydersbond TA, et al. 2013. Determinants of plasma concentration of 

perfluoroalkyl substances in pregnant Norwegian women. Environ Int 54:74-84.

Braun JM, Chen A, Romano ME, et al. 2016a. Prenatal perfluoroalkyl substance exposure and child 

adiposity at 8 years of age: The HOME study. Obesity (Silver Spring, Md.) 24(1):231-237. 

10.1002/oby.21258. 
PERFLUOROALKYLS 652

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Braun JM, Chen A, Romano ME, et al. 2016b. Supplemental material for: Prenatal perfluoroalkyl 

substance exposure and child adiposity at 8 years of age: The HOME study. [Obesity 24(1):231-

237]. Obesity (Silver Spring, Md.) 24(1):231-237. 

http://onlinelibrary.wiley.com/store/10.1002/oby.21258/asset/supinfo/oby21258-sup-0001-

suppinfo01.docx?v=1&s=cac722d8275d428f198a62d78041881f25813e38. 

Braun JM, Kalkbrenner AE, Just AC, et al. 2014. Gestational exposure to endocrine-disrupting 

chemicals and reciprocal social, repetitive, and stereotypic behaviors in 4- and 5-year-old children: 

The HOME study. Environ Health Perspect 122(5):513-520. 10.1289/ehp.1307261. 

+Brewster DW, Birnbaum LS. 1989. The biochemical toxicity of perfluorodecanoic acid in the mouse is 

different from that of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 99:544-554.

Brochot C, Smith TJ, Bois FY. 2007. Development of a physiologically based toxicokinetic model for 

butadiene and four major metabolites in humans: Global sensitivity analysis for experimental design 

issues. Chem Biol Interact 167(3):168-183. 10.1016/j.cbi.2007.02.010. 

Buck RC, Franklin J, Berger U, et al. 2011. Perfluoroalkyl and polyfluoroalkyl substances in the 

environment: Terminology, classification, and origins. Integr Environ Assess Manag 7(4):513-541. 

Buck Louis GM, Chen Z, Schisterman EF, et al. 2015. Perfluorochemicals and human semen quality: 

The LIFE study. Environ Health Perspect 123(1):57-63. 10.1289/ehp.1307621. 

Buck Louis GM, Peterson CM, Chen Z, et al. 2012. Perfluorochemicals and endometriosis. The ENDO 

study. Epidemiology 23(6):799-805.

Buist SCN, Klaassen CD. 2004. Rat and mouse differences in gender-predominant expression of organic 

anion transporter (OAT1-3; SLC22A6-9) mRNA levels. Drug Metab Dispos 32(6):620-625.

Burns DC, Ellis DA, Li H, et al. 2008. Experimental pΚa determination for perfluorooctanoic acid 

(PFOA) and the potential impact of pKa concentration dependence on laboratory-measured 

phenomena and environmental modeling. Environ Sci Technol 42(24):9283-9288.

Buser MC, Scinicariello F. 2016. Perfluoroalkyl substances and food allergies in adolescents. Environ 

Int 88:74-79. 10.1016/j.envint.2015.12.020. 

+Butenhoff JL, Bjork JA, Chang SC, et al. 2012a. Toxicological evaluation of ammonium 

perfluorobutyrate in rats: Twenty-eight-day and ninety-day oral gavage studies. Reprod Toxicol 

33(4):513-530.

+Butenhoff JL, Chang S, Ehresman DJ, et al. 2009a. Evaluation of potential reproductive and 

developmental toxicity of potassium perfluorohexanesulfonate in Sprague Dawley rats. Reprod 

Toxicol 27:331-341.

+Butenhoff JL, Chang SC, Olsen GW, et al. 2012b. Chronic dietary toxicity and carcinogenicity study 

with potassium perfluorooctanesulfonate in Sprague Dawley rats. Toxicology 293(1-3):1-15. 

+Butenhoff J, Costa G, Elcombe C, et al. 2002. Toxicity of ammonium perfluorooctanoate in male 

Cynomolgus monkeys after oral dosing for 6 months. Toxicol Sci 69(1):244-257.

+Butenhoff JL, Ehresman DJ, Chang SC, et al. 2009b. Gestational and lactational exposure to potassium 

perfluorooctanesulfonate (K+PFOS) in rats: Developmental neurotoxicity. Reprod Toxicol 27(3-

4):319-330.

Butenhoff JL, Gaylor DW, Moore JA, et al. 2004a. Characterization of risk for general population 

exposure to perfluorooctanoate. Regul Toxicol Pharmacol 39(3):363-380.

+Butenhoff JL, Kennedy GL, Frame SR, et al. 2004b. The reproductive toxicology of ammonium 

perfluorooctanoate (APFO) in the rat. Toxicology 196(1-2):95-116.

Butenhoff JL, Kennedy GL, Hinderliter PM, et al. 2004c. Pharmacokinetics of perfluorooctanoate in 

Cynomolgus monkeys. Toxicol Sci 82:394-406.

Butenhoff JL, Kennedy GL, Jung R, et al. 2014. Evaluation of perfluorooctanoate for potential 

genotoxicity. Toxicol Rep 1:252-270.

Butenhoff JL, Pieterman E, Ehresman DJ, et al. 2012c. Distribution of perfluorooctanesulfonate and 

perfluorooctanoate into human plasma lipoprotein fractions. Toxicol Lett 210(3):360-365. 

10.1016/j.toxlet.2012.02.013. 
PERFLUOROALKYLS 653

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Butt CM, Mabury SA, Kwan M, et al. 2008. Spatial trends of perfluoroalkyl compounds in ringed seals 

(Phoca hispida) from the Canadian Arctic. Environ Toxicol Chem 27(3):542-553. 

Butt CM, Mabury SA, Muir DCG, et al. 2007a. Prevalence of long-chained perfluorinated carboxylates 

in seabirds from the Canadian Arctic between 1975 and 2004. Environ Sci Technol 41:3521-3528. 

Butt CM, Muir DCG, Stirling I, et al. 2007b. Rapid response of arctic ringed seals to changes in 

perfluoroalkyl production. Environ Sci Technol 41(1):42-49. 

Calafat AM, Kuklenyik Z, Caudill SP, et al. 2006a. Perfluorochemicals in pooled serum samples from 

United States residents in 2001 and 2002. Environ Sci Technol 40:2128-2134. 

Calafat AM, Kuklenyik Z, Reidy JA, et al. 2007a. Serum concentrations of 11 polyfluoroalkyl 

compounds in the U.S. population: Data from the National Health and Nutrition Examination 

Survey (NHANES) 1999-2000. Environ Sci Technol 41:2237-2242. 

Calafat AM, Needham LL, Kuklenyik Z, et al. 2006b. Perfluorinated chemicals in selected residents of 

the American continent. Chemosphere 63:490-496. 

Calafat AM, Wong L, Kuklenyik Z, et al. 2007b. Polyfluoroalkyl chemicals in the U.S. population: 

Data from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 and 

comparisons with NHANES 1999-2000. Environ Health Perspect 115:1596-1602. 

Cariou R, Veyrand B, Yamada A, et al. 2015. Perfluoroalkyl acid (PFAA) levels and profiles in breast 

milk, maternal and cord serum of French women and their newborns. Environ Int 84:71-81. 

Carr CK, Watkins AM, Wolf CJ, et al. 2013. Testing for departures from additivity in mixtures of 

perfluoroalkyl acids (PFAAs). Toxicology 306:169-175. 10.1016/j.tox.2013.02.016. 

CAS. 2008. Registry. Columbus, OH: Chemical Abstracts Service. http://stnweb.cas.org/. March 14, 

2008. 

+Case MT, York RG, Christian MS. 2001. Rat and rabbit oral developmental toxicology studies with

two perfluorinated compounds. Int J Toxicol 20(2):101-109. 

Cattley RC, DeLuca J, Elcombe C, et al. 1998. Do peroxisome proliferating compounds pose a 

hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol 27:47-60. 

CDC. 2013. Fourth national report on human exposure to environmental chemicals. Updated tables,

September 2013. U.S. Department of Health and Human Services, Centers for Disease Control and

Prevention.

CDC. 2015. Fourth national report on human exposure to environmental chemicals. February 2015.

U.S. Department of Health and Human Services, Centers for Disease Control and Prevention.

https://www.cdc.gov/biomonitoring/pdf/fourthreport_updatedtables_feb2015.pdf. May 25, 2017.

CDC. 2018. Fourth national report on human exposure to environmental chemicals. Updated Tables,

March 2018. Atlanta, GA: Centers for Disease Control and Prevention, Department of Health and

Human Services.

https://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Volume1_Mar2018.pdf.

April 23, 2018.

Celik A, Eke D, Ekinci SY, et al. 2013. The protective role of curcumin on perfluorooctane sulfonateinduced genotoxicity: Single cell gel electrophoresis and micronucleus test. Food Chem Toxicol 

53:249-255. 

CEMN. 2008. CEMC focussing on ionizing surfactants. Canadian Environmental Modelling Network. 

http://www.trentu.ca/academic/aminss/envmodel/cemn/NewsReports/CEMNnews200804.pdf. June 

24, 2008. 

Chan E, Burstyn I, Cherry N, et al. 2011. Perfluorinated acids and hypothyroxinemia in pregnant 

women. Environ Res 111(4):559-564. 

Chang ET, Adami H, Boffetta P, et al. 2014. A critical review of perfluorooctanoate and 

perfluorooctanesulfonate exposure and cancer risk in humans. Crit Rev Toxicol 44:1-81. 

Chang S, Das K, Ehresman DJ, et al. 2008a. Comparative pharmacokinetics of perfluorobutyrate 

(PFBA) in rats, mice, monkeys, and humans and relevance to human exposure via drinking water. 

Toxicol Sci 104(1):40-53. 
PERFLUOROALKYLS 654

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

+Chang S, Ehresman DJ, Bjork JA, et al. 2009. Gestational and lactational exposure to potassium 

perfluorooctanesulfonate (K+PFOS) in rats: Toxicokinetics, thyroid hormone status, and related 

gene expression. Reprod Toxicol 27(3-4):387-399.

Chang S, Noker PE, Gorman GS, et al. 2012. Comparative pharmacokinetics of 

perfluorooctanesulfonate (PFOS) in rats, mice, and monkeys. Reprod Toxicol 33(4):428-440.

+Chang S, Thibodeaux JR, Eastvold ML, et al. 2008b. Thyroid hormone status and pituitary function in 

adult rats given oral doses of perfluorooctanesulfonate (PFOS). Toxicology 243:330-339.

Château-Degat ML, Pereg D, Dallaire R, et al. 2010. Effects of perfluorooctanesulfonate exposure on 

plasma lipid levels in the Inuit population of Nunavik (Northern Quebec). Environ Res 110(7):710-

717.

ChemIDplus. 2008. Perfluoroalkyls. ChemIDplus. Bethesda, MD: U.S. National Library of Medicine. 

http://sis.nlm.nih.gov/chemical.html. July 10, 2008.

ChemIDplus. 2017. Ammonium perfluorooctanoate. Bethesda, MD: ChemIDplus. U.S. National 

Library of Medicine. http://sis.nlm.nih.gov/chemical.html. December 22, 2017.

Chen MH, Ha EH, Liao HF, et al. 2013. Perfluorinated compound levels in cord blood and 

neurodevelopment at 2 years of age. Epidemiology 24(6):800-808. 

10.1097/EDE.0b013e3182a6dd46.

Chen MH, Ha EH, Wen TW, et al. 2012a. Perfluorinated compounds in umbilical cord blood and 

adverse birth outcomes. PLoS ONE 7(8):e42474.

+Chen T, Zhang L, Yue JQ, et al. 2012b. Prenatal PFOS exposure induces oxidative stress and apoptosis 

in the lung of rat off-spring. Reprod Toxicol 33(4):538-545.

Chen YM, Guo LH. 2009. Fluorescence study on site-specific binding of perfluoroalkyl acids to human 

serum albumin. Arch Toxicol 83(3):255-261. 

+Cheng J, Fujimura M, Zhao W, et al. 2013. Neurobehavioral effects, c-Fos/Jun expression and tissue 

distribution in rat offspring prenatally co-exposed to MeHg and PFOA: PFOA impairs Hg retention. 

Chemosphere 91(6):758-764.

Cheng W, Ng CA. 2017. A permeability-limited physiologically based pharmacokinetic (PBPK) model 

for perfluorooctanoic acid (PFOA) in male rats. Environ Sci Technol 51(17):9930-9939. 

10.1021/acs.est.7b02602.

Cheng X, Klaassen CD. 2008a. Critical role of PPAR-α in perfluorooctanoic acid- and 

perfluorodecanoic acid-induced downregulation of oatp uptake transporters in mouse livers. Toxicol 

Sci 106(1):37-45. 10.1093/toxsci/kfn161. 

Cheng X, Klaassen CD. 2008b. Perfluorocarboxylic acids induce cytochrome P450 enzymes in mouse 

liver through activation of PPAR-alpha and CAR transcription factors. Toxicol Sci 106(1):29-36. 

10.1093/toxsci/kfn147. 

Chengelis CP, Kirkpatrick JB, Myers NR, et al. 2009. Comparison of the toxicokinetic behavior of 

perfluorohexanoic acid (PFHxA) and nonafluorobutane-1-sulfonic acid (PFBS) in Cynomolgus 

monkeys and rats. Reprod Toxicol 27:400-406.

Christensen KY, Maisonet M, Rubin C, et al. 2011. Exposure to polyfluoroalkyl chemicals during 

pregnancy is not associated with offspring age at menarche in a contemporary British cohort. 

Environ Int 37(1):129-135.

Christensen KY, Raymond M, Thompson BA, et al. 2016. Perfluoroalkyl substances in older male 

anglers in Wisconsin. Environ Int 91:312-318. 10.1016/j.envint.2016.03.012.

Clara M, Gans O, Weiss S, et al. 2009. Perfluorinated alkylated substances in the aquatic environment: 

An Austrian case study. Water Res 43(18):4760-4768. 10.1016/j.watres.2009.08.004.

Clarke BO, Smith SR. 2011. Review of 'emerging' organic contaminants in biosolids and assessment of 

international research priorities for the agricultural use of biosolids. Environ Int 37(1):226-247. 

10.1016/j.envint.2010.06.004.

Clewell HJ, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. Toxicol 

Ind Health 1(4):111-131.
PERFLUOROALKYLS 655

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Conder JM, Hoke RA, De Wolf W, et al. 2008. Are PFCAs bioaccumulative? A critical review and 

comparison with regulatory criteria and persistent lipophilic compounds. Environ Sci Technol 

42(4):995-1003.

Consonni D, Straif K, Symons JM, et al. 2013. Cancer risk among tetrafluoroethylene synthesis and 

polymerization workers. Am J Epidemiol 178(3):350-358. 

+Cook JC, Murray SM, Frame SR, et al. 1992. Induction of Leydig cell adenomas by ammonium 

perfluorooctanoate: A possible endocrine-related mechanism. Toxicol Appl Pharmacol 113(2):209-

217.

Corsini E, Luebke RW, Germolec DR, et al. 2014. Perfluorinated compounds: Emerging POPs with 

potential immunotoxicity. Toxicol Lett 230(2):263-270. 10.1016/j.toxlet.2014.01.038. 

Corton JC, Cunningham ML, Hummer BT, et al. 2014. Mode of action framework analysis for receptormediated toxicity: The peroxisome proliferator-activated receptor alpha (PPARα) as a case study. 

Crit Rev Toxicol 4444(1):1-49. 10.3109/10408444.2013.835784. 

Costa G. 2004. Report on the meeting held on Friday 20th and Saturday 21st 2004 at the Inn at 

Montchanin Village (Wilmington, USA) with 3M and DuPont delegations. DuPont. Submitted to 

the U.S. Environmental Protection Agency. AR226-1866.

Costa G, Sartori S, Consonni D. 2009. Thirty years of medical surveillance in perfluooctanoic acid 

production workers. J Occup Environ Med 51(3):364-372.

+Cui L, Zhou QF, Liao CY, et al. 2009. Studies on the toxicological effects of PFOA and PFOS on rats 

using histological observation and chemical analysis. Arch Environ Contam Toxicol 56(2):338-349.

+Curran I, Hierlihy SL, Liston V, et al. 2008. Altered fatty acid homeostasis and related toxicologic 

sequelae in rats exposed to dietary potassium perfluorooctanesulfonate (PFOS). J Toxicol Environ 

Health A 71(23):1526-1541.

Dai J, Li M, Jin Y, et al. 2006. Perfluorooctanesulfonate and perfluorooctanoate in red panda and giant 

panda from China. Environ Sci Technol 40:5647-5652.

Dallaire R, Ayotte P, Pereg D, et al. 2009. Determinants of plasma concentrations of 

perfluorooctanesulfonate and brominated organic compounds in Nunavik Inuit adults (Canada). 

Environ Sci Technol 43(13):5130-5136.

Dalsager L, Christensen N, Husby S, et al. 2016. Association between prenatal exposure to 

perfluorinated compounds and symptoms of infections at age 1-4 years among 359 children in the 

Odense Child Cohort. Environ Int 96:58-64. 

Darrow LA, Groth AC, Winquist A, et al. 2016. Modeled perfluorooctanoic acid (PFOA) exposure and 

liver function in a mid-Ohio Valley community. Environ Health Perspect [Advance publication]. 

10.1289/ehp.1510391. 

Darrow LA, Howards PP, Winquist A, et al. 2014. PFOA and PFOS serum levels and miscarriage risk. 

Epidemiology 25(4):505-512. 10.1097/ede.0000000000000103. 

Darrow LA, Stein CR, Steenland K. 2013. Serum perfluorooctanoic acid and perfluorooctane sulfonate 

concentrations in relation to birth outcomes in the Mid-Ohio Valley, 2005-2010. Environ Health 

Perspect 121(10):1207-1213.

+Das KP, Grey BE, Zehr RD, et al. 2008. Effects of perfluorobutyrate exposure during pregnancy in the 

mouse. Toxicol Sci 105(1):173-181. 

+Das KP, Grey BE, Rosen MB, et al. 2015. Developmental toxicity of perfluorononanoic acid in mice. 

Reprod Toxicol 51:133-144. 10.1016/j.reprotox.2014.12.012.

Das KP, Wood CR, Lin MT, et al. 2017. Perfluoroalkyl acids-induced liver steatosis: Effects on genes 

controlling lipid homeostasis. Toxicology 378:37-52. 10.1016/j.tox.2016.12.007. 

Dauchy X, Boiteux V, Rosin C, et al. 2012. Relationship between industrial discharges and 

contamination of raw water resources by perfluorinated compounds. Part I: Case study of a 

fluoropolymer manufacturing plant. Bull Environ Contam Toxicol 89(3):525-530. 10.1007/s00128-

012-0704-x.

Davis KL, Aucoin MD, Larsen BS, et al. 2007. Transport of ammonium perfluorooctanoate in 

environmental media near a fluoropolymer manufacturing facility. Chemosphere 67:2011-2019.
PERFLUOROALKYLS 656

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

de Cock M, de Boer MR, Lamoree M, et al. 2014. First year growth in relation to prenatal exposure to 

endocrine disruptors - a Dutch prospective cohort study. Int J Environ Res Public Health 

11(7):7001-7021. 10.3390/ijerph110707001. 

Delinsky AD, Strynar MJ, McCann PJ, et al. 2010. Geographical distribution of perfluorinated 

compounds in fish from Minnesota lakes and rivers. Environ Sci Technol 44(7):2549-2554. 

10.1021/es903777s. 

Delinsky AD, Strynar MJ, Nakayama SF, et al. 2009. Determination of ten perluorinated compounds in 

bluegill sunfish (Lepomis macrochirus) fillets. Environ Res 109:975-984. 

D'eon JC, Mabury SA. 2007. Production of perfluorinated carboxylic acids (PFCAs) from the 

biotransformation of polyfluoroalkyl phosphate surfactants (PAPS): Exploring routes of human 

contamination. Environ Sci Technol 41(13):4799-4805.

D'eon JC, Crozier PW, Furdui VI, et al. 2009. Observation of a commercial fluorinated material, the 

polyfluoroalkyl phosphoric acid diesters, in human sera, wastewater treatment plant sludge, and 

paper fibers. Environ Sci Technol 43(12):4589-4594.

D'eon JC, Hurley MD, Wallington TJ, et al. 2006. Atmospheric chemistry of n-methyl perfluorobutane 

sulfonamidoethanol, C4F9SO2N (Ch3)CH2CH2OH: Kinetics and mechanism of reaction with OH. 

Environ Sci Technol 40:1862-1868.

De Silva AO, Benskin JP, Martin LJ, et al. 2009. Disposition of perfluorinated acid isomers in SpragueDawley rats. Part 2: Subchronic dose. Environ Toxicol Chem 28(3):555-567.

De Silva AO, Mabury SA. 2006. Isomer distribution of perfluorocarboxylates in human blood: Potential 

correlation to source. Environ Sci Technol 40:2903-2909.

De Silva AO, Spencer C, Scott BF, et al. 2011. Detection of a cyclic perfluorinated acid, 

perfluoroethylcyclohexane sulfonate, in the Great Lakes of North America. Environ Sci Technol 

45:8060-8066. 

de Vos MG, Huijbregts MAJ, van den Heuvel-Greve MJ, et al. 2008. Accumulation of perfluorooctane 

sulfonate (PFOS) in the food chain of the Western Scheldt estuary: Comparing field measurements 

with kinetic modeling. Chemosphere 70:1766-1773.

+DeWitt JC, Copeland CB, Luebke RW. 2009. Suppression of humoral immunity by perfluorooctanoic 

acid is independent of elevated serum corticosterone concentration in mice. Toxicol Sci 109:106-

112.

+DeWitt JC, Copeland CB, Strynar MJ, et al. 2008. Perfluorooctanoic acid-induced immunomodulation 

in adult C57BL/6J or C57BL/6N female mice. Environ Health Perspect 116(5):644-650.

DeWitt JC, Peden-Adams MM, Keller JM, et al. 2012. Immunotoxicity of perfluorinated compounds: 

Recent developments. Toxicol Pathol 40(2):300-311. 10.1177/0192623311428473. 

+DeWitt JC, Williams WC, Creech NJ, et al. 2016. Suppression of antigen-specific antibody responses 

in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting. J 

Immunotoxicol 13(1):38-45. 10.3109/1547691x.2014.996682.

Dhingra R, Darrow LA, Klein M, et al. 2016a. Perfluorooctanoic acid exposure and natural menopause: 

A longitudinal study in a community cohort. Environ Res 146:323-330. 

10.1016/j.envres.2015.12.037. 

Dhingra R, Lally C, Darrow LA, et al. 2016b. Perfluorooctanoic acid and chronic kidney disease: 

Longitudinal analysis of a Mid-Ohio Valley community. Environ Res 145:85-92. 

10.1016/j.envres.2015.11.018. 

Dinglasan-Panlilio MJA, Mabury SA. 2006. Significant residual fluorinated alcohols present in various 

fluorinated materials. Environ Sci Technol 40:1447-1453.

Dixon D, Reed CE, Moore AB, et al. 2012. Histopathologic changes in the uterus, cervix and vagina of 

immature CD-1 mice exposed to low doses of perfluorooctanoic acid (PFOA) in a uterotrophic 

assay. Reprod Toxicol 33(4):506-512. 10.1016/j.reprotox.2011.10.011. 

Dobraca D, Israel L, McNeel S, et al. 2015. Biomonitoring in California firefighters: Metals and 

perfluorinated chemicals. J Occup Environ Med 57(1):88-97. 10.1097/jom.0000000000000307.
PERFLUOROALKYLS 657

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

DOE. 2016a. Table 3: Protective Action Criteria (PAC) Rev. 29 based on applicable 60-minute AEGLs, 

ERPGs, or TEELs. The chemicals are listed by CASRN. May 2016. Oak Ridge, TN: U.S. 

Department of Energy. https://sp.eota.energy.gov/pac/teel/Revision_29_Table3.pdf. February 28, 

2017. 

DOE. 2016b. Protective Action Criteria (PAC) with AEGLs, ERPGs, & TEELs: Rev. 29 for Chemicals 

of Concern - May 2016. Oak Ridge, TN: U.S. Department of Energy. 

https://energy.gov/ehss/protective-action-criteria-pac-aegls-erpgs-teels-rev-29-chemicals-concernmay-2016. February 28, 2017.

Domingo JL, Ericson-Jogsten I, Perello G, et al. 2012a. Human exposure to perfluorinated compounds 

in Catalonia, Spain: Contribution of drinking water and fish and shellfish. J Agric Food Chem 

60(17):4408-4415.

Domingo JL, Jogsten IE, Eriksson U, et al. 2012b. Human dietary exposure to perfluoroalkyl substances 

in Catalonia, Spain. Temporal trend. Food Chem 135:1575-1582.

Donauer S, Chen A, Xu Y, et al. 2015. Prenatal exposure to polybrominated diphenyl ethers and 

polyfluoroalkyl chemicals and infant neurobehavior. J Pediatr 166(3):736-742. 

10.1016/j.jpeds.2014.11.021.

+Dong GH, Liu MM, Wang D, et al. 2011. Sub-chronic effect of perfluorooctanesulfonate (PFOS) on 

the balance of type 1 and type 2 cytokine in adult C57BL6 mice. Arch Toxicol 85(10):1235-1244.

Dong GH, Tung KY, Tsai CH, et al. 2013. Serum polyfluoroalkyl concentrations, asthma outcomes, and 

immunological markers in a case-control study of Taiwanese children. Environ Health Perspect 

121(4):507-513.

+Dong GH, Zhang YH, Zheng L, et al. 2009. Chronic effects of perfluorooctanesulfonate exposure on 

immunotoxicity in adult male C57BL/6 mice. Arch Toxicol 83(9):805-815.

DRBC. 2013. Contaminants of emerging concern in the tidal Delaware River: Pilot monitoring survey 

2007-2009. Delaware River Basin Commission. 

http://www.nj.gov/drbc/library/documents/contaminants-of-emerging-concernAug2013rev.pdf. July 

6, 2017. 

Ducatman AM, Zhang J, Fan H. 2015a. Letter to the editor. (Prostate-specific antigen and 

perfluoroalkyl acids in the C8 health study population. J Occup Environ Med 57(1):111-114). J 

Occup Environ Med 57(6):e61. 10.1097/jom.0000000000000470. 

Ducatman A, Zhang J, Fan H. 2015b. Prostate-specific antigen and perfluoroalkyl acids in the C8 health

study population. J Occup Environ Med 57(1):111-114. 10.1097/jom.0000000000000319.

DuPont. 2008. Information on PFOA. http://repanet.de/PFOA2/en_US/index.html. April 07, 2008.

DWQI. 2015. Maximum contaminant level recommendation for perfluorononanoic acid in drinking 

water. Trenton, NJ: New Jersey Drinking Water Quality Institute. 

http://www.nj.gov/dep/watersupply/pdf/pfna-recommend-final.pdf. December 18, 2017. 

DWQI. 2017a. Maximum contaminant level recommendation for perfluorooctanoic acid in drinking 

water. Trenton, NJ: New Jersey Drinking Water Quality Institute. 

http://www.nj.gov/dep/watersupply/pdf/pfoa-recommend.pdf. December 18, 2017.

DWQI. 2017b. Public review draft: Perfluorooctane sulfonate (PFOS) (CAS #: 1763-23-1; Chemical 

Formula: C8HF17O3S). Health-based maximum contaminant level support document. Trenton, NJ: 

Health Effects Subcommitttee, New Jersey Drinking Water Quality Institute. 

http://www.nj.gov/dep/watersupply/pdf/dwqi-pfos-mcl-draft.pdf. December 18, 2017. 

Eggen T, Moeder M, Arukwe A. 2010. Municipal landfill leachates: A significant source for new and 

emerging pollutants. Sci Total Environ 408:5147-5157. 

Ehresman DJ, Froehlich JW, Olsen GW, et al. 2007. Comparison of human whole blood, plasma, and 

serum matrices for the determination of perfluorooctanesulfonate (PFOS), perfluorooctanoate 

(PFOA), and other fluorochemicals. Environ Res 103:176-184.

Eke D, Celik A. 2016. Curcumin prevents perfluorooctane sulfonate-induced genotoxicity and oxidative 

DNA damage in rat peripheral blood. Drug Chem Toxicol 39(1):97-103. 

10.3109/01480545.2015.1041601. 
PERFLUOROALKYLS 658

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

+Elcombe CR, Elcombe BM, Foster JR, et al. 2010. Hepatocellular hypertrophy and cell proliferation in 

Sprague-Dawley rats following dietary exposure to ammonium perfluorooctanoate occurs through 

increased activation of the xenosensor nuclear receptors PPARα and CAR/PXR. Arch Toxicol 

84(10):787-798.

+Elcombe CR, Elcombe BM, Foster JR, et al. 2012b. Evaluation of hepatic and thyroid responses in 

male Sprague Dawley rats for up to eighty-four days following seven days of dietary exposure to 

potassium perfluorooctanesulfonate. Toxicology 293(1-3):30-40.

+Elcombe CR, Elcombe BM, Foster JR, et al. 2012a. Hepatocellular hypertrophy and cell proliferation 

in Sprague-Dawley rats from dietary exposure to potassium perfluorooctanesulfonate results from 

increased expression of xenosensor nuclear receptors PPARα and CAR/PXR. Toxicology 293(1-

3):16-29.

Eldasher LM, Wen X, Little MS, et al. 2013. Hepatic and renal Bcrp transporter expression in mice 

treated with perfluorooctanoic acid. Toxicology 306:108-113.

Ellis DA, Martin JW, De Silva AO, et al. 2004. Degradation of fluorotelomer alcohols: A likely 

atmospheric source of perfluorinated carboxylic acids. Environ Sci Technol 27:3316-3321.

Emmett EA, Shofer FS, Zhang H, et al. 2006a. Community exposure to perfluorooctanoate: 

Relationships between serum concentrations and exposure sources. J Occup Environ Med 48:759-

770.

Emmett EA, Zhang H, Shofer FS, et al. 2006b. Community exposure to perfluorooctanoate: 

Relationships between serum levels and certain health parameters. J Occup Environ Med 48(8):771-

779.

Emmett EA, Zhang H, Shofer FS, et al. 2009. Development and successful application of a "communityfirst" communication model for community-based environmental health research. J Occup Environ 

Med 51(2):146-156.

EPA. 1988. Recommedations for and documentation of biological values for use in risk assessment. 

Washington, DC: U.S. Environmental Protection Agency. PB88179874. 

EPA. 2002. Perfluoroalkyl sulfonates; significant new use rule. U.S. Environmental Protection Agency. 

Fed Regist 67(236):72854-72867.

EPA. 2005a. Draft risk assessment of the potential human health effects associated with exposure to 

perfluorooctanoic acid and its salts. U.S. Environmental Protection Agency. 

http://www.epa.gov/opptintr/pfoa/pubs/pfoarisk.pdf. June 26, 2007.

EPA. 2005b. Toxic chemical release inventory reporting forms and instructions: Revised 2004 version. 

Section 313 of the Emergency Planning and Community Right-to-Know Act (Title III of the 

Superfund Amendments and Reauthorization Act of 1986). U.S. Environmental Protection Agency. 

Office of Environmental Information. EPA260B05001.

EPA. 2005c. Guidelines for carcinogen risk assessment. Washington, DC: U.S. Environmental 

Protection Agency. EPA630P03001F. 

http://www.epa.gov/raf/publications/pdfs/CANCER_GUIDELINES_FINAL_3-25-05.PDF. 

December 10, 2014. 

EPA. 2006. SAB review of EPA's draft risk assessment of potential human health effects associated with 

PFOA and its salts. U.S. Environmental Protection Agency. 

http://yosemite.epa.gov/sab/sabproduct.nsf/A3C83648E77252828525717F004B9099/$File/sab_06_

006.pdf. April 24, 2008.

EPA. 2007a. Perfluoroalkyl sulfonates; significant new use rule. U.S. Environmental Protection 

Agency. Fed Regist 72:57222-57235.

EPA. 2007b. Quarterly MOU status report #6: Phase II monitoring/sampling work plan, DuPont 

Washington Works (PFOA site-related environmental assessment program), Appendices 3.1 through 

5.1. U.S. Environmental Protection Agency. EPA-HQ-OPPT-2004-0113-0242.1. 

http://www.regulations.gov/fdmspublic/component/main?main=DocketDetail&d=EPA-HQ-OPPT2004-0113. May 18, 2009.
PERFLUOROALKYLS 659

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

EPA. 2008a. Perfluorooctanoic acid (PFOA) and fluorinated telomers. U.S. Environmental Protection 

Agency. http://www.epa.gov/oppt/pfoa/. May 29, 2008. 

EPA. 2008b. Non-confidential IUR production volume information. Inventory updating reporting. U.S. 

Environmental Protection Agency. http://www.epa.gov/opptintr/iur/tools/data/2002-vol.htm. July 

09, 2008.

EPA. 2008c. Perfluoroalkyls. Substance registry system. U.S. Environmental Protection Agency. 

http://www.epa.gov/srs/. July 10, 2008. 

EPA. 2008d. Quarterly MOU status report #10: Phase II monitoring/sampling work plan, DuPont 

Washington Works (PFOA site-related environmental assessment program), text, tables 4.1 through 

5.10. U.S. Environmental Protection Agency. EPA-HQ-OPPT-2004-0113-0430. 

http://www.regulations.gov/fdmspublic/component/main?main=DocketDetail&d=EPA-HQ-OPPT2004-0113. May 18, 2009. 

EPA. 2009a. PFOS chromium electroplater study. Cleveland, OH: U.S. Environmental Protection 

Agency- Region 5. 

EPA. 2009b. Perfluorocarboxylic acid content in 116 articles of commerce. Research Triangle Park, 

NC: U.S. Environmental Protection Agency, National Risk Management Research Laboratory, 

Office of Research and Development. EPA600R09033. 

EPA. 2009c. Method 537. Determination of selected perfluorinated alkyl acids in drinking water by 

solid phase extraction and liquid chromatography/tandem mass spectrometry (LC/MS/MS). U.S. 

Environmental Protection Agency. 

http://www.epa.gov/microbes/documents/Method%20537_FINAL_rev1.1.pdf. May 5, 2014. 

EPA. 2009d. National primary drinking water regulations. Washington, DC: Office of Ground Water 

and Drinking Water, U.S. Environmental Protection Agency. EPA816F090004. 

https://www.epa.gov/sites/production/files/2016-06/documents/npwdr_complete_table.pdf. 

February 28, 2017. 

EPA. 2010. Quarterly MOU Status Report #17. Phase II. Monitoring/sampling work plan. DuPont 

Washington Works (OPPT-2004-0113 PFOA site-related environmental asssessment program). 

U.S. Environmental Protection Agency. Project No: 18984356.05013. 

EPA. 2014. Health effects document for perfluorooctanoic acid (PFOA). U.S. Environmental Protection 

Agency. EPA822R14001. https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=P100IRZ1.txt. 

December 21, 2017.

EPA. 2015. Long-chain perfluoroalkyl carboxylate and perfluoroalkyl sulfonate chemical substances: 

Significan new use rule. Fed Regist 80(13):2885-2898. 

EPA. 2016a. 2010/2015 PFOA Stewardship Program- 2014 annual progress reports. U.S. 

Environmental Protection Agency. https://www.epa.gov/assessing-and-managing-chemicals-undertsca/20102015-pfoa-stewardshiip-program-2014-annual-progress#summary. August 08, 2016. 

EPA. 2016b. Compiled AEGL values. Acute Exposure Guideline Levels (AEGLs) Values. U.S. 

Environmental Protection Agency. https://www.epa.gov/sites/production/files/2016-

03/documents/compiled_aegl_update_.pdf. February 28, 2017. 

EPA. 2016c. The Third Unregulated Contaminant Monitoring Rule (UCMR 3): Data summary, July 

2016. U.S. Environmental Protection Agency, Office of Water.

EPA. 2016d. Chemical Data Access Tool (CDAT). U.S. Environmental Protection Agency. 

https://java.epa.gov/oppt_chemical_search/. December 09, 2016. 

EPA. 2016e. Drinking water health advisory for perfluorooctanoic acid (PFOA). U.S. Environmental 

Protection Agency. https://www.epa.gov/sites/production/files/2016-

05/documents/pfoa_health_advisory_final-plain.pdf. March 3, 2017. 

EPA. 2016f. Drinking water health advisory for perfluorooctane sulfonate (PFOS). U.S. Environmental 

Protection Agency. https://www.epa.gov/sites/production/files/2016-

05/documents/pfos_health_advisory_final-plain.pdf. March 3, 2017. 

EPA. 2016g. Toxic chemical release inventory reporting forms and instructions: Revised 2016 version. 

Section 313 of the Emergency Planning and Community Right-to-Know Act (Title III of the 
PERFLUOROALKYLS 660

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Superfund Amendments and Reauthorization Act of 1986). U.S. Environmental Protection Agency, 

Office of Environmental Information. EPA740B16001. 

https://ofmpub.epa.gov/apex/guideme_ext/guideme_ext/r/files/static/v3321/rfi/RY_2016_RFI.pdf. 

July 5, 2017. 

EPA. 2016h. Health effects support document for perfluorooctanoic acid (PFOA). U.S. Environmental 

Protection Agency. EPA822R16003. https://www.epa.gov/sites/production/files/2016-

05/documents/pfoa_hesd_final-plain.pdf. July 6, 2017.

EPA. 2016i. Health effects support document for perfluorooctane sulfate (PFOS). U.S. Environmental 

Protection Agency. EPA822R16002. https://www.epa.gov/sites/production/files/2016-

05/documents/pfos_hesd_final_508.pdf. July 6, 2017.

EPA. 2016j. Lifetime health advisories and health effects support documents for perfluorooctanoic acid 

and perfluoroactoane sulfonates. Federal Register. U.S. Environmental Protection Agency. Vol. 81 

FR 33250 (May 25, 2016). https://www.epa.gov/sites/production/files/2016-05/documents/2016-

12361.pdf. December 18, 2017.

+Era S, Harada KH, Toyoshima M, et al. 2009. Cleft palate caused by perfluorooctane sulfonate is 

caused mainly by extrinsic factors. Toxicology 256(1-2):42-47.

EPA. 2017. The third Unregulated Contaminant Monitoring Rule (UCMR 3): Data summary, January 

2017. U.S. Environmental Protection Agency. https://www.epa.gov/sites/production/files/2017-

02/documents/ucmr3-data-summary-january-2017.pdf. July 6, 2017.

Ericson I, Domingo JL, Nadal M, et al. 2009. Levels of perfluorinated chemicals in municipal drinking 

water from Catalonia, Spain: Public health implications. Arch Environ Contam Toxicol 57(4):631-

638. 10.1007/s00244-009-9375-y.

Ericson I, Gómez M, Nadal M, et al. 2007. Perfluorinated chemicals in blood of residents in Catalonia 

(Spain) in relation to age and gender: A pilot study. Environ Int 33:616-623.

Eriksen KT, Raaschou-Nielsen O, McLaughlin JK, et al. 2013. Association between plasma PFOA and 

PFOS levels and total cholesterol in a middle-aged Danish population. PLoS ONE 8(2):e56969.

Eriksen KT, Raaschou-Nielsen O, Sorensen M, et al. 2010. Genotoxic potential of the perfluorinated 

chemicals PFOA, PFOS, PFBS, PFNA and PFHxA in human HepG2 cells. Mutat Res 700(1-2):39-

43. 10.1016/j.mrgentox.2010.04.024. 

Eriksen KT, Sorensen M, McLaughlin JK, et al. 2009. Perfluorooctanoate and perfluorooctanesulfonate 

plasma levels and risk of cancer in the general Danish population. J Natl Cancer Inst 101(8):605-

609.

Fábrega F, Kumar V, Schuhmacher M, et al. 2014. PBPK modeling for PFOS and PFOA: Validation 

with human experimental data. Toxicol Lett 230(2):244-251.

Fábrega F, Nadal M, Schuhmacher M, et al. 2016. Influence of the uncertainty in the validation of PBPK 

models: A case-study for PFOS and PFOA. Regul Toxicol Pharmacol 77:230-239. 

10.1016/j.yrtph.2016.03.009

+Fairley KJ, Purdy R, Kearns S, et al. 2007. Exposure to the immunosuppresant, perfluorooctanoic acid, 

enhances the murine IgE and airway hyperreactivity response to ovalbumin. Toxicol Sci 97(2):375-

383.

+Fang X, Feng Y, Shi Z, et al. 2009. Alterations of cytokines and MAPK signaling pathways are related 

to the immunotoxic effect of perfluorononanoic acid. Toxicol Sci 108(2):367-376. 

10.1093/toxsci/kfp019. 

+Fang X, Feng Y, Wang J, et al. 2010. Perfluorononanoic acid-induced apoptosis in rat spleen involves 

oxidative stress and the activation of caspase-independent death pathway. Toxicology 267(1-3):54-

59. 10.1016/j.tox.2009.10.020. 

+Fang X, Gao G, Xue H, et al. 2012a. Exposure of perfluorononanoic acid suppresses the hepatic insulin 

signal pathway and increases serum glucose in rats. Toxicology 294(2-3):109-115.

+Fang X, Gao G, Xue H, et al. 2012b. In vitro and in vivo studies of the toxic effects of 

perfluorononanoic acid on rat hepatocytes and Kupffer cells. Environ Toxicol Pharmacol 34(2):484-

494.
PERFLUOROALKYLS 661

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

+Fang X, Zhang L, Feng Y, et al. 2008. Immunotoxic effects of perfluorononanoic acid on BALB/c 

mice. Toxicol Sci 105(2):312-321.

Fasano WJ, Carpenter SC, Gannon SA, et al. 2006. Absorption, distribution, metabolism, and 

elimination of 8-2 fluorotelomer alcohol in the rat. Toxicol Sci 91(2):341-355.

Fasano WJ, Kennedy GL, Szostek B, et al. 2005. Penetration of ammonium perfluorooctanoate through 

rat and human skin in vitro. Drug Chem Toxicol 28(1):79-90.

FDA. 2013. Everything added to food in the United States (EAFUS). Washington, DC: U.S. Food and 

Drug Administration. http://www.accessdata.fda.gov/scripts/fcn/fcnnavigation.cfm?rpt=eafuslisting. 

February 28, 2017.

Fei C, Olsen J. 2011. Prenatal exposure to perfluorinated chemicals and behavioral or coordination 

problems at age 7 years. Environ Health Perspect 119(4):573-578.

Fei C, McLaughlin JK, Lipworth L, et al. 2009. Maternal levels of perfluorinated chemicals and 

subfecundity. Hum Reprod 24(5):1200-1205.

Fei C, McLaughlin JK, Lipworth L, et al. 2008b. Prenatal exposure to perfluorooctanoate (PFOA) and 

perfluorooctanesulfonate (PFOS) and maternally reported developmental milestones in infancy. 

Environ Health Perspect 116(10):1391-1395.

Fei C, McLaughlin JK, Tarone RE, et al. 2007. Perfluorinated chemicals and fetal growth: A study 

within the Danish National Birth Cohort. Environ Health Perspect 115:1677-1682.

Fei C, McLaughlin JK, Tarone RE, et al. 2008a. Fetal growth indicators and perfluorinated chemicals: 

A study in the Danish National Birth Cohort. Am J Epidemiol 168(1):66-72.

Fei C, McLaughlin JK, Lipworth L, et al. 2010. Prenatal exposure to PFOA and PFOS and risk of 

hospitalization for infectious diseases in early childhood. Environ Res 110(8):773-777. 

10.1016/j.envres.2010.08.004. 

Fei C, Weinberg CR, Olsen J. 2012. Commentary: Perfluorinated chemicals and time to pregnancy: A 

link based on reverse causation? Epidemiology 23(2):264-266.

Feng Y, Fang X, Shi Z, et al. 2010. Effects of PFNA exposure on expression of junction-associated 

molecules and secretory function in rat Sertoli cells. Reprod Toxicol 30(3):429-437. 

10.1016/j.reprotox.2010.05.010. 

Feng Y, Shi Z, Fang X, et al. 2009. Perfluorononanoic acid induces apoptosis involving the Fas death 

receptor signaling pathway in rat testis. Toxicol Lett 190(2):224-230. 10.1016/j.toxlet.2009.07.020. 

Fenton SE, Reiner JL, Nakayama SF, et al. 2009. Analysis of PFOA in dosed CD-1 mice. Part 2. 

Disposition of PFOA in tissues and fluids from pregnant and lactating mice and their pups. Reprod 

Toxicol 27(3-4):365-372.

Fernández Freire P, Pérez Martin JM, Herrero O, et al. 2008. In vitro assessment of the cytotoxic and 

mutagenic potential of perfluorooctanoic acid. Toxicol in Vitro 22:1228-1233.

Filgo AJ, Quist EM, Hoenerhoff MJ, et al. 2015a. Perfluorooctanoic Acid (PFOA)-induced liver lesions 

in two strains of mice following developmental exposures: PPARalpha is not required. Toxicol 

Pathol 43(4):558-568. 10.1177/0192623314558463. 

Filgo AJ, Quist EM, Hoenerhoff MJ, et al. 2015b. Supplemental data to perfluorooctanoic acid (PFOA)-

induced liver lesions in two strains of mice following developmental exposures: PPARalpha is not 

required. [Toxicol Pathol 43(4):558-568]. Toxicol Pathol 10.1177/0192623314558463. 

Fisher M, Arbuckle TE, Wade M, et al. 2013. Do perfluoroalkyl substances affect metabolic function 

and plasma lipids? Analysis of the 2007-2009, Canadian Health Measures Survey (CHMS) Cycle 1. 

Environ Res 121:95-103.

Fisher M, Arbuckle TE, Liang CL, et al. 2016. Concentrations of persistent organic pollutants in 

maternal and cord blood from the maternal-infant research on environmental chemicals (MIREC) 

cohort study. Environ Health 15(1):59. 

Fitz-Simon N, Fletcher T, Luster MI, et al. 2013. Reductions in serum lipids with a 4-year decline in 

serum perfluorooctanoic acid and perfluorooctanesulfonic acid. Epidemiology 24(4):569-576.
PERFLUOROALKYLS 662

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Florentin A, Deblonde T, Diguio N, et al. 2011. Impacts of two perfluorinated compounds (PFOS and 

PFOA) on human hepatoma cells: Cytotoxicity but no genotoxicity? Int J Hyg Environ Health 

214(6):493-499.

Food Standards Agency. 2006. FSIS 11/06. Fluorinated chemicals: UK dietary intakes. Food 

Standards Agency. http://www.food.gov.uk/multimedia/pdfs/fsis1106.pdf. June 28, 2008.

Foreman JE, Chang SC, Ehresman DJ, et al. 2009. Differential hepatic effects of perfluorobutyrate 

mediated by mouse and human PPAR-α. Toxicol Sci 110(1):204-211. 10.1093/toxsci/kfp077. 

Forns J, Iszatt N, White RA, et al. 2015. Perfluoroalkyl substances measured in breast milk and child 

neuropsychological development in a Norwegian birth cohort study. Environ Int 83:176-182. 

Franko J, Meade BJ, Frasch HF, et al. 2012. Dermal penetration potential of perfluorooctanoic acid 

(PFOA) in human and mouse skin. J Toxicol Environ Health A 75(1):50-62.

Frisbee SJ, Brooks AP, Jr., Maher A, et al. 2009. The C8 health project: Design, methods, and 

participants. Environ Health Perspect 117(12):1873-1882.

Frisbee SJ, Shankar A, Knox SS, et al. 2010. Perfluorooctanoic acid, perfluorooctanesulfonate, and 

serum lipids in children and adolescents: Results from the C8 Health Project. Arch Pediatr Adolesc 

Med 164(9):860-869.

Fromme H, Midasch O, Twardella D, et al. 2007a. Occurrence of perfluorinated substances in an adult 

German population in southern Bavaria. Int Arch Occup Environ Health 80:313-319.

Fromme H, Mosch C, Morovitz M, et al. 2010. Pre- and postnatal exposure to perfluorinated compounds 

(PFCs). Environ Sci Technol 44(18):7123-7129.

Fromme H, Schlummer M, Moller A, et al. 2007b. Exposure of an adult population to perfluorinated 

substances using duplicate diet portions and biomonitoring data. Environ Sci Technol 41:7928-

7933.

Fromme H, Tittlemier SA, Volkel W, et al. 2009. Perfluorinated compounds-exposure assessment for 

the general population in western countries. Int J Hyg Environ Health 212(3):239-270.

Fu J, Gao Y, Wang T, et al. 2015. Elevated levels of perfluoroalkyl acids in family members of 

occupationally exposed workers: The importance of dust transfer. Scientific reports 5:9313. 

10.1038/srep09313.

Fu Y, Wang T, Fu Q, et al. 2014a. Associations between serum concentrations of perfluoroalkyl acids 

and serum lipid levels in a Chinese population. Ecotoxicol Environ Saf 106:246-252. 

10.1016/j.ecoenv.2014.04.039. 

Fu Y, Wang T, Wang P, et al. 2014b. Effects of age, gender and region on serum concentrations of 

perfluorinated compounds in general population of Henan, China. Chemosphere 110:104-110. 

10.1016/j.chemosphere.2014.02.020.

+Fuentes S, Colomina MT, Rodriguez J, et al. 2006. Interactions in developmental toxicology: 

Concurrent exposure to perfluorooctane sulfonate (PFOS) and stress in pregnant mice. Toxicol Lett 

164(1):81-89.

Fuentes S, Colomina MT, Vicens P, et al. 2007a. Influence of maternal restraint stress on the longlasting effects induced by prenatal exposure to perfluorooctane sulfonate (PFOS) in mice. Toxicol 

Lett 171:162-170.

Fuentes S, Colomina MT, Vicens P, et al. 2007b. Concurrent exposure to perfluoroactane sulfonate and 

restraint stress during pregnancy in mice: Effects on postnatal development and behavior of the 

offspring. Toxicol Sci 98:589-598.

+Fuentes S, Vicens P, Colomina MT, et al. 2007c. Behavioral effects in adult mice exposed to 

perfluorooctane sulfonate (PFOS). Toxicology 242:123-129.

Fujii Y, Harada KH, Koizumi A. 2013. Occurrence of perfluorinated carboxylic acids (PFCAs) in 

personal care products and compounding agents. Chemosphere 93(3):538-544.

Fujii Y, Niisoe T, Harada KH, et al. 2015a. Toxicokinetics of perfluoroalkyl carboxylic acids with 

different carbon chain lengths in mice and humans. J Occup Health 57(1):1-12. 10.1539/joh.14-

0136-OA. 
PERFLUOROALKYLS 663

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Fujii Y, Niisoe T, Harada KH, et al. 2015b. Supplemental materials: Toxicokinetics of perfluoroalkyl 

carboxylic acids with different carbon chain lengths in mice and humans. J Occup Health 57(1):1-

12. 

Fujii Y, Yan J, Harada KH, et al. 2012. Levels and profiles of long-chain perfluorinated carboxylic acids 

in human breast milk and infant formulas in East Asia. Chemosphere 86(3):315-321.

Furdui F, Stock N, Ellis DA, et al. 2007. Spatial distribution of perfluoroalkyl contaminants in lake trout 

from the Great Lakes. Environ Sci Technol 41:1554-1559.

Gallo V, Leonardi G, Brayne C, et al. 2013. Serum perfluoroalkyl acids concentrations and memory 

impairment in a large cross-sectional study. BMJ Open 3(6):e002414.

Gallo V, Leonardi G, Genser B, et al. 2012. Serum perfluorooctanoate (PFOA) and perfluorooctane 

sulfonate (PFOS) concentrations and liver function biomarkers in a population with elevated PFOA 

exposure. Environ Health Perspect 120(5):655-660.

Gao B, He X, Liu W, et al. 2015. Distribution of perfluoroalkyl compounds in rats: Indication for using 

hair as bioindicator of exposure. J Expo Sci Environ Epidemiol 25(6):632-638. 

Gauthier SA, Mabury SA. 2005. Aqueous photolysis of 8:2 fluorotelomer alcohol. Environ Toxicol 

Chem 24(8):1837-1846.

Geiger SD, Xiao J, Shankar A. 2014a. No association between perfluoroalkyl chemicals and 

hypertension in children. Integrated blood pressure control 7:1-7. 10.2147/ibpc.s47660. 

Geiger SD, Xiao J, Ducatman A, et al. 2014b. The association between PFOA, PFOS and serum lipid 

levels in adolescents. Chemosphere 98:78-83. 10.1016/j.chemosphere.2013.10.005. 

Geiger SD, Xiao J, Shankar A. 2013. Positive association between perfluoroalkyl chemicals and 

hyperuricemia in children. Am J Epidemiol 177(11):1255-1262.

Gellrich V, Brunn H, Stahl T. 2013. Perfluoroalkyl and polyfluoroalkyl substances (PFASs) in mineral 

water and tap water. J Environ Sci Health A Tox Hazard Subst Environ Eng 48(2):129-135. 

10.1080/10934529.2013.719431.

Genuis SJ, Beesoon S, Birkholz D. 2013. Biomonitoring and elimination of perfluorinated compounds 

and polychlorinated biphenyls through perspiration: Blood, urine, and sweat study. ISRN 

toxicology 2013:483832. 

George ME, Andersen ME. 1986. Toxic effects of nonadecafluoro-n-decanoic acid in rats. Toxicol Appl 

Pharmacol 85:169-180.

Gewurtz SB, Bhavsar SP, Crozier PW, et al. 2009. Perfluoroalkyl contaminants in window film: 

Indoor/outdoor, urban/rural, and winter/summer contamination and assessment of carpet as a 

possible source. Environ Sci Technol 43(19):7317-7323.

Gewurtz SB, Bhavsar SP, Petro S, et al. 2014. High levels of perfluoroalkyl acids in sport fish species 

downstream of a firefighting training facility at Hamilton International Airport, Ontario, Canada. 

Environ Int 67:1-11. 10.1016/j.envint.2014.02.005.

Giesy JP, Kannan K. 2001. Global distribution of perfluorooctane sulfonate in wildlife. Environ Sci 

Technol 35(7):1339-1342.

Gilliland FD, Mandel JS. 1993. Mortality among employees of a perfluorooctanoic acid production 

plant. J Occup Med 35(9):950-954.

Gilliland FD, Mandel JS. 1996. Serum perfluorooctanoic acid and hepatic enzymes, lipoproteins, and 

cholesterol: A study of occupationally exposed men. Am J Ind Med 29(5):560-568.

Gleason JA, Post GB, Fagliano JA. 2015. Associations of perfluorinated chemical serum concentrations 

and biomarkers of liver function and uric acid in the US population (NHANES), 2007-2010. 

Environ Res 136:8-14. 10.1016/j.envres.2014.10.004. 

Glynn A, Berger U, Bignert A, et al. 2012. Perfluorinated alkyl acids in blood serum from primiparous 

women in Sweden: Serial sampling during pregnancy and nursing, and temporal trends 1996-2010. 

Environ Sci Technol 46:9071-9079. 

Goecke CM, Jarnot BM, Reo NV. 1992. A comparative toxicological investigation of 

perfluorocarboxylic acids in rats by fluorine-19 NMR spectroscopy. Chem Res Toxicol 5(4):512-

519.
PERFLUOROALKYLS 664

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Goecke-Flora CM, Reo NV. 1996. Influence of carbon chain length on the hepatic effects of 

perfluorinated fatty acids. A 19F- and 31P-NMR investigation. Chem Res Toxicol 9(4):689-695.

+Gortner EG, Lamprecht EG, Case MT. 1982. Oral teratology study of T-3141CoC in rabbits. St. Paul, 

MN: Riker Laboratories, Inc.

Gotoh Y, Kato Y, Stieger B, et al. 2002. Gender difference in the Oatp1-mediated tubular reabsorption 

of estradiol 17β-D-glucuronide in rats. Am J Physiol Endocrinol Metab 282:E1245-E1254.

Goudarzi H, Nakajima S, Ikeno T, et al. 2016. Prenatal exposure to perfluorinated chemicals and 

neurodevelopment in early infancy: The Hokkaido Study. Sci Total Environ 541:1002-1010. 

10.1016/j.scitotenv.2015.10.017.

Govarts E, Remy S, Bruckers L, et al. 2016. Combined effects of prenatal exposures to environmental 

chemicals on birth weight. Int J Environ Res Public Health 13(5) 10.3390/ijerph13050495. 

Grandjean P, Budtz-Jorgensen E. 2013. Immunotoxicity of perfluorinated alkylates: Calculation of 

benchmark doses based on serum concentrations in children. Environ Health 12(1):35.

Grandjean P, Andersen EW, Budtz-Jorgensen E, et al. 2012. Serum vaccine antibody concentrations in 

children exposed to perfluorinated compounds. J Am Med Assoc 307(4):391-397.

Grandjean P, Heilmann C, Weihe P, et al. 2017. Serum vaccine antibody concentrations in adolescents 

exposed to perfluorinated compounds. Environ Health Perspect. 125(7):077018. 10.1289/EHP275. 

Granum B, Haug LS, Namork E, et al. 2013. Pre-natal exposure to perfluoroalkyl substances may be 

associated with altered vaccine antibody levels and immune-related health outcomes in early 

childhood. J Immunotoxicol 10(4):373-379.

+Grasty RC, Bjork JA, Wallace KB, et al. 2005. Effects of prenatal perfluorooctane sulfonate (PFOS) 

exposure on lung maturation in the perinatal rat. Birth Defects Res B Dev Reprod Toxicol 74:405-

416.

+Grasty RC, Wolf DC, Grey BE, et al. 2003. Prenatal window of susceptibility to perfluorooctane 

sulfonate-induced neonatal mortality in the Sprague-Dawley rat (corrigendum in Birth Defects Res B 

77(1):86). Birth Defects Res B 68(6):465-471.

Grice MM, Alexander BH, Hoffbeck R, et al. 2007. Self-reported medical conditions in 

perfluorooctanesulfonyl fluoride manufacturing workers. J Occup Environ Med 49(7):722-729.

+Griffith FD, Long JE. 1980. Animal toxicity studies with ammonium perfluorooctanoate. Am Ind Hyg 

Assoc J 41(8):576-583.

Gump BB, Wu Q, Dumas AK, et al. 2011. Perfluorochemical (PFC) exposure in children: Associations 

with impaired response inhibition. Environ Sci Technol 45(19):8151-8159.

Guo R, Sim WJ, Lee ES, et al. 2010. Evaluation of the fate of perfluoroalkyl compounds in wastewater 

treatment plants. Water Res 44(11):3476-3486. 10.1016/j.watres.2010.03.028.

+Guruge KS, Hikono H, Shimada N, et al. 2009. Effect of perflluorooctane sulfonate (PFOS) on 

influenza A virus-induced mortality in female B6C3F1 mice. J Toxicol Sci 34(6):687-691.

Guruge KS, Yeung LW, Yamanaka N, et al. 2006. Gene expression profiles in rat liver treated with 

perfluorooctanoic acid (PFOA). Toxicol Sci 89(1):93-107.

Gützkow KB, Haug LS, Thomsen C, et al. 2012. Placental transfer of perfluorinated compounds is 

selective. A Norwegian mother and child sub-cohort study. Int J Hyg Environ Health 215(2):216-

219.

+Hadrup N, Pedersen M, Skov K, et al. 2016. Perfluorononanoic acid in combination with 14 chemicals 

exerts low-dose mixture effects in rats. Arch Toxicol 90(3):661-675. 10.1007/s00204-015-1452-6. 

HAES. 2017. GEF-Reduction and phase-out of PFOS in priority sectors in China. Environmenstal & 

Social Management Framework. Hubei Academy of Environmental Sciences, Foreign Economic 

Cooperation Office, Ministry of Environmental Protection (FECO). 

http://documents.worldbank.org/curated/en/2752514607008/Environmental-and-social-managementframework. February 28, 2017.

Hall AP, Elcombe CR, Foster JR, et al. 2012. Liver hypertrophy: A review of adaptive (adverse and 

non-adverse) changes- conclusions from the 3rd International ESTP Expert Workshop. Toxicol 

Pathol 40:971-994. 
PERFLUOROALKYLS 665

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Halldorsson TI, Rytter D, Haug LS, et al. 2012. Prenatal exposure to perfluorooctanoate and risk of 

overweight at 20 years of age: A prospective cohort study. Environ Health Perspect 120(5):668-

673.

+Hallgren S, Fredriksson A, Viberg H. 2015. More signs of neurotoxicity of surfactants and flame 

retardants - neonatal PFOS and PBDE 99 cause transcriptional alterations in cholinergic genes in the 

mouse CNS. Environ Toxicol Pharmacol 40(2):409-416. 10.1016/j.etap.2015.06.014. 

Hamm MP, Cherry NM, Chan E, et al. 2010. Maternal exposure to perfluorinated acids and fetal growth. 

J Expo Sci Environ Epidemiol 20(7):589-597.

Hamm MP, Martin JW, Chan E, et al. 2009. Maternal exposure to perfluorinated acids and fetal growth 

restriction. Am J Epidemiol 169(Suppl. 11):S43. 

Han X, Hinderliter PM, Snow TA, et al. 2004. Binding of perfluorooctanoic acid to rat liver-form and 

kidney-form α2u-globulins. Drug Chem Toxicol 27(4):341-360.

Han X, Kemper RA, Jepson GW. 2005. Subcellular distribution and protein binding of 

perfluorooctanoic acid in rat liver and kidney. Drug Chem Toxicol 28(2):197-209.

Han X, Snow TA, Kemper RA, et al. 2003. Binding of perfluorooctanoic acid to rat and human plasma 

proteins. Chem Res Toxicol 16:775-781.

Hanhijarvi H, Ophaug RH, Singer L. 1982. The sex-related difference in perfluorooctanoate excretion in 

the rat. Proc Soc Exp Biol Med 171:50-55.

Hanhijarvi H, Ylinen M, Kojo A, et al. 1987. Elimination and toxicity of perfluorooctanoic acid during 

subchronic administration in the Wistar rat. Pharmacol Toxicol 61(1):66-68.

Hansen KJ, Johnson HO, Eldridge JS, et al. 2002. Quantitative characterization of trace levels of PFOS 

and PFOA in the Tennessee River. Environ Sci Technol 36:1681-1685.

Hanssen L, Dudarev AA, Huber S, et al. 2013. Partition of perfluoroalkyl substances (PFASs) in whole 

blood and plasma, assessed in maternal and umbilical cord samples from inhabitants of arctic Russia 

and Uzbekistan. Sci Total Environ 447:430-437.

Hanssen L, Rollin H, Odland JO, et al. 2010. Perfluorinated compounds in maternal serum and cord 

blood from selected areas of South Africa: Results of a pilot study. J Environ Monit 12(6):1355-

1361.

Harada K, Inoue K, Morikawa A, et al. 2005a. Renal clearance of perfluorooctane sulfonate and 

perfluorooctanoate in humans and their species-specific excretion. Environ Res 99:253-261.

Harada K, Nakanishi S, Saito N, et al. 2005b. Airborne perfluorooctanoate may be a substantial source 

contamination in Kyoto area, Japan. Bull Environ Contam Toxicol 74:64-69.

Harada K, Nakanishi S, Sasaki K, et al. 2006. Particle size distribution and respiratory deposition 

estimates of airborne perfluorooctanoate and perfluorooctanesulfonate in Kyoto area, Japan. Bull 

Environ Contam Toxicol 76(2):306-310.

Harada KH, Koizumi A. 2009. Environmental and biological monitoring of persistent fluorinated 

compounds in Japan and their toxicities. Environ Health Prev Med 14(1):7-19.

Harada KH, Hashida S, Kaneko T, et al. 2007. Biliary excretion and cerebrospinal fluid partition of 

perfluorooctanoate and perfluorooctane sulfonate in humans. Environ Toxicol Pharmacol 

24(2):134-139.

Hardell E, Karrman A, van Bavel B, et al. 2014. Case-control study on perfluorinated alkyl acids 

(PFAAs) and the risk of prostate cancer. Environ Int 63:35-39.

Hardisty JF, Willson GA, Brown WR, et al. 2010. Pathology Working Group review and evaluation of 

proliferative lesions of mammary gland tissues in female rats fed ammonium perfluorooctanoate 

(APFO) in the diet for 2 years. Drug Chem Toxicol 33(2):131-137.

Harris LA, Barton HA. 2008. Comparing single and repeated dosimetry data for perfluorooctane 

sulfonate in rats. Toxicol Lett 181(3):148-156.

+Harris MW, Birnbaum LS. 1989. Developmental toxicity of perfluorodecanoic acid in C57BL/6N 

mice. Fundam Appl Toxicol 12:442-448.

+Harris MW, Uraih LC, Birnbaum LS. 1989. Acute toxicity of perfluorodecanoic acid in C57BL/6 mice 

differs from 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fundam Appl Toxicol 13:723-726.
PERFLUOROALKYLS 666

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

+Haughom B, Spydevold O. 1992. The mechanism underlying the hypolipemic effect of 

perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid. 

Biochim Biophys Acta 1128(1):65-72.

Heilmann C, Budtz-Jorgensen E, Nielsen F, et al. 2010. Serum concentrations of antibodies against 

vaccine toxoids in children exposed perinatally to immunotoxicants. Environ Health Perspect 

118(10):1434-1438. 10.1289/ehp.1001975. 

Hekster FM, Laane RW, de Voogt P. 2003. Environmental and toxicity effects of perfluoroalkylated 

substances. Rev Environ Contam Toxicol 179:99-121.

Henderson WM, Smith MA. 2007. Perfluorooctanoic acid and perfluorononanoic acid in fetal and 

neonatal mice following in utero exposure to 8-2 fluorotelomer alcohol. Toxicol Sci 95(2):452-461.

Hinderliter PM, DeLorme MP, Kennedy GL. 2006a. Perfluorooctanoic acid: Relationship between 

repeated inhalation exposures and plasma PFOA concentration in the rat. Toxicology 222:80-85.

Hinderliter PM, Han X, Kennedy GL, et al. 2006b. Age effect on perfluorooctanoate (PFOA) plasma 

concentration in post-weaning rats following oral gavage with ammonium perfluorooctanoate 

(APFO). Toxicology 225:195-203.

Hinderliter PM, Mylchreest E, Gannon SA, et al. 2005. Perfluorooctanoate: Placental and lactational 

transport pharmacokinetics in rats. Toxicology 211:139-148.

+Hines EP, White SS, Stanko JP, et al. 2009. Phenotypic dichotomy following developmental exposure 

to perfluorooctanoic acid (PFOA) in female CD-1 mice: Low doses induce elevated serum leptin 

and insulin, and overweight in mid-life. Mol Cell Endocrinol 304(1-2):97-105.

+Hoberman AM, York RG. 2003. Oral (gavage) combined repeated dose toxicity study of T-7706 with 

the reproduction/developmental toxicity screening test. Argus Research. 

Hoffman K, Webster TF, Bartell SM, et al. 2011. Private drinking water wells as a source of exposure to 

perfluorooctanoic acid (PFOA) in communities surrounding a fluoropolymer production facility. 

Environ Health Perspect 119(1):92-97.

Hoffman K, Webster TF, Weisskopf MG, et al. 2010. Exposure to polyfluoroalkyl chemicals and 

attention deficit/hyperactivity disorder in U.S. children 12-15 years of age. Environ Health Perspect 

118(12):1762-1767.

Hölzer J, Midasch O, Rauchfuss K, et al. 2008. Biomonitoring of perflluorinated compounds in children 

and adults exposed to perfluorooctanoate-contaminated drinking water. Environ Health Perspect 

116(5):651-657.

Houde M, Bujas TD, Small J, et al. 2006a. Biomagnification of perfluoroalkyl compounds in the 

bottlenose dolphin (Tursiops truncatus) food web. Environ Sci Technol 40:4138-4144.

Houde M, Martin JW, Letcher RJ, et al. 2006b. Biological monitoring of polyfluoroalkyl substances: A 

Review. Environ Sci Technol 40(11):3463-3473.

Houde M, Wells RS, Fair PA, et al. 2005. Polyfluoroalkyl compounds in free-ranging bottlenose 

dolphins (Tursiops truncatus) from the Gulf of Mexico and the Atlantic Ocean. Environ Sci Technol 

39:6591-6598.

Høyer BB, Ramlau-Hansen CH, Obel C, et al. 2015a. Pregnancy serum concentrations of perfluorinated 

alkyl substances and offspring behaviour and motor development at age 5-9 years--a prospective 

study. Environ Health 14:2. 10.1186/1476-069x-14-2. 

Høyer BB, Ramlau-Hansen CH, Vrijheid M, et al. 2015b. Anthropometry in 5- to 9-Year-Old 

Greenlandic and Ukrainian Children in Relation to Prenatal Exposure to Perfluorinated Alkyl 

Substances. Environ Health Perspect 123(8):841-846. 10.1289/ehp.1408881. 

Hsu V, de LTVM, Zhao P, et al. 2014. Towards quantitation of the effects of renal impairment and 

probenecid inhibition on kidney uptake and efflux transporters, using physiologically based 

pharmacokinetic modelling and simulations. Clin Pharmacokinet 53(3):283-293. 10.1007/s40262-

013-0117-y. 

+Hu Q, Strynar MJ, DeWitt JC. 2010. Are developmentally exposed C57BL/6 mice insensitive to 

suppression of TDAR by PFOA? J Immunotoxicol 7(4):344-349.
PERFLUOROALKYLS 667

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Hu W, Jones PD, Upham BL, et al. 2002. Inhibition of gap junctional intercellular communication by 

perfluorinated compounds in rat liver and dolphin kidney epithelial cell lines in vitro and SpragueDawley rats in vivo. Toxicol Sci 68(2):429-426.

Hu XC, Andrews DQ, Lindstrom M, et al. 2016. Detection of poly-and perfluoroalkyl substances 

(PFASs) in U.S. drinking water linked to industrial sites, military fire training areas and wastewater 

treatment plants. Environ Sci Technol Lett 3:344-350. DOI: 10.1021/acs.estlett.6b00260. 

Humblet O, Dias-Ramirez LG, Balmes JR, et al. 2014. Perfluoroalkyl chemicals and asthma among 

children 12-19 years of age: NHANES (1999-2008). Environ Health Perspect 122(10):1129-1133.

Hundley SG, Sarrif AM, Kennedy GL. 2006. Absorption, distribution, and excretion of ammonium 

perfluorooctanoate (APFO) after oral administration to various species. Drug Chem Toxicol 

29(2):137-145.

Hurley MD, Andersen MPS, Wallington TJ, et al. 2004. Atmospheric chemistry of perfluorinated 

carboxylic acids: Reaction with OH radicals and atmospheric lifetimes. J Phys Chem 108:615-620.

IARC. 2017. Agents classified by the IARC Monographs, Volumes 1–117. Lyon, France: International 

Agency for Research on Cancer. 

http://monographs.iarc.fr/ENG/Classification/List_of_Classifications.pdf. February 28, 2017.

ICRP. 1981. Report of the task group on reference man. ICRP Publication 28. International 

Commission on Radiological Protection. Oxford: Pergamon Press, 32-40.

+Ikeda T, Aiba K, Fukuda K, et al. 1985. The induction of peroxisome proliferation in rat liver by 

perfluorinated fatty acids, metabolically inert derivatives of fatty acids. J Biochem (Tokyo)98:475-

482.

Innes KE, Ducatman AM, Luster MI, et al. 2011. Association of osteoarthritis with serum levels of the 

environmental contaminants perfluorooctanoate and perfluorooctane sulfonate in a large 

Appalachian population. Am J Epidemiol 174(4):440-450.

Innes KE, Wimsatt JH, Frisbee S, et al. 2014. Inverse association of colorectal cancer prevalence to 

serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in a large 

Appalachian population. BMC Cancer[electronic resource]. 

http://www.bilomedcentral.com/1471/14/45. December 10, 2011.

Inoue K, Okada F, Ito R, et al. 2004. Perfluorooctane sulfonate (PFOS) and related perfluorinated 

compounds in human maternal and cord blood samples: Assessment of PFOS exposure in a 

susceptible population during pregnancy. Environ Health Perspect 112:1204-1207.

IRIS. 2017. IRIS quick list. Integrated Risk Information System. Washington, DC: U.S. 

Environmental Protection Agency. 

https://cfpub.epa.gov/ncea/iris_drafts/simple_list.cfm?list_type=alpha. February 28, 2017.

Issemann I, Green S. 1990. Activation of a member of a steroid hormone receptor superfamily by 

peroxisome proliferators. Nature 347:645-650. 

Itoh S, Araki A, Mitsui T, et al. 2016. Association of perfluoroalkyl substances exposure in utero with 

reproductive hormone levels in cord blood in the Hokkaido Study on Environment and Children's 

Health. Environ Int 94:51-59. 10.1016/j.envint.2016.05.011. 

+Iwai H, Hoberman AM. 2014. Oral (gavage) combined developmenal and perinatal/posnatal 

reproduction toxicity study of ammonium salt of perfluoroinated hexanoic acid in mice. Int J 

Toxicol 33(3):219-237. 

+Iwai H, Yamashita K. 2006. A fourteen-day repeated dose oral toxicity study of APFO in rats. Drug 

Chem Toxicol 29:323-332.

Jacquet N, Maire MA, Landkocz Y, et al. 2012. Carcinogenic potency of perfluorooctane sulfonate 

(PFOS) on Syrian hamster embryo (SHE) cells. Arch Toxicol 86(2):305-314.

Jahnke A, Berger U, Ebinghaus R, et al. 2007a. Latitudinal gradient of airborne polyfluorinated alkyl 

substances in the marine atmosphere between Germany and South Africa (53° N-33° S). Environ 

Sci Technol 41(9):3055-3061.
PERFLUOROALKYLS 668

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Jahnke A, Huber S, Temme C, et al. 2007b. Development and application of a simplified sampling 

method for volatile polyfluorinated alkyl substances in indoor and environmental air. J Chromatogr 

A 1164:1-9.

Jain RB. 2013. Association between thyroid profile and perfluoroalkyl acids: Data from NHNAES 

2007-2008. Environ Res 126:51-59. 10.1016/j.envres.2013.08.006. 

Jain RB. 2015. Estimation of the total concentration of perfluoroalkyl acids (PFAA) in human serum: 

Data from NHANES 2005-2012. Chemosphere 134:387-394. 10.1016/j.chemosphere.2015.04.104.

Jandacek RJ, Rider T, Keller ER, et al. 2010. The effect of olestra on the absorption, excretion and 

storage of 2,2',5,5' tetrachlorobiphenyl; 3,3',4,4' tetrachlorobiphenyl; and perfluorooctanoic acid. 

Environ Int 36(8):880-883.

Jensen MS, Norgaard-Pedersen B, Toft G, et al. 2012. Phthalates and perfluorooctanesulfonic acid in 

human amniotic fluid: Temporal trends and timing of amniocentesis in pregnancy. Environ Health 

Perspect 120(6):897-903.

Jensen TK, Andersen LB, Kyhl HB, et al. 2015. Association between perfluorinated compound exposure 

and miscarriage in Danish pregnant women. PLoS ONE 10(4):e0123496. 

10.1371/journal.pone.0123496. 

Ji K, Kim S, Kho Y, et al. 2012. Serum concentrations of major perfluorinated compounds among the 

general population in Korea: Dietary sources and potential impact on thyroid hormones. Environ 

Int 45:78-85.

Jiang Q, Lust RM, Dewitt JC. 2013. Perfluorooctanoic acid induced-developmental cardiotoxicity: Are 

peroxisome poliferator activated receptor α (PPARα) and bone morphorgenic protein 2 (BMP2) 

pathways involved? J Toxicol Environ Health A 76(11):635-650. 10.1080/15287394.2013.789415. 

Jiang Q, Lust RM, Strynar MJ, et al. 2012. Perflurooctanoic acid induces developmental cardiotoxicity 

in chicken embryos and hatchlings. Toxicology 293(1-3):97-106. 10.1016/j.tox.2012.01.005.

Jiang Q, Ma W, Wu J, et al. 2016. Perfluorooctanoic acid-induced toxicity in primary cultures of 

chicken embryo cardiomyocytes. Environ Toxicol 31(11):1580-1590. 10.1002/tox.22162. 

http://dx.doi.org/10.1002/tox.22162.

Jin C, Sun Y, Islam A, et al. 2011. Perfluoroalkyl acids including perfluorooctane sulfonate and 

perfluorohexane sulfonate in firefighters. J Occup Environ Med 53(3):324-328. 

10.1097/JOM.0b013e31820d1314.

Jin YH, Liu W, Sato I, et al. 2009. PFOS and PFOA in environmental and tap water in China. 

Chemosphere 77(5):605-611.

Joensen UN, Bossi R, Leffers H, et al. 2009. Do perfluoroalkyl compounds impair human semen 

quality? Environ Health Perspect 117(6):923-927.

Joensen UN, Veyrand B, Antignac JP, et al. 2013. PFOS (perfluorooctanesulfonate) in serum is 

negatively associated with testosterone levels, but not with semen quality, in healthy men. Hum 

Reprod 28(3):599-608.

Jogsten IE, Perello G, Llebaria X, et al. 2009. Exposure to perfluorinated compounds in Catalonia, 

Spain, through consumption of various raw and cooked foodstuffs, including packaged food. Food 

Chem Toxicol 47:1577-1583.

Johansson JH, Berger U, Vestergren R, et al. 2014. Temporal trends (1999-2010) of perfluoroalkyl acids 

in commonly consumed food items. Environ Pollut 188:102-108. 10.1016/j.envpol.2014.01.026.

Johansson N, Eriksson P, Viberg H. 2009. Neonatal exposure to PFOS and PFOA in mice results in 

changes in proteins which are important for neuronal growth and synaptogenesis in the developing 

brain. Toxicol Sci 108(2):412-418.

+Johansson N, Fredriksson A, Eriksson P. 2008. Neonatal exposure to perfluorooctane sulfonate (PFOS) 

and perfluorooctanoic acid (PFOA) causes neurobehavioural defects in adult mice. Neurotoxicology 

29:160-169.

Johnson JD. 1995a. Final report. Analytical study, single-dose dermal absorption/toxicity study of 

T6049 in rabbits. In vivo reference number: HWI#6329-130. 3M. SCD Division.
PERFLUOROALKYLS 669

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Johnson JD. 1995b. Final report. Analytical study, single-dose dermal absorption/toxicity study of 

T6053 in rabbits (lithium perfluorooctane sulfonate). In vivo study reference number: HWI#6329-

137. 3M. SCD Division.

Johnson JD, Ober RE. 1979. Absorption of FC-95-

14C in rats after a single oral dose. 3M. Submitted to 

the U.S. Environmental Protection Agency's Administrative Record. AR226-0007. 

Johnson JD, Ober RE. 1980. Extent and route of excretion and tissue distribution of total carbon-14 in 

rats after a single intravenous dose of FC-95-

14C. 3M. Submitted to the U.S. Environmental 

Protection Agency's Administrative Record. AR226-0006. 

Johnson JD, Ober RE. 1999a. Absorption of FC-143-

14C in rats after a single oral dose. In: Exploratory 

28-day oral toxicity study with telomer alcohol, telomer acrylate, PFHS, and PFOS (POS control) by 

daily gavage in the rat, w/CVR LTR DTD, 051500 (Sanitized). 3M. Submitted to the U.S. 

Environmental Protection Agency under TSCA Section FYI. OTS05001378S. 

Johnson JD, Ober RE. 1999b. Extent and route of excretion and tissue distribution of total carbon-14 in 

male and female rats after a single IV dose of FC-143-

14C. In: Exploratory 28-day oral toxicity 

study with telomer alcohol, telomer acrylate, PFHS, and PFOS (POS control) by daily gavage in the 

rat, w/CVR letter dated, 051500 (Sanitized). 3M. Submitted to the U.S. Environmental Protection 

Agency under TSCA Section FYI. OTS05001378S.

Johnson JD, Gibson SJ, Ober RE. 1984. Cholestyramine-enhanced fecal elimination of carbon-14 in rats 

after administration of ammonium [14C]perfluorooctanoate or potassium [14C]perflorooctanesulfonate. Fundam Appl Toxicol 4:972-976.

Jones CM. 2016. 2010/1015 PFOA Stewardship Program. Docket ID number EPA-HQ-OPPT-2006-

0621. https://www.regulations.gov/document?D=EPA-HQ-OPPT-2006-0621-0115. February 28, 

2017.

Jørgensen KT, Specht IO, Lenters V, et al. 2014a. Perfluoroalkyl substances and time to pregnancy in 

couples from Greenland, Poland and Ukraine. Environ Health 13:116. 10.1186/1476-069x-13-116. 

Jørgensen KT, Specht IO, Lenters V, et al. 2014b. Supplemental files to "Perfluoroalkyl substances and 

time to pregnancy in couples from Greenland, Poland and Ukraine" [Environ Health 13:116. 

10.1186/1476-069x-13-116]. Environ Health 10.1186/1476-069x-13-116. 

Jurado-Sanchez B, Ballesteros E, Gallego M. 2014. Analytical method for biomonitoring of 

perfluoroalkyl acids in human urine. Talanta 128:141-146. 10.1016/j.talanta.2014.04.071.

Kaiser MA, Larsen BS, Kao CPC, et al. 2005. Vapor pressures of perfluorooctanoic, -

nonanoic, -decanoic, -undecanoic, and -dodecanoic acids. J Chem & Eng Data 50:1841-1843.

Kang H, Choi K, Lee HS, et al. 2016. Elevated levels of short carbon-chain PFCAs in breast milk among 

Korean women: Current status and potential challenges. Environ Res 148:351-359. 

Kannan K, Choi JW, Iseki Net al. 2002a. Concentrations of perfluorinated acids in livers of birds from 

Japan and Korea. Chemosphere 49(3):225-231.

Kannan K, Corsolini S, Falandysz J, et al. 2002b. Perfluorooctanesulfonate and related fluorinated 

hydrocarbons in marine mammals, fishes, and birds from coasts of the Baltic and the Mediterranean 

Seas. Environ Sci Technol 36(15):3210-3216.

Kannan K, Franson JC, Bowerman WW, et al. 2001a. Perfluorooctane sulfonate in fish-eating water 

birds including bald eagles and albatrosses. Environ Sci Technol 35(15):3065-3070.

Kannan K, Hansen KJ, Wade TL, et al. 2002c. Perfluorooctane sulfonate in oysters, Crassostrea 

virginica, from the Gulf of Mexico and the Chesapeake Bay, USA. Arch Environ Contam Toxicol 

42(3):313-318.

Kannan K, Koistinen J, Beckmen K, et al. 2001b. Accumulation of perfluorooctane sulfonate in marine 

mammals. Environ Sci Technol 35:1593-1598.

Kannan K, Newsted J, Halbrook RS, et al. 2002d. Perfluorooctanesulfonate and related fluorinated 

hydrocarbons in mink and river otters from the United States. Environ Sci Technol 36:2566-2571.

Kannan K, Perrotta E, Thomas NJ. 2006. Association between perfluorinated compounds and 

pathological conditions in southern sea otters. Environ Sci Technol 40:4943-4948.
PERFLUOROALKYLS 670

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Kannan K, Tao L, Sinclair E, et al. 2005. Perfluorinated compounds in aquatic organisms at various 

trophic levels in a Great Lakes food chain. Arch Environ Contam Toxicol 48:559-566.

Karnes C, Winquist A, Steenland K. 2014. Incidence of type II diabetes in a cohort with substantial 

exposure to perfluorooctanoic acid. Environ Res 128:78-83. 10.1016/j.envres.2013.11.003. 

Kärrman A, Ericson I, van Bavel B, et al. 2007. Exposure of perfluorinated chemicals through lactation: 

Levels of matched human milk and serum and a temporal trend, 1996-2004, in Sweden. Environ 

Health Perspect 115:226-230.

Kärrman A, van Bavel B, Jarnberg U, et al. 2005. Development of a solid-phase extraction-HPLC/single 

quadrupole MS method for quantification of perfluorochemicals in whole blood. Anal Chem 

77:864-870.

Katakura M, Kudo N, Tsuda T, et al. 2007. Rat organic anion transporter 3 and organic anion 

transporting polypeptide 1 mediate perfluorooctanoic acid transport. J Health Sci 53:77-83.

Kataria A, Trachtman H, Malaga-Dieguez L, et al. 2015. Association between perfluoroalkyl acids and 

kidney function in a cross-sectional study of adolescents. Environ Health 14:89. 10.1186/s12940-

015-0077-9. 

Kato K, Calafat AM, Needham LL. 2009a. Polyfluoroalkyl chemicals in house dust. Environ Res 

109(12):518-523.

Kato K, Calafat AM, Wong LY, et al. 2009b. Polyfluoroalkyl compounds in pooled sera from children 

participating in the National Health and Nutrition Examination Survey 2001-2002. Environ Sci 

Technol 43(7):2641-2647.

Kato K, Wong LY, Chen A, et al. 2014. Changes in serum concentrations of maternal poly- and 

perfluoroalkyl substances over the course of pregnancy and predictors of exposure in a multiethnic 

cohort of Cincinnati, Ohio pregnant women during 2003-2006. Environ Sci Technol 48(16):9600-

9608. 

Kauck EA, Diesslin AR. 1951. Some properties of perfluorocarboxylic acids. Ind Eng Chem 

43(10):2332-2334.

Kawabata K, Matsuzaki H, Nukui S, et al. 2017. Perfluorododecanoic acid induces cognitive deficit in 

adult rats. Toxicol Sci 157(2):421-428. 10.1093/toxsci/kfx058. 

Kawamoto K, Oashi T, Oami K, et al. 2010. Perfluorooctanoic acid (PFOA) but not perfluorooctane 

sulfonate (PFOS) showed DNA damage in comet assay on Paramecium caudatum. J Toxicol Sci 

35(6):835-841.

+Kawamoto K, Sato I, Tsuda S, et al. 2011. Ultrasonic-induced tonic convulsion in rats after subchronic 

exposure to perfluorooctane sulfonate (PFOS). J Toxicol Sci 36(1):55-62.

+Kawashima Y, Kobayashi H, Miura H, et al. 1995. Characterization of hepatic responses of rat to 

administration of perfluorooctanoic and perfluorodecanoic acids at low levels. Toxicology 

99(3):169-178.

+Keil DE, Mehlmann T, Butterworth L, et al. 2008. Gestational exposure to perfluorooctane sulfonate 

(PFOS) suppresses immune function in B6C3F1 mice. Toxicol Sci 103(1):77-85.

Keller JM, Kannan K, Taniyasu S, et al. 2005. Perfluorinated compounds in the plasma of loggerhead 

and Kemp’s ridley sea turtles from the southeastern coast of the United States. Environ Sci Technol 

39:9101-9108.

Kelly J, Solem L. 2009. Identification of a major source of perfluorooctane sulfonate (PFOS) at a 

wastewater treatment plant in Brainerd, Minnesota. Reprod Toxicol 27:417-428.

Kelly BC, Ikonomou MG, Blair JD, et al. 2007. Food web-specific biomagnification of persistent 

organic pollutants. Science 317:236-238.

Kemper RA. 2003. Perfluorooctanoic acid: Toxicokinetics in the rat. Association of Plastics 

Manufactures of Europe. Submitted to the U.S. Environmental Protection Agency's Administrative 

Record. AR226-1499. 

Kemper RA, Nabb DL. 2005. In vitro studies in microsomes from rat and human liver, kidney, and 

intestine suggest that perfluorooctanoic acid is not a substrate for microsomal UDPglucuronosyltransferases. Drug Chem Toxicol 28(3):281-287.
PERFLUOROALKYLS 671

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

+Kennedy GL. 1985. Dermal toxicity of ammonium perfluorooctanoate. Toxicol Appl Pharmacol 

81(2):348-355.

+Kennedy GL. 1987. Increase in mouse liver weight following feeding of ammonium 

perfluorooctanoate and related fluorochemicals. Toxicol Lett 39(2-3):295-300.

Kennedy GL, Butenhoff JL, Olsen GW, et al. 2004. The toxicology of perfluorooctanoate. Crit Rev 

Toxicol 34(4):351-384.

+Kennedy GL, Hall GT, Brittelli MR, et al. 1986. Inhalation toxicity of ammonium perfluorooctanoate. 

Food Chem Toxicol 24(12):1325-1329.

Kerstner-Wood C, Coward L, Gorman G. 2003. Protein binding of perfluorohexane sulfonate, 

perfluorooctane sulfonate and perfluorooctanoate to plasma (human, rat, and monkey), and various 

human-derived plasma protein fractions. Southern Research Institute. Submitted to the U.S. 

Environmental Protection Agency's Administrative Record. AR226-1354. 

Khalil N, Chen A, Lee M, et al. 2016. Association of perfluoroalkyl substances, bone mineral density, 

and osteoporosis in the U.S. Population in NHANES 2009-2010. Environ Health Perspect 

124(1):81-87. 10.1289/ehp.1307909. 

Kielsen K, Shamin Z, Ryder LP, et al. 2016. Antibody response to booster vaccination with tetanus and 

diphtheria in adults exposed to perfluorinated alkylates. J Immunotoxicol 13(2):270-273. 

Kim S, Kannan K. 2007. Perfluorinated acids in air, rain, snow, surface runoff, and lakes: Relative 

importance of pathways to contamination of urban lakes. Environ Sci Technol 41:8328-8334.

Kim DH, Kim UJ, Kim HY, et al. 2016a. Perfluoroalkyl substances in serum from South Korean infants 

with congenital hypothyroidism and healthy infants - Its relationship with thyroid hormones. 

Environ Res 147:399-404. 10.1016/j.envres.2016.02.037. 

Kim SJ, Heo SH, Lee DS, et al. 2016b. Gender differences in pharmacokinetics and tissue distribution of 

3 perfluoroalkyl and polyfluoroalkyl substances in rats. Food Chem Toxicol 97:243-255.

Kim SK, Lee KT, Kang CS, et al. 2011. Distribution of perfluorochemicals between sera and milk from 

the same mothers and implications for prenatal and postnatal exposures. Environ Pollut 159(1):169-

174.

+Kinney LA, Chromey NC, Kennedy Jr GL. 1989. Acute inhalation toxicity of ammonium 

perfluorononanoate. Food Chem Toxicol 21(1):46-68.

Kishi R, Nakajima T, Goudarzi H, et al. 2015. The association of prenatal exposure to perfluorinated 

chemicals with maternal essential and long-chain polyunsaturated fatty acids during pregnancy and 

the birth weight of their offspring: The Hokkaido Study. Environ Health Perspect 123(10):1038-

1045. 10.1289/ehp.1408834. 

Kissa E. 2001. Fluorinated surfactants and repellents. 2nd ed. Revised and expanded. New York, NY: 

Marcel Dekker, Inc., 1-101, 198-269, 349-379, 451-487.

Kjeldsen LS, Bonefeld-Jørgensen EC. 2013. Perfluorinated compounds affect the function of sex 

hormone receptors. Environ Sci Pollut Res Int 20(11):8031-8044. 

Klaunig JE, Babich MA, Baetcke KP, et al. 2003. PPARα agonist-induced rodent tumors: Modes of 

action and human relevance. Crit Rev Toxicol 33(6):655-780.

Klaunig JE, Hocevar BA, Kamendulis LM. 2012. Mode of action analysis of perfluorooctanoic acid 

(PFOA) tumorigenicity and human relevance. Reprod Toxicol 33(4):410-418.

+Klaunig JE, Shinohara M, Iwai H, et al. 2015. Evaluation of the chronic toxicity and carcinogenicity of 

perfluorohexanoic acid (PFHxA) in Sprague-Dawley rats. Toxicol Pathol 43(2):209-220. 

10.1177/0192623314530532. 

Knox SS, Jackson T, Frisbee SJ, et al. 2011a. Perfluorocarbon exposure, gender and thyroid function in 

the C8 Health Project. J Toxicol Sci 36(4):403-410. 

Knox SS, Jackson T, Javins B, et al. 2011b. Implications of early menopause in women exposed to 

perfluorocarbons. J Clin Endocrinol Metab 96(6):1747-1753. I 10.1210/jc.2010-2401. 

Kobayashi Y, Hirokawa N, Ohshiro N, et al. 2002. Differential gene expression of organic anion 

transporters in male and female rats. Biochem Biophys Res Commun 290:482-487.
PERFLUOROALKYLS 672

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Konwick BJ, Tomy GT, Ismail N, et al. 2008. Concentrations and patterns of perfluoroalkyl acids in 

Georgia, USA surface waters near and distant to a major use source. Environ Toxicol Chem 

27(10):2011-2018.

+Koskela A, Finnila MA, Korkalainen M, et al. 2016. Effects of developmental exposure to 

perfluorooctanoic acid (PFOA) on long bone morphology and bone cell differentiation. Toxicol 

Appl Pharmacol 301:14-21. 10.1016/j.taap.2016.04.002. 

Kotthoff M, Muller J, Jurling H, et al. 2015. Perfluoroalkyl and polyfluoroalkyl substances in consumer 

products. Environ Sci Pollut Res Int 22(19):14546-14559. 10.1007/s11356-015-4202-7.

Koustas E, Lam J, Sutton P, et al. 2014. The Navigation Guide - evidence-based medicine meets 

environmental health: Systematic review of nonhuman evidence for PFOA effects on fetal growth. 

Environ Health Perspect 122(10):1015-1027.

Krishnan K, Andersen ME, Clewell HJ, et al. 1994. Physiologically based pharmacokinetic modeling of 

chemical mixtures. In: Yang RSH, ed. Toxicology of chemical mixtures: Case studies, 

mechanisms, and novel approaches. San Diego, CA: Academic Press, 399-437.

Kristensen SL, Ramlau-Hansen CH, Ernst E, et al. 2013. Long-term effects of prenatal exposure to 

perfluoroalkyl substances on female reproduction. Hum Reprod 28(12):3337-3348. 

10.1093/humrep/det382. 

Kroschwitz JI, Howe-Grant M. 1994. Perfluorooctanoic. Kirk-Othmer encyclopedia of chemical 

toxicology. 4th ed. Vol. 11. New York, NY: John Wiley & Sons, Inc., 551.

Krusic PJ, Roe DC. 2004. Gas-phase NMR technique for studying the thermolysis of materials: 

Thermal decomposition of ammonium perfluorooctanoate. Anal Chem 76(13):3800-3803.

Krusic PJ, Marchione AA, Roe DC. 2005. Gas-phase NMR studies of the thermolysis of 

perfluroooctanoic acid. J Fluor Chem 126:1510-1516.

Kubwabo C, Stewart B, Zhu J, et al. 2005. Occurrence of perfluorosulfonates and other 

perfluorochemicals in dust from selected homes in the city of Ottawa, Canada. J Environ Monit 

7:1074-1078.

Kudo N, Kawashima Y. 1997. Fish oil-feeding prevents perfluorooctanoic acid-induced fatty liver in 

mice. Toxicol Appl Pharmacol 145(2):285-293. 

Kudo N, Kawashima Y. 2003. Induction of triglyceride accumulation in the liver of rats by 

perfluorinated fatty acids with different carbon chain lengths: Comparison with induction of 

peroxisomal ß-oxidation. Biol Pharm Bull 26(1):47-51.

Kudo N, Bandai N, Suzuki E, et al. 2000. Induction by perfluorinated fatty acids with different carbon 

chain length of peroxisomal β-oxidation in the liver of rats. Chem Biol Interact 124:119-132.

Kudo N, Iwase Y, Okayachi H, et al. 2005. Induction of hepatic peroxisome proliferation by 8-2 telomer 

alcohol feeding in mice: Formation of perfluorooctanoic acid in the liver. Toxicol Sci 86(2):231-

238.

Kudo N, Katakura M, Sato Y, et al. 2002. Sex hormone-regulated renal transport of perfluorooctanoic 

acid. Chem Biol Interact 139:301-316.

Kudo N, Mizuguchi H, Yamamoto A, et al. 1999. Alterations by perfluorooctanoic acid of glycerolipid 

metabolism in rat liver. Chem Biol Interact 118:69-83. 

Kudo N, Sakai A, Mitsumoto A, et al. 2007. Tissue distribution and hepatic subcellular distribution of 

perfluorooctanoic acid at low dose are different from those at high dose in rats. Biol Pharm Bull 

30(8):1535-1540.

Kudo N, Suzuki E, Katakura M, et al. 2001. Comparison of the elimination between perfluorinated fatty 

acids with different carbon chain length in rats. Chem Biol Interact 134:203-216.

Kudo N, Suzuki-Nakajima E, Mitsumoto A, et al. 2006. Responses of the liver to perfluorinated fatty 

acids with different carbon chain length in male and female mice: In relation to induction of 

hepatomegaly, peroxisomal β-oxidation and microsomal 1-acylglycerophosphocholine 

acyltransferase. Biol Pharm Bull 29(9):1952-1957.
PERFLUOROALKYLS 673

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Kuklenyik Z, Reich JA, Tully JS, et al. 2004. Automated solid-phase extraction and measurement of 

perfluorinated organic acids and amides in human serum and milk. Environ Sci Technol 

38(13):3698-3704.

Kunleda H, Shinoda K. 1976. Krafft points, critical micelle concentrations, surface tension, and 

solubilizing power of aqueous solutions of fluorinated surfactants. J Phys Chem 80:2468-2470.

Kvist L, Giwercman YL, Jonsson BA, et al. 2012. Serum levels of perfluorinated compounds and sperm 

Y:X chromosome ratio in two European populations and in Inuit from Greenland. Reprod Toxicol 

34(4):644-650.

Landsteiner A, Huset C, Johnson J, et al. 2014. Biomonitoring for perfluorochemicals in a Minnesota 

community with known drinking water contamination. J Environ Health 77(5):14-19.

+Lau C, Thibodeaux JR, Hanson RG, et al. 2003. Exposure to perfluorooctane sulfonate during 

pregnancy in rat and mouse. II: Postnatal evaluation. Toxicol Sci 74(2):382-392.

+Lau C, Thibodeaux JR, Hanson RG, et al. 2006. Effects of perfluorooctanoic acid exposure during 

pregnancy in the mouse. Toxicol Sci 90(2):510-518.

Lee CK, Kang SG, Lee JT, et al. 2015a. Effects of perfluorooctane sulfuric acid on placental PRLfamily hormone production and fetal growth retardation in mice. Mol Cell Endocrinol 401:165-172. 

10.1016/j.mce.2014.10.026. 

Lee ES, Han S, Oh JE. 2016. Association between perfluorinated compound concentrations in cord 

serum and birth weight using multiple regression models. Reprod Toxicol 59:53-59. 

10.1016/j.reprotox.2015.10.020. 

Lee YJ, Kim M-K, Bae J, et al. 2013. Concentrations of perfluoroalkyl compounds in maternal and 

umbilical cord sera and birth outcomes in Korea. Chemosphere 90(5):1603-1609. 

Lee YY, Wong CK, Oger C, et al. 2015b. Prenatal exposure to the contaminant perfluorooctane 

sulfonate elevates lipid peroxidation during mouse fetal development but not in the pregnant dam. 

Free Radic Res 49(8):1015-1025. 10.3109/10715762.2015.1027199. 

+Lefebvre DE, Curran I, Armstrong C, et al. 2008. Immunomodulatory effects of dietary potassium 

perfluorooctane sulfonate (PFOS) exposure in adult Sprague-Dawley rats. J Toxicol Environ Health 

A 71(23):1516-1525.

Lemieux P, Strynar M, Tabor D, et al. 2007. Emissions of fluorinated compounds from the combustion 

of carpeting. In: International conference on incineration and thermalk treatment technologies. 

May 14-18, 2007. Phoenix, Arizona. U.S. Environmental Protection Agency. 

http://www.epa.gov/nhsrc/pubs/paperFluorCompounds101007.pdf. December 7, 2009.

Lenters V, Portengen L, Rignell-Hydbom A, et al. 2016a. Prenatal phthalate, perfluoroalkyl acid, and 

organochlorine exposures and term birth weight in three birth cohorts: Multi-pollutant models based 

on elastic net regression. Environ Health Perspect 124(3):365-372. 10.1289/ehp.1408933. 

Lenters V, Portengen L, Rignell-Hydbom A, et al. 2016b. Supplemental material to prenatal phthalate, 

perfluoroalkyl acid, and organochlorine exposures and term birth weight in three birth cohorts: 

Multi-pollutant models based on elastic net regression. [Environ Health Perspect 124(3):365-372]. 

10.1289/ehp.1408933. 

Leonard RC. 2006. Ammonium perfluorooctanoate: Phase II. Retrospective cohort mortality analyses 

related to a serum biomarker of exposure in a polymer production plant. Wilmington, DE: E.I. du 

pont de Nemours and Company.

Leonard RC, Kreckmann KH, Sakr CJ, et al. 2008. Retrospective cohort mortality study of workers in a 

polymer production plant including a reference population of regional workers. Ann Epidemiol 

18:15-22.

Lewis RC, Johns LE, Meeker JD. 2015. Serum biomarkers of exposure to perfluoroalkyl substances in 

relation to serum testosterone and measures of thyroid function among adults and adolescents from 

NHANES 2011-2012. Int J Environ Res Public Health 12(6):6098-6114. 

Li L, Zhai Z, Liu J, et al. 2015. Estimating industrial and domestic environmental releases of 

perfluorooctanoic acid and its salts in China from 2004 to 2012. Chemosphere 129:100-109. 

10.1016/j.chemosphere.2014.11.049.
PERFLUOROALKYLS 674

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Li N, Hartley DP, Cherrington NJ, et al. 2002. Tissue expression, ontogeny, and inducibility of rat 

organic anion transporting polypeptide. J Pharmacol Exp Ther 301(2):551-560.

+Li X, Ye L, Ge Y, et al. 2016. In utero perfluorooctane sulfonate exposure causes low body weights of 

fetal rats: A mechanism study. Placenta 39:125-133. 10.1016/j.placenta.2016.01.010. 

Li Y, Fletcher T, Mucs D, et al. 2018. Half-lives of PFOS, PFHxS and PFOA after end of exposure to 

contaminated drinking water. Occup Environ Med 75(1):46-51. 10.1136/oemed-2017-104651.

Li Y, Ramdhan DH, Naito H, et al. 2011. Ammonium perfluorooctanoate may cause testosterone 

reduction by adversely affecting testis in relation to PPARα. Toxicol Lett 205(3):265-272. 

http://dx.doi.org/10.1016/j.toxlet.2011.06.015. 

Lide DR. 2005. Pentadecalfluorooctanoic acid, nondecalfluorodecanoic acid, and heptafluroobutanoic 

acid. In: CRC handbook of chemistry and physics. 86th ed. Boca Raton, FL: Taylor and Francisk, 

3-412, 3-372, 3-398.

+Lieder PH, Chang SC, York RG, et al. 2009a. Toxicological evaluation of potassium 

perfluorobutanesulfonate in a 90-day oral gavage study with Sprague-Dawley rats. Toxicology 

255:45-52.

+Lieder PH, York RG, Hakes DC, et al. 2009b. A two-generation oral gavage reproduction study with 

potassium perfluorobutanesulfonate (K+

PFBS) in Sprague-Dawley rats. Toxicology 259:33-45.

Lien GW, Huang CC, Shiu JS, et al. 2016. Perfluoroalkyl substances in cord blood and attention 

deficit/hyperactivity disorder symptoms in seven-year-old children. Chemosphere 156:118-127. 

10.1016/j.chemosphere.2016.04.102.

Lien GW, Huang CC, Wu KY, et al. 2013. Neonatal-maternal factors and perfluoroalkyl substances in 

cord blood. Chemosphere 92(7):843-850. 

Liew Z, Ritz B, Bonefeld-Jorgensen EC, et al. 2014. Prenatal exposure to perfluoroalkyl substances and 

the risk of congenital cerebral palsy in children. Am J Epidemiol 180(6):574-581. 

10.1093/aje/kwu179. 

Liew Z, Ritz B, von Ehrenstein OS, et al. 2015. Attention deficit/hyperactivity disorder and childhood 

autism in association with prenatal exposure to perfluoroalkyl substances: A nested case-control 

study in the Danish National Birth Cohort. Environ Health Perspect 123(4):367-373. 

10.1289/ehp.1408412.

Lim TC, Wang B, Huang J, et al. 2011. Emission inventory for PFOS in China: Review of past 

methodologies and suggestions. Sci World J 11:1963-1980. 

Lin CY, Chen PC, Lin YC, et al. 2009. Association among serum perfluoroalkyl chemicals, glucose 

homeostasis, and metabolic syndrome in adolescents and adults. Diabetes Care 32(4):702-707.

Lin CY, Lin LY, Chiang CK, et al. 2010. Investigation of the associations between low-dose serum 

perfluorinated chemicals and liver enzymes in US adults. Am J Gastroenterol 105(6):1354-1363.

Lin CY, Lin LY, Wen TW, et al. 2013a. Association between levels of serum perfluorooctane sulfate 

and carotid artery intima-media thickness in adolescents and young adults. Int J Cardiol 

168(4):3309-3316. 10.1016/j.ijcard.2013.04.042. 

Lin CY, Lin LY, Wen TW, et al. 2013b. Supplemental material: Association between levels of serum 

perfluoroctane sulfate and carotid artery intima-media thickness in adolescents and young adults. Int 

J Cardiol 168:3309-3316. 

Lin LY, Wen LL, Su TC, et al. 2014. Negative association between serum perfluorooctane sulfate 

concentration and bone mineral density in US premenopausal women: NHANES, 2005-2008. The 

Journal of clinical endocrinology and metabolism 99(6):2173-2180. 10.1210/jc.2013-3409. 

Lind L, Zethelius B, Salihovic S, et al. 2014. Circulating levels of perfluoroalkyl substances and 

prevalent diabetes in the elderly. Diabetologia 57(3):473-479. 10.1007/s00125-013-3126-3. 

Lindstrom AB, Strynar MJ, Delinsky AD, et al. 2011. Application of WWTP biosolids and resulting 

perfluorinated compound contamination of surface and well water in Decatur, Alabama, USA. 

Environ Sci Technol 45:8015-8021. 

Liu J, Li J, Liu Y, et al. 2011. Comparison on gestation and lactation exposure of perfluorinated 

compounds for newborns. Environ Int 37(7):1206-1212.
PERFLUOROALKYLS 675

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Liu J, Lee LS, Nies LF, et al. 2007. Biotransformation of 8:2 fluorotelomer alcohol in soil and by soil 

bacteria isolates. Environ Sci Technol 41:8024-8030.

Liu L, Liu W, Song J, et al. 2009. A comparative study on oxidative damage and distributions of 

perfluorooctane sulfonate (PFOS) in mice at different postnatal developmental stages. J Toxicol Sci 

34(3):245-254. 

+Liu RCM, Hurtt ME, Cook JC, et al. 1996. Effect of the peroxisome proliferator, ammonium 

perfluorooctanoate (C8), on hepatic aromatase activity in adult male Crl:CD BR (CD) rats. Toxicol 

Sci 30(2):220-228.

Liu W, Li X, Xu L, et al. 2010. Influence of gestation, regular bleeding and intermittent exposure on 

blood perfluorooctane sulfonate levels in mice: Potential factors inducing sex difference and 

affecting exposure evaluation. J Toxicol Sci 35(3):309-316.

Liu X, Guo Z, Krebs KA, et al. 2014. Concentrations and trends of perfluorinated chemicals in potential 

indoor sources from 2007 through 2011 in the US. Chemosphere 98:51-57. 

10.1016/j.chemosphere.2013.10.001.

Llorca M, Farre M, Pico Y, et al. 2010. Infant exposure of perfluorinated compounds: Levels in breast 

milk and commercial baby food. Environ Int 36(6):584-592.

Loccisano AE, Campbell JL, Jr., Andersen ME, et al. 2011. Evaluation and prediction of 

pharmacokinetics of PFOA and PFOS in the monkey and human using a PBPK model. Regul 

Toxicol Pharmacol 59(1):157-175.

Loccisano AE, Campbell JL, Jr., Butenhoff JL, et al. 2012a. Comparison and evaluation of 

pharmacokinetics of PFOA and PFOS in the adult rat using a physiologically based pharmacokinetic 

model. Reprod Toxicol 33(4):452-467.

Loccisano AE, Campbell JL, Jr., Butenhoff JL, et al. 2012b. Evaluation of placental and lactational 

pharmacokinetics of PFOA and PFOS in the pregnant, lactating, fetal and neonatal rat using a 

physiologically based pharmacokinetic model. Reprod Toxicol 33(4):468-490.

Loccisano AE, Longnecker MP, Campbell JL, Jr., et al. 2013. Development of PBPK models for PFOA 

and PFOS for human pregnancy and lactation life stages. J Toxicol Environ Health A 76(1):25-57.

Loewen M, Halldorson T, Wang F, et al. 2005. Fluorotelomer carboxylic acids and PFOS in rainwater 

from an urban center in Canada. Environ Sci Technol 39:2944-2951.

Loganathan BG, Sajwan KS, Sinclair E, et al. 2007. Perfluoroalkyl sulfonates and perfluorocarboxylates 

in two wastewater treatment facilities in Kentucky and Georgia. Water Res 41(20):4611-4620. 

doi.org/10.1016/j.watres.2007.06.045. 

+Long Y, Wang Y, Ji G, et al. 2013. Neurotoxicity of perfluorooctane sulfonate to hippocampal cells in 

adult mice. PLoS ONE 8(1):e54176.

Looker C, Luster MI, Calafat AM, et al. 2014. Influenza vaccine response in adults exposed to 

perfluorooctanoate and perfluorooctanesulfonate. Toxicol Sci 138(1):76-88.

Loos R, Locoro G, Huber T, et al. 2008. Analysis of perfluorooctanoate (PFOA) and other 

perfluorinated compounds (PFCs) in the River Po watershed in N-Italy. Chemosphere 71:306-313.

López-Doval S, Salgado R, Pereiro N, et al. 2014. Perfluorooctane sulfonate effects on the reproductive 

axis in adult male rats. Environ Res 134:158-168. 

Lopez-Espinosa MJ, Fletcher T, Armstrong B, et al. 2011. Association of perfluorooctanoic acid 

(PFOA) and perfluorooctane sulfonate (PFOS) with age of puberty among children living near a 

chemical plant. Environ Sci Technol 45(19):8160-8166.

Lopez-Espinosa MJ, Mondal D, Armstrong B, et al. 2012. Thyroid function and perfluoroalkyl acids in 

children living near a chemical plant. Environ Health Perspect 120(7):1036-1041. 

10.1289/ehp.1104370. 

+Lopez-Espinosa MJ, Mondal D, Armstrong BG, et al. 2016. Perfluoroalkyl substances, sex hormones, 

and insulin-like growth factor-1 at 6-9 years of age: A Cross-sectional analysis within the C8 Health 

Project. Environ Health Perspect 124:1269-1275. 10.1289/ehp.1509869.
PERFLUOROALKYLS 676

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Lorber M, Egeghy PP. 2011. Simple intake and pharmacokinetic modeling to characterize exposure of 

Americans to perfluoroctanoic acid, PFOA. Environ Sci Technol 45(19):8006-8014. 

10.1021/es103718h. 

Lou I, Wambaugh JF, Lau C, et al. 2009. Modeling single and repeated dose pharmacokinetics of PFOA 

in mice. Toxicol Sci 107(2):331-341. 

Loveless SE, Finlay C, Everds NE, et al. 2006. Comparative responses of rats and mice exposed to 

linear/branched, linear, or branched ammonium perfluorooctanoate (APFO). Toxicology 220:203-

217. 

+Loveless SE, Hoban D, Sykes G, et al. 2008. Evaluation of the immune system in rats and mice 

administered linear ammonium perfluorooctanoate. Toxicol Sci 105(1):86-96.

Lu R, Kanai N, Bao Y, et al. 1996. Regulation of renal oatp mRNA expression by testosterone. Am J 

Physiol 270:F332-F337. 

Lubojevic M, Herak-Kramberger CM, Hagos Y, et al. 2004. Rat renal cortical OAT1 and OAT3 exhibit 

gender differences determined by both androgen stimulation and estrogen inhibition. Am J Physiol 

287:F124-F138.

+Luebker DJ, Case MT, York RG, et al. 2005a. Two-generation reproduction and cross-foster studies of 

perfluorooctanesulfonate (PFOS) in rats. Toxicology 215(1-2):126-148.

Luebker DJ, Hansen KJ, Bass NM, et al. 2002. Interactions of fluorochemicals with rat liver fatty acidbinding protein. Toxicology 176:175-185.

+Luebker DJ, York RG, Hansen KJ, et al. 2005b. Neonatal mortality from in utero exposure to 

perfluorooctanesulfonate (PFOS) in Sprague-Dawley rats: Dose-response, and biochemical and 

pharmacokinetic parameters. Toxicology 215(1-2):149-169.

Lundin JI, Alexander BH, Olsen GW, et al. 2009. Ammonium perfluorooctanoate production and 

occupational mortality. Epidemiology 20(6):921-928.

Luo Z, Shi X, Hu Q, et al. 2012. Structural evidence of perfluorooctane sulfonate transport by human 

serum albumin. Chem Res Toxicol 25(5):990-992.

Lv Z, Li G, Li Y, et al. 2013. Glucose and lipid homeostasis in adult rat is impaired by early‐life 

exposure to perfluorooctane sulfonate. Environ Toxicol 28(9):532-542. 

+Lv QY, Wan B, Guo LH, et al. 2015. In vivo immunotoxicity of perfluorooctane sulfonate in BALB/c 

mice: Identification of T-cell receptor and calcium-mediated signaling pathway disruption through 

gene expression profiling of the spleen. Chem Biol Interact 240:84-93. 10.1016/j.cbi.2015.07.015. 

Lyngsø J, Ramlau-Hansen CH, Hoyer BB, et al. 2014. Menstrual cycle characteristics in fertile women 

from Greenland, Poland and Ukraine exposed to perfluorinated chemicals: A cross-sectional study. 

Human reproduction (Oxford, England) 29(2):359-367. 10.1093/humrep/det390. 

MacNeil J, Steenland NK, Shankar A, et al. 2009. A cross-sectional analysis of type II diabetes in a 

community with exposure to perfluorooctanoic acid (PFOA). Environ Res 109(8):997-1003.

+Macon MB, Villanueva LR, Tatum-Gibbs K, et al. 2011. Prenatal perfluorooctanoic acid exposure in 

CD-1 mice: Low-dose developmental effects and internal dosimetry. Toxicol Sci 122(1):134-145.

MacPherson IR, Bissett D, Petty RD, et al. 2011. A first-in-human phase I clinical trial of CXR1002 in 

patients (pts) with advanced cancer. J Clin Oncol 29(Suppl; abstr 3063). 

Maestri L, Negri S, Ferrari M, et al. 2006. Determination of perfluorooctanoic acid and 

perflluorooctanesulfonate in human tissues by liquid chromatography/single quadrupole mass 

spectrometry. Rapid Commun Mass Spectrom 20(18):2728-2734.

Maher JM, Aleksunes LM, Dieter MZ, et al. 2008. Nrf2- and PPARα-mediated regulation of hepatic 

Mrp transporters after exposure to perfluorooctanoic acid and perfluorodecanoic acid. Toxicol Sci 

106(2):319-328. 10.1093/toxsci/kfn177. 

Maisonet M, Terrell ML, McGeehin MA, et al. 2012. Maternal concentrations of polyfluoroalkyl 

compounds during pregnancy and fetal and postnatal growth in British girls. Environ Health 

Perspect 120(10):1432-1437.
PERFLUOROALKYLS 677

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Maisonet M, Calafat AM, Marcus M, et al. 2015a. Prenatal exposure to perfluoroalkyl acids and serum 

testosterone concentrations at 15 years of age in female ALSPAC study participants. Environ Health 

Perspect 123(12):1325-1330. 10.1289/ehp.1408847. 

Maisonet M, Nayha S, Lawlor DA, et al. 2015b. Prenatal exposures to perfluoroalkyl acids and serum 

lipids at ages 7 and 15 in females. Environ Int 82:49-60. 10.1016/j.envint.2015.05.001. 

Mak YL, Taniyasu S, Yeung LW, et al. 2009. Perfluorinated compounds in tap water from China and 

several other countries. Environ Sci Technol 43(13):4824-4829.

Maloney EK, Waxman DJ. 1999. trans-Activation of PPARα and PPARγ by structurally diverse 

environmental chemicals. Toxicol Appl Pharmacol 161:209-218.

Mann PC, Frame SR. 2004. FC-143: Two year oral toxicity-oncogenicity study in rats. Peer review of 

ovaries. Newark, DE: E.I. du Pont de Nemours and Company. Du Pont Project ID 15261. U.S. 

EPA AR226.

Manzano-Salgado CB, Casas M, Lopez-Espinosa MJ, et al. 2015. Transfer of perfluoroalkyl substances 

from mother to fetus in a Spanish birth cohort. Environ Res 142:471-478. 

10.1016/j.envres.2015.07.020

Martin JW, Ellis DA, Mabury SA. 2006. Atmospheric chemistry of perfluoroalkanesulfonamides: 

Kinetic and product studies of the OH radical and CI atom initiated oxidation of N-ethyl 

perfluorobutanesulfonamide. Environ Sci Technol 40:864-872.

Martin JW, Smithwick MM, Braune BM, et al. 2004a. Identification of long-chain perfluorinated acids 

in biota from the Canadian Arctic. Environ Sci Technol 38(2):373-380.

Martin JW, Whittle DM, Muir DCG, et al. 2004b. Perfluoroalkyl contaminants in a food web from Lake 

Ontario. Environ Sci Technol 38:5379-5385.

Martin MT, Brennan RJ, Hu W, et al. 2007. Toxicogenomic study of triazole fungicides and 

perfluoroalkyl acids in rat livers predicts toxicity and categorizes chemicals based on mechanisms of 

toxicity. Toxicol Sci 97:595-613.

Mattsson K, Rignell-Hydbom A, Holmberg S, et al. 2015. Levels of perfluoroalkyl substances and risk 

of coronary heart disease: Findings from a population-based longitudinal study. Environ Res 

142:148-154. 10.1016/j.envres.2015.06.033.

MDH. 2007. Groundwater health risk limits. St. Paul, MN: Minnesota Department of Health. 

http://www.health.state.mn.us/divs/eh/groundwater/hrltable.html. July 1, 2008.

MDH. 2009. East Metro perfluorochemical biomonitoring pilot project. Minnesota Department of 

Health, Minnesota Environment, Exposure and Health. 

http://www.health.state.mn.us/divs/hpcd/tracking/biomonitoring/projects/pfcfinalrpt2009.pdf. May 

5, 2014.

MDH. 2014. Perfluorochemicals in homes and gardens study. Minnesota Department of Health. 

http://www.health.state.mn.us/divs/eh/hazardous/topics/pfcs/index.html.

MDH. 2017a. Human health-based water guidance table. Saint Paul, Minnesota: Minnesota 

Department of Health. http://www.health.state.mn.us/divs/eh/risk/guidance/gw/table.html. 

December 18, 2017. 

MDH. 2017b. Perfluorochemicals (PFCs) and health. Saint Paul, Minnesota: Minnesota Department of 

Health. http://www.health.state.mn.us/divs/eh/hazardous/topics/pfcshealth.html. December 18, 

2017. 

MECDC. 2016. Maine CDC maximum exposure guidelines (MEGs) for drinking water. Augusta, ME: 

Maine Center for Disease Control and Prevention. 

http://maineenvironmentallaboratory.com/newsite/wp-content/uploads/megtable2016.pdf. December 

18, 2017.

Meesters RJ, Schröder HF. 2004. Perfluorooctane sulfonate- a quite mobile anionic anthropogenic 

surfactant, ubiquitously found in the environment. Water Sci Technol 50(5):235-242.

Melzer D, Rice N, Depledge MH, et al. 2010. Association between serum perfluorooctanoic acid 

(PFOA) and thyroid disease in the U.S. National Health and Nutrition Examination Survey. Environ 

Health Perspect 118(5):686-692.
PERFLUOROALKYLS 678

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Michigan Department of Environmental Quality. 2016. Rule 57 water quality values. Lansing, MI: 

Michigan Department of Environmental Quality. http://www.michigan.gov/documents/deq/wrdswas-rule57_372470_7.pdf. December 18, 2017.

Midasch O, Drexler H, Hart N, et al. 2007. Transplacental exposure of neonates to 

perfluorooctanesulfonate and perfluorooctanoate: A pilot study. Int Arch Occup Environ Health 

80:643-648.

Min JY, Lee KJ, Park JB, et al. 2012. Perfluorooctanoic acid exposure is associated with elevated 

homocysteine and hypertension in US adults. Occup Environ Med 69(9):658-662.

Minata M, Harada KH, Kärrman A, et al. 2010. Role of peroxisome proliferator-activated receptor- α in 

hepatobiliary injury induced by ammonium perfluorooctanoate in mouse liver. Ind Health 48:96-

107.

Mondal D, Lopez-Espinosa MJ, Armstrong B, et al. 2012. Relationships of perfluorooctanoate and 

perfluorooctane sulfonate serum concentrations between mother-child pairs in a population with 

perfluorooctanoate exposure from drinking water. Environ Health Perspect 120(5):752-757.

Mondal D, Weldon RH, Armstrong BG, et al. 2014. Breastfeeding: A potential excretion route for 

mothers and implications for infant exposure to perfluoroalkyl acids. Environ Health Perspect 

122(2):187-192. 

Monroy R, Morrison K, Teo K, et al. 2008. Serum levels of perfluoroalkyl compounds in human 

maternal and umbilical cord blood samples. Environ Res 108:56-62.

Moody CA, Field JA. 1999. Determination of perfluorocarboxylates in groundwater impacted by firefighting activity. Environ Sci Technol 33(16):2800-2806.

Moody CA, Hebert GN, Strauss SH, et al. 2003. Occurrence and persistence of perfluorooctanesulfonate 

and other perfluorinated surfactants in groundwater at a fire-training area at Wurtsmith Air Force 

Base, Michigan, USA. J Environ Monit 5:341-345.

Mogensen UB, Grandjean P, Nielsen F, et al. 2015b. Breastfeeding as an exposure pathway for 

perfluorinated alkylates. Environ Sci Technol 49(17):10466-10473. 10.1021/acs.est.5b02237. 

Mogensen UB, Grandjean P, Heilmann C, et al. 2015a. Structural equation modeling of immunotoxicity 

associated with exposure to perfluorinated alkylates. Environ Health 14:47 10.1186/s12940-015-

0032-9. 

Morello-Frosch R, Cushing LJ, Jesdale BM, et al. 2016. Environmental chemicals in an urban 

population of pregnant women and their newborns from San Francisco. Environ Sci Technol 

50:12464-12472.

Moriwaki H, Takata Y, Arakawa R. 2003. Concentrations of perfluorooctane sulfonate (PFOS) and 

perfluorooctanoic acid (PFOA) in vacuum cleaner dust collected in Japanese homes. J Environ 

Monit 5:753-757.

Mundt DJ, Mundt KA, Luippold RS, et al. 2007. Clinical epidemiological study of employees exposed 

to surfactant blend containing perfluorononanoic acid. Occup Environ Med 64:589-594.

Murakami M, Imamura E, Shinohara H, et al. 2008. Occurrence and sources of perfluorinated 

surfactants in rivers in Japan. Environ Sci Technol 42(17):6566-6572.

Nabb DL, Szostek B, Himmelstein MW, et al. 2007. In vitro metabolism of 8-2 fluorotelomer alcohol: 

Interspecies comparisons and metabolic pathway refinement. Toxicol Sci 100(2):333-344.

Nakagawa H, Hirata T, Terada T, et al. 2008. Roles of organic anion transporters in the renal excretion 

of perfluorooctanoic acid. Basic Clin Pharmacol Toxicol 103(1):1-8.

Nakagawa H, Terada T, Harada KH, et al. 2009. Human organic anion transporter hOAT4 is a 

transporter of perfluorooctanoic acid. Basic Clin Pharmacol Toxicol 105(2):136-138.

Nakayama S, Strynar MJ, Helfant L, et al. 2007. Perfluorinated compounds in the Cape Fear drainage 

basin in North Carolina. Environ Sci Technol 41(15):5271-5276.

Nakagawa T, Ramdhan D, Tanaka N, et al. 2012. Modulation of ammonium perfluorooctanoate-induced 

hepatic damage by genetically different PPARα in mice. Arch Toxicol 86(1):63-74. 
PERFLUOROALKYLS 679

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

NAS/NRC. 1989. Report of the oversight committee. In: Biologic markers in reproductive toxicology. 

Washington, DC: National Academy of Sciences, National Research Council, National Academy 

Press, 15-35.

NCDENR. 2012. Memorandum: NCSAB recommendation for the revision of the IMAC for 

perfluorooctanoic acid (PFOA). August 10, 2012. Raleigh, NC: North Carolina Department of 

Environment and Natural Resources Division of Air Quality. 

https://ncdenr.s3.amazonaws.com/s3fspublic/Air%20Quality/toxics/risk/sab/LAA/20120808%20PFOA%20Final%20Risk%20Assessment

%20signed.pdf. December 18, 2017. 

NDEP. 2016. Basic comparison levels. Carson City, NE: Nevada Division of Environmental 

Protection. https://ndep.nv.gov/uploads/documents/july-2017-ndep-bcls.pdf. December 18, 2017.

Needham LL, Grandjean P, Heinzow B, et al. 2011. Partition of environmental chemicals between 

maternal and fetal blood and tissues. Environ Sci Technol 45(3):1121-1126.

Nelson JW, Hatch EE, Webster TF. 2010. Exposure to polyfluoroalkyl chemicals and cholesterol, body 

weight, and insulin resistance in the general U.S. population. Environ Health Perspect 118(2):197-

202.

+Ngo HT, Hetland RB, Sabaredzovic A, et al. 2014. In utero exposure to perfluorooctanoate (PFOA) or 

perfluorooctane sulfonate (PFOS) did not increase body weight or intestinal tumorigenesis in 

multiple intestinal neoplasia (Min/+) mice. Environ Res 132:251-263. 

10.1016/j.envres.2014.03.033. 

Nilsson R, Beije B, Preat V, et al. 1991. On the mechanism of the hepatocarcinogenicity of peroxisome 

proliferations. Chem Biol Interact 78:235-250.

NIOSH. 2016. Index of Chemical Abstracts Service Registry Numbers (CAS No.). NIOSH pocket 

guide to chemical hazards. Index of Chemical Abstracts Service Registry Numbers (CAS No.). 

Atlanta, GA: National Institute for Occupational Safety and Health, Centers for Disease Control and 

Prevention. https://www.cdc.gov/niosh/npg/npgdcas.html. February 28, 2017.

Noker PE, Gorman GS. 2003. A pharmacokinetic study of potassium perfluorooctanesulfonate in the 

Cynomolgus monkey. St. Paul, MN: 3M Corporation.

Nolan LA, Nolan JM, Shofer FS, et al. 2009. The relationship between birth weight, gestational age and 

perfluorooctanoic acid (PFOA)-contaminated public drinking water. Reprod Toxicol 27:231-238.

Nolan LA, Nolan JM, Shofer FS, et al. 2010. Congenital anomalies, labor/delivery complications, 

maternal risk factors and their relationship with perfluorooctanoic acid (PFOA)-contaminated public 

drinking water. Reprod Toxicol 29(2):147-155.

North Carolina Department of Environmental Quality. 2013. Appendix 1: Interim maximum allowable 

concentrations (IMACs). Raleigh, NC: North Carolina Department of Environmental Quality. 

https://files.nc.gov/ncdeq/documents/files/IMAC%20table_5-22-13.pdf. December 19, 2017.

NTP. 2016a. CASRN Index in MS Excel. Report on carcinogens, Fourteenth Edition. Research 

Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, 

National Toxicology Program. https://ntp.niehs.nih.gov/pubhealth/roc/index-1.html#P. February 

28, 2017.

NTP. 2016b. NTP Monograph on immunotoxicity associated with exposure to perfluorooctanoic acid 

(PFOA) and perfluorooctane sulfonate (PFOS). Research Triangle Park, NC: U.S. Department of 

Health and Human Services, Public Health Service, National Toxicology Program. 

https://ntp.niehs.nih.gov/ntp/ohat/pfoa_pfos/pfoa_pfosmonograph_508.pdf. December 21, 2017.

Oda Y, Nakayama S, Harada KH, et al. 2007. Negative results of umu genotoxicity test of fluorotelomer 

alcohols and perfluorinated alkyl acids. Environ Health Prev Med 12:217-219.

Ode A, Kallen K, Gustafsson P, et al. 2014. Fetal exposure to perfluorinated compounds and attention 

deficit hyperactivity disorder in childhood. PLoS ONE 9(4):e95891. 

10.1371/journal.pone.0095891.

Ode A, Rylander L, Lindh CH, et al. 2013. Determinants of maternal and fetal exposure and temporal 

trends of perfluorinated compounds. Environ Sci Pollut Res Int 20(11):7970-7978.
PERFLUOROALKYLS 680

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

OECD. 2002. Hazard assessment of perfluorooctane sulfonate (PFOS) and its salts. Organisation for 

Economic Co-operation and Development. ENV/JM/RD(2002)17/FINAL. 

http://www.oecd.org/dataoecd/23/18/2382880.pdf. July 02, 2007.

OECD. 2006a. Results of the 2006 survey on production and use of PFOS, PFAS, PFOA, PFCA, their 

related substances and products/mixtures containing these substances. Organisation for Economic 

Co-operation and Development.

OECD. 2006b. SIDS initial assessment report after SIAM 22. Ammonium perfluorooctanoate and 

perfluorooctanoic acid. Organisation for Economic Co-operation and Development. 

http://www.oecd.org/document/63/0,3343,en_2649_34379_1897983_1_1_1_1,00.html. May 18, 

2009.

OECD. 2007. Report of an OECD workshop on perfluorocarboxylic acids (PFCAs) and precursors. 

Organisation for Economic Co-operation and Development. 

http://www.olis.oecd.org/olis/2007doc.nsf/LinkTo/NT00002AB6/$FILE/JT03229256.PDF. April 

02, 2008.

Ohmori K, Kudo N, Katayama K, et al. 2003. Comparison of the toxicokinetics between 

perfluorocarboxylic acids with different carbon chain length. Toxicology 184:135-140.

Okada E, Sasaki S, Saijo Y, et al. 2012. Prenatal exposure to perfluorinated chemicals and relationship 

with allergies and infectious diseases in infants. Environ Res 112:118-125.

Okada E, Sasaki S, Kashino I, et al. 2014. Prenatal exposure to perfluoroalkyl acids and allergic diseases 

in early childhood. Environ Int 65:127-134. 10.1016/j.envint.2014.01.007. 

Olsen GW. 2015. PFAS biomonitoring in higher exposed populations, Chapter 4. In: Dewitt JC, ed. 

Toxicological effects on perfluoroalkyl and polyfouroalkyl substances. London: Humana Press, 77-

125.

Olsen GW, Zobel LR. 2007. Assessment of lipid, hepatic, and thyroid parameters with serum 

perfluorooctanoate (PFOA) concentrations in fluorochemical production workers. Int Arch Occup 

Environ Health 81:231-246.

Olsen GW, Burlew MM, Marshall JC, et al. 2004a. Analysis of episodes of care in a 

perfluorooctanesulfonyl fluoride production facility. J Occup Environ Hyg 46(8):837-846.

Olsen GW, Burris JM, Burlew MM, et al. 2003a. Epidemiologic assessment of worker serum 

perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations and medical 

surveillance examinations. J Occup Environ Med 45(3):260-270.

Olsen GW, Burris JM, Burlew MM, et al. 2000. Plasma cholecystokinin and hepatic enzymes, 

cholesterol and lipoproteins in ammonium perfluorooctanoate production workers. Drug Chem 

Toxicol 23(4):603-620.

Olsen GW, Burris JM, Ehresman DJ, et al. 2007a. Half-life of serum elimination of 

perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired 

fluorochemical production workers. Environ Health Perspect 115:1298-1305.

Olsen GW, Burris JM, Mandel JH, et al. 1998a. An epidemiologic investigation of clinical chemistries, 

hematology and hormones in relation to serum levels of perfluorooctane sulfonate in male 

fluorochemical production employees. St. Paul, MN: 3M Company. AR226-0030.

Olsen GW, Burris JM, Mandel JH, et al. 1999. Serum perfluorooctane sulfonate and hepatic and lipid 

clinical chemistry tests in fluorochemical production employees. J Occup Environ Med 41(9):799-

806.

Olsen GW, Butenhoff JL, Zobel LR. 2009. Perfluoroalkyl chemicals and human fetal development: An 

epidemiologic review with clinical and toxicological perspectives. Reprod Toxicol 27(3-4):212-230.

Olsen GW, Church TR, Hansen KJ, et al. 2004b. Quantitative evaluation of perfluorooctanesulfonate 

(PFOS) and other fluorochemicals in the serum of children. J Child Health 2(1):53-76.

Olsen GW, Church TR, Larson EB, et al. 2004c. Serum concentrations of perfluorooctanesulfonate and 

other fluorochemicals in an elderly population from Seattle, Washington. Chemosphere 54:1599-

1611.
PERFLUOROALKYLS 681

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Olsen GW, Church TR, Miller JP, et al. 2003b. Perfluorooctanesulfonate and other fluorochemicals in 

the serum of American Red Cross adult blood donors. Environ Health Perspect 111:1892-1901. 

Olsen GW, Ehresman DJ, Buehrer BD, et al. 2012. Longitudinal assessment of lipid and hepatic clinical 

parameters in workers involved with the demolition of perfluoroalkyl manufacturing facilities. J 

Occup Environ Med 54(8):974-983. 

Olsen GW, Gilliland FD, Burlew MM, et al. 1998b. An epidemiologic investigation of reproductive 

hormones in men with occupational exposure to perfluorooctanoic acid. J Occup Environ Med 

40(7):614-622. 

Olsen GW, Hansen KJ, Stevenson LA, et al. 2003c. Human donor liver and serum concentrations of 

perfluorooctanesulfonate and other perfluorochemicals. Environ Sci Technol 37:888-891. 

Olsen GW, Huang HY, Helzlsouer KJ, et al. 2005. Historical comparison of perfluorooctanesulfonate, 

perfluorooctanoate, and other fluorochemicals in human blood. Environ Health Perspect 

113(5):539-545. 

Olsen GW, Mair DC, Church TR, et al. 2008. Decline in perfluorooctanesulfonate and other 

polyfluoroalkyl chemicals in American Red Cross adult blood donors, 2000-2006. Environ Sci 

Technol 42(13):4989-4995. 

Olsen GW, Mair DC, Lange CC, et al. 2017a. Per- and polyfluoroalkyl substances (PFAS) in American 

Red Cross adult blood donors, 2000-2015. Environ Res 157:87-95. 10.1016/j.envres.2017.05.013. 

Olsen GW, Mair DC, Lange CC, et al. 2017b. Supplemental file. Per-and polyfluoroalkyl substances 

(PFAS) in American Red Cross adult blood donors, 2000-2015 [Environ Res 157:87-95]. Environ 

Res 10.1016/j.envres.2017.05.013. 

Olsen GW, Mair DC, Reagan WK, et al. 2007b. Preliminary evidence of a decline in 

perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations in American Red 

Cross blood donors. Chemosphere 68(1):105-111. 

+Onishchenko N, Fischer C, Wan Ibrahim WN, et al. 2011. Prenatal exposure to PFOS or PFOA alters

motor function in mice in a sex-related manner. Neurotox Res 19(3):452-461. 

Orata F, Quinete N, Werres F, et al. 2009. Determination of perfluorooctanoic acid and perfluorooctane 

sulfonate in Lake Victoria Gulf water. Bull Environ Contam Toxicol 82:218-222. 

OSHA. 2013. Subpart Z - Toxic and hazardous substances. Air contaminants. Occupational Safety and 

Health Standards. Code of Federal Regulations 29 CFR 1910.1000. 

http://www.gpo.gov/fdsys/pkg/CFR-2014-title29-vol6/pdf/CFR-2014-title29-vol6-sec1910-

1000.pdf. March 4, 2015. 

OSHA. 2014a. Appendix A to Part 1926.55-1970 American Conference of Governmental Industrial 

Hygienists’ threshold limit values of airborne contaminants. Occupational Safety and Health 

Standards. Code of Federal Regulations 29 CFR 1926.55 http://www.gpo.gov/fdsys/pkg/CFR2014-title29-vol8/pdf/CFR-2014-title29-vol8-sec1926-55.pdf. March 4, 2015. 

OSHA. 2014b. Subpart Z - Toxic and hazardous substances. Air contaminants. Table Z - Shipyards. 

Occupational Safety and Health Standards. Code of Federal Regulations 29 CFR 1915.1000. 

http://www.gpo.gov/fdsys/pkg/CFR-2013-title29-vol7/pdf/CFR-2013-title29-vol7-sec1915-

1000.pdf. March 4, 2015. 

Osuna CE, Grandjean P, Weihe P, et al. 2014. Autoantibodies associated with prenatal and childhood 

exposure to environmental chemicals in Faroese children. Toxicol Sci 142(1):158-166. 

10.1093/toxsci/kfu163. 

+Pastoor TP, Lee KP, Perri MA, et al. 1987. Biochemical and morphological studies of ammonium

perfluorooctanoate-induced hepatomegaly and peroxisome proliferation. Exp Mol Pathol 47(1):98-

109. 

Paustenbach DJ, Panko JM, Scott PK, et al. 2007. A methodology for estimating human exposure to 

perfluorooctanoic acid (PFOA): A retrospective exposure assessment of a community (1951-2003). 

J Toxicol Environ Health A 70(1):28-57. 

+Peden-Adams MM, Keller JM, Eudaly JG, et al. 2008. Suppression of humoral immunity in mice

following exposure to perfluorooctane sulfonate. Toxicol Sci 104(1):144-154. 
PERFLUOROALKYLS 682

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

+Pereiro N, Moyano R, Blanco A, et al. 2014. Regulation of corticosterone secretion is modified by 

PFOS exposure at different levels of the hypothalamic-pituitary-adrenal axis in adult male rats. 

Toxicol Lett 230(2):252-262. 10.1016/j.toxlet.2014.01.003. 

Perez F, Nadal M, Navarro-Ortega A, et al. 2013. Accumulation of perfluoroalkyl substances in human 

tissues. Environ Int 59:354-362. 10.1016/j.envint.2013.06.004.

+Perkins RG, Butenhoff JL, Kennedy GL, et al. 2004. 13-Week dietary toxicity study of ammonium 

perfluorooctanoate (APFO) in male rats. Drug Chem Toxicol 27(4):361-378.

+Permadi H, Lundgren B, Andersson K, et al. 1992. Effects of perfluoro fatty acids on xenobioticmetabolizing enzymes, enzymes which detoxify reactive forms of oxygen and lipid peroxidation in 

mouse liver. Biochem Pharmacol 44(6):1183-1191.

+Permadi H, Lundgren B, Andersson K, et al. 1993. Effects of perfluoro fatty acids on peroxisome 

proliferation and mitochondrial size in mouse liver: Dose and time factors and effect of chain 

length. Xenobiotica 23(7):761-770.

Peters JM, Gonzalez FJ. 2011. Why toxic equivalency factors are not suitable for perfluoroalkyl 

chemicals. American Chemical Society. Chem Res Toxicol 24(10):1601-1609. 

10.1021/tx200316x. 

Pinney SM, Biro FM, Windham GC, et al. 2014. Serum biomarkers of polyfluoroalkyl compound 

exposure in young girls in Greater Cincinnati and the San Francisco Bay Area, USA. Environ Pollut 

184:327-334. 10.1016/j.envpol.2013.09.008.

Plastics Europe. 2012. Guide for the safe handling of fluoropolymer resins, November 2012. Plastics 

Europe, Association of Plastics Manufacturers.

Porpora MG, Lucchini R, Abballe A, et al. 2013. Placental transfer of persistent organic pollutants: A 

preliminary study on mother-newborn pairs. Int J Environ Res Public Health 10(2):699-711.

Post GB, Louis JB, Cooper KR, et al. 2009. Occurrence and potential significance of perfluorooctanoic 

acid (PFOA) detected in New Jersey public drinking water systems. Environ Sci Technol 

43(12):4547-4554.

Post GB, Louis JB, Lippincott RL, et al. 2013. Occurrence of perfluorinated compounds in raw water 

from New Jersey public drinking water systems. Environ Sci Technol 47(23):13266-13275. 

10.1021/es402884x.

Power MC, Webster TF, Baccarelli AA, et al. 2013. Cross-sectional association between polyfluoroalkyl 

chemicals and cognitive limitation in the National Health and Nutrition Examination Survey. 

Neuroepidemiology 40(2):125-132.

Powley CR, George SW, Russell MH, et al. 2008. Polyfluorinated chemicals in a spatially and 

temporally integrated food web in the Western Arctic. Chemosphere 70:664-672.

Powley CR, Michalczyk MJ, Kaiser MA, et al. 2005. Determination of perfluorooctanoic acid (PFOA) 

extractable from the surface of commercial cookware under simulated cooking conditions by 

LC/MS/MS. Analyst 130(9):1299-1302.

Predieri B, Iughetti L, Guerranti C, et al. 2015. High levels of perfluorooctane sulfonate in children at 

the onset of diabetes. Int J Endocrinol 2015:234358. 10.1155/2015/234358. 

Prevedouros K, Cousins I T, Buck RC, et al. 2006. Sources, fate and transport of perfluorocarboxylates. 

Environ Sci Technol 40(1):32-44.

Qazi MR, Abedi MR, Nelson BD, et al. 2010a. Dietary exposure to perfluorooctanoate or 

perfluorooctane sulfonate induces hypertrophy in centrilobular hepatocytes and alters the hepatic 

immune status in mice. Int Immunopharmacol 10(11):1420-1427.

+Qazi MR, Nelson BD, Depierre JW, et al. 2010b. 28-Day dietary exposure of mice to a low total dose 

(7 mg/kg) of perfluorooctanesulfonate (PFOS) alters neither the cellular compositions of the thymus 

and spleen nor humoral immune responses: Does the route of administration play a pivotal role in 

PFOS-induced immunotoxicity? Toxicology 267(1-3):132-139. 10.1016/j.tox.2009.10.035. 
PERFLUOROALKYLS 683

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Qazi MR, Bogdanska J, Butenhoff JL, et al. 2009a. High-dose, short-term exposure of mice to 

perfluorooctanesulfonate (PFOS) or perfluorooctanoate (PFOA) affects the number of circulating 

neutrophils differently, but enhances the inflammatory responses of macrophages to 

lipopolysaccharide (LPS) in a similar fashion. Toxicology 262(3):207-214.

Qazi MR, Nelson BD, DePierre JW, et al. 2012. High-dose dietary exposure of mice to 

perfluorooctanoate or perfluorooctane sulfonate exerts toxic effects on myeloid and B-lymphoid 

cells in the bone marrow and these effects are partially dependent on reduced food consumption. 

Food Chem Toxicol 50(9):2955-2963.

Qazi MR, Xia Z, Bogdanska J, et al. 2009b. The atrophy and changes in the cellular compositions of the 

thymus and spleen observed in mice subjected to short-term exposure to perfluorooctanesulfonate 

are high-dose phenomena mediated in part by peroxisome proliferator-activated receptor-alpha 

(PPARα). Toxicology 260(1-3):68-76.

Qin XD, Qian Z, Vaughn MG, et al. 2016. Positive associations of serum perfluoroalkyl substances with 

uric acid and hyperuricemia in children from Taiwan. Environ Pollut 212:519-524. 

10.1016/j.envpol.2016.02.050. 

Quaak I, de Cock M, de Boer M, et al. 2016. Prenatal exposure to perfluoroalkyl substances and 

behavioral development in children. Int J Environ Res Public Health 13(5). 

10.3390/ijerph13050511.

Quinete N, Wu Q, Zhang T, et al. 2009. Specific profiles of perfluorinated compounds in surface and 

drinking waters and accumulation in mussels, fish, and dolphins from southeastern Brazil. 

Chemosphere 77(6):863-869. 10.1016/j.chemosphere.2009.07.079.

Quinones O, Snyder SA. 2009. Occurrence of perfluoroalkyl carboxylates and sulfonates in drinking 

water utilities and related waters from the United States. Environ Sci Technol 43(24):9089-9095.

Quist EM, Filgo AJ, Cummings CA, et al. 2015a. Hepatic mitochondrial alteration in CD-1 mice 

associated with prenatal exposures to low doses of perfluorooctanoic acid (PFOA). Toxicol Pathol 

43(4):546-557. 10.1177/0192623314551841. 

Quist EM, Filgo AJ, Cummings CA, et al. 2015b. Supplemental data: Hepatic mitochondrial alteration 

in CD-1 mice associated with prenatal exposures to low doses of perfluorooctanoic acid (PFOA). 

(Toxicol Pathol 43(4):546-557). Toxicol Pathol 43:546-557. 

Raleigh KK, Alexander BH, Olsen GW, et al. 2014. Mortality and cancer incidence in ammonium 

perfluorooctanoate production workers. Occup Environ Med 71(7):500-506. 10.1136/oemed-2014-

102109.

Rankin K, Lee H, Tseng PJ, et al. 2014. Investigating the biodegradability of a fluorotelomer-based 

acrylate polymer in a soil-plant microcosm by indirect and direct analysis. Environ Sci Technol 

48(21):12783-12790. 

Raymer JH, Michael LC, Studabaker WB, et al. 2012. Concentrations of perfluorooctane sulfonate 

(PFOS) and perfluorooctanoate (PFOA) and their associations with human semen quality 

measurements. Reprod Toxicol 33(4):419-427.

+Rebholz SL, Jones T, Herrick RL, et al. 2016. Hypercholesterolemia with consumption of PFOA-laced 

Western diets is dependent on strain and sex of mice. Toxicology reports 3:46-54. 

10.1016/j.toxrep.2015.11.004. 

Reiner JL, Nakayama SF, Delinsky AD, et al. 2009. Analysis of PFOA in dosed CD1 mice. Part 1. 

Methods development for the analysis of tissues and fluids from pregnant and lactating mice and 

their pups. Reprod Toxicol 27(3-4):360-364. 10.1016/j.reprotox.2008.10.006. 

Ren H, Vallanat B, Nelson DM, et al. 2009. Evidence for the involvement of xenobiotic-responsive 

nuclear receptors in transcriptional effects upon perfluoroalkyl acid exposure in diverse species. 

Reprod Toxicol 27(3-4):266-277. 10.1016/j.reprotox.2008.12.011. 

RePORTER. 2017. Perflouroalkyls. National Institutes of Health, Research Portfolio Online Reporting 

Tools. http://projectreporter.nih.gov/reporter.cfm. February 28, 2017.
PERFLUOROALKYLS 684

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Ribes D, Fuentes S, Torrente M, et al. 2010. Combined effects of perfluorooctane sulfonate (PFOS) and 

maternal restraint stress on hypothalamus adrenal axis (HPA) function in the offspring of mice. 

Toxicol Appl Pharmacol 243(1):13-18.

Robledo CA, Yeung E, Mendola P, et al. 2015a. Preconception maternal and paternal exposure to 

persistent organic pollutants and birth size: The LIFE study. Environ Health Perspect 123(1):88-94. 

10.1289/ehp.1308016. 

Robledo CA, Yeung E, Mendola P, et al. 2015b. Supplemental material to preconception maternal and 

paternal exposure to persistent organic pollutants and birth size: The LIFE study. [Environ Health 

Perspect 123(1):88-94]. Environ Health Perspect 10.1289/ehp.1308016. 

Rockwell CE, Turley AE, Cheng X, et al. 2013. Acute immunotoxic effects of perfluorononanoic acid 

(PFNA) in C57BL/6 Mice. Clin Exp Pharmacol Suppl 4. 10.4172/2161-1459.S4-002. 

http://www.ncbi.nlm.nih.gov/pubmed/25568816. 

Rockwell CE, Turley AE, Cheng X, et al. 2017. Persistent alterations in immune cell populations and 

function from a single dose of perfluorononanoic acid (PFNA) in C57B1/6 mice. Food Chem 

Toxicol 100:24-33. 

Rodriguez CE, Setzer RW, Barton HA. 2009. Pharmacokinetic modeling of perfluorooctanoic acid 

during gestation and lactation in the mouse. Reprod Toxicol 27(3-4):373-386.

+Rogers JM, Ellis-Hutchings RG, Grey BE, et al. 2014. Elevated blood pressure in offspring of rats 

exposed to diverse chemicals during pregnancy. Toxicol Sci 137(2):436-446. 

10.1093/toxsci/kft248. 

Romano ME, Xu Y, Calafat AM, et al. 2016. Maternal serum perfluoroalkyl substances during 

pregnancy and duration of breastfeeding. Environ Res 10.1016/j.envres.2016.04.034.

Rosen MB, Abbott BD, Wolf DC, et al. 2008a. Gene profiling in the livers of wild-type and PPARα-null 

mice exposed to perfluorooctanoic acid. Toxicol Pathol 36(4):592-607. 

Rosen MB, Das KP, Rooney J, et al. 2017. PPARα-independent transcriptional targets of perfluoroalkyl 

acids revealed by transcript profiling. Toxicology [In press].

Rosen MB, Lee JS, Ren H, et al. 2008b. Toxicogenomic dissection of the perfluorooctanoic acid 

transcript profile in mouse liver: Evidence for the involvement of nuclear receptors PPARα and 

CAR. Toxicol Sci 103(1):46-56. 

Rosen MB, Schmid JR, Corton JC, et al. 2010. Gene expression profiling in wild-type and pparalphanull mice exposed to perfluorooctane sulfonate reveals PPARα-independent effects. PPAR Res 

10.1155/2010/794739. 

+Rosen MB, Schmid JE, Das KP, et al. 2009. Gene expression profiling in the liver and lung of 

perfluorooctane sulfonate-exposed mouse fetuses: Comparison to changes induced by exposure to 

perfluorooctanoic acid. Reprod Toxicol 27:278-288.

Rosen MB, Thibodeaux JR, Wood CR, et al. 2007. Gene expression profiling in the lung and liver of 

PFOA-exposed mouse fetuses. Toxicology 239:15-33.

Rotander A, Toms LM, Aylward L, et al. 2015. Elevated levels of PFOS and PFHxS in firefighters 

exposed to aqueous film forming foam (AFFF). Environ Int 82:28-34. 

10.1016/j.envint.2015.05.005.

RTECS. 2008. Perfluoroalkyls. Hamilton, Ontario: Registry of Toxic Effects on Chemical Substances. 

Canadian Centre for Occupational Health and Safety. Symyx Software, Inc. May 29, 2008.

Rumsby PC, McLaughlin CL, Hall T. 2009. Perfluorooctane sulphonate and perfluorooctanoic acid in 

drinking and environmental waters. Philos Trans A Math Phys Eng Sci 367(1904):4119-4136. 

10.1098/rsta.2009.0109.

Ryu MH, Jha A, Ojo OO, et al. 2014. Chronic exposure to perfluorinated compounds: Impact on airway 

hyperresponsiveness and inflammation. Am J Physiol Lung Cell Mol Physiol 307(10):L765-L774. 

Sakr CJ, Kreckmann KH, Green JW, et al. 2007b. Cross-sectional study of lipids and liver enzymes 

related to a serum biomarker of exposure (ammonium perfluorooctanoate or APFO) as part of a 

general health survey in a cohort of occupationally exposed workers. J Occup Environ Med 

49:1086-1096.
PERFLUOROALKYLS 685

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Sakr CJ, Leonard RC, Kreckmann KH, et al. 2007a. Longitudinal study of serum lipids and liver 

enzymes in workers with occupational exposure to ammonium perfluorooctanoate. J Occup Environ 

Med 49:872-879.

Sakr CJ, Symons JM, Kreckmann KH, et al. 2009. Ischaemic heart disease mortality study among 

workers with occupational exposure to ammonium perfluorooctanoate. Occup Environ Med 66:699-

703.

+Salgado R, Pereiro N, Lopez-Doval S, et al. 2015. Initial study on the possible mechanisms involved in 

the effects of high doses of perfluorooctane sulfonate (PFOS) on prolactin secretion. Food Chem 

Toxicol 83:10-16. 10.1016/j.fct.2015.05.013.

Salvalaglio M, Muscionico I, Cavallotti C. 2010. Determination of energies and sites of binding of 

PFOA and PFOS to human serum albumin. J Phys Chem B 114(46):14860-14874.

Sato I, Kawamoto K, Nishikawa Y, et al. 2009. Neurotoxicity of perfluorooctane sulfonate (PFOS) in 

rats and mice after single oral exposure. J Toxicol Sci 34(5):569-574.

Savitz DA, Stein CR, Bartell SM, et al. 2012a. Perfluorooctanoic acid exposure and pregnancy outcome 

in a highly exposed community. Epidemiology 23(3):386-392.

Savitz DA, Stein CR, Elston B, et al. 2012b. Relationship of perfluorooctanoic acid exposure to 

pregnancy outcome based on birth records in the Mid-Ohio Valley. Environ Health Perspect 

120(8):1201-1207.

Savu PM. 1994a. Fluorinated higher carboxylic acids. In: Kirk-Othmer encyclopedia of chemical 

technology. John Wiley & Sons, Inc., 1-7. 

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/fluosavu.a01/current/pdf. 

April 01, 2008.

Savu P. 1994b. Fluorine-containing polymers, perfluoroalkanesulfonic acids. In: Kirk-Othmer 

encyclopedia of chemical technology. John Wiley & Sons, Inc., 1-7. 

http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/perfsavu.a01.current/pdf. 

April 01, 2008.

Schaider LA, Balan SA, Blum A, et al. 2017. Fluorinated compounds in U.S. fast food packaging. 

Environ Sci Tech Lett 4(3):105-111. 10.1021/acs.estlett.6b00435. 

Schecter A, Colacino J, Haffner D, et al. 2010. Perfluorinated compounds, polychlorinated biphenyls, 

and organochlorine pesticide contamination in composite food samples from Dallas, Texas, USA. 

Environ Health Perspect 118(6):796-802.

Schultz MM, Barofsky DF, Field JA. 2003. Fluorinated alkyl surfactants. Environ Eng Sci 20(5):487-

501.

Schultz MM, Barofsky DF, Field JA. 2006a. Quantitative determination of fluorinated alkyl substances 

by large-volume-injection liquid chromatography tandem mass spectrometry. Characterization of 

municipal wastewaters. Environ Sci Technol 40:289-295.

Schultz MM, Higgins CP, Huset CA, et al. 2006b. Fluorochemical mass flows in a municipal 

wastewater treatment facility. Environ Sci Technol 40(23):7350-7367.

+Seacat AM, Luebker DJ. 2000. Toxicokinetic study of perfluorooctane sulfonamide (PFOS; T-7132.2) 

in rats. 3M Strategic Toxicology Laboratory. Submitted to the U.S. Environmental Protection 

Agency's Administrative Record. AR226-1030A011. 

+Seacat AM, Thomford PJ, Hansen KJ, et al. 2002. Subchronic toxicity studies on 

perfluorooctanesulfonate potassium salt in Cynomolgus monkeys. Toxicol Sci 68(1):249-264.

+Seacat AM, Thomford PJ, Hansen KJ, et al. 2003. Sub-chronic dietary toxicity of potassium 

perfluorooctanesulfonate in rats. (Erratum in: Toxicology 2003 192(2-3):263-264). Toxicology 

183(1-3):117-133.

Seals R, Bartell SM, Steenland K. 2011. Accumulation and clearance of perfluorooctanoic acid (PFOA) 

in current and former residents of an exposed community. Environ Health Perspect 119(1):119-124.

Sepulvado JG, Blaine AC, Hundal LS, et al. 2011. Occurrence and fate of perfluorochemicals in soil 

following the land application of municipal biosolids. Environ Sci Technol 45(19):8106-8112. 

10.1021/es103903d.
PERFLUOROALKYLS 686

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Shankar A, Xiao J, Ducatman A. 2011a. Perfluoroalkyl chemicals and chronic kidney disease in US 

adults. Am J Epidemiol 174(8):893-900.

Shankar A, Xiao J, Ducatman A. 2011b. Perfluoroalkyl chemicals and elevated serum uric acid in US 

adults. Clin Epidemiol 3:251-258.

Shankar A, Xiao J, Ducatman A. 2012. Perfluorooctanoic acid and cardiovascular disease in US adults. 

Arch Intern Med 172(18):1397-1403.

Shapiro GD, Dodds L, Arbuckle TE, et al. 2016. Exposure to organophosphorus and organochlorine 

pesticides, perfluoroalkyl substances, and polychlorinated biphenyls in pregnancy and the 

association with impaired glucose tolerance and gestational diabetes mellitus: The MIREC Study. 

Environ Res 147:71-81. 10.1016/j.envres.2016.01.040. 

+Shi Z, Zhang H, Ding L, et al. 2009. The effect of perfluorododecanoic acid on endocrine status, sex 

hormones and expression of steroidogenic genes in pubertal female rats. Reprod Toxicol 27(3-

4):352-359. 

+Shi Z, Zhang H, Liu Y, et al. 2007. Alterations in gene expression and testosterone synthesis in the 

testes of male rats exposed to perfluorododecanoic acid. Toxicol Sci 98(1):206-215.

Shin HM, Vieira VM, Ryan PB, et al. 2011. Environmental fate and transport modeling for 

perfluorooctanoic acid emitted from the Washington Works Facility in West Virginia. Environ Sci 

Technol 45(4):1435-1442.

Shipley JM, Hurst CH, Tanaka SS, et al. 2004. trans-Activation of PPAR(beta) and induction of 

PPAR(beta) target genes by perfluorooctane-based chemicals. Toxicol Sci 80(1):151-160.

Shoeib M, Harner T, Ikonomou M, et al. 2004. Indoor and outdoor air concentrations and phase 

partitioning of perfluoroalkyl sulfonamides and polybrominated diphenyl ethers. Environ Sci 

Technol 38:1313-1320.

Shoeib M, Harner T, Vlahos P. 2006. Perfluorinated chemicals in the arctic atmosphere. Environ Sci 

Technol 40:7577-7583.

Shrestha S, Bloom MS, Yucel R, et al. 2015. Perfluoroalkyl substances and thyroid function in older 

adults. Environ Int 75:206-214. 10.1016/j.envint.2014.11.018. 

Siegemund G, Schwertfeger W, Feiring A, et al. 2005. Fluorine compounds, organic. Ullmann's 

Encyclopedia of Industrial Chemistry. Wiley-VCH Verlag GmbH & Co. 

http://mrw.interscience.wiley.com/emrw/9783527306732/ueic/article/a11_349/current/abstract. 

April 01, 2008.

Simcik MF. 2005. Global transport and fate of perfluorochemicals. J Environ Monit 7:759-763.

Simcik MF, Dorweiler KJ. 2005. Ratio of perfluorochemical concentrations as a tracer of atmospheric 

deposition to surface waters. Environ Sci Technol 39:8678-8683.

Simpson C, Winquist A, Lally C, et al. 2013. Relation between perfluorooctanoic acid exposure and 

strokes in a large cohort living near a chemical plant. Environ Res 127:22-28. 

10.1016/j.envres.2013.10.002.

Sinclair E, Kannan K. 2006. Mass loading and fate of perfluoroalkyl surfactants in wastewater treatment 

plants. Environ Sci Technol 40(5):1408-1414.

Sinclair E, Kim SK, Akinleye HB, et al. 2007. Quantitation of gas-phase perfluoroalkyl surfactants and 

fluorotelomer alcohols released from nonstick cookware and microwave popcorn bags. Environ Sci 

Technol 41:1180-1185.

Sinclair E, Mayack DT, Roblee K, et al. 2006. Occurrence of perfluoroalkyl surfactants in water, fish, 

and birds from New York State. Arch Environ Contam Toxicol 50:398-401.

Sinclair E, Taniyasu S, Yamashita N, et al. 2004. Perfluorooctanoic acid and perfluorooctane sulfonate 

in Michigan and New York waters. Organohalogen Compounds 66:4069-4073.

Skuladottir M, Ramel A, Rytter D, et al. 2015. Examining confounding by diet in the association 

between perfluoroalkyl acids and serum cholesterol in pregnancy. Environ Res 143(Pt A):33-38. 

10.1016/j.envres.2015.09.001. 
PERFLUOROALKYLS 687

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Small MJ. 2009. Final report of the peer consultation panel conducting the review for the scientific peer 

consultation process for a site environmental assessment program as part of the Dupont-EPA 

memorandum of understanding and Phase II Workplan. Pittsburgh, PA: Carnegie Mellon 

University, Civil and Environmental Engineering and Engineering and Public Policy. 

Smit LA, Lenters V, Hoyer BB, et al. 2015. Prenatal exposure to environmental chemical contaminants 

and asthma and eczema in school-age children. Allergy 70(6):653-660. 10.1111/all.12605. 

Smithwick M, Mabury SA, Solomon KR, et al. 2005a. Circumpolar study of perfluoroalkyl 

contaminants in polar bears (Ursus maritimus). Environ Sci Technol 39(15):5517-5523.

Smithwick M, Muir DC, Mabury SA, et al. 2005b. Perfluoroalkyl contaminants in liver tissue from East 

Greenland polar bears (Ursus maritimus). Environ Toxicol Chem 24(4):981-986.

Smithwick M, Norstrom RJ, Mabury SA, et al. 2006. Temporal trends of perfluoroalkyl contaminants in 

polar bears (Ursus maritimus) from two locations in the North American arctic, 1972-2002. Environ 

Sci Technol 40:1139-1143.

So MK, Taniyasu S, Lam PKS, et al. 2006a. Alkaline digestion and solid phase extraction method for 

perfluorinated compounds in mussels and oysters from South China and Japan. Arch Environ 

Contam Toxicol 50:240-248.

So MK, Yamashita N, Taniyasu S, et al. 2006b. Health risks in infants associated with exposure to 

perfluorinated compounds in human breast milk from Zhoushan, China. Environ Sci Technol 

40:2924-2929.

+Sobolewski M, Conrad K, Allen JL, et al. 2014. Sex-specific enhanced behavioral toxicity induced by 

maternal exposure to a mixture of low dose endocrine-disrupting chemicals. Neurotoxicology 

45:121-130. 10.1016/j.neuro.2014.09.008. 

+Son H, Kim S, Shin HI, et al. 2008. Perfluorooctanoic acid-induced hepatic toxicity following 21-day 

oral exposure in mice. Arch Toxicol 82:239-246.

+Son HY, Lee S, Tak EN, et al. 2009. Perfluorooctanoic acid alters T lymphocyte phenotypes and 

cytokine expression in mice. Environ Toxicol 24(6):580-588.

SPARC. 2008. Macroscopic pka. Sparc Performs Automated Reasoning in Chemistry. 

http://sparc.chem.ugs.edu/sparc/display/ShowMacro.cfm. May 08, 2008.

Specht IO, Hougaard KS, Spano D, et al. 2012. Sperm DNA integrity in relation to exposure to 

environmental perfluoralkyl substances. A study of spouses of pregnant women in three 

geographical regions. Reprod Toxicol 33:577-583.

Spliethoff HM, Tao L, Shaver SM, et al. 2008. Use of newborn screening program blood spots for 

exposure assessment: Declining levels of perfluorinated compounds in New York State infants. 

Environ Sci Technol 42(14):5361-5367. 

Staels B, Dallongeville J, Auwerx J, et al. 1998. Mechanism of action of fibrates on lipid and lipoprotein 

metabolism. Circulation 98:2088-2093. 

+Staples RE, Burgess BA, Kerns WD. 1984. The embryo-fetal toxicity and teratogenic potential of 

ammonium perfluorooctanoate (APFO) in the rat. Fundam Appl Toxicol 4:429-440.

Starkov AA, Wallace KB. 2002. Structural determinants of fluorochemical-induced mitochondrial 

dysfunction. Toxicol Sci 66(2):244-252.

Starling AP, Engel SM, Richardson DB, et al. 2014b. Perfluoroalkyl substances during pregnancy and 

validated preeclampsia among nulliparous women in the Norwegian Mother and Child Cohort 

Study. Am J Epidemiol 179(7):824-833. 10.1093/aje/kwt432.

Starling AP, Engel SM, Whitworth KW, et al. 2014a. Perfluoroalkyl substances and lipid concentrations 

in plasma during pregnancy among women in the Norwegian Mother and Child Cohort Study. 

Environ Int 62:104-112. 10.1016/j.envint.2013.10.004. 

Stasinakis AS, Petalas AV, Mamais D, et al. 2008. Application of the OECD 301F respirometric test for 

the biodegradability assessment of various potential endocrine disrupting chemicals. Bioresour 

Technol 99:3458-3467.

Steenland K, Woskie S. 2012. Cohort mortality study of workers exposed to perfluorooctanoic acid. Am 

J Epidemiol 176(10):909-917.
PERFLUOROALKYLS 688

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Steenland K, Fletcher T, Savitz DA. 2010a. Epidemiologic evidence on the health effects of 

perfluorooctanoic acid (PFOA). Environ Health Perspect 118(8):1100-1108.

Steenland K, Jin C, MacNeil J, et al. 2009a. Predictors of PFOA levels in a community surrounding a 

chemical plant. Environ Health Perspect 117(7):1083-1088.

Steenland K, Tinker S, Frisbee S, et al. 2009b. Association of perfluorooctanoic acid and 

perfluorooctane sulfonate with serum lipids among adults living near a chemical plant. Am J 

Epidemiol 170(10):1268-1278.

Steenland K, Tinker S, Shankar A, et al. 2010b. Association of perfluorooctanoic acid (PFOA) and 

perfluorooctane sulfonate (PFOS) with uric acid among adults with elevated community exposure to 

PFOA. Environ Health Perspect 118(2):229-233.

Steenland K, Zhao L, Winquist A, et al. 2013. Ulcerative colitis and perfluorooctanoic acid (PFOA) in a 

highly exposed population of community residents and workers in the Mid-Ohio Valley. Environ 

Health Perspect 121(8):900-905.

Steenland K, Zhao L, Winquist A. 2015. A cohort incidence study of workers exposed to 

perfluorooctanoic acid (PFOA). Occup Environ Med 72(5):373-380. 10.1136/oemed-2014-102364.

Stein CR, Savitz DA. 2011. Serum perfluorinated compound concentration and attention 

deficit/hyperactivity disorder in children 5-18 years of age. Environ Health Perspect 119(10):1466-

1471.

Stein CR, McGovern KJ, Pajak AM, et al. 2016a. Perfluoroalkyl and polyfluoroalkyl substances and 

indicators of immune function in children aged 12-19 y: National Health and Nutrition Examination 

Survey. Pediatr Res 79(2):348-357. 10.1038/pr.2015.213. 

Stein CR, Ge Y, Wolff MS, et al. 2016b. Perfluoroalkyl substance serum concentrations and immune 

response to FluMist vaccination among healthy adults. Environ Res 149:171-178. 

10.1016/j.envres.2016.05.020. 

Stein CR, Savitz DA, Bellinger DC. 2013. Perfluorooctanoate and neuropsychological outcomes in 

children. Epidemiology 24(4):590-599.

Stein CR, Savitz DA, Bellinger DC. 2014a. Perfluorooctanoate exposure in a highly exposed community 

and parent and teacher reports of behaviour in 6-12-year-old children. Paediatr Perinat Epidemiol 

28(2):146-156. 10.1111/ppe.12097. 

Stein CR, Savitz DA, Bellinger DC. 2014b. Supporting information to perfluorooctanoate exposure in a 

highly exposed community and parent and teacher reports of behaviour in 6-12-year-old children. 

Paediatr Perinat Epidemiol 10.1111/ppe.12097. 

Stein CR, Savitz DA, Elston B, et al. 2014c. Perfluorooctanoate exposure and major birth defects. 

Reprod Toxicol 47:15-20. 10.1016/j.reprotox.2014.04.006. 

Stein CR, Savitz DA, Dougan M. 2009. Serum levels of perfluorooctanoic acid and perfluorooctane 

sulfonate and pregnancy outcome. Am J Epidemiol 170(7):837-846.

Stock NL, Lau FK, Ellis DA, et al. 2004. Polyfluorinated telomer alcohols and sulfonamides in the 

North American troposphere. Environ Sci Technol 38:991-996.

Strøm M, Hansen S, Olsen SF, et al. 2014. Persistent organic pollutants measured in maternal serum and 

offspring neurodevelopmental outcomes--a prospective study with long-term follow-up. Environ Int 

68:41-48. 10.1016/j.envint.2014.03.002.

Strynar MJ, Lindstrom AB. 2008. Perfluorinated compounds in house dust from Ohio and North 

Carolina, USA. Environ Sci Technol 42:3751-3756.

Strynar MJ, Lindstrom AB, Nakayama SF, et al. 2012. Pilot scale application of a method for the 

analysis of perfluorinated compounds in surface soils. Chemosphere 86:252-257. 

Su TC, Kuo CC, Hwang JJ, et al. 2016. Serum perfluorinated chemicals, glucose homeostasis and the 

risk of diabetes in working-aged Taiwanese adults. Environ Int 88:15-22. 

10.1016/j.envint.2015.11.016. 

Suh CH, Cho NK, Lee CK, et al. 2011. Perfluorooctanoic acid-induced inhibition of placental prolactinfamily hormone and fetal growth retardation in mice. Mol Cell Endocrinol 337(1-2):7-15.
PERFLUOROALKYLS 689

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Sundström M, Chang SC, Noker PE, et al. 2012. Comparative pharmacokinetics of 

perfluorohexanesulfonate (PFHxS) in rats, mice, and monkeys. Reprod Toxicol 33(4):441-451.

Sweeney LM, Tyler TR, Kirman CR, et al. 2001. Proposed occupational exposure limits for select 

ethylene glycol ethers using PBPK models and Monte Carlo simulations. Toxicol Sci 62(1):124-

139. 

Takacs ML, Abbott BD. 2007. Activation of mouse and human peroxisome proliferator-activated 

receptors (a, b/d, c) by perfluorooctanoic acid and perfluorooctane sulfonate. Toxicol Sci 95(1):108-

117.

Takagi A, Sai K, Umemura T, et al. 1991. Short-term exposure to the peroxisome proliferators, 

perfluorooctanoic acid and perfluorodecanoic acid, causes significant increase of 8-

hydroxydeoxyguanosine in liver DNA of rats. Cancer Lett 57(1):55-60.

+Takahashi M, Ishida S, Hirata-Koizumi M, et al. 2014. Repeated dose and reproductive/developmental 

toxicity of perfluoroundecanoic acid in rats. J Toxicol Sci 39(1):97-108.

+Tan X, Xie G, Sun X, et al. 2013. High fat diet feeding exaggerates perfluorooctanoic acid-induced 

liver injury in mice via modulating multiple metabolic pathways. PLoS ONE 8(4):e61409.

Tan Y, Clewell HJ, Andersen ME. 2008. Time dependencies in perfluorooctylacids disposition in rat 

and monkeys: A kinetic analysis. Toxicol Lett 177:38-47.

Tatum-Gibbs K, Wambaugh JF, Das KP, et al. 2011. Comparative pharmacokinetics of 

perfluorononanoic acid in rat and mouse. Toxicology 281(1-3):48-55. 10.1016/j.tox.2011.01.003.

Tao L, Kannan K, Aldous KM, et al. 2008a. Biomonitoring of perfluorochemicals in plasma of New 

York State personnel responding to the World Trade Center disaster. Environ Sci Technol 

42(9):3472-3478.

Tao L, Kannan K, Wong CM, et al. 2008b. Perfluorinated compounds in human milk from 

Massachusetts, U.S.A. Environ Sci Technol 42(8):3096-3101.

Tarazona JV, Rodriguez C, Alonso E, et al. 2016. Toxicokinetics of perfluorooctane sulfonate in rabbits 

under environmentally realistic exposure conditions and comparative assessment between mammals 

and birds. Toxicol Lett 241:200-206. 10.1016/j.toxlet.2015.11.002. 

Tardiff RG, Carson ML, Sweeney LM, et al. 2009. Derivation of a drinking water equivalent level 

(DWEL) related to the maximum contaminant level goal for perfluorooctanoic acid (PFOA), a 

persistent water soluble compound. Food Chem Toxicol 47(10):2557-2589. 

Taylor KW, Hoffman K, Thayer KA, et al. 2014. Polyfluoroalkyl chemicals and menopause among 

women 20-65 years of age (NHANES). Environ Health Perspect 122(2):145-150. 

10.1289/ehp.1306707.

+Thibodeaux JR, Hanson RG, Rogers JM, et al. 2003. Exposure to perfluorooctane sulfonate during 

pregnancy in rat and mouse. I: Maternal and prenatal evaluations. Toxicol Sci 74(2):369-381.

+Thomford PJ. 2001. 4-Week capsule toxicity study with ammonium perfluorooctanoate (APFO) in 

Cynomolgus monkeys. APME Ad-Hoc APFO toxicology working group. 

+Thomford PJ. 2002a. 4-week capsule toxicity study with perfluorooctane sulfonic acid potassium salt 

(PFOS; T-6295) in Cynomolgus monkeys. St. Paul, MN: 3M. 

+Thomford PJ. 2002b. 104-Week dietary chronic toxicity and carcinogenicity study with 

perfluorooctane sulfonic acid potassium salt (PFOS; T-6295) in rats. St. Paul, MN: 3M. 

Thompson J, Lorber M, Toms LM, et al. 2010. Use of simple pharmacokinetic modeling to characterize 

exposure of Australians to perfluorooctanoic acid and perfluorooctane sulfonic acid. Environ Int 

36(4):390-397. 10.1016/j.envint.2010.02.008.

Thomsen C, Haug LS, Stigum H, et al. 2010. Changes in concentrations of perfluorinated compounds, 

polybrominated diphenyl ethers, and polychlorinated biphenyls in Norwegian breast-milk during 

twelve months of lactation. Environ Sci Technol 44(24):9550-9556.

Timmermann CA, Rossing LI, Grontved A, et al. 2014. Adiposity and glycemic control in children 

exposed to perfluorinated compounds. J Clin Endocrinol Metab 99(4):E608-614. 10.1210/jc.2013-

3460. 
PERFLUOROALKYLS 690

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Tittlemier S, Ryan JJ, Van Oostdam J. 2004. Presence of anionic perfluorinated organic compounds in 

serum collected from northern Canadian populations. Organohalogen Compounds 66:3959-3964.

Tittlemier SA, Pepper K, Seymour C, et al. 2007. Dietary exposure of Canadians to perfluorinated 

carboxylates and perfluorooctane sulfonate via consumption of meat, fish, fast foods, and food items 

prepared in their packaging. J Agric Food Chem 55:3203-3210.

Toft G, Jonsson BA, Bonde JP, et al. 2016. Perfluorooctane sulfonate concentrations in amniotic fluid, 

biomarkers of fetal Leydig Cell Function, and cryptorchidism and hypospadias in Danish boys 

(1980-1996). Environ Health Perspect 124(1):151-156. 10.1289/ehp.1409288. 

Toft G, Jonsson BA, Lindh CH, et al. 2012. Exposure to perfluorinated compounds and human semen 

quality in Arctic and European populations. Hum Reprod 27(8):2532-2540.

Toms LL, Calafat AM, Kato K, et al. 2009. Polyfluoroalkyl chemicals in pooled blood serum from 

infants, children, and adults in Australia. Environ Sci Technol 43(11):4194-4199.

Tomy GT, Budakowski W, Halldorson T, et al. 2004. Fluorinated organic compounds in an eastern 

arctic marine food web. Environ Sci Technol 38:6475-6481.

Trudel D, Horowitz L, Wormuth M, et al. 2008. Estimating consumer exposure to PFOS and PFOA. 

Risk Anal 28(2):251-269.

Tsai MS, Lin CY, Lin CC, et al. 2015. Association between perfluoroalkyl substances and reproductive 

hormones in adolescents and young adults. Int J Hyg Environ Health 218(5):437-443. 

10.1016/j.ijheh.2015.03.008.

+Tucker DK, Macon MB, Strynar MJ, et al. 2015. The mammary gland is a sensitive pubertal target in 

CD-1 and C57Bl/6 mice following perinatal perfluorooctanoic acid (PFOA) exposure. Reprod 

Toxicol 54:26-36. 10.1016/j.reprotox.2014.12.002. 

Uhl SA, James-Todd T, Bell ML. 2013. Association of osteoarthritis with perfluorooctanoate and 

perfluorooctane sulfonate in NHANES 2003-2008. Environ Health Perspect 121(4):447-452.

Upham BL, Deocampo ND, Wurl B, et al. 1998. Inhibition of gap junctional intercellular 

communication by perfluorinated fatty acids is dependent on the chain length of the fluorinated tail. 

Int J Cancer 78:491-495.

Upham BL, Park JS, Babica P, et al. 2009. Structure-activity-dependent regulation of cell 

communication by perfluorinated fatty acids using in vivo and in vitro model systems. Environ 

Health Perspect 117(4):545-551. 10.1289/ehp.11728. 

URS. 2012. MOU Phase III - future work plan data assessment DuPont Washington Works, 

Washington, West Virginia, PFOA site-related environmental assessment program (OPPT-2004-

0113 PFOA). In: Docket EPA-HQ-2004-0113-0517. Supporting documents: Letter to Dr. Maria 

Doa, Director, Chemical Control Division, USEPA, from Andrew S. Hartten, Principal Remediation 

Project Manager, DuPont Corporate Remediation Group. URS Corporation. 

https://www.regulations.gov/document?D=EPA-HQ-OPPT-2004-0113-0516 February 28, 2017.

Vagi SJ, Azziz-Baumgartner E, Sjodin A, et al. 2014. Exploring the potential association between 

brominated diphenyl ethers, polychlorinated biphenyls, organochlorine pesticides, perfluorinated 

compounds, phthalates, and bisphenol A in polycystic ovary syndrome: A case-control study. BMC 

Endoc Disord 14:86. 10.1186/1472-6823-14-86.

Vanden Heuvel JP, Davis JW, Sommers R, et al. 1992a. Renal excretion of perfluorooctanoic acid in 

male rats: Inhibitory effect of testosterone. J Biochem Toxicol 7(1):31-36.

Vanden Heuvel JP, Kuslikis BI, Peterson RE. 1992b. Covalent binding of perkuorinated fatty acids to 

proteins in the plasma, liver and testes of rats. Chem Biol Interact 82:318-328.

Vanden Heuvel JP, Kuslikis BI, Shrago E, et al. 1991a. Inhibition of long-chain acyl-CoA synthetase by 

the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes. Biochem Pharmacol 

42(2):295-302.

Vanden Heuvel JP, Kuslikis BI, Van Rafelghem MJ, et al. 1991b. Disposition of perfluorodecanoic acid 

in male and female rats. Toxicol Appl Pharmacol 107:450-459.

Vanden Heuvel JP, Kuslikis BI, Van Rafelghem MJ, et al. 1991c. Tissue distribution, metabolism, and 

elimination of perfluorooctanoic acid in male and female rats. J Biochem Toxicol 6(2):83-92.
PERFLUOROALKYLS 691

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Vanden Heuvel JP, Thompson JT, Frame SR, et al. 2006. Differential activation of nuclear receptors by 

perfluorinated fatty acid analogs and natural fatty acids: A comparison of human, mouse, and rat 

peroxisome proliferator-activated receptor-α, -ß, and -γ, liver x receptor-ß, and retinoid x receptor-α. 

Toxicol Sci 92(2):476-489.

+van Otterdijk FM. 2007a. Repeated dose 28-day oral toxicity study with MTDID-8391 by daily gavage 

in the rat, followed by a 21-day recovery period. 3M. 

van Otterdijk FM. 2007b. Repeated dose 90-day oral toxicity study with MTDID 8391 by daily gavage 

in the rat followed by a 3-week recovery period. 3M. 

Vélez MP, Arbuckle TE, Fraser WD. 2015. Maternal exposure to perfluorinated chemicals and reduced 

fecundity: The MIREC study. Hum Reprod 30(3):701-709. 10.1093/humrep/deu350.

Vermont Department of Health. 2017. Drinking water guidance. Burlington, VT: Vermont Department 

of Health. 

http://www.healthvermont.gov/sites/default/files/documents/pdf/ENV_DW_Guidance.pdf. 

December 19, 2017.

Verner MA, Loccisano AE, Morken NH, et al. 2015. Associations of perfluoroalkyl substances (PFAS) 

with lower birth weight: An evaluation of potential confounding by glomerular filtration rate using a 

physiologically based pharmacokinetic model (PBPK). Environ Health Perspect 123(12):1317-

1324. 

Verner MA, Longnecker MP. 2015. Comment on "Enhanced elimination of perfluorooctanesulfonic acid 

by menstruating women: Evidence from population-based pharmacokinetic modeling." Environ Sci 

Technol 49(9):5836-5837. 10.1021/acs.est.5b00187.

Verner MA, Ngueta G, Jensen ET, et al. 2016. A simple pharmacokinetic model of prenatal and 

postnatal exposure to perfluoroalkyl substances (PFASs). Environ Sci Technol 50(2):978-986. 

Verreault J, Berger U, Gabrielsen GW. 2007. Trends of perfluorinated alkyl substances in herring gull 

eggs from two coastal colonies in northern Norway: 1983-2003. Environ Sci Technol 41:6671-

6677.

Verreault J, Houde M, Gabrielsen GW, et al. 2005. Perfluorinated alkyl substances in plasma, liver, 

brain, and eggs of glaucous gulls (Larus hyperboreus) from the Norwegian Arctic. Environ Sci 

Technol 39:7439-7445.

Vested A, Ramlau-Hansen CH, Olsen SF, et al. 2013. Associations of in utero exposure to 

perfluorinated alkyl acids with human semen quality and reproductive hormones in adult men. 

Environ Health Perspect 121(4):453-458.

Vestergaard S, Nielsen F, Andersson AM, et al. 2012. Association between perfluorinated compounds 

and time to pregnancy in a prospective cohort of Danish couples attempting to conceive. Hum 

Reprod 27(3):873-880.

Vestergren R, Cousins IT. 2009. Tracking the pathways of human exposure to perfluorocarboxylates. 

Environ Sci Technol 43(15):5565-5575.

Vestergren R, Cousins IT, Trudel D, et al. 2008. Estimating the contribution of precursor compounds in 

consumer exposure to PFOS and PFOA. Chemosphere 73(10):1617-1624.

Vesterholm Jensen D, Christensen J, Virtanen HE, et al. 2014. No association between exposure to 

perfluorinated compounds and congenital cryptorchidism: A nested case-control study among 215 

boys from Denmark and Finland. Reproduction 147(4):411-417. 

+Vetvicka V, Vetvickova J. 2013. Reversal of perfluorooctanesulfonate-induced immunotoxicity by a 

glucan-resverarol-vitamin C combination. Oriental Pharmacy and Experimental Medicine 13(1):77-

84. 

+Viberg H, Lee I, Eriksson P. 2013. Adult dose-dependent behavioral and cognitive disturbances after a 

single neonatal PFHxS dose. Toxicology 304:185-191.

Vieira VM, Hoffman K, Shin M, et al. 2013. Perfluorooctanoic acid exposure and cancer outcomes in a 

contaminated community: A geographic analysis. Environ Health Perspect 121(3):318-323.
PERFLUOROALKYLS 692

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Völkel W, Genzel-Boroviczeny O, Demmelmair H, et al. 2008. Perfluorooctane sulphonate (PFOS) and 

perfluorooctanoic acid (PFOA) in human breast milk: Results of a pilot study. Int J Hyg Environ 

Health 211:440-446.

von Ehrenstein OS, Fenton SE, Kato K, et al. 2009. Polyfluoroalkyl chemicals in the serum and milk of 

breastfeeding women. Reprod Toxicol 27(3-4):239-245.

Vuong AM, Yolton K, Webster GM, et al. 2016. Prenatal polybrominated diphenyl ether and 

perfluoroalkyl substance exposures and executive function in school-age children. Environ Res 

147:556-564. 10.1016/j.envres.2016.01.008.

Wallace K, Kissling G, Melnick R, et al. 2013. Structure-activity relationships for perfluoroalkaneinduced in vitro interference with rat liver mitochondrial respiration. Toxicol Lett 222(3):257-264. 

Wallington TJ, Hurley MD, Xia J, et al. 2006. Formation of C7F15COOH (PFOA) and other 

perfluorocarboxylic acids during the atmospheric oxidation of 8:2 fluorotelomer alcohol. Environ 

Sci Technol 40:924-930.

Walters M, Bjork J, Wallace K. 2009. Perfluorooctanoic acid stimulated mitochondrial biogenesis and 

gene transcription in rats. Toxicology 264(1):10-15. 

Wambaugh JF, Barton HA, Setzer RW. 2008. Comparing models for perfluorooctanoic acid 

pharmacokinetics using Bayesian analysis. J Pharmacokinet Pharmacodyn 35(6):683-712. 

10.1007/s10928-008-9108-2. 

Wambaugh JF, Setzer RW, Pitruzzello AM, et al. 2013. Dosimetric anchoring of in vivo and in vitro

studies for perfluorooctanoate and perfluorooctanesulfonate. Toxicol Sci 136(2):308-327. 

10.1093/toxsci/kft204. 

Wan HT, Mruk DD, Wong CK, et al. 2014a. Perfluorooctanesulfonate (PFOS) perturbs male rat Sertoli 

cell blood-testis barrier function by affecting F-actin organization via p-FAK-Tyr(407): An in vitro

study. Endocrinology 155(1):249-262. 10.1210/en.2013-1657. 

+Wan HT, Zhao YG, Wong MH, et al. 2011. Testicular signaling is the potential target of 

perfluorooctanesulfonate-mediated subfertility in male mice. Biol Reprod 84(5):1016-1023.

+Wan HT, Zhao YG, Leung PY, et al. 2014b. Perinatal exposure to perfluorooctane sulfonate affects 

glucose metabolism in adult offspring. PLoS ONE 9(1):e87137. 10.1371/journal.pone.0087137. 

Wang IJ, Hsieh W-S, Chen C-Y, et al. 2011. The effect of prenatal perfluorinated chemicals exposures 

on pediatric atopy. Environ Res 111(6):785-791.

Wang J, Zhang Y, Zhang W, et al. 2012. Association of perfluorooctanoic acid with HDL cholesterol 

and circulating miR-26b and miR-199-3p in workers of a fluorochemical plant and nearby residents. 

Environ Sci Technol 46(17):9274-9281.

Wang J, Yan S, Zhang W, et al. 2015a. Integrated proteomic and miRNA transcriptional analysis reveals 

the hepatotoxicity mechanism of PFNA exposure in mice. J Proteome Res 14(1):330-341. 

10.1021/pr500641b. 

Wang N, Szostek B, Buck RC, et al. 2005a. Fluorotelomer alcohol biodegradation–direct evidence that 

perfluorinated carbon chains breakdown. Environ Sci Technol 39:7516-7528.

Wang N, Szostek B, Folsom PW, et al. 2005b. Aerobic biotransformation of 14c-labeled 8-2 telomer B 

alcohol by activated sludge from a domestic sewage treatment plant. Environ Sci Technol 39:531-

538.

Wang Y, Adgent M, Su PH, et al. 2016. Prenatal exposure to perfluorocarboxylic acids (PFCAs) and 

fetal and postnatal growth in the Taiwan maternal and infant cohort study. Environ Health Perspect 

10.1289/ehp.1509998. 

Wang Y, Liu W, Zhang Q, et al. 2015c. Effects of developmental perfluorooctane sulfonate exposure on 

spatial learning and memory ability of rats and mechanism associated with synaptic plasticity. Food 

Chem Toxicol 76:70-76. 10.1016/j.fct.2014.12.008. 

Wang Y, Rogan WJ, Chen PC, et al. 2014. Association between maternal serum perfluoroalkyl 

substances during pregnancy and maternal and cord thyroid hormones: Taiwan maternal and infant 

cohort study. Environ Health Perspect 122(5):529-534. 10.1289/ehp.1306925. 
PERFLUOROALKYLS 693

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Wang Y, Rogan WJ, Chen HY, et al. 2015b. Prenatal exposure to perfluroalkyl substances and children's 

IQ: The Taiwan maternal and infant cohort study. Int J Hyg Environ Health 218(7):639-644. 

10.1016/j.ijheh.2015.07.002. 

Wang Y, Starling AP, Haug LS, et al. 2013a. Association between perfluoroalkyl substances and thyroid 

stimulating hormone among pregnant women: A cross-sectional study. Environ Health 12(1):76. 

10.1186/1476-069x-12-76.

Wang Y, Yeung LWY, Taniyasu S, et al. 2008. Perfluorooctane sulfonate and other fluorochemicals in 

waterbird eggs from south China. Environ Sci Technol 42(21):8146-8151.

Wang Z, Cousins IT, Scheringer M, et al. 2013b. Fluorinated alternatives to long-chain perfluoroalkyl 

carboxylic acids (PFCAs), perfluoroalkane, sulfonic acids (PFSAs) and their potential precursors. 

Environ Int 60:242-248.

Wania F. 2007. A global mass balance analysis of the source of perfluorocarboxylic acids in the Arctic 

Ocean. Environ Sci Technol 41:4529-4535.

Washburn ST, Bingman TS, Braitwaite SK, et al. 2005. Exposure assessment and risk characterization 

for perfluorooctanoate in selected consumer articles. Environ Sci Technol 39:3904-3910.

Washington JW, Ellington J, Jenkins TM, et al. 2009. Degradability of an acrylate-linked, fluorotelomer 

polymer in soil. Environ Sci Technol 43(17):6617-6623. 

Washington JW, Jenkins TM. 2015. Abiotic hydrolysis of fluorotelomer-based polymers as a source of 

perfluorocarboxylates at the global scale. Environ Sci Technol 49(24):14129-14135. 

10.1021/acs.est.5b03686.

Washington JW, Jenkins TM, Rankin K, et al. 2015. Decades-scale degradation of commercial, sidechain, fluorotelomer-based polymers in soils and water. Environ Sci Technol 49(2):915-823. 

Washino N, Saijo Y, Sasaki S, et al. 2009. Correlations between prenatal exposure to perfluorinated 

chemicals and reduced fetal growth. Environ Health Perspect 117:660-667.

Watkins DJ, Josson J, Elston B, et al. 2013. Exposure to perfluoroalkyl acids and markers of kidney 

function among children and adolescents living near a chemical plant. Environ Health Perspect 

121(5):625-630.

Weaver YM, Ehresman DJ, Butenhoff JL, et al. 2010. Roles of rat renal organic anion transporters in 

transporting perflluorinated carboxylates with different chain lengths. Toxicol Sci 113(2):305-314.

Webster GM, Rauch SA, Marie NS, et al. 2016. Cross-sectional associations of serum perfluoroalkyl 

acids and thyroid hormones in U.S. adults: Variation according to TPOAb and iodine status 

(NHANES 2007-2008). Environ Health Perspect 124(7):935-942. 10.1289/ehp.1409589. 

Wei S, Chen LQ, Taniyasu S, et al. 2007a. Distribution of perfluorinated compounds in surface 

seawaters between Asia and Antarctica. Mar Pollut Bull 54:1813-1838. 

Wei Y, Dai J, Liu M, et al. 2007b. Estrogen-like properties of perfluorooctanoic acid as revealed by 

expressing hepatic estrogen-responsive genes in rare minnows (Gobiocyris rarus). Environ Toxicol 

Chem 26(11):2440-2447.

Wen LL, Lin LY, Su TC, et al. 2013. Association between serum perfluorinated chemicals and thyroid 

function in U.S. adults: The national health and nutrition examination survey 2007-2010. J Clin 

Endocrinol Metab 98(9):E1456-1464. 10.1210/jc.2013-1282. 

+White SS, Calafat AM, Kuklenyik Z, et al. 2007. Gestational PFOA exposure of mice is associated 

with altered mammary gland development in dams and female offspring. Toxicol Sci 96(1):133-

144.

+White SS, Kato K, Jia LT, et al. 2009. Effects of perfluorooctanoic acid on mouse mammary gland 

development and differentiation resulting from cross-foster and restricted gestational exposures. 

Reprod Toxicol 27(3-4):289-298.

+White SS, Stanko JP, Kato K, et al. 2011. Gestational and chronic low-dose PFOA exposures and 

mammary gland growth and differentiation in three generations of CD-1 mice. Environ Health 

Perspect 119(8):1070-1076.

Whitworth KW, Haug LS, Baird DD, et al. 2012a. Perfluorinated compounds in relation to birth weight 

in the Norwegian Mother and Child Cohort Study. Am J Epidemiol 175(12):1209-1216.
PERFLUOROALKYLS 694

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Whitworth KW, Haug LS, Baird DD, et al. 2012b. Perfluorinated compounds and subfecundity in 

pregnant women. Epidemiology 23(2):257-263. 

WHO. 2010. Guidelines for indoor air quality: Selected pollutants. Geneva, Switzerland: World Health 

Organization. http://www.euro.who.int/__data/assets/pdf_file/0009/128169/e94535.pdf. January 

08, 2014. 

WHO. 2017. Guidelines for drinking-water quality. Geneva, Switzerland: World Health Organization. 

http://apps.who.int/iris/bitstream/10665/254637/1/9789241549950-eng.pdf?ua=1. February 28, 

2017. 

Wilhelm M, Kraft M, Rauchfuss K, et al. 2008. Assessment and management of the first German case of 

a contamination with perfluorinated compounds (PFC) in the Region Sauerland, North RhineWestphalia. J Toxicol Environ Health A 71:725-733. 

Wilhelm M, Holzer J, Dobler L, et al. 2009. Preliminary observations on perfluorinated compounds in 

plasma samples (1977-2004) of young German adults from an area with perfluorooctanoatecontaminated drinking water. Int J Hyg Environ Health 212(2):142-145. 

Winquist A, Steenland K. 2014a. Modeled PFOA exposure and coronary artery disease, hypertension, 

and high cholesterol in community and worker cohorts. Environ Health Perspect 122(12):1299-

1305. 10.1289/ehp.1307943. 

Winquist A, Steenland K. 2014b. Perfluorooctanoic acid exposure and thyroid disease in community and 

worker cohorts. Epidemiology 25(2):255-264. 10.1097/ede.0000000000000040. 

+Wolf CJ, Fenton SE, Schmid JE, et al. 2007. Developmental toxicity of perfluorooctanoic acid in the

CD-1 mouse after cross-foster and restricted gestational exposures. Toxicol Sci 95(2):462-473. 

Wolf CJ, Rider CV, Lau C, et al. 2014. Evaluating the additivity of perfluoroalkyl acids in binary 

combinations on peroxisome proliferator-activated receptor-alpha activation. Toxicology 316:43-54. 

10.1016/j.tox.2013.12.002. 

Wolf CJ, Schmid JE, Lau C, et al. 2012. Activation of mouse and human peroxisome proliferatoractivated receptor-alpha (PPARa) by perfluoroalkyl acids (PFAAs): Further investigation of C4-

C12 compounds. Reprod Toxicol 33:546-551. 

Wolf CJ, Takacs ML, Schmid JE, et al. 2008a. Activation of mouse and human peroxisome proliferatoractivated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths. 

Toxicol Sci 106(1):162-171. 

+Wolf CJ, Zehr RD, Schmid JE, et al. 2010. Developmental effects of perfluorononanoic Acid in the

mouse are dependent on peroxisome proliferator-activated receptor-alpha. PPAR Res 2010 

10.1155/2010/282896. 

Wolf DC, Moore T, Abbott BD, et al. 2008b. Comparative hepatic effects of perfluorooctanoic acid and 

WY 14,643 in PPAR-α knockout and wild-type mice. Toxicol Pathol 36(4):632-639. 

10.1177/0192623308318216. 

Wong F, MacLeod M, Mueller JF, et al. 2014. Enhanced elimination of perfluorooctane sulfonic acid by 

menstruating women: Evidence from population-based pharmacokinetic modeling. Environ Sci 

Technol 48(15):8807-8814. 

Wong F, MacLeod M, Mueller JF, et al. 2015. Response to comment on "Enhanced elimination of 

perfluorooctane sulfonic acid by menstruating women: Evidence from population-based 

pharmacokinetic modeling." Environ Sci Technol 49(9):5838-5839. 

Worley RR, Fisher J. 2015a. Application of physiologically-based pharmacokinetic modeling to explore 

the role of kidney transporters in renal reabsorption of perfluorooctanoic acid in the rat. Toxicol 

Appl Pharmacol 289(3):428-441. 10.1016/j.taap.2015.10.017. 

Worley RR, Fisher J. 2015b. Supplementary material: Application of physiologically-based 

pharmacokinetic modeling to explore the role of kidney transporters in renal reabsorption of 

perfluorooctanoic acid in the rat. Toxicol Appl Pharmacol 289(3):428-441. 

Worley RR, Moore SM, Tierney BC, et al. 2017a. Per- and polyfluoroalkyl substances in human serum 

and urine samples from a residentially exposed community. Environ Int 106:135-143. 

10.1016/j.envint.2017.06.007. 
PERFLUOROALKYLS 695

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Worley RR, Yang X, Fisher J. 2017b. Physiologically based pharmacokinetic modeling of human 

exposure to perfluorooctanoic acid suggests historical non drinking-water exposures are important 

for predicting current serum concentrations. Toxicol Appl Pharmacol 330:9-21. 

10.1016/j.taap.2017.07.001.

Woskie SR, Gore R, Steenland K. 2012. Retrospective exposure assessment of perfluorooctanoic acid 

serum concentrations at a fluoropolymer manufacturing plant. Ann Occup Hyg 56(9):1025-1037. 

10.1093/annhyg/mes023. 

Wu LL, Gao HW, Gao NY, et al. 2009. Interaction of perfluorooctanoic acid with human serum 

albumin. BMC Struct Biol 9:31.

Wu XM, Bennett DH, Calafat AM, et al. 2015. Serum concentrations of perfluorinated compounds 

(PFC) among selected populations of children and adults in California. Environ Res 136:264-273. 

10.1016/j.envres.2014.09.026. 

+Xia W, Wan Y, Li YY, et al. 2011. PFOS prenatal exposure induce mitochondrial injury and gene 

expression change in hearts of weaned SD rats. Toxicology 282(1-2):23-29.

Xiao F, Simcik MF, Halbach TR, et al. 2015. Perfluorooctane sulfonate (PFOS) and perfluorooctanoate 

(PFOA) in soils and groundwater of a U.S. metropolitan area: Migration and implications for human 

exposure. Water Res 72:64-74.

+Xie Y, Yang Q, Nelson BD, et al. 2003. The relationship between liver peroxisome proliferation and 

adipose tissue atrophy induced by peroxisome proliferator exposure and withdrawal in mice. 

Biochem Pharmacol 66(5):749-756.

+Xing J, Wang G, Zhao J, et al. 2016. Toxicity assessment of perfluorooctane sulfonate using acute and 

subchronic male C57BL/6J mouse models. Environ Pollut 210:388-396. 

10.1016/j.envpol.2015.12.008. 

Xu J, Shimpi P, Armstrong L, et al. 2016. PFOS induces adipogenesis and glucose uptake in association 

with activation of Nrf2 signaling pathway. Toxicol Appl Pharmacol 290:21-30. 

+Yahia D, El-Nasser MA, Abedel-Latif M, et al. 2010. Effects of perfluorooctanoic acid (PFOA) 

exposure to pregnant mice on reproduction. J Toxicol Sci 35(4):527-533.

+Yahia D, Tsukuba C, Yoshida M, et al. 2008. Neonatal death of mice treated with perfluorooctane 

sulfonate. J Toxicol Sci 33(2):219-226.

Yamada A, Maeda K, Kamiyama E, et al. 2007. Multiple human isoforms of drug transporters contribute 

to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-

receptor. Drug Metab Dispos 35(12):2166-2176. 10.1124/dmd.107.017459. 

Yamada T, Taylor PH, Buck RC, et al. 2005. Thermal degradation of fluorotelomer treated articles and 

related materials. Chemosphere 61:974-984.

Yamaguchi M, Arisawa K, Uemura H, et al. 2013. Consumption of seafood, serum liver enzymes, and 

blood levels of PFOS and PFOA in the Japanese population. J Occup Health 55(3):184-194. 

Yamashita N, Kannan K, Taniyasu S, et al. 2005. A global survey of perfluorinated acids in oceans. 

Mar Pollut Bull 51:658-668.

Yamashita N, Taniyasu S, Petrick G, et al. 2008. Perfluorinated acids as novel chemical tracers of global 

circulation of ocean waters. Chemosphere 70:1247-1255.

Yang CH, Glover KP, Han X. 2009. Organic anion transporting polypeptide (Oatp) 1a1-mediated 

perfluorooctanoate transport and evidence for a renal reabsorption mechanism of Oatp1a1 in renal 

elimination of perfluorocarboxylates in rats. Toxicol Lett 190(2):163-171.

Yang CH, Glover KP, Han X. 2010. Characterization of cellular uptake of perfluorooctanoate via 

organic anion-transporting polypeptide 1A2, organic anion transporter 4, and urate transporter 1 for 

their potential roles in mediating human renal reabsorption of perfluorocarboxylates. Toxicol Sci 

117(2):294-302.

Yang L, Li J, Lai J, et al. 2016a. Placental transfer of perfluoroalkyl substances and associations with 

thyroid hormones: Beijing prenatal exposure study. Sci Rep 6:21699. 10.1038/srep21699. 
PERFLUOROALKYLS 696

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Yang L, Wang Z, Shi Y, et al. 2016b. Human placental transfer of perfluoroalkyl acid precursors: 

Levels and profiles in paired maternal and cord serum. Chemosphere 144:1631-1638. 

10.1016/j.chemosphere.2015.10.063. 

+Yang Q, Abedi-Valugerdi M, Xie Y, et al. 2002a. Potent suppression of the adaptive immune response 

in mice upon dietary exposure to the potent peroxisome proliferator, perfluorooctanoic acid. Int 

Immunopharmacol 2(2-3):389-397.

+Yang Q, Xie Y, Alexson SE, et al. 2002b. Involvement of the peroxisome proliferator-activated 

receptor alpha in the immunomodulation caused by peroxisome proliferators in mice. Biochem 

Pharmacol 63(10):1893-1900.

+Yang Q, Xie Y, Depierre JW. 2000. Effects of peroxisome proliferators on the thymus and spleen of 

mice. Clin Exp Immunol 122(2):219-226.

+Yang Q, Xie Y, Eriksson AM, et al. 2001. Further evidence for the involvement of inhibition of cell 

proliferation and development in thymic and splenic atrophy induced by the peroxisome proliferator 

perfluorooctanoic acid in mice. Biochem Pharmacol 62(8):1133-1140.

Yao PL, Ehresman DJ, Rae JM, et al. 2014. Comparative in vivo and in vitro analysis of possible 

estrogenic effects of perfluorooctanoic acid. Toxicology 326:62-73. 10.1016/j.tox.2014.10.008. 

Yao X, Zhong L. 2005. Genotoxic risk and oxidative DNA damage in HepG2 cells exposed to 

perfluorooctanoic acid. Mutat Res 587:38-44.

Yarwood G, Kemball-Cook S, Keinath M, et al. 2007. High-resolution atmospheric modeling of 

fluorotelomer alcohols and perfluorocarboxylic acids in the North American troposphere. Environ 

Sci Technol 41:5756-5762.

Ye X, Kato K, Wong LY, et al. 2018a. Per- and polyfluoroalkyl substances in sera from children 3 to 11 

years of age participating in the National Health and Nutrition Examination Survey 2013-2014. Int J 

Hyg Environ Health 221(1):9-16. 10.1016/j.ijheh.2017.09.011. 

Ye X, Kato K, Wong LY, et al. 2018b. Supporting information to "Per- and polyfluoroalkyl substances 

in sera from children 3 to 11 years of age participating in the National Health and Nutrition 

Examination Survey 2013-2014" [Int J Hyg Environ Health 221(1):9-16. 

10.1016/j.ijheh.2017.09.011]. Int J Hyg Environ Health 

https://www.sciencedirect.com/science/article/pii/S1438463917305886#sec0045. December 19, 

2017.

Ye X, Strynar MJ, Nakayama SF, et al. 2008. Perfluorinated compounds in whole fish homogenates 

from the Ohio, Missouri, and Upper Mississippi Rivers, USA. Environ Pollut 156(3):1227-1232. 

10.1016/j.envpol.2008.03.014. 

Yeung LW, Robinson SJ, Koschorreck J, et al. 2013. Part II. A temporal study of PFOS and its 

precursors in human plasma from two German cities in 1982-2009. Environ Sci Technol 

47(8):3875-3882. 10.1021/es4004153. 

Ylinen M, Auriola S. 1990. Tissue distribution and elimination of perfluorodecanoic acid in the rat after 

single intraperitoneal administration. Pharmacol Toxicol 66:45-48.

Ylinen M, Kojo A, Hanhijarvi H, et al. 1990. Disposition of perfluorooctanoic acid in the rat after single 

and subchronic administration. Bull Environ Contam Toxicol 44:46-53.

Yoo H, Washington JW, Jenkins TM, et al. 2011. Quantitative determination of perfluorochemicals and 

flurotelomer alcohols in plants from biosolid-amended fields using LC/MS/MS and GC/MS. 

Environ Sci Technol 45.

Young CJ, Furdui VI, Franklin J, et al. 2007. Perfluorinated acids in Arctic snow: New evidence for 

atmospheric formation. Environ Sci Technol 41:3455-3461.

Yu J, Hu J, Tanaka S, et al. 2009c. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid 

(PFOA) in sewage treatment plants. Water Res 43(9):2399-2408.

+Yu WG, Liu W, Jin YH. 2009a. Effects of perfluorooctane sulfonate on rat thyroid hormone 

biosynthesis and metabolism. Environ Toxicol Chem 28(5):990-996.
PERFLUOROALKYLS 697

8. REFERENCES

***DRAFT FOR PUBLIC COMMENT***

Yu WG, Liu W, Jin YH, et al. 2009b. Prenatal and postnatal impact of perfluorooctane sulfonate (PFOS) 

on rat development: A cross-foster study on chemical burden and thyroid hormone system. Environ 

Sci Technol 43(21):8416-8422.

Yuan G, Peng H, Huang C, et al. 2016. Ubiquitous occurrence of fluorotelomer alcohols in eco-friendly 

paper-made food-contact materials and their implication for human exposure. Environ Sci Technol 

50:942-950.

Zeng H-c, Zhang L, Li Y-y, et al. 2011. Inflammation-like glial response in rat brain induced by prenatal 

PFOS exposure. Neurotoxicology 32(1):130-139. 

Zeng XW, Qian Z, Emo B. 2015. The association between perfluoroalkyl chemicals and serum lipid 

levels in children. Sci Total Environ 512-513:364-370

Zhang C, Sundaram R, Maisog J, et al. 2015a. A prospective study of prepregnancy serum 

concentrations of perfluorochemicals and the risk of gestational diabetes. Fertil Steril 103(1):184-

189.

Zhang H, Shi Z, Liu Y, et al. 2008. Lipid homeostasis and oxidative stress in the liver of male rats 

exposed to perfluorododecanoic acid. Toxicol Appl Pharmacol 227:16-25.

Zhang L, Ren X-M, Wan B, et al. 2014. Structure-dependent binding and activation of perfluorinated 

compounds on human peroxisome proliferator-activated receptor γ. Toxicol Appl Pharmacol 

279(3):275-283. 

Zhang T, Sun H, Lin Y, et al. 2011. Perfluorinated compounds in human blood, water, edible freshwater 

fish, and seafood in China: Daily intake and regional differences in human exposures. J Agric Food 

Chem 59:11168-11176.

Zhang T, Sun H, Qin X, et al. 2015b. PFOS and PFOA in paired urine and blood from general adults and 

pregnant women: Assessment of urinary elimination. Environ Sci Pollut Res Int 22(7):5572-5579. 

10.1007/s11356-014-3725-7. 

Zhang X, Chen L, Fei XC, et al. 2009. Binding of PFOS to serum albumin and DNA: Insight into the 

molecular toxicity of perfluorochemicals. BMC Mol Biol 10:16.

Zhang X, Lohmann R, Dassuncao C, et al. 2016. Source attribution of poly-and perfluoroalkyl 

substances (PFASs) in surface waters from Rhode Island and New York metropolitan area. Environ 

Sci Technol Lett 3:316-321. 10.1021/acs.estlett.6b00255. 

Zhang Y, Beesoon S, Zhu L, et al. 2013. Biomonitoring of perfluoroalkyl acids in human urine and 

estimates of biological half-life. Environ Sci Technol 47(18):10619-10627. 10.1021/es401905e. 

Zhao G, Wang J, Wang X, et al. 2011. Mutagenicity of PFOA in mammalian cells: Role of 

mitochondria-dependent reactive oxygen species. Environ Sci Technol 45(4):1638-1644.

Zhao H, Qu B, Guan Y, et al. 2016. Influence of salinity and temperature on uptake of perfluorinated 

carboxylic acids (PFCAs) by hydroponically grown wheat (Triticum aestivum L.). Springer Plus 

5:541.

+Zheng L, Dong GH, Jin YH, et al. 2009. Immunotoxic changes associated with a 7-day oral exposure 

to perfluorooctanesulfonate (PFOS) in adult male C57BL/6 mice. Arch Toxicol 83(7):679-689.

Zhu Y, Qin XD, Zeng XW, et al. 2016. Associations of serum perfluoroalkyl acid levels with T-helper 

cell-specific cytokines in children: By gender and asthma status. Sci Total Environ 559:166-173. 

10.1016/j.scitotenv.2016.03.187. 
PERFLUOROALKYLS A-1

***DRAFT FOR PUBLIC COMMENT***

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS

MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the 

most 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 risk 

of 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.

MRLs are derived for hazardous substances using the NOAEL/uncertainty factor approach. They are 

below levels that might cause adverse health effects in the people most sensitive to such chemicalinduced 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 substance-induced 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 to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

are 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 health 

principle 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 that 

have been shown to be nontoxic in laboratory animals.
PERFLUOROALKYLS A-2

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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 

F-57, Atlanta, Georgia 30329-4027.
PERFLUOROALKYLS A-3

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

INTRODUCTION 

Overview of Epidemiological Studies

A large number of epidemiology studies have evaluated a wide range of potential health outcomes 

resulting from exposure to perfluoroalkyls, particularly PFOA and PFOS. The epidemiology 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 in 

West 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 health 

studies conducted in Europe. 

Most of the epidemiology studies lack environmental monitoring data and there is a potential for multiple 

sources of exposure (inhalation and oral). However, the majority of the epidemiology studies used serum 

perfluoroalkyl levels as a biomarker of exposure. One limitation of the C8 Health Studies is that 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, as compared 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 health outcomes. As an 

alternative to using older serum PFOA levels, several C8 Health Studies estimated serum levels based on 

data on the release of PFOA from the facility and pharmacokinetic modeling. Of the three categories of 

subjects examined in the epidemiology 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, the geometric mean concentration 

of PFOA in the U.S. population was 3.92 ng/mL in 2005–2006 (CDC 2013). 

Identification of Adverse Health Effects Based on Epidemiological Studies—Weight-ofEvidence Approach. Although a large number of epidemiology studies have examined the potential 

of perfluoroalkyl compounds to induce adverse health effects, most of the studies were cross-sectional in 

design and do not establish causality. Epidemiology studies have found statistically significant 

associations between serum perfluoroalkyl levels and several health effects, although the results were not 

consistent across studies. Many of the studies 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 high serum PFOA levels. Given the inconsistencies, a weightof-evidence approach was used to evaluate whether the available data supported a link 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, and plausibility. 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 is within 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. 
PERFLUOROALKYLS A-4

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Using this weight-of-evidence approach, the available epidemiology data identify several potential health 

hazards of PFOA, PFOS, PFHxS, PFNA, and PFDeA in humans as listed below. 

PFOA

• Pregnancy-induced hypertension/pre-eclampsia 

• Liver damage, as evidenced by increases in serum enzymes and decreases in serum bilirubin 

levels 

• Increases in serum lipids, particularly total cholesterol and LDL cholesterol 

• Increased risk of thyroid disease 

• Decreased antibody response to vaccines 

• Increased risk of asthma diagnosis

• Increased risk of decreased fertility 

• Small (<20 g or 0.7 ounces per 1 ng/mL increase in blood perfluoroalkyl level) decreases in birth 

weight 

PFOS

• Pregnancy-induced hypertension/pre-eclampsia 

• Liver damage, as evidenced by increases in serum enzymes and decreases in serum bilirubin 

levels 

• Increases in serum lipids, particularly total cholesterol and LDL cholesterol 

• Increased risk of thyroid disease 

• Decreased antibody response to vaccines 

• Increased risk of decreased fertility 

• Small (<20 g or 0.7 ounces per 1 ng/mL increase in blood perfluoroalkyl level) decreases in birth 

weight 

PFHxS

• Liver damage, as evidenced by increases in serum enzymes and decreases in serum bilirubin 

levels 

• Decreased antibody response to vaccines 

PFNA

• Increases in serum lipids, particularly total cholesterol and LDL cholesterol 

• Decreased antibody response to vaccines 

PFDeA

• Increases in serum lipids, particularly total cholesterol and LDL cholesterol 

• Decreased antibody response to vaccines 

Limitations of Epidemiological Data. There are sufficient epidemiology data to identify possible 

sensitive targets for many of the perfluoroalkyls; however, there are two major limitations to establishing 

dose-response relationships for these effects and using the epidemiology 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. 

Uncertainty in Exposure Estimates. In general, the epidemiology studies provide a one-time serum 

perfluoroalkyl concentration, but lack information on actual environmental exposure concentration or 

doses, 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), 
PERFLUOROALKYLS A-5

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

they likely do not reflect historical exposure levels or exposure levels at the onset of the effect. This is 

especially 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 at 

least 10 years prior to the onset of the studies. Additionally, data from NHANES suggest that most 

perfluoroalkyl levels are declining in the general population; for example, the geometric mean serum 

levels of PFOA and PFOS declined from 5.21 and 30.4 ng/mL, respectively, in 1999–2000 to 2.08 and 

6.31 ng/mL in 2011–2012. In contrast, levels of PFNA have increased during that time frame; the 

geometric mean went from 0.551 ng/mL in 1999–2000 to 1.26 ng/mL in 2009–2010 and then decreased 

to 0.881 ng/mL in 2011–2012. 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 in 

communities 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 is 

the likely primary route of exposure for the general population.

Uncertainty due to Co-Exposure to Other Perfluoroalkyl Compounds. Based on NHANES data, the 

U.S. general population is exposed to a variety of perfluoroalkyl compounds. A number of studies 

reported a high degree of correlation between perfluoroalkyl compounds; however, most studies did not 

control for exposure to other perfluoroalkyls. Given that many of the perfluoroalkyl compounds have 

similar targets of toxicity, it is likely that several perfluoroalkyls contributed to the observed effects. The 

potential interactions between different perfluoroalkyl compounds have not been fully elucidated. 

In summary, the epidemiology 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 perfluoroalkyl compounds; however, more than 80% 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 epidemiology studies.

Limitations of Laboratory Animal Studies for Derivation of MRLs. Use of controlled animal 

studies eliminates the uncertainties regarding effective doses and co-exposure to other perfluoroalkyl 

compounds. 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 and rodents), and show pronounced sex differences within certain 

species (e.g., faster elimination in female rats). As a result, there is some uncertainty associated with 
PERFLUOROALKYLS A-6 

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

extrapolation of external dose-response relationships from animals to humans. Although progress has 

been made in modeling toxicokinetics of PFOA and PFOS in rats and nonhuman primates, no models for 

humans have been developed to simulate the substantial differences in toxicokinetics of these compounds 

between humans and nonhuman primates or between humans and rats (Andersen et al. 2006; Tan et al. 

2008). An additional uncertainty in the animal data is the relevance of effects associated with activation 

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 PPARα agonists 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 epidemiology studies 

• Identify laboratory animal studies that have evaluated dose-response relationships for toxicity 

targets identified in epidemiology studies

• Estimate a point of departure (POD) using animal serum perfluoroalkyl levels for sensitive 

endpoints 

• Calculate human equivalent doses (HEDs) using the assumption that a serum concentration 

resulting in an effect in a laboratory 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 epidemiology studies 

Predicting Mean Serum PFOA and PFOS Concentrations in Laboratory Animals. Timeweighted average (TWA) serum concentrations corresponding to external doses (mg/kg/day) and 

exposure durations (days) were predicted with a pharmacokinetic (PK) model for the animal species, 

strain, and sex used in the studies (Wambaugh et al. 2013). The TWA serum concentration was 

calculated as follows (Equation A-1): 

ED

C C AUC

TWA = 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 of were simulated as 12 hourly doses of 1/12 of the total daily dose, 

followed by 12 hours with no dosing. This assumes that the animals consumed water during a 12-hour 

active period. 

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 
PERFLUOROALKYLS A-7 

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

(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 average 

relative percent difference (MATLAB - R) was 4.6% (range: -11–20). 

The Wambaugh et al. (2013) model was selected over other available pharmacokinetic models because it

provided sex- and strain-specific parameters for rats, mice, and monkeys, which allowed for comparisons 

of HEDs across strains and species.

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 the 

laboratory animal data were converted to an equivalent dose in humans, which is defined as the 

continuous ingestion dose (mg/kg/day) that would result in steady-state serum concentrations of 

perfluoroalkyl equal to the serum concentration (μg/mL) selected as the POD.

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 in 

which elimination kinetics are adequately represented by observed serum elimination t1/2 values for the 

specific perfluoroalkyl compound, 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 volume of distribution to yield a steady-state serum concentration (Equation A-2): 

d

SS

SS V

BB C = 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): 

SS eSS D BBAF ⋅=⋅ k Eq. (A-3) 

Rearrangement of Equation A-3 allows calculation of the steady-state body burden corresponding to a 

given external dosage (Equation A-4): 

e

SS

SS k

D AF BB ⋅ = Eq. (A-4) 
PERFLUOROALKYLS A-8 

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

The relationship between the elimination rate constant (ke, day-1) and the elimination half-life (t1/2, day), is 

given in Equation A-5: 

2/1

)2ln(

t

ke = Eq. (A-5) 

Combining Equations A-2 and A-3 yields an expression relating the external steady-state dosage and 

steady-state serum concentration (Equation A-6): 

AF

VkC D deSS

SS

⋅⋅ = Eq. (A-6) 

The above estimates of CSS/DSS are sensitive to the input parameters, t1/2, AF, and Vd. 

PFOA and PFOS. Several studies have estimated PFOA and PFOS half-lives (t1/2) in workers (Costa et 

al. 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 estimated 

half-lives were 3.8 years (1,387 days) and 5.4 years (1,971 days), respectively. Costa et al. (2009) 

reported a half-life for PFOA of 5.1 years (1,862 days) 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 mitigation of exposures from drinking 

water. The estimated half-life for PFOA was 2.3 years (840 days). A fourth study estimated half-lives in 

a cross-sectional study of residents served by the Lubeck Public Service 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 are shown 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 a longer 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 half-life (Seals et al. 2011). 

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 range. 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) PFOS t1/2 (days) Exposure type Number Source

1,387 1971 Occupational 26 Olsen et al. (2007a)

1,862 NA Occupational 16 Costa et al. (2009)

840 NA Environmental 200 Bartell et al. (2010)

PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid
PERFLUOROALKYLS A-9

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-2. Serum PFOA and PFOS Concentrations Measured in Fluorochemical

Production Workers

PFOA (ppb) PFOS (ppb)

Initial 408 (72, 5,100) 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 PFOS

PFOA Vd (L/kg) PFOS Vd (L/kg) Source

0.18 (male)

0.20 (female)

NA

NA

Butenhoff et al. (2004c)

NA

NA

0.20 (male)

0.27 (female)

Chang et al. (2012)

0.3 0.3 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 t1⁄2 was derived from longitudinal measurements of 

serum concentrations of PFHxS in a group of retired fluorochemical production workers (24 males and 

2 females) observed for a 5-year period; the estimated half-life was 8.5 years (3,102 days) (Olsen et al. 

2007a). The range of initial serum concentrations was 16–1,295 ng/mL (mean of 290 ng/mL), and the 

final concentrations ranged from 10 to 1,740 ng/mL (mean of 182 ng/mL). Estimates of the t1⁄2 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 range.

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) estimate 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 factor 

of oral doses of PFHxS. Sundström et al. (2012), based on comparison of the AUC for oral and 

intravenous administration, estimate 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 that 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 estimated 

to be at approximately 30 min.” These latter observations suggest approximately complete 

bioavailability. The AUC for male rats following oral exposure was not available, and the AUC after 
PERFLUOROALKYLS A-10

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

intravenous administration was done in only one male rat. (Sundström et al. 2012). A study conducted by 

Kim et al. (2016) in rats estimated an approximately 100% oral bioavailability based on Cmax value and 

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 perfluoroalkyl 

compounds, 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 the other groups; therefore, the three other groups were combined. The lower 

perfluoroalkyl levels were likely 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 group for 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, the 

estimate volume 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) are 

provided 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) 1,400a 2,000a 3,100a 900b

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 0.287f 0.2e

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). f

Estimates 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-11

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanoic acid (PFOA) 

335-67-1 

June 2018 

Final, Pre-Public Comment 

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 the 

studies 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 and 

eye 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), and 

decreases in maternal weight gain at 10 mg/m3 and maternal deaths and decreases in neonatal body 

weight 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): Selene Chou
PERFLUOROALKYLS A-12

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanoic acid (PFOA) 

335-67-1 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-13

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanoic acid (PFOA)

335-67-1 

June 2018 

Final, Pre-Public Comment 

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 were 

identified for PFOA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-14

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanoic acid (PFOA) 

335-67-1 

June 2018 

Final, Pre-Public Comment 

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 triglyceride 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; Wolf 

et 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 in 

rats and mice were not considered relevant to human risk assessment. 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 the potential 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 et al. 1996). A number of studies have evaluated the 

developmental toxicity of PFOA. In the only acute-duration developmental toxicity study in rats, no 

alterations in fetal body weight or malformations were observed 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 in pup body weight (White et al. 2007, 2009; Wolf et al. 2007), 

alterations in spontaneous activity (Johansson et al. 2008), and delays in mammary gland development 

(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-15

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-5. Summary of the Adverse Effects Observed in Laboratory Animals 

Following Acute-Duration Oral Exposure

Species and 

exposure 

duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Immunological

Mouse

10 days

11.5 Decreased spleen and thymus 

weights

Yang et al. 2001

Mouse

10 days

7.5 15 Altered response to sRBC DeWitt et al. 2009

Mouse

7 days

20 Altered response to sRBC, 

decreased antibody formation

Vetvicka and 

Vetvickova 2013

Mouse

7 days

24 Decreased response to horse red 

blood cells

Yang et al. 2002a

Reproductive

Rat

14 days

0.2 2 2-Fold increase in serum estradiol

levels

Liu et al. 1996

Rat

14 days

1 10 63% increase in serum estradiol 

levels

Cook et al. 1992

Rat

14 days

25 184% increase in serum estradiol 

levels

Biegel et al. 1995

Developmental

Mouse

GDs 6–17

0.5 Decreased litter weight on PND 2 Hu et al. 2010

Mouse

PND 10

0.58 Decreased spontaneous behavior 

and altered response to cholinergic 

stimulant

Johansson et al. 

2008

Mouse

GDs 8–17 or 12–

17

5 Altered mammary gland 

development, decreased pup body 

weight on PND 20

White et al. 2007

Mouse

GDs 8–17 

5 Delayed mammary gland 

development, decreased pup body 

weight on PND 20

White et al. 2007

Mouse

Various GDs

5 Delayed mammary gland 

development; decreased pup body 

weight at weaning

White et al. 2009

Wolf et al. 2007

GD = gestation day; LOAEL = lowest-observed-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) and 

decreased response to a cholinergic stimulant in adult mice exposed to PFOA on PND 10. Neither study 

identified NOAEL values. 

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-16

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Provisional MRL: 

Critical Effect:

Reference:

Point of Departure:

Uncertainty Factor:

LSE Graph Key:

Species:

Perfluorooctanoic acid (PFOA) 

335-67-1 

June 2018 

Final, Pre-Public Comment 

Oral

Intermediate

3x10-6 mg/kg/day

Altered activity and skeletal alterations in offspring 

Onishchenko et al. 2011; Koskela et al. 2016 

0.000821 mg/kg/day

300

61, 67 

Mouse 

MRL Summary: A provisional intermediate-duration oral MRL of 3x10-6 mg/kg/day was derived for 

PFOA based on altered activity at 5–8weeks of age and 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; 

Onishchenko et al. 2011). 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 the 

liver, 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 is 

limited to studies that identified LOAEL values of ≤4 mg/kg/day. Although these studies identified the 

lowest 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, and 

decreases 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 the 

rodents are likely due to peroxisome proliferation and are not considered relevant for human risk 

assessment (Hall et al. 2012). Consistent with the Hall et al. (2012) criteria, the increases in liver weight 

and hepatocellular hypertrophy, in the absence of other degenerative alterations, were not considered 

adverse. 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 exposed for 28 days (Loveless et al. 2008). In utero exposure has also resulted in liver effects in

offspring (Filgo et al. 2015a; Quist et al. 2015a); the lowest maternal LOAEL identified in these studies 

was 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. 

Hepatic effects 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, 
PERFLUOROALKYLS A-17

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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 intermediateduration 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 gland development 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 as high as 1 mg/kg/day, based on normal growth and 

survival in F2 pups (White et al. 2011). Given that milk production was adequate to support growth, the 

biological significance of the delayed development of the mammary gland is uncertain and was not 

considered a suitable basis for the MRL. Other developmental effects include increases in locomotor 

activity (Cheng et al. 2013; Onishchenko et al. 2011; Sobolewski et al. 2014) at ≥0.1 mg/kg/day, reduced 

ossification of proximal phalanges and advanced preputial separation at ≥1 mg/kg/day (Lau et al. 2006), 

altered long bone morphology and decreased bone mineral density in 13- and 17-month-old mice 

following in utero exposure to 0.3 mg/kg/day (Koskela et al. 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 and 

exposure 

duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Hepatic

Mouse

GDs 1–17

0.01 Hepatocellular hypertrophy and 

periportal inflammation in offspring

Quist et al. 

2015a, 2015b

Mouse

28 days

0.29 0.96 Moderate to severe hepatocellular 

hypertrophy and focal necrosis

Loveless et al. 

2008

Mouse

GDs 1–17 

(examined at 

18 months of 

age)

0.3 1 Increased severity of chronic 

inflammation in liver

Filgo et al. 

2015a, 2015b

Rat

70–90 days

1 3 Increased liver weight, 

hepatocellular hypertrophy and 

necrosis

Butenhoff et al. 

2004b

Monkey

26 weeks

3 Increased absolute liver weight Butenhoff et al. 

2002

Immunological

Mouse

15 days

0.94 1.88 Reduced antibody response DeWitt et al. 

2016

Mouse

15 days

1.88 3.75 Reduced sRBC response DeWitt et al. 

2008
PERFLUOROALKYLS A-18

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-6. Summary of the Adverse Effects Observed in Laboratory Animals 

Following Intermediate-Duration Oral Exposure

Species and 

exposure 

duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Reproductive

Mouse

GDs 1–17

0.0024 Delayed mammary gland 

development in dams (3-generation 

study)

White et al. 

2011

Mouse

GDs 1–17

1 Delayed mammary gland 

development in dams (singlegeneration study)

White et al. 

2011

Developmental

Mouse

GD 7–PND 22

0.0024 Impaired development of mammary 

glands

White et al. 

2011

Mouse

GDs 10–17

0.01 Impaired development of mammary 

glands

Macon et al. 

2011

Mouse

GDs 1–17

0.01 Impaired development of mammary 

glands

Tucker et al. 

2015

Mouse

GD 7–PND 21

0.1 Neurodevelopmental Sobolewski et 

al. 2014

Mouse

GDs 1–21

0.3 Neurodevelopmental Onishchenko et 

al. 2011

Mouse

GDs 1–21

0.3 Skeletal alterations Koskela et al. 

2016

Mouse

GDs 1–17

0.3 Impaired development of mammary 

glands

Macon et al. 

2011

Mouse

GDs 1–17

0.3 0.6 Decreased pup survival Abbott et al. 

2007

Mouse

GDs 1–17

1 Reduced ossification of proximal 

phalanges and advanced preputial 

separation 

Lau et al. 2006

Rat

GD 1–PND 21

1.6 Neurodevelopmental Cheng et al. 

2013

Mouse

GDs 1–17

0.1 3 Decreased number of successful 

births

Ngo et al. 2014

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

GD = gestation day; LOAEL = lowest-observed-effect level; NOAEL = no-observed-adverse-effect level; 

PND = postnatal day; sRBC = sheep red blood cell

Selection of the Principal Study: As outlined in the MRL approach section, serum PFOA levels were 

predicted 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 not 

available for Wistar rats (Cheng et al. 2013), male CD-1 mice (Loveless et al. 2008), or 129S1/SvlmJ 
PERFLUOROALKYLS A-19

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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 and 

exposure 

duration

Dose

(mg/kg/day)

Predicted TWA 

serum PFOA

(μg/mL) Effect Reference

Hepatic

CD

Mouse

28 days

0.29

Not calculated

Moderate to severe 

hepatocellular hypertrophy and 

focal necrosis at 0.96 mg/kg/day

Loveless et al. 

2008 0.96

9.6

129/Sv

Mouse

GDs 1–17

0.01 0.423 Increased severity of chronic 

inflammation in liver of offspring 

aged 18 months at 1 mg/kg/day

Filgo et al. 

2015a, 2015b 0.1 4.21

0.3 12.5

1 39.2

5 102

SpragueDawley

Rat

70–90 days

1 60.4 Increased liver weight, 

hepatocellular hypertrophy and 

necrosis at 10 mg/kg/day

Butenhoff et al. 

2004b 3 136

10 222

30 242

Cynomolgus

Monkey

6 months

3 68.5 Increased liver weight at 

3 mg/kg/day

Butenhoff et al. 

2002 10 93.8

20/30 113

Immunological

C58BL/6N

Mouse

15 days

0.94 21.4 Reduced antibody response at 

1.88 mg/kg/day

DeWitt et al. 

2016 1.88 42.5

3.75 58.4

7.5 83.5

C57BL/6N

Mouse

15 days

0.94 21.4 Reduced sRBC response at 

3.75 mg/kg/day

DeWitt et al. 

2008 1.88 42.5

3.75 58.4

7.5 83.5

15 109

30 149

Developmental

C57BL/6

Mouse

GD 7–

PND 21

0.1 2.23 Neurodevelopmental effects 

(increased horizontal and vertical 

activity and decreased resting 

activity) at 0.1 mg/kg/day

Sobolewski et al. 

2014

C57BL/6

Mouse

GDs 1–21

0.3 8.29 Skeletal alterations at 

0.3 mg/kg/day

Koskela et al. 

2016

C57BL/6

Mouse

0.3 8.29 Neurodevelopmental (decreased 

number of inactive periods, 

Onishchenko et 

al. 2011
PERFLUOROALKYLS A-20

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-7. Summary of the Predicted TWA Serum PFOA levels in Laboratory 

Animals Following Intermediate-Duration Oral Exposure

Species and 

exposure 

duration

Dose

(mg/kg/day)

Predicted TWA 

serum PFOA

(μg/mL) Effect Reference

GDs 1–21 altered novelty induced activity) 

at 0.3 mg/kg/day

129S1/SvlmJ

Mouse

GDs 1–17

0.1

Not calculated

Decreased pup survival at 

0.6 mg/kg/day

Abbott et al. 2007

0.3

0.6

1

3

5

10

20

CD-1

Mouse

GDs 1–17

1 39.2 Reduced ossification of proximal 

phalanges and advanced 

preputial separation at 

1 mg/kg/day

Lau et al. 2006

3 83.6

5 102

10 125

20 155

40 205

Wistar

Rat

GD 1–PND 21

1.6 Not calculated Neurodevelopmental effects 

(increased locomotor activity in 

males and decreased activity in 

females) at 1.6 mg/kg/day

Cheng et al. 2013

C57BL/6J

Mouse

GDs 1–17

0.1 2.43 Decreased number of successful 

births at 3 mg/kg/day

Ngo et al. 2014

3 62.0

SV/129

Mouse

GDs 1–17

3 Not calculated Reduced pups per litter on 

PND 20 at 3 mg/kg/day

Albrecht et al. 

2013

CD-1

Mouse

GDs 1–17

3 84.8 Reduced weight gain, delayed 

eye opening at 3 mg/kg/day

Wolf et al. 2007

5 102

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 amenable to BMD modeling were from the DeWitt et al. (2008) 

and DeWitt et al. (2016) immunotoxicity studies. The results of the BMD modeling are presented at the 

end of this worksheet. 

HEDs were calculated for each potential PODs (NOAEL, LOAEL, or BMDL value) identified in 

laboratory animal studies using the first order single-compartment model previously discussed and the 

assumption that humans would have similar effects as the laboratory animal at a given serum 
PERFLUOROALKYLS A-21

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

concentration. The HEDs for each POD are presented in Table A-8. The potential PODHED values were 

divided by an uncertainty factor to calculate candidate MRLs; these values are also presented in 

Table A-8. The candidate MRLs range from 7.4x10-7 mg/kg/day for neurodevelopmental effects in mice 

(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, the 

Onishchenko et al. (2011) and Koskela et al. (2016) studies, which identified the second lowest LOAEL 

(serum PFOA concentration) of 8.29 μg/mL, were selected as the basis for the MRL; it is noted that these 

two studies used the offspring from the same animals.
PERFLUOROALKYLS A-22

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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)

PODHEDa

(mg/kg/day) Total UF

Candidate 

MRLs 

(mg/kg/day)

NOAEL or 

BMDL LOAEL

Neurodevelopmental effects 

(increased horizontal and vertical 

activity and decreased resting 

activity) in mice (Sobolewski et al. 

2014)

2.23 0.000221 300b 7.4x10-7

Neurodevelopmental effects 

(decreased number of inactive 

periods, altered novelty induced 

activity) in mice (Onishchenko et al. 

2011)

8.29 0.000821 300b 2.7x10-6

Skeletal alterations in mice (Koskela 

et al. 2016)

8.29 0.000821 300b 2.7x10-6

Decreased number of successful 

births in mice (Ngo et al. 2014)

2.43 62.0 0.000241 30c 8.0x10-6

Reduced ossification of proximal 

phalanges and advanced preputial 

separation in mice (Lau et al. 2006)

39.2 0.00388 300b 1.3x10-5

Reduced weight gain and delayed 

eye opening (Wolf et al. 2007)

84.8 0.00840 300b 2.8x10-5

Reduced response to dinitrophenylficoll (DNP) antigen in female mice 

(DeWitt et al. 2016)

12.23

(BMDL1SD)

0.00121 30c 4.0x10-5

Increased severity of chronic 

inflammation in liver of offspring 

aged 18 months (Filgo et al. 2015a, 

2015b)

12.5 39.2 0.00124 30c 4.1x10-5

Reduced response to sRBC in 

female mice (DeWitt et al. 2008)

33.49 

(BMDL1SD)

0.00332 30c 1.1x10-4

Increased liver weight, 

hepatocellular hypertrophy, and 

necrosis in male rats (Butenhoff et 

al. 2004b)

136 222 0.0135 30c 4.5x10-4

aBased on the NOAEL or BMDL; based on LOAEL if there was no NOAEL or BMDL.

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
PERFLUOROALKYLS A-23

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Summary of the Principal Study:

Onishchenko et al. 2011. Prenatal exposure to PFOS or PFOA alters motor function in mice in a sexrelated manner. Neurotox Res 19:452-461. 

Koskela et al. 2016. Effects of developmental exposure to perfluorooctanoic acid (PFOA) on long bone 

morphology and bone cell differentiation. Toxicol Appl Pharmacol 301:14-21.

Neurobehavioral effects were assessed in offspring of C57BL/6/Bk1 mice that 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 body weights to provide 0.3 mg/kg/day, followed by evaporation of 

ethanol; controls received food with ethanol applied and then evaporated. 

Onishchenko et al. (2011) study: Endpoints examined in the included maternal body weight during 

pregnancy; litter size and sex ratio; body, brain and liver weights in pups at birth; and PFOA 

concentrations in whole brain and liver tissue samples from pups at birth. Pups were subcutaneously 

injected with microtransponders on PND 21, and tested (6–10/sex/group) for novelty-induced locomotor 

activity and circadian activity over 48 hours at age 5–8 weeks, elevated maze and forced swimming 

performance at age 5–8 weeks, and muscle strength and coordination at age 3–4 months. The locomotor 

test measured distance traveled in the first 30 minutes in a new cage. Circadian activity was measured as 

number of antenna crossings in the new cage over 48 hours, with activity in the first 3 hours analyzed 

separately as adaptation to a novel environment. The elevated plus maze test recorded number of entries 

and time spent in open or closed areas as indicators of anxiety-like behavior. The forced swimming test 

measured immobility duration (total of times floating passively for ≥2 seconds) as an indicator of 

depression-like behavior. Muscle strength was evaluated by latency to fall in a hanging wire test. Motor 

coordination was evaluated by latency to fall in an accelerating rotarod test.

Prenatal PFOA exposure was associated with increases in global activity and exploratory activity in adult 

offspring as indicated by statistically significant (p<0.05 compared with controls) increased circadian 

activity in males (44–48% higher number of crossings over 48 hours in a new cage, occurring in both 

12-hour dark phases and in the intervening 12-hour light phase, but not in the initial 3-hour novelty 

phase), and decreased total number of inactive periods in males and females (approximately 40 and 25% 

lower, respectively). No alterations were observed in the forced swimming test or hanging wire test. 

Mean PFOA concentrations in brain and liver tissue samples at birth were 0.7 and 16.3 μg/g in exposed 

pups and below detection limits in control pups.

Koskela et al. (2016) study: Groups of five 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. 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 was also observed. There were no differences in femoral cortical bone area or femoral 

mineral density. In the tibia, 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 were no significant differences in the tibial medullary area or the endosteal perimeter. 
PERFLUOROALKYLS A-24

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

There was a trend for increasing maximum force (Fmax); however, the effect was not statistically 

significant. There were no 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 were significantly higher (4–5 times) than controls at 13 and 17 months. 

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

Provisional MRL = LOAELHED ÷ UFs

0.000821 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 the 

findings from epidemiology studies is presented in the MRL introduction section. 

Benchmark Dose Modeling: BMD modeling was conducted for the DeWitt et al. (2008) and DeWitt et 

al. (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 the 

fit 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 from 

these 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 the 

data 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-25

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-9. T-Cell Independent IgM Antibody Response in C57BL/6N Female Mice 

Immunized with Sheep Red Blood Cells 

Number of 

animals per group

Administered 

dose 

(mg/kg/day)

Predicted TWA serum 

PFOA concentration 

(μg/mL)

IgM antibody titersa 

[mean serum IgM titer 

(log2) to reach 0.5 OD] SEa

8 0 0 7.28 0.13

8 0.94 21.4 7.39 0.07

8 1.88 42.5 7.08 0.10

8 3.75 58.4 6.75b 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 

animals per 

group

Administered 

dose 

(mg/kg/day)

Predicted TWA serum 

PFOA concentration 

(μg/mL)

T-cell independent IgM antibody 

responsea [mean serum titer 

(log2) to reach 0.5 OD] SDa

8 0 0 11.38 0.56

8 0.94 21.4 11.01 1.11

8 1.88 42.5 9.67b 1.34

8 3.75 58.4 9.81b 1.46

8 7.5 83.5 9.62b 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 are 

presented in Tables A-11 and A-12. For the DeWitt et al. (2008) data, the Hill model with constant 

variance 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 the 

estimated 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-26

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-11. T-Cell Independent IgM Antibody Response in C57BL/6N Female 

Mice Immunized With Sheep Red Blood Cells Using Predicted TWA Serum 

PFOA as the Dose Metric (DeWitt et al. 2008)

Model

Test for 

significant 

difference 

p-valuea

Variance

p-valueb

Means

p-valueb

Scaled residualsc

AIC

BMD1SD

(ng/mL)

BMDL1SD

(ng/mL)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Constant variance

Exponential 

(model 2)d

<0.0001 0.46 0.08 1.73 0.72 1.73 -50.41 ND ND

Exponential 

(model 3)d

<0.0001 0.46 0.10 0.16 -1.30 1.33 -50.61 42.55 26.37

Exponential 

(model 4)d

<0.0001 0.46 0.08 1.73 0.72 1.73 -50.41 ND ND

Exponential 

(model 5)d

<0.0001 0.46 0.36 -0.14 0.09 0.67 -52.34 44.11 33.33

Hilld,e <0.0001 0.46 0.41 -0.05 0.06 0.60 -52.47 43.57 33.49

Linearf <0.0001 0.46 0.09 1.69 0.67 1.69 -50.66 ND ND

Polynomial 

(2-degree)f

<0.0001 0.46 0.08 0.10 -1.41 1.43 -50.00 ND ND

Polynomial 

(3-degree)f

<0.0001 0.46 0.08 0.10 -1.41 1.43 -50.00 ND ND

Polynomial 

(4-degree)f

<0.0001 0.46 0.08 0.10 -1.41 1.43 -50.00 ND ND

Powerd <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 Power 

models. 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). 

f

Coefficients restricted to be negative.

AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMDL = 95% lower confidence limit on the BMD (subscripts denote 

benchmark 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-27

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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

 6.2

 6.4

 6.6

 6.8

 7

 7.2

 7.4

 7.6

 0 10 20 30 40 50 60 70 80

Mean Response

dose

Hill Model, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL

09:21 02/16 2017

BMDL BMD

Hill
PERFLUOROALKYLS A-28

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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

Test for 

significant 

difference 

p-valuea

Variance

p-valueb

Means

p-valueb

Scaled residualsc

AIC

BMD1SD

(ng/mL)

BMDL1SD

(ng/mL)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Constant variance

Exponential 

(model 2)d

0.0029 0.12 0.34 -1.47 -0.17 -1.47 54.00 45.00 29.56

Exponential 

(model 3)d

0.0029 0.12 0.34 -1.47 -0.17 -1.47 54.00 45.00 29.56

Exponential 

(model 4)d,e

0.0029 0.12 0.31 1.01 -1.06 -1.06 54.97 29.22 12.23

Exponential 

(model 5)d

0.0029 0.12 0.71 0.00 -0.08 0.29 54.76 26.62 18.75

Hilld 0.0029 0.12 0.93 0.00 -0.08 0.29 52.76 23.66 19.11

Linearf 0.0029 0.12 0.30 -1.52 -0.23 -1.52 54.27 47.96 32.63

Polynomial 

(2-degree)f

0.0029 0.12 0.30 -1.52 -0.23 -1.52 54.27 47.96 32.63

Polynomial 

(3-degree)f

0.0029 0.12 0.30 -1.52 -0.23 -1.52 54.27 47.96 32.63

Polynomial 

(4-degree)f

0.0029 0.12 0.30 -1.52 -0.23 -1.52 54.27 47.96 32.63

Powerd 0.0029 0.12 0.30 -1.52 -0.23 -1.52 54.27 47.96 32.63

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, all models provided adequate fit to the means. BMDLs for models providing adequate fit were not 

considered to be sufficiently close (differed by >2-fold, but <3-fold). In order to remain conservative, the model with 

the lowest BMDL was selected (Exponential 4).

f

Coefficients restricted to be negative.

AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMDL = 95% lower confidence limit on the BMD (subscripts denote 

benchmark 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-29

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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

Agency Contacts (Chemical Managers): Selene Chou

 8.5

 9

 9.5

 10

 10.5

 11

 11.5

 12

 0 10 20 30 40 50 60 70 80

Mean Response

dose

Exponential 4 Model, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL

08:25 02/16 2017

BMDL BMD

 

Exponential 4
PERFLUOROALKYLS A-30

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanoic acid (PFOA) 

335-67-1 

June 2018 

Final, Pre-Public Comment 

Oral

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFOA.

Rationale for Not Deriving an MRL: Intermediate-duration studies have identified the immune system 

as a sensitive target of PFOA toxicity. However, the potential immunotoxicity of PFOA has not been 

investigated in chronic-duration studies. Given the uncertainty that the chronic studies identified the most 

sensitive endpoint, a chronic-duration oral MRL for PFOA is not recommended at this time. 

The chronic oral animal database for PFOA is limited to dietary exposure studies in male rats (3M 1983) 

or male and female rats (Biegel et al. 2001). The lowest LOAEL identified in the 3M (1983) study was 

1.5 mg/kg/day for tubular hyperplasia in the ovaries and inflammation of salivary gland in 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 the diet for 2 years resulted in decreases in body weight gain, 

increases in Leydig cell hyperplasia, and pancreatic acinar cell hyperplasia in male rats. 

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-31

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctane sulfonic acid (PFOS)

1763-23-1 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-32

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctane sulfonic acid (PFOS)

1763-23-1 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-33

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctane sulfonic acid (PFOS)

1763-23-1 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-34

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctane sulfonic acid (PFOS)

1763-23-1 

June 2018 

Final, Pre-Public Comment 

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 are 

sensitive targets. The liver effects consisted of decreases in serum lipids, increases in liver weight, and 

hepatocellular 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 for 

peroxisome proliferators, these effects were not considered relevant for human risk assessment. 

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 in 

post-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 the 

adverse effect levels for the immunological and developmental effects are presented in Table A-13. 

Table A-13. Summary of the Adverse Effects Observed in Laboratory Animals 

Following Acute-Duration Oral Exposure to PFOS

Species and 

exposure 

duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Immunological

Mouse

7 days

5 Impaired response to T-cell 

mitogens; suppressed response to 

sRBC

Zheng et al. 2009

Mouse

7 days

20 Inhibition of T lymphocyte 

proliferation in 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
PERFLUOROALKYLS A-35

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-13. Summary of the Adverse Effects Observed in Laboratory Animals 

Following Acute-Duration Oral Exposure to PFOS

Species and 

exposure 

duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Developmental

Mouse

GDs 11–16

0.5 Increased post-implantation losses Lee et al. 2015a

Mouse

Once

0.75 Decreased motor activity Johansson et al. 

2008

Rabbit

GDs 6–20

1 2.5 Decreased fetal body weight Case et al. 2001

Mouse

GDs 15–18

4.5 Decreased number of live pups per 

litter on PND 15

Abbott et al. 2009

Mouse

GDs 12–18

6 Reduced pup body weight on 

PNDs 4 and 8

Fuentes et al. 

2007b

Mouse

Once

11.3 Altered spontaneous behavior in 

pups

Hallgren et al. 

2015

Rat

GDs 19–20

25 Decreased neonatal survival Grasty et al. 2003

Rat

GDs 2–5, 6–9, 

10–13, 14–17, or 

17–20

25 Decreased neonatal survival Grasty et al. 2003

Mouse

GDs 11–15

50 Cleft palate and reduced fetal 

body weight 

Era et al. 2009

GD = gestation day; LOAEL = lowest-observed-effect level; NK = natural killer; NOAEL = no-observed-adverseeffect level; perfluorooctane sulfonic acid; PND = postnatal day; sRBC = sheep red blood cell

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-36

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Provisional MRL:

Critical Effect:

Reference:

Point of Departure:

Uncertainty Factor:

Modifying Factor:

LSE Graph Key:

Species:

Perfluorooctane sulfonic acid (PFOS)

1763-23-1 

June 2018 

Final, Pre-Public Comment 

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

34 

Rat

MRL Summary: A provisional intermediate-duration oral MRL of 2x10-6 mg/kg/day was derived for 

PFOS based on 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 from animals 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 the 

developing 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 values 

of ≤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). 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 is considerable 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 mice 

administered 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 

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; these 

include 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 
PERFLUOROALKYLS A-37

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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 epidemiology studies. These effects include liver damage and increases in serum lipids, decreased 

antibody response to vaccines, and small decreases in birth weight; epidemiology studies have not 

consistently 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 and 

exposure 

duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Hepatic

Monkey

26 weeks

0.03 0.75 Increased liver weight, decreased 

serum cholesterol, hepatocellular 

hypertrophy, lipid vacuolation

Seacat et al. 

2002

Neurological

Mouse

3 months

0.43 2.15 Impaired spatial learning and 

memory

Long et al. 2013

Immunological

Mouse

28 days

0.00016 0.00166 Suppressed response to sRBC Peden-Adams et 

al. 2008

Mouse

21 days

0.005 0.025 Decreased resistance to influenza 

virus

Guruge et al. 

2009

Mouse

60 days

0.0083 0.083 Impaired response to sRBC Dong et al. 2009

Mouse 

60 days

0.0167 0.083 Impaired response to sRBC Dong et al. 2011

Developmental

Mouse

GDs 1–21

0.3 Decreased locomotion, muscle 

strength, motor coordination in 

adult offspring

Onishchenko et 

al. 2011

Rat

84 days

0.1 0.4 Delayed eye opening Luebker et al. 

2005a

Rat

67 days

0.4 Decreased pup weight Luebker et al. 

2005b

Rat

GD 1–PND 1

0.8 Decreases spatial learning Wang et al. 

2015c

Rat

GD 0–PND 20

0.3 1 Increased locomotor activity and 

concurrent failure to habituate to 

Butenhoff et al. 

2009b
PERFLUOROALKYLS A-38

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-14. Summary of the Adverse Effects Observed in Laboratory Animals 

Following Intermediate-Duration Oral Exposure to PFOS

Species and 

exposure 

duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

test environment in male pups on 

PND 17

Mouse

GDs 1–17

1 Delayed eye opening Lau et al. 2003

Mouse

GDs 0–17

1 Increased sternal defects Yahia et al. 2008

Rat

GDs 1–21

0.1 2 Increased postnatal mortality and 

severe lung histopathology

Chen et al. 2012b

Rat

GDs 2–21

0.6 2 Increased neonatal mortality Xia et al. 2011

GD = gestation day; LOAEL = lowest-observed-effect level; NK = natural killer; NOAEL = no-observed-adverseeffect 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) were 

predicted 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 and 

exposure 

duration

Dose

(mg/kg/day)

Predicted TWA

serum PFOS

(μg/mL) Effect Reference

Hepatic

Cynomolgus

Monkey

26 weeks

0.03 (males) 7.81 Increased liver weight, 

decreased serum cholesterol, 

hepatocellular hypertrophy, mild 

bile stasis, lipid vacuolation at 

0.75 mg/kg/day

Seacat et al. 

2002 0.15 (males) 37.8

0.75 (males) 150

0.03 (females) 7.72

0.15 (females) 37.6

0.75 (females) 146

Neurological

C57BL/6

Mouse

3 months

0.43

Not calculated

Impaired spatial learning and 

memory at 2.15 mg/kg/day

Long et al. 2013

2.15

10.75
PERFLUOROALKYLS A-39

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-15. Summary of the Predicted TWA Serum PFOS levels in Laboratory 

Animals Following Intermediate-Duration Oral Exposure

Species and 

exposure 

duration

Dose

(mg/kg/day)

Predicted TWA

serum PFOS

(μg/mL) Effect Reference

Immunological

B6C3F1

Mouse

28 days

0.00016

Not calculated

Suppressed response to sRBC 

at 0.00166 mg/kg/day

Peden-Adams et 

al. 2008 0.00166

0.00331

0.0166

0.0331

B6C3F1

Mouse

21 days

0.005

Not calculated

Decreased resistance to 

influenza virus at 

0.025 mg/kg/day

Guruge et al. 

2009 0.025

C57BL/6N

Mouse

60 days

0.0083

Not calculated

Impaired response to sRBC at 

0.083 mg/kg/day

Dong et al. 2009

0.083

0.41667

0.8333

2.0833

C57BL/6N

Mouse 

60 days

0.0083

Not calculated

Impaired response to sRBC at 

0.083 mg/kg/day

Dong et al. 2011

0.0167

0.083

0.41667

0.8333

Developmental

C57BL/6

Mouse

GDs 1–21

0.3 Not calculated Decreased locomotion, muscle 

strength, motor coordination in 

adult offspring at 0.3 mg/kg/day

Onishchenko et 

al. 2011

SpragueDawley

Rat

84 days

0.1 7.43 Delayed eye opening in F1 pups 

and transient decrease in F2 pup 

body weight during lactation at 

0.4 mg/kg/day

Luebker et al. 

2005a 0.4 29.7

1.6 119

3.2 238

SpragueDawley 

Rat

67 days

0.4 24.1 Decreased pup weight per litter 

at birth and on LD 5 at 0.4 

mg/kg/day

Luebker et al. 

2005b 0.8 48.1

1 60.1

1.2 72.2

1.6 96.2

3.2 120

Wistar

Rat

GD 1–PND 1

0.8 Not calculated Decreases spatial learning at 

0.8 mg/kg/day

Wang et al. 

2015c
PERFLUOROALKYLS A-40

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-15. Summary of the Predicted TWA Serum PFOS levels in Laboratory 

Animals Following Intermediate-Duration Oral Exposure

Species and 

exposure 

duration

Dose

(mg/kg/day)

Predicted TWA

serum PFOS

(μg/mL) Effect Reference

SpragueDawley

Rat

GD 0–

PND 20

0.1 3.75 Increased locomotor activity and 

concurrent failure to habituate to 

test environment in male pups 

on PND 17 at 1 mg/kg/day

Butenhoff et al. 

2009b 0.3 11.3

1 37.5

CD-1

Mouse

GDs 1–17

1 31.9 Delayed eye opening at 

1 mg/kg/day

Lau et al. 2003

5 146

10 216

15 244

20 260

ICR

Mouse

GDs 0–17

1 Not calculated Increased sternal defects at 

1 mg/kg/day

Yahia et al. 2008

SpragueDawley

Rat

GDs 1–21

0.1 2.01 Increased postnatal mortality 

and severe lung histopathology 

at 2 mg/kg/day

Chen et al. 2012b

2 40.1

SpragueDawley

Rat

GDs 2–21

0.1 1.92 Increased neonatal mortality at 

2 mg/kg/day

Xia et al. 2011

0.6 11.5

2 38.3

GD = gestation day; LD = lactation day; 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 is 

presented 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 the 

assumption 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 were 

divided by a total uncertainty factor to calculate candidate MRLs; these values are also presented in 

Table 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 et 

al. (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 

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). 
PERFLUOROALKYLS A-41

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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) PODHEDa

(mg/kg/day) Total UF

Candidate 

MRLs 

NOAEL LOAEL (mg/kg/day)

Increased rat pup mortality and 

lung histopathology (Chen et al. 

2012b)

2.01 40.1 0.000139 300b 4.6x10-7

Decreased rat pup weight at birth 

and on PND 4 (Luebker et al. 

2005b)

24.1 0.00167 3,000c 5.6x10-7

Delayed eye opening in mouse 

pups (Lau et al. 2003)

31.9 0.00221 3,000c 7.4x10-7

Neurodevelopmental effects in 

male rat pups (Butenhoff et al. 

2009b)

11.3 37.5 0.000780 300b 2.6x10-6

Delayed eye opening and 

decreased F2 rat pup body weight 

(Luebker et al. 2005a)

7.43 29.7 0.000515 300b 1.7x10-6

Increased neonatal mortality in rat 

pups (Xia et al. 2011)

11.5 38.3 0.000797 300b 2.7x10-6

Hepatic effects in monkeys 

(Seacat et al. 2002)

37.8 150 0.00262 300b 8.7x10-6

aBased on the NOAEL or the LOAEL if NOAEL was not identified. bUncertainty factors (UF) of 3 for extrapolation from animals to humans with dosimetric adjustments and 10 for 

human variability and modifying 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.

LOAEL = lowest-observed-effect level; MRL = Minimal Risk Level; NOAEL = no-observed-adverse-effect level; 

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, and 

31.9 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. 

Summary of the Principal Study:

Luebker DJ, Case MT, York RG, et al. 2005a. Two-generation reproduction and cross-foster studies of 

perfluorooctanesulfonate (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 the 
PERFLUOROALKYLS A-42

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

remaining 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 were 

sacrificed 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 serum 

from 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-dose 

parental 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 high-dose parental

females was significantly lower during cohabitation and gestation (11% reduced). Absolute and relative 

food consumption were significantly reduced in high-dose parental females during premating and 

gestation (>15%) and in 1.6 mg/kg/day parental females during lactation. Administration of PFOS did 

not affect any mating or fertility parameter. Estrous cycling was not affected. Examination of 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 high-dose parental females included 

reduced number of implantations per delivered litter, decreased gestational length, increased number of 

dams with all pups dying on PND 1–4 (also at 1.6 mg/kg/day). Observation of 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 was noted 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). Follow-up observations of 0.1 and 0.4 mg/kg/day offspring showed no 

alterations in body weight or food consumption, 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 was significantly reduced at 0.4 mg/kg/day on PND 7 (13%). Serum and 

liver PFOS increased with dose.

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 calculated 

using 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 than

developmental toxicity
PERFLUOROALKYLS A-43

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Provisional 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 a 

more sensitive effect than developmental toxicity. 

Table A-17. Measured Serum PFOS Levels at the NOAEL and LOAEL Doses for 

Immunological Effects 

Effect, species and 

exposure duration

Dose

(mg/kg/day)

Measured mean 

serum PFOS

(μg/mL) Reference

Impaired response to sRBC in 

mice exposed for 60 days

NOAEL 0.0083 0.674 Dong et al. 2009

LOAEL 0.083 7.132

Impaired response to sRBC in 

mice exposed for 60 days

NOAEL 0.0167 2.36 Dong et al. 2011

LOAEL 0.083 10.75

Decreased resistance to 

influenza virus in mice 

exposed for 21 days

NOAEL 0.005 0.189 Guruge et al. 

2009 LOAEL 0.025 0.670

Suppressed response to sRBC 

in mice exposed for 28 days

NOAEL 0.00016 0.0178 Peden-Adams et 

al. 2008 LOAEL 0.00166 0.0915

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; this 

estimated TWA concentration was used to calculated 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 

from the Luebker et al. (2005a) study and lends to support to using the additional uncertainty factor of 

10 to account 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 the 

findings from epidemiology studies is presented in the MRL introduction section.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-44

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctane sulfonic acid (PFOS)

1763-23-1 

June 2018 

Final, Pre-Public Comment 

Oral

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFOS. 

Rationale for Not Deriving an MRL: Immune function was not examined following chronic-duration 

oral exposure in laboratory animal studies; in intermediate-duration animal studies, the lowest LOAEL 

doses were for immunological effects. 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 in 

female rats. Thus, the 1.04 mg/kg/day dose was identified as the lowest LOAEL for this study. 

Epidemiology 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): Selene Chou
PERFLUOROALKYLS A-45

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexane sulfonic acid (PFHxS) 

355-46-4 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-46

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexane sulfonic acid (PFHxS) 

355-46-4 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-47

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexane sulfonic acid (PFHxS)

355-46-4 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-48

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexane sulfonic acid (PFHxS) 

355-46-4 

June 2018 

Final, Pre-Public Comment 

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 of 

pharmacokinetic 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 not 

considered 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 in 

laboratory animals and calculating HEDs for these serum concentrations. For PFOA and PFOS, the 

Wambaugh et al. (2013) pharmacokinetic model was utilized for predicting the TWA serum 

perfluoroalkyl concentrations. However, strain-, sex-, and compound-specific model parameters are not 

available 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 perfluoroalkyl compounds; however, there are limited 

data available that would allow for comparison of the toxicity and toxicokinetic properties of different 

perfluoroalkyl compounds. 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): Selene Chou
PERFLUOROALKYLS A-49

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Provisional MRL:

Critical Effect:

Reference:

Point of Departure:

Uncertainty Factor:

Modifying Factor:

LSE Graph Key:

Species:

Perfluorohexane sulfonic acid (PFHxS)

355-46-4 

June 2018 

Final, Pre-Public Comment 

Oral

Intermediate

2x10-5 mg/kg/day

Thyroid follicular cell damage

Butenhoff et al. 2009a; Hoberman and York 2003 

0.0047 mg/kg/day

30 

10 

32 

Rat

MRL Summary: A provisional intermediate-duration oral MRL of 2x10-5 mg/kg/day was derived for 

PFHxS based on thyroid follicular cell damage in adult male rats administered via gavage PFHxS for a 

minimum of 42 days (Butenhoff et al. 2009a; Hoberman and York 2003). 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 with dosimetric adjustments and 10 for human variability) and a modifying factor of 10 for 

database limitations.

Selection of the Critical Effect: Two intermediate-duration studies in laboratory animals have been 

identified for PFHxS. In a developmental toxicity study, increased incidences of thyroid follicular cells 

hypertrophy, and hyperplasia were observed in F0 male rats administered ≥3 mg/kg/day (Butenhoff et al. 

2009a; Hoberman and York 2003). Increased liver weight and centrilobular hepatocellular hypertrophy 

were also observed in the males at ≥3 mg/kg/day. No reproductive or developmental effects were 

reported. Liver effects (decreases in serum lipids, increases in hepatic triglyceride levels, and increases 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). Using the Hall et al. (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. 

Selection of the Principal Study: Since the liver effects were not considered relevant to humans, the 

Butenhoff et al. (2009a) study was selected as the principal study. Thyroid effects in male rats was noted 

as the most sensitive endpoint in this study, with a LOAEL of 3 mg/kg/day and a NOAEL of 

1 mg/kg/day. 

Summary of the Principal Study:

Butenhoff JL, Chang SC, Ehresman DJ, et al. 2009a. Evaluation of potential reproductive and 

developmental toxicity of potassium perfluorohexanesulfonate in Sprague Dawley rats. Reprod Toxicol 

27:331-341. 

Hoberman AM, York RG. 2003. Oral (gavage) combined repeated dose toxicity study of T-7706 with 

the reproduction/developmental toxicity screening test. Argus Research. 
PERFLUOROALKYLS A-50

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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 (a 

minimum 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 evaluated 

included: body weight, food consumption, estrous cycling, functional observational battery (FOB; tests of 

autonomic 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; weight 

of 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 

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 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 and 

10 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. 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 any of 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 not affected. 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. 

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: 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 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 PFHxS model parameters for humans are presented in Table A-4. The NOAELHED is 

0.0047 mg/kg/day
PERFLUOROALKYLS A-51

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

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

• 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 in 

particular studies examining immunotoxicity, a sensitive endpoint for other perfluoroalkyl 

compounds, and general toxicity.

Provisional 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 the 

findings from epidemiology studies is presented in the MRL introduction section.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-52

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexane sulfonic acid (PFHxS) 

355-46-4 

June 2018 

Final, Pre-Public Comment 

Oral

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFHxS. 

Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals were 

identified for PFHxS.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-53

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorononanoic acid (PFNA) 

375-95-1 

June 2018 

Final, Pre-Public Comment 

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 et 

al. 1989) was not considered suitable for derivation of an inhalation MRL due to its lack of 

histopathological examination and short exposure duration. 

In the only available inhalation exposure study for PFNA, Kinney et al. (1989) noted labored breathing in 

rats during and after a 4-hour nose-only exposure to 590 mg/m3

 exposure; the study also reported an 

increase in relative liver weight 5 days after exposure to ≥67 mg/m3

. 

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-54

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorononanoic acid (PFNA) 

375-95-1 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-55

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorononanoic acid (PFNA) 

375-95-1 

June 2018 

Final, Pre-Public Comment 

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 were 

identified for PFNA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-56

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorononanoic acid (PFNA) 

375-95-1 

June 2018 

Final, Pre-Public Comment 

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 of examined the toxicity of PFNA in rats and mice exposed for acute durations. 

These studies 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 in 

liver 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). 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): Selene Chou
PERFLUOROALKYLS A-57

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Provisional MRL: 

Critical Effect:

Reference:

Point of Departure:

Uncertainty Factor:

Modifying Factor:

LSE Graph Key:

Species:

Perfluorononanoic acid (PFNA) 

375-95-1 

June 2018 

Final, Pre-Public Comment 

Oral

Intermediate

3x10-6 mg/kg/day

Decreased body weight and developmental delays

Das et al. 2015 

0.001 mg/kg/day

30 

10 

35 

Mouse 

MRL Summary: A provisional intermediate-duration oral MRL of 3x10-6 mg/kg/day was derived for 

PFNA based on 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 

dosimetric adjustments 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. 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 size and 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 et al. 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). A summary of developmental 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

Dose

(mg/kg/day) Effect Reference

129S1/svlm mouse

GDs 1–18

(offspring followed until 

PND 21)

0.83 No effects reported Wolf et al. 2010

1.1 Decreased litter size and pup 

survival

1.5 No effects reported

2.0 Decreased number of live pups per 

litter and decreased pup body 

weight gain

CD-1 mouse

GDs 1–17

(offspring followed until

PND 287

1 No effects reported Das et al. 2015

3 Decreased body weight gain and 

delayed eye opening, preputial 

separation, and vaginal opening
PERFLUOROALKYLS A-58

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Table A-18. Summary of the Adverse Effects Observed in Laboratory Animals 

Following Intermediate-Duration Oral Exposure to PFNA

Species and exposure 

duration

Dose

(mg/kg/day) Effect Reference

5 Decreased postnatal survival, 80% 

mortality between PND 2 and 10

10 Full litter resorption

Sprague-Dawley rat

GDs 1–20

offspring followed through 

PND 434)

5 Decreased birth weight, increased 

blood pressure at 10 weeks of age; 

reduced nephron endowment

Rogers et al. 2014

GD = gestation day; PFNA perfluorononanoic acid; PND = postnatal day

Selection of the Principal Study: Developmental toxicity, including decreases in pup survival, 

developmental delays, and decreases in birth weight have been observed in three 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 the principal study for the MRL.

Table A-19. Summary of Estimated TWA Serum PFNA levels in Laboratory 

Animals Following Intermediate-Duration Oral Exposure 

Species and exposure 

duration

Dose

(mg/kg/day)

Estimated 

TWA serum 

PFNA 

(μg/mL) Effect Reference

129S1/svlm mouse

GDs 1–18

(offspring followed until 

PND 21)

0.83 4.47 No effects reported Wolf et al. 

2010 1.1 11.6 Decreased litter size and pup 

survival

1.5 10.5 No effects reported

2.0 17.6 Decreased number of live pups 

per litter and decreased pup body 

weight gain

CD-1 mouse

GDs 1–17

(offspring followed until 

PND 287

1 6.8 No effects reported Das et al. 

2015 3 10.9 Decreased body weight gain and 

delayed eye opening, preputial 

separation, and vaginal opening

5 39.7 Decreased postnatal survival, 80% 

mortality between PND 2 and 10

10 NA Full litter resorption

Sprague-Dawley rat

GDs 1–20

(offspring followed 

through PND 434)

5 Not 

calculated

Decreased birth weight, increased

blood pressure at 10 weeks of 

age; reduced nephron endowment

Rogers et 

al. 2014

GD = gestation day; PFNA perfluorononanoic acid; PND = postnatal day
PERFLUOROALKYLS A-59

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

Summary of the Principal Study:

Das KP, Grey BE, Rosen MB, Wood CR, Tatum-Gibbs KR, Zehr RD, Strynar MJ, Lindstrom AB, Lau C. 

2015. Developmental toxicity of perfluorononanoic acid in mice. Reprod Toxicol. 51:133-44. 

Groups of 8–10 timed-pregnant female CD-1 mice were administered via gavage 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 the remaining mice were 

allowed to give birth. Pups were observed for postnatal survival up to PND 24 as well 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 in 

controls). 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 in 

dams 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 body 

weight. 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 

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 male 

pups from the 3 and 5 mg/kg dose groups and in females from the 5 mg/kg dose group. The changes in 

males were dose-related and persisted from PND 25 to 287. Weight reduction in females was less 

substantial in comparison with males 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, and vaginal opening) was significantly delayed (by 2–7 days) at 3 and 5 mg/kg/day. 

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 (serum concentrations 

were provided to ATSDR).

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 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 PFNA model parameters for humans are presented in Table A-4. 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
PERFLUOROALKYLS A-60

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

• 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. In 

particular, no studies were identified that examined immunotoxicity, a sensitive endpoint for 

other perfluoroalkyl compounds, or general toxicity.

Provisional MRL = NOAELHED ÷ (UFs x MF)

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 the

findings from epidemiology studies is presented in the MRL introduction section.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-61

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorononanoic acid (PFNA) 

375-95-1 

June 2018 

Final, Pre-Public Comment 

Oral

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFNA. 

Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals were 

identified for PFNA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-62

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorodecanoic acid (PFDeA)

335-76-2 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for 

PFDeA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFDeA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-63

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorodecanoic acid (PFDeA)

335-76-2 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Intermediate 

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL 

for PFDeA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFDeA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-64

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorodecanoic acid (PFDeA)

335-76-2 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for 

PFDeA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFDeA.

Agency Contacts (Chemical Managers): Selene Chou 
PERFLUOROALKYLS A-65

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorodecanoic acid (PFDeA)

335-76-2 

June 2018 

Final, Pre-Public Comment 

Oral

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFDeA. 

Rationale for Not Deriving an MRL: The available acute oral database for PFDeA was not considered 

adequate for derivation of an MRL because the study identifying the lowest adverse effect level did not 

measure serum PFDeA levels, which are needed to estimate HEDs.

Several laboratory animal studies have examined the acute oral toxicity of PFDeA; most were limited in 

scope. The lowest LOAEL was 1 mg/kg/day for decreases in fetal weight in mice administered PFDeA 

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 Birnbaum 

1989). Another developmental toxicity study did not report alterations in performance on 

neurobehavioral tests in 2–4-month-old mice administered 10.8 mg/kg/day PFDeA 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 in mice at 80 mg/kg/day (Harris et al. 1989), decreases in spleen weight in mice at 

80 mg/kg/day (Harris et al. 1989), and atrophy and lymphoid depletion in thymus and spleen in mice at 

160 mg/kg/day (Harris et al. 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).

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 these 

serum concentrations. For PFOA and PFOS, the Wambaugh et al. (2013) pharmacokinetic model was 

utilized for predicting the TWA serum perfluoroalkyl concentrations. However, strain-, sex-, and 

compound-specific model parameters are not available for other perfluoroalkyls. The Harris and 

Birnbaum (1989) study, which identified the lowest adverse effect level, did not measure maternal serum 

PFDeA levels. Thus, HEDs could not be calculated using animal serum PFDeA 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 perfluoroalkyl 

compounds. 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): Selene Chou
PERFLUOROALKYLS A-66

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorodecanoic acid (PFDeA)

335-76-2 

June 2018 

Final, Pre-Public Comment 

Oral

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for 

PFDeA.

Rationale for Not Deriving an MRL: No intermediate-duration oral studies in laboratory animals were 

identified for PFDeA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-67

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorodecanoic acid (PFDeA)

335-76-2 

June 2018 

Final, Pre-Public Comment 

Oral

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFDeA.

Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals were 

identified for PFDeA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-68

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroundecanoic acid (PFUA) 

2058-94-8 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for 

PFUA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFUA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-69

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroundecanoic acid (PFUA) 

2058-94-8 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL 

for PFUA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFUA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-70

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroundecanoic acid (PFUA) 

2058-94-8 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for 

PFUA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFUA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-71

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroundecanoic acid (PFUA) 

2058-94-8 

June 2018 

Final, Pre-Public Comment 

Oral

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFUA. 

Rationale for Not Deriving an MRL: No acute-duration oral studies in laboratory animals were 

identified for PFUA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-72

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroundecanoic acid (PFUA) 

2058-94-8 

June 2018 

Final, Pre-Public Comment 

Oral

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for 

PFUA.

Rationale for Not Deriving an MRL: Intermediate-duration oral database was considered inadequate for 

derivation of an MRL for PFUA because the only available study did not measure serum PFUA levels, 

which are needed to calculated HEDs (see MRL approach in Appendix A introduction). 

One study was identified that examined the oral toxicity of PFUA 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): Selene Chou
PERFLUOROALKYLS A-73

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroundecanoic acid (PFUA) 

2058-94-8 

June 2018 

Final, Pre-Public Comment 

Oral

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFUA. 

Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals were 

identified for PFUA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-74

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroheptanoic acid (PFHpA) 

375-85-9 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-75

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroheptanoic acid (PFHpA) 

375-85-9 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-76

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroheptanoic acid (PFHpA) 

375-85-9 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-77

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroheptanoic acid (PFHpA) 

375-85-9 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-78

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroheptanoic acid (PFHpA) 

375-85-9 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-79

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluoroheptanoic acid (PFHpA) 

375-85-9 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-80

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutane sulfonic acid (PFBuS) 

375-73-5 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for 

PFBuS.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFBuS.

Agency Contacts (Chemical Managers): Selene Chou 
PERFLUOROALKYLS A-81

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutane sulfonic acid (PFBuS) 

375-73-5 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL 

for PFBuS.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFBuS.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-82

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutane sulfonic acid (PFBuS) 

375-73-5 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for 

PFBuS.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFBuS.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-83

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutane sulfonic acid (PFBuS) 

375-73-5 

June 2018 

Final, Pre-Public Comment 

Oral

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFBuS.

Rationale for Not Deriving an MRL: No acute-duration oral studies in laboratory animals were 

identified for PFBuS.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-84

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutane sulfonic acid (PFBuS)

375-73-5 

June 2018 

Final, Pre-Public Comment 

Oral

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for 

PFBuS.

Rationale for Not Deriving an MRL: Laboratory animal studies for other perfluoroalkyl compounds 

have identified immunotoxicity and developmental toxicity as sensitive endpoints; these potential targets 

have not been investigated for PFBuS. Thus, the database was considered inadequate for identifying a 

critical endpoint and evaluating dose-response relationships.

Limited data available on the toxicity of PFBuS in laboratory animals have identified the liver, kidneys, 

stomach, and hematological systems as targets of toxicity. Decreases in hemoglobin and hematocrit 

levels were observed in male rats administered 200 mg/kg/day PFBuS 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 male rats 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 PFBuS for 28 days (3M 2001) or 600 mg/kg/day for 90 days (Lieder et al. 

2009a). 

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-85

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutane sulfonic acid (PFBuS) 

375-73-5 

June 2018 

Final, Pre-Public Comment 

Oral

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFBuS. 

Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals were 

identified for PFBuS.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-86

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutyric acid (PFBA)

375-22-4 

June 2018 

Final, Pre-Public Comment

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): Selene Chou
PERFLUOROALKYLS A-87

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutyric acid (PFBA)

375-22-4 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-88

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutyric acid (PFBA)

375-22-4 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-89

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutyric acid (PFBA)

375-22-4 

June 2018 

Final, Pre-Public Comment 

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 perfluoroalkyl compounds 

have identified immunotoxicity and developmental toxicity as sensitive endpoints following acuteduration oral exposure; these potential targets have not been investigated for PFBA. Thus, the database 

was considered inadequate 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 of 

potential 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 by 

electron microscopy. In a similar study, dietary administration of approximately 78 mg/kg/day PFBA to 

male 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 in 

deactivation of reactive oxygen species; however, PFBA did not have a significant effect on parameters of 

peroxisomal 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): Selene Chou
PERFLUOROALKYLS A-90

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutyric acid (PFBA)

375-22-4 

June 2018 

Final, Pre-Public Comment 

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 considered 

adequate 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 on the more sensitive endpoints, data from females is needed in order to 

estimate 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 the 

pups at maternal doses of PFBA of 35 mg/kg/day. In the 28- and 90-day studies, hyperplasia/hypertrophy 

of 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): Selene Chou
PERFLUOROALKYLS A-91

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorobutyric acid (PFBA)

375-22-4 

June 2018 

Final, Pre-Public Comment 

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 were 

identified for PFBA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-92

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorododecanoic acid (PFDoA) 

307-55-1 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for 

PFDoA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFDoA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-93

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorododecanoic acid (PFDoA) 

307-55-1 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL 

for PFDoA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFDoA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-94

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorododecanoic acid (PFDoA) 

307-55-1 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for 

PFDoA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFDoA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-95

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorododecanoic acid (PFDoA) 

307-55-1 

June 2018 

Final, Pre-Public Comment 

Oral

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFDoA. 

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 PFDoA. Shi et al. (2007) reported decreases in 

body 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 cholesterol 

levels at 10 mg/kg/day. In the second study, Zhang et al. (2008) found increases in liver weight and 

hepatic triglyceride and cholesterol levels in rats administered via gavage ≥5 mg/kg/day for 14 days; these 

liver 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 not 

considered suitable for the derivation of an MRL. 

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-96

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorododecanoic acid (PFDoA) 

307-55-1 

June 2018 

Final, Pre-Public Comment 

Oral

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for 

PFDoA.

Rationale for Not Deriving an MRL: One intermediate-duration study examined the oral toxicity of 

PFDoA. In this study, decreases in serum estradiol and increases in serum cholesterol were observed in 

pubertal females exposed to 3 mg/kg/day PFDoA on PNDs 24–72 (Shi et al. 2009). 

Given the limited number of endpoints examined in this study, including the lack of histopathological 

examination, the database was not considered adequate for identifying the critical target of toxicity and 

thus for derivation of an MRL.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-97

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorododecanoic acid (PFDoA) 

307-55-1 

June 2018 

Final, Pre-Public Comment 

Oral

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFDoA. 

Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals were 

identified for PFDoA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-98

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanesulfonamide (PFOSA)

754-91-6 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL for 

PFOSA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFOSA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-99

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanesulfonamide (PFOSA)

754-91-6 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL 

for PFOSA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFOSA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-100

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanesulfonamide (PFOSA)

754-91-6 

June 2018 

Final, Pre-Public Comment 

Inhalation 

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL for 

PFOSA.

Rationale for Not Deriving an MRL: No inhalation studies in laboratory animals were identified for 

PFOSA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-101

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanesulfonamide (PFOSA)

754-91-6 

June 2018 

Final, Pre-Public Comment 

Oral

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFOSA. 

Rationale for Not Deriving an MRL: The acute-duration database for PFOSA was not considered 

adequate 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 immunological 

effects (sensitive targets for other perfluoroalkyl compounds) were not examined. 

One laboratory animal study evaluated the acute oral toxicity of PFOSA. 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 

PFOSA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-102

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanesulfonamide (PFOSA)

754-91-6 

June 2018 

Final, Pre-Public Comment 

Oral

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL for 

PFOSA.

Rationale for Not Deriving an MRL: No intermediate-duration oral studies in laboratory animals were 

identified for PFOSA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-103

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorooctanesulfonamide (PFOSA)

754-91-6 

June 2018 

Final, Pre-Public Comment 

Oral

Chronic 

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL for PFOSA. 

Rationale for Not Deriving an MRL: No chronic-duration oral studies in laboratory animals were 

identified for PFOSA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-104

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexanoic acid (PFHxA) 

307-24-4 

June 2018 

Final, Pre-Public Comment 

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 were 

identified for PFHxA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-105

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexanoic acid (PFHxA) 

307-24-4 

June 2018 

Final, Pre-Public Comment 

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): Selene Chou
PERFLUOROALKYLS A-106

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexanoic acid (PFHxA) 

307-24-4 

June 2018 

Final, Pre-Public Comment 

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 were 

identified for PFHxA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-107

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexanoic acid (PFHxA) 

307-24-4 

June 2018 

Final, Pre-Public Comment 

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 for 

derivation 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 are 

needed to estimate HEDs.

Two developmental toxicity studies conducted by Iwai and Hoberman (2014) examined the acute toxicity 

of 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 the 

measured 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): Selene Chou
PERFLUOROALKYLS A-108

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexanoic acid (PFHxA) 

307-24-4 

June 2018 

Final, Pre-Public Comment 

Oral

Intermediate

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL for PFHxA. 

Rationale for Not Deriving an MRL: No intermediate-duration oral studies in laboratory animals were 

identified for PFHxA.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS A-109

APPENDIX A

***DRAFT FOR PUBLIC COMMENT***

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Perfluorohexanoic acid (PFHxA) 

307-24-4 

June 2018 

Final, Pre-Public Comment 

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 considered 

adequate for derivation of a chronic MRL because the only study available did not measure serum PFHxA 

levels and elimination half-life data are not available for humans. These toxicokinetic data are needed to 

derive 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, an 

elimination half-life has not been estimated in humans.

Agency Contacts (Chemical Managers): Selene Chou
PERFLUOROALKYLS B-1

***DRAFT FOR PUBLIC COMMENT***

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 biological 

monitoring 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 the 

assessment 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 

***DRAFT FOR PUBLIC COMMENT***

Table B-1. Inclusion Criteria for the Literature Search and Screen

Other noncancer effects

Cancer

Toxicokinetics

Absorption

Distribution

Metabolism

Excretion

PBPK models

Biomarkers

Biomarkers of exposure

Biomarkers of effect

Interactions with other chemicals

Potential for human exposure

Releases to the environment

Air

Water

Soil

Environmental fate

Transport 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, and May 2016: 

• PubMed

• National 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

***DRAFT FOR PUBLIC COMMENT***

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 Substance 

priority 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 and 

identifying additional references. ATSDR also identified reports from the grey literature, which included 

unpublished research reports, technical reports from government agencies, conference proceedings and 

abstracts, and theses and dissertations. 

Table B-2. Database Query Strings Post Public Comment Searches

Database

search date Query string

PubMed

05/24/2016 ((((("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 "1-

Perfluorobutanesulfonic 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-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 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-1-

sulphonic 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 sulfonic 

acid "[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 "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 (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 "1,1,2,2,3,3,4,4,4-

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-Perfluorobutanesulfonic 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-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 
PERFLUOROALKYLS B-4

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-2. Database Query Strings Post Public Comment Searches

Database

search date Query string

"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-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 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-1-

sulphonic 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 sulfonic 

acid "[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 "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] OR 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 335-67-1[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] 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 "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 

(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 335-76-

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-
PERFLUOROALKYLS B-5

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-2. Database Query Strings Post Public Comment Searches

Database

search date Query string

55-1[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] 

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 "chemically 

induced"[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 and 

inhibitors"[MeSH Terms] OR "alkanesulfonic acids/blood"[MeSH Terms] OR "alkanesulfonic 

acids/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 and

inhibitors"[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-n-
PERFLUOROALKYLS B-6

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-2. Database Query Strings Post Public Comment Searches

Database

search date Query string

octanoic 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 sulfonic 

acid "[tw] OR "Heptadecafluoro-1-octanesulfonic acid"[tw] OR "heptadecafluoro-1-octane sulfonic 

acid"[tw] OR "Heptadecafluorooctane-1-sulphonic acid"[tw] OR "heptadecafluorooctane sulfonic 

acid"[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 acid1-

Perfluorooctanesulfonic acid"[tw] OR "Perfluorohexane sulfonic acid"[tw] OR "pfhxs"[tw] OR 

"perfluorohexanesulfonic acid"[tw] OR "perfluorohexanesulfonate"[tw] OR "1,1,2,2,3,3,4,4,5,5,6,6,6-

Tridecafluorohexane-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-1-

butanesulfonic acid"[tw] OR "1-Perfluorobutanesulfonic acid"[tw] OR "Nonafluoro-1-butanesulfonic 

acid"[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 "Perfluorolauric 

acid"[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])

Toxcenter

05/25/2016 FILE 'TOXCENTER' ENTERED AT 08:37:55 ON 25 MAY 2016

L1 5994 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 5967 SEA L1 NOT TSCATS/FS 

L3 5731 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) 

L7 QUE (ACUTE OR SUBACUTE OR LD50# OR LD(W)50 OR LC50# OR 

 LC(W)50) 

L8 QUE (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 OR 
PERFLUOROALKYLS B-7

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-2. Database Query Strings Post Public Comment Searches

Database

search date Query string

 DIETARY 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? OR 

 OVUM?) 

L15 QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?) 

L16 QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? OR 

 TERATOGEN?) 

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?) 

L25 QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR CARCINOM?) 

L26 QUE (GENETOX? OR GENOTOX? OR MUTAGEN? OR GENETIC(W)TOXIC?) 

L27 QUE (NEPHROTOX? OR HEPATOTOX?) 

L28 QUE (ENDOCRIN? OR ESTROGEN? OR ANDROGEN? OR HORMON?) 

L29 QUE (OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?) 

L30 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 

L38 1318 SEA L4 AND L37 

L39 1148 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
PERFLUOROALKYLS B-8

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-2. Database Query Strings Post Public Comment Searches

Database

search date Query string

09/19/2013 FILE 'TOXCENTER' ENTERED AT 09:10:51 ON 19 SEP 2013

L1 3993 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 

L3 3782 SEA L2 NOT PATENT/DT 

L4 2796 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) 

L8 QUE (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?) 

L12 QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET? OR DRINKING(

 W)WATER?) 

L13 QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR PERMISSIBLE))

L14 QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?) 

L15 QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM? OR 

 OVUM?) 

L16 QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?) 

L17 QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? OR 

 TERATOGEN?) 

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 
PERFLUOROALKYLS B-9

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-2. Database Query Strings Post Public Comment Searches

Database

search date Query string

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 

 SAVE TEMP L50 PERFLUOROALKYLS/A PFOA/A

L51 217 SEA L50 AND BIOSIS/FS 

L52 471 SEA L50 AND CAPLUS/FS 

L53 220 SEA L52 AND 4-?/CC 

L54 1 SEA L50 NOT (MEDLINE/FS OR BIOSIS/FS OR CAPLUS/FS) 

L55 438 SEA L51 OR L53 OR L54 

L56 689 SEA L55 OR L52 

 D SCAN L55

ToxLine

05/24/2016 ((("C11-PFA" OR "et-pfosa-acoh" OR "Henicosafluoroundecanoic acid" OR "heptadecafluoro-1-

octane sulfonic acid" OR "Heptadecafluoro-1-octanesulfonic acid" OR "heptadecafluorooctane 

sulfonic acid" OR "Heptadecafluorooctane-1-sulphonic acid" OR "Heptadecafluorooctane-1-sulphonic 

acid1-Perfluorooctanesulfonic 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-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 acid 

amide" 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") 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 ("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" 
PERFLUOROALKYLS B-10

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-2. Database Query Strings Post Public Comment Searches

Database

search date Query string

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-1-

sulphonic 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 "Glycine, N-ethyl-N-((1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-

heptadecafluorooctyl)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 1 

sulphonic acid" OR "heptadecafluorooctane sulfonic acid" OR "perfluorooctane sulfonate" OR 

"perfluorooctylsulfonic acid" OR "perfluorooctane sulphonic acid" OR "perfluorooctanesulfonic acid" 

OR "perfluorooctanesulfonate" OR "heptadecafluorooctane 1 sulphonic acid1 perfluorooctanesulfonic 

acid" 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 pfosa 

acoh" 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

Source Query and number screened when available

TSCATSa

5/23/2016

9/18/2013

Compounds searched: 335-67-1; 1763-23-1; 355-46-4; 2991-50-6; 2355-31-9; 335-76-2; 375-73-

5; 375-85-9; 375-95-1; 754-91-6; 2058-94-8; 307-55-1; 375-22-4

NTP

5/23/2016 "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 
PERFLUOROALKYLS B-11

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

"Perfluorooctylsulfonic acid" OR "perfluorooctane sulphonic acid" OR "perfluorooctanesulfonic 

acid" 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 sulfonic 

acid" 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-butanesulfonic 

acid" 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 "Perfluorobutyric 

acid"

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-1-

sulphonic 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

NIH RePORTER

2/28/2017 Text Search: "1,1,2,2,3,3,4,4,4-Nonafluoro-1-butanesulfonic acid" OR "1,1,2,2,3,3,4,4,4-

Nonafluorobutane-1-sulphonic 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" OR "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 
PERFLUOROALKYLS B-12

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

amide" 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; 375-73-

5; 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 for 

recent TSCA submissions.

The May 2016 results were: 

• Number of records identified from PubMed, TOXLINE, and TOXCENTER (after duplicate 

removal): 1,153

• Number of records identified from other strategies: 209

• Total number of records to undergo literature screening: 1,363

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 for 

relevance. Studies that were considered relevant (see Table B-1 for inclusion criteria) were moved to the 

second 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: 1,363

• Number of studies considered relevant and moved to the next step: 457

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: 457

• Number of studies cited in the previous draft of the toxicological profile: 639

• Total number of studies cited in the profile: 968

A summary of the results of the literature search and screening is presented in Figure B-1.
PERFLUOROALKYLS B-13

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***

Figure B-1. May 2016 Literature Search Results and Screen for Perfluoroalkyls
PERFLUOROALKYLS C-1

***DRAFT FOR PUBLIC COMMENT***

APPENDIX C. USER'S GUIDE

Chapter 1. Relevance to Public Health

This chapter provides an overview of U.S. exposures, a summary of health effects based on evaluations of 

existing 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 health 

endpoints 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 oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant 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 near 

a 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 human 

occupational 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 and 

Section 3.4 Interactions with Other Substances, provide important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified 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-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to 

protect sensitive subpopulations (people who are most susceptible to the health effects caused by the 

substance) 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 the 

inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a 
PERFLUOROALKYLS C-2

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

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 dose 

concentrations 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 substance 

using 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 the 

tables 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), and 

chronic (≥365 days)—are presented within each relevant route of exposure. In this example, two 

oral 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 per

group. 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 in 

these 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

***DRAFT FOR PUBLIC COMMENT***

more complete review of the dosing regimen, refer to the appropriate sections of the text or the 

original 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 these 

systems. In the example of key number 51, three endpoints (body weight, hematological, and 

hepatic) were investigated.

(8) NOAEL. A NOAEL is the highest exposure level at which no adverse effects were seen in the 

organ 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 the 

gradation of effects with increasing dose. A brief description of the specific endpoint used to 

quantify 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 of 

carcinogenesis 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 report 

doses 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 found 

in 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 the 

reader 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, health 

effects observed within the chronic exposure period are illustrated.
PERFLUOROALKYLS C-4

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***

(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 are 

graphically 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 the 

extrapolation from the exposure level of 6.1 mg/kg/day (see entry 51 in the sample LSE table) to 

the 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 symbol 

refers 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

***DRAFT FOR PUBLIC COMMENT***
PERFLUOROALKYLS C-6 

APPENDIX C

***DRAFT FOR PUBLIC COMMENT***
PERFLUOROALKYLS D-1 

***DRAFT FOR PUBLIC COMMENT***

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 interpretation 

of 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 fast 

answers 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 are 

reported 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, and 

chronic). 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. 

Pediatrics: 

 Section 3.2 Children and Other Populations that are Unusually Susceptible

 Section 3.3 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 the 

evaluation 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 to 

hazardous materials.

Fact Sheets (ToxFAQsTM) provide answers to frequently asked questions about toxic substances (see 

https://www.atsdr.cdc.gov/toxfaqs/Index.asp).
PERFLUOROALKYLS D-2 

APPENDIX D

***DRAFT FOR PUBLIC COMMENT***

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 the 

workplace. 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 and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (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 for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human 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 of 

physicians and other health care providers specializing in the field of occupational and 

environmental 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 with 

recognized 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 and 

treatment 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/.
PERFLUOROALKYLS E-1

***DRAFT FOR PUBLIC COMMENT***

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 the 

surfaces 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 of 

organic 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 or 

sediment.

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 to 

either experimental toxicology or epidemiology data. For example, a BMD10 would be the dose 

corresponding 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 are 

feasible. 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 the 

surrounding 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 and 

its appropriate control.

Carcinogen—A chemical capable of inducing cancer.

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular 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 is 

identified 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 same 

disease or exposure. These reports may suggest potential topics for scientific research, but are not actual 

research studies.
PERFLUOROALKYLS E-2

APPENDIX E

***DRAFT FOR PUBLIC COMMENT***

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 a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome, and who are disease-free at start of follow-up. Often, at 

least one exposed group is compared to one unexposed group, while in other cohorts, exposure is a 

continuous 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 of 

human 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 point 

in 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 to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

effect 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 or 

other 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 of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration 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 from 

the 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 have 

adverse cumulative or delayed effects on health.
PERFLUOROALKYLS E-3

APPENDIX E

***DRAFT FOR PUBLIC COMMENT***

Immunotoxicity—Adverse effect on the functioning of the immune system that may result from 

exposure 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 for 

a 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 that 

has 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 a 

defined 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 severity 

of adverse effects between the exposed population and its appropriate control.

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus.

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function.

Metabolism—Process in which chemical substances are biotransformed in the body that could result in 

less 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 and 

duration 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.
PERFLUOROALKYLS E-4

APPENDIX E

***DRAFT FOR PUBLIC COMMENT***

Morbidity—The state of being diseased; the morbidity rate is the incidence or prevalence of a disease in 

a 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 of 

death or pathological conditions.

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

hazardous 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 not 

exposed 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 control 

of 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 the 

physiologically-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. 
PERFLUOROALKYLS E-5

APPENDIX E

***DRAFT FOR PUBLIC COMMENT***

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 with 

realistic 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 of 

magnitude) 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 the 

daily oral exposure of the human population to a potential hazard that is likely to be without risk of 

deleterious 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 or 

under 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 exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort.

Risk—The possibility or chance that some adverse effect will result from a given exposure to a hazardous 

substance.

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, existing health 

condition, or an inborn or inherited characteristic that is associated with an increased occurrence of 

disease or other health-related event or condition.
PERFLUOROALKYLS E-6

APPENDIX E

***DRAFT FOR PUBLIC COMMENT***

Risk Ratio/Relative Risk—The ratio of the risk among persons with specific risk factors compared to the 

risk among persons without risk factors. A risk ratio that is greater than 1 indicates greater risk of disease 

in 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 a 

Time-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 the 

living organism.

Toxics Release Inventory (TRI)—The TRI is an EPA program that tracks toxic chemical releases and 

pollution 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 to 

account 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 from 

data 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.
PERFLUOROALKYLS F-1

***DRAFT FOR PUBLIC COMMENT***

APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

AAPCC American Association of Poison Control Centers

ACGIH American Conference of Governmental Industrial Hygienists

ACOEM American College of Occupational and Environmental Medicine

ACMT American College of Medical Toxicology

ADI acceptable daily intake

ADME absorption, distribution, metabolism, and excretion

AEGL Acute Exposure Guideline Level

AIC Akaike’s information criterion 

AIHA American Industrial Hygiene Association 

ALT alanine aminotransferase

AOEC Association of Occupational and Environmental Clinics

AP alkaline phosphatase

APFO ammonium perfluorooctanoate

AST aspartate aminotransferase

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry

AWQC Ambient Water Quality Criteria

BCF bioconcentration factor

BMD/C benchmark dose or benchmark concentration

BMDX dose that produces a X% change in response rate of an adverse effect

BMDLX 95% lower confidence limit on the BMDX

BMDS Benchmark Dose Software 

BMR benchmark response

BUN blood urea nitrogen 

C centigrade

CAA Clean Air Act

CAS Chemical Abstract Services

CDC Centers for Disease Control and Prevention

CEL cancer effect level

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFR Code of Federal Regulations

Ci curie

CI confidence interval

cm centimeter

CPSC Consumer Products Safety Commission

CWA Clean Water Act

DHHS Department of Health and Human Services

DNA deoxyribonucleic acid

DOD Department of Defense

DOE Department of Energy

DWEL drinking water exposure level

EAFUS Everything Added to Food in the United States

ECG/EKG electrocardiogram

EEG electroencephalogram

EPA Environmental Protection Agency

ERPG emergency response planning guidelines 

Et-PFOSAAcOH 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid

F Fahrenheit
PERFLUOROALKYLS F-2

APPENDIX F

***DRAFT FOR PUBLIC COMMENT***

F1 first-filial generation

FDA Food and Drug Administration

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FR Federal Register

FSH follicle stimulating hormone

g gram

GC gas chromatography

gd gestational day

GGT γ-glutamyl transferase 

GRAS generally recognized as safe

HEC human equivalent concentration 

HED human equivalent dose 

HHS Department of Health and Human Services 

HPLC high-performance liquid chromatography

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer

IDLH immediately dangerous to life and health

IRIS Integrated Risk Information System 

Kd adsorption ratio

kg kilogram

kkg kilokilogram; 1 kilokilogram is equivalent to 1,000 kilograms and 1 metric ton

Koc organic carbon partition coefficient

Kow octanol-water partition coefficient

L liter

LC liquid chromatography

LC50 lethal concentration, 50% kill

LCLo lethal concentration, low

LD50 lethal dose, 50% kill

LDLo lethal dose, low

LDH lactic dehydrogenase

LH luteinizing hormone

LOAEL lowest-observed-adverse-effect level

LSE Level of Significant Exposure

LT50 lethal time, 50% kill

m meter

mCi millicurie

MCL maximum contaminant level

MCLG maximum contaminant level goal

Me-PFOSAAcOH 2-(N-methyl-perfluorooctane sulfonamide) acetic acid

MF modifying factor

mg milligram

mL milliliter

mm millimeter

mmHg millimeters of mercury

mmol millimole

MRL Minimal Risk Level

MS mass spectrometry

MSHA Mine Safety and Health Administration

Mt metric ton

NAAQS National Ambient Air Quality Standard
PERFLUOROALKYLS F-3

APPENDIX F

***DRAFT FOR PUBLIC COMMENT***

NAS National Academy of Science

NCEH National Center for Environmental Health

ND not detected

ng nanogram

NHANES National Health and Nutrition Examination Survey

NIEHS National Institute of Environmental Health Sciences

NIOSH National Institute for Occupational Safety and Health

NLM National Library of Medicine

nm nanometer

nmol nanomole

NOAEL no-observed-adverse-effect level

NPL National Priorities List

NR not reported

NRC National Research Council

NS not specified

NTP National Toxicology Program

OR odds ratio

OSHA Occupational Safety and Health Administration

PAC Protective Action Criteria

PAH polycyclic aromatic hydrocarbon

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PEHSU Pediatric Environmental Health Specialty Unit

PEL permissible exposure limit

PEL-C permissible exposure limit-ceiling value

PFBA perfluorobutyric acid

PFBuS Perfluorobutane sulfonic acid

PFDeA perfluorodecanoic acid

PFDoA perfluorododecanoic acid

PFHpA perfluoroheptanoic acid

PFHxA perfluorohexanoic acid

PFHxS perfluorohexane sulfonic acid

PFNA perfluorononanoic acid

PFOA perfluorooctanoic acid

PFOSA perfluorooctane sulfonamide

PFOS perfluorooctane sulfonic acid

PFUA perfluoroundecanoic acid

pg picogram

PND postnatal day

POD point of departure

ppb parts per billion

ppbv parts per billion by volume

ppm parts per million

ppt parts per trillion

REL recommended exposure level/limit

REL-C recommended exposure level-ceiling value

RfC reference concentration

RfD reference dose

RNA ribonucleic acid

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange
PERFLUOROALKYLS F-4

APPENDIX F

***DRAFT FOR PUBLIC COMMENT***

SD standard deviation

SE standard error

SGOT serum glutamic oxaloacetic transaminase (same as aspartate aminotransferase or AST)

SGPT serum glutamic pyruvic transaminase (same as alanine aminotransferase or ALT)

SIC standard industrial classification

SMR standardized mortality ratio

sRBC sheep red blood cell

STEL short term exposure limit

T1/2 Half-life

TLV threshold limit value

TLV-C threshold limit value-ceiling value

TRI Toxics Release Inventory

TSCA Toxic Substances Control Act

TWA time-weighted average

UF uncertainty factor

U.S. United States

USDA United States Department of Agriculture

USGS United States Geological Survey

USNRC U.S. Nuclear Regulatory Commission

VOC volatile organic compound

WBC white blood cell

WHO World Health Organization

> greater than

≥ greater than or equal to

= equal to

< less than

≤ less than or equal to

% percent

α alpha

β beta

γ gamma

δ delta

μm micrometer

μg microgram

q1

* cancer slope factor

– negative

+ positive

(+) weakly positive result

(–) weakly negative result