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TOXICOLOGICAL PROFILE FOR
 

PERFLUOROALKYLS
 


 


 


 


 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

May 2009 
 

 

 

PERFLUOROALKYLS ii 

DISCLAIMER
 

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 

This information is distributed solely for the purpose of pre dissemination public comment under 

applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic 

Substances and Disease Registry. It does not represent and should not be construed to represent any 

agency determination or policy. 

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PERFLUOROALKYLS iii 

UPDATE STATEMENT
 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch
 

1600 Clifton Road NE
 

Mailstop F-62
 

Atlanta, Georgia 30333
 

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PERFLUOROALKYLS iv 

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PERFLUOROALKYLS v 

FOREWORD 

This toxicological profile for perfluoroalkyls was prepared consistent with guidelines developed by the 

Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency 

(EPA) for the preparation of toxicological profiles. The original guidelines were published in the Federal 

Register on April 17, 1987. While Perfluoroalkyls are not found on the ATSDR list of Priority Hazardous 

Substances, ATSDR has determined that a profile for these substances was necessary because data 

indicate that some perfluoroalkyls are found in the blood of the U.S. general population and in the 

environment. The agency also determined that it was important to characterize the current available 

information regarding the health effects from exposure in order to support and inform public health 

responses and activities by ATSDR and others. This profile will be revised and republished as necessary. 

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

information for the hazardous substance described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a hazardous 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 public health statement that describes, in nontechnical language, a substance’s relevant 

toxicological properties. Following the public health statement is information concerning levels of 

significant human exposure and, where known, significant health effects. 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 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 hazardous substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, subacute, 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 levels of exposure that present a 

significant risk to human health of acute, subacute, and chronic health effects; 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. We plan 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. 

Comments should be sent to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mail Stop F-62
 

Atlanta, Georgia 30333
 

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PERFLUOROALKYLS vi 

Background Information 

The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization 

Act (SARA) of 1986 (Public Law 99 499) which amended the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to 

prepare toxicological profiles for hazardous substances most commonly found at facilities on the 

CERCLA National Priorities List and that pose the most significant potential threat to human health, as 

determined by ATSDR and the EPA. The availability of the revised priority list of 275 hazardous 

substances was announced in the Federal Register on December 7, 2005 (70 FR 72840). For prior 

versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); 

October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067); 

October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); February 28, 1994 (59 FR 9486); 

April 29, 1996 (61 FR 18744); November 17, 1997 (62 FR 61332); October 21, 1999(64 FR 56792); 

October 25, 2001 (66 FR 54014) and November 7, 2003 (68 FR 63098). Section 104(i)(3) of CERCLA, 

as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on 

the list. 

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

peer-reviewed. Staff 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 was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR. 

Howard Frumkin M.D., Dr.P.H. Richard Besser, M.D. 

Director Acting Administrator 

National Center for Environmental Health/ Agency for Toxic Substances and 

Agency for Toxic Substances and Disease Registry 

Disease Registry 

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PERFLUOROALKYLS vii 

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 will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?
 

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or Fax: (770) 488-4178 

1-888-232-6348 (TTY) 

E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 

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PERFLUOROALKYLS viii 

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. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incFidents 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 (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

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. 

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, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-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. 

Referrals 

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. 

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PERFLUOROALKYLS ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Selene Chou, Ph.D. 

Dennis Jones, DVM, Ph.D. 

Hana R. Pohl, M.D., Ph.D.
 

Amanda Cadore, M.P.H. 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA 

Fernando T. Llados, Ph.D.
 

Gary L. Diamond, Ph.D.
 

Daniel J. Plewak, B.S. 

Syracuse Research Corporation, North Syracuse, NY 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1. Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3. Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4. Green Border Review. Green Border review assures the consistency with ATSDR policy. 

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PERFLUOROALKYLS x 

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PERFLUOROALKYLS xi 

PEER REVIEW
 

A peer review panel was assembled for perfluoroalkyls. The panel consisted of the following members: 

1.	 Abby Benninghoff, Ph.D., Faculty Research Associate, Department of Environmental and 

Molecular Toxicology, Oregon State University, Corvallis, Oregon; 

2.	 Edward Emmett, M.D., Professor and Deputy Director, Center of Excellence in Environmental 

Toxicology, University of Pennsylvania, Philadelphia, Pennsylvania; 

3.	 Lynn R. Goldman, M.D., M.P.H., Professor of Environmental Health Science, Johns Hopkins 

University, Baltimore, Maryland; and 

4.	 David A. Savitz, Ph.D., Charles W. Bluhdorn Professor of Community and Preventive Medicine, 

Director, Disease Prevention and Public Health Institute, Mount Sinai School of Medicine, New 

York, New York. 

These experts collectively have knowledge of perfluoroalkyls' physical and chemical properties, 

toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and 

quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer 

review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, 

and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

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

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PERFLUOROALKYLS xii 

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PERFLUOROALKYLS xiii

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CONTENTS

DISCLAIMER..............................................................................................................................................ii

UPDATE STATEMENT.............................................................................................................................iii

FOREWORD................................................................................................................................................v

QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii

CONTRIBUTORS.......................................................................................................................................ix

PEER REVIEW ...........................................................................................................................................xi

CONTENTS...............................................................................................................................................xiii

LIST OF FIGURES ..................................................................................................................................xvii

LIST OF TABLES.....................................................................................................................................xix

1. PUBLIC HEALTH STATEMENT..........................................................................................................1

1.1 WHAT ARE PERFLUOROALKYLS?......................................................................................2

1.2 WHAT HAPPENS TO PERFLUOROALKYLS WHEN THEY ENTER THE 

ENVIRONMENT? .....................................................................................................................2

1.3 HOW MIGHT I BE EXPOSED TO PERFLUOROALKYLS?..................................................3

1.4 HOW CAN PERFLUOROALKYLS ENTER AND LEAVE MY BODY?...............................4

1.5 HOW CAN PERFLUOROALKYLS AFFECT MY HEALTH?................................................4

1.6 HOW CAN PERFLUOROALKYLS AFFECT CHILDREN?...................................................6

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO 

PERFLUOROALKYLS?............................................................................................................6

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED 

TO PERFLUOROALKYLS? .....................................................................................................7

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? ................................................................................................7

1.10 WHERE CAN I GET MORE INFORMATION?.......................................................................8

2. RELEVANCE TO PUBLIC HEALTH ...................................................................................................9

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO PERFLUOROALKYLS 

IN THE UNITED STATES........................................................................................................9

2.2 SUMMARY OF HEALTH EFFECTS .....................................................................................11

2.3 MINIMAL RISK LEVELS (MRLs).........................................................................................21

3. HEALTH EFFECTS..............................................................................................................................33

3.1 INTRODUCTION ....................................................................................................................33

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE..................................33

3.2.1 Inhalation Exposure ..............................................................................................................35

3.2.1.1 Death..............................................................................................................................35

3.2.1.2 Systemic Effects.............................................................................................................39

3.2.1.3 Immunological and Lymphoreticular Effects................................................................53

3.2.1.4 Neurological Effects ......................................................................................................53

3.2.1.5 Reproductive Effects......................................................................................................54

3.2.1.6 Developmental Effects...................................................................................................54

3.2.1.7 Cancer............................................................................................................................55

3.2.2 Oral Exposure........................................................................................................................55

3.2.2.1 Death..............................................................................................................................55

3.2.2.2 Systemic Effects.............................................................................................................57

3.2.2.3 Immunological and Lymphoreticular Effects..............................................................131

3.2.2.4 Neurological Effects ....................................................................................................133

3.2.2.5 Reproductive Effects....................................................................................................135
 

PERFLUOROALKYLS xiv 

3.2.2.6 Developmental Effects.................................................................................................138
 

3.2.2.7 Cancer..........................................................................................................................148
 

3.2.3 Dermal Exposure.................................................................................................................149
 

3.2.3.1 Death............................................................................................................................149
 

3.2.3.2 Systemic Effects...........................................................................................................150
 

3.2.3.3 Immunological and Lymphoreticular Effects..............................................................156
 

3.2.3.4 Neurological Effects ....................................................................................................157
 

3.2.3.5 Reproductive Effects....................................................................................................157
 

3.2.3.6 Developmental Effects.................................................................................................157
 

3.2.3.7 Cancer..........................................................................................................................157
 

3.2.4 Other Routes of Exposure ...................................................................................................157
 

3.3 GENOTOXICITY...................................................................................................................160
 

3.4 TOXICOKINETICS ...............................................................................................................161
 

3.4.1 Absorption...........................................................................................................................161
 

3.4.1.1 Inhalation Exposure .....................................................................................................161
 

3.4.1.2 Oral Exposure ..............................................................................................................162
 

3.4.1.3 Dermal Exposure .........................................................................................................163
 

3.4.2 Distribution .........................................................................................................................164
 

3.4.2.1 Inhalation Exposure .....................................................................................................164
 

3.4.2.2 Oral Exposure ..............................................................................................................164
 

3.4.2.3 Dermal Exposure .........................................................................................................172
 

3.4.3 Metabolism..........................................................................................................................172
 

3.4.3.1 Inhalation Exposure .....................................................................................................172
 

3.4.3.2 Oral Exposure ..............................................................................................................172
 

3.4.3.3 Dermal Exposure .........................................................................................................172
 

3.4.4 Elimination and Excretion...................................................................................................172
 

3.4.4.1 Inhalation Exposure .....................................................................................................172
 

3.4.4.2 Oral Exposure ..............................................................................................................173
 

3.4.4.3 Dermal Exposure .........................................................................................................181
 

3.4.4.4 Other Routes of Exposure............................................................................................181
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models...........181
 

3.4.5.1 Tan et al. (2008) Models..............................................................................................184
 

3.5 MECHANISMS OF ACTION................................................................................................191
 

3.5.1 Pharmacokinetic Mechanisms.............................................................................................191
 

3.5.2 Mechanisms of Toxicity......................................................................................................193
 

3.5.3 Animal-to-Human Extrapolations.......................................................................................197
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS .......................198
 

3.7 CHILDREN’S SUSCEPTIBILITY ........................................................................................202
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT..................................................................205
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Perfluoroalkyls..............................206
 

3.8.2 Biomarkers Used to Characterize Effects Caused by Perfluoroalkyls................................207
 

3.9 INTERACTIONS WITH OTHER CHEMICALS..................................................................207
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ............................................207
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................208
 

3.11.1 Reducing Peak Absorption Following Exposure.............................................................208
 

3.11.2 Reducing Body Burden ...................................................................................................208
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects..........................................209
 

3.12 ADEQUACY OF THE DATABASE.....................................................................................209
 

3.12.1 Existing Information on Health Effects of Perfluoroalkyls.............................................209
 

3.12.2 Identification of Data Needs............................................................................................213
 

3.12.3 Ongoing Studies ..............................................................................................................224
 

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4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................227
 

4.1 CHEMICAL IDENTITY........................................................................................................227
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES .....................................................................227
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................239
 

5.1 PRODUCTION.......................................................................................................................239
 

5.2 IMPORT/EXPORT.................................................................................................................245
 

5.3 USE.........................................................................................................................................245
 

5.4 DISPOSAL .............................................................................................................................245
 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................247
 

6.1 OVERVIEW ...........................................................................................................................247
 

6.2 RELEASES TO THE ENVIRONMENT ...............................................................................250
 

6.2.1 Air .......................................................................................................................................251
 

6.2.2 Water...................................................................................................................................255
 

6.2.3 Soil ......................................................................................................................................256
 

6.3 ENVIRONMENTAL FATE...................................................................................................257
 

6.3.1 Transport and Partitioning...................................................................................................257
 

6.3.2 Transformation and Degradation ........................................................................................262
 

6.3.2.1 Air................................................................................................................................262
 

6.3.2.2 Water............................................................................................................................263
 

6.3.2.3 Sediment and Soil ........................................................................................................264
 

6.3.2.4 Other Media .................................................................................................................264
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ..............................264
 

6.4.1 Air .......................................................................................................................................264
 

6.4.2 Water...................................................................................................................................271
 

6.4.3 Sediment and Soil ...............................................................................................................281
 

6.4.4 Other Environmental Media................................................................................................284
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE.....................................286
 

6.6 EXPOSURES OF CHILDREN ..............................................................................................293
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES...........................................302
 

6.8 ADEQUACY OF THE DATABASE.....................................................................................303
 

6.8.1 Identification of Data Needs ...............................................................................................303
 

6.8.2 Ongoing Studies..................................................................................................................307
 

7. ANALYTICAL METHODS................................................................................................................309
 

7.1 BIOLOGICAL MATERIALS ................................................................................................309
 

7.2 ENVIRONMENTAL SAMPLES...........................................................................................310
 

7.3 ADEQUACY OF THE DATABASE.....................................................................................311
 

7.3.1 Identification of Data Needs ...............................................................................................313
 

7.3.2 Ongoing Studies..................................................................................................................314
 

8. REGULATIONS, ADVISORIES, AND GUIDELINES.....................................................................315
 

9. REFERENCES ....................................................................................................................................319
 

10. GLOSSARY ......................................................................................................................................359
 

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PERFLUOROALKYLS xvi 

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1
 

B. USER’S GUIDE.................................................................................................................................. B-1
 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1
 

D. INDEX ................................................................................................................................................D-1
 

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LIST OF FIGURES 

3-1. Levels of Significant Exposure to Perfluorooctanoate - Inhalation .................................................... 43 

3-2. Levels of Significant Exposure to Other Perfluoroalkyls - Inhalation ............................................... 45 

3-3. Levels of Significant Exposure to Perfluorooctanoate - Oral ............................................................. 78 

3-4. Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral ................................................. 94 

3-5. Levels of Significant Exposure to Other Perfluoroalkyls - Oral....................................................... 110 

3-6. Tissue Concentrations of 14C in Male and Female Rats Following a Single Oral Gavage 

Dose of [14C]PFOA at 1, 5, or 25 mg/kg ......................................................................................... 166

3-7. 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 ........................... 168

3-8. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for 

a Hypothetical Chemical Substance................................................................................................. 183

3-9. Structure of PBPK Model of PFOA and PFOS in the Rat and Monkey........................................... 185

3-10. Existing Information on Health Effects of PFOA .......................................................................... 210

3-11. Existing Information on Health Effects of PFOS ........................................................................... 211
PERFLUOROALKYLS xviii 

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PERFLUOROALKYLS xix 

LIST OF TABLES
 

3-1. Levels of Significant Exposure to Perfluorooctanoate - Inhalation.................................................... 40
 

3-2. Levels of Significant Exposure to Other Perfluoroalkyls - Inhalation ............................................... 44
 

3-3. Levels of Significant Exposure to Perfluorooctanoate - Oral............................................................. 58
 

3-4. Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral ................................................. 82
 

3-5. Levels of Significant Exposure to Other Perfluoroalkyls - Oral......................................................... 98
 

3-6. Levels of Significant Exposure to Perfluorooctanoate - Dermal...................................................... 151
 

3-7. Tissue Distribution and Excretion of 14C-Radioactivity From Both Sexes of Rats, Mice, 

Hamsters, and Rabbits Dosed with 14C-Labeled APFO...................................................................169
 

3-8. Summary Elimination Half-times for Perfluoroalkyls Estimated in Humans and Experimental
 

Animals............................................................................................................................................175
 

3-9. Parameters Used in the Male and Female Rat Model for Exposure to PFOS and PFOA ................186
 

3-10. Parameters Used in the Male and Female Monkey Model for Exposure to PFOS.........................187
 

4-1. Chemical Identity of Perfluoroalkyls................................................................................................228
 

4-2. Physical and Chemical Properties of Perfluoroalkyls.......................................................................233
 

5-1. Content (ppm) and Percent Reduction of PFOA, PFOA Homologues, or PFOA Precursors
 

in Products from the 2006 U.S. Operations of Fluoropolymer/Fluorotelomer Companies.............240
 

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

Inventory Update Rule.....................................................................................................................243
 

6-1. Reported Emissions of PFOA, PFOA Homologues, or PFOA Precursors in Products from
 

the 2006 U.S. Operations of Fluoropolymer/Fluorotelomer Companies.........................................252
 

6-2. Global Historical PFCA Production and Emissions Summary ........................................................254
 

6-3. Biological Monitoring of PFOA and PFOS in the Arctic.................................................................259
 

6-4. Concentrations of Perfluoroalkyl in Outdoor Air.............................................................................265
 

6-5. Concentrations of Perfluoroalkyl in Indoor Air................................................................................271
 

6-6. Concentrations of PFOA and PFOS in Surface Water (ng/L)..........................................................274
 

6-7. Concentrations of Other Perfluoroalkyls in Surface Water..............................................................276
 

6-8. Concentrations of Perfluoroalkyls in Surface Water and Groundwater at Fluorochemical
 

Industrial Facilities ..........................................................................................................................278
 

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6-9. Concentrations of PFOA and PFOS in Ocean Water .......................................................................280
 

6-10. Concentrations of Perfluoroalkyls in Soil and Sediment at Fluorochemical Industrial
 

Facilities.........................................................................................................................................282
 

6-11. Concentrations of PFOA and PFOS in Human Serum Collected in the United States ..................287
 

6-12. Concentrations of Other Perfluoroalkyls in Human Serum Collected in the United States...........289
 

6-13. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for Perfluoroalkyl Workers........294
 

6-14. Percent Detection and Levels of PFOA and PFOS in Children’s Serum, Umbilical Cord 

Blood, and Breast Milk..................................................................................................................296
 

6-15. Percent Detection and Levels of Other Perfluoroalkyls in Children’s Serum, Umbilical
 

Cord Blood, and Breast Milk .........................................................................................................299
 

6-16. Ongoing Studies on Perfluoroalkyls...............................................................................................308
 

7-1. Analytical Methods for Determining Perfluoroalkyls in Biological Samples..................................311
 

8-1. Regulations, Advisories, And Guidelines Applicable to Perfluoroalkyls.........................................316
 

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PERFLUOROALKYLS 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about perfluoroalkyls and the effects of exposure to them. 

Thirteen perfluoroalkyls are discussed in this profile. The names of these perfluoroalkyls are as follows: 

perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorododecanoic acid 

(PFDoA), perfluorodecanoic acid (PFDeA), perfluorobutyric acid (PFBA), perfluoroheptanoic acid 

(PFHpA), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUA), perfluorohexane sulfonic 

acid (PFHxS), perfluorobutane sulfonic acid (PFBuS), perfluorooctanesulfonamide (PFOSA), 

2-(N-methyl-perfluorooctane sulfonamide) acetic acid (Me-PFOSA-AcOH), and 2-(N-ethylperfluorooctane sulfonamido) acetic acid (Et-PFOSA-AcOH). Seven of these substances are 

perfluoroalkyl carboxylic acids (PFOA, PFDoA, PFDeA, PFBA, PFHpA, PFNA, and PFUA), three are 

perfluoroalkyl sulphonic acids (PFOS, PFHxS, and PFBuS), and three are perfluoroalkyl sulfonamides 

(PFOSA, Me-PFOSA-AcOH, and Et-PFOSA-AcOH). 

When a substance is released either from a large area, such as an industrial plant, or from a container, 

such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You 

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, 

eating, or drinking the substance, or by skin contact. Most human exposures to perfluoroalkyls are to 

PFOA and PFOS. Most human exposures to perfluoroalkyls are expected to be through contaminated 

food and drinking water. 

If you are exposed to perfluoroalkyls, many factors will determine whether you will be harmed. These 

factors include the dose (how much), the duration (how long), and pathway (how you contact the 

perfluoroalkyls). Other important factors are any other chemicals you are exposed to, your age, sex, diet, 

family traits, lifestyle, and state of health. 

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PERFLUOROALKYLS 2 

1. PUBLIC HEALTH STATEMENT 

1.1 WHAT ARE PERFLUOROALKYLS? 

Description Perfluoroalkyls are stable chemicals made of a carbon chain surrounded by 

fluorine atoms and an acid or amide group located at the end of the carbon 

chain. 

These substances are unique because they repel oil, grease, and water. 

Uses 

• Manufacturing 

• Consumer 

products 

Perfluoroalkyls have been made in large amounts in the United States. 

PFOA and PFOS are the two perfluoroalkyl compounds made in the largest 

amounts. 

PFOS and PFOA each had a reported produced volume between 

15,000 and 500,000 pounds during 2002. 

Over the past several years, facilities either have stopped production or have 

begun changing manufacturing practices to reduce releases and the 

amounts of these chemicals in their products. 

Perfluoroalkyls have been used in surface protection products such as 

carpet and clothing treatments and coatings for paper and cardboard 

packaging. 

Perfluoroalkyls have been used in fire-fighting foams. 

Some facilities have announced that they will begin replacing many of the 

perfluoroalkyls that have been used in the above applications with other 

substances. 

1.2 WHAT HAPPENS TO PERFLUOROALKYLS WHEN THEY ENTER THE 

ENVIRONMENT? 

Releases to the 

environment 

Perfluoroalkyls are not found naturally in the environment, but are there 

because of the action of humans. Perfluoroalkyls can be released into the 

environment when facilities and people use products that contain them. 

Perfluoroalkyls have been released into the environment near facilities that 

made or used these substances, and in many cases, contaminated the 

groundwater. These types of releases appear to be decreasing based on 

reports provided by these facilities. 

Perfluoroalkyls may be formed in the environment when other related 

chemicals degrade. 

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PERFLUOROALKYLS 3 

1. PUBLIC HEALTH STATEMENT 

Break down 

• Air Perfluoroalkyls break down very slowly in air, but are expected to fall out of 

the air to the ground within days to weeks. 

• Water Perfluoroalkyls are very stable in water and are not known to break down in 

water. These chemicals may be carried over great distances by ocean 

currents. 

• Soil Perfluoroalkyls are not known to break down in soil. These substances may 

be carried through soil by groundwater. 

1.3 HOW MIGHT I BE EXPOSED TO PERFLUOROALKYLS? 

Perfluoroalkyls have been widely found in human blood, indicating that human exposure to these 

substances is common. 

Air Perfluoroalkyls have been found in both air and dust. 

You may be exposed to perfluoroalkyls by breathing air containing these 

substances. Ingestion of dust may also be a source of exposure. 

Water and soil Perfluoroalkyls have been found in surface water, groundwater, soil, and 

sediment, especially near facilities that have made or used these 

substances. They have also been found at remote locations such as the 

Arctic and the open ocean. 

Drinking water contaminated with PFOA released from a nearby 

fluorochemical facility was found to be a major source of exposure to that 

substance. 

Perfluoroalkyls have also been detected in bird eggs, fish, polar bears, etc. 

Food and human In addition to drinking water, food is expected to be an important source of 

breast milk exposure to perfluoroalkyls based on the amounts found in food samples. 

Human breast milk may contribute to the exposure of infants to 

perfluoroalkyls since these substances have been detected in human breast 

milk. 

Consumer Perfluoroalkyls have been widely used in many consumer products (see 

products Section 1.1). 

The presence of these substances in carpet treatments could be an 

important source of exposure to perfluoroalkyls, especially for children. 

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PERFLUOROALKYLS 4 

1. PUBLIC HEALTH STATEMENT 

Workplace People who work where perfluoroalkyls are made or used may be exposed 

to these substances. 

Levels of PFOS and PFOA measured in the blood of some people who have 

worked at these locations were higher than levels in people from the same 

communities who did not work at these locations. 

Workplace exposure may also occur for people with jobs that require 

frequent handling or use of perfluoroalkyls. 

1.4 HOW CAN PERFLUOROALKYLS ENTER AND LEAVE MY BODY?
 

Enter your body 

• Inhalation When you breathe air containing perfluoroalkyl compounds, some will enter 

your body through your lungs, but there is limited information on how fast, 

how much, or what specific perfluoroalkyl may preferentially enter the body. 

• Ingestion Perfluoroalkyl compounds in food or water may enter your body through the 

digestive tract. 

• Dermal contact If your skin comes into contact with dusts or aerosols of perfluoroalkyl, or 

with liquids containing perfluoroalkyls, it is possible that a small amount may 

enter the body through your skin. 

Leave your body Once in your body, perfluoroalkyls tend to remain unchanged for long 

periods of time. The most commonly used perfluoroalkyls (PFOA and 

PFOS) stay in the body for many years. It takes approximately 4 years for 

the level in the body to go down by half, even if no more is taken in. It 

appears that, in general, the shorter the carbon-chain length, the faster the 

perfluoroalkyl leaves the body. PFOA, PFOS, PFHxS, and PFNA are 

measureable in the serum of most U.S. citizens. 

1.5 HOW CAN PERFLUOROALKYLS AFFECT MY HEALTH?
 

Workers Inhalation/dermal—Long-term exposure to perfluoroalkyls at work has not 

been associated with significant adverse health effects, but two studies in 

workers found changes in sex hormones and cholesterol associated with 

the levels of PFOA in blood. 

General 

population 

Little research has been done on the general population to answer the 

question of whether perfluoroalkyls may be associated with adverse health 

effects. 

Ingestion—A single study of people whose drinking water contained 

perfluoroalkyls did not find problems in a number of clinical measures 

tested. The study did not, however, examine developmental risks for 

children or cancer. The 326-person study was too small to address these 

issues. 

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PERFLUOROALKYLS 5 

1. PUBLIC HEALTH STATEMENT 

Laboratory 

animals 

One way to learn about the effects of perfluoroalkyls is to see how they 

affect test animals. 

Inhalation—Short-term exposure of rats to very high levels of PFOA has 

caused irritation of the eyes and the nose. 

Short-term exposure of rats to lower levels of PFOA caused damage to the 

liver and weight loss. 

Ingestion—Feeding food or capsules containing perfluoroalkyls to animals 

mainly produced alterations in the liver of the animals. It also reduced their 

growth, possibly because these chemicals affect the way the body 

processes food the animals eat. 

Dermal—Short-term application of large amounts of PFOA to the skin of 

animals has caused skin irritation and changes in the liver. These liver 

effects indicate that PFOA can be absorbed into the body through the skin 

and affect other parts of the body. 

Cancer The information available does not prove that perfluoroalkyls cause cancer 

in humans, but the evidence is not conclusive. Some increases in prostate 

and bladder cancer have been seen, but the cause is not certain. 

Feeding PFOA and PFOS to rats caused them to develop tumors. Some 

scientists believe that based on the way this happens in rats, and the 

differences between rats and humans, humans would not be expected to 

get cancer. Others believe that it is possible for perfluoroalkyls to cause 

cancer in humans, and the studies in rats should not be dismissed. More 

research is needed to clarify this issue. 

The International Agency for Research on Cancer and the Department of 

Health and Human Services have not yet evaluated the carcinogenicity of 

perfluoroalkyls. The EPA has begun an evaluation. 

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PERFLUOROALKYLS 6 

1. PUBLIC HEALTH STATEMENT 

1.6 HOW CAN PERFLUOROALKYLS AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

Effects in children A study of people, including children, in an area of southeastern Ohio, 

whose drinking water was contaminated with PFOA found no short-term 

adverse health effects associated with PFOA. However, the study found the 

highest levels of PFOA in the blood of young children and older adults. The 

study did not look for cancer or delays in childhood development. The 

levels of PFOA in the blood from these people were much higher than those 

found in the general population of the United States. 

Three studies of pregnant women found that as the levels of PFOA in the 

mother’s blood increased there was a tendency for the newborn babies to 

have slightly lower birth weight. However, another study that looked at 

exposure to PFOA in drinking water did not find such an association. Based 

on both animal and human study reports, developmental effects are the 

greatest concern in regards to potential adverse effects from PFOA 

exposure. 

Laboratory One way to learn about the effects of perfluoroalkyls is to see how they 

animals affect test animals. 

Birth defects were seen in mice born to females exposed to relatively high 

amounts of PFOS during pregnancy. 

Exposure to PFOA and PFOS has resulted in increased early death and 

delayed development of mice and rat pups, but this did not occur in animals 

exposed to PFBA or PFHxS. 

Human breast 

milk 

Perfluoroalkyl compounds have been found in the breast milk of women, but 

there are no studies that looked at whether the health of the babies was 

affected by drinking this milk. Levels of perfluoroalkyls in breast milk are 

much lower than in the mother’s blood indicating that these substances are 

not concentrated during the production of mother’s milk. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO PERFLUOROALKYLS?
 

Consumer 

products 

Families may choose to use products that do not contain perfluoroalkyls. 

Drinking water Families whose tap or well water that contains perfluoroalkyls may choose 

to drink or cook with bottled water or to install activated carbon water filters. 

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PERFLUOROALKYLS	 7 

1. PUBLIC HEALTH STATEMENT 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 

PERFLUOROALKYLS? 

Detecting Perfluoroalkyl compounds can be measured in blood, but this is not a 

exposure routine test that can be performed in a doctor’s office. You should, however, 

see a physician if you believe that you have been exposed to high levels of 

perfluoroalkyls. 

Perfluoroalkyls have been measured in blood samples from a representative 

sample of the U.S. general population; mean serum PFOA and PFOS 

concentrations were reported to be 3.9 and 20.7 μg/L, respectively. 

Elevated serum PFOA levels were reported in Little Hocking, Ohio, 

community residents who had environmental exposure to PFOA from a 

nearby industrial facility through contaminated drinking water; the median 

serum PFOA concentration was 354 μg/L. 

Higher serum perfluoroalkyl concentrations have been reported in 

fluorochemical product workers. Mean serum PFOA and PFOS levels for 

263 employees in a Decatur, Alabama, 3M facility were 1,780 and 

1,320 μg/L, respectively. 

Measuring The presence of perfluoroalkyl compounds in your blood may indicate that 

exposure you have been exposed to and absorbed perfluoroalkyls into your body. 

The presence of perfluoroalkyl compounds in your blood does not 

necessarily mean that you will suffer adverse health effects. Additional 

studies are needed to help determine the health effects associated with 

exposure to perfluoroalkyls. There are a number of studies underway that 

should help to answer questions about the health effects of perfluoroalkyls. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. Regulations 

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the 

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic 

substances. Recommendations provide valuable guidelines to protect public health, but cannot be 

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National 

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 

Regulations and recommendations can be expressed as doses, intakes, or amounts in air, water, and food 

that are expected to be safe, usually based on levels that affect animals. Sometimes these not-to-exceed 

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PERFLUOROALKYLS 8 

1. PUBLIC HEALTH STATEMENT 

levels differ among federal organizations because they used different exposure times (an 8-hour workday 

or a 24-hour day), different animal studies, or other factors. 

Recommendations and regulations are also updated periodically as more information becomes available. 

For the most current information, check with the federal agency or organization that provides it. The U.S. 

EPA (2009) provisional drinking water advisory for PFOA and PFOS are 0.4 and 0.2 ppb, respectively. 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics 

specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous 

substances. 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may 

request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical 

assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing 

to: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine
 

1600 Clifton Road NE
 

Mailstop F-62
 

Atlanta, GA 30333
 

Fax: 1-770-488-4178
 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS)
 

5285 Port Royal Road
 

Springfield, VA 22161
 

Phone: 1-800-553-6847 or 1-703-605-6000
 

Web site: http://www.ntis.gov/
 

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PERFLUOROALKYLS 9 

2. RELEVANCE TO PUBLIC HEALTH
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO PERFLUOROALKYLS IN 

THE UNITED STATES 

Perfluoroalkyls constitute a class of compounds that have been used extensively in surface coating and 

protectant formulations due to their unique surfactant properties. Major applications have included 

protectants for paper and cardboard packaging products, carpets, leather products, and textiles that 

enhance water, grease, and soil repellency. Perfluoroalkyls have also been used as processing aids in the 

manufacture of fluoropolymers such as nonstick coatings on cookware. 

Perfluoroalkyls are human-made substances that do not occur naturally in the environment. Large 

amounts of perfluoroalkyls, especially PFOS and PFOA, have been released to the 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. 

Information regarding current releases of shorter-chain perfluoroalkyls that are not included under phaseout regulations, such as perfluorobutyric acid (PFBA) and perfluorobutane sulfonic acid (PFBuS), have 

not been located. Production of PFBA in the United States appears to have ceased, although some is 

reportedly imported for commercial use. In the environment, perfluoroalkyls can also be formed from 

environmental degradation of precursor compounds and releases during the use of consumer products 

containing perfluoroalkyls. 

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

biodegradation, photoxidation, direct photolysis, and hydrolysis. The perfluoroalkyl carboxylic acids and 

sulfonic acids have very low volatility due to their ionic nature. As a group, perfluoroalkyls are persistent 

in soil and water. Perfluoroalkyls are mobile in soil and leach into groundwater. Perfluoroalkyls have 

been detected in environmental media and biota in many parts of the world, including oceans and the 

Arctic, indicating that long-range transport of these substances is taking place. 

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) have been measured in outdoor 

urban air samples at concentrations up to 46 and 919 pg/m3

, respectively. Concentrations of other 

perfluoroalkyls measured in outdoor air are generally <1 pg/m3

. Reported concentrations of 

perfluoroalkyls measured in four indoor air samples were <5 pg/m3

. PFOA, PFOS, and perfluorohexane 

sulfonic acid (PFHxS) have been detected in indoor dust samples at concentrations of <2.29–3,700, 

<4.56–5,065, and <4.56–4,305 ng/g, respectively. Reported concentrations of perfluoroalkyls measured 

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PERFLUOROALKYLS 10 

2. RELEVANCE TO PUBLIC HEALTH 

in surface water samples are generally <50 ng/L. Background concentrations of perfluoroalkyls in 

groundwater, drinking water, soil, and sediment have not been established. Perfluoroalkyls have been 

detected in different types of foods at reported concentrations ranging from 0.05 to 10,000 ng/g fresh 

weight. Perfluoroalkyls have also been detected in consumer products such as treated carpeting, treated 

apparel, and paper food packaging. Elevated concentrations of perfluoroalkyls have been measured in air, 

water, soil, and sediment near fluorochemical industrial facilities. 

The highest concentrations of perfluoroalkyls in animals are measured in apex predators, such as polar 

bears, which indicates that these substances biomagnify in food webs. The bioaccumulation potential of 

perfluoroalkyls is reported to increase with increasing chain length. In living organisms, perfluoroalkyls 

bind to protein albumin in blood, liver, and eggs and do not accumulate in fat tissue. However, some 

perfluoroalkyls such as PFOA, PFOS, and PFHxS have a very low rate of elimination from serum. 

Elimination half-lives of several years have been estimated. A much faster elimination half-life of about 

75 days was estimated for PFBA. 

Mean PFOA, PFOS, and PFHxS serum concentrations reported in various studies of the general 

population in the United States are 2.1–9.6, 14.7–55.8, and 1.5–3.9 ng/mL (ppb), respectively. Mean 

concentrations of perfluoroheptanoic acid (PFHpA), perfluorononanoic acid (PFNA), perfluorodecanoic 

acid (PFDeA), perfluoroundecanoic acid (PFUA), perfluorododecanoic acid (PFDoA), PFBuS, PFBA, 

perfluorooctane sulfonamide (PFOSA), 2 (N-methyl-perfluorooctane sulfonamide) acetic acid (MePFOSA-AcOH), and 2-(N ethyl-perfluorooctane sulfonamide) acetic acid (Et-PFOSA-AcOH) are 

generally <1 ng/mL in these studies. 

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 were food and 

water ingestion, dust ingestion, and hand-to-mouth transfer from mill-treated carpets. 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. 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 larger. Based on these 

exposure pathways, adult uptake doses estimated for high-exposure scenarios were approximately 30 and 

47 ng/kg/day for PFOS and PFOA, respectively. 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. These 

estimated intakes are significantly lower than the doses administered to laboratory animals. 

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PERFLUOROALKYLS 11 

2. RELEVANCE TO PUBLIC HEALTH 

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. Maximum concentrations of other perfluoroalkyl 

compounds were <0.18 ng/mL. In most umbilical cord samples, the concentrations of PFOS and PFOA 

were 4.9–11.0 and 1.6–3.7, respectively. Other perfluoroalkyls have been detected less frequently, with 

maximum concentrations <2.6 ng/mL. 

Estimated onsite intake of PFOA by individuals working at a fluorochemical facility ranged from 

3.2x10-6 to 2.4 ng/kg/day. This amount reflects combined inhalation, oral, and dermal exposure. 

Individuals who perform jobs that require frequent contact with perfluoroalkyl containing products, such 

as individuals who install and treat carpets, are expected to have occupational exposure to these 

substances. Individuals who work at or are located near fluorochemical facilities 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. Drinking water was expected to be the major exposure pathway for individuals living 

near one fluorochemical facility. The estimated offsite intake of PFOA by local residents living near a 

fluorochemical production facility to PFOA from contaminated environmental media ranged from 

0.011 to 260 ng/kg/day. 

2.2 SUMMARY OF HEALTH EFFECTS 

Information regarding the effects of exposure to perfluoroalkyl compounds in humans is derived mainly 

from health evaluations of subjects exposed in occupational settings, epidemiologic studies of relatively 

highly exposed communities, and from much more limited data regarding exposures of the general 

population. Measurements of the concentrations of several perfluoroalkyl compounds in human blood 

can be compared with levels measured in studies with experimental animals. For the most part, no 

significant adverse effects have been identified in these populations, but some potentially adverse changes 

in clinical tests associated with serum levels of perfluoroalkyl compounds have been reported. Most of 

the health evaluations have focused on detecting possible hepatic and endocrine effects and alterations in 

lipid metabolism based on the extensive data available from studies in animals. 

A study of 371 subjects from the general population who experienced significant environmental exposure 

to PFOA via the water supply found no significant deviations in hematology parameters, liver and kidney 

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PERFLUOROALKYLS 12 

2. RELEVANCE TO PUBLIC HEALTH 

function tests, or thyroid stimulating hormone (TSH) levels among the study subjects. Approximately 

50% of the subjects were female and there were 43 children under the age of 18. The results were the 

same when the analysis included all of the individuals as a group and when separate analyses were done 

for adults and children. The population median serum PFOA concentration was 354 ng/mL (ppb) and the 

interquartile range was 184–571 ng/mL. The study did not evaluate reproductive or cancer outcomes in 

the group, but neonates born to women from this cohort were evaluated for birth weight and gestational 

age. 

In a study of 115 workers with a mean serum concentration of PFOA of 3,300 ng/mL (range <1,000– 

26,000 ng/mL [ppb]), tests of liver function and serum lipid profiles were within normal limits. Similar 

finding have been reported in other cross-sectional studies that measured serum levels of PFOS and in a 

longitudinal analysis that also included women. In the latter study, mean serum concentrations of PFOS 

and PFOA were 1,320 and 1,780 ng/mL, respectively. In a larger study of 506 workers from three 

chemical plants, serum PFOA was negatively associated with serum high-density lipoproteins (HDL) for 

the three facilities combined, possibly as a consequence of uncontrolled residual confounding due to 

different demographic profiles at these sites, but not in the individual plants. Serum PFOA levels in this 

study ranged from 7 to 92,030 ng/mL (arithmetic mean 2,210 ng/mL). In a longitudinal study of 

454 workers with multiple PFOA measurements, in which an average of 10.8 years elapsed between the 

first (mean 1,040 ng/mL) and last (mean 1,160 ng/mL) serum PFOA measurement, serum PFOA was 

positively associated with total serum cholesterol, with an increase of 1.06 mg/dL of cholesterol per 

1,000 ng/mL increase in PFOA. In addition, PFOA was negatively associated with total bilirubin and 

positively with serum aspartate aminotransferase (AST) activity, but not with alanine aminotransferase 

(ALT) or γ-glutamyltransferase (GGT) activity. A cross-sectional study of 1,025 active workers at the 

same plant found a modest but statistically significant association between PFOA and total cholesterol, 

low-density lipoproteins (LDL), very low density lipoprotein (VLDL), and GGT activity. A positive 

relationship between PFOA and total cholesterol was also observed in Italian workers. These and other 

occupational studies also evaluated other health outcomes such as pulmonary function, 

electrocardiograms, hematological parameters, renal function, and thyroid hormone levels and found no 

consistent deviations from normal ranges. Two studies independently reported a significant increase in 

serum estradiol associated with increasing PFOA levels in male workers. A study found that workers 

with the highest PFOA levels had mean estradiol levels 10% higher than the other groups. The 

investigators could not rule out that high body mass index (BMI, kg body weight/height in meters2

) 

values in these workers were confounding the results. Another study found a significant association 

between increased serum estradiol and testosterone with increasing PFOA in a study of 1,025 men 

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PERFLUOROALKYLS 13 

2. RELEVANCE TO PUBLIC HEALTH 

occupationally exposed to PFOA. A retrospective cohort mortality analysis of 6,027 workers exposed to 

PFOA at a polymer production facility found a statistically significant increase in mortality due to 

diabetes mellitus among male workers. However, the lack of agreement with other studies of PFOA 

workers and the lack of any animal toxicology findings to support this association suggest that the 

findings may have been due to chance, but follow-up of these results is warranted. That study also found 

no significant association between exposure to PFOA and mortality due to ischemic heart disease. A 

health evaluation of workers exposed to PFNA found no significant associations between exposure to 

PFNA and liver parameters. Exposure was categorized based on work histories; serum PFNA levels were 

not available. 

Limited information regarding developmental effects of perfluoroalkyl compounds in humans is 

available. A study of self-reported health outcomes in relation to occupational exposures to PFOS at a 

PFOS-based fluorochemical manufacturing facility that included 263 women reported that birth weight of 

singleton births, adjusted for maternal age at birth, gravidity, and smoking status, did not vary between 

exposure groups; however, the most important determinant of birth weight that was not accounted for in 

the study was length of gestation. PFOS serum concentrations ranged from 110 to 1,970 ng/mL. In a 

recent study of the general population in the United States, both PFOA and PFOS in cord blood 

(respective medians were 1.6 and 5 ng/mL) were negatively associated with birth weight, ponderal index 

(ratio of birth weight in grams to length in centimeters cubed, multiplied by 100), and head 

circumference. No significant associations were observed between either PFOS or PFOA concentrations 

and newborn length or gestational age. A study of 1,400 Danish women reported that birth weight was 

inversely associated with plasma levels of PFOA collected during the first trimester (mean 35.3 ng/mL). 

Neither PFOA nor PFOS was statistically associated with length of gestation. Neither head 

circumference nor ponderal index was evaluated. In a follow-up evaluation of the same cohort, maternal 

PFOA levels were associated with smaller abdominal circumference and birth length. A study of 

428 Japanese women and their infants reported a negative correlation between birth weight and maternal 

PFOS, but not PFOA, serum levels; neither PFOS or PFOA was associated with birth size (length and 

head and chest circumference). The blood levels of PFOA and PFOS in the studies of the general 

population are significantly lower than those reported in the worker and animal studies (see below). 

Further research will be needed to determine the significance of the findings with respect to human 

health. However, in yet a more recent follow-up of the Danish cohort, the investigators found little 

evidence that the prenatal levels of PFOA and PFOS reported influence motor or mental developmental 

milestones in early childhood. Other much smaller studies of Japanese and Chinese women did not find 

correlations between PFOS in maternal blood and TSH and T4 in cord blood or between PFOA and PFOS 

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PERFLUOROALKYLS 14 

2. RELEVANCE TO PUBLIC HEALTH 

in breast milk and infant weight, but their small sample size limits the conclusions that can drawn from 

them. A study of women exposed to high levels of PFOA in the drinking water (6.78 μg/L) found that 

neonatal birth weight and gestational age were not significantly different than those from neonates born to 

women who consumed water with significantly lower levels of PFOA. These results indicate that the 

negative associations between birth weight and PFOA in some of the studies mentioned above may be 

non-causal. 

There is no conclusive evidence that exposure to perfluoroalkyl compounds produces cancer in humans 

based on a limited number of studies. In a retrospective cohort mortality study of 2,788 male and 

749 workers at a plant that produced PFOA, male workers categorized as being exposed for at least 

10 years had a 3.3-fold increase (95% confidence interval [CI] 1.02–10.6) in prostate cancer mortality 

compared to those with no employment in PFOA production. Due to the small number of cases involved, 

the investigators cautioned that the results should not be over-interpreted. In another retrospective 

mortality study of 2,083 workers exposed to PFOS, the most significant finding was an increased risk of 

death from bladder cancer for the entire cohort; three cases were observed and 0.62 were expected 

(standardized mortality ratio [SMR] 4.81, 95% CI 0.99–14.05) and all of them worked in a high-exposure 

group. All three cases occurred among workers from the high-exposure group (0.19 expected) (SMR 

16.12, 95% CI 3.32–47.41) and all of them had worked in high-exposure jobs for at least 5 years. The 

geometric mean serum PFOS levels were 900 ng/mL for workers in the high-exposure group and 

100 ng/mL for those assigned to a low-exposure group. A reanalysis of this cohort identified a total of 

11 cases of bladder cancer, 6 from surveys and 5 from death certificates. The standardized incidence 

ratios (SIRs) were 1.28 (95% CI 0.64–2.29) for the entire cohort and 1.74 (95% CI 0.64–3.79) for those 

ever working in a high-exposure job. However, compared with those in the lowest cumulative exposure 

category, the high-exposure workers had a 1.5–2.0-fold increased risk. While the results did indicate an 

excess risk of bladder cancer among the highest exposed workers, study limitations such as uncertainty in 

case ascertainment and the size of the cohort did not allow for a conclusive exposure response analysis. 

A retrospective cohort mortality study of workers (n=6,027) at a polymer production plant did not find 

significantly increased mortality rates due to cancer among the workers. Specific sites evaluated included 

the liver and biliary passages, pancreas, kidney and urinary tract, bronchus, trachea or lungs, and prostate. 

However, comparisons using the population of DuPont workers residing in West Virginia (DuPont 

Region 1) and seven neighboring states reference rates (but not the general population of the United 

States or the West Virginia general population reference rates) showed a statistically non-significant 

increase in SMR for kidney cancer mortality in males (12 cases in males and no cases in females) 

(SMR=195 [95% CI 95–323; p>0.05]). 

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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. 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 significantly 

higher than those reported in perfluoroalkyl workers or in the general population. It is important to note 

that there are profound differences in the toxicokinetics of perfluoroalkyls between humans and 

experimental animals. The half-life of PFOA and PFOS is approximately 4 years 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. 

Regardless of the route of exposure, the liver is a main target for perfluoroalkyl compounds in animals 

(the effects of perfluoroalkyl compounds in laboratory animals do not appear to be route-specific). Liver 

toxicity in rodents results from the ability of these compounds (with some structural restrictions) to 

activate the peroxisome proliferator-activated receptor-α (PPARα), a member of the nuclear receptor 

superfamily. Studies of PPARα in various species have shown that rats and mice are the most sensitive 

species to PPARα agonists, whereas guinea pigs, nonhuman primates, and humans are less responsive, 

and hamsters fall in between. Activation of the 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, an increased CYP450-mediated ω-hydroxylation of lauric acid, and 

alterations in lipid metabolism. PPARα regulates lipid homeostasis through the modulation of expression 

of genes involved in fatty acid uptake, activation, and oxidation. 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. 

The liver was the most sensitive target for perfluoroalkyl compounds in the very limited inhalation 

database, which consists of a few studies with PFOA dusts and one study with PFNA dusts. In male rats, 

absolute and relative liver weight increased and microscopic examination showed hepatocellular 

hypertrophy and necrosis following intermittent head-only exposure to 7.6 mg/m3 PFOA dusts for 

2 weeks. In the study with PFNA, nose-only exposure of male rats to 67 mg/m3 (the lowest concentration 

tested) PFNA dusts for 4 hours induced a significant increase in liver weight; no histological evaluation 

was performed. Liver histopathology was also reported in rats following intermittent dermal application 

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of 20 mg/kg PFOA to male rats for 2 weeks. In mice, application of 6.2 mg/kg, but not 2.5 mg/kg, PFOA 

to the skin once a day for 4 days also induced hepatomegaly. 

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 include 

hepatomegaly, due to hypertrophy rather than hyperplasia and proliferation of smooth endoplasmic 

reticulum and predominantly of peroxisomes vs. mitochondria, confirmed by increased activity of 

biochemical markers and light and electron microscopy. Reductions in serum cholesterol and 

triacylglycerols are commonly seen most likely due to reduced synthesis and esterification of cholesterol 

together with enhanced oxidation of fatty acids in the liver. It is important to note also that there appears 

to be different sensitivities for different end points. For example, in male rats dosed with PFOA for 

14 days, absolute liver weight and β-oxidation activity were significantly increased at 2 mg/kg/day, 

whereas hepatic microsomal concentration of total cytochrome P-450 was significantly increased at 

20 mg/kg/day. In general, longer-term studies with PFOA have shown that the hepatic effects are 

reversible once dosing ceases, and recovery tends to parallel the decline in blood levels of PFOA. Studies 

in mice have provided similar results. However, studies in PPARα-null mice suggested that 

hepatomegaly induced by PFOA is not a PPARα-dependent process in mice since PFOA induced 

hepatomegaly to the same extent in wild mice and PPARα-null mice, but failed to increase acyl-CoA 

oxidase activity in PPARα-null mice. PFOA increased absolute liver weight in monkeys treated with 

≥3 mg/kg/day for 26 weeks, an effect that was associated with significant mitochondrial proliferation, but 

not peroxisome proliferation. 

PFOS increased liver weight and induced hepatocyte hypertrophy and vacuolation in a 14-week study in 

rats and in a 2-year study in rats. However, the hepatic effects did not seem to be related to peroxisome 

proliferation, since no significant increases in hepatic peroxisomal enzyme activity were reported 

compared with acute-duration studies. Some have postulated the existence of an exposure threshold, 

which was not achieved rapidly enough to produce an increase in palmitoyl-CoA oxidase, and suggested 

that a mechanism may exist in vivo for an adaptive down-regulation of the hepatic peroxisome 

proliferation response to PFOS treatment. PFOS induced an increase in absolute liver weight, decreased 

serum cholesterol, and hepatocellular hypertrophy and lipid vacuolation in monkeys in a 26-week study. 

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. 

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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. Significant peroxisome activity seems to require a carbon length >7, but increases over 

control levels have been reported with a four-carbon chain length. Studies have shown that the 

differential activity is not directly related to the carbon length per se, but to differential accumulation in 

the liver. Hydrophobicity, which increases as carbon length increases, seems to favor biliary 

enterohepatic recirculation resulting in a more protracted toxicity. While perfluoroalkyl compounds share 

many effects on lipid metabolism, treatment of rats with perfluorodecanoic acid (PFDeA) does not result 

in the characteristic hypolipidemia associated with peroxisome proliferation, but instead results in the 

accumulation of lipids in the liver, apparently by diverting fatty acids from oxidation toward esterification 

in the liver. In addition, in an acute dietary study comparing the hepatic effects of PFOA and PFDeA, 

PFDeA was considerably more toxic to hepatocytes than PFOA, as reflected by the production of lipid 

droplets containing amorphous material, a sign of acute metabolic disorders. 

PFOA and PFOS have induced developmental effects in rodents, but no consistent teratogenicity has been 

reported. 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, and delays in 

mammary gland differentiation, eye opening, vaginal opening, and first estrus. These effects occurred 

generally in the absence of 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. 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 study that exposed mice at various times 

during pregnancy showed that developmental effects were progressively more severe as the exposure 

began earlier, but it could not be determined whether this was due to a higher cumulative dose or to a 

developmentally sensitive period. Cross-fostering experiments showed that gestational exposure was 

sufficient to induce postnatal deficits in body weight and developmental delays. 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. No fetal toxicity or teratogenicity was reported in offspring 

from rabbits exposed to up to 50 mg/kg/day PFOA on gds 6–18, suggesting that rabbits are less 

susceptible than mice to the developmental effects of PFOA, although comparing administered doses is 

probably not very informative. 

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Studies conducted with wild 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. There was no effect of strain or PPARα expression on serum PFOA levels. The 

mechanism of reduced postnatal viability has not been elucidated. However, treatment of pregnant mice 

with PFOA induced a substantial delay in maternal mammary gland differentiation on PND 10 and 

20 and alterations in milk protein gene expression, which could explain, at least in part, the delayed 

growth development in the exposed offspring. Alterations in gene expression in both fetal liver and lung 

have been reported following exposure of mice to PFOA during pregnancy. 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, transcriptionalrelated changes were predominantly associated with fatty acid catabolism. 

PFOS significantly decreased birth weight and survival in neonatal rats exposed in utero and 

cross-fostering exposed pups with unexposed dams failed to improve survival rates. PFOS serum levels 

of pups at birth associated with significant decreased survival were approximately ≥70,000ng/mL. 

Dosing rats late during gestation (gds 17–20) causes significantly more lethality than dosing early (gds 2– 

5). Since pups had difficulty breathing within minutes of birth and their lungs resembled prenatal lungs, 

the possibility that early death was due to immature lungs was examined. However, experiments with 

agents known to enhance terminal lung maturation and accelerate surfactant production failed to reverse 

the delaying effects of PFOS, suggesting that neonatal mortality was not due to lung immaturity. Mean 

serum PFOS levels in rat pups and dams on PND 21 associated with neonatal mortality were 

approximately 89,000 ng/mL in a study in which dams were exposed to PFOS before and during 

gestation. Delays in eye opening have been reported in developmental studies in rats and mice. 

Neurological evaluations of pups from mice exposed to 6 mg/kg/day PFOS on gds 12–18 showed no 

significant or consistent alterations compared with controls, but administration of a single gavage dose of 

PFOS to 10-day-old male mice induced alterations in spontaneous activity when tested at the age of 2 or 

4 months. Serum PFOS levels were not available in these studies. Evaluation of immunological 

parameters in 8-week-old pups from mice exposed to PFOS during gestation showed reduced natural 

killer cell activity, suppressed IgM response to immunization, and alterations in splenic and thymic 

lymphocyte subpopulations. 

In contrast to results obtained with PFOA and PFOS, PFBA exhibited much reduced developmental 

toxicity in mice, whereas PFHxS was not a developmental toxicant in rats exposed to up to 10 mg/kg/day 

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PFHxS for a period that included premating, gestation, and lactation. Administration of PFBA (35– 

350 mg/kg/day) to pregnant mice on gds 1–17 had no significant effect on a comprehensive number of 

developmental parameters evaluated including neonate weight gain and viability. On gd 18, maternal 

serum PFBA was 2,000–4,000 ng/mL with no apparent dose-response relationship. In pups, serum PFBA 

was 400–600 ng/mL on PND 1 and 110–150 ng/mL on PND 10. The milder response compared to PFOA 

was attributed by the investigators to faster elimination of PFBA as well as to lower biochemical potency. 

Serum levels of PFHxS were not available in a study. 

PFOA induced immunological alterations in adult mice characterized by thymus and spleen atrophy and 

alterations in thymocytes and splenocytes. Since no alterations in thymocytes and splenocytes could be 

seen in studies in vitro, the investigators suggested that the thymic and splenic atrophy induced by PFOA 

may involve an indirect pathway, possibly via alteration of fatty acid transport and/or metabolism. 

Experiments in PPARα-null mice indicated that the effects of PFOA on the spleen were PPARαdependent, whereas those in the thymus were only partially dependent. The effects reported occurred 

with PFOA doses in the range of 10–30 mg/kg/day. The results from a more recent study suggest that 

suppression of parameters of humoral immunity can occur at doses as low as 3.75 mg/kg/day 

administered for 15 days; this dosing level resulted in a mean PFOA serum level of 75,000 ng/mL. 

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. 

Neither PFOA nor PFOS affected fertility parameters in 2-generation reproductive studies in rats, and 

neither did PFHxS in a reproductive study in rats. However, PFOA delayed mammary gland 

differentiation in mice dosed during gestation. In general, acute- and intermediate-duration studies did 

not find morphological alterations in the sex organs from rats or monkeys. However, PFOA significantly 

increased the incidences of Leydig cell hyperplasia, vascular mineralization in the testes, and tubular 

hyperplasia in the ovaries in rats in 2-year dietary studies. PFOA increased serum estradiol levels in male 

rats by increasing the activity of aromatase (the enzyme that coverts testosterone into estradiol) in the 

liver. The increase in serum estradiol was thought to be responsible for a decrease in the weight of the 

accessory sex organ unit, a decrease in serum testosterone, and Leydig cell hyperplasia and adenoma. 

Serum estradiol was also found elevated in male rats treated acutely with perfluorododecanoic acid 

(PFDoA). 

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Oral exposure to PFOA and PFOS has induced alterations in serum thyroid hormone levels in animals. 

Most of these studies reported reductions in total serum thyroxine (TT4) without significant alterations in 

serum TSH levels and no alterations in thyroid gland histology. Thus, there has been no suggestion of a 

hypothyroid response due to exposure to perfluoroalkyl. Results from a recent study suggest that the 

reduction in TT4 can be explained by a perfluoroalkyl-induced displacement of thyroxine (T4) from 

serum binding proteins. This, in turn, could lead to an increased tissue uptake and turnover of T4, which 

would result in a lowering of serum TT4 while rebalancing the equilibrium between bound and free T4. 

Reduced serum TT4 was also reported in rats treated with PFDeA by intraperitoneal injection. 

Hypertrophy/hyperplasia of the thyroid follicular cells was reported in intermediate-duration studies in 

rats dosed with PFBA and PFHxS. According to the investigators, this is probably a compensatory 

response of the thyroid to hepatocellular hypertrophy, leading in turn to an increase plasma turnover of 

thyroxine and associated stimulation of TSH. 

PFOA, as many other PPARα agonists, induced hepatocellular adenomas, Leydig cell adenomas, and 

pancreatic acinar cell adenomas in rats. The issue, which has been extensively reviewed, is whether the 

mode(s) of action is relevant for risk assessment in humans. A review of the literature concluded that 

although humans possess PPARα at sufficient levels to mediate the human hypolipidemic response to 

therapeutic fibrate drugs, there are enough qualitatively and quantitative differences between the response 

of the human liver to PPARα agonists and that of rats due to differences in gene promoters, receptors 

activities, and receptor levels that make the mode of action for liver tumors unlikely to be operative in 

humans. An expert panel convened by EPA’s Science Advisory Board to review this and other issues 

related to the toxicity of PFOA agreed that, collectively, 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. A 

majority of the panel members also expressed the view that it is possible that PPARα agonism may not be 

the only mode of action for PFOA, that not all steps in the pathway of PPARα-mediated liver tumors have 

been demonstrated, that other hepatoproliferative lesions require clarification, and that extrapolation of 

the PPRAα-mediated mode of action across humans of all ages is not supported. As mentioned above, 

increased serum estradiol due to induction of hepatic aromatase activity by PFOA was proposed as a 

mode of action for PFOA-induced Leydig cell tumors in rats. A second mode of action involves 

inhibition of testosterone biosynthesis with consequence increases in circulating luteinizing hormone 

(LH), which promotes Leydig cell proliferation. A review of the data concluded that there is inadequate 

evidence to link PPARα and induction of Leydig cell tumors, such that PFOA may pose a carcinogenic 

risk for humans, even though an intermediate-duration study in Cynomolgus monkeys did not find 

treatment-related alterations in serum estradiol or testosterone, suggesting that PFOA is unlikely to induce 

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Leydig cell tumors in humans because humans are less sensitive than rats to LH stimulation. The 

mechanism of PFOA-induced pancreatic acinar cell tumors has not been elucidated. The available 

evidence suggests that the 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. However, a number of factors, including 

differences in the expression of PPARα and CCKA receptors, in exocrine secretion regulation, and in 

types of pancreatic cancers between humans and rodents, suggest that PFOA probably does not represent 

a significant cancer hazard for humans. EPA’s expert panel agreed that the available evidence is 

inadequate to support a PPARα-mediated mode of action for the induction of Leydig cell tumors and 

pancreatic acinar cell tumors, and that at the time the review was conducted, there were insufficient data 

to characterize the mode of action of PFOA-induced testicular and pancreatic tumors. Under EPA’s 

Cancer Guidelines, in the absence of sufficient data to establish a mode of action, the animal tumor 

responses are presumed to be relevant to humans. The EPA has encouraged a cancer risk assessment for 

each of the PFOA-induced tumors where data permit. 

PFOS did not induce malignant tumors in a bioassay conducted in rats, but it increased the incidence of 

liver hepatocellular adenoma and thyroid follicular cell adenoma. A mode of action for PFOS-induced 

tumors has not been proposed. 

2.3 MINIMAL RISK LEVELS (MRLs) 

No MRLs were derived for perfluoroalkyl compounds for the reasons detailed below. 

Human Data. No studies are available regarding controlled exposures of volunteers to perfluoroalkyl 

compounds. As summarized in Section 2.2, health evaluations have been conducted of workers exposed 

to perfluoroalkyls (Olsen and Zobel 2007; Olsen et al. 1998, 1999, 2003a) and of members of the general 

population known to have been environmentally exposed to these compounds primarily via drinking 

water (Emmett et al. 2006b). A small number of studies that examined developmental outcomes in 

relation to perfluoroalkyl body burdens in the general population are also available (Apelberg et al. 

2007b; Fei et al. 2007, 2008a, 2008b; Washino et al. 2009). Direct exposure data are not available for the 

occupational exposures. In the cohort studied by Emmett et al. (2006b), the average concentration of 

PFOA in water that the subjects may have consumed over a period of 3 years before the health assessment 

was conducted was 3.5 μg/L. Median serum PFOA levels in residents were 105 times the level in their 

residential drinking water. Blood levels of perfluoroalkyl compounds have been measured both in 

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workers and in members of the general population. As indicated in the preceding section, no significant 

health effects have been associated with specific serum levels of perfluoroalkyl compounds, although 

minor alterations in serum lipids and in serum estradiol levels in male workers have been reported (Costa 

2004; Olsen et al. 1998; Sakr et al. 2007b). 

It could be proposed that measured serum levels of perfluoroalkyls in the populations for whom health 

data are available be considered body burdens corresponding to no-observed-adverse-effect levels 

(NOAELs) or perhaps lowest-observed-adverse-effect levels (LOAELs) if the alterations reported in 

workers are considered adverse. The health evaluations of workers have mainly focused on liver effects 

and serum lipids profiles. However, there are concerns that other end points, such as immunological and 

neurological effects, have not been adequately evaluated in exposed human populations. Therefore, there 

is significant uncertainty in relying on these existing workers studies as the basis for a risk assessment. 

The same concern applies to the population studied by Emmett et al. (2006b) since only a limited number 

of end points were examined in that study. Defining NOAELs or LOAELs associated with specific 

perfluoroalkyl body burdens from the developmental studies is also problematic. In one study, levels of 

PFOA and PFOS in cord blood were negatively associated with birth weight (Apelberg et al. 2007b). In 

another study, PFOA in maternal blood collected in the first trimester was negatively associated with birth 

weight (Fei et al. 2007). In yet an additional study, PFOS, but not PFOA, in maternal blood collected in 

the second trimester of pregnancy was negatively associated with birth weight (Washino et al. 2009). 

None of these studies was sufficient to establish a cause-and-effect relationship between PFOA/PFOS 

serum levels and birth weight. In addition, there is some question as to whether the magnitude of the 

decrease in birth weight is actually considered to be an adverse effect. Moreover, a follow-up of the Fei 

et al. (2007) study found “no convincing associations between developmental milestones in early 

childhood and levels of PFOA or PFOS measured in maternal plasma early in pregnancy” (Fei et al. 

2008b). Thus, it is difficult to define points of departure for MRL derivation with any degree of 

confidence based on the human data available at this time. Furthermore, even if a wide range of end 

points had been examined in the studies available and points of departure could have been defined, there 

is currently not enough information regarding the pharmacokinetics of this group of compounds in 

humans to facilitate estimations of exposure levels resulting in measurable body burdens of 

perfluoroalkyls. 

A model has been created to estimate the total daily consumer exposure of PFOA and PFOS in North 

America and Europe occurring through various pathways (Trudel et al. 2008). Similar studies have been 

conducted by others (Fromme et al. 2008). Since blood levels of PFOA and PFOS (and other 

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perfluoroalkyl) in the U.S. population have been measured (e.g., Calafat et al. 2007b), efforts to examine 

combined exposure and body burden information may be useful. 

Animal Data. Inspection of the animal database would suggest that there are studies, particularly by 

the oral route, of PFOS and PFOA in animals that established dose-response relationships that could be 

used for MRL derivation. However, at this time, derivation of MRLs for PFOA or PFOS based on animal 

studies would be highly uncertain, 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, non-human primates, and in 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), animal species (i.e., 

slower in humans compared to non-human primates and rodents), and show pronounced gender 

differences within certain species (i.e., faster elimination in female rats). As a result, extrapolation of 

external dose-response relationships from animals to humans would be highly uncertain. Although 

progress has been made in modeling toxicokinetics of PFOA and PFOS in rats and nonhuman primates 

(i.e., Cynomolgus monkeys), no models for humans have been developed to simulate the substantial 

differences in toxicokinetics of these compounds between humans and non-human primates, or humans 

and rats (Andersen et al. 2006; Tan et al. 2008). Important characteristics of the toxicokinetics of 

perfluoroalkyls that would contribute to uncertainty in extrapolation of dose-response relationships across 

species include those discussed below. 

Inter-species Variation in Elimination Rate. The elimination rate for PFOA in female rats (half-life 

[t1/2]≈4 hours at low doses) is approximately 40 times faster than in male rats (t1/2≈160 hours), 120 times 

faster than in Cynomolgus monkeys (t1/2≈20 days), and approximately 6,000 times faster than in humans 

(t1/2≈1,000 days). Elimination of PFOS in male rats (t1/2≈180 hours) is approximately 20 times faster than 

in Cynomolgus monkeys (t1/2≈150 days), and approximately 240 times faster than in humans 

(t1/2≈1,800 days) (Hundley et al. 2006). There are two important implications of these large differences in 

elimination rates. First, 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. For example, steady-state serum 

concentrations achieved in humans may be approximately 6,000 times greater than in female rats, at the 

same external dosages. Second, exposure durations required to achieve steady state would be expected to 

be much longer in humans than in monkeys or rats. Assuming an elimination t1/2 of 1,000 days for PFOA 

in humans, a constant rate of intake for 12 years would be required to achieve 95% of steady state. 

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Steady state (i.e., 95%) would be achieved in approximately 90 days in monkeys, 30 days in male rats 

(t1/2≈160 hours), and 1 day in female rats (t1/2≈4 hours). As a result of these large differences in kinetics, 

the extrapolation of internal doses (i.e., serum concentrations of PFOA) achieved during intermediateduration exposures in rats or monkeys could only be appropriate for human populations where the 

exposure was of sufficient duration to reach steady-state serum concentrations. Given uncertainties in 

knowing the duration of exposure in any human population, there are significant limitations in directly 

extrapolating across species for the purpose of deriving MRLs. For PFBA, interspecies variability of 

elimination rate exceeded that expected for allometric scaling of body weight (Chang et al. 2008a). The 

monkey:rodent ratio for half-time was approximately 14 for female mice and 20–40 for female rats. 

Based on body weight alone, one would predict ratios of approximately 4.5 and 2.5, respectively. 

Dose- and Sex-dependences of Elimination. In addition to faster elimination rate of PFOA and PFOS in 

female rats compared to male rats, elimination rate and renal clearance of PFOA in female rats appear to 

be dependent on dose (Kemper 2003). Dose- and gender-dependence of elimination of PFOA have been 

attributed, in part, to capacity-limited tubular secretion of PFOA, which may be hormonally regulated by 

androgens and estrogens (Kudo et al. 2002; Vanden Heuvel et al. 1992a). Dose-dependence of 

elimination rates in humans have not been studied and all reported estimates of elimination rates of PFOA 

(or PFOS) in humans are based on subjects whose serum perfluoroalkyl concentrations were substantially 

lower (i.e., >100 times lower) than those observed in rat studies. Therefore, extrapolation of external 

dose dependences or serum concentration dependences of elimination rates of PFOA or PFOS observed in 

rats to humans would be highly uncertain (as would the assumption that clearance is completely 

independent of dose or serum concentration in humans). Dose- and gender-dependence of elimination 

also exist for PFBA (Chang et al. 2008a). In male mice, half-times decreased as the dose increased in the 

range 10–100 mg/kg/day. The male:female ratio for half-time elimination was approximately 2–5 for 

mice, 5–6 for rats, and 1 for monkeys. 

Maternal-fetal Transfer. Although some information is available on fetal transfer (i.e., tissue levels; 

(Hinderliter et al. 2005) of PFOA in rats, information on humans is limited to a few studies of 

maternal:infant serum ratios of PFOA and PFOS (Inoue et al. 2004b; Midasch et al. 2007). This 

information does not provide a basis for a reliable extrapolation of fetal doses that would occur in 

developmental studies conducted in rats (or mice) to equivalent fetal doses in humans. 

Structure Specificity of Elimination Rate. A trend for decreasing elimination rate with increasing 

perfluoroalkyl chain length is evident from comparison of the elimination rates in rats (Chang et al. 

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2. RELEVANCE TO PUBLIC HEALTH 

2008a; Ohmori et al. 2003). The elimination rate of PFDeA in male rats was estimated to be 

approximately 7 times slower than PFOA in male rats and approximately 150 times slower than PFOA in 

female rats. Structure-activity relationships for elimination rates in humans have not been explored, 

making extrapolations of the relationships observed in rats to humans highly uncertain. Therefore, 

extrapolation of dose-response relationships for PFOA or PFOS to other perfluoroalkyls would be highly 

uncertain. 

Physiologically-based Pharmacokinetic (PBPK) Models. Modeling of the toxicokinetics of PFOA and 

PFOS is currently in the research phase, and is currently focused on developing modeling approaches to 

simulate dose-dependencies and gender differences in kinetics that have been observed in monkeys and 

rats. Human PBPK models have not been reported. Features of the PBPK models of monkeys and rats 

that have been explored to simulate the complex kinetics observed in these animals include: (1) timedependent variation in protein binding and volume of distribution of PFOA in monkeys; and (2) capacity 

limited renal tubular reabsorption of PFOA with gender-specific and species-specific values for the Vmax 

and Km in rats. Although the models have been successfully calibrated to observations, they do not fully 

capture dose-dependencies that have been observed in either species. Furthermore, the time- and dosedependent features of the models have not been extrapolated to humans or other species (Andersen et al. 

2006; Tan et al. 2008). Therefore, in their current state of development, these models cannot be reliably 

extrapolated to simulating external-internal dose relationships in humans. 

Although MRL derivation is not recommended for perfluoroalkyls at this time based on the information 

summarized above, relevant information from animal studies that could have been considered for MRL 

derivation (i.e., studies with the LOAELs) for perfluoroalkyls with at least a minimal size database is 

summarized below. 

Perfluorobutyric Acid (PFBA). Relatively few toxicity studies have been conducted in animals exposed 

to PFBA by a relevant route of exposure. Ikeda et al. (1985) reported that administration of 

approximately 20 mg/kg/day PFBA in the diet to male Sprague-Dawley 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 C57BL/6 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 

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(Permadi et al. 1993). Since only one dietary level was used in these studies, dose-response relationships 

could not be constructed. A much more recent acute-duration (5-day) oral gavage study in rats is also 

available (3M 2007a). In that study, three dose levels were tested and the highest dose used 

(184 mg/kg/day), had no significant effect on a wide range of end points including body and organ 

weights, hematology and clinical chemistry, and histopathology, and thus, constituted the study NOAEL. 

Data regarding serum levels of PFBA were not available in any of these studies. 

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 (van Otterdiijk 2007a, 2007b). In the developmental 

study, PFBA administered to pregnant mice on gds 1–17 did not affect newborn weight gain or viability, 

as usually seen with PFOA and PFOS (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. Both the 28-day and 90-day studies 

identified LOAELs of 30 mg/kg/day for liver hypertrophy and alterations in the follicular epithelium of 

the thyroid in male rats (van Otterdiijk 2007a, 2007b). In addition, the 90-day study reported 

hematological alterations, also in male rats dosed with 30 mg/kg/day PFBA. The NOAEL for these 

effects was 6 mg/kg/day. 

PFHxS. A single study of PFHxS was available for review. The study evaluated the reproductive and 

developmental effects of this perfluoroalkyl compound in male and female rats exposed from premating 

until PND 21 (females) (Hoberman and York 2003). Doses of 0, 0.3, 1, 3, or 10 mg/kg/day were 

administered by oral gavage. PFHxS did not significantly affect any reproductive or developmental 

parameter nor did it induce maternal toxicity assessed by clinical chemistry and hematology tests and 

organ histopathology. PFHxS did induce hematological alterations in male rats at ≥0.3 mg/kg/day and 

liver and thyroid effects at ≥3 mg/kg/day. The thyroid effects were thought to be a compensatory 

response to liver hypertrophy. 

PFBuS. A 28-day gavage study in rats was available for review for this chemical (3M 2001). The study 

evaluated a wide variety of end points including hematology, clinical chemistry, and histopathology of all 

major organs and tissues. In addition, the rats were subjected to neurobehavioral testing during week 4 of 

the study; the tests assessed sensory reactivity to stimuli, grip strength, and motor activity. The 

administered doses were 0, 100, 300, or 900 mg/kg/day PFBuS. Following the treatment period, rats 

from the control and high-dose groups were allowed to recover for approximately 14 days. Significant 

increases in absolute and relative liver weight were reported in high-dose males and in absolute and 

relative kidney weight in high-dose females. There were no chemical-related histopathological alterations 

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in the organs and tissues examined. The only notable neurobehavioral effect was a significant decrease in 

tail flick latency to a thermal stimulus in males from all treated groups relative to controls. 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 alteration. 

PFDeA. Studies potentially useful for MRL derivation were limited to acute-duration oral studies. Most 

of these studies provided information on liver effects and were, in general, of limited scope. The lowest 

LOAEL was 2.4 mg/kg/day in rats for increased absolute liver weight and doses of 9.5 mg/kg/day 

increased the number of lipid droplets containing amorphous material, indicating marked toxicity to 

hepatocytes; the NOAEL was 1.2 mg/kg/day (Kawashima et al. 1995). The 9.5 mg/kg/day dose also 

induced significant weight loss associated with significantly reduced food consumption. Reduced weight 

gain was also reported in pregnant mice dosed with 6.4 mg/kg/day on gds 6–18 (Harris et al. 1989); the 

NOAEL was 3 mg/kg/day. The reduced maternal weight gain may have been responsible, in part, for a 

significant decrease in fetal weight. Other repeated dose studies tested much higher doses of PFDeA 

(Ikeda et al. 1985; Permadi et al. 1992, 1993). The limited database would have been insufficient for 

MRL derivation, especially due to the lack of information on postnatal viability in offspring from rodents, 

which was significantly reduced at relatively low maternal doses in studies with PFOA and PFOS. Data 

on serum levels of PFDeA were not available in any of the studies reviewed. 

PFOA—Inhalation Exposure. Only two relatively low-exposure inhalation studies were available for 

PFOA. In one study, male CD rats were exposed head-only 6 hours/day, 5 days/week for 2 weeks to 

ammonium perfluorooctanoate (APFO) dusts (Kennedy et al. 1986), whereas in the other study, a 

developmental study, pregnant Sprague-Dawley rats were exposed whole-body to APFO dusts 

6 hours/day on gds 6–15 (Staples et al. 1984). The lowest LOAEL was 7.6 mg/m3 for exposure 

concentration-related increases in absolute and relative liver weight and histological alterations in the 

liver; no significant effects were reported at 1 mg/m3 (Kennedy et al. 1986). Serum PFOA levels were 

not monitored in this study, but a toxicokinetics study in male rats exposed nose-only 6 hours/day, 

5 days/week for 3 weeks reported that PFOA serum levels in a group exposed to 10 mg/m3 had achieved a 

steady-state concentration of approximately 20,000 ng/mL by day 14 of the study (Hinderliter et al. 

2006a). Kennedy et al. (1986) also examined several organs and tissues microscopically and reported that 

no significant alterations were observed. In the developmental study, an exposure concentration of 

25 mg/m3 induced a 10% decrease in newborn body weight on PND 1; this exposure concentration 

decreased weight gain in the dams by 37% on gds 6–15 (Staples et al. 1984). Serum PFOA levels were 

not monitored in this study. 

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PFOA—Oral Exposure. Acute-duration oral studies were available in rats and mice and provided 

information on systemic, immuno/lymphoreticular, reproductive, and developmental effects. The 

systemic effects described were mostly alterations in liver and body weight as well as alterations in lipid 

metabolism. The lowest LOAEL identified for systemic effects was 1 mg/kg/day for a 35% increase in 

absolute liver weight in mice dosed with PFOA in the diet for 10 days (Yang et al. 2001). This was 

accompanied by a significant increase in peroxisome proliferation, as measured by increases in acyl-CoA 

oxidase activity. That dose was the lowest dose tested in the study. In subsequent studies, Yang et al. 

(2002b) reported that exposure of PPARα-null mice to PFOA induced hepatomegaly to the same extent 

than in wild mice, but failed to increase acyl-CoA oxidase activity, suggesting that, at least in mice, 

hepatomegaly induced by PFOA is not a PPARα-dependent process. Blood levels of PFOA were not 

monitored in these studies. A LOAEL of 2 mg/kg/day and NOAEL of 0.2 mg/kg/day were identified for 

a significant increase in absolute and relative liver weight and increases in hepatic β-oxidation activity 

and serum estradiol levels in rats in a 14-day dietary study (Liu et al. 1996). The increase in serum 

estradiol was attributed, at least in part, to induction of hepatic aromatase activity by PFOA. Serum 

PFOA values were not available in the Liu et al. (1996) study. A serious LOAEL of 5 mg/kg/day was 

identified for reduced body weight (35–43%) at weaning in pups from mice exposed to PFOA on gds 7– 

17 (Wolf et al. 2007). Exposure to PFOA did not significantly affect maternal weight or weight gain 

during pregnancy. The 5 mg/kg/day dose level was the lowest dose level tested. At weaning, the mean 

PFOA levels were 37,000 ng/mL in dams’ blood and 25,000 ng/mL in pups. An additional study from 

the same group of investigators showed that neonatal viability, including postnatal pup weight gain, was a 

PPARα-dependent effect (Abbott et al. 2007). A relative low LOAEL of 0.58 mg/kg/day for 

neurodevelopmental effects was also identified in a study in which mice were administered a single 

gavage dose of PFOA at the age of 10 days and were tested for spontaneous behavior at the age of 2 and 

4 months (Johansson et al. 2008); no NOAEL was defined in this study. Information regarding blood 

levels of PFOA in the treated mice was not available. 

Intermediate-duration oral studies of PFOA in animals also indicate that the liver is a main target. The 

lowest LOAEL for liver effects was 0.5 mg/kg/day for significant increases in absolute and relative liver 

weight in mice in two 21-day dietary studies (Kennedy 1987; Son et al. 2008). In the Kennedy (1987) 

study, the NOAEL was 0.2 mg/kg/day; no NOAEL was defined in the Son et al. (2008) study. Neither 

one of these studies had information on concentrations of PFOA in serum. In a 13-week dietary study in 

male rats, the lowest LOAEL was 0.64 mg/kg/day for minimal to moderate hepatocellular hypertrophy; 

the NOAEL was 0.06 mg/kg/day (Perkins et al. 2004). Hepatic palmitoyl CoA-oxidase, a marker of 

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peroxisome proliferation, was significantly increased only on week 4 of the study in the 0.64 mg/kg/day 

dose group. Mean serum PFOA levels in this group were 55,000, 46,000, and 41,000 ng/mL on weeks 4, 

7, and 13 of the study, respectively. A relatively low serious LOAEL of 0.6 mg/kg/day for reduced pup 

survival from birth to weaning was identified in a developmental study in mice; the NOAEL was 

0.3 mg/kg/day (Abbott et al. 2007). At weaning, the mean level of PFOA in serum from dams in the 

0.6 mg/kg/day was 5,200 ng/mL; the corresponding serum level of PFOA in the pups was 3,800 ng/mL. 

As indicated above, experiments conducted with PPARα-null mice showed that the expression of PPARα 

was required for induction of postnatal lethality by PFOA and that one functional copy of the gene was 

sufficient to significantly increase postnatal lethality (Abbott et al. 2007). In a 26-week study with 

Cynomolgus monkeys, the study LOAEL was 3 mg/kg/day (the lowest dose tested) for a 36% increase in 

absolute liver weight attributed to significant mitochondrial proliferation (Butenhoff et al. 2002). No 

significant hepatic peroxisomal proliferation was detected. Serum PFOA levels appeared to reach a 

steady state by week 6 of the study, and in the 3 mg/kg/day dose group, this concentration of PFOA was 

approximately 77,000 ng/mL. 

The chronic oral animal database for PFOA is limited to two studies, both dietary studies in rats (3M 

1983; Biegel et al. 2001). The study by Biegel et al. (2001) investigated the role of peroxisome 

proliferation on hepatic, Leydig cell, and pancreatic acinar cells tumorigenesis. The study used only one 

dose level in addition to controls. Treatment with PFOA induced a significant increase in relative liver 

weight at all time points except at 24 months relative to both controls. Hepatic beta-oxidation activity 

was significantly elevated at all times, but cell proliferation was not increased in the liver. Pancreatic 

acinar cell proliferation was increased at 15, 18, and 21 months. Serum estradiol was increased during the 

first year of the study, serum LH at 6 and 18 months, and serum follicle-stimulating hormone (FSH) at 

6 months; changes in serum testosterone did not show any consistent pattern. Treatment with PFOA 

increased the incidence of hepatocellular adenomas, but there were no hepatocellular carcinomas in the 

treated group. PFOA also increased the incidence of Leydig cell adenomas and the incidence of 

pancreatic acinar cell adenomas. Due to the limited scope of the study and the use of only one dose level, 

a preferential target cannot be defined. The study conducted by 3M (1983) was a standard 2-year 

bioassay in male and female rats dosed with 0, 1.5, or 15 mg/kg/day PFOA. Significant effects attributed 

to the low dose included significantly increased serum transaminases and inflammation of the salivary 

glands, both in males. Liver lesions occurred in the high-dose group, principally in males. PFOA at the 

high-dose level increased the incidence of fibroadenoma of the female mammary gland and of Leydig cell 

adenomas. 

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The serious LOAEL of 0.6 mg/kg/day for developmental effects in mice in the intermediate-duration 

study of Abbott et al. (2007) would have likely precluded using the 2-year 3M (1983) study as basis for 

derivation of a chronic-duration oral MRL for PFOA since the lowest dose in the 2-year study was 

1.5 mg/kg/day. 

PFOS. No inhalation data were available for PFOS. The oral database for PFOS is less extensive than 

that for PFOA. Acute-duration oral studies with PFOS have described effects on body weight, liver 

weight, serum and liver lipid profiles, and developmental effects in rodents. The lowest LOAEL was 

0.75 mg/kg for alterations in motor activity in 2- and 4-month-old male mice that were treated with a 

single gavage dose of PFOS at 10 days of age (Johansson et al. 2008). A sensitive effect was also a 

significant reduction in body weight gain in pregnant rabbits administered 1 mg/kg/day PFOS by gavage 

on gds 6–20; food consumption was not affected during this period (Case et al. 2001). A lower dose of 

0.1 mg/kg/day caused a 13% reduction in body weight gain, but the difference with controls did not 

achieve statistical significance. No significant developmental effects were reported in the fetuses of does 

dosed with 1 mg/kg/day PFOS and sacrificed on gd 29. The closest LOAEL was 2.5 mg/kg/day for a 

10% reduction in weight in rabbit fetuses in the Case et al. (2001) study. This may have been due, at least 

in part, to the significant reduction in maternal weight gain during treatment (47%) and posttreatment 

(33%) in does from this dose group. Serum levels of PFOS were not available in this study. 

The intermediate-duration oral database for PFOS consists essentially of a 4-week capsule study in 

monkeys (Thomford 2002a), a 26-week capsule study in monkeys (Seacat et al. 2002), a 4- and a 14-week 

dietary study in rats (Seacat et al. 2003), two 2-generation reproductive studies (gavage) in rats (Luebker 

et al. 2005a, 2005b), and developmental studies in rats and mice (Keil et al. 2008; Lau et al. 2003; 

Thibodeaux et al. 2003); the 2-generation studies also provided information on developmental effects. 

Several data sets could have been evaluated as possible basis for an intermediate-duration oral MRL for 

PFOS. Monkeys dosed with 0.75 mg/kg/day, the highest dose tested, showed increased liver weight, 

decreased serum cholesterol, and hepatocellular hypertrophy and lipid vacuolation; the NOAEL was 

0.15 mg/kg/day (Seacat et al. 2002). At termination of dosing, the mean PFOS serum level corresponding 

to the LOAEL was 171,000 ng/mL in females and 173,000 ng/mL in males. Similar results were reported 

in rats (Seacat et al. 2003). A LOAEL of 1.33 mg/kg/day, the highest dose tested, was established for 

increased liver weight, increased serum ALT, and hepatocyte hypertrophy and vacuolation; the NOAEL 

was 0.34 mg/kg/day. The mean serum PFOS level corresponding to the LOAEL in males was 

148,000 ng/mL. A developmental study in rats reported a steep dose-response for postnatal survival of 

the pups, a serious LOAEL (Lau et al. 2003). Maternal doses of 2 mg/kg/day on gds 2–21 decreased 

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survival at weaning by approximately 60% compared with approximately 80% in controls (estimated 

from a figure in the paper). Maternal doses of 1 mg/kg/day appeared not to affect survival significantly. 

The concentrations of PFOS in serum of pups on PND 5 corresponding to the 1 and 2 mg/kg/day maternal 

doses were approximately 30,000 and 60,000 ng/mL. Maternal serum levels of PFOS were not available. 

Significant decreased pup survival was also reported in a 2-generation study in rats (Luebker et al. 

2005b). The viability index on PND 5 in pups from dams dosed with 1.6 mg/kg/day PFOS (premating 

and during gestation) was 49.3% compared with 97.3, 97.6, 93.1, 88.8, and 81.7% in groups dosed with 0, 

0.4, 0.8, and 1.2 mg/kg/day PFOS, respectively. Serum PFOS levels on PND 5 were not available for the 

group with 49.3% viability index, but the mean concentrations in groups dosed with 1.2 and 2 mg/kg/day 

were 147,000 and 138,000 ng/mL, respectively. 

A 2-year bioassay for PFOS also identified the liver as a main target (Thomford 2002b). In that study, 

rats were fed a diet that provided approximately 0, 0.03, 0.1, 0.4, or 1.5 mg/kg/day PFOS. A significant 

increase in the incidence of cystic hepatocellular degeneration was reported in males dosed with 

≥0.1 mg/kg/day PFOS, and this dose level constitutes the study LOAEL; the NOAEL was 

0.03 mg/kg/day. At higher dose levels, hepatotoxicity was characterized by centrilobular hypertrophy, 

centrilobular eosinophilic hepatocytic granules, and centrilobular hepatocytic vacuolation. No significant 

alterations were reported in other tissues and organs or in clinical chemistry and hematology test results. 

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3.1 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 and older in the National Health and 

Nutrition Examination Survey (NHANES) 2003–2004 (Calafat et al. 2007b). These compounds include: 

perfluorobutane sulfonic acid (PFBuS), perfluorohexane sulfonic acid (PFHxS), perfluoroheptanoic acid 

(PFHpA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid 

(PFDeA), perfluoroundecanoic acid (PFUA), perfluorododecanoic acid (PFDoA), perfluorooctane 

sulfonic acid (PFOS), perfluorooctane sulfonamide (PFOSA), 2-(N-methyl-perfluorooctane sulfonamide) 

acetic acid (Me-PFOSA-AcOH), and 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid (Et-PFOSAAcOH). Also included in this document is perfluorobutyric acid (PFBA). 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

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 first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure 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, 

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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 end point 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 end points. 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 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. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure. 

Information on the health effects of humans exposed to perfluoroalkyl compounds is available mainly 

from workplace exposure to these compounds and from a relatively few studies conducted on the general 

population. Although workplace exposure to perfluoroalkyl compounds may occur by the inhalation, 

oral, and dermal routes, the discussion of health effects in workers has been placed in Section 3.2.1, 

Inhalation Exposure, as this route may be more important than oral and dermal in occupational settings. 

The discussion of health effects in the general population can be found in Section 3.2.2, Oral Exposure 

based on reports of predominant exposure via drinking water and food items. It should be made clear, 

however, that based principally on results from studies in animals that indicate that the health effects of 

these substances are independent of the route of exposure, conclusions can be drawn across exposure 

routes. 

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3.2.1 Inhalation Exposure 

Several studies have been conducted of workers exposed to perfluoroalkyl compounds. These types of 

studies have inherent limitations that can bias the results both towards finding nonexistent effects and 

failing to detect a true effect. Some of these limitations include: (1) low participations rates, (2) lack of 

inclusion of workers who were employed for a short period of time, workers who retired, or workers who 

died, (3) comparing rates of mortality or morbidity between workers, supposedly healthy enough to work, 

and members of the general population who may be too infirm to work (the “healthy worker effect”), 

(4) use of unreliable measures of health outcome such as self reports of health conditions, (5) potential 

exposure to more than one chemical, (6) studies where the comparison group (control) is also exposed 

and is therefore not a true control, (7) poor measures of exposure, and (8) small study size that have 

inadequate statistical power to detect relationships between exposures and adverse outcomes. Most of the 

occupational studies summarized below suffer from one or several of these limitations, yet ATSDR 

believes that, collectively, they provide useful information that future studies will help refute or confirm. 

3.2.1.1 Death 

There are no reports of human deaths from accidental or intentional acute exposure to high concentrations 

of PFOA or PFOS, but several studies have examined potential associations between mortality and longterm exposure in occupational settings. For example, Gilliland and Mandel (1993) conducted a 

retrospective cohort mortality evaluation of 2,788 male and 749 female workers employed between 1947 

and 1983 at a plant that produced PFOA. Workers employed ≥1 month in the Chemical Division of the 

plant were categorized as exposed and those who either never worked or worked for <1 month in the 

Chemical Division formed the unexposed group. The effects of latency, duration of employment, and 

work in the Chemical Division were examined using stratified SMR analyses. The SMR for all causes of 

death in women was 0.75 (95% CI 0.56–0.99). There was no association with duration of employment or 

latency for deaths from all causes, cancer, and cardiovascular diseases. The SMR for all causes of death 

in men was 0.77 (95% CI 0.69–0.86) using Minnesota rates for comparison; similar results were obtained 

when the expected number of male deaths was based on U.S. mortality rates. Among men, there was no 

association between any cause of death and duration of employment. The SMR for prostate cancer was 

2.03 (95% CI 0.55–4.59) in the Chemical Division group and 0.58 (95% CI 0.07–2.09) in the nonChemical Division men. Ten years of employment in the Chemical Division was associated with a 

3.3-fold increase (95% CI 1.02–10.6) in prostate cancer mortality compared to no employment in PFOA 

production. The investigators concluded that since the findings in the study are based on a small number 

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of cases and could have resulted from chance or unrecognized confounding from exposure to other 

factors, the association between PFOA and prostate cancer should not be overinterpreted. 

Alexander et al. (2003) conducted a retrospective mortality study of a cohort of employees at a 

perfluorooctanesulphonyl fluoride (PFOSF) based fluorochemical production facility in Decatur, 

Alabama, who had at least 1 year of cumulative employment at the facility. This criterion was met by 

2,083 workers. The geometric mean serum PFOS level for workers in the chemical plant in the facility 

was 900 ng/mL and that for those in the film plant in the facility was 100 ng/mL. Based on job history 

and serum PFOS levels, workers were assigned to one of three groups: high-exposure (n=982), lowexposure (n=289), or non-exposed (n=812). Male workers made 83% of the cohort and 84% of the highexposure group. The mortality experience of the cohort was compared to that of the state of Alabama. 

Age-, gender-, and calendar-period-adjusted SMRs were computed for all causes and specific causes of 

death using the Alabama reference data. The all-cause and cause-specific mortality rates for the entire 

cohort were lower than expected compared to the general population of Alabama, 145 observed and 

230 expected (SMR 0.63, 95% CI 0.53–0.74). A similar pattern was observed for all deaths from cancer 

(gastrointestinal tract, respiratory system, breast, malignant melanoma, and lymphatic and hematopoietic 

cancers) and non-malignant causes (cerebrovascular disease, all heart disease, respiratory disease, and 

cirrhosis of the liver). There were two deaths from liver cancer in the entire cohort and 1.24 were 

expected (SMR 1.61, 95% CI 0.20–5.82). The most significant finding was an increased risk of death 

from bladder cancer for the entire cohort, 3 observed and 0.62 expected (SMR 4.81, 95% CI 0.99–14.05). 

All three cases occurred among workers from the high-exposure group (0.19 expected) (SMR 16.12, 95% 

CI 3.32–47.41) and all of them had worked in high-exposure jobs for at least 5 years. A reanalysis of this 

cohort that included all current, retired, and former employees (total=1,895) was subsequently conducted 

by Alexander and Olsen (2007). Included in the study was also information from 188 deceased workers. 

The exposure assessment followed the method used in the previous study. Workers were assigned to a 

high-exposure (serum PFOS 1,300–1,970 ng/mL), low-exposure (390–890 ng/mL), and no direct 

exposure (110–290 ng/mL). Eleven cases of bladder cancer were identified from surveys (n=6) and death 

certificates (n=5). The SIRs were 1.28 (95% CI 0.64–2.29) for the entire cohort and 1.74 (95% CI 0.64– 

3.79) for those ever working in a high-exposure job. However, compared with those in the lowest 

cumulative exposure category, the high-exposure workers had a 1.5–2.0-fold increased risk. While the 

results did indicate an excess risk of bladder cancer among the highest exposed workers, study limitations 

such as uncertainty in case ascertainment and the size of the cohort, acknowledged by the investigators, 

need to be considered in the interpretation of the results. 

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PERFLUOROALKYLS 37 

3. HEALTH EFFECTS 

A study was conducted of DuPont employees at the Washington Works, West Virginia, polymermanufacturing facility (Leonard 2006). The study’s objective was to determine whether workplace 

exposure to PFOA was related to increased mortality risk for any cause. The study was part of an overall 

project that also comprised a cross-sectional surveillance that analyzed several types of clinical data and 

serum PFOA (as biomarker of exposure) for potential relationships (see Sakr et al. [2007b] under Hepatic 

Effects). Approximately one-half of the employees at the site had been assigned to ammonium 

perfluorooctanoate (APFO) areas at some time in their careers. The study also utilized job history 

information as well as serum PFOA data to classify each member of the historical cohort by level of 

potential occupational exposure for a more detailed analysis of ischemic heart disease. The cohort was 

defined as all individuals who had ever worked at the plant at any time between January 1, 1948 (plant 

start-up) and December 31, 2002. The cohort (n=6,027; 4,872 males) was ascertained primarily through 

the DuPont Epidemiology Registries and additional members were identified from plant-based work 

history records. Results from the cross-sectional study indicated that workers in all areas across the entire 

plant site showed some measurable level of serum PFOA ranging from 5 to 9,550 ng/mL. SMRs were 

calculated for all causes of death, death from all cancers combined, and disease-specific causes of death 

by comparing the cohort rates for three reference populations: the general population of the United States, 

the West Virginia general population, and the population of DuPont workers residing in West Virginia 

(DuPont Region 1) and seven neighboring states in the region. Cox proportional hazards models (CPHM) 

provided an internal comparison based on exposure categories of serum PFOA for mortality due to 

ischemic heart disease. These categories were based on the cumulative exposure calculated for each 

member of the cohort based on the categorization of jobs. In turn, cumulative exposure was used to 

derive the average exposure intensity for each cohort member based on the job history data. Mortality 

rate ratios (MMRs) for ischemic heart disease were estimated using lagged exposure (5, 10, 15, and 

20 years) to reduce any bias introduced by the healthy worker survivor effect. Three job-exposure 

categories were formed based on job-specific PFOA serum level information: category 1 consisted of all 

no APFO-use division jobs and APFO-use jobs within the same serum PFOA level range as those 

employees who had never had a job assignment in any APFO-use division (median serum PFOA 

<250 ng/mL; mean 210 ng/mL); category 2 consisted of APFO-use jobs with a median serum PFOA 

between 250 and 750 ng/mL (mean, 430 ng/mL); and category 3 consisted of all APFO-use jobs with 

median serum PFOA >750 ng/mL (mean, 1,690 ng/mL). Mean serum levels served as intensity factors 

for the three job-exposure categories. Validation of the exposure classification was done in a longitudinal 

study dataset (Sakr et al. 2007a). 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PERFLUOROALKYLS 38 

3. HEALTH EFFECTS 

Almost all SMRs comparing Washington Works mortality rates for defined causes to the United States 

and West Virginia population mortality rates were below 100, indicating no differences in the mortality 

rates between the compared populations. The SMRs for all causes based on comparison to DuPont 

Region 1 population was 94 (95% CI 87–100) for males and 147 (95% CI 101–207) for females. 

Comparisons using DuPont region 1 reference rates showed a statistically nonsignificant increase in SMR 

for kidney cancer mortality in males (12 cases in males and no cases in females) (SMR=195; [95% CI 

95–323; p>0.05) and a statistically significant increase in diabetes mortality (SMR=197; 95% CI 123– 

298; p<0.05) in males and females combined (20 cases in males and 2 cases in females). Leonard (2006) 

pointed out that while few kidney cancer cases had been employed in APFO areas, the data from the 

study were inadequate for examining in appropriate detail rare outcomes such kidney cancer. Regarding 

diabetes mortality, the investigator noted that the lack of agreement with other studies of PFOA workers 

and the lack of any animal toxicology findings to support the association suggested that the finding may 

have been due to chance; however, future surveillance should follow-up on these results. Proportional 

hazards analyses of ischemic heart disease mortality showed an increase in the model based on equal 

distribution of cases across cumulative exposure categories in one lagged analysis (the 10-year lag 

period). Other exposure lags showed no effect and results for a second set of models using a different set 

of exposure cutpoints were attenuated toward the null. Moreover, none of the hazard estimates 

themselves were statistically significant. A limitation of the study acknowledged by the investigator 

(Leonard 2006) included the potential loss to follow-up of decedents prior to 1979, a period where 

exposures may have been less well-controlled, causing potential bias towards the null due to the healthy 

worker survivor effect. Also, a major limitation was likely to be the lack of accounting for confounding 

by other occupational and non-occupational risk factors such as information about the major risk factors 

for cardiovascular disease (smoking, diet, and other life-style factors) and use of medications such as 

statins or anti-hypertensive medications. 

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). 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). The exposure concentrations ranged from 380 to 5,700 mg/m3

. Deaths 

occurred in all exposed groups and all deaths occurred within 48 hours of exposure. Rats dying during 

exposure had hyperinflated lungs. 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 days 12, 13, and 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 39 

3. HEALTH EFFECTS 

17 of gestation compared with no deaths in groups exposed to ≤10 mg/m3 (Staples et al. 1984). The cause 

of death was not reported. 

An LC50 of 820 mg/m3 was calculated for male CD rats exposed nose-only to APFO dusts for 4 hours 

(Kinney et al. 1989). No deaths occurred in rats (n=10) exposed to 67 mg/m3 and one rat exposed to 

590 mg/m3 died 12 days after exposure. None of six rats exposed to 620 mg/m3 died. Four out of six rats 

exposed to 910 mg/m3 died 9–11 days after exposure, whereas all rats exposed to 1,600 mg/m3 died 4– 

8 days after exposure. All rats exposed to 4,600 mg/m3 died during exposure. 

Unpublished information summarized by OECD (2002) indicates that an LC50 of 5,200 mg/m3 was 

calculated for PFOS in male and female Sprague-Dawley rats exposed to 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. 

3.2.1.2 Systemic Effects 

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each 

species and duration category for PFOA are recorded in Table 3-1 and plotted in Figure 3-1. Data for 

PFNA from Kinney et al. (1989) are recorded in Table 3-2 and plotted in Figure 3-2. 

Respiratory Effects. Unspecified pulmonary function tests conducted on workers potentially 

exposed to PFOA in a fluoropolymers production plant were within normal limits (Sakr et al. 2007b). 

This cross-sectional study assessed a total of 1,025 workers whose serum PFOA levels ranged from 5 to 

9,550 ng/mL. 

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). 

***DRAFT FOR PUBLIC COMMENT*** 
Ref

142

980

43

25

97

1860018600

143

380

380

380 810380

810380

Table 3-1 Levels of Significant Exposure to Perfluorooctanoate - Inhalation 

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(CD) 

4 hr 

System 

NOAEL 

(mg/m3) 

Less Serious 

(mg/m3) 

Serious 

(mg/m3) 

980 M (LC50) 

2 Rat 

(SpragueDawley) 

Gd 6-15 6 hr/d 25 F (3/12 deaths on Gd 12, 13, and 17) 

Systemic 

3 Rat 

(albino) 

1 hr (NS) Resp 18600 (red nasal discharge; dry rales) 

Ocular 18600 (red material around the 

eyes; lacrimation) 

4 Rat 

(CD) 

4 hr Resp 380 M (pulmonary edema) 

Gastro Hepatic Ocular 

380 M 380 M 

380 M (stomach irritation) 

810 M (liver enlargement) 

810 M (corneal opacity and 

corrosion) 

Bd Wt 380 M (weight loss for 1-2 days 

after exposure) 

Che

KeAmStaAmGrifAmKeAm

erence

***DRAFT FOR PUBLIC COMMENT***

mical Form 

nnedy et al. 1986 

monium perfluorooc

ples et al. 1984 

monium perfluorooc

fith and Long 1980 

monium perfluorooc

nnedy et al. 1986 

monium perfluorooc
17

84848484841

7.6

848484847.6

84

115

10

25

1

10 25

Table 3-1 Levels of Significant Exposure to Perfluorooctanoate - Inhalation (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

5 Rat 

(CD) 

2 wk 6 hr/d 5 d/wk 

6 Rat 

(SpragueDawley) 

Gd 6-15 6 hr/d 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt Hepatic Bd Wt 

LOAEL 

NOAEL 

(mg/m3) 

Less Serious 

(mg/m3) 

Serious 

(mg/m3) 

Reference Chemical Form 

84 M 

Kennedy et al. 1986 Ammonium perfluorooc

84 M 84 M 

84 M 84 M 

1 M 7.6 M (increased absolute and 

relative liver weight; hepatocellular hypertrophy and necrosis) 

84 M 

84 M 

84 M 

84 M 

7.6 M 84 M (7% body weight loss by 

exposure day 5) 

10 F 25 F (18% increase absolute 

liver weight) 

Staples et al. 1984 Ammonium perfluorooc

1 F 10 F (12% decrease weight 

gain on Gd 6-15) 

25 F (37% decrease weight 

gain on Gd 6-15) 
139

84

98

18600

140

84

141

84

42

10

25

Table 3-1 Levels of Significant Exposure to Perfluorooctanoate - Inhalation (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

Immuno/ Lymphoret 

7 Rat 2 wk 

6 hr/d (CD) 5 d/wk 

Neurological 

8 Rat 1 hr 

(albino) (NS) 

9 Rat 2 wk 

6 hr/d (CD) 5 d/wk 

Reproductive 

10 Rat 2 wk 

6 hr/d (CD) 5 d/wk 

Developmental 

11 Rat Gd 6-15 

6 hr/d (SpragueDawley) 

System 

NOAEL Less Serious Serious 

(mg/m3) (mg/m3) (mg/m3) 

84 M 

18600 (excessive salivation) 

84 M 84 M 

10 25 (10% decreased

neonatal body weight onpnd 1)

Reference Chemical Form 

Kennedy et al. 1986 

Ammonium perfluoroocGriffith and Long 1980 Ammonium perfluorooc

Kennedy et al. 1986 

Ammonium perfluorooc

Kennedy et al. 1986 

Ammonium perfluoroocStaples et al. 1984 Ammonium perfluorooc

a The number corresponds to entries in Figure 3-1. Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; Gastro = gastrointestinal; Gd = gestational day; Hemato = hematologic

Immuno/Lymphoret = immunological/lymphoreticular; LOAEL = lowest-observed-adverse-effect level; M = male; Musc/skel = musculoskeletal; NOAEL = no-observlevel; NS = not specified; pnd = post-natal day; Resp = respiratory; wk = week(s) 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Ocular Body Weight Immuno/Lymphor Neurological Reproductive Developmental 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Leve

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans for effects

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans other than

l 

q-Cow a-Sheep g-Guinea Pig Cancer 

Systemic 

mg/m3

100000 

3r 3r 8r 

10000 

1000 1r 4r 4r 

4r 4r 4r 4r 4r 

100 5r 5r 5r 5r 5r 5r 5r 5r 5r 5r 7r 9r 10r 

2r 6r 6r 11r 

10 6r 6r 11r 

5r 5r 

1 5r 6r 

0.1 

PERFLUOROALKYLS

3. HEALTH EFFECTS

43

***DRAFT FOR PUBLIC COMMENT***

Figure 3-1 Levels of Significant Exposure to Perfluorooctanoate - Inhalation 

Acute (≤14 days) 
191

820

192

67

59067

67

590

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

System 

NOAEL 

(mg/m3) 

Less Serious 

(mg/m3) 

Serious 

(mg/m3) 

Reference Chemical Form 

1 Rat 

(CD) 

4 hr 820 M (14-day LC50) Kinney et al. 1989 

Systemic 

2 Rat 

(CD) 

4 hr Resp 67 M 590 M (lung noise; labored 

breathing during and after exposure) 

Kinney et al. 1989 

Hepatic 67 M (28% increase in 

absolute liver weight 5 days after exposure) 

Bd Wt 67 M 590 M (final body weight 

reduced 18% five days after exposure) 

a The number corresponds to entries in Figure 3-2. Bd Wt = body weight; hr = hour(s); LC50 = lethal concentration, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse= respiratory 

Table 3-2 Levels of Significant Exposure to Perfluorononanoic Acid - Inhalation 

LOAEL 

***DRAFT FOR PUBLIC COMMENT***
Death 

Respiratory Hepatic Body Weight 

Systemic 

mg/m3

1000 

1r 

2r 2r 

100 

2r 2r 2r 

10 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level

PERFLUOROALKYLS

3. HEALTH EFFECTS

45

***DRAFT FOR PUBLIC COMMENT***

Figure 3-2 Levels of Significant Exposure to Perfluorononanoic Acid - Inhalation 

Acute (≤14 days) 
 

 

 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 46 

3. HEALTH EFFECTS 

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). 

Unpublished data summarized by OECD (2002) indicate that 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. 

Cardiovascular Effects. Information regarding cardiovascular effects of exposure to PFOS or PFOA 

in humans is limited to the observation of no alterations in the electrocardiograms (EKG) in a 

cross-sectional study of 1,025 workers potentially exposed to PFOA (Sakr et al. 2007b). Serum PFOA 

levels ranged from 5 to 9,550 ng/mL. It is likely that other occupational studies also conducted EKG 

assessments among workers, but no specific information was reported, as the main interest of most 

studies had been the evaluation of effects on the liver and on lipids. It should also be mentioned that a 

retrospective cohort mortality analysis of workers in the same plant studied by Sakr et al. (2007b) found 

no convincing evidence of increased mortality due to heart disease in general or ischemic heart disease 

specifically (Leonard 2006). 

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). 

Gastrointestinal Effects. A study is available that evaluated self-reported health outcomes in 

relation to occupational exposures to PFOS at a PFOS-based fluorochemical manufacturing facility in 

Decatur, Alabama (Grice et al. 2007). The study cohort consisted of 1,400 employees (263 women) and 

included all current, retired, and former employees with a cumulative employment of at least 1 year. 

Based on PFOS serum concentrations, the workers were classified as having had no direct workplace 

exposure to PFOS-based fluorochemicals (0.11–0.29 mg/L), low-potential workplace exposure (0.39– 

0.89 mg/L), and high-potential workplace exposure (1.30–1.97 mg/L). The study found no association 

between self-reported incidence of gastric ulcer and having worked in a job with either low or high 

exposure to PFOS. 

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, and 

large intestine from male rats exposed intermittently nose-only to up to 84 mg/m3 APFO dusts for 

2 weeks (Kennedy et al. 1986). Unpublished data summarized by OECD (2002) indicate that distension 

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PERFLUOROALKYLS 47 

3. HEALTH EFFECTS 

of the small intestine was observed in rats exposed to lethal concentrations of PFOS dusts (1,890– 

45,970 mg/m3

) for 1 hour. 

Hematological Effects. Unspecified hematological parameters monitored in 115 male employees at 

two PFOS manufacturing plants in Decatur, Alabama and Antwerp, Belgium were not associated with 

serum PFOS levels (Olsen et al. 1999). Levels of PFOS measured ranged from <1,000 to 26,000 ng/mL, 

with a mean of 3,300 ng/mL. Subsequent studies of workers at these plants that included women and a 

6-year longitudinal assessment of hematological parameters in relation to PFOS and PFOA values 

reported no substantial changes associated with the levels of these compounds measured in the study 

(<2 μg/mL) (Olsen et al. 2003a). The specific parameters monitored included percent hematocrit, 

hemoglobin, red blood cells, white blood cells, and platelet count. A cross-sectional study of 

1,025 workers potentially exposed to PFOA reported no alterations in complete blood count among the 

workers (Sakr et al. 2007b). Serum PFOA levels ranged from 5 to 9,550 ng/mL. 

No treatment-related hematological alterations were reported in male rats exposed intermittently noseonly 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. 

Musculoskeletal Effects. No information was located regarding musculoskeletal effects in humans 

following inhalation exposure to perfluoroalkyl compounds. The only information in animals is that 

examination of the sternebrae from male rats exposed head-only to up to 84 mg/m3 APFO dusts for up to 

2 weeks was unremarkable (Kennedy et al. 1986). 

Hepatic Effects. Several reports have evaluated liver function and lipid profiles in workers exposed 

to PFOA and/or PFOS, and for the most part, no significant associations have been found. A 

cross-sectional study of 115 workers exposed to PFOA found no significant clinical toxicity at the serum 

PFOA levels measured (<1,000–26,000 ng/mL, mean 3,300 ng/mL) (Gilliland and Mandel 1996). The 

investigators measured serum cholesterol, LDL, HDL and activities of AST, ALT, and GGT. It should be 

noted, however, that in obese workers only, AST and ALT activities increased with increasing PFOA, 

which the investigators thought had biological plausibility because obesity has been associated with 

elevation of transaminases through fatty infiltration. 

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PERFLUOROALKYLS 48 

3. HEALTH EFFECTS 

A similar study was conducted with PFOS in male workers at plants in Decatur, Alabama and Antwerp, 

Belgium (Olsen et al. 1999). In 1995, the mean serum PFOS for 178 workers was 2,190 ng/mL (range 0– 

12,830 ng/mL); in 1997, the mean for 149 workers was 1,750 ng/mL (range 100–9930 ng/mL). In 

addition to cholesterol, HDL, VLDL, and serum hepatic enzymes, the authors conducted other clinical 

chemistry tests. For both years, 95% of the measured PFOS levels were <6,000 ng/mL. Because the 

employees from the two plants were dissimilar by age, BMI, and self-reported alcohol use, the authors 

conducted combined analyses as well as separate analyses by plant location. The results of the clinical 

chemistry tests were unremarkable. In addition, there were no substantial changes in serum hepatic 

enzymes, cholesterol, or lipoproteins at PFOS levels <6,000 ng/mL. No conclusions were drawn from the 

few workers with serum PFOS ≥6,000 ng/mL due to their small number (7 in 1995 and 5 in 1997 data). 

Some methodological issues that, according to the investigators, should be considered in evaluating the 

results included the cross-sectional design of the study, a less-than-ideal rate of voluntary participation 

among eligible fluorochemical production workers, the fact that serum PFOS may not reflect body burden 

since, in laboratory animals, it accumulates primarily in the liver, and the fact that the two cross-sectional 

analyses could not be viewed as independent studies because 61 workers were studied in both years. 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 potential confounding factors, there were no 

substantial changes in lipid or hepatic parameters consistent with the known toxicological effects of 

PFOA or PFOS in laboratory animals (Olsen et al. 2003a). In this study, the mean serum concentrations 

of PFOS and PFOA for 263 Decatur employees were 1,320 and 1,780 ng/mL, respectively. Workers at 

the Antwerp plant (n=255) had mean PFOA and PFOS serum values approximately 50% lower than those 

at the Decatur plant. 

A more recent assessment of 506 employees who did not take cholesterol-lowering medications at three 

fluorochemical production plants (Cottage Grove, Minnesota; Decatur, Alabama; Antwerp, Belgium) 

reported no statistically significant association between serum PFOA levels with total cholesterol or LDL 

(Olsen and Zobel 2007). PFOA was negatively associated with HDL for the three facilities combined, but 

not in individual sites. This was attributed to lower HDL values in two of the three locations and to 

markedly different demographic factors (i.e., BMI). Serum PFOA levels in this study ranged from 7 to 

92,030 ng/mL (arithmetic mean 2,210 ng/mL, 95% CI 1,660–2,770 ng/mL). Serum triglycerides were 

significantly positively associated with PFOA, but not consistently by locations. Although the 

investigators stated that a biological association cannot be ruled out, they discuss several issues that could 

have contributed to the finding, including non-adherence to fasting requirements by some shift production 

workers and/or the effect of postprandial metabolic responses in shift workers. Olsen and Zobel (2007) 

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PERFLUOROALKYLS 49 

3. HEALTH EFFECTS 

noted that there is evidence that postprandial serum triglyceride levels are higher among night shift 

workers than day workers. The study also found no statistically significant associations between PFOA 

and hepatic enzymes for the three facilities combined, although some modest positive associations were 

observed between PFOA and hepatic enzymes (ALT and GGT) at one of the three facilities. 

Two additional studies of workers at a facility that manufactures fluoropolymers in West Virginia are 

available. Sakr et al. (2007a) examined the relationship between serum PFOA and lipids and liver 

enzymes in a longitudinal study of 454 workers using a linear mixed effects model. The cohort 

comprised employees 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, the analyses showed serum PFOA positively associated with total 

cholesterol, with an increase of 1.06 mg/dL of cholesterol per 1,000 ng/mL increase in PFOA (p=0.001). 

Serum PFOA was not associated with changes in triglycerides or other lipoproteins. In addition, PFOA 

was negatively associated with total bilirubin and positively with serum AST activity, but not ALT or 

GGT. Limitations of the study discussed by the investigators included lack of information regarding 

lipid-lowering medications and alcohol intake, the fact that the studied workers represented only 16% of 

all workers who ever worked in the PFOA area, and exposure and outcome were not always measured on 

the same date. The same groups of investigators conducted a cross-sectional study of 1,025 active 

workers (76% males) at the same plant with potential exposure to PFOA (Sakr et al. 2007b). Serum 

PFOA levels ranged from 5 to 9,550 ng/mL among the total participants. After adjustment for 

confounders, which included control for cholesterol-lowering medications, there was a modest but 

statistically significant positive association between PFOA and total cholesterol, LDL, VLDL, and GGT 

activity. No associations were found for HDL, bilirubin, or ALT and AST activities. Strengths of the 

study included a large sample size that included female workers, same-day measurement of health 

outcome and marker of exposure, and control for cholesterol-lowering medications. Among the 

limitations are no information on baseline lipid levels and dietary intake, and the cross-sectional design of 

the study. 

A small study of Italian perfluoroalkyl workers (n=35) studied over a period of 4 years also reported a 

positive association between serum levels of PFOA and increased total cholesterol (p=0.03), which 

appeared to have been due to an increase in non-HDL cholesterol (Costa 2004). No significant 

association was found between serum PFOA and HDL cholesterol, LDL cholesterol, non-HDL/LDL 

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PERFLUOROALKYLS 50 

3. HEALTH EFFECTS 

cholesterol, or total triglycerides. The study also found no significant association between PFOA and 

protein metabolism or liver function. 

A health evaluation of workers exposed to PFNA is also available (Mundt et al. 2007). The cohort 

consisted of 630 employees at a U.S. polymer production facility using PFNA at any time between 

January 1, 1989 and July 1, 2003. Complete work histories, which were available for all employees, 

provided the basis for categorizing the employees into high-, low-, or no-exposure groups. Records were 

abstracted for height, weight, date of exam, and 32 clinical chemistry variables (lipid profile and hepatic 

enzymes among them). A limited number of blood samples obtained before the start of the study were 

used to validate the exposure categories, but were insufficient for use in any analysis (actual values were 

not provided). Annual cross-sectional analyses and longitudinal analyses that accounted for multiple 

measurements per person were conducted separately for men and women by exposure group. After 

adjusting for age and BMI, some small but not clinically significant differences between groups were 

found. However, these observations were not consistent between men and women or over the five 

analysis windows. Seven variables (total cholesterol, GGT, AST, ALT, alkaline phosphatase [AP], 

bilirubin, and triglycerides) that were examined in separate longitudinal models showed no significant 

increase or decrease by unit increase in exposure intensity score. 

Information from 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 high-exposure group, absolute and relative liver 

weight were still significantly increased 28 days after exposure ceased (Kennedy et al. 1986). The 

activities of serum enzymes markers of liver function were unremarkable expect for AP that was 

significantly increased in the mid- and high-exposure groups immediately after exposure on day 10 and 

remained elevated in the high-exposure group on day 14 of recovery. Histopathological changes were 

restricted to the mid- and high-exposure 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 follow cessation of exposure. 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

. 

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PERFLUOROALKYLS 51 

3. HEALTH EFFECTS 

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. 

Unpublished data summarized by OECD (2002) indicate that 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. 

Renal Effects. Kidney function, assessed by levels of blood urea nitrogen (BUN) and serum 

creatinine, were not associated with exposure to PFOS and/or PFOA in the epidemiological assessment 

conducted by Olsen et al. (2003a) or with exposure to PFNA in the study conducted by Mundt et al. 

(2007). 

No gross or microscopic alterations were observed in the kidneys from male rats exposed intermittently 

head-only to up to 84 mg/m3 APFO dusts for 2 weeks (Kennedy et al. 1986). 

Endocrine Effects. The possible association between serum PFOA levels and hormone levels was 

investigated in two cross-sectional studies of male workers at a PFOA production plant (Olsen et al. 

1998). The studies were conducted in 1993 (n=11) and 1995 (n=80). Eleven hormones were assayed: 

cortisol, dehydroepiandrosterone sulfate, estradiol, FSH, 17α-hydroxyprogesterone, free testosterone, 

total testosterone, LH, prolactin, TSH, and sex hormone-binding globulin. Simple and stratified analysis 

of variance, Pearson correlation coefficients, and ordinary multivariable regressions were used to evaluate 

associations between serum PFOA levels and each hormone, with adjustments for potential confounding 

variables. For stratified analyses, workers were divided into four PFOA categories: 0–1,000, 1,000– 

<10,000, 10,000–<30,000, and ≥30,000 ng/mL. The results did not show significant associations between 

PFOA exposure and hormone levels, but workers with the highest serum PFOA levels had mean estradiol 

levels 10% greater than workers in other groups. The interpretation of the higher levels of estradiol was 

limited by the small number of workers in the high-exposure groups (four in 1994 and five in 1995) and 

the fact that estradiol levels were confounded by BMI. Taken together, the results showed no significant 

hormonal changes at the levels of PFOA measured. Limitations included the cross-sectional design of the 

study and the fact that the two studies could not be viewed as independent studies because 68 workers 

were studied in both years. In the cross-sectional study of 1,025 workers conducted by Sakr et al. (2007b) 

discussed previously, in men, serum estradiol and testosterone were significantly positively associated 

with serum PFOA in linear regression models. The investigators could not find an explanation for this 

finding, but it confirmed the finding of elevated estradiol reported by Olsen et al. (1998). 

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PERFLUOROALKYLS 52 

3. HEALTH EFFECTS 

In the epidemiological assessment conducted at two perfluorooctanyl-manufacturing locations 

summarized above under Hepatic Effects (Olsen et al. 2003a), workers did not show evidence of altered 

thyroid function as assessed by measurements of serum levels of TSH, thyroxine (T4), free T4 (FT4), 

triiodothyronine (T3), thyroid hormone binding ratio, and free thyroxine index. Mean concentrations of 

PFOS and PFOA for employees at one plant were 1.32 and 1.78 μg/mL, respectively. Mean PFOS and 

PFOS-serum values at the other plant were approximately 50% lower. Olsen and Zobel (2007) also found 

no significant associations between serum PFOA and THS or T4 values in a study of 506 employees at 

three fluorochemical production facilities. Serum PFOA levels in this study ranged from 7 to 

92,030 ng/mL (arithmetic mean 2,210 ng/mL, 95% CI 1,660–2,770 ng/mL). Similar results were 

reported in the cross-sectional study of PFOA workers conducted by Sakr et al. (2007b). In that study, 

serum TSH, T4, and T3 uptake were within normal limits. 

In the epidemiology study of 630 workers exposed to PFNA described above under Hepatic Effects 

(Mundt et al. 2007), there was no indication that exposure to PFNA affected thyroid function as assessed 

by serum levels of TSH, T4, T3 uptake, and free T4 index five times over a 25-year period. In this study, 

exposure was ascertained by work histories; levels of PFNA in serum were not available. 

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). 

Dermal Effects. No studies were located regarding dermal effects in humans following inhalation 

exposure to perfluoroalkyl compounds. The only relevant information in animals is that intermittent 

head-only exposure of male rats to up to 84 mg/m3 APFO dusts for 2 weeks did not result in 

histopathologic changes in abdominal skin (Kennedy et al. 1986). 

Ocular Effects. No information was located regarding ocular effects in humans following inhalation 

exposure to perfluoroalkyl compounds. 

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 

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PERFLUOROALKYLS 53 

3. HEALTH EFFECTS 

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. 

Body Weight Effects. Male rats that survived a 4-hour exposure to 380 mg/m3 APFO dusts lost 

weight for 1–2 days after exposure for 4 hours, but resumed normal weight gain thereafter (Kennedy et al. 

1986). Male rats exposed 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. In a developmental study, 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. 

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). Exposure to 67 mg/m3 had no significant effect on body weight. 

3.2.1.3 Immunological and Lymphoreticular Effects 

No information was located regarding immunological and lymphoreticular effects in humans following 

inhalation exposure to perfluoroalkyl compounds. 

Examination of the spleen and thymus of male rats exposed intermittently to up to 84 mg/m3 APFO dusts 

for 2 weeks did not reveal any gross or microscopic treatment-related alterations (Kennedy et al. 1986). 

The exposure concentration of 84 mg/m3 is presented as a NOAEL for lymphoreticular effects in 

Table 3-1 and Figure 3-1. 

3.2.1.4 Neurological Effects 

No information was located regarding neurological effects in humans following inhalation exposure to 

perfluoroalkyl compounds. 

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). 

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PERFLUOROALKYLS 54 

3. HEALTH EFFECTS 

The exposure concentration of 84 mg/m3 is presented as a NOAEL for neurological effects in Table 3-1 

and Figure 3-1. 

3.2.1.5 Reproductive Effects 

The only relevant information regarding reproductive effects in humans is that regarding serum levels of 

sex hormones in male workers (see above under Endocrine Effects) in studies by Olsen et al. (1998) and 

Sakr et al. 2007b). Assays for dehydroepiandrosterone sulfate, estradiol, FSH, 17α-hydroxyprogesterone, 

free testosterone, total testosterone, LH, prolactin, and sex hormone-binding globulin provided no 

evidence for associations between PFOA exposure and hormone levels, but workers with the highest 

serum PFOA levels had mean estradiol levels 10% greater than workers in other groups (Olsen et al. 

1998). The interpretation of the higher levels of estradiol was limited by the small number of workers in 

the high-exposure groups (four in 1994 and five in 1995) and the fact that estradiol levels were 

confounded by BMI. In the cross-sectional study of workers conducted by Sakr et al. (2007b), serum 

estradiol and testosterone were significantly associated with serum PFOA in linear regression models. 

The investigators could not find an explanation for this finding. 

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 treatment-related alterations (Kennedy et 

al. 1986). 

The exposure concentration of 84 mg/m3 is presented as a NOAEL for reproductive effects in Table 3-1 

and Figure 3-1. 

3.2.1.6 Developmental Effects 

In the study of self-reported health conditions and exposure to PFOS, conducted by Grice et al. (2007), 

mentioned earlier under Gastrointestinal Effects, the women were asked to fill a questionnaire that 

assessed pregnant outcome history including number of pregnancies, the month and year the pregnancy 

ended, the outcome of the pregnancy, and the weight of the live-born children, as well as tobacco use. 

The results of the analyses showed that birth weight of singleton births, adjusted for maternal age at birth, 

gravidity, and smoking status did not vary between exposure groups. An important determinant of birth 

weight that was not accounted for in the study was length of gestation. 

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PERFLUOROALKYLS 55 

3. HEALTH EFFECTS 

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 postnatal day 1, but the difference over controls 

was no longer significant on postnatal day 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. 

The concentrations of 10 and 25 mg/m3 are presented as a NOAEL and LOAEL, respectively, for 

developmental effects in Table 3-1 and Figure 3-1. 

3.2.1.7 Cancer 

In the study by Grice et al. (2007) of self-reported health conditions mentioned earlier, the risk of colon 

cancer, melanoma, and prostate cancer was not associated with any of the PFOS-exposure categories for 

analyses that included all self-reported or only validated cancers. 

Studies that found increased risk of death due to prostate and bladder cancers in perfluororalkyl workers 

are summarized in Section 3.2.1.1. It should also be mentioned that a retrospective cohort mortality 

analysis of workers with measurable exposure to PFOA at a polymer production facility in West Virginia 

found no convincing evidence of increased deaths due to malignant neoplasms at sites that included the 

liver and biliary passages, pancreas, kidney and urinary tract, bronchus, trachea or lungs, and prostate 

(Leonard 2006; see Section 3.2.1.1). 

No studies were located regarding cancer in animals following inhalation exposure to perfluoroalkyl 

compounds. 

3.2.2 Oral Exposure 

3.2.2.1 Death 

No reports of deaths in humans exposed orally to perfluoroalkyl compounds were located in the literature. 

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). The 

doses ranged from 100 to 2,150 mg/kg. One male in 100 mg/kg group died on day 7; all animals in the 

2,150 mg/kg group died on day 1. Nonlethal signs observed included ptosis, piloerection, hypoactivity, 

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PERFLUOROALKYLS 56 

3. HEALTH EFFECTS 

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 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. 

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 reports 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. 

In a 14-day study, all mice (n=10) administered approximately 54 mg/kg/day PFNA died before the study 

period ended; no deaths occurred 5.3 mg/kg/day (Kennedy 1987). 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 (n=10) 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. 

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PERFLUOROALKYLS 57 

3. HEALTH EFFECTS 

LOAEL values for death and LD50s in each species and duration category are recorded in Table 3-3 and 

plotted in Figure 3-3. 

3.2.2.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, musculoskeletal, dermal, 

ocular, or body weight effects in humans exposed orally to perfluoroalkyl compounds. 

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each 

species and duration category are recorded in Tables 3-3, 3-4, and 3-5 and plotted in Figures 3-3, 3-4, and 

3-5. 

Respiratory Effects. Dosing of male and female CD rats with up to approximately 110 mg/kg/day 

APFO did not induce gross or microscopic changes in the lungs (Griffith and Long 1980; Perkins et al. 

2004). However, 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 in 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). 

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) in 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 1.5 mg PFOS/kg/day in the diet for 104 weeks did not induce significant gross or microscopic 

alterations in the lungs and trachea (Thomford 2002b). 

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 respiratory tract (3M 

2007a; van Otterdiijk 2007a, 2007b). Examination of the respiratory tract of rats exposed to up to 

10 mg/kg/day PFHxS by gavage in a reproductive study (40–60 days of dosing) showed no treatment­

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9

100

3

680430

6

10001130

93

180195

148

1

10

10

25

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Monkey 

(Rhesus) 

2 wk 1 x/d (G) 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

2 Rat 

(albino) 

once (GO) 

3 Rat 

(albino) 

28 d ad lib (F) 

4 Mouse 

(CD) 

28 d ad lib (F) 

Systemic 

5 Rat 

(CD) 

14 d 1 x/d (GW) 

Hepatic 1 M 10 M (46% increase in relative 

liver weight) 

Bd Wt 10 M 25 M (14% reduction in final 

body weight) 

Serious 

(mg/kg/day) 

100 (unspecified number out 

of 4 died on week 2) 

680 M (LD50) 430 F (LD50) 

1000 M (5/5 died before end of 

1st week of study) 

1130 F (5/5 died before end of 

1st week of study) 

180 M (5/5 died before 2nd

week of study)

195 F (5/5 died before 2nd

week of study)

Reference Chemical Form 

Griffith and Long 1980 Ammonium perfluoroocGriffith and Long 1980 Ammonium perfluoroocGriffith and Long 1980 Ammonium perfluoroocGriffith and Long 1980 Ammonium perfluoroocCook et al. 1992 Ammonium perfluorooc

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral 

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154

16

16

195

20

49

5

50

50

175

2.4

4.7

38

179

0.2

2

2

20

LOAEL 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Hepatic 16 M (66% increase in Haughom and Spydevo

absolute liver weight) Ammonium perfluorooc

Bd Wt 16 M Hepatic 20 M (45% increase in relative Ikeda et al. 1985 

liver weight) Perfluorooctanoic acid 

Hepatic 5 M 50 M (2-fold increased mean Iwai and Yamashita 200

relative liver weight) Ammonium perfluorooc

Bd Wt 50 M Hepatic 2.4 M 4.7 M (significant increase in Kawashima et al. 1995 

absolute and relative liver Perfluorooctanoic acid weight) 

Bd Wt 38 M Hepatic 0.2 M 2 M (34% increase in Liu et al. 1996 

absolute and relative liver Ammonium perfluorooc

weight) 

Bd Wt 2 M 20 M (14% lower final body 

weight) 

a 

Key to Species 

Figure (Strain) 

6 Rat 

(Wistar) 

7 Rat 

(SpragueDawley) 

8 Rat 

(SpragueDawley) 

9 Rat 

(Wistar) 

10 Rat 

(CD) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

7 d ad lib (F) 14 d ad lib (F) 14 d 1 x/d (GW) 1 wk ad lib (F) 14 d 1 x/d (G) 

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

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152

5050

116

100

183

5.3

182

78

78

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

1, 3, 7 d 1 x/d (GW) 

Hepatic 50 M (2-fold increase in 

relative and absolute liver weight) 

Pastoor et al. 1987 Ammonium perfluorooc

Gd 6-15 1 x/d (GO) 

Bd Wt Bd Wt 

50 M (17% weight loss) 

100 F (33% reduced body 

weight gain during Gd 6-15) 

Staples et al. 1984 Ammonium perfluorooc

14 d ad lib (F) 

Hepatic 5.3 (123-155% increase in 

absolute liver weight in 14 days) 

Kennedy 1987 Ammonium perfluorooc

2-10 d ad lib (F) 

Hepatic 78 M (74% increase in 

absolute liver weight) 

Permadi et al. 1992 Perfluorooctanoic acid 

Bd Wt 78 M (25% body weight loss 

after 10 days of treatment) 

a 

Key to Species 

Figure (Strain) 

11 Rat 

(SpragueDawley) 

12 Rat 

(SpragueDawley) 

13 Mouse 

(CD-1) 

14 Mouse 

(C57BL/6N) 

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

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181

78

78

130

5

20

153

2424

23

30

LOAEL 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Hepatic 78 M (74% increase in 

absolute liver weight in 5 days) 

Permadi et al. 1993 Perfluorooctanoic acid 

Bd Wt 78 M (25% body weight loss 

after 5 days of treatment) 

Hepatic 5 F (significant increase in 

relative liver weight) 

Wolf et al. 2007 Ammonium perfluorooc

Bd Wt 20 F Hepatic 24 M (2-fold increase in 

absolute liver weight) 

Xie et al. 2003 Perfluorooctanoic acid 

Bd Wt 24 M (>10% reduced final body 

weight) 

Hepatic 30 M (over 90% increase in 

absolute and relative liver weight) 

Yang et al. 2000 Perfluorooctanoic acid 

Bd Wt 30 M (17% decrease in final 

body weight) 

a 

Key to Species 

Figure (Strain) 

15 Mouse 

(C57BL/6N) 

16 Mouse 

(CD-1) 

17 Mouse 

(C57BL/6N) 

18 Mouse 

(C57BL/6) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

2-10 d ad lib (F) Gd 7-17 Gd 10-17 Gd 13-17 Gd 15-17 1 x/d (GW) 7 d ad lib (F) 10 d ad lib (F) 

30

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

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145

1

31

3333

147

50

144

30

28

11.5

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

19 Mouse 

(C57BL/6) 

10 d ad lib (F) 

Hepatic 1 M (35% increase in 

absolute liver weight) 

Yang et al. 2001 Perfluorooctanoic acid 

20 Mouse 

(C57BL/6) 

7 d ad lib (F) 

Hepatic 33 M (86% increase in 

absolute liver weight) 

Yang et al. 2002b Perfluorooctanoic acid 

Bd Wt 33 M (14% decreased mean 

body weight) 

Immuno/ Lymphoret 

21 Rat 

(SpragueDawley) 

14 d 1 x/d (GW) 

50 M Iwai and Yamashita 200

Ammonium perfluorooc

22 Mouse 

(C57BL/6) 

10 d ad lib (F) 

30 M (86% reduction in 

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

Yang et al. 2000 Perfluorooctanoic acid 

23 Mouse 

(C57BL/6) 

10 d ad lib (F) 

11.5 M (40% to 50% decrease in 

spleen and thymus weights) 

Yang et al. 2001 Perfluorooctanoic acid 

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

LOAEL 

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29

24

146

33

173

25

149

1

10

180

0.2

2

44

100

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

24 Mouse 

(C57BL/6) 

10 d ad lib (F) 

24 M (decreased humoral 

response to immunization with horse red blood cells) 

Yang et al. 2002a Perfluorooctanoic acid 

25 Mouse 

(C57BL/6) 

7 d ad lib (F) 

33 M (40% reduction in spleen 

weight and 79% reduction in thymus weight) 

Yang et al. 2002b Perfluorooctanoic acid 

Reproductive 

26 Rat 

(CD) 

14 d 1 x/d (GW) 

25 M (184% increase in serum 

estradiol) 

Biegel et al. 1995 Ammonium perfluorooc

27 Rat 

(CD) 

14 d 1 x/d (GW) 

1 M 10 M (63% increase in serum 

estradiol) 

Cook et al. 1992 Ammonium perfluorooc

28 Rat 

(CD) 

Developmental 

29 Rat 

(SpragueDawley) 

14 d 1 x/d (G) Gd 6-15 1 x/d (GO) 

0.2 M 

100 

2 M (2-fold increase in serum 

estradiol) 

Liu et al. 1996 Ammonium perfluoroocStaples et al. 1984 Ammonium perfluorooc

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

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246

0.58

33

5

129

5

233

50

86

30

a 

Key to 

Figure 

Species 

(Strain) 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

30 Mouse 

(CD-1) 

once (G) 0.58 M (decreased motor activity) Johansson et al. 2008 Ammonium perfluorooc

31 Mouse 

(CD-1) 

Gd 8-17 Gd 12-17 1 x/d (GW) 

5 F (altered mammary gland 

development in female pups; reduced pup's weight on pnd 20) 

White et al. 2007 Ammonium perfluorooc

32 Mouse 

(CD-1) 

Gd 7-17 1 x/d (GW) 

5 (reduced pup body 

weight at weaning, 43% in males and 35% in females) 

Wolf et al. 2007 Ammonium perfluorooc

33 Rabbit 

(New Zealand) 

Gd 6-18 1 x/d (GW) 

INTERMEDIATE EXPOSURE Death 

34 Monkey 

(Rhesus) 

90 d 1 x/d (G) 

50 F 

30 (1 male and 2 females 

died during weeks 7-12) 

Gortner et al. 1982 Perfluorooctanoic acid Griffith and Long 1980 Ammonium perfluorooc

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

Exposure/ LOAEL 

***DRAFT FOR PUBLIC COMMENT***
92

5458

50

2020202020

3

203

10

202010

a 

Key to 

Figure 

Species 

(Strain) 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

35 Mouse 

(CD) 

28 d ad lib (F) 

54 M (4/5 died before end of 

4th week) 

Griffith and Long 1980 Ammonium perfluorooc

58 F (5/5 died before 4th week 

of study) 

Systemic 

36 Monkey 

(Cynomolgus) 

26 wk 1 x/d (C) 

Resp 20 M Butenhoff et al. 2002 

Ammonium perfluorooc

Cardio 20 M Gastro 20 M Hemato 20 M Musc/skel Hepatic 

20 M 

3 M (36% increase in 

absolute liver weight) 

Renal 20 M Endocr 3 M 10 M (significant decrease in 

serum TT4 and FT4) 

Dermal 20 M Ocular 20 M Bd Wt 10 M 20 M (body weight 12% lower 

20

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

Exposure/ LOAEL 

than control by week 10) 

***DRAFT FOR PUBLIC COMMENT***
87

1010 3030101010

30

10

30

235

20202020

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

37 Monkey 

(Rhesus) 

90 d 1 x/d (G) 

Cardio 10 Griffith and Long 1980 

Ammonium perfluorooc

Gastro Hemato 

10 

30 

30 (emesis) 

Hepatic Renal 

10 10 

Endocr 10 30 (difuse lipid depletion in 

adrenals) 

Bd Wt 10 30 (33% body weight loss by 

week 6) 

38 Monkey 

(Cynomolgus) 

30 d 1x/d (C) 

Hemato 20 M Thomford 2001 

Ammonium perfluorooc

Hepatic Endocr 

20 M 20 M 

Bd Wt 20 M 

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
166

13.613.6

122

33

10

30

3

10

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

39 Rat 

(CD) 

1 yr ad lib (F) 

Hepatic 13.6 M (increased relative liver 

weight) 

Biegel et al. 2001 Ammonium perfluorooc

Bd Wt 13.6 M (more than 10% reduced 

weight gain) 

40 Rat 

(SpragueDawley) 

70-90 d 1 x/d (GW) 

Hepatic 3 M (increased absolute and 

relative liver weight) 

Butenhoff et al. 2004 Ammonium perfluorooc

Renal 3 M (increased absolute and 

relative kidney weight) 

Endocr 10 M 30 M (hypertrophy and/or 

vacuolation of zona glomerulosa of adrenal gland) 

Bd Wt 3 M 10 M (>11% reduced body 

weight) 

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
8

1101101101101101

3

11011011011030110

100

91

3

10

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

110 F Griffith and Long 1980 

Ammonium perfluorooc

110 F 110 F 110 F 110 F 

1 M 3 M (hepatocyte hypertrophy; 

50% increase in absolute liver weight) 

110 F 110 F 110 F 110 F 

30 M 100 M (33% reduction in final 

mean body weight)

110 F 

3 M (hepatocyte hypertrophy) Griffith and Long 1980 

Ammonium perfluorooc

10 M 30 M (11% reduction in final 100 M (33% reduction in final 

body weight) body weight) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

41 Rat 

(CD) 

90 d ad lib (F) 

42 Rat 

(CD) 

28 d ad lib (F) 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt Hepatic Bd Wt 

30 100

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
47

6.50.06

0.64

6.5

131

0.6

1

10

206

7.5 15

5

5.45.4 5.8

a 

Key to 

Figure 

43 44 45 46 

Species 

(Strain) 

Rat (CD) Mouse (NS) Mouse (C57BL/6N) Mouse (CD) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

13 wk ad lib (F) Gd 1-17 1 x/d (GW) 15 d ad lib (W) 28 d ad lib (F) 

System 

Resp Hepatic Bd Wt Hepatic Bd Wt Bd Wt Hepatic Bd Wt 

NOAEL 

(mg/kg/day) 

6.5 M 

0.06 M 

6.5 M 0.6 F 

10 F 

7.5 F 

LOAEL 

Less Serious 

(mg/kg/day) 

0.64 M (minimal to moderate 

hepatocellular hypertrophy) 

1 F (increased absolute and 

relative liver weight of dams on pnd 22) 

5.4 M (3-fold or greater 

increased absolute and relative liver weight) 

5.4 M (final body weight 20% 

lower than controls) 

Serious

(mg/kg/day)

15 F (weight loss) 

5.8 F (final body weight 25% 

lower than controls) 

Reference Chemical Form 

Perkins et al. 2004 Ammonium perfluoroocAbbott et al. 2007 Ammonium perfluoroocDewitt et al. 2008 Ammonium perfluoroocGriffith and Long 1980 Ammonium perfluorooc

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
184

0.2

0.5

114

1

5

10

174

0.5

472.6 18

36

3

5

a 

Key to 

Figure 

47 48 49 50 

Species 

(Strain) 

Mouse (CD-1) Mouse (CD-1) Mouse (ICR) Mouse (CD-1) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

21 d ad lib (F) Gd 1-17 1 x/d (GW) 21 d ad lib (W) Gd 1-17 1 x/d (GW) 

System 

Hepatic Hepatic Bd Wt Hepatic Renal Bd Wt Hepatic Bd Wt 

NOAEL 

(mg/kg/day) 

0.2 

5 F 

47 M 

2.6 M 

5 F 

Less Serious Serious 

(mg/kg/day) (mg/kg/day) 

0.5 (39-41% increase in 

absolute liver weight in 21 days) 

1 F (38% increase in

absolute liver weight)

10 F (32% reduced weight 

gain during pregnancy) 

0.5 M (27% increase in relative 

liver weight) 

18 M (significant weight loss) 

3 F (significant increase in

relative and absolutematernal liver weight onpnd 22)

Reference Chemical Form 

Kennedy 1987 Ammonium perfluoroocLau et al. 2006 Ammonium perfluoroocSon et al. 2008 Ammonium perfluoroocWolf et al. 2007 Ammonium perfluorooc

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

LOAEL 
83

20

88

10

30

94

110

207

1.88

3.75

84

20

89

10

30

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

Immuno/ Lymphoret 

51 Monkey 

(Cynomolgus) 

26 wk 1 x/d (C) 

System 

NOAEL 

(mg/kg/day) 

20 M 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Butenhoff et al. 2002 

Ammonium perfluorooc

52 Monkey 

(Rhesus) 

90 d 1 x/d (G) 

10 30 (atrophy of lymphoid 

follicles in spleen and lymph nodes) 

Griffith and Long 1980 Ammonium perfluorooc

53 Rat 

(albino) 

90 d ad lib (F) 

110 F Griffith and Long 1980 

Ammonium perfluorooc

54 Mouse 

(C57BL/6N) 

15 d ad lib (W) 

Neurological 

55 Monkey 

(Cynomolgus) 

26 wk 1 x/d (C) 

1.88 F 

20 M 

3.75 F (reduced SRBC-specific 

response to IgM antibody titers) 

Dewitt et al. 2008 Ammonium perfluoroocButenhoff et al. 2002 Ammonium perfluorooc

56 Monkey 

(Rhesus) 

90 d 1 x/d (G) 

10 30 (hypoactivity and 

prostration) 

Griffith and Long 1980 Ammonium perfluorooc

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
95

110

150

6.5

85

20

90

100

237

20

13.6

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

57 Rat 

(albino) 

90 d ad lib (F) 

110 F Griffith and Long 1980 

Ammonium perfluorooc

58 Rat 

(CD) 

13 wk ad lib (F) 

Reproductive 

59 Monkey 

(Cynomolgus) 

26 wk 1 x/d (C) 

6.5 M 

20 M 

Perkins et al. 2004 Ammonium perfluoroocButenhoff et al. 2002 Ammonium perfluorooc

60 Monkey 

(Rhesus) 

90 d 1 x/d (G) 

100 Griffith and Long 1980 

Ammonium perfluorooc

61 Monkey 

(Cynomolgus) 

30 d 1x/d (C) 

20 M Thomford 2001 

Ammonium perfluorooc

62 Rat 

(CD) 

1 yr ad lib (F) 

13.6 M (significant increase in 

serum estradiol at 1, 3, 6, 9, and 12 months) 

Biegel et al. 2001 Ammonium perfluorooc

176

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

LOAEL 

***DRAFT FOR PUBLIC COMMENT***
21

30

96

100110

151

6.5

52

5

121

3

30

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

70-90 d 1 x/d (GW) 

30 Butenhoff et al. 2004 

Ammonium perfluorooc

90 d ad lib (F) 

100 M 110 F 

Griffith and Long 1980 Ammonium perfluorooc

13 wk ad lib (F) 

6.5 M Perkins et al. 2004 

Ammonium perfluorooc

Gd 1-17 Gd 8-17 1 x/d Gd 12-17 (GW) 

5 F (delayed mammary gland 

differentiation) 

White et al. 2007 Ammonium perfluorooc

70-90 d 1 x/d (GW) 

3 M (hepatocellular 

hypertrophy and less commonly necrosis in F1 males) 

30 (increased number of 

dead pups on postnatal day 6-8) 

Butenhoff et al. 2004 Ammonium perfluorooc

a 

Key to Species 

Figure (Strain) 

63 Rat 

(SpragueDawley) 

64 Rat 

(albino) 

65 Rat 

(CD) 

66 Mouse 

(CD-1) 

Developmental 

67 Rat 

(SpragueDawley) 

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

LOAEL 

***DRAFT FOR PUBLIC COMMENT***
39

0.3

0.6

32

3 5

178

5

37

3

5

a 

Key to Species 

Figure (Strain) 

68 Mouse 

(NS) 

69 Mouse 

(CD-1) 

70 Mouse 

(CD-1) 

71 Mouse 

(CD-1) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

Gd 1-17 1 x/d (GW) 

System 

NOAEL 

(mg/kg/day) 

0.3 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

0.6 (significantly reduced 

pups survival from birth to weaning) 

Gd 1-17 1 x/d (GW) Gd 1-17 1 x/d (GW) Gd 1-17 1 x/d (GW) 

3 3 

(20% lower body weight 

of pups on pnd 23) 

(reduced weight gain 

through lactation; delayed eye opening and hair growth) 

5 5 5 

(significantly increased 

full litter resorptions) 

(increased prenatal loss; 

40% reduced neonatal body weight on pnd 5 and 10) 

(decreased pup survival 

from birth to weaning) 

Reference Chemical Form 

Abbott et al. 2007 Ammonium perfluoroocLau et al. 2006 Ammonium perfluoroocWhite et al. 2007 Ammonium perfluoroocWolf et al. 2007 Ammonium perfluorooc

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

LOAEL 
160

1.5 15151515

1.515

15151.5

151.5

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

CHRONIC EXPOSURE Systemic 

72 Rat 

(SpragueDawley) 

2 yr ad lib (F) 

System 

Resp 

NOAEL 

(mg/kg/day) 

1.5 M 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

15 M (lung hemorrhage) 

Reference Chemical Form 

3M 1983 Perfluorooctanoic acid 

Cardio 15 Gastro 15 Hemato 15 Hepatic 1.5 M (significanly increased 

serum transaminases) 

Renal 15 M (significantly increased 

relative kidney weight at 1 year) 

Endocr 15 Ocular 15 Bd Wt 1.5 F 15 F (10.3% lower terminal 

body weight) 

Other 1.5 M (inflammation of the 

salivary gland) 

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
165

13.613.613.6

162

15

161

15

163

1.5

151.5

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

73 Rat 

(CD) 

2 yr ad lib (F) 

Hepatic 13.6 M (increased relative liver 

weight) 

Biegel et al. 2001 Ammonium perfluorooc

Bd Wt 13.6 M (more than 10% 

reduction in weight gain most of the study) 

Other 13.6 M (increased incidence of 

acinar cell hyperplasia in pancreas) 

Immuno/ Lymphoret 

74 Rat 

(SpragueDawley) 

2 yr ad lib (F) 

15 3M 1983 

Perfluorooctanoic acid 

Neurological 

75 Rat 

(SpragueDawley) 

2 yr ad lib (F) 

15 3M 1983 

Perfluorooctanoic acid 

Reproductive 

76 Rat 

(SpragueDawley) 

2 yr ad lib (F) 

1.5 M 15 M (vascular mineralization 

in the testes) 

3M 1983 Perfluorooctanoic acid 

1.5 F (tubular hyperplasia in 

the ovaries) 

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
167

13.6

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

77 Rat 

(CD) 

2 yr ad lib (F) 

13.6 M (increased incidence of 

Leydig cell hyperplasia; elevated serum LH at 18 

Biegel et al. 2001 Ammonium perfluorooc

months) 

a The number corresponds to entries in Figure 3-3. ad lib = ad libitum; ALT = alanine aminotransferase; Bd Wt = body weight; (C) = capsule; Cardio = cardiovascular; d = day(s); Endocr = endocrine; (F) = feed; F = Fthyroxine; (G) = gavage; Gastro = gastrointestinal; Gd = gestational day; (GO) = gavage in oil; (GW) = gavage in water; Hemato = hematological; Immuno/Lymphorimmunological/lymphoreticular; LD50 = lethal dose, 50% kill; LH = luteinizing hormone; LOAEL = lowest-observed-adverse-effect level; M = male; Musc/skel = musNOAEL = no-observed-adverse-effect level; NS = not specified; pnd = post-natal day; PPARalpha = peroxisome proliferator-activated receptor alpha; TT4 = total threspiratory; (W) = drinking water; wk = week(s); x = time(s); yr = year(s) 

Table 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
Death 

Hepatic Body Weight Immuno/Lymphor Reproductive Developmental 

Systemic 

mg/kg/day 

10000 

3r 1000 3r 

2r 

2r 

4m 4m 

100 1k 12r 29r 

14m 15m 14m 15m 

8r 11r 8r 11r 21r 33h 

9r

18m 20m 18m 20m 22m 25m

17m 17m 5r 24m 26r

7r 16m 10r 

6r 6r 

23m 10 5r 5r 27r 

13m 16m 8r 9r 31m 32m

9r 10r 10r 28r 

1 19m 5r 27r 

30m 

10r 28r 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level 

Figure 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral
	

Acute (≤14 days)

PERFLUOROALKYLS

3. HEALTH EFFECTS

78

***DRAFT FOR PUBLIC COMMENT***
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Ocular Body Weight 

Systemic 

mg/kg/day 

1000 

41r 41r 41r 41r 41r 41r 41r 41r 41r 100 

35m 35m 49m 

34k 37k 37k 37k 40r 37k 

36k 36k 36k 36k 38k 36k 38k 36k 38k 36k 36k 36k 

39r 

10 37k 37k 37k 37k 36k 37k 40r 36k 

43r 46m 

36k 50m 40r 41r 42r 40r 36k 

1 44m 48m 41r 

44m 43r

47m 49m 

47m 

0.1 

43r 

0.01 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level 

PERFLUOROALKYLS

3. HEALTH EFFECTS

79

***DRAFT FOR PUBLIC COMMENT***

Figure 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (Continued)
 

Intermediate (15-364 days)
Body Weight 

Immuno/Lymphor Neurological Reproductive Developmental 

1000 

Systemic
	

mg/kg/day 

41r 53r 57r 64r 100 41r 42r 60k 64r 

41r 42r 52k 56k 63r 67r 

38k 51k 55k 59k 61k 49m 45m 39r 62r 

10 37k 44m 48m 40r 42r 52k 56k 

45m 43r 58r 65r 46m 46m 48m 50m 66m 69m 70m 71m 

54m 

40r 69m 71m 67r 49m 

54m 

1 

68m 

68m 

0.1 

0.01 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level

Figure 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (Continued)
 

Intermediate (15-364 days)

PERFLUOROALKYLS

3. HEALTH EFFECTS

80

***DRAFT FOR PUBLIC COMMENT***
Respiratory 

Cardiovascular Gastrointestinal Hematological Hepatic Endocrine Ocular Body Weight Immuno/Lymphor Neurological Reproductive 

100 

Renal 

Other 

Systemic
	

mg/kg/day 

72r 72r 72r 72r 72r 72r 72r 72r 74r 75r 76r 

73r 73r 73r 77r 

10 

72r 72r 72r 72r 76r 76r 

1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk

 for effects

 other than

 Cancer 

Minimal Risk Leve

Figure 3-3 Levels of Significant Exposure to Perfluorooctanoate - Oral (Continued)

Chronic (≥365 days)
	 PERFLUOROALKYLS

3. HEALTH EFFECTS

81

***DRAFT FOR PUBLIC COMMENT***

l 
171

15

117

25

155

15

15

157

1.5

3

66

159

6

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Systemic 

1 Rat 

(SpragueDawley) 

once (GW) 

System 

Endocr 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

15 (transient decrease in 

serum TT4) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Chang et al. 2008b Potassium perfluorooctasulfonate 

2 Rat 

(SpragueDawley) 

4 d Gd 2-5, 6-9, 10-13, 14-17, 17-20 1 x/d (GW) 

Bd Wt 25 F (weight loss during 

treatment when treated on Gd 2-5 or 6-9) 

Grasty et al. 2003 Potassium perfluorooctasulfonate 

3 Rat 

(Wistar) 

7 d ad lib (F) 

Hepatic 15 M (40% increase in 

absolute liver weight) 

Haughom and SpydevoPotassium perfluorooctasulfonate 

Bd Wt 15 M 

4 Mouse 

(CD-1) 

Gd 6-18 1 x/d (GW) 

Hepatic 1.5 F 3 F (21% increase in 

absolute liver weight) 

Fuentes et al. 2006 Potassium perfluorooctasulfonate 

Endocr 6 F Bd Wt 6 F 

5 Mouse 

(CD-1) 

Gd 12-18 1 x/d (GW) 

Bd Wt 6 F Fuentes et al. 2007 

Potassium perfluorooctasulfonate 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral 

***DRAFT FOR PUBLIC COMMENT***
Exposure/ 

Duration/ 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

LOAEL 

53

0.1

1

196

2.5

3.75

55

25

56

25

120

25

156

6

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

6 Rabbit 

(New Zealand) 

Gd 6-20 1 x/d (GW) 

Bd Wt 0.1 F Case et al. 2001 

Potassium perfluorooctasulfonate 

1 F (21% decreased mean 

maternal body weight gain on Gd 7-21; no effect on food consumption) 

Reproductive 

7 Rabbit 

(New Zealand) 

Gd 6-20 1 x/d (GW) 

Developmental 

8 Rat 

(SpragueDawley) 

2 d Gd 19-20 1 x/d (GW) 

2.5 F Case et al. 2001 

Potassium perfluorooctasulfonate 

3.75 F (10 out 22 does aborted 

between Gd 22 and 28) 

Grasty et al. 2003 Potassium perfluorooctasulfonate 

25 (decreased neonatal 

survival) 

9 Rat 

(SpragueDawley) 

4 d Gd 2-5, 6-9, 10-13, 14-17, 17-20 (GW) 

Grasty et al. 2003 Potassium perfluorooctasulfonate 

25 (decreased neonatal 

survival) 

10 Rat 

(SpragueDawley) 

Gd 19-20 1 x/d (G) 

Grasty et al. 2005 Potassium perfluorooctasulfonate 

25 (increased neonatal 

mortality) 

11 Mouse 

(CD-1) 

Gd 6-18 1 x/d (GW) 

6 Fuentes et al. 2006 

Potassium perfluorooctasulfonate 

***DRAFT FOR PUBLIC COMMENT***
158

6

245

0.75

54

1

2.5 3.75

a 

Key to Species 

Figure (Strain) 

12 Mouse 

(CD-1) 

13 Mouse 

(CD-1) 

14 Rabbit 

(New Zealand) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Gd 12-18 1 x/d (GW) 

Fuentes et al. 2007 Potassium perfluorooctasulfonate 

6 (reduced body weight of 

pups on postnatal days 4 and 8) 

once (G) 

Johansson et al. 2008 Potassium perfluorooctasulfonate 

0.75 M (decreased motor 

activity) 

Gd 6-20 1 x/d (GW) 

Case et al. 2001 Potassium perfluorooctasulfonate 

1 F 2.5 F (10% decreased mean 

fetal body weight) 

3.75 F (24% reduced fetal body 

weight) 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
ure/ 

tion/ 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

LOAEL 

77

0.750.750.750.750.750.15

0.75

0.750.15

0.75

0.750.750.150.75

0.75

a 

Key to 

Figure 

Species 

(Strain) 

Expos

Dura

Frequency 

(Route) 

INTERMEDIATE EXPOSURE Systemic 

15 Monkey 

(Cynomolgus) 

26 wk 1 x/d (C) 

System 

Resp 

NOAEL 

(mg/kg/day) 

0.75 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Seacat et al. 2002 Potassium perfluorooctasulfonate 

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 and lipid vacuolation) 

Renal 0.75 Endocr 0.15 0.75 (increased TSH and 

decreased total T3) 

Dermal 0.75 Ocular 0.75 Bd Wt 0.15 M 

0.75 F 

0.75 M (13.5% reduction in final 

body weight) 

***DRAFT FOR PUBLIC COMMENT***
238

2222222

124

1.6

3.2

128

0.40.4

1.6

2

Exposure/ LOAEL 

Duration/ 

a 

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) 

16 Monkey 

(Cynomolgus) 

4 wk 1 x/d (C) 

Resp 2 

Hemato 2 Hepatic Renal 

2 2 

Endocr 2 Ocular 2 Bd Wt 2 

17 Rat 

(SpragueDawley) 

80 d 1 x/d (GW) 

Bd Wt 1.6 3.2 (>10% reduction in body 

weight) 

18 Rat 

(SpragueDawley) 

90 d 1 x/d (G) 

Hepatic 0.4 F (16% reduction in serum 

total cholesterol on pnd 5) 

Endocr 0.4 F (46% reduction in total 

T4 on pnd 5) 

Bd Wt 1.6 F 2 F (22% reduction in body 

weight gain during premating; food consumption reduced 5.8%) 

Reference Chemical Form 

Thomford 2002a Potassium perfluorooctasulfonate Luebker et al. 2005a Potassium perfluorooctasulfonate Luebker et al. 2005b Potassium perfluorooctasulfonate 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
104

1.771.771.771.771.771.77

108

0.34

1.33

0.34

1.33

0.4

1.56

1.561.561.56

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

1.77 F Seacat et al. 2003 

Potassium perfluorooctasulfonate 

1.77 F 1.77 F 1.77 F 1.77 F 1.77 F 

Seacat et al. 2003 

0.34 M 1.33 M (45% increase in 

segmented neutrophils) Potassium perfluoroocta

sulfonate 

0.34 M 1.33 M (increase absolute and 

relative liver weight; increased serum ALT; hepatocyte hypertrophy and vacuolation) 

0.4 F 1.56 F (significantly increased 

BUN) 

1.56 F 1.56 F 1.56 F 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) 

19 Rat 

(SpragueDawley) 

4 wk ad lib (F) 

20 Rat 

(SpragueDawley) 

14 wk ad lib (F) 

System 

Hemato 

Hepatic Renal Endocr Ocular Bd Wt Hemato 

Hepatic Renal Endocr Ocular Bd Wt 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
81

1

51

1

2

5

80

1

5

15

20

20

101

0.75

239

2

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

21 Rat 

(SpragueDawley) 

Gd 2-20 (GW) Hepatic 1 F 5 F (27% increased liver weight) Thibodeaux et al. 2003 Potassium perfluoroocta

sulfonate 

Endocr 1 F (reduced total and free 

T4 and T3) 

Bd Wt 1 F 2 F (>10% decreased mean 

body weight gain) 

5 F (approximately 33% 

reduced body weight gain) 

22 Mouse 

(CD-1) 

Gd 1-17 (GW) Hepatic 1 F 5 F (21-27% increase in absolute and relative liver 

weight) 

Thibodeaux et al. 2003 Potassium perfluorooctasulfonate 

Endocr 15 F 20 F (decreased total T4 on 

GD6) 

Immuno/ Lymphoret 

23 Monkey 

(Cynomolgus) 

26 wk 1 x/d (C) 

Bd Wt 20 F 

0.75 Seacat et al. 2002 

Potassium perfluorooctasulfonate 

24 Monkey 

(Cynomolgus) 

4 wk 1 x/d (C) 

2 Thomford 2002a 

Potassium perfluorooctasulfonate 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
105

1.77

110

1.56

102

0.75

106

1.77

111

1.56

103

0.15

0.75

2

a 

Key to 

Figure 

Species 

(Strain) 

Expos

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

25 Rat 

(SpragueDawley) 

4 wk ad lib (F) 

1.77 F Seacat et al. 2003 

Potassium perfluorooctasulfonate 

26 Rat 

(SpragueDawley) 

14 wk ad lib (F) 

1.56 F Seacat et al. 2003 

Potassium perfluorooctasulfonate 

Neurological 

27 Monkey 

(Cynomolgus) 

26 wk 1x/d (C) 

0.75 Seacat et al. 2002 

Potassium perfluorooctasulfonate 

28 Rat 

(SpragueDawley) 

4 wk ad lib (F) 

29 Rat 

(SpragueDawley) 

14 wk ad lib (F) 

Reproductive 

30 Monkey 

(Cynomolgus) 

26 w 1 x/d (C) 

1.77 F 1.56 F 0.15 0.75 M (significant decrease in 

serum estradiol on day 62, 91, and 182). 

Seacat et al. 2003 Potassium perfluorooctasulfonate Seacat et al. 2003 Potassium perfluorooctasulfonate Seacat et al. 2002 Potassium perfluorooctasulfonate 

31 Monkey 

(Cynomolgus) 

4 wk 1 x/d (C) 

2 M Thomford 2002a 

Potassium perfluorooctasulfonate 

ure/ 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

LOAEL 

240

***DRAFT FOR PUBLIC COMMENT***
123

3.2

127

2

107

1.511.77

112

1.331.56

58

1

2

1.6

a 

Key to 

Figure 

Species 

(Strain) 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

32 Rat 

(SpragueDawley) 

80 d 1 x/d (GW) 

3.2 Luebker et al. 2005a 

Potassium perfluorooctasulfonate 

33 Rat 

(SpragueDawley) 

90 d 1 x/d (G) 

2 F Luebker et al. 2005b 

Potassium perfluorooctasulfonate 

34 Rat 

(SpragueDawley) 

4 wk ad lib (F) 

1.51 M 1.77 F 

Seacat et al. 2003 Potassium perfluorooctasulfonate 

35 Rat 

(SpragueDawley) 

14 wk ad lib (F) 

1.33 M 1.56 F 

Seacat et al. 2003 Potassium perfluorooctasulfonate 

Developmental 

36 Rat 

(SpragueDawley) 

Gd 2-21 1 x/d (GW) 

1 (reduced serum T4 in 

pups) 

2 (approximately 60% 

survival at weaning vs. 80% in controls) 

Lau et al. 2003 Potassium perfluorooctasulfonate 

37 Rat 

(SpragueDawley) 

90 d 1 x/d (GW) 

1.6 F (increased pup mortality 

during pnd 1-4) 

Luebker et al. 2005a Potassium perfluorooctasulfonate 

125

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

Exposure/ LOAEL 

***DRAFT FOR PUBLIC COMMENT***
60

0.4 1.6

126

0.4

1.6

82

10

177

0.1

1

57

1

10

79

1

5 20

a 

Key to Species 

Figure (Strain) 

38 Rat 

(SpragueDawley) 

39 Rat 

(SpragueDawley) 

40 Rat 

(SpragueDawley) 

41 Mouse 

(B6C3F1) 

42 Mouse 

(CD-1) 

43 Mouse 

(CD-1) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) 

80 d 1 x/d (GW) 

0.4 (slight but significant 

delayed eye opening) 

1.6 (decreased pup survival 

to post-partum day 21) 

90 d 1 x/d (GW) 

0.4 (>10% decrease in mean 

pup weight per litter on pnd 5) 

1.6 (approximately 50% 

decrease mean pup survival per litter on postnatal day 5) 

Gd 2-20 1 x/d (GW) 

10 F (increased incidences of 

cleft palate) 

Gd 1-17 1 x/d (GW) 

0.1 M 1 M (42.% suppressed NK 

cell activity in 8-week old mice) 

Gd 1-17 1 x/d (GW) 

1 (delayed eye opening) 10 (approximately 50% 

postnatal survival at weaning vs. 90% in controls) 

Gd 1-17 (GW) 1 F 5 F (increased incidences of sternal defects) 20 F (reduced percentage of live fetuses) 

Reference Chemical Form 

Luebker et al. 2005a Potassium perfluorooctasulfonate Luebker et al. 2005b Potassium perfluorooctasulfonate Thibodeaux et al. 2003 Potassium perfluorooctasulfonate Keil et al. 2008 Potassium perfluorooctasulfonate Lau et al. 2003 Potassium perfluorooctasulfonate Thibodeaux et al. 2003 Potassium perfluorooctasulfonate 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

LOAEL 
210

1.51.51.51.51.50.03

0.1

1.51.51.51.50.4

1.5

211

1.5

212

1.5

Duration/ 

a Frequency Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

CHRONIC EXPOSURE Systemic 

44 Rat 

(SpragueDawley) 

Immuno/ Lymphoret 

45 Rat 

(SpragueDawley) 

Neurological 

46 Rat 

(SpragueDawley) 

104 wk ad lib Resp 1.5 (F) 

Cardio 1.5 Gastro 1.5 Hemato 1.5 Musc/skel 1.5 Hepatic 0.03 M 0.1 M (increased incidence of 

cystic hepatocellular degeneration) 

Renal 1.5 Endocr 1.5 Dermal 1.5 Ocular 1.5 Bd Wt 0.4 F 1.5 F (14% reduction in final 

body weight) 

104 wk ad lib 1.5 

(F) 104 wk ad lib 1.5 (F) 

Reference Chemical Form 

Thomford 2002b Potassium perfluorooctasulfonate Thomford 2002b Potassium perfluorooctasulfonate Thomford 2002b Potassium perfluorooctasulfonate 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***

Exposure/ LOAEL 
213

1.5

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

Reproductive 

47 Rat 

(SpragueDawley) 

104 wk ad lib (F) 

1.5 Thomford 2002b 

Potassium perfluorooctasulfonate 

a The number corresponds to entries in Figure 3-4. ad lib = ad libitum; ALT = alanine aminotransferase; Bd Wt = body weight; BUN = blood urea nitrogen; (C) = capsule; Cardio = cardiovascular; d = day(s); Endocr = feed; F = Female; (G) = gavage; Gastro = gastrointestinal; Gd = gestational day; (GW) = gavage in water; Hemato = hematological; Immuno/Lymphoret = immunological/lymphoreticular; LOAEL = lowest-observed-adverse-effect level; M = male; Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect leveday; ppd = post-partum day; Resp = respiratory; T3 = triiodothyronine; T4 = thyroxine; TSH= thyroid-stimulating hormone; wk = week(s); x = time(s) 

Table 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
Hepati

EndocrBody ReprodDevelo

100 

3r 

10 

4m 

7h 

4m 

7h 

4m 

1 6h 

13m 

0.1 6h 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Le

2r 8r 9r 10r 

1r 3r 

4m 5m 11m 12m 

14h 

14h 

14h 

c 

ine

Weight 

uctive 

pmental 

Systemic

mg/kg/day 

Figure 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral 

Acute (≤14 days) 

PERFLUOROALKYLS ***DRAFT FOR PUBLIC COMMENT***

3. HEALTH EFFECTS

vel 

94
Respiratory 

100 

22m 22m 

22m 

10 

22m 21r 21r 

17r 32r 

16k 16k 16k 16k 16k 16k 16k 18r 21r 24k 31k 33r

19r 19r 19r 19r 19r 19r 25r 28r 34r

20r 20r 20r 17r 18r 20r 26r 29r 34r 35r

20r 20r 35r 

1 22m 21r 21r 21r 

15k 15k 15k 15k 15k 15k 15k 15k 15k 15k 15k 15k 23k 27k 30k 

18r 20r 18r 

20r 20r 

15k 15k 15k 30k 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level 

Cardiovascular 

Gastrointestinal 

Hematological 

Musculoskeletal 

Hepatic 

Renal 

Endocrine 

Dermal 

Ocular 

Body Weight 

Immuno/Lymphor 

Neurological 

Reproductive 

Figure 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (Continued)
 

Intermediate (15-364 days)
	

Systemic

PERFLUOROALKYLS ***DRAFT FOR PUBLIC COMMENT***

3. HEALTH EFFECTS

mg/kg/day 

95
Developme

100 

43m 

10 42m 

1 41m 42m 

0.1 41m 

43m 

43m 

36r 

40r 

37r 38r 39r 

36r 

38r 39r 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level 

ntal 

Figure 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (Continued)
 

mg/kg/day 

Intermediate (15-364 days)

PERFLUOROALKYLS ***DRAFT FOR PUBLIC COMMENT***

3. HEALTH EFFECTS

96
Respiratory 

Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Ocular Body Weight Immuno/Lymphor Neurological Reproductive 

mg/kg/day 

10 

44r 44r 44r 44r 44r 44r 44r 44r 44r 44r 45r 46r 47r 

1 

0.1 

.01 

44r 

44r 

44r 

0

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level 

Figure 3-4 Levels of Significant Exposure to Perfluorooctane Sulfonate - Oral (Continued)

Chronic (≥365 days) 

Systemic 

PERFLUOROALKYLS ***DRAFT FOR PUBLIC COMMENT***

3. HEALTH EFFECTS

97
185

120

197

54

223

184184184184184184184184184

203

20

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) System 

Resp

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Bd Wt Hepatic 

NOAEL 

(mg/kg/day) 

184 184

184184184

184184

184184

Less Serious 

(mg/kg/day) 

20 M (biochemical and 

ultrastructural evidence of peroxisome proliferation) 

Serious 

(mg/kg/day) 

120 F (LD50 in 30-day 

observation period) 

54 (all 10 mice died before 

day 14) 

Reference Chemical Form 

Harris et al. 1989 Kennedy 1987 3M 2007a Ikeda et al. 1985 

ACUTE EXPOSUREDeath 

1 Mouse 

(C57BL/6N) 

2 Mouse 

(CD-1) 

Systemic 

3 Rat 

(SpragueDawley) 

4 Rat 

(SpragueDawley) 

once (GO) 14 d ad lib (F) 5 d 1 x/d (GW) 14 d ad lib (F) 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral 

***DRAFT FOR PUBLIC COMMENT***

LOAEL 
204

1.2

2.4

4.7

9.5

205

55

194

5

10

1

5

188

40

a 

Key to 

Figure 

Species 

(Strain) 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

5 Rat 

(Wistar) 

1 wk ad lib (F) 

Hepatic 1.2 M 2.4 M (approximately 30% 

increase absolute liver weight) 

Kawashima et al. 1995 

Bd Wt 4.7 M 9.5 M (approximately 32% 

weight loss) 

6 Rat 

(SpragueDawley) 

once (GW) Hepatic 5 M Seacat and Luebker 20

Bd Wt 5 M 

7 Rat 

(SpragueDawley) 

14 d 1 x/d (GW) 

Hepatic 5 M 10 M (35% increase in total 

serum cholesterol) 

Shi et al. 2007 

Bd Wt 1 M 5 M (25% reduction in final 

body weight) 

8 Mouse 

(C57BL/6N) 

once (GO) Hepatic 40 F (69% increase in absolute liver weight in 2 

days) 

Brewster and Birnbaum 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

Exposure/ LOAEL 

***DRAFT FOR PUBLIC COMMENT***
190

3

6.4 12.8

186

40

8020

8040

80

198

0.5

199

78

78

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) 

LOAEL 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

9 Mouse 

(C57BL/6N) 

Gd 6-15 1 x/d (GO) 

Bd Wt 3 F 6.4 F (no weight gain on Gd 

6-18) 

12.8 F (weight loss during Gd 

6-18) 

Harris and Birnbaum 19

10 Mouse 

(C57BL/6N) 

once (GO) Cardio 40 F 80 F (significant decrease in relative heart weight) Harris et al. 1989 

Hepatic 20 F (85% increase in relative 

liver weight; peroxisome proliferation) 

Renal Bd Wt 

80 F 40 F 80 F (12% reduction in final 

body weight) 

11 Mouse 

(CD-1) 

14 d ad lib (F) 

Hepatic 0.5 (50-70% increase in 

absolute liver weight) 

Kennedy 1987 

12 Mouse 

(C57BL/6N) 

10 d ad lib (F) 

Hepatic 78 M (63% increase in 

absolute liver weight) 

Permadi et al. 1992 

Bd Wt 78 M 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
200

78

78

201

78

78

202

78

78

224

184

187

40

80

160

a 

Key to 

Figure 

Species 

(Strain) 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

13 Mouse 

(C57BL/6N) 

10 d ad lib (F) 

Hepatic 78 M (36% increase in 

absolute liver weight) 

Permadi et al. 1992 

Bd Wt 78 M (33% weight loss) 

14 Mouse 

(C57BL/6N) 

10 d ad lib (F) 

Hepatic 78 M (63% increase in 

absolute liver weight) 

Permadi et al. 1993 

Bd Wt 78 M 

15 Mouse 

(C57BL/6N) 

10 d ad lib (F) 

Hepatic 78 M (36% increase in 

absolute liver weight) 

Permadi et al. 1993 

Immuno/ Lymphoret 

16 Rat 

(SpragueDawley) 

5 d 1 x/d (GW) 

Bd Wt 

184 

78 M (33% weight loss) 

3M 2007a 

17 Mouse 

(C57BL/6N) 

once (GO) 40 F 80 F (28% decrease in relative spleen weight) 160 F (atrophy and lymphoid depletion of thymus and 

spleen) 

Harris et al. 1989 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

Exposure/ LOAEL 

***DRAFT FOR PUBLIC COMMENT***
225

184

226

184

193

1

5

189

3

6.4

10.8

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

5 d 1 x/d (GW) 

184 3M 2007a 

5 d 1 x/d (GW) 

184 3M 2007a 

14 d 1 x/d (GW) 

1 M 5 M (decreased serum 

testosterone and estradiol) 

Shi et al. 2007 

Gd 6-15 1 x/d (GO) 

3 6.4 (33% decrease fetal 

weight per litter) 

Harris and Birnbaum 19

once (G) 10.8 M Johansson et al. 2008 

a 

Key to Species 

Figure (Strain) 

Neurological 

18 Rat 

(SpragueDawley) 

Reproductive 

19 Rat 

(SpragueDawley) 

20 Rat 

(SpragueDawley) 

Developmental 

21 Mouse 

(C57BL/6N) 

22 Mouse 

(CD-1) 

247

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
241

900900900900900300

900

300

900

900900900

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

INTERMEDIATE EXPOSURE Systemic 

23 Rat 

(SpragueDawley) 

28 d 1 x/d (GW) 

System 

Resp 

NOAEL 

(mg/kg/day) 

900 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

3M 2001 

Cardio 900 Gastro 900 Hemato 900 Musc/skel 900 Hepatic 300 M 900 M (increased absolute and 

relative liver weight) 

Renal 300 F 900 F (increased absolute and 

relative kidney weight) 

Endocr 900 Ocular 900 Bd Wt 900 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

LOAEL 

***DRAFT FOR PUBLIC COMMENT***
227

10101010

0.3

110

3

310

10

110

3

10

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

24 Rat 42-56 d Resp 10 1 x/d (SpragueDawley) (GW)

Cardio 10 Gastro 10 Hemato 10 F 0.3 M Hepatic 1 M 3 M 

10 F 

Renal 3 M 10 M 

10 F 

Endocr 1 M 3 M 

10 F 

Bd Wt 10 

Hoberman and York 20

(increased prothrombin 

time) 

(increased liver weight; 

hypertrophy of centrilobular hepatocytes) 

(increased BUN) (hypertrophy-hyperplasia 

of thyroid follicular cells) 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

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215

1501501501501506

30

1506

30

150150150

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

25 Rat 

(SpragueDawley) 

28 d 1 x/d (GW) 

Resp 150 van Otterdiijk 2007a 

Cardio 150 Gastro 150 Hemato 150 Musc/skel Hepatic 

150 

6 M 30 M (increased absolute and 

relative liver weight) 

Renal 150 Endocr 6 M 30 M (hyperplasia/hypertrophy 

of follicular epithelium of the thyroid) 

Dermal 150 Ocular 150 Bd Wt 150 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
219

3030306

30

306

30

306

30

303030

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

30 van Otterdiijk 2007b 

30 

30 

6 30 M (reduced erythrocyte 

counts, hemoglobin, and hematocrit) 

30 

6 M 30 M (diffuse panlobular 

hepatocyte hypertrophy) 

30 

6 M 30 M (hypertrophy/hyperplasia 

of follicular epithelium of the thyroid gland) 

30 30 

30 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

26 Rat 

(SpragueDawley) 

90 d 1 x/d (GW) 

Resp 

Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Dermal Ocular Bd Wt 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
209

35

175

242

900

231

10

217

150

220

30

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

LOAEL 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

27 Mouse 

(CD-1) 

18 d Gd 1-17 1 x/d (GW) 

Hepatic 35 F 175 F (significant increase in 

absolute and relative liver weight) 

Das et al. 2008 

Immuno/ Lymphoret 

28 Rat 

(SpragueDawley) 

28 d 1 x/d (GW) 

900 3M 2001 

29 Rat 

(SpragueDawley) 

42-56 d 1 x/d (GW) 

10 Hoberman and York 20

30 Rat 

(SpragueDawley) 

28 d 1 x/d (GW) 

150 van Otterdiijk 2007a 

31 Rat 

(SpragueDawley) 

90 d 1 x/d (GW) 

30 van Otterdiijk 2007b 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
244

900

230

10

216

30 150

221

30

243

900

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

28 d 1 x/d (GW) 

900 3M 2001 

42-56 d 1 x/d (GW) 

10 Hoberman and York 20

28 d 1 x/d (GW) 

30 M 150 M (delayed pupillary reflex) van Otterdiijk 2007a 

90 d 1 x/d (GW) 

30 van Otterdiijk 2007b 

28 d 1 x/d (GW) 

900 3M 2001 

a 

Key to Species 

Figure (Strain) 

Neurological 

32 Rat 

(SpragueDawley) 

33 Rat 

(SpragueDawley) 

34 Rat 

(SpragueDawley) 

35 Rat 

(SpragueDawley) 

Reproductive 

36 Rat 

(SpragueDawley) 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

***DRAFT FOR PUBLIC COMMENT***
228

10

218

150

222

30

229

10

208

35

Duration/ 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) Reference Chemical Form 

42-56 d 1 x/d (GW) 

10 Hoberman and York 20

28 d 1 x/d (GW) 

150 van Otterdiijk 2007a 

90 d 1 x/d (GW) 

30 van Otterdiijk 2007b 

42-56 d 1 x/d (GW) 

10 F Hoberman and York 20

18 d Gd 1-17 1 x/d (GW) 

35 (eye opening delayed 

approximately 1 day) 

Das et al. 2008 

a 

Key to Species 

Figure (Strain) 

37 Rat 

(SpragueDawley) 

38 Rat 

(SpragueDawley) 

39 Rat 

(SpragueDawley) 

Developmental 

40 Rat 

(SpragueDawley) 

41 Mouse 

(CD-1) 

a The number corresponds to entries in Figure 3-5. ad lib = ad libitum; Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; (F) = feed; F = Female; Gastro = gastrointestinal; Gd = gestation

gavage in water; Immuno/Lymphoret = immunological/lymphoreticular; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; NOAno-observed-adverse-effect level; NS = not specified; PFBA = perfluorobutyric acid; PFDeA = perfluorodecanoic acid; PFDoA = perfluorododecanoic acid; PFNA = acid; PFOSA = perfluorooctanatesulfonamide; wk = week(s); x = time(s) 

Table 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (continued) 

Exposure/ LOAEL 

***DRAFT FOR PUBLIC COMMENT***
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Body Weight 

Systemic

mg/kg/day 

1000 

3r 3r 3r 3r 3r 3r 3r 3r 3r 

1m 

100 

10m 12m 13m 14m 15m 10m 10m 12m 13m 14m 15m 

2m 

10m 8m 10m 

10m 4r 

9m 

10 7r 5r 

9m 

6r 7r 6r 7r 5r 

9m 

5r 

5r 

1 7r 

11m 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level 

PERFLUOROALKYLS

3. HEALTH EFFECTS

110

***DRAFT FOR PUBLIC COMMENT***

Figure 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral 

Acute (≤14 days) 
Immuno/Lymphor 

Neurological Reproductive Developmental 

mg/kg/day 

1000 

16r 18r 19r 17m 

100 

17m 

17m 

10 22m

21m 

20r 

21m 

1 20r 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer 

Minimal Risk Level 

Figure 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (Continued)
 

Acute (≤14 days)

PERFLUOROALKYLS

3. HEALTH EFFECTS

111

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Respiratory 

Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Ocular Body Weight Immuno/Lymphor Neurological Reproductive Developmental 

Systemic 

mg/kg/day 

1000 23r 23r 23r 23r 23r 23r 23r 23r 23r 23r 28r 32r 36r 

23r 23r 

27m 25r 25r 25r 25r 25r 25r 25r 25r 25r 30r 34r 38r 

100 

27m 41m 26r 26r 26r 26r 26r 25r 26r 26r 25r 26r 26r 26r 26r 31r 34r 35r 39r 

10 24r 24r 24r 24r 24r 24r 24r 24r 24r 29r 33r 37r 40r 

26r 25r 26r 25r 26r 

24r 24r 24r 

1 24r 24r 

24r 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

 for effects

 other than

 Cancer

 Minimal Risk Level 

PERFLUOROALKYLS

3. HEALTH EFFECTS

112

***DRAFT FOR PUBLIC COMMENT***

Figure 3-5 Levels of Significant Exposure to Other Perfluoroalkyls - Oral (Continued)
 

Intermediate (15-364 days)
	
 

 

 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 113 

3. HEALTH EFFECTS 

related effects (Hoberman and York 2003). Dosing of rats with up to 900 mg/kg/day PFBuS by gavage 

for 28 days had no significant effect on the gross or microscopic morphology of the lungs and trachea 

(3M 2001). 

Cardiovascular Effects. 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 and 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). 

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 1.5 mg/kg/day of PFOS in the diet for 2 years 

had no significant gross or microscopic changes in the heart (Thomford 2002b). 

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; van Otterdiijk 2007a, 2007b). Dosing of rats with up to 10 mg/kg/day PFHxS by gavage for 40– 

60 days did not cause morphological alterations in the heart (Hoberman and York 2003). Similar lack of 

morphological alterations were reported in the heart and aorta from rats dosed with up to 900 mg/kg/day 

PFBuS by gavage for 28 days (3M 2001). 

Death in female C57BL/6N mice following administration of 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 of ≤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). 

Gastrointestinal Effects. No significant gross or microscopic alterations of the gastrointestinal tract 

were observed in male and female rats exposed to up 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 up 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

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PERFLUOROALKYLS 114 

3. HEALTH EFFECTS 

duration study in which Cynomolgus monkeys were exposed to up to 20 mg/kg/day APFO in a capsule 

for 26 weeks, no treatment-related alterations in the gastrointestinal tract were observed at termination 

(Butenhoff et al. 2002). 

Treatment of rats with up to approximately 1.5 mg/kg/day PFOS via the diet for 2 years did not induce 

morphological alterations in the gastrointestinal tract (Thomford 2002b). 

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; van Otterdiijk 2007a, 2007b). Similar findings were reported in intermediate-duration 

gavage studies in rats given doses of up to 10 mg/kg/day PFHxS or 900 mg/kg/day PFBuS (3M 2001; 

Hoberman and York 2003). 

Hematological Effects. Information on hematological parameters is available from a study of 

371 residents in the Little Hocking water district in southeastern Ohio where significant environmental 

exposure to PFOA via the water supply has been described (Emmett et al. 2006a). The cohort consisted 

of persons who had resided in the district for at least 2 years. The median age of the study group was 

50 years, 53.4% were females, and there were 43 children under the age of 18. The average PFOA 

concentration in the water supplied by the Little Hocking Water Association over a period of 3 years 

before the health evaluation was conducted was 3.5 μg/L. The population median serum PFOA was 

354 ng/mL (ppb) and the interquartile range was 184–571 ng/mL. Hematology parameters evaluated 

included hemoglobin, hematocrit, red blood cell indices, white cell count, and platelet count. No 

significant correlation between any of the parameters examined and serum PFOA was observed, whether 

the analysis included all the individuals as a group or separate analyses were done for adults or children. 

Assuming that adults consume 2 L of water per day and have a mean body weight of 70 kg, the daily dose 

of PFOA via the drinking water would have been 0.1 μg/kg/day. This rough estimate does not include 

exposure via food or contact with consumer products. 

No significant hematological alterations were reported in male and female rats dosed with up to 

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 in 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 0, 1.5, or 

15 mg/kg/day APFO, hematology tests performed at various times during the study showed changes in 

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PERFLUOROALKYLS 115 

3. HEALTH EFFECTS 

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). 

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). 

However, dosing with 1.3–1.6 mg/kg/day for 14 weeks resulted in a significant increase (45%) in 

segmented neutrophiles (Seacat et al. 2003). The biological significance of this finding was not discussed 

by the investigators. In a 4-week study, 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) in 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 high-dose 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 up to approximately 1.5 mg/kg/day PFOS in the diet 

(Thomford 2002b). 

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; van Otterdiijk 2007a). However, 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 (van Otterdiijk 2007b). This dose level also caused a reduction in 

mean corpuscular hemoglobin and reduced mean corpuscular hemoglobin 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. 

Treatment of male rats with doses ≥0.3 mg/kg/day PFHxS by gavage for at least 42 days significantly 

increased prothrombin time (Hoberman and York 2003). Doses ≥1 mg/kg/day significantly decreased 

hemoglobin concentration, whereas ≥3 mg/kg/day decreased erythrocyte count and hematocrit. 

Treatment of female rats with up to 10 mg/kg/day PFHxS did not significantly alter hematological 

parameters (Hoberman and York 2003). No significant hematological alterations were reported in rats 

dosed with up to 900 mg/kg/day PFBuS by gavage for 28 days (3M 2001). 

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PERFLUOROALKYLS 116 

3. HEALTH EFFECTS 

Musculoskeletal Effects. No gross or microscopic alterations were reported in the sternum from rats 

following dietary dosing with approximately up to 100–110 mg/kg/day APFO for 90 days (Griffith and 

Long 1980) or in the femur, sternum, and thigh skeletal muscle from Cynomolgus monkeys dosed with 

up to 20 mg/kg/day APFO in a capsule for 26 weeks (Butenhoff et al. 2002). 

Treatment of monkeys with up to 0.75 mg/kg/day PFOS (potassium salt) in 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 1.5 mg/kg/day PFOS in the 

diet for 2 years (Thomford 2002b). 

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 in skeletal muscle (van Otterdiijk 2007a, 2007b). Treatment of rats with up to 900 mg/kg/day 

PFBuS by gavage for 28 days did not induce morphological alterations in skeletal muscle (3M 2001). 

Hepatic Effects. No evidence of adverse liver function was observed among the 371 individuals with 

high levels of PFOA in the water supply and verified high serum PFOA levels evaluated by Emmett et al. 

(2006b). The assessment included total serum cholesterol, serum transaminases, alkaline phosphatase, 

and serum bilirubin. In 13 individuals with liver disease (information provided by the individuals), the 

mean serum PFOA was higher than in individuals without liver disease (527 vs. 441 ng/mL), but the 

difference was not statistically significant. 

The liver is the main target organ for perfluoroalkyl compounds in animals following short- or long-term 

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. Due to the high volume of 

information on this subject, representative examples are summarized below. 

Administration of doses of 16 mg/kg/day PFOA to rats via the diet for 7 days resulted in a 66% increase 

in absolute liver weight (Haughom and Spydevold 1992). These investigators also reported a rapid 

reduction in serum cholesterol and triacylglycerols, possibly due to reduced activity of hydroxymethyl 

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PERFLUOROALKYLS 117 

3. HEALTH EFFECTS 

glutaric acid Co-A reductase (HMG-CoA reductase), the rate-limiting enzyme in cholesterol synthesis 

and of acyl-CoA cholesterol acetyl transferase, the enzyme responsible for esterification of cholesterol. 

These findings suggested that the hypolipidemic effects of PFOA may result from impaired production of 

lipoprotein particles due to reduced synthesis and esterification of cholesterol together with enhanced 

oxidation of fatty acids in the liver. 

Administration of a range of doses between 0.2 and 40 mg/kg/day PFOA to male rats for 14 days induced 

a dose-related increase in absolute liver weight, which achieved statistical significance with a 

2 mg/kg/day dose level (34% increase) (Liu et al. 1996). β-Oxidation activity was also significantly 

increased at this dose level, whereas hepatic microsomal concentration of total cytochrome P-450 was 

significantly increased at 20 mg/kg/day, suggesting different sensitivities for different end points. 

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 total deoxyribonucleic acid (DNA) was not significantly changed, indicating that 

the hepatomegaly represented hypertrophy rather than hyperplasia (Pastoor et al. 1987). In this study, 

treatment with PFOA increased membrane-bound enzymes such as cytochrome P-450 content and the 

activity of benzphetamine N-demethylase, indicating proliferation of the smooth endoplasmic reticulum. 

However, soluble enzymes such as glutathione S-transferase and UPD-glucuronyltransferase were not 

affected. The activity of carnitine acetyltransferase was disproportionally increased relative to carnitine 

palmitoyltransferase, indicating predominant proliferation of peroxisomes vs. mitochondria. Light and 

electron microscopy confirmed the proliferation of the endoplasmic reticulum, mitochondria, and 

peroxisomes. Preferential proliferation of peroxisomes over mitochondria, as measured by specific 

markers, was also reported by Iwai and Yamashita (2006) in a similar study in rats. 

In mice, administration of a relatively low dose of 1 mg/kg/day PFOA for 10 days resulted in a 

35% increase in absolute liver weight, which correlated with a significant increase in peroxisome 

proliferation, as measured by increased acyl-CoA oxidase activity (Yang et al. 2001). However, in a 

subsequent study, the same group of investigators reported that exposure of PPARα-null mice to PFOA 

induced hepatomegaly to the same extent as in wild mice, but failed to increase acyl-CoA oxidase 

activity, suggesting that, at least in mice, hepatomegaly induced by PFOA is not a PPARα-dependent 

process (Yang et al. 2002b). 

Intermediate-duration studies in male rats have reported liver effects at relatively low doses of PFOA. 

For example, in a 13-week dietary study, palmitoyl CoA oxidase activity was significantly increased in 

the 1.94 and 6.5 mg/kg/day groups on weeks 4, 7, and 13 and in the 0.64 mg/kg/day group on week 4 

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PERFLUOROALKYLS 118 

3. HEALTH EFFECTS 

(Perkins et al. 2004). The maximum increase occurred on week 7. By recovery day 21, enzyme activity 

was comparable in all groups. There were no major incidences of gross lesions among the various 

groups. Liver weight relative to body weight was significantly increased at ≥0.64 mg/kg/day on week4 

and at ≥1.94 mg/kg/day on weeks 7 and 13. The level of PFOA in blood in the 0.64 mg/kg/day group on 

week 4 was 55,000 ng/mL. Liver to brain weight was also increased at 1.94 and 6.5 mg/kg/day on weeks 

4 and 7. In rats allowed to recover after treatment ceased, relative liver weights were comparable among 

groups on recovery day 21. Absolute liver weight also increased at ≥0.64 mg/kg/day on weeks 4, 7, and 

13. Microscopic changes in the liver occurred at ≥0.64 mg/kg/day and consisted of minimal-to-slight 

hepatocellular hypertrophy. By recovery day 21, the microscopic changes had disappeared. Serum levels 

of PFOA increased proportionally with dose, but there was no increase after week 4. A maximum 

concentration of PFOA of 159,000 ng/mL was detected in high-dose rats on week 4. By day 21 of 

recovery, levels of PFOA in serum were below or near the detection limit (700 ng/mL). 

Treatment of male and female mice with approximately 5.3 mg/kg/day PFOA in the diet for 21 days 

induced a 39–41% increase in absolute liver weight (Kennedy 1987). The same dose of PFNA for 

14 days increased absolute liver weight by 178–190% (Kennedy 1987). In mice dosed with 

approximately 5–6 mg/kg/day for 28 days, absolute liver weight of males and females was increased 2– 

3-fold (Griffith and Long 1980). All livers that were examined microscopically showed panlobular 

diffuse hypertrophy of hepatocytes accompanied by focal to multifocal cytoplasmic lipid vacuoles. In a 

developmental study, maternal absolute liver weight dams treated with 1 mg/kg/day on gds 1–17 

increased by 38% by gd 18 relative to controls; the concentration of PFOA in serum on gd 18 was 

approximately 22,000 ng/mL (Lau et al. 2006). In another developmental study, absolute and relative 

weight of rats exposed to 1 mg/kg/day on gds 1–17 was significantly increased at weaning; in dams that 

had live pups at weaning, serum PFOA was 9,290 ng/mL, whereas in dams that had no pups surviving till 

weaning, serum PFOA was 26,300 ng/mL (Abbott et al. 2007). In a more recent study, administration of 

0.5 mg/kg/day PFOA in the drinking water for 21 days induced a 27% increase in relative liver weight; 

doses of 47 mg/kg/day induced a 262% increase (Son et al. 2008). Serum ALT was significantly 

increased at 2.6 mg/kg/day (3-fold) and AST at 18 mg/kg/day (3-fold). Doses of 18 mg/kg/day induced 

disruption of the hepatic plate and marked hepatocytomegaly with acidophilic cytoplasm. Mice dosed 

with 47 mg/kg/day also showed diffuse hepatic damage characterized by multifocal coagulation and 

liquifaction necrosis. There was no inflammatory reaction. In a study of wild-type mice and PPARα-null 

mice exposed to PFOA during gds 1–17, absolute liver weight was significantly increased in wild mice at 

1 mg/kg/day and in PPARα-null mice at 3 mg/kg/day (Abbott et al. 2007), in agreement with the findings 

of Yang et al. (2002b) that suggested that hepatomegaly is not a PPARα-dependent process in mice. 

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PERFLUOROALKYLS 119 

3. HEALTH EFFECTS 

Rhesus monkeys appear to be far less sensitive to the liver effects of PFOA than rats and mice since daily 

gavage administration of up to 10 mg/kg/day for 90 days did not induce gross or microscopic alterations 

in the liver or alter the activity of serum transaminases (Griffith and Long 1980). In a preliminary study 

to a 26-week capsule study in Cynomolgus monkeys, administration of up to 20 mg/kg/day PFOA for 

4 weeks did not affect gross or microscopic liver morphology and did not induce alterations in clinical 

tests used to assess liver function (Thomford 2001). In addition, cell proliferation was not increased in 

the liver. In the 26-week study, administration of 3, 10, or 20 mg/kg/day PFOA in a capsule caused no 

significant treatment-related effects on clinical chemistry in the 3 and 10 mg/kg/day dose groups, but 

serum triglycerides were significantly increased in the high-dose group on days 31, 63, and 91 (Butenhoff 

et al. 2002). Dose-dependent increases in absolute liver weight (associated with mitochondrial 

proliferation) occurred in all ammonium PFOA-treated groups, in the absence of histopathologic evidence 

of hepatotoxicity (36, 38, 50% increase in the 3, 10, and 30 mg/kg/day groups, respectively). Relative 

liver weight was increased 19, 22, and 57% in the treated groups after 6 months of dosing. Except for the 

high-dose group, there were no significant changes in hepatic DNA content or enzymes that are specific 

markers of subcellular fractions. Mean PFOA serum concentrations at or after week 6 in the 3, 10, and 

20 mg/kg/day dose groups were 77,000, 86,000, and 158,000 ng/mL, respectively. 

A 2-year dietary study in male and female rats dosed with 1.5 or 15 mg/kg/day PFOA reported significant 

clinical alterations only in males consisting of increased serum ALT (low- and high-dose at 3, 6, 12, and 

18 months), increased AST (low- and high-dose at 6 months, high-dose at 24 months), increased albumin 

(low- and high-dose at 3 and 6 months; high-dose at 12, 18, and 24 months), increased AP (low- and 

high-dose at 3 and 6 months; high-dose at 12, 18, and 24 months), and decreased creatine phosphokinase 

(low- and high-dose at 3 months) (3M 1983). At the 1-year interim sacrifices, high-dose males (low-dose 

rats were not evaluated) had statistically significantly elevated relative liver weight (20%). Histological 

evaluations at the 1-year time point (only control and high-dose rats were examined) revealed effects 

confined mostly to the liver of males consisting of diffuse hepatomegalocytosis, hepatocellular necrosis, 

portal mononuclear cell infiltration, and mild hepatocellular vacuolation (females). Significant 

histopathology after 2 years of treatment was restricted to rats in the high-dose group and included 

megalocytosis in the liver (males and females), cystoid degeneration in the liver (males), and portal 

mononuclear cell infiltration (males). 

Studies in animals also suggest that the liver is the main target following oral exposure to PFOS. Rats 

dosed with 15 mg/kg/day PFOS for 7 days had a 40% increase in absolute liver weight (Haughom and 

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Spydevold 1992). As with PFOA, PFOS induced a significant and rapid reduction in cholesterol and 

triacylglycerols in serum. PFOS also increased markedly the concentration of triacyglycerols in the liver, 

suggesting that it inhibits excretion of these compounds from the liver; this effect was not seen with 

PFOA. 

In a 4-week dietary study with PFOS in rats, relative liver weight in high-dose males (1.51 mg/kg/day) 

and females (1.77 mg/kg/day) was increased 22 and 8%, respectively (Seacat et al. 2003). Absolute liver 

weights were not significantly altered. Liver palmitoyl CoA oxidase, as an index of peroxisome 

proliferation, was not elevated when tested in one laboratory and was less than doubled in high-dose 

males when measured in a different laboratory, suggesting no significant peroxisome proliferation. Light 

microscopy of the liver did not show any abnormal findings; cell proliferation was not statistically 

increased. Extending the exposure to 14 weeks resulted in the following statistically significant changes 

in high-dose males (1.33 mg/kg/day): increased absolute liver weight (30%); increased relative liver 

weight (34%); decreased serum cholesterol (42%); and increased serum ALT activity (80%). High-dose 

females (1.56 mg/kg/day) only showed a significant increase in relative liver weight (30%). The 

concentration of PFOS in liver and serum increased proportionally with cumulative dose. Females had 

31–42% higher serum PFOS than males; liver concentrations were comparable. After 14 weeks of 

treatment, the mean serum PFOS concentrations in high-dose males (1.33 mg/kg/day) and females 

(1.56 mg/kg/day) were 148,000 and 223,000 ng/mL, respectively. As a percentage of the cumulative 

dose, the amount of PFOS in serum remained relatively constant among groups and between sexes; 

however, in the liver, it varied widely with a range of 15–57%. Assays for palmitoyl CoA oxidase in the 

liver provided no evidence of peroxisome proliferation. There was also no evidence of cell proliferation. 

For the most part, morphological changes were restricted to the liver of high-dose rats and consisted of 

centrilobular hepatocyte hypertrophy and midzonal to centrilobular vacuolation. 

Treatment of Cynomolgus monkeys with up to 2 mg/kg/day PFOS in 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 longer-term study in Cynomolgus monkeys dosed with 0, 0.03, 0.15, or 

0.75 mg/kg/day PFOS, absolute liver weight in high-dose males and females was increased 55 and 47%, 

respectively, relative to controls after 183 days of treatment (Seacat et al. 2002). Liver weight relative to 

body weight and brain weight was also significantly increased in high-dose males and females. No 

anatomic pathology occurred in low- or mid-dose animals. The average liver/serum PFOS concentration 

ranged from 0.9/1 to 2.7/1, without a dose-response relationship. The average percent of the cumulative 

dose of PFOS found in the liver at termination ranged from 4.4 to 8.7% without apparent correlation to 

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dose or gender. The mean concentrations of PFOS in serum in high-dose males and females after 

183 days of treatment were 173,000 and 171,000 ng/mL, respectively. Significant clinical chemistry 

changes consisted of a decrease in total cholesterol in high-dose males and females on days 91, 153, and 

182. On day 182, total cholesterol decreased to 35 and 53% of predosing values in males and females, 

respectively. The HDL concentration was significantly lower in low- and high-dose males on days 153 

and 182 and in mid- and high-dose females on days 153 and 182. Serum bilirubin was significantly lower 

in high-dose males on days 91, 153, and 182. Liver peroxisome proliferation was significantly increased 

in high-dose females, but not enough to be considered biologically significant. Cell proliferation in liver 

was not significantly altered at day 182. Light microscopy of liver sections showed centrilobular 

vacuolation, hypertrophy, and mild bile stasis in some high-dose monkeys. Electron microscopy showed 

lipid-droplet accumulation in some high-dose males and females. Increased glycogen content was also 

noted in the high-dose group. Observations conducted during a recovery period of up to 1 year showed 

that the elimination of PFOS from serum of high-dose monkeys appeared to be multiphasic, whereas that 

for the mid-dose group was linear. For both groups, the elimination half-life was approximately 

200 days. There were no differences between males and females. PFOS in liver decreased substantially 

during the recovery period. One year after cessation of treatment, PFOS in liver from mid-dose monkeys 

were approximately 19% of the concentration measured at the end of treatment. Serum cholesterol in 

high-dose monkeys returned to pretreatment levels by day 36; HDL values returned to control levels 

within 61 days of cessation of treatment in the mid- and high-dose groups. Samples of liver collected 

after 7 months of recovery showed complete recovery of pathology by light and electron microscopy. 

The same observations were made after 1 year of recovery. 

In a 2-year study of PFOS in rats, at termination, hepatotoxicity characterized by centrilobular 

hypertrophy, centrilobular eosinophilic hepatocytic granules, and centrilobular hepatocytic vacuolation 

was noted in rats that received doses of PFOS of approximately 0.4 and 1.5 mg/kg/day in the diet 

(Thomford 2002b). Also reported was a significant increase in the incidence of eosiniphillic clear cell 

altered foci and cystic hepatocellular degeneration in male rats dosed with ≥0.1 mg/kg/day PFOS. 

Observations made in a group of rats treated only for 52 weeks and allowed to continue in the study for an 

additional year showed that hepatoxicity 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. Treatment with PFOS did not induce 

peroxisome proliferation or cell proliferation in the liver. 

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Considerable less information exists on liver effects in animals exposed orally to other perfluoroalkyl 

compounds. 

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. Administration of approximately 20 mg/kg/day 

PFBA in the diet to male Sprague-Dawley rats for 2 weeks did not significantly affect relative liver 

weight, but the same dose of PFOA induced a 45% increase (Ikeda et al. 1985). Catalase activity in liver 

homogenates was increased 42% by PFBA and by 56% by PFOA; both chemicals induced peroxisome 

proliferation. Dietary administration of doses of approximately 78 mg/kg/day PFBA to male 

C57BL/6 mice for 10 days induced a 63% increase in absolute weight, compared with 90 and 36% for 

PFOA and PFDeA, respectively (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 which 

were not as marked as those induced by PFOA. Doses of 78 mg/kg/day PFBA also had no significant 

effect on parameters of peroxisomal fatty acid β-oxidation (Permadi et al. 1993). 

More recent intermediate-duration studies with PFBA that evaluated a wide range of end points suggest 

that the liver is a target for this perfluoroalkyl compound. Dosing rats with 30 mg/kg/day PFBA by 

gavage for 28 days resulted in a significant increase in absolute and relative liver weight; the NOAEL was 

6 mg/kg/day (van Otterdiijk 2007a). The 30 mg/kg/day also significantly decreased serum cholesterol. 

Doses 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, the highest dose tested, 30 mg/kg/day, 

increased absolute liver weight by 23%, increased serum alkaline phosphatase activity, and reduced total 

serum protein (van Otterdiijk 2007b). Microscopically, PFBA caused diffuse panlobular hepatocyte 

hypertrophy. None of these effects were observed after a 21-day recovery period; the NOAEL was 

6 mg/kg/day. 

An intermediate-duration study with PFHxS in rats reported that gavage doses ≥3 mg/kg/day induced a 

significant increase in absolute liver weight and in liver/body weight and liver/brain weight ratios in 

males (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, decreased serum triglycerides at 10 mg/kg/day, and increased serum albumin, alkaline 

phosphatase activity, and albumin/globulin ratio at 10 mg/kg/day. None of these alterations were 

observed in female rats. Treatment of male rats with 900 mg/kg/day PFBuS by gavage for days induced a 

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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. 

Administration of single gavage doses of ≥20 mg/kg PFDeA to female C57BL/6N mice resulted in 

significant and dose-related increases in relative liver weight, assessed 30 days after dosing (Harris et al. 

1989). In mice treated with 20 mg/kg, the lowest dose tested, relative liver weight increased 85% relative 

to controls. All treated mice that survived until the end of the study (30 days) showed periportal to 

panlobular hepatocellular hypertrophy characterized by swollen hepatocytes with abundant granular 

eosinophilic cytoplasm and enlarged and hyperchromatic nuclei. Also present were bile duct hyperplasia 

and hepatocellular necrosis. Ultrastructurally, the hepatocytes showed proliferation of peroxisomes, 

increases in smooth endoplasmic reticulum, and disruption of the rough endoplasmic reticulum. Time 

course studies showed significant elevations in liver weight (69%) in mice 2 days after treatment with 

40 mg/kg PFDeA (Brewster and Birnbaum 1989). That dose level also significantly increased hepatic 

acyl-CoA oxidase activity and hepatic lipids after 2 days of treatment. In both the Harris et al. (1989) and 

Brewster and Birnbaum (1989) studies, experiments conducted in congenic mice differing at the Ah locus 

showed that the hepatic morphological and biochemical effects of PFDeA are independent of the 

Ah receptor. 

Kawashima et al. (1995) compared the effects of lower dietary doses of PFDeA (1.2–9.5 mg/kg/day) and 

PFOA (2.4–38 mg/kg/day) on hepatic effects in male rats in a 7-day dietary study. PFDeA was 

considerably more potent than PFOA in reducing body weight gain and food consumption, and causing 

hepatomegaly, but PFDeA was only 1.5-times more potent than PFOA in inducing biochemical markers 

of peroxisome proliferation. Both chemicals had comparable potencies in elevating hepatic cholesterol 

and triacylglycerol, but only PFOA elevated hepatic phospholipids. PFDeA lowered the activity of 

GSH-related enzymes in the same manner as PFOA. Electron microscopy showed that both compounds 

increased cell size and caused peroxisome proliferation, but 9.5 mg/kg/day PFDeA increased the number 

of lipid droplets containing amorphous material, indicating marked toxicity to hepatocytes. 

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 with 1 or 

5 mg/kg/day PFDoA, there was a trend for decreased serum triglycerides but the differences with controls 

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were not statistically significant (Zhang et al. 2008). Liver triglycerides and liver cholesterol were not 

affected at these dose levels. Single doses of ≥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]). 

Renal Effects. In the community health evaluation conducted by Emmett et al. (2006a) mentioned 

above, neither BUN nor serum creatinine levels were significantly associated with serum PFOA levels, so 

that there was no evidence for impaired kidney function. 

Significantly elevated absolute and relative kidney weight was reported in male rats dosed daily 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 effected (Son et al. 

2008). Treatment of Cynomolgus with daily doses of up to 20 mg/kg/day APFO in a capsule for 

26 weeks (Butenhoff et al. 2002) or of 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), and BUN and urinalyses (several times during the study) were not 

significantly affected (3M 1983). 

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) for 4 weeks (Seacat et al. 

2003). However, 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) in 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 

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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 0.4 or 1.5 mg/kg/day PFOS in the diet for 53 weeks 

in a 2-year study (Thomford 2002b). However, there were no significant gross or microscopic alterations 

in the kidneys at week 53 or at termination. 

No alterations in renal morphology or clinical indication of impaired renal function was reported in rats 

treated with PFBA in doses of up to 184 mg/kg/day for 5 days, 150 mg/kg/day for 28 days, or 

30 mg/kg/day by gavage for 90 days (3M 2007a; van Otterdijk 2007a, 2007b). 

Male rats treated by gavage with 10 mg/kg/day PFHxS for at least 42 days showed a significant increase 

in BUN, but there were no significant gross or microscopic alterations in the kidneys (Hoberman and 

York 2003). The NOAEL was 3 mg/kg/day. No significant effect on BUN was reported in female rats. 

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 liver 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. 

Administration of a single dose of up to 80 mg/kg PFDeA to female C57BL/6N mice by gavage did not 

induce gross of 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. 

Endocrine Effects. Serum level of TSH were not correlated with PFOA in the health evaluation of 

371 individuals whose water supply had high levels of PFOA and whose mean serum PFOA levels were 

significantly higher than the general U.S. population (Emmett et al. 2006a). Separate analyses of adults 

and children (≤18 years old) did not change the results. In addition, study individuals with thyroid 

disease (information provided by the individual) had lower levels of PFOA (387 ng/mL) than individuals 

without thyroid disease (451 ng/mL), but the difference between the two groups was not statistically 

significant. 

Effects on the levels of hormones related to reproductive function are discussed in Section 3.2.2.3, 

Reproductive Effects. 

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In a 2-generation study in rats, daily treatment of the parental generation with 0, 1, 3, 10, or 30 mg/kg/day 

APFO by gavage in water for 70–90 days produced an increased incidence of hypertrophy and/or 

vacuolation of the zona glomerulosa of the adrenal gland from high-dose males (Butenhoff et al. 2004b). 

The respective incidences were 0/10, 0/10, 0/10, 2/10, and 7/10. This effect was also observed in 

F1 generation males treated with the same dose level. No explanation was apparent for this finding. In 

rats dosed with up to 15 mg/kg/day APFO in the diet for 2 years, there were no significant 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, however, 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 and 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 in a capsule to Cynomolgus monkeys for 4 weeks did not 

significantly alter free thyroxine (FT4), total thyroxine (TT4), free triiodothyronine (FT3), total 

trioodothyronine (TT3), or TSH (Thomford 2001). Serum T4 and TT4 were significantly reduced in 

Cynomolgus monkeys dosed with 10 mg/kg/day APFO in 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 FT3, TT3, or 

TSH, and thyroid histology was unremarkable. 

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/day by gavage in water (only dose level tested) reduced 

serum TT4 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 TT4. 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). 

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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 of ≥0.4 mg/kg/day (the lowest dose tested) caused a significant and dose-related 

reduction in TT4 in maternal serum on postpartum day 5 (Luebker et al. 2005b). FT4 and TSH were not 

significantly affected. Exposure of pregnant rats to ≥1 mg/kg/day PFOS on gds 2–20 induced significant 

reductions in TT4 and FT4 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 TT4 on gd 6 in mice dosed with 20 mg/kg/day PFOS on gds 1–17 

(Thibodeaux et al. 2003). No alterations in TT4 were reported in mice dosed with 15 mg/kg/day. No 

information was provided regarding other thyroid hormones. 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 TT3 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 TT3 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 1.5 mg/kg/day PFOS in the diet for 2 years (Thomford 2002b). 

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). However, 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 (van Otterdiijk 2007a, 2007b). These changes were not 

observed following a 3-week recovery period. Van Otterdiijk (2007a, 2007b) suggested that the thyroid 

lesion likely reflected an increase in thyroxine producing follicular cells in response to feedback 

mechanisms from the increase turnover of thyroxine by the hypertrophic hepatocytes. None of these 

studies measured thyroid hormones or TSH in serum. 

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Changes in the thyroid similar to those reported for PFBA by van Otterdiijk (2007b) were reported in 

male rats treated with ≥3 mg/kg/day PFHxS for at least 42 days (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 plasma turnover of thyroxine 

and associated stimulation of TSH. Neither thyroid hormones nor TSH were measured in the study. 

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. 

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). The toxicological significance of this finding was not discussed by the investigators. 

Dermal Effects. The only information available in animals is that exposure of rats to up 

approximately 100–110 mg/kg/day APFO via the diet for 90 days did not induce gross or microscopic 

alterations in the skin (Griffith and Long 1980). Similar results were reported in 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). 

Administration of up to approximately 1.5 mg/kg/day PFOS to rats in the diet for 2 years did not induce 

morphological alterations in the skin (Thomford 2002b). 

There were no significant gross or microscopic alterations in the skin of rats treated with up to 

150 mg/kg/day PFBA for 28 days or 30 mg/kg/day PFBA for 90 days (van Otterdiijk 2007a, 2007b). 

Ocular Effects. Examination of the eyes from rats fed a diet that provided up to approximately 100– 

110 mg/kg/day APFO 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). 

No gross or microscopic alterations were observed in the eyes from rats exposed through the diet to up to 

1.77 mg/kg/day PFOS in the diet for 4 weeks or up to 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 in a capsule for 

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4 weeks (Thomford 2002a), or up to 0.75 mg/kg/day PFOS in a capsule for 26 weeks (Seacat et al. 2002), 

or in rats dosed with up to 1.5 mg/kg/day in the diet for 2 years (Thomford 2002b). 

Examination of the eyes of rats treated with up to 150 mg/kg/day PFBA for 28 days or 30 mg/kg/day for 

90 days did not reveal any significant alterations (van Otterdiijk 2007a, 2007b) (see also Neurological 

Effects). Gross and microscopic examinations of the eyes of rats treated with up to 900 mg/kg/day 

PFBuS for 28 days were unremarkable (3M 2001). 

Body Weight Effects. Reductions in body weight or body weight gain are typical, although not 

particularly sensitive, responses of rodents to exposure to perfluoroalkyl compounds. In many cases, this 

effect is not associated with reduced food intake, and in some cases, exposed animal 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 PPARαnull mice did not cause a reduction in weight gain, suggesting that the effect on body weight is a specific 

effect of peroxisome proliferators rather than a toxic effect (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 during gds 1–17 with ≥10 mg/kg/day APFO (Lau et al. 2006). 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). 

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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). 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 results in significant reductions in weight gain (Grasty et al. 2003). In pregnant mice, 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, 2007a, 2007b). Pregnant rabbits appeared to be more sensitive as 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 in 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 2-year dietary study in 

rats, final mean body weight of females that received doses of approximately 1.5 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 (Thomford 2002b). No significant effect (<10% difference 

with controls) was seen in females dosed with ≤0.4 mg/kg/day PFOS. 

Information for other perfluoroalkyl compounds discussed in this document is limited. For example, 

dosing of male C57BL/6 mice with approximately 78 mg/kg/day PFBA via the diet for 10 days did not 

significantly alter body weight compared to ad libitum controls, but the same dose of PFOA or PFDeA 

caused 13 and 33% reductions in body weight, respectively (Permadi et al. 1992). Dosing with 

184 mg/kg/day PFBA for 5 days also did not affect body weight (3M 2007a). Similar findings were 

reported in rats dosed with 150 mg/kg/day PFBA for 28 days or 30 mg/kg/day PFBA for 90 days (van 

Otterdiijk 2007a, 2007b). 

Treatment of rats with up to 10 mg/kg/day PFHxS by gavage for 40–60 days did not significantly affect 

body weight (Hoberman and York 2003). Mean terminal body weights were within 10% of the body 

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weight of a control group. Food consumption was not affected by treatment with PFHxS. Similar results 

were reported in rats administered up to 900 mg/kg/day PFBuS by gavage for 28 days (3M 2001). 

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). 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 et al. 1989). Food consumption data 

were not provided in any of these studies. 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological and lymphoreticular effects in humans following oral 

exposure to perfluoroalkyl compounds. 

Limited information was located regarding immunological end points in rats exposed to perfluoroalkyl 

compounds. In an acute-duration study, male rats were exposed to up to 50 mg/kg/day PFOA by gavage 

for 14 days (Iwai and Yamashita 2006). This treatment did not significantly affect the absolute or relative 

spleen weight nor did it alter lymphocyte subsets or the numbers of T cells, natural killer (NK) cells, or 

helper T cells. Intermediate-duration studies did not find morphological alterations in lymphoreticular 

organs from rats dosed with approximately 110 mg/kg/day PFOS (Griffith and Long 1980) and similar 

results were reported in a 2-year study in rats dosed with up to 15 mg/kg/day PFOA (3M 1983). 

Dosing of Cynomolgus monkeys with up to 20 mg/kg/day PFOA in a capsule for 4 weeks did not affect 

the gross or microscopic morphology of the spleen (Thomford 2001). Similar results were reported in a 

26-week study in Cynomolgus monkeys (Butenhoff et al. 2002). However, dosing of Rhesus monkeys 

with 30 mg/kg/day PFOA by gavage 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). 

A series of studies in mice have been conducted by Yang and coworkers. Treatment of male mice with 

30 mg/kg/day PFOA for 10 days induced severe thymus atrophy (Yang et al. 2000). Absolute and 

relative thymus weights were reduced 86 and 83%, respectively. Total and relative thymic DNA content 

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was significantly decreased. Absolute and relative spleen weights were reduced 30 and 23%, 

respectively, and total DNA in the spleen was reduced by half, but relative DNA content was unchanged. 

In a time course study, liver weight was significantly increased by day 2, but thymus and spleen weight 

were decreased by day 5. After 7 days of treatment with PFOA, the total number of thymocytes and 

splenocytes decreased significantly. Surface marker analysis showed that PFOA dramatically altered the 

phenotypic distribution of thymocytes. Analysis of isolated splenocytes showed decreases in the number 

of T cells (CD3) and in B cells (CD19). There were also decreases in both T-helper (CD4+

) and 

T-cytotoxic cells (CD8+

) in the splenocytes. Flow cytometry experiments showed that PFOA inhibited 

thymocyte proliferation, but in splenocytes, it only decreased the proportion of cells in the S phase. 

PFOA did not affect thymocytes or splenocytes in vitro, suggesting that thymic and splenic atrophy by 

PFOA may involve an indirect pathway, perhaps via altering fatty acid transport and/or metabolism 

(Yang et al. 2001). In a subsequent study, Yang et al. (2002a) reported that treatment of male mice with 

approximately 24 mg/kg/day PFOA significantly decreased both the numbers of splenocytes producing 

antibodies toward horse red blood cell (HRBC) and the titers of specific anti-HRBC antibodies in the 

sera, suggesting that PFOA also impairs splenocyte function. To determine the possible involvement of 

PPARα in the immunomodulation caused by PFOA, Yang et al. (2002b) conducted experiments in wild 

and PPARα-null mice (KO). In wild mice, PFOA induced significant reductions in spleen weight (40%) 

and thymus weight (79%), as well as in splenocytes and thymocytes. In KO mice, PFOA did not affect 

spleen weight or the number of splenocytes, but partially decreased thymus weight and the number of 

thymocytes, indicating that the effect on the spleen is PPARα-dependent, whereas the decrease in thymus 

weight is only partially dependent. Also attenuated in KO mice was the decrease in the size of the CD4+ 

and CD8+ population of cells in the thymus and in the number of thymocytes in the S and G2/M phases of 

the cell cycle. In addition, the response of splenocytes isolated from the spleen of null mice treated with 

PFOA was not reduced. Collectively, the data indicated that PPARα plays a major role in the 

immunomodulation caused by PFOA in mice. 

Recently, Dewitt et al. (2008) conducted dose-response analysis studies of PFOA in female C57BL/6N 

mice and reported a LOAEL of 3.75 mg/kg/day PFOA, the lowest dose tested, for reduced sheep red 

blood cells (SRBC)-specific IgM antibody titers, suggesting that immunomodulation can occur at doses 

of PFOA lower than those tested by Yang and coworkers (Yang et al. 2002a). In the Dewitt et al. (2008) 

study, the mice were immunized with SRBC on day 11 of a 15-day dosing period via drinking water; 

analysis of SRBC-specific IgM antibodies was conducted in blood collected on day 16 of the study. The 

mean serum PFOA level in the mice dosed with 3.75 mg/kg/day was 75,000 ng/mL on day 16 and 

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decreased to 35,000 ng/mL 15 days later. In this study, delayed-type hypersensitivity (DTH) responses 

were not affected by dosing with up to 30 mg/kg/day PFOA for15 days. 

Less information is available for PFOS. Rats treated with 1.77 mg/kg/day PFOS for 4 weeks, 

1.56 mg/kg/day for 14 weeks, or 1.5 mg/kg/day for 2 years did not show significant morphological 

alterations in the spleen, thymus, and mesenteric lymph nodes (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). 

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; van Otterdiijk 2007a, 2007b). Similar findings 

were reported an intermediate-duration study in which rats were dosed with PFHxS in doses of up to 

10 mg/kg/day (Hoberman and York 2003) and in rats dosed with up to 900 mg/kg/day PFBuS for 28 days 

(3M 2001). 

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. 

Reliable NOAELs and LOAELs for immunological and lymphoreticular effects are presented in 

Tables 3-3, 3-4, and 3-5 and are plotted in Figures 3-3, 3-4, and 3-5. 

3.2.2.4 Neurological Effects 

No studies were located regarding neurological effects in humans following oral exposure to 

perfluoroalkyl compounds. 

The nervous system does not appear to be a sensitive target for perfluoroalkyl compounds, but 

comprehensive testing has not been conducted. Exposure of rats to up to approximately 110 mg/kg/day 

PFOA via the diet for 90 days did not induce gross or microscopic alterations in the brain, spinal cord, or 

peripheral nerves (Griffith and Long 1980). Similar results were reported in rats fed a diet that provided 

approximately 15 mg/kg/day PFOA for 2 years (3M 1983). 

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Rhesus monkeys exposed to doses of PFOA that caused lethality (≥30 mg/kg/day by gavage) showed 

signs of hypoactivity and prostration, but examination of the brain did not reveal treatment-related 

alterations (Griffith and Long 1980). Treatment of Cynomolgus monkeys with doses of up to 

20 mg/kg/day PFOA in a capsule did not induce morphological alterations in the brain or sciatic nerve 

(Butenhoff et al. 2002). 

Treatment of rats with up to 1.6–1.8 mg/kg/day PFOS for 4 or 14 weeks did not induce morphological 

alterations in the brain (Seacat et al. 2003). Administration of up to 1.5 mg/kg/day PFOS to rats in the 

diet for 2 years did not induce gross or microscopic alterations in the brain, spinal cord, or sciatic nerve 

(Thomford 2002b). Similarly, dosing Cynomolgus monkeys with up to 0.75 mg/kg/day PFOS for 

26 weeks did not cause alterations in the brain, spinal cord, or sciatic nerve (Seacat et al. 2002). 

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 and 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 (van Otterdiijk 2007a). Results from other tests 

including hearing ability, static righting reflex, grip strength, and motor activity were comparable between 

groups and histological examination of the brain (including the optic nerve), spinal cord, and sciatic nerve 

was 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 vs. 7/39 in high-dose 

rats; p=0.071 according to the Fisher Exact Test) (van Otterdiijk 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 toxicologically significant by the investigator. 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. 

In a reproductive study in rats dosed with PFHxS, a functional observation battery and motor activity tests 

were conducted in males on exposure days 36 and 39 and in females on postpartum day 17 (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. In a 

28-day study with PFBuS in rats, neurobehavioral tests that assessed sensory reactivity to stimuli, grip 

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strength, and motor activity were conducted on week 4 (3M 2001). The only notable effect was a 

significant decrease in tail flick latency to a thermal stimulus in males from all treated groups (100, 300, 

or 900 mg/kg/day) relative to controls. 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. 

Reliable NOAELs and LOAELs for neurological effects are presented in Tables 3-3 and 3-4 and are 

plotted in Figures 3-3 and 3-4. 

3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following oral exposure to 

perfluoroalkyl compounds. 

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 

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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 were well correlated with 

total hepatic aromatase activity (Liu et al. 1996). Significant increases in serum estradiol were also 

reported during the first year of treatment of male rats with 13.6 mg/kg/day PFOA in a 2-year dietary 

study (Biegel et al. 2001). 

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 weeks 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). 

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). 

This was suggested as a plausible mechanism to explain, at least in part, a delayed growth development in 

exposed offspring. The concentrations of PFOA in whole blood from dams and pups on PND 20 were 

45,000 and 33,000 ng/mL, respectively. 

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Multigeneration studies with PFOS in 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). However, treatment of rabbits with 3.75 mg/kg/day PFOS by gavage on gds 6–20 

resulted in 10 out of 22 does having abortions between gds 22 and 28 (Case et al. 2001). Dietary 

exposure of rats to 1.3–1.8 mg/kg/day 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 in 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 1.5 mg/kg/day PFOS 

did not induce gross or microscopic alterations in the reproductive organs (Thomford 2002b). 

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; van Otterdiijk 2007a, 2007b). 

A reproductive study was conducted in rats dosed by gavage with 0, 0.3, 1, 3, or 10 mg/kg/day PFHxS 

(Hoberman and York 2003). Exposure of males began 14 days before cohabitation and continued until 

1 day before sacrifice (a minimum of 42 days of exposure). Females were dosed starting 14 days before 

cohabitation and continued until 1 day before sacrifice on PND 21 or gd 25 (rats that did not deliver a 

litter). Treatment with PFHxS did not significantly alter sex organ weights, nor did it induce 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. Also, estrous cycling 

was not affected by dosing with PFHxS. The reproductive NOAEL for PFHxS was 10 mg/kg/day. 

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). 

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 of 

testosterone at 5 and 10 mg/kg/day, no significant effect on FSH levels, and a significant decrease in 

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serum estradiol only at 5 mg/kg/day. Alterations in the ultrastructure of the testes were seen in the midand high-dose 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 high-dose group. Assessment of 

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. 

Reliable NOAELs and LOAELs for reproductive effects are presented in Tables 3-3, 3-4, and 3-5 and are 

plotted in Figures 3-3, 3-4, and 3-5. 

3.2.2.6 Developmental Effects 

Recent studies are available that examined the relationship between levels of PFOA and PFOS in 

maternal and/or cord blood and developmental outcomes in the general population. For example, 

Apelberg et al. (2007b) conducted a hospital-based cross-sectional study of singleton deliveries in 

Baltimore, Maryland. Univariate and multivariate regression analyses were performed to examine the 

associations between PFOS and PFOA and gestational age, birth weight, head circumference, length, and 

ponderal index (ratio of birth weight in grams to length in centimeters cubed, times 100). Information on 

maternal (n=293) health conditions was obtained from the medical record; infant anthropometric 

measures were obtained from the infant medical record. The median concentration of PFOA and PFOS in 

cord blood serum samples were 1.6 ng/mL (range 0.3–7.1 ng/mL) and 5 ng/mL (range <0.2–34.8 ng/mL), 

respectively. After adjusting for potential confounders, both PFOA and PFOS were negatively associated 

with birth weight, ponderal index, and head circumference. In the fully-adjusted model, a natural 

logarithm-unit increase in cord concentration was associated with a decrease in mean birth weight of 69 g 

(95% CI 149–10) for PFOS and 104 g (95% CI 213–5) for PFOA; the corresponding changes in head 

circumference were 0.32 and 0.41 cm. No association was found between PFOS and PFOA 

concentrations and serum total cholesterol triglycerides, and total lipids. No significant associations were 

observed between either PFOS or PFOA concentrations and newborn length or gestational age. 

Limitations discussed by the investigators that could have influenced the results included issues related to 

the analytical method used to measure the chemicals, possible measurement errors in the anthropometric 

measurements, the use of medical records as the principal source for data on potential confounders, lack 

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of information regarding the diet of the subjects, and the fact that the study population represented a 

group of individuals with more risk factors for adverse birth outcomes than the United States as a whole. 

The investigators suggested cautious interpretation of the findings until the results can be replicated. 

A similar study was conducted among a selected cohort of 1,400 Danish women (Fei et al. 2007). PFOS 

and PFOA were measured in blood samples collected twice during gestation, once in the first trimester 

and once in the second trimester; an umbilical cord blood sample was obtained shortly after birth. 

Analyses of the variance and linear regression were used to assess the relationship between birth weight 

and length of gestation and maternal plasma PFOA and PFOS levels. Mean PFOA and PFOS levels in 

maternal plasma collected in the first trimester were 35.3 and 5.6 ng/mL, respectively. The respective 

concentrations in the second trimester were 29.9 and 4.5 ng/mL. Umbilical cord levels of PFOA and 

PFOS were 11.0 and 3.7 ng/mL, respectively. Potential confounders adjusted for in the analyses included 

maternal age, parity, socio-economic status, pre-pregnancy BMI, smoking during pregnancy, infant sex, 

and gestational week at blood drawing. Also evaluated were alcohol use, fish intake, protein, fat, 

carbohydrate, and energy intake. After adjusting for potential confounders, birth weight was inversely 

associated with plasma levels of PFOA in the first blood sample; the regression coefficient was 

-10.63 (5% CI 20.79–0.47). Infants born to mothers with PFOA levels in the three highest quartiles had 

an adjusted average birth weight of 96, 98, and 105 g lower than infants born to mothers in the lowest 

quartile, respectively. The effects of PFOA on birth weight were more pronounced in preterm and 

post-term babies, but did not differ significantly by sex or parity. Neither PFOA nor PFOS was 

statistically associated with length of gestation. A potentially important covariate not included in the 

analyses was maternal weight gain. 

In a follow-up report, Fei et al. (2008a) present data on placental weight, birth length, and head and 

abdominal circumferences in relation to maternal serum PFOA and PFOS levels. Covariates included 

gestational age, infant sex, maternal age, parity, socio-occupational status, prepregnancy body mass 

index, smoking during pregnancy, gestational week at blood drawing, alcohol drinking, nutritional 

factors, weight gain during pregnancy, hypertension and diabetes during pregnancy, and mode of 

delivery. The investigators categorized PFOA and PFOS levels into quartiles using the lowest quartile as 

the reference group and also analyzed exposure data as continuous variables. Maternal PFOS levels were 

not associated with any of the fetal growth indicators in the stratified analysis or with PFOS as a 

continuous variable. In the stratified analysis, after adjustment for confounders, only birth lengths in the 

second and fourth quartiles of PFOA exposure were statistically significantly lower than in the first 

quartile; the difference between the highest and lowest quartiles was 0.49 cm (95% CI 0.16–0.81). In the 

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analysis of PFOA as a continuous variable, after adjustments, only abdominal circumference and birth 

length were statistically negatively associated with maternal PFOA levels. For each ng/mL increase in 

maternal PFOA level, birth length decreased by 0.069 cm (95% CI 0.024–0.113) and abdominal 

circumference decreased by 0.059 cm (95% CI 0.012–0.106). A mechanism by which PFOA could 

impair fetal growth was not apparent. 

In yet an additional study from the same group of investigators, Fei et al. (2008b) examined exposure to 

PFOS and PFOA and neurodevelopmental or musculoskeletal development using data on developmental 

milestones in early childhood from the Danish National Birth Cohort. The investigators randomly 

selected 1,400 pairs of pregnant women and their children among 43,045 women who met the sampling 

criteria. Blood samples were drawn from the mother twice during pregnancy and from the child (cord 

blood) shortly after birth. Only blood samples taken during the first trimester were used in the analysis. 

Subjects were divided a priori into four categories on the basis of quartiles of maternal PFOA and PFOS 

exposure during pregnancy. Midwives assessed Apgar score 5 minutes after birth following standardized 

procedures. Motor and mental development of infants was reported by the mothers using highly 

structured questionnaires when the infants were around 6 and 18 months of age. The motor domains 

assessed gross and fine motor functioning, whereas the mental domains assessed the child’s attention and 

cognitive functions, language development, and social-personal development. Potential confounders that 

were considered in the models included maternal age, maternal occupational and educational status, 

parity, pre-pregnancy BMI, smoking and alcohol consumption during pregnancy, gestational week at 

blood drawing, child’s sex, child’s age at mother’s interview, breast-feeding after the child turned 

6 months of age, out-of-home day care, how many hours the mother spent with the child every day, and 

home density (total number of rooms divided by the total number of persons in the house). No significant 

association was found between levels of PFOA or PFOS and Apgar scores or time to achieve 

developmental milestones at the ages examined. However, children whose mothers had higher PFOS 

levels were more likely to start sitting without support at a later age (p for trend along quartiles = 0.041). 

PFOS was also associated with a later age to “use word-like sounds to tell what he/she wants.” Potential 

limitations discussed included the risk of differential recall bias leading to misclassification and the fact 

that children can also be exposed through breast milk or by contact with products containing PFOA and 

PFOS making difficult to ascertain how these sources may have influenced the results. Fei et al. (2008b) 

concluded that the results provided little evidence to support influence of prenatal PFOA and PFOS, at the 

levels found in the general population, on motor or mental developmental milestones in early childhood. 

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Washino et al. (2009) examined the correlation between serum level of PFOA and PFOS and birth weight 

and birth size (length, chest circumference, and head circumference) in a group of 428 Japanese women 

and their infants. After the second trimester of pregnancy, the subjects completed a questionnaire that 

included information regarding dietary habits, smoking status, alcohol and caffeine intake, household 

income, and educational level. Information for exclusion criteria and potential confounders, which 

included pre-pregnancy BMI, pregnancy complications, gestational age, infant gender, parity, infant 

diseases, and birth weight and size, was obtained from medical records. Blood samples were collected 

after the second trimester of pregnancy. The geometric mean serum PFOS and PFOA levels were 4.9 and 

1.2 ng/mL, respectively. Multiple regression analyses were performed to determine the correlations 

between PFOA and PFOS and birth weight and birth size. The mean birth weight was 3,058 g. In the 

fully-adjusted model, adjustments were made for maternal age, maternal educational level, smoking status 

during pregnancy, maternal BMI, parity, infant gender, gestational age, and blood sampling period. No 

correlation was found between serum levels of PFOA and birth weight or birth size whether the analyses 

were conducted in the total population or separately in male (n=198) and female (n=230) infants. For 

PFOS, there was a significant negative correlation between serum levels and birth weight in the fullyadjusted model. A log10-unit increase in PFOS level correlated with a decrease in mean birth weight of 

148.8 g (95% CI, 297–0.5; p=0.049). In the separate analyses of male and female infants, the correlation 

remained significant only in females. 

A small study of 15 Japanese women that analyzed PFOS, PFOA, and PFOSA in maternal and cord blood 

did not find any significant correlation between PFOS concentrations and age bracket, birth weight, or 

levels of TSH and free T4 in cord blood (Inoue et al. 2004b). Maternal blood was sampled between 

gestation weeks 38 and 41 and cord blood was sampled immediately after birth. PFOS concentrations in 

maternal and cord samples were 4.9–7.6 and 1.6–5.3 ng/mL, respectively. PFOSA was not detected in 

maternal or cord samples, whereas PFOA was detect only in 3 out of 15 maternal samples (<0.5– 

2.3 ng/mL). No correlation was found between TSH and free T4 in cord blood and PFOS in maternal 

blood, which according to the investigators, may have been due to a sample size too small to detect a 

relationship. Another small study of 19 women from China found no statistical significant correlation 

between concentrations of PFOS (0.045–0.36 ng/mL) and PFOS (0.047–0.21 ng/mL) in breast milk and 

infant weight (So et al. 2006b). Maximum concentrations of other perfluoroalkyl compounds in breast 

milk were 0.1 ng/mL for PFHxS, 0.062 ng/mL for PFNA, 0.015 ng/mL for PFDeA, and 0.056 ng/mL for 

PFUA. Limited conclusions can be drawn from these two studies due to their small sample size and thus, 

inadequate statistical power. 

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Recently, Nolan et al. (2009) published the results of a study of the relationship between high maternal 

exposure to PFOA via the drinking water and mean birth weights, incidence of low birth weight, 

incidence of preterm birth, and mean gestational age of single neonates born to mother residing within zip 

codes fully or partially serviced by Little Hocking Water Association (LHWA) in Washington County, 

Ohio (see above under Hematological effects for further details of the cohort). Women were assigned to 

one of three categories based on their water service: those serviced exclusively by LHWA only (mean 

water PFOA 6.78 μg/L), those serviced partially by LHWA, and those entirely outside the service area of 

the LHWA (mean water PFOA ≤0.007 μg/L). A total of 1,555 singleton neonates were studied: 

168 from the LHWA area only, 212 from the area served partially by the LHWA, and 1,175 from the area 

not serviced by the LHWA. Univariate and multiple regression models were adjusted for maternal age, 

gestational age, sex, race, and population-level socioeconomic status. Mean birth weight for the entire 

cohort, regardless of water service category, was 3,264 g (±547 g). The results of the analysis showed 

that zip codes comprising services provided exclusively or partially by the LHWA were not associated 

with low birth weight, lowered mean birth weight, preterm birth, or reduced mean gestational age as 

compared to zip codes entirely outside the area serviced by the LHWA and national birth metrics. The 

study did find, however, that decreasing gestational age and maternal age 20–24 years were associated 

with an increased likelihood of low birth weight, while maternal age <24 years, female sex, and 

decreasing gestational age were associated with lowered mean birth weight. Potential study limitations 

discussed by the investigators include the lack of individual exposure levels that might have introduced 

exposure misclassification, socioeconomic status misclassification, lack of information regarding 

confounding known to influence birth weight and gestational age (i.e., parity, smoking status, asthma, 

hypertension, infection, and the mother’s nutritional status prior to pregnancy), use of a data set with live 

neonates only, and reporting errors in the Ohio Department of Health database. 

Developmental studies with PFOA have been conducted mostly in mice. Treatment of pregnant mice on 

gds 1–17, 8–17, or 12–17 with 5 mg/kg/day by gavage in water resulted in significant reductions in 

neonate body weight on PND 5, 10, and 20 ranging from 25 to 40% of control values (White et al. 2007). 

The doses tested did not significantly affect maternal weight or weight gain. Prenatal loss also was 

significantly increased in dams dosed on gds 1–17, 20% per live litter compared to 5.7–7.7% in groups 

dosed for shorter periods and controls. This study also reported that examination of the female pups on 

PND 10 or 20 showed significant delay in the development of the mammary gland among all treated 

groups. PFOA concentrations in whole blood from pups on PND 10 were higher than maternal levels 

(40,000–50,000 vs. 12,000–35,000 ng/mL). By PND 20, PFOA in the blood of pups had decreased 

nearly by half, whereas maternal levels remained almost unchanged. In a study that tested a range of 

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doses (1–40 mg/kg/day on gds 1–17), treatment with PFOA resulted in a drastic reduction in body weight 

gain in dams dosed with ≥10 mg/kg/day (Lau et al. 2006). All pregnancies were lost at 40 mg/kg/day. 

Maternal serum concentrations of PFOA on gd 18 ranged from approximately 22,000 ng/mL in mice 

dosed with 1 mg/kg/day PFOA to approximately 270,000 ng/mL in mice dosed with 40 mg/kg/day 

PFOA. The incidences of full litter resorptions (and percentages) in the 0, 1, 3, and 5 mg/kg/day groups 

were 3/45 (6.7%), 2/17 (11.8%), 1/17 (5.9%), and 7/27 (25.9%), respectively. Pair-wise comparison of 

the incidence in the control and 5 mg/kg/day groups by the Fisher’s exact test gave a p-value <0.05. 

Among litters with viable fetuses at term, prenatal loss was observed only at 20 mg/kg/day and fetal body 

weight was reduced only at 20 mg/kg/day. Reduced ossification of the sternebrae occurred at 

≥10 mg/kg/day and enlarged fontanel at ≥1 mg/kg/day, but with no clear dose-response relationship. Tail 

and limb defects occurred at ≥5 mg/kg/day and microcardia at ≥10 mg/kg/day. Most neonates in the 

10 and 20 mg/kg/day group did not survive the first day of life. Survival at 5 mg/kg/day on postnatal day 

23 was about 70% vs. approximately 80% in controls. On PND day 23, body weight of pups in the 

3 mg/kg/day group was about 20% lower than in controls, but recovered subsequently. Significant delays 

in eye opening were reported at 5 mg/kg/day, in vaginal opening at 20 mg/kg/day, and in first estrus at 

5 mg/kg/day; male pups in the 1 mg/kg/day group showed accelerated preputial separation. 

Wolf et al. (2007) conducted a study in which pregnant mice were exposed to 0 or 5 mg/kg/day PFOA on 

gds 7–17, 10–17, 13–17, or 15–17. Exposure to PFOA did not affect maternal weight or weight gain 

during pregnancy. Eye opening was significantly delayed at 5 mg/kg/day in the groups exposed on 

gds 7–17 and 10–17 compared to controls. The delay was progressively more severe as the exposure 

began earlier, but it could not be determined whether this was due to a higher total dose or to a 

developmentally sensitive period. Pup body weights on PND 22 were reduced in all exposed groups. In 

males, a maximum reduction of approximately 43% occurred in the group exposed on gds 7–17; in 

females, the reduction was approximately 35%. Mean PFOA levels were 37,000 ng/mL in dam’s blood 

from this group at weaning and 25,000 ng/mL in pups. After weaning, male pups in the gds 7–17 and 10– 

17 groups continued to exhibit delayed growth. Wolf et al. (2007) also conducted a cross-foster study to 

determine the relative contributions of gestational versus lactational exposures to the developmental 

toxicity of PFOA. The results showed that gestational exposure was sufficient to produce postnatal body 

deficits and developmental delays in the pups. 

A study was conducted with wild 129S1/SvlmJ wild-type mice (WT) and PPARα knockout mice (KO) to 

determine if PPARα mediates PFOA-induced developmental toxicity (Abbott et al. 2007). Doses ranged 

between 0.1 and 20 mg/kg/day and were administered on gds 1–17. Maternal body weight and weight 

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gain were not affected by PFOA. The percent litter loss was significantly increased in WT pups at 

≥0.6 mg/kg/day and in KO pups at ≥5 mg/kg/day. Birth weight of pups was not significantly affected in 

either mouse type. Relative liver weight at weaning was significantly increased at ≥0.1 mg/kg/day in 

WT pups and at 3 mg/kg/day in KO pups. Survival of pups from birth to weaning was significantly 

reduced at ≥0.6 mg/kg/day in WT pups, but was not affected in KO pups. Studies of heterozygous pups 

born to WT and KO dams showed that the expression of PPARα was required for induction of postnatal 

lethality by PFOA and that one functional copy of the gene was sufficient to significantly increase 

postnatal lethality. Eye opening was significantly delayed in WT pups at ≥1 mg/kg/day, but was not 

delayed in KO pups. The weight of pups at weaning was reduced by 18 and 14% in males and females, 

respectively, at 1 mg/kg/day in WT mice and was not significantly affected in KO mice. At weaning, 

mean levels of PFOA in serum from dams in the 0.6 mg/kg/day were 5,200 ng/mL; the corresponding 

serum level of PFOA in the pups was 3,800 ng/mL. There was no effect of strain or PPARα expression 

on serum PFOA levels. 

Treatment of 10-day-old male mice with a single dose of 0.58 or 8.70 mg/kg PFOA by gavage resulted in 

significant decreases in locomotion and total activity relative to controls when tested at the age of 2 and 

4 months (Johansson et al. 2008). Mice exposed to 8.70 mg/kg/day PFOA also showed decreased 

habituation capability and decreased activity in response to an injection of nicotine. 

Exposure of artificially-inseminated New Zealand rabbits to up to 50 mg/kg/day PFOA by gavage on 

gds 6–18 did not cause embryotoxicity or teratogenicy (Gortner et al. 1982). Maternal toxicity 

manifested as reduced weight gain on gds 6–9 was reported in does treated with 50 mg/kg/day; no 

significant effects were observed in does treated with 5 mg/kg/day PFOA. 

The developmental effects of PFOS have been studied in rats, mice, and rabbits. In pregnant rats treated 

on gds 2–21 with doses ranging from 1 to 10 mg/kg/day PFOS, pup survival decreased in a dose-related 

fashion (Lau et al. 2003). Over 95% of the pups in the 5 and 10 mg/kg/day groups did not survive the 

first day of life; PFOS levels in serum from these pups was >100 μg/mL. On PND 21, survival in 

controls was approximately 80 vs. 60% in the 2 mg/kg/day group. Cross-fostering exposed pups with 

unexposed dams failed to improve survival. Unexposed pups nursed by exposed dams survived a 3-day 

postnatal observation period. PFOS in serum from 5-day-old pups was slightly lower than at parturition 

(approximately 30,000, 60,000, and 85,000 ng/mL in pups from rats dosed with 1, 2, or 3 mg/kg/day, 

respectively). PFOS was also found in the liver of pups at parturition at levels similar to those found in 

blood. The body weight of pups at birth was significantly reduced at ≥2 mg/kg/day and remained reduced 

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until day 35 in the 5 mg/kg/day group. Pups had significantly lower total and free T4 as early as PND 2 

(all groups). Free T4 remained lower up to PND day 35. There were no significant changes in T3 or 

TSH. Eye opening was significantly delayed (1 day) at ≥2 mg/kg/day, but neither vaginal opening nor 

preputial separation was affected by PFOS. The activity of choline acetyltransferase was significantly 

depressed in the prefrontal cortex on PND 35 at ≥3 mg/kg/day but not in the hippocampus. Learning in a 

T-maze was not affected. 

Studies in rats have also shown that the later the dosing is during gestation the lower the survival rate 

(Grasty et al. 2003). The same group of investigators studied whether neonatal death might be due to 

lung immaturity of pups since newborns had trouble breathing within minutes of birth and the lungs taken 

shortly after birth resembled lungs of prenatal animals. However, experiments conducted with 

therapeutic agents known to enhance terminal lung maturation and accelerate surfactant production failed 

to reverse the delaying effects of PFOS, suggesting that neonatal mortality was not due to lung 

immaturity (Grasty et al. 2005). 

Studies in which female rats were exposed to PFOS by gavage for some period before mating and 

exposure continued during gestation showed significantly reduced weight and decreased viability during 

PND 1–21 at maternal doses ≥1.6 mg/kg/day PFOS (Luebker et al. 2005a). Examination of dead 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). Sexual maturation was not affected in F1 males or females and no effects were noted in the 

neurobehavioral tests conducted on PND 24 and 70. Reproductive performance of F1 rats was not 

affected. Cross-foster experiments showed that neonatal mortality was greatest in the group exposed both 

in utero and during lactation suggesting that pre- and postnatal exposure to PFOS was additive. In a 

similar study, the following significant effects were reported in dams allowed to deliver naturally: 

decreased gestation length (≥0.8 mg/kg/day), increased number of dams with all pups dying on PND 1–5 

(≥2 mg/kg/day), decreased pups birth weight (≥0.4 mg/kg/day), decreased pup’s weight per litter on 

PND 5 (≥0.4 mg/kg/day), and decreased mean pup survival per litter (≥1.6 mg/kg/day) (Luebker et al. 

2005b). Mean maternal serum PFOS levels in the 0.4, 0.8, 1, and 1.2 mg/kg/day groups were 27,000, 

43,000, 52,000, and 86,000 ng/mL, respectively. The corresponding mean PFOS levels in the blood of 

pups were 36,000, 53,000, 84,000, and 147,000 ng/mL. 

A study in mice showed that treatment with 10 mg/kg/day PFOS on gds 1–17 decreased postnatal 

survival at weaning by almost 50% (Lau et al. 2003), no significant effect was reported at 5 mg/kg/day. 

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Most pups from dams treated with 15 and 20 mg/kg/day did not survive for 24 hours after birth. The 

investigators estimated an LD50 of 10 mg/kg for the pups. Eye opening was significantly delayed (about 

1 day) at 1, 5, and 10 mg/kg/day. A similar study in mice also dosed on gds 1–17 reported a significant 

decrease in percent live fetuses at 20 mg/kg/day, increased absolute (18%) and relative (27%) liver weight 

at 20 mg/kg/day, increased cleft palate at 15 mg/kg/day, sternal defects at 5 mg/kg/day, enlarged right 

atrium at 10 mg/kg/day, and ventricular septal defects at 20 mg/kg/day (Thibodeaux et al. 2003). Levels 

of PFOS in maternal serum at term in the 10, 15, and 20 mg/kg/day groups were approximately 175,000, 

230,000, and 250,000 ng/mL, respectively. 

Evaluation of neurological end points in pups from mice exposed to 6 mg/kg/day PFOS on gds 12–18 

showed no significant alterations compared with controls (Fuentes et al. 2007a, 2007b). Evaluation of 

motor and reflex maturation showed isolated differences between treated and control pups. Postnatal 

resistance to backward pull was reduced on PND 10 and 11, but not PND 12. Postnatal time to climb a 

vertical screen was altered on PND 11, but not PND 10 or 12. Forelimb grip strength was reduced on 

PND 11, but not PND 9, 13, or 15. Evaluation of the 22-day-old pup's brain showed no effect on 

myelination pattern. Open field activity tests showed no significant difference between treated and 

control animals. In the rotarod test, there were also no significant differences in performance between 

treated and control mice. In male NMRI mice, treatment with a single gavage dose of 0.75 or 11.3 mg/kg 

PFOS at the age of 10 days resulted in alterations in spontaneous motor activity and habituation 

capability, and in an altered motor response to an injection of nicotine when tested at the ages of 2 or 

4 months old (Johansson et al. 2008). 

A recent study also examined immunological end points in 4- and 8-week-old pups from mice dosed with 

0.1, 1, or 5 mg/kg/day PFOS on gds 1–17 (Keil et al. 2008). Spleen and thymus cellularity were not 

affected. No immunological deficits were evident on week 4. On week 8, NK cell activity was reduced 

by 42.5 and 32.1% in the 1 and 5 mg/kg/day males, respectively, and by 35.1% in the 5 mg/kg/day 

females. The primary IgM response to SRBC was only measured at 8 weeks of age and was suppressed 

by 53% in high-dose males, but it was not affected in females. Evaluation of splenic and thymic 

lymphocyte subpopulations showed a 21% reduction in splenic B220+ cells in 4-week high-dose females 

and a 25% decrease in thymic CD3+ and 28% decrease in thymic CD4+ in 8-week high-dose males. 

Nitrate production by peritoneal macrophages was not significantly altered in any group. 

In a study in rabbits dosed with up to 3.75 mg/kg/day PFOS on gds 6–20, the only significant 

developmental effects were a reduction in fetal body weight by approximately 10% at 2.5 mg/kg/day and 

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24% at 3.75 mg/kg/day (Case et al. 2001). There were no significant effects on numbers of corpora lutea, 

implantations, resorptions, or fetuses alive and dead. Skeletal examination revealed some reversible 

delays in ossification (sternebrae, hyoid, metacarpal, and pubic bones) at 2.5 and 3.75 mg/kg/day. 

Maternal body weight gain was significantly reduced during gds 7–21 (13, 21, and 47% in the 0.1, 1, and 

2.5 mg/kg/day groups, respectively). During gds 21–29, maternal body weight gain was significantly 

reduced at 1 and 2.5 mg/kg/day. In the group dose with 2.5 mg/kg/day, food consumption was reduced 

about 8% during gds 7–21 and 13% during gds 21–29. 

A recent study examined the developmental effects of PFBA in mice (Das et al. 2008). In that study, 

pregnant mice were administered 0, 35, 175, or 350 mg/kg/day PFBA by gavage on gds 1–17. A 

significant increase in full litter resorptions was reported in mice dosed with 350 mg/kg/day. However, 

there were no significant effects on number of implants, number of live fetuses, or fetal weight. PFBA 

did not affect newborn survival or weight gain on PND 1–21 or 22–291. In the pups, both absolute and 

relative liver weights were increased at 175 mg/kg/day on PND 1, but not on PND 10. Significant delays 

were seen in eye opening (approximately 1 day) at maternal doses of 35 mg/kg/day, in vaginal opening at 

175 mg/kg/day (2 days), and in preputial separation at 350 mg/kg/day (2 days). PFBA did not 

significantly affect gene expression in fetal liver. Maternal serum/liver ratios of PFBA ranged between 

35 and 55%; slightly higher ratios were seen in pups livers. On gd 18, maternal serum PFBA was 2,000– 

4,000 ng/mL with no apparent dose-response relationship. In pups, serum PFBA was 400–600 ng/mL on 

PND 1 and 110–150 ng/mL on PND 10. The milder response compared with PFOA was attributed by the 

investigators to faster elimination of PFBA as well as to lower biochemical potency. 

Exposure of female rats to PFHxS by gavage to up to 10 mg/kg/day PFHxS for a period that included 

premating, gestation, and lactation did not significantly affect any developmental parameter 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, and pups weight. Also, necropsy of the pups 

showed no significant effects on pups’ liver weight (Hoberman and York 2003). The developmental 

NOAEL for PFHxS was 10 mg/kg/day. 

Limited information regarding PFDeA is available from a study by Harris et al. (1989). Pregnant 

C57BL/6N mice were administered 0, 0.03, 0.1, 0.3, 1, 3, 6.4, or 12.8 mg/k/g/day PFDeA by gavage in 

corn oil on gds 6–15 and were sacrificed on gd 18. Net maternal body weight gain for the period gds 6– 

18 was severely depressed in the 6.4 and 12.8 groups; food consumption data were not provided. The 

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number of live fetuses per litter was significantly decreased in the 12.8 mg/kg/day group (4.6 vs. 7.2 in 

controls). Fetal body weight per litter was decreased at maternal doses ≥0.1 mg/kg/day, but only at 

6.4 mg/kg/day was the difference with controls >10% (33% at 6.4 mg/kg/day and 50% at 

12.8 mg/kg/day). Treatment with PFDeA did not induce soft tissue or skeletal malformations. Variations 

in ossification of the braincase were found in all fetuses examined from the 12.8 mg/kg/day dose group. 

Treatment of male mice with a single dose of 0.72 or 10.8 mg/kg by gavage at the age of 10 days did not 

induce significant alterations in spontaneous motor activity tests or in habituation capability when tested 

at the ages of 2 or 4 months old (Johansson et al. 2008). 

Reliable NOAELs and LOAELs for developmental effects are presented in Tables 3-3, 3-4, and 3-5 and 

are plotted in Figures 3-3, 3-4, and 3-5. 

3.2.2.7 Cancer 

There are no studies of cancer in humans exposed orally to perfluoroalkyl compounds. 

Two studies have examined the carcinogenic potential of PFOA in rats. In the first one, male and female 

Sprague-Dawley rats were fed a diet that provided 0, 1.5, or 15 mg/kg/day PFOA for 2 years (3M 1983). 

Gross and microscopic evaluation of tissues and organs was done at the 1-year mark and at termination. 

Treatment with PFOA did not affect survival. Terminal body weight was reduced 4.5% in males and 

10.3% in females; food consumption was not significantly affected. Significant neoplastic lesions 

consisted of fibroadenoma of the mammary gland (females, 22, 42, 48% incidence in control, low-, and 

high-dose groups, respectively) and Leydig cell adenoma (males, 0, 4, 14%); in both cases, the incidence 

in the high-dose groups was significantly different than in controls. High incidence of pituitary adenoma 

occurred among all groups, including controls. The incidence of hepatocellular carcinoma was not 

significantly increased (males, 6, 2, 10%; females, 0, 0, 2%). The investigators did not consider PFOA 

carcinogenic in the rat under the conditions of the study. In the second study, male and female SpragueDawley rats were fed a diet that provided 0 or 13.6 mg/kg/day PFOA for 2 years (Biegel et al. 2001). 

Survival in treated rats and pair-fed rats was increased relative to controls. Treatment with PFOA 

increased the incidence of hepatocellular adenomas (13 vs. 3 or 1% in ad libitum controls or controls pairfed), but there were no hepatocellular carcinomas in the treated group. PFOA also increased the 

incidence of Leydig cell adenomas (11 vs. 0 or 3% in ad libitum controls and pair-fed controls). In 

addition, PFOA increased the incidence of pancreatic acinar cell adenomas (9 vs. 0 and 1% in the control 

groups); a pancreatic carcinoma was observed in one treated rat. Hepatic peroxisome proliferation was 

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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 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 was also found to act as 

a promoter in male Wistar rats in an initiation-selection-promotion protocol (Nilsson et al. 1991). In a 

feeding study in rainbow trout, PFOA was a promoter of liver tumors by a mechanism involving 

estrogenic signaling, independent of peroxisome proliferation (Tilton et al. 2008). 

A 2-year bioassay for PFOS in Sprague-Dawley rats was conducted (Thomford 2002b); male and female 

rats were administered approximately 0, 0.03, 0.1, 0.4, or 1.5 mg/kg/day PFOS in the diet. An additional 

group was treated with 1.5 mg/kg/day for 52 weeks and kept on a control diet during the second year of 

the study (recovery group). PFOS induced a significant positive trend of liver hepatocellular adenoma in 

males, which was associated with a significant increase in the high-dose group over controls (7/60 vs. 

0/60). No hepatocellular adenomas were seen in the recovery group (0/40). High-dose males from the 

recovery group showed a significant increase in thyroid follicular cell adenoma relative to controls 

(9/39 vs. 3/60). No significant increase in this type of tumor was observed in the high-dose males dosed 

with PFOS 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 high-dose group relative to controls 

(5/60 vs. 0/60). Only one case of hepatocellular carcinoma was observed in the study and occurred in a 

high-dose female. In females, there were also significant negative trends for mammary adenoma and 

fibroadenoma carcinoma combined. 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No reports of death in humans following dermal exposure to perfluoroalkyl compounds were identified in 

the literature. 

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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. 

The LD50 values for rats and rabbits are presented in Table 3-6. 

3.2.3.2 Systemic Effects 

No information was located regarding systemic effects in humans following dermal exposure to 

perfluoroalkyl compounds. 

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each 

species and duration category are recorded in Table 3-6. 

Respiratory Effects. No gross or microscopic alterations 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). 

Cardiovascular Effects. No morphological alterations were seen in the heart from male rats in the 

study conducted by Kennedy (1985). 

Gastrointestinal Effects. 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). 

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133

mg/kg 

132 mg/kg134

mg/kg mg/kg

mg/kg

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE 

Death 

(CD) Rat once 

System NOAEL Less Serious 

7000 M 

mg/kg 

Serious 

(14 day LD50) 

Reference Chemical Form 

Kennedy 1985 

Ammonium perfluorooc

(New Zealand) Rabbit once 

4300 M 

mg/kg 

(14 day LD50) Kennedy 1985 Ammonium perfluorooc

Systemic 

(CD) Rat once Dermal 3000 B 

mg/kg 

5000 B 

mg/kg 

(mild skin irritation) Kennedy 1985 Ammonium perfluorooc

Bd Wt 3000 B 

mg/kg 

(transient weight loss) 

Table 3-6 Levels of Significant Exposure to Perfluorooctanoate - Dermal 

LOAEL 

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135

mg/kg

mg/kg

mg/kg

mg/kg

mg/kg

mg/kg

mg/kgmg/kg mg/kg mg/kg

mg/kgmg/kg mg/kg

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

Rat 2 wk Resp 2000 M (CD) 6 hr/d 5 d/wk mg/kg 

Cardio 2000 M 

mg/kg 

Gastro 2000 M 

mg/kg 

Hemato 2000 M 

mg/kg 

Hepatic 20 M (foci of coagulative 

mg/kg necrosis) 

Renal 2000 M 

mg/kg 

Endocr 2000 M 

mg/kg 

Dermal 20 M 200 M (skin irritation) 2000 M (acute necrotizing 

mg/kg mg/kg mg/kg dermatitis) 

Ocular 2000 M

mg/kg

Bd Wt 20 M 200 M (14% weight loss) 

mg/kg mg/kg 

Kennedy 1985 Ammonium perfluorooc

Table 3-6 Levels of Significant Exposure to Perfluorooctanoate - Dermal (continued) 

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169

mg/kg mg/kg

mg/kg

100

mg

99

mg

137

mg/kg

170

mg/kg

mg/kg

138

mg/kg 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

Mouse (BALB/c) 

Rabbit (albino) 

Rabbit (albino) 

4 d 1 x/d once (NS) 24 hr (NS) 

Hepatic 2.5 F 

mg/kg 

6.25 F 

mg/kg 

Bd Wt 50 F 

mg/kg 

Ocular 100 

mg 

Dermal 500 

mg 

2000 M 

mg/kg 

12.5 F 

mg/kg 

18.8 F 

mg/kg 

2000 M 

mg/kg 

(52% increase in absolute liver weight) 

(moderate eye irritation) 

(increased serum IgE following ovalbumin challenge) 

Fairley et al. 2007 Perfluorooctanoic acid Griffith and Long 1980 Ammonium perfluoroocGriffith and Long 1980 Ammonium perfluorooc

Kennedy 1985 

Ammonium perfluorooc

Fairley et al. 2007 Perfluorooctanoic acid 

Kennedy 1985 

Ammonium perfluorooc

Rat (CD) Mouse (BALB/c) 

Neurological 

Rat (CD) 

Immuno/ Lymphoret 

2 wk 6 hr/d 5 d/wk 4 d 1 x/d 2 wk 6 hr/d 5 d/wk 

Table 3-6 Levels of Significant Exposure to Perfluorooctanoate - Dermal (continued) 

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136

mg/kg 

Exposure/ 

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

Reproductive 

Rat 2 wk Kennedy 1985 

2000 M (CD) 6 hr/d 

Ammonium perfluorooc

5 d/wk mg/kg 

Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = Female; Gastro = gastrointestinal; Hemato = hematological; hr = hour(s); IgE = Immuno/Lymphoret = immunological/lymphoreticular; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observelevel; NS = not specified; Resp = respiratory; wk = week(s); x = time(s) 

Table 3-6 Levels of Significant Exposure to Perfluorooctanoate - Dermal (continued) 

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3. HEALTH EFFECTS 

Hematological Effects. 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 up to 2,000 mg/kg/day APFO for 2 weeks showed inconsistent alterations 

or changes of unlikely biological significance (Kennedy 1985). 

Musculoskeletal Effects. No information was located regarding musculoskeletal effects in animals 

following dermal exposure to perfluoroalkyl compounds. 

Hepatic Effects. 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 

concentration of organofluorine on the 10th day of exposure was 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. 

Renal Effects. No gross or microscopic alterations were seen in the kidneys from rats that received 

applications of up to 2,000 mg/kg/day APFO to the shaven skin for 2 weeks in the Kennedy (1985) study. 

Endocrine Effects. The only relevant 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. 

Dermal Effects. Application of as single dose of 5,000 mg/kg of an aqueous paste of APFO to a 

clipped are 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 the 2-week study, acute 

necrotizing dermatitis was seen in two out of five high-dose rats after the 10th treatment; doses of 

200 mg/kg/day produced skin irritation. Application of 500 mg/kg (only dose tested) APFO to the intact 

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or abraded skin of young rabbits and left covered for 24 hours was non-irritating, as scored according to 

the Draize procedure immediately after removal of the cover and 48 hours later (Griffith and Long 1980). 

Ocular Effects. Examination of the eyes of rats following the 9th dermal treatment in the Kennedy 

(1985) study of APFO did not reveal any significant gross alteration. 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. 

Body Weight Effects. 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 daily for 4 days up to 50 mg/kg/day PFOA on the dorsal surface of the ears (Fairley et al. 

2007). 

3.2.3.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological and lymphoreticular effects in humans following 

dermal exposure to perfluoroalkyl compounds. 

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 

coexposed 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. 

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In the 2-week study conducted by Kennedy (1985), treatment of rats with dermal doses of up to 

2,000 mg/kg/day PFOA did not induce gross or microscopic alterations in the spleen, thymus, or lymph 

nodes. 

Data from Fairley et al. (2007) and Kennedy (1985) are presented in Table 3-6. 

3.2.3.4 Neurological Effects 

No studies were located regarding neurological effects in humans following dermal exposure to 

perfluoroalkyl compounds. 

No gross or microscopic alterations were reported in the brain from rats in the Kennedy (1985) study. 

3.2.3.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans following dermal exposure to 

perfluoroalkyl compounds. 

No gross or microscopic alterations were reported in the testes from rats in the Kennedy (1985) study. 

The dose level of 2,000 mg/kg/day is presented as a NOAEL for reproductive effects in Table 3-6. 

3.2.3.6 Developmental Effects 

No studies were located regarding developmental effects in humans or animals following dermal 

exposure to perfluoroalkyl compounds. 

3.2.3.7 Cancer 

No studies were located regarding cancer effect effects in humans or animals following dermal exposure 

to perfluoroalkyl compounds. 

3.2.4 Other Routes of Exposure 

Considerable information on the toxicity of PFDeA has been gathered from studies that administered the 

chemical to experimental animals by intraperitoneal injection. Some of this information is summarized 

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3. HEALTH EFFECTS 

below. For the most part, these studies have demonstrated that the liver is the primary target for PFDeA 

toxicity and that PFDeA has a higher toxic potency than PFOA. 

In male Fischer-344 rats, the intraperitoneal LD50 for PFDeA for a 30-day observation period was 

41 mg/kg (43 mg/kg in females), compared with 189 mg/kg for PFOA (George and Andersen 1986; 

Olson and Andersen 1983). While PFOA injection produced no mortality after 5 days, significant 

lethality in the second and third weeks occurred with PFDeA. These investigators also studied the effect 

of a single 50 mg/kg intraperitoneal dose on various parameters in rats sacrificed at 2, 4, 8, and 16 days 

after treatment. Body weight and food consumption decreased significantly; in the 16-day observation 

period, mean body weight decreased from 207 to 109 g. In a pair-fed group, body weight did not 

decrease as much as in the PFDeA-treated rats, and dehydration was ruled out as significant cause for the 

lost weight. In rats treated with PFOA, there was only a transient decrease in food consumption and body 

weight decreased in the first day and then paralleled controls. Similar differences between the effects of 

PFOA and PFDeA were reported by Goecke et al. (1992). Treatment with PFDeA increased liver weight, 

but had little effect on the testes, kidneys, adrenals, and heart compared to the pair-fed controls up to 

observation day 8. On day 16, the weight of the testes, adrenals, and heart was significantly decreased 

relative to pair-fed controls. PFDeA caused marked, prolonged alteration in liver lipids, which differed 

from changes caused by PFOA. Liver from PFDeA-treated rats showed relative increases in palmitate 

and oleate and relative decreases stearate, arachidonate, and docosahexaenoate; maximal effects were 

observed by day 8. In a subsequent study, rats were administered a single intraperitoneal dose of 

50 mg/kg PFDeA and were monitored for up to 30 days after dosing, tissues were processed for 

histological examination (George and Andersen 1986). Significant changes were found in the thymus 

(thymic atrophy), testes (atrophy and degeneration of seminiferous tubules), stomach (inflammation, 

hyperkeratosis, edema), bone marrow (hypocellularity), kidney (fatty changes in proximal tubular 

epithelium), and liver (swelling of liver cells with some necrosis). The changes in the thymus, testes, and 

liver were still seen 30 days after dosing. Hematology and clinical chemistry tests did not show 

significant alterations except for a decrease in serum protein levels. Analysis of liver samples showed no 

significant effects on phospholipid or total lipid levels, but free cholesterol levels were lower and 

cholesterol esters were higher on days 8 and 16 in PFDeA-treated rats than in controls. A general shift in 

the ratio of saturated to unsaturated fatty acids was observed. 

The effects of PFDeA on heart function also have been studied. Langley and Pilcher (1985) reported that 

administration of a single injection of 75 mg/kg significantly decreased heart rate in male Wistar rats 4– 

8 days after dosing relative to pair-fed control group. This effect was attributed, at least partly, to 

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alterations in circulating thyroid hormones (see below). Pilcher and Langley (1986) studied the effects of 

PFDeA on the isolated perfused heart from male Wistar rats 6–8 days following a single intraperitoneal 

injection of 75 mg/kg PFDeA. Specifically, the investigators measured heart rate and right ventricular 

pressure in response to sympathetic nerve stimulation or infusion of norepinephrine. Treatment with 

PFDeA reduced both responses to the same extent, indicating that the effects may have been mediated by 

an action of the myocardium rather than on the releases of norepinephrine in response to stimulation of 

the sympathetic nerves. β-Receptor binding studies conducted 8 days after dosing showed that maximum 

binding capacity was reduced without significant changes in receptor affinity. A follow-up study from 

the same group of investigators reported that injection of PFDeA reduced the apparent number of 

β-receptor binding sites, which could have been due to alteration in the lipid composition of different 

myocardial membranes. The reduced number of β-receptors was reflected in a reduced ability of 

norepinephrine to activate adenylate cyclase (Pilcher et al. 1987). 

The effects of PFDeA on the thyroid gland have also been studied. Administration of a single 

intraperitoneal dose of 80 mg/kg, but not 40 mg/kg, PFDeA to male Sprague-Dawley rats resulted in a 

significant reduction in thyroid gland weight 7 days after dosing relative to ad libitum controls 

(Van Rafelghem et al. 1987a). Pair-fed controls also exhibited a significant reduction in body weight, but 

not as marked as the treated rats, suggesting that the hypophagia only partially accounted for the 

reduction in thyroid gland weight. Thyroid gland histology did not reveal significant alterations due to 

treatment with PFDeA or to hypophagia. Treatment with PFDeA caused a significant reduction in plasma 

T4 level even at the lowest dose tested, 20 mg/kg, relative to ad libitum or pair-fed controls. Plasma T3 

levels were not significantly affected by PFDeA and neither was T3 uptake, suggesting that PFDeA 

treatment did not induce marked alterations in the levels of thyroid-binding proteins in the plasma. 

PFDeA induced a slight decrease in basal metabolic rate (8% at 80 mg/kg) and did not significantly affect 

thermogenesis or body core temperatures. The results suggested that the overt toxicity of PFDeA is not 

due to effects on functional thyroid status. Similar findings regarding T4 were reported by Gutshall et al. 

(1988). These investigators also showed that supplementation with T4 reversed the hypophagia, but not 

the decrease in T4 concentration, suggesting that PFDeA reduces circulating T4 independent of its 

hypophagic effect. Somewhat divergent results regarding plasma T3 levels and body temperature were 

reported by Langley and Pilcher (1985). These investigators reported that a single intraperitoneal 

injection of 75 mg/kg PFDeA reduced T3 levels and body temperature in male Wistar rats during a 3– 

8-day period following dosing. Van Rafelghem et al. (1987a) speculated that the difference in rat age and 

strain could have contributed to the difference in results. Subsequent studies by Gutshall et al. (1989) 

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suggested that the reduction in T4 and T3 levels induced by PFDeA in rats result from reduced 

responsiveness of the pituitary and/or displacement of the hormones from plasma protein binding sites. 

A study of the comparative toxicity of PFDeA in rats, mice, hamsters, and guinea pigs was conducted by 

Van Rafelghem et al. (1987b). Male animals were injected once with PFDeA and were observed for up to 

28 days after dosing. The study showed that, with some variation, the toxic potency of PFDeA was 

essentially the same in the four species studied. A severe body weight reduction was apparent in the four 

species studied. However, while rats stopped eating for 5–6 days 6 days after dosing, hamsters continued 

to consume food at a reduced level. PFDeA caused marked hepatomegaly in rats, mice, and hamsters and 

a moderate swelling in guinea pigs. Microscopic examination of the liver showed similar alterations in 

the species studied consisting of a panlobular swelling of the parenchymal cells. PFDeA induced thymic 

atrophy in hamsters, mice, and guinea pigs. PFDeA also induced seminiferous tubular degeneration in the 

testes from rats, but not mice; the lesion in hamsters and guinea pigs was less severe than in rats. 

Ultrastructurally, the liver from all species showed disruption of the rough endoplasmic reticulum, 

rounding and swelling of the mitochondria, and mild to extensive proliferation of peroxisomes. The latter 

response was greatest in mice and almost absent in guinea pigs. Accumulation of lipid droplets in liver 

cells was more pronounced in treated hamsters and guinea pigs then in rats and mice. 

3.3 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) 

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. 

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 both cases in a dose-related manner (Yao and Zhong 

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2005). These effects were accompanied by a significant increase in reactive oxygen species, which the 

investigators suggested caused the DNA damage. 

The results of various mutagenicity studies with PFOA in microorganisms were summarized by Griffith 

and Long (1980). The tests used Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and 

TA1538, as well as Saccharomyces cerevisiae with or without metabolic activation. All tests yielded 

negative results. 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). 

OECD (2002) summarized unpublished mutagenicity studies conducted with PFOS. PFOS was negative 

in all assays that tested. It did not induce reverse mutations in S. typhimurium or in Escherichia coli with 

or without metabolic activation. It 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 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). 

3.4 TOXICOKINETICS 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Studies of the absorption of perfluoroalkyls in humans following inhalation exposure were not located. 

However, serum concentrations of perfluoroalkyls in workers in fluorochemical production industry have 

been reported (see Table 6-13). 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 6-11) 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 in male 

rats at 9 hours (3 hours after cessation of exposure) 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 

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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 Section 3.4.1.2, Equations 1 and 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 3.4.2.1). 

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). 

3.4.1.2 Oral Exposure 

Studies of absorption of perfluoroalkyls through the gastrointestinal tract in humans are not available. 

However, 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 a study of residents in the Little Hocking water district in southeastern Ohio 

(Emmett et al. 2006a) and in two studies of children and adults in Germany (Hölzer et al. 2008; Wilhelm 

et al. 2008a). Emmett et al. (2006a) reported that the number of glasses of tap water ingested per day was 

a statistically significant factor in the best-fit model for PFOA exposure. Hölzer et al. (2008) reported 

that consumption of tap water at home was a significant predictor of PFOA blood concentrations. 

Greater than 95% of an oral dose of ammonium [14C]PFOA was absorbed in rats that received a single 

oral gavage doses ranging from 0.1 to 25 mg/kg (Kemper 2003). 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 3.4.4.2). Fasting appears to 

increase absorption of PFOA. Plasma PFOA concentrations in rats, 24 hours following an oral gavage 

dose of 10 mg ammonium PFOA/kg, were 2–3 times when administered to fasted rats, compared to fed 

rats (Hinderliter et al. 2006b). The estimated absorption fractions of ingested [14C]PFOA or [14C]PFOS 

(administered as a 4.2. mg/kg oral dose) were >93 and >95% in rats, respectively (Johnson and Ober 

1979, 1999a). The estimated absorption fraction of PFBA (administered as 30 mg/kg oral dose of PFBA) 

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was >95% in rats (Chang et al. 2008a). Cumulative excretion of PFBA 96 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). 

The highest observed concentrations of 14C in plasma occurred in male rats at approximately 10 hours 

(range 7.5–15 hours) following a 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 half-time (ke) of 0.0044 hour-1 (range 

0.004–0.005). The corresponding absorption t1/2 of approximately 1.5 hours (ka=0.35 hour-1) can be 

calculated from these observations (Equations 1 and 2): 

k 1

tmax = ln a ⋅ Eq. (1) ke (ka − ke ) 

ln(2) t1/ 2 = Eq. (2) k 

Absorption rate appears to be greater in female rats compared to male rats (tmax = time of maximum 

concentration of 14C; k = elimination constant). The time to peak concentrations of 14C in plasma 

occurred at approximately 1.1 hour (range 0.6–1.5 hours) following single oral doses ranging from 0.1 to 

25 mg/kg 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 half-time from the 

observations made at all doses (0.1, 1, 5, and 25 mg/kg), based on Equations 1 and 2, was approximately 

0.25 hours (range 0.12–0.38 hours). 

3.4.1.3 Dermal Exposure 

Dermal exposures of rats to ammonium PFOA has been shown to produce systemic (e.g., liver) toxicity 

(see Section 3.3.3). Estimates of the amount or rates of dermal absorption in humans or animals have not 

been reported; however, dermal penetration of PFOA has been studied in preparations of isolated rat and 

human epidermis (Fasano et al. 2005). These studies indicate that the rat skin may be more permeable to 

PFOA than human skin and that PFOA is not well absorbed across human skin. Approximately 0.048% 

of a dose of PFOA (150 L/cm2 of a 20% aqueous solution of ammonium PFOA; approximately 30 mg 

ammonium PFOA/cm2

) applied to isolated human epidermis was absorbed in 48 hours. When applied to 

isolated rat epidermis at the same dose, 1.44% of the applied dose was absorbed in 40 hours. The 

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estimated dermal penetration coefficient was 9.49x10-7 cm/hour in the isolated human epidermis and 

3.25x10-5 cm/hour in the isolated rat epidermis. 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

Studies of the tissue distribution of perfluoroalkyls in humans or animals following inhalation exposure 

were not located. Serum concentrations of perfluoroalkyls in workers in fluorochemical production 

industry have been reported (see Table 6-13). Occupational exposures in these workers are likely to have 

included inhalation of aerosols of perfluoroalkyls. 

3.4.2.2 Oral Exposure 

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 difference between plasma and serum and whole blood corresponded to volume displacement by red 

blood cells, suggesting that these perfluoroalkyls do not enter cellular components of blood or become 

attached to them. 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 (Johnson and Ober 1999a). RBC:plasma (or 

serum) ratios of 0.2–0.3 have also been observed in rats following intravenous injection of PFOA 

(Johnson and Ober 1999b; 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 biding sites (Han et al. 2003). A 

component of the binding of PFOA and PFDeA to serum albumin appears to be covalent, and may 

involve the sulfhydryl moiety of albumin (Vanden Heuvel et al. 1992b). Given a dissociation constant of 

0.4 mM and an albumin concentration of approximately 0.6 mM, >90% of PFOA in serum would be 

expected to be bound to albumin when the serum concentration of PFOA is <1 mM (<440 mg/L). This is 

consistent with observations of the bound fraction of perfluoroalkyls in plasma of rats that received an 

oral 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; 

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PERFLUOROALKYLS 165 

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Ohmori et al. 2003; Kerstner-Wood et al. 2003). Perfluoroalkyls also bind to plasma gamma-globulin, 

alpha-globulin, 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 concentrations were 

17.7 ng/mL (95% CI 13.0–22.5, range <6.9 [limit of quantification]–57 ng/mL, n=24) and were not 

different in males (18.2 ng/mL, n=13) and females (17.2 ng/mL, n=11). Mean liver concentration 

was18.8 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, exhibit profound species and gender 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 gender differences in elimination kinetics of 

absorbed perfluoroalkyls and dose-dependence of elimination kinetics (see Section 3.4.4). 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 relative to 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. 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 oral 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. The highest concentrations of 14C were observed in blood, liver, and kidney (Figure 3-6). 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 gender 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 

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Figure 3-6. Tissue Concentrations of C in Male and Female Rats Following a 

Single Oral Gavage Dose of [14C]PFOA at 1, 5, or 25 mg/kg
 

14

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, F 

Blood, F 

Liver, F 

Kidney, M 

Source: Kemper 2003 

PERFLUOROALKYLS 166 

3. HEALTH EFFECTS 

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in kidney was observed following the 25 mg/kg dose (Figure 3-6). 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 gender difference and dose-dependencies 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 3-7). 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. Gender 

differences in tissue distribution of PFOA in rats are not explained by gender 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 3.4.2). 

A comparison of PFOA disposition in rats, mice, hamsters, and rabbits, showed pronounced species and 

gender differences (Hundley et al. 2006; Table 3-7). In this study, rats, mice, hamsters, or rabbits 

received an oral dose of 10 mg ammonium [14C]PFOA/kg and tissue 14C in tissues was measured at 

120 or 168 hours (rabbits) hours following the dose. 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; whereas, 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; 

however, 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, one day following the dose (Seacat and Luebker 2000). 

Gender differences in elimination that give rise to gender 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 g/g (one male) or 50 g/g (one female) at the low dose and 45 g/g (one male) and 72 g/g (one 

female) at the higher dose, with corresponding serum concentrations of 3 and 7 g/mL, and 9 and 

10 g/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 

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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 168 

3. HEALTH EFFECTS 

Figure 3-7. 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 

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Table 3-7. 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
 

a

The rabbits were sacrificed 168 hours after dosing; all other animals were sacrificed 120 hours after dosing.

b

The 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. c

Represents the μg equivalents for the entire organ. 

APFO = ammonium perfluorooctanoate 

Source: Hundley et al. 2006 

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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 3.4.2). In 

Cynomolgus monkeys that received daily oral doses of PFOSA (0, 0.03, 0.15, or 0.75 mg PFOSA/kg/day) 

for 26 weeks, liver concentrations of PFOSA 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). 

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, gender differences were noted in the subcellular distribution of 14C in 

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; 

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 appears to be bond 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 2μ-globulin; however, dissociation constants were estimated to 

approximately 1.5 and >2 mM (for a single binding site) for the proteins isolated from rat kidney of urine. 

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) 

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Maternal-fetal Transfer. Perfluoroalkyls can be transferred to the fetus during pregnancy. A study of 

mother-infant pairs in Japan found a relatively high correlation (r2

=0.88) between concentrations of PFOS 

in cord serum at birth (from umbilical vein), and maternal serum measured between gestation week 38 

and 41 (Inoue et al. 2004b). Cord serum concentrations of PFOS ranged from 1.6 to 5.3 ng/mL (n=15), 

whereas maternal serum concentrations ranged from 4.9 to 17.6 ng/mL (n=15). This same study 

attempted to measure maternal and cord serum concentrations of PFOA and PFOSA; however, levels 

were below the limit of detection in most maternal samples and in all cord samples (PFOS and PFOA 

detection limit <0.5 ng/mL; PFOSA <1.0 ng/mL). A study of 11 mother-infant pairs in Germany also 

found significant a correlation between concentrations of PFOS in maternal plasma, measured within 1– 

2 hours of birth, and cord plasma measured at birth (r=0.72), but not for PFOA (r=0.42; Midasch et al. 

2007). Cord plasma PFOS concentrations were approximately 0.60 (range: 0.41–80, n=11) of maternal 

serum concentrations (range 7.8–16.4 ng/mL). Cord plasma PFOA concentrations were approximately 

1.26 (range 0.91–1.95, n=11) of maternal serum concentrations (range 1.5–4.0 ng/mL). 

Maternal-fetal transfer of PFOA has also been studied in rats (Hinderliter et al. 2005). 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). Fetal plasma concentrations of PFOA measured on gestation day 21 were approximately 0.4 of 

maternal plasma concentration. 

Maternal-infant Transfer. Perfluoroalkyls can be transferred to nursing infants. Measurements of 

perfluoroalkyl concentrations in paired samples of serum and human milk collected from Swedish women 

(n=12) found mean milk:serum concentration ratios of 0.01 for PFOS, 0.12 for PFOA (only one milk 

sample was above the limit of detection of 0.01 ng/mL), 0.02 for PFHxS, and 0.07 for PFOSA (Kärrman 

et al. 2007a). Mean maternal serum concentrations were 20.7 ng/mL (range 8.2–48) for PFOS, 3.8 ng/mL 

(range 2.4–5.3) for PFOA, 4.7 ng/mL (range 1.8–11.8) for PFHxS, and 0.24 ng/mL (range <0.10–0.49) 

for PFOSA. Annual composite samples collected from 25–90 Swedish women during the period 1996– 

2004 had perfluoroalkyl concentration ranges of 0.1–0.26 ng/mL for PFOS and 0.016–0.051 ng/L for 

PFHxS (most milk concentrations for PFOA and PFOSA were below the limits of detection). 

Concentration ranges for perfluoroalkyls in breast milk collected from women (n=19) in China were 45– 

360 ng/L for PFOS, 47–210 ng/L for PFOA, and 1.1–14 for PFHxs (So et al. 2006b). No data were 

located regarding concentrations of perfluoroalkyls in human milk in the U.S. population. 

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Studies conducted in rats provide further support for maternal-infant transfer of PFOA through breast 

milk (Hinderliter et al. 2005). 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 were approximately 0.1 of maternal 

plasma concentration. 

3.4.2.3 Dermal Exposure 

Studies of the distribution of perfluoroalkyls in humans or animals following dermal exposure were not 

located. 

3.4.3 Metabolism 

3.4.3.1 Inhalation Exposure 

Studies of metabolism of inhaled perfluoroalkyls in humans or animals were not located. 

3.4.3.2 Oral Exposure 

Studies conducted in rodents and nonhuman primates have not found quantitatively significant 

metabolism of perfluoroalkyls PFOA, PFOS, or PFDeA (Goecke et al. 1992; Vanden Heuvel et al. 1991b, 

1991c; Ylinen and Auriola 1990). PFOA was not metabolized when incubated with microsomal fractions 

of human or rat intestine, kidney, or liver homogenates (Kemper and Nabb 2005). 

3.4.3.3 Dermal Exposure 

Studies of metabolism of perfluoroalkyls in humans or animals following dermal exposures were not 

located. 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

Studies of the elimination of inhaled perfluoroalkyls in humans were not located. Studies conducted in 

animals indicate that elimination of absorbed perfluoroalkyls will be similar for various routes of 

absorption (e.g., oral, intravenous, intraperitoneal; see Section 3.4.4.2). The pronounced gender 

difference in elimination rates in rats (faster elimination in females) was observed in rats following 

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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 days 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. 

3.4.4.2 Oral Exposure 

Absorbed PFOA and PFOS are excreted in urine in humans. 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 3.4.2), <0.1% of filtered perfluoroalkyls were 

excreted in urine, suggesting extensive reabsorption of filtered PFOA and PFOS in the renal tubule. 

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 (Butenhoff et al. 

2004c; Hanhijarvi et al. 1982, 1987; Hundley et al. 2006; Johnson and Ober 1979, 1980, 1999a, 1999b; 

Kemper 2003; Kudo et al. 2001; Vanden Heuvel et al. 1991b, 1991c). Perfluoroalkyls are secreted in bile 

and undergo extensive reabsorption from the gastrointestinal tract (Kudo et al. 2001; Vanden Heuvel et al. 

1991a, 1991b). 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 glomerular 

filtration rate (GFR) was approximately 10 mL/minute/kg; therefore, urinary excretion of PFOA was 

approximately 6% of the rate of glomerular filtration of PFOA in males and 146% in females. These 

estimates indicate that net renal tubular reabsorption of filtered PFOA occurred in male rats, whereas net 

renal tubular secretion of PFOA occurred in female rats (i.e., clearance of free PFOA in plasma >GFR). 

The pronounced gender 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 3.5.1). 

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Rates of elimination of perfluoroalkyls vary substantially across chemical species and animal species, and 

show gender differences and age-dependencies within certain species. Table 3-8 summarizes estimates of 

the elimination half-times (t1/2) for perfluoroalkyls in humans and experimental animals. The elimination 

t1/2 of PFOA has been estimated in humans, nonhuman primates, and rats. Estimates in humans are based 

on measurements of the decline in serum PFOA concentrations in retired fluorochemical production 

workers in the United States (Olsen et al. 2007a) or measurements of renal 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 3-8 as follows (Equations 3 and 4): 

Cl ke = Eq. (3) V 

ln(2) t1/ 2 = Eq. (4) ke 

where ke is the elimination rate (e.g., day-1), Cl is the renal clearance (e.g., mL/day), and V is the volume 

of distribution (L/kg). Estimated t1/2 values for PFOA in humans range from 841–1,292 days and are not 

appreciably different in males and females. When interpreting these numbers, it must be kept in mind 

that they are based on evaluations of populations of limited size in relatively few studies. The Olsen et al. 

(2007a) study provided estimates of t1/2 values of 1,221 and 1,223 days in two females; the group mean 

(22 males, 2 females) was 1,272 days (95% CI 1,083–1,495). Serum concentrations of PFOA in these 

subjects ranged from 17 to 5,100 ng/mL. Estimates of t1/2 values were similar, 841–1,292 days, in the 

Harada et al. (2005a) study, in subjects whose serum PFOA concentrations ranged from 3 to 21 ng/mL. 

Elimination of PFOA in Cynomolgus monkeys and rats is considerably faster than in humans. Following 

cessation of 6 months of oral dosing with PFOA at 10 mg/kg/day, the t1/2 was estimated to be 

approximately 20.1 days in male monkeys (Butenhoff et al. 2004c). Estimates made in Cynomolgus 

monkeys that received an intravenous dose of 10 mg/kg PFOA were 20.9 (±12.5 sd) days in males and 

32.6 (±8.0 sd) in females (Butenhoff et al. 2004c). In rats, elimination of PFOA exhibits pronounced 

gender differences, with faster elimination in females than in males. Estimates of t1/2 values in male rats 

ranged from 115 to 202 hours, for oral dosing, and from 105 to 216 hours for parenteral dosing (i.e., 

intraperitoneal or intravenous). By contrast, estimates for female rats ranged from 3.2 to 16.2 hours for 

oral dosing, and from 1.9 to 24 hours for parenteral dosing. Pronounced dose dependence appears in the 

t1/2 estimates in female rats. Following an oral dose of PFOA of 0.1, 1, 5, or 25 mg/kg, the 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). The divergence in elimination kinetics between male 

and female rats appears to be age-dependent, with faster elimination becoming evident in female rats after 

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Table 3-8. Summary Elimination Half-times for Perfluoroalkyls
 

Estimated in Humans and Experimental Animals
 

Species, age, and Exposure 

gender Route Dose duration Elimination half-time Reference 

PFOA—Human 

Human (n=26), NA NA NA 1,273 days Olsen et al. 2007a 

adult, M (24) F (2) (95% CI: 1,083–1,495) 

Human (n=5), NA NA NA 841 days Harada et al. 2005a 

22±0.9, M 

Human (n=5), NA NA NA 953 days Harada et al. 2005a 

68±5, M 

Human (n=5), NA NA NA 1,292 days Harada et al. 2005a 

23±3, F 

Human (n=5), NA NA NA 1,053 days Harada et al. 2005a 

69±5, F 

PFOS—Human 

Human (n=26), NA NA NA 1,751 days Olsen et al. 2007a 

adult, M (24) F (2) (95% CI: 1,461–2,099) 

Human (n=5), NA NA NA 2,701 days Harada et al. 2005a 

22±0.9, M 

Human (n=5), NA NA NA 1,053 days Harada et al. 2005a 

68±5, M 

Human (n=5), NA NA NA 1,632 days Harada et al. 2005a 

23±3, F 

Human (n=5), NA NA NA 1,669 days Harada et al. 2005a 

69±5, F 

PFHxS—Human 

Human (n=26), NA NA NA 2,662 days Olsen et al. 2007a 

adult, M (24) F (2) (95% CI: 2,112–3,355) 

PFBA—Human 

Human (n=3), NA NA NA 81 hours (SD 41) Chang et al. 2008b 

adult, M 

Human (n=9), NA NA NA 72 hours (SD 38) Chang et al. 2008b 

adult, M (7) F (2) 

PFOA—Nonhuman primate 

Cynomolgus Oral 10 6 months 20.1 days Butenhoff et al. 2004c 

monkey, adult, M mg/kg/day 

Cynomolgus IV 10 mg/kg 1 day 20.9 days (SD 12.5) Butenhoff et al. 2004c 

monkey, adult, M 

Cynomolgus IV 10 mg/kg 1 day 32.6 days (SD 8.0) Butenhoff et al. 2004c 

monkey, adult, F 

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Table 3-8. Summary Elimination Half-times for Perfluoroalkyls
 

Estimated in Humans and Experimental Animals
 

Species, age, and Exposure 

gender Route Dose duration Elimination half-time Reference 

PFOS—Nonhuman primate 

Cynomolgus Oral 0.15 6 months 170 days Seacat et al. 2002 

monkey, adult, M mg/kg/day 

Cynomolgus Oral 0.75 6 months 170 days Seacat et al. 2002 

monkey, adult, M mg/kg/day 

Cynomolgus IV 2 mg/kg 1 day 132 days (SD 13) Noker and Gorman 

monkey, adult, M 2003 

Cynomolgus Oral 0.15 6 months 170 days Seacat et al. 2002 

monkey, adult, F mg/kg/day 

Cynomolgus Oral 0.75 6 months 170 days Seacat et al. 2002 

monkey, adult, F mg/kg/day 

Cynomolgus IV 2 mg/kg 1 day 110 days (SD 26) Noker and Gorman 

monkey, adult, F 2003 

PFBA—Nonhuman primate 

Cynomolgus IV 10 mg/kg 1 day 40.3 hours (SD 2.4) Chang et al. 2008b 

monkey, adult, M 

Cynomolgus IV 10 mg/kg 1 day 41.0 hours (SD 4.7) Chang et al. 2008b 

monkey, adult, F 

PFOA—Rat 

Rat (CR), adult, M Oral 11.4 mg/kg 1 day 115 hours Johnson and Ober 

1980a 

Rat (SD), adult, M Oral 0.1 mg/kg 1 day 202 hours (SD 38) Kemper 2003 

Rat (SD), adult, M Oral 1 mg/kg 1 day 138 hours (SD 32) Kemper 2003 

Rat (SD), adult, M Oral 5 mg/kg 1 day 174 hours (SD 29) Kemper 2003 

Rat (SD), adult, M Oral 25 mg/kg 1 day 157 hours (SD 38) Kemper 2003 

Rat (SD), adult, M IV 1 mg/kg 1 day 185 hours (SD 19) Kemper 2003 

Rat (Wistar), IV 21.5 mg/kg 1 day 136 hours (SD 24) Kudo et al. 2002 

adult, M 

Rat (Wistar), IV 20.1 mg/kg 1 day 135 hours (SD 29) Ohmori et al. 2003 

adult, M 

Rat (SD), adult, M IP 3.9 mg/kg 1 day 216 hours (SE 30.9) Vanden Heuvel et al. 

1991c 

Rat (Wistar), IP 50 mg/kg 1 day 105 hours Ylinen et al. 1990 

adult, M 

Rat (SD), adult, F Oral 0.1 mg/kg 1 day 3.2 hours (SD 0.9) Kemper 2003 

Rat (SD), adult, F Oral 1 mg/kg 1 day 3.5 hours (SD 1.1) Kemper 2003 

Rat (SD), adult, F Oral 5 mg/kg 1 day 4.6 hours (SD 0.6) Kemper 2003 

Rat (SD), adult, F Oral 25 mg/kg 1 day 16.2 hours (SD 9.9) Kemper 2003 

Rat (SD), adult, F IV 1 mg/kg 1 day 2.8 hours (SD 0.5) Kemper 2003 

Rat (Wistar), IV 21.5 mg/kg 1 day 1.9 hours (SD 0.7) Kudo et al. 2002 

adult, F 

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Table 3-8. Summary Elimination Half-times for Perfluoroalkyls
 

Estimated in Humans and Experimental Animals
 

Species, age, and Exposure 

gender Route Dose duration Elimination half-time Reference 

Rat (Wistar), IV 20.1 mg/kg 1 day 1.9 hours (SD 0.7) Ohmori et al. 2003 

adult, F 

Rat (SD), adult, F IP 3.9 mg/kg 1 day 2.9 hours (SE 0.2) Vanden Heuvel et al. 

1991c 

Rat (Wistar), IP 50 mg/kg 1 day 24 hours Ylinen et al. 1990 

adult, F 

PFOS—Rat 

Rat, adult, M Oral 4.2 mg/kg 1 day 179 hours Johnson and Ober 

1979 

PFOSA—Rat 

Rat (SD), adult, M Oral 5.0 mg/kg 1 day 125 hours Seacat and Luebker 

2000 

PFDeA—Rat 

Rat (SD), adult, M IP 4.8 mg/kg 1 day 1,008 hours Vanden Heuvel et al. 

1991b 

Rat (Wistar), IV 25 mg/kg 1 day 958 hours (SD 207) Ohmori et al. 2003 

adult, M 

Rat (Wistar), IV 25 mg/kg 1 day 1,406 hours (SD 140) Ohmori et al. 2003 

adult, F 

Rat (SD), adult, F IP 4.8 mg/kg 1 day 552 hours Vanden Heuvel et al. 

1991b 

PFNA—Rat 

Rat (Wistar), IV 22.6 mg/kg 1 day 710 hours (SD 55) Ohmori et al. 2003 

adult, M 

Rat (Wistar), IV 22.6 mg/kg 1 day 58.6 hours (SD 9.8) Ohmori et al. 2003 

adult, F 

PFHpA—Rat 

Rat (Wistar), IV 17.7 mg/kg 1 day 2.4 hours (SD 1.2) Ohmori et al. 2003 

adult, M 

Rat (Wistar), IV 17.7 mg/kg 1 day 1.2 hours (SD 0.2) Ohmori et al. 2003 

adult, F 

PFBA—Rat 

Rat (SD), adult, M Oral 30 mg/kg 1 day 9.22 hours (SE 0.75) Chang et al. 2008b 

Rat (SD), adult, F Oral 30 mg/kg 1 day 1.76 hours (SE 0.26) Chang et al. 2008b 

Rat (SD), adult, M IV 30 mg/kg 1 day 6.38 hours (SE 0.53) Chang et al. 2008b 

Rat (SD), adult, F IV 30 mg/kg 1 day 1.03 hours (SE 0.03) Chang et al. 2008b 

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3. HEALTH EFFECTS 

Table 3-8. Summary Elimination Half-times for Perfluoroalkyls
 

Estimated in Humans and Experimental Animals
 

Species, age, and Exposure 

gender Route Dose duration Elimination half-time Reference 

PFBA—Mouse 

Mouse (CD1), Oral 10 mg/kg 1 day 13.34 hours (SE 4.55) Chang et al. 2008b 

adult, M 

Mouse (CD1), Oral 30 mg/kg 1 day 16.3 hours (SE 7.2) Chang et al. 2008b 

adult, M 

Mouse (CD1), Oral 100 mg/kg 1 day 5.22 hours (SE 2.27) Chang et al. 2008b 

adult, M 

Mouse (CD1), Oral 10 mg/kg 1 day 2.87 hours (SE 0.30) Chang et al. 2008b 

adult, F 

Mouse (CD1), Oral 30 mg/kg 1 day 3.08 hours (SE 0.26) Chang et al. 2008b 

adult, F 

Mouse (CD1), Oral 100 mg/kg 1 day 2.79 hours (SE 0.3) Chang et al. 2008b 

adult, F 

CI = confidence interval; F = female; 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
 

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PERFLUOROALKYLS 179 

3. HEALTH EFFECTS 

30 days of age, consistent with the timing of sexual maturation and involvement of sex hormones in the 

modulation of the renal excretion of PFOA in rats (Hinderliter et al. 2006b). Collectively, these studies 

show that elimination rates of PFOA vary substantially across species. The elimination rate in female rats 

(t1/2≈4 hours at low doses) is approximately 40 times faster than in male rats (t1/2≈160 hours), 120 times 

faster than in Cynomolgus monkeys (t1/2≈20 days), and approximately 6,000 times faster than in humans 

(t1/2≈1,000 days). Furthermore, in addition to faster elimination rate in female rats compared to male rats, 

elimination rate and renal clearance of PFOA appeared to decrease as dose increased. This dose 

dependence has been attributed to a capacity-limited renal tubular secretion of PFOA in female rats (see 

Section 3.5.1). Gender differences in elimination of PFOA have also been observed in hamsters; 

however, unlike the rat, male hamsters excreted absorbed PFOA more rapidly than female hamsters. 

Following a single oral gavage dose of 10 mg/kg as ammonium [14C]PFOA, cumulative excretion of 14C 

in urine at 24 hours postdosing was 96.4% of the dose in female rats and 8.7% in male rats; 25.% in 

female hamsters and 84.5% in male hamsters; 4.1% in male and female mice; and 90.5 and 80.2% in 

female and male rabbits, respectively (Hundley et al. 2006). 

Elimination t1/2 values for PFOS in humans, nonhuman primates, and rats are summarized in Table 3-8. 

In general, PFOS t1/2 values are higher than those for PFOA (i.e., elimination of PFOS is slower than 

PFOA); however, as with PFOA, substantial interspecies variability is evident in the t1/2 values for PFOS. 

Analysis of kinetics of serum PFOS concentrations in retired U.S. fluorochemical production workers 

(24 males, 2 females) yielded an estimate of 1,751 days (95% CI 1,461–2,099) for the serum elimination 

t1/2 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 1,792 and 2,474 days. Estimates based on renal 

clearance of PFOS from serum in subjects from the general population of Japan ranged from 1,053 to 

2,701 days; these subjects had serum PFOS concentrations that ranged from 4 to 49 ng/mL. Estimates in 

males (2,701, 1,053 days) were similar to females (1,632, 1,699 days). Estimates of the elimination t1/2 in 

Cynomolgus monkeys were similar across studies, doses and routes (oral, intravenous) and ranged from 

110 to 170 days (Noker and Gorman 2003; Seacat et al. 2002). Estimates for male and female 

Cynomolgus monkeys were similar; t1/2=170 days, in monkeys that received 0.15 or 0.75 mg 

PFOS/kg/day for 6 months (Seacat et al. 2002). Plasma PFOS kinetics in male rats that received a single 

oral gavage dose of 4.2 mg/kg PFOS yielded an estimate of 179 hours for the elimination t1/2 (Johnson 

and Ober 1979). Comparisons of the elimination kinetics of PFOS in male and female rats have not been 

reported. Collectively, these estimates indicate that elimination of PFOS in male rats (t1/2≈180 hours) 

occurs approximately 20 times faster than in Cynomolgus monkeys (t1/2≈150 days), and approximately 

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PERFLUOROALKYLS 180 

3. HEALTH EFFECTS 

240 times faster than in humans (t1/2≈1,800 days). In each of these species, elimination of PFOS was 

slower than PFOA. 

Estimates of elimination rates for PFHxS and PFBA in humans are also available (Table 3-8). Analysis 

of kinetics of serum PFHxS concentrations in retired U.S. fluorochemical production workers (24 males, 

2 females) yielded an estimate of 2,662 days (95% CI 2,112–3,355) 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 4,458 and 4,885 days. 

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 days (±41 sd). In a larger study of nine workers (seven males, two females), 

the mean t1/2 was 72 days (±38 sd). Estimates for the two female subjects were 56 and 118 days. The 

combined mean value for the 12 estimates was 75 days (±38 sd). Based on these observations, the PFBA 

is eliminated substantially faster in humans than perfluoroalkyls having longer carbon chain lengths (e.g., 

PFHxS, PFOA, PFOS). Studies conducted in Cynomolgus monkeys and rats provide further evidence for 

more rapid elimination of PFBA compared to PFOA or PFOS. Elimination t1/2 values for male and 

female Cynomolgus monkeys that received an intravenous dose of 10 mg/kg PFBA were 40.3 hours 

(±2.4 sd) and 41.0 hours (±4.7 sd), respectively (Chang et al. 2008a). Elimination rates in rats following 

an oral gavage dose of 30 mg PFBA/kg were approximately 4 times faster in female rats 

(t1/2=1.8 hours±0.3, standard error [SE]) compared to male rats (t1/2=9.2 hours ±0.8, SE; Chang et al. 

2008a). Elimination rates in female mice were 2–4 times faster than in male mice. In mice that received 

an oral dose of 30 mg PFBA/kg, the t1/2 in female mice was 3.1 hours (±0.3, SE) compared to 

16.3 (±7.2 hours, SE) in male mice (Chang et al. 2008a). Elimination rates in male mice appeared to be 

dose-dependent, based on lower mean values for t1/2 in mice that received an oral dose of 100 mg 

PFBA/kg (t1/2=5.2 hours ±2.3, SE) compared to mice that received 10 mg/kg (t1/2=13.3 hours ±4.6, SE) or 

30 mg/kg (t1/2=16.3 hours ±7.2, SE); however, these estimates were based on three animals per dose 

group, and the means are not significantly different (p>0.05; Fisher's least significant difference). 

A trend for decreasing elimination rate with increasing perfluoroalkyl chain length is also evident from 

comparison of the elimination rates in male and female rats that received an equimolar intravenous dose 

of PFHpA (17.7 mg/kg), PFOA (20.1 mg/kg), PFNA (22.6 mg/kg), or PFDeA (25.0 mg/kg). In both male 

and female rats, t1/2 values increased with increasing chain length; in males, t1/2 values for the series 

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PERFLUOROALKYLS 181 

3. HEALTH EFFECTS 

(PFHpA to PFDeA) were 2.4, 135, 710, and 958 hours in males and 1.2, 1.9, 59, and 1,406 hours, in 

females (Ohmori et al. 2003). Eliminations rates of PFHpA, PFOA, and PFNA were faster in females 

than in males, whereas rates for PFDeA were faster in males. 

3.4.4.3 Dermal Exposure 

Studies on excretion of perfluoroalkyls following dermal exposure of humans or animals were not 

located. Routes and rates of excretion of perfluoroalkyls absorbed through the skin are expected to be the 

same as that following absorption from other routes (see Section 3.4.4.2). 

3.4.4.4 Other Routes of Exposure 

Selected studies in which elimination rates (i.e., half-times) of perfluoroalkyls have been determined are 

summarized in Table 3-8. In general, elimination t1/2 values are similar following intravenous, 

intraperitoneal, oral exposures, suggesting that 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). 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (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 end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

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PERFLUOROALKYLS 182 

3. HEALTH EFFECTS 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-8 shows a conceptualized representation of a PBPK model. 

If PBPK models for perfluoroalkyls exist, the overall results and individual models are discussed in this 

section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species 

extrapolations. 

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Ingestion 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km GI 

Tract 

Feces 

Urine

 Chemicals 

contacting skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

PERFLUOROALKYLS 183 

3. HEALTH EFFECTS 

Figure 3-8. Conceptual Representation of a Physiologically Based
 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance
 

Inhaled chemical Exhaled chemical 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 

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V d = Vdc tk 

tV 

+

d ⋅ + max Eq. (a) 

0 

PERFLUOROALKYLS 184 

3. HEALTH EFFECTS 

PBPK models for perfluoroalkyls are discussed in this section in terms of their use in risk assessment, 

tissue dosimetry, and dose, route, and species extrapolations. PBPK models for PFOA and PFOS in rats 

and monkeys have been reported (Tan et al. 2008). 

3.4.5.1 Tan et al. (2008) Models 

Tan et al. (2008; Andersen et al. 2006) developed a model for simulating the kinetics of plasma and 

urinary PFOA in male and female rats, PFOS in male rats, and PFOS in male and female monkeys. The 

general structure of the Tan et al. (2008) model is depicted in Figure 3-9. Values for parameters for the 

rat and monkey models are presented in Tables 3-9 and 3-10. The model includes compartments 

representing a central compartment (which includes plasma), liver, other tissues, renal glomerular filtrate, 

and a kidney storage compartment (for simulating the time delay between glomerular filtration and 

urinary excretion). Absorption from the gastrointestinal tract is simulated as a first-order process 

constrained by absorption fractions of 0.94 and 0.98 for PFOA in male and female rats; and 0.96 for 

PFOS in male rats (values for monkeys were not reported). Absorbed PFOA and PFOS are assumed to be 

delivered to the liver where saturable binding to liver proteins occurs. Exchanges between unbound (free) 

PFOA or PFOS in liver with the free pool in the central compartment are assumed to be flow-limited 

(governed by liver blood flow) with equilibrium determined by the liver:blood partition coefficient. 

Exchanges between the lumped compartment representing other tissues and the free pool in the central 

compartment are represented as first order processes with plasma-to-tissue and tissue-to-plasma rate 

constants. 

A time dependence in the volume of distribution in the central compartment was introduced into the 

models for PFOA and PFOS in the male rat (but not in the female rat or monkey models) to achieve 

agreement between model predictions and observed kinetics of PFOA and PFOS in plasma. The timedependence is simulated with a Michaelis-Menten function (Equation a): 

where Vd is the volume of distribution the central compartment (L/kg body weight) at time, t; Vdc is the 

volume (L/kg) at t=0; and k0 is the time (hour) at which the changing fraction of the volume is half of 

maximum. The time dependence results in the volume of distribution of PFOA in the central 

compartment increasing from initial values of 0.06–0.41, with 188 hours for the time at which half of 

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Liver Compartment 

(Liver volume; Free fraction in liver; Saturable binding) 

Central Compartment 

(Volume of distribution; Free fraction in serum; Plasma concentration) 

Tissue Compartment 

(Amount in tissue) 

Storage Compartment 

Filtrate Compartment 

(Volume of renal filtrate; Renal filtration rate; 

Saturable resorption) 

Fecal elimination 

Urinary elimination 

Input (iv) PL QL 

k13 k31 

Qfil Tm , Kt 

PERFLUOROALKYLS 185 

3. HEALTH EFFECTS 

Figure 3-9. Structure of PBPK Model of PFOA and PFOS in the Rat and Monkey 

Input (oral) 

Source: Tan et al. 2008 

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3. HEALTH EFFECTS 

Table 3-9. Parameters Used in the Male and Female Rat Model for Exposure to
 

PFOS and PFOA
 

Values 

PFOS PFOA 

Parameters Unit Male Male Female 

Body weight (BW) kg 0.285 0.197–0.27 0.175–0.2 

Cardiac output (Qcc), Qc = QccBW0.74 L/hour/kg 14 14 14 

Liver volume as percent BW (VLC) L/kg 0.034 0.034 0.034 

Blood flow to liver as percent cardiac output 0.183 0.183 0.183 

(QLC) 

Volume of distribution at time 0 (Vdc0) L/kg 0.05 0.06 0.11 

Maximum increase in volume of distribution L/kg 0.01 0.35 0 

(Vdmax) 

Volume adjustment constant (k0) hour 0.11 188 Not applicable 

Oral absorption rate (kabs) hour-1 25.1 11.5 31.3 

Free fraction of PFOS in blood at time zero 0.087 0.006 0.045 

(Free0) 

Free fraction adjustment factor (δ) 0.94 0.35 0 

Free fraction adjustment factor (kfree) 7.34 1.1 Not applicable 

Liver:blood partition coefficient (PL) 6.51 1.56 1.9 

Maximum association rate constant (kon_max) μg/hour 1.19 17.1 3.43 

Binding affinity constant (KB) μg/L 0.0036 100 6.06 

Disassociation constant (koff) hour-1 0.015 1.02 0 

Transport maximum as percent BW (Tmc) μg/kg/hour 125.3 516 9.35 

Transport affinity constant (KT) μg/L 16.7 209 50 

Rate constant to urine (ku) hour-1 96.2 15.9 0.32 

Renal plasma filtration rate as fraction of 0.028 0.028 0.028 

cardiac output (Qfilc) 

Volume of renal filtrate (Vfil) L 0.01 L 0.01 0.01 

Rate constant from liver to feces (kfeces) hour-1 0.3 0.49 1.6x10-6 

Fraction of dose that goes directly to feces 0.041 0.062 0.024 

(Funabsorbed) 

Transfer rate constant from intake to fecal hour-1 0.0054 hour-1 0.001 0.037 

elimination (kf) 

Rate constant from central to tissue (k13) hour-1 1.91 hour-1 1.84 0.65 

Rate constant from tissue to central (k31) hour-1 0.001 hour-1 0.37 0.007 

Source: Tan et al. 2008 

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3. HEALTH EFFECTS 

Table 3-10. Parameters Used in the Male and Female Monkey Model for Exposure 

to PFOS 

Parameters Unit Male Female 

Body weight (BW) kg 6.5 3.9 

Cardiac output (Qcc), Qc = QccBW0.74 L/hour/kg 15 15 

Liver volume as percent BW (VLC) L/kg 0.05 0.05 

Blood flow to liver as percent cardiac output (QLC) 0.2 0.2 

Volume of distribution at time 0 (Vdc0) L/kg 0.11 0.17 

Maximum increase in volume of distribution (Vdmax) 0 0 

Volume adjustment constant (k0) Not applicable Not applicable 

Free fraction of PFOS in blood at time zero (Free0) 0.017 0.015 

Free fraction adjustment factor (δ) 0.74 0.74 

Free fraction adjustment factor (kfree) 0.009 0.009 

Liver:blood partition coefficient (PL) 1 1 

Maximum association rate constant (kon_max) 0 0 

Binding affinity constant (KB) Not applicable Not applicable 

Disassociation constant (koff) 0 0 

Transport maximum as percent BW (Tmc) mg/kg/hour 182.8 104.2 

Transport affinity constant (KT) mg/L 2.66 2.34 

Rate constant to urine (ku) hour-1 0.005 0.004 

Renal plasma filtration rate as fraction of 

cardiac output (Qfilc) 0.034 0.034 

Volume of renal filtrate (Vfil) L 0.01 0.01 

Rate constant from liver to feces (kfeces) hour-1 0.18 0.32 

Rate constant from central to tissue (k13) hour-1 3.60 1.61 

Rate constant from tissue to central (k31) hour-1 0.05 0.04 

Source: Tan et al. 2008 

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 Eq. (c) 

gfT 

gfm 

CK 

CT

T 

+

⋅ =

PERFLUOROALKYLS 188 

3. HEALTH EFFECTS 

maximum increase occurs. For PFOS, the initial value of 0.05 increases to 0.061 and achieves half of the 

maximum change in 0.11 hours. 

Time dependence was also introduced into the binding parameters for PFOA in the central compartment 

of male rats, and for PFOS in male rats and in male and female monkeys (Equation b): 

−k free ⋅t Free = Free 0 ⋅(1− δ ⋅(1− e )) Eq. (b) 

where Free is the free fraction in the central compartment at time, t; Free0 is the free fraction at t=0,  is 

an adjustment factor, and kfree is the rate constant for the change in free fraction (hour-1). The time 

dependence results in a decrease in the free fraction for PFOA in the male rat from an initial value of 

0.006–0.004 L/kg, with a half-time for the change of approximately 0.6 hours. Corresponding changes 

for PFOS in the male rat are 0.087–0.052 L/kg with a half-time of approximately 0.094 hours. 

Corresponding changes for PFOS in monkeys are 0.0017–0.0044 L/kg in males and 0.0015–0.0039 L/kg 

in females; with a half-time of approximately 77 hours in both males and females. Mechanistic 

explanations for these species- and gender-specific time-dependences have not been elucidated. 

Transfer of PFOA and PFOS 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 net rate resulting from glomerular filtration of the free fraction in plasma and renal tubular 

reabsorption, which removes PFOA and PFOS from the glomerular filtrate. Renal tubular reabsorption is 

simulated as a capacity-limited process with a Michaelis-Menten function (Equation c): 

where T is the rate of reabsorptive transport (μg/hour/kg body weight), Tm is the maximum rate of 

transport (μg/hour/kg body weight), Cgf is the concentration of PFOA or PFOS in the glomerular filtrate 

(μg/L), and KT is the concentration in the glomerular filtrate (μg/L) at which reabsorptive transport rate is 

half of maximum. A “storage” compartment in kidney simulates the time delay between entrance of 

PFOA or PFOS into the glomerular filtrate and its appearance in urine. Transfer from the storage 

compartment to urine is first-order. Parameter values for renal tubular reabsorption of PFOA in rats result 

in lower reabsorptive clearances from the glomerular filtrate (Tm/KT=0.19) in male rats compared to 

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PERFLUOROALKYLS 189 

3. HEALTH EFFECTS 

female rats (Tm/KT=7.5) and urinary clearances from plasma that are approximately 10-fold higher in 

male rats. 

Validation of the model. Description of the optimization of parameter values and evaluation of the 

rat and monkey models model are described in Tan et al. (2008). Initial PFOS parameter values for the 

male rat model were established based on data reported in single intravenous and oral dosing studies 

(Johnson and Ober 1979, 1980). All PFOS parameters were fit to achieve agreement with the time course 

for PFOS in plasma and cumulative excretion of PFOS in urine and feces. The predicted plasma 

elimination t1/2 was approximately 300 hours (based on Figure 6 of Tan et al. 2008) compared to 

179 hours reported in Johnson and Ober (1979). The predicted liver PFOS concentrations 89 days after a 

simulated dose of 4.2 mg PFOS/kg was 21.55 μg/g, compared to the reported value of 20.56 μg/g 

(Johnson and Ober 1980). 

Parameter values for PFOA for the male and female rat models were established based on single oral 

dosing studies (Kemper 2003). This study found substantially faster elimination kinetics of PFOA in 

female rats compared to male rats and a dose-dependent decrease in elimination in female rats. Following 

a single oral dose of ≤5 mg/kg, the observed elimination half-time in the female rat was approximately 

10–50 times that in males (see Section 3.4.4.2). The rat PFOA models reproduced the gender differences 

in the elimination rates of PFOA from plasma. However, better agreement was achieved with observed 

plasma and excretory kinetics in male rats than in females. Contributing to this outcome may have been 

failure to correctly capture in the model pharmacokinetics processes underlying the dose-dependence in 

elimination kinetics observed in female rats; in particular, renal tubular mechanisms which may involve 

both reabsorption and secretion in rats (see Section 3.5.1). Also unexplained are the pharmacokinetics 

bases for the time-dependence in volume of distribution and plasma binding of PFOA, which improved 

model fits to observations on male rats, but did not improve model fits to the observations on female rats. 

Parameter values for PFOS in monkeys were initially established based on single intravenous dosing 

studies conducted on Cynomolgus monkeys (Noker and Gorman 2003). This study found similar 

elimination half-time values for PFOS in male (t1/2=132±13 hours) and female (t1/2=110±25 hours) 

monkeys; these observations were reproduced in the models. Introducing time-dependency of plasma 

binding of PFOS (i.e., decreasing free fraction with increasing time after dose) improved fits to observed 

plasma and urine PFOS kinetics following a single intravenous dose of 2 mg PFOS/kg administered to 

male or female monkeys. The models, with parameters optimized to the observations from the 

intravenous study, were implemented to simulate plasma PFOS kinetics in Cynomolgus monkeys, 

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observed during and following repeated oral doses of 0.03, 0.15, or 0.75 mg PFOS/kg/day for 26 weeks 

(Butenhoff et al. 2002). Predicted plasma kinetics before and after cessation of dosing reproduced 

observations for the two lower doses; however, predictions were less satisfactory for the 0.75 mg/kg/day 

dose. Improved fit to the 0.75 mg/kg/day observations were achieved by introducing a time-dependency 

in the volume of distribution of the central compartment (increasing volume with increasing time after 

dose). The mechanistic underpinnings to this adjustment have not been elucidated. 

Risk assessment. The rat and monkey models reported in Tan et al. (2008) have not been applied to 

risk assessments and several characteristics of the models, in their current form, limit their use in risk 

assessment (e.g., intra- or interspecies extrapolation). The models use species- and gender-specific time 

dependent parameter values that alter the volume of distribution and free fraction of PFOA or PFOS in 

plasma. Given the absence of an understanding of mechanisms for these time-dependencies, scaling of 

parameter values across species (i.e., to humans) would be highly uncertain. The rat model did not 

capture observed dose-dependencies of elimination kinetics in female rats. This may have resulted from 

an inadequate parameterization of gender- and dose-dependent clearance mechanisms, which would 

introduce additional uncertainty into intra- or inter-species extrapolations. Renal clearance mechanisms 

for PFOA and PFOS appear to be modulated by sex hormones, which may give rise to age dependence 

and other sources of variability in elimination kinetics related to sex hormone status, in addition to gender 

differences. The influence of sex hormones on elimination of PFOA and PFOS are not simulated in 

current models. 

Target tissues. The rat and monkey models include parameters for predicting levels of PFOA or 

PFOS in plasma, liver (a toxicity target), urine, and feces. 

Species extrapolation. Evaluation of the robustness of extrapolation of the rat or monkey models to 

other species has not been reported. It should be noted that the extreme differences in pharmacokinetics 

among species, particularly with humans, create an unusual degree of difficulty in making extrapolations 

to humans from animal models. 

Interroute extrapolation. The rat and monkey models include parameters for simulating 

gastrointestinal absorption of PFOA or PFOS. Evaluations of the robustness of the models for predicting 

kinetics following exposures to other routes have not been reported. 

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3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. Studies conducted in rodents indicate that >93% of an ingested dose of PFOA and PFOS 

is absorbed and that absorption occurs with an approximate half-time of 0.25–1.5 hours (see 

Section 3.4.1.2 for discussion of Chang et al. 2008a; Hinderliter et al. 2006b; Hundley et al. 2006; 

Johnson and Ober 1979, 1980; Kemper 2003). Mechanisms of absorption of perfluoroalkyls have not 

been elucidated and may involve (1) diffusive transfer of the non-ionized fraction out of the stomach 

lumen; (2) transport in the small intestine mediated by organic anion transporters; and/or (3) absorption in 

association with absorptive transport of lipids. 

Distribution. Perfluoroalkyls in plasma bind to serum albumin and various other plasma proteins 

including gamma-globulin, alpha-globulin, alpha-2-macroglobulin, transferrin, and beta-lipoproteins (Han 

et al. 2003, 2005; Ohmori et al. 2003; Kerstner-Wood et al. 2003; Vanden Heuvel et al. 1992b; Ylinen 

and Auriola 1990). The dissociation constant for binding of PFOA to serum albumin 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). A component of the binding of PFOA and PFDeA to serum 

albumin appears to be covalent, and may involve the sulfhydryl moiety of albumin (Vanden Heuvel et al. 

1992b). 

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 

facilitates entry of PFOA into renal tubular cells (Kudo et al. 2002; Vanden Heuvel et al. 1992a). The 

subcellular distribution of PFOA is gender- 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; however, protein complexes formed have not been fully 

characterized. A component of intracellular binding appears to be covalent (Vanden Heuvel et al. 1992b). 

PFOA exhibits a low affinity for binding to rat kidney and urine 2μ-globulin (dissociation constants 

1.5 and >2 mM, respectively; Han et al. 2004). 

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Metabolism. Studies conducted in rodents and nonhuman primates have not found quantitatively 

significant metabolism of perfluoroalkyls PFOA, PFOS, or PFDeA (Goecke et al. 1992; Vanden Heuvel 

et al. 1991b, 1991c; Ylinen and Auriola 1990). PFOA was not metabolized when incubated with 

microsomal fractions of human or rat intestine, kidney, or liver homogenates (Kemper and Nabb 2005). 

Excretion. Urinary excretion of PFOA in rats appears to involve glomerular filtration, reabsorption of 

PFOA from tubular fluid, and secretion of PFOA into tubular fluid (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; KerstnerWood et al. 2003; Vanden Heuvel et al. 1992a, 1992b; Ylinen and Auriola 1990). 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. Evidence in support of this includes the 

following: 

(1) 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). 

(2) Urinary excretion and renal clearance of PFOA are decreased by treatment with probenecid, a 

competitive inhibitor of organic anion secretion in the kidney (Kudo et al. 2002; Vanden Heuvel 

et al. 1992a). 

(3) Urinary elimination rate and renal clearance in adult rats increase following castration and the 

increase is attenuated with testosterone replacement (Kudo et al. 2002; Vanden Heuvel et al. 

1992a). 

(4) Gender differences and hormone-mediated changes in renal clearance in adult rats correlate with 

differences and changes in expression of genes for organic anion transporters in the basolateral 

membrane (OAT1, OAT2) and luminal membrane (oatp1) of kidney (Kudo et al. 2002). 

(5) Gender differences in elimination kinetics in rats develop at approximately the same time of 

sexual maturation (Hinderliter et al. 2006b). 

Perfluoroalkyls (PFOA, PFDeA) are secreted in bile and undergo extensive reabsorption from the 

gastrointestinal tract (Kudo et al. 2001; Vanden Heuvel et al. 1991a, 1991b). 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 gender influence on biliary secretion (compared to the 

gender influence on renal clearance) may reflect a relative gender insensitivity of OAT2 (or other organic 

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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). 

3.5.2 Mechanisms of Toxicity 

Some information regarding mechanisms of toxicity presented below has been extracted from reviews by 

Cattley et al. (1998), Maloney and Waxman (1999), Corton et al. (2000), and Klaunig et al. (2003). 

The liver is a main target for perfluoroalkyl compounds in animals. Liver toxicity in rodents results from 

the ability of these compounds (with some structural restrictions) to activate the peroxisome proliferatoractivated receptor-α (PPARα), a member of the nuclear receptor superfamily that mediates a broad range 

of biological responses (Issemann and Green 1990). Peroxisome proliferators directly regulate gene 

transcription through a heterodimeric receptor complex, composed of PPARα and the retinoid X receptor. 

The activated receptor complex regulates transcription by binding to a DNA direct repeat motif (also 

termed PPAR response element or PPRE) located in the promoters of peroxisome proliferators responsive 

genes. Studies of PPARα in various species have shown that rats and mice are the most sensitive species 

to PPARα agonists, whereas guinea pigs, nonhuman primates and humans are less responsive, and 

hamsters fall in between. PPARα cDNA from humans has been cloned and shown to be indistinguishable 

from the rodent PPARα in overall structure. The DNA binding domains of the human and rodent PPARα 

are virtually 100% homologous. Several explanations have been offered for the species-specific effects 

of peroxisome proliferators including: (1) differences in the ability of PPARα to be activated by 

peroxisome proliferators, (2) differences in the inducibility of PPARα after exposure to peroxisome 

proliferators (human PPARα required higher PFOA concentrations than mouse PPARα for maximal 

activation in a COS-1 cell transfection assay), and (3) differences in pattern and levels of tissue-specific 

expression of PPARα; the level of expression of PPARα in human liver is about 1–10% of the levels 

found in rat and mouse liver. Although humans are refractory to the many effects induced by peroxisome 

proliferators in rodents, humans have a functional PPARα as suggested by the pharmacological reductions 

in serum triglycerides and cholesterol in patients treated with the peroxisome proliferator clofibrate, a 

response known to be mediated by the PPARα in mice. In addition to PPARα, two other PPAR subtypes 

encoded by separate genes, PPARβ/δ and PPARγ, have been cloned. 

Some recent studies in vitro have provided insights regarding the interaction of PFOA and PFOS with 

PPARs. For example, PFOS was found to activate both mouse and human PPARα in a COS-1 cell-based 

luciferase reporter trans-activation assay with no significant difference in the responsiveness of two 

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PPARs (Shipley et al. 2004). PFOS activated mouse and human PPARα to the same maximum extent as 

the prototypical PPARα agonist Wy-14,643, but substantially higher concentrations were required to elicit 

a PPAR transcriptional response. In a similar study, human, mouse and rat PPARα were activated by 

PFOA and PFOS, PPARβ/δ was less sensitive, and only PFOA activated the mouse receptor 

(Vanden Heuvel et al. 2006). Both PFOA and PFOS also activated human, mouse and rat PPARγ, but 

both chemicals appeared to be only partial agonists of this receptor. In similar experiments conducted by 

Takacs and Abbott (2007), PFOA had more transactivity than PFOS with both the mouse and human 

PPARs. PFOA significantly increased the activity of mouse and human PPARα and mouse PPARβ/δ 

relative to vehicle control, but not the human PPARβ/δ. PFOS significantly increased activation of 

mouse PPARα and PPARβ/δ, but not the human PPARβ/δ. Neither PFOA nor PFOS activated the mouse 

or human PPARγ. As discussed by Vanden Heuvel et al. (2006), although these studies provide valuable 

information regarding the mechanism of action of PFOA and PFOS, it should be kept in mind that they 

only measure the first of many steps in the complex regulation of gene transcription. Moreover, the 

validity of comparing sensitivity across species based on reporter data may be questionable since the 

comparisons are made between species under conditions where the receptors are equivalently expressed 

and in the same cellular environment and where ligand-independent potential sources of species 

differences are removed. 

Activation of the 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, an increased CYP450-mediated ω-hydroxylation of lauric acid, and alterations in lipid 

metabolism. PPARα regulates lipid homeostasis through the modulation of expression of genes involved 

in fatty acid uptake, activation, and oxidation. 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). 

Several studies published in recent years have studied the effects of PFOS and PFOA on gene expression 

with the intent of identifying critical target pathways for the biological effects of these substances. Some 

examples are summarized below. 

Gene expression profiling studies in male and female Sprague-Dawley rats showed that administration of 

5 mg/kg/day PFOS by gavage for 3 or 21 days resulted in significant (>3-fold change) induction or 

suppression of some 400 genes in the liver out of 8,000 functionally annotated genes and expressed 

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sequence tags on the array (Hu et al. 2005). The largest groups of genes induced by PFOS were the 

cytochrome P450s and genes that coded for lipid metabolizing enzymes. Also induced significantly were 

genes involved in hormone regulation and other regulatory processes. PFOS suppressed genes involved 

in signal transduction pathways and in regulating nervous system functions. Of the various pathways 

represented by the altered genes, the peroxisomal fatty acid β-oxidation pathway seemed to be the 

pathway most affected by PFOS. In contrast, exposure to PFOS did not enhance the expression of genes 

involved in mitochondrial fatty acid β-oxidation. The effects on peroxisome fatty acid β-oxidation did 

not seem to be receptor-mediated since PPARα mRNA expression was not affected. The study by Hu et 

al. (2005) also showed that PFOS may not be a typical peroxisome proliferator as it also increased the 

activities of carboxylesterase and CYP2B1, a response characteristic of phenobarbital inducible systems, 

and it did not induce CYP4A, which is strongly induced by other peroxisome proliferators. This 

suggested that PFOS may exert its biological effects via other mechanism of action including being a 

substrate for fatty acid metabolism, alteration of peroxisomal membrane permeability, or uncoupling of 

mitochondrial membrane potential (Hu et al. 2002a; Starkov and Wallace 2002). 

PFOS significantly (90-fold) induced the activity of the cytosolic enzyme long-chain acyl-CoA hydrolase, 

an enzyme that cleaves acyl-CoA to free fatty acid and CoA (Hu et al. 2005). The resulting increase in 

cytosolic free fatty acid concentrations is consistent with observations made in rodents and primates, 

which exhibit hepatocellular hypertrophy and lipid vacuolation and could be caused by accumulation of 

free fatty acids (Seacat et al. 2002). In addition, PFOS suppressed (2.5-fold) the activity of HMG CoA 

reductase, the rate-limiting enzyme in cholesterol synthesis, which is consistent with the earlier findings 

of Haughom and Spydevold (1992) who suggested that the hypolipidemic effects of PFOS may result 

from impaired production of lipoprotein particles due to reduced synthesis and esterification of 

cholesterol together with enhanced oxidation of fatty acids in the liver. Hu et al. (2005) also conducted 

experiments in H4IIE rat hepatoma cells in vitro and reported differences in gene expression profiles 

between the in vitro and in vivo control samples. This, according to the investigators, could be explained 

by the differences in exposure system, dosage, toxicokinetics, toxicodynamics, and levels of organization 

and functional integration, which make the in vivo exposure more complicated than the in vitro exposure 

A study similar to that of Hu et al. (2005) was conducted with PFOA by Guruge et al. (2006) in male 

Sprague-Dawley rats administered various doses (1–15 mg/kg/day) of PFOA by gavage for 21 days. The 

largest categories of genes induced were involved in transport and metabolism of fatty acids and lipids. 

Treatment with PFOA also induced genes involved in cell communication, adhesion, growth, apoptosis, 

regulation of hormone, proteolysis and peptidolysis, and signal transduction. The largest groups of genes 

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suppressed were related to transport, inflammation and immune response, and cell adhesion. Guruge et 

al. (2006) also reported significant suppression of several genes involved in apoptosis, regulation of 

hormone, metabolisms, and G-protein coupled receptor protein signaling pathway. The number of genes 

induced or suppressed was found to be directly proportional to the dose over the 1–10 mg/kg/day dose 

range. Comparisons with the PFOS study (Hu et al. 2005) showed that of the 23 genes that were upregulated by PFOS, 12 genes were also up-regulated by PFOA. However, 7 genes were unchanged and 

4 could not be found in the PFOA study. Of the 19 genes that were suppressed by PFOS, only 1 was 

found to be suppressed and all others but 1 were not affected by exposure to PFOA. A more detailed 

analysis of genes which were up- or down-regulated by all doses of PFOA showed that a large number of 

genes associated with lipid or fatty acid metabolism were altered by PFOA and some of the genes were 

linked with pathways of fatty acid degradation and mitochondrial fatty acid β-oxidation. Of interest was 

the observation that genes responsible for metabolism of unsaturated fatty acid and for the transfer of fatty 

acids for oxidation were significantly up-regulated suggesting an increased transfer of activated fatty 

acids or PFOA across the membrane of the mitochondria. Since PFOA significantly induced genes 

coding for peroxisome proliferation but had no effect on the expression of catalase, Guruge et al. (2006) 

suggested the possibility that potentially toxic hydrogen peroxide was produced in peroxisomes that could 

have caused oxidative stress or oxidative damage to proteins and DNA. Also of interest was the 

suppression of genes that might affect regulation of food intake and energy homeostasis; reduced food 

intake is commonly seen in studies with PFOA and PFOS in rodents. Similar to PFOS, PFOA downregulated genes involved in the synthesis of cholesterol, which might affect membrane fluidity and gap 

junction intercellular communication (Hu et al. 2002; Upham et al. 1998). Lastly, PFOA suppressed 

some genes involved in the transport of organic anions that might play a role in the urinary elimination of 

PFOA, which would result in a negative feedback that would inhibit elimination of PFOA in the male rat. 

Recently, Rosen et al. (2008) examined transcript profiles in the livers of wild-type mice and PPARα-null 

mice exposed orally to PFOA for 7 days. The investigators found that in wild-mice, PFOA altered 2.4% 

of the total number of genes studied (n=45,101), including 641 up-regulated and 451 down-regulated 

genes. In PPARα-null mice, PFOA altered only 0.3% of the genes studied including 104 up-regulated 

and 52 down-regulated genes, suggesting that PPARα was required for the majority of transcriptional 

changes following PFOA exposure in the mouse liver. More than 12% of the PPARα-independent genes 

regulated by PFOA coded for proteins involved in lipid homeostasis. In general, PFOA increased the 

expression of these genes in both wild-type mice and PPARα-null mice, but the absolute expression was 

lower in PPARα-null mice than in wild-mice. PFOA suppressed genes involved in amino acid 

metabolism in both strains of mice, but to a lesser extent in PPARα-null mice than in wild-mice. In 

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PPARα-null mice, PFOA increased the expression of genes involved in xenobiotic metabolism, including 

those involved in phase I (oxidation), phase II (conjugation), and phase III (transport) functions. Since 

PFOA highly induced a gene known to be a target for the nuclear receptor CAR (constitutive activated/ 

androstane receptor), the investigators compared the PFOA transcript profiles with those of livers from 

mice exposed to CAR activators. The results of experiments in wild-type and CAR-null mice showed a 

strong similarity in the direction and magnitude of the change between the PFOA PPARα-null genes and 

genes regulated by CAR activators. This suggested that PFOA can alter a subset of genes through 

activation of CAR and possibly PPARγ in PPARα-null mice. It should be mentioned that studies in fish 

have shown that PFOA can also activate the hepatic estrogen receptor (Tilton et al. 2008; Wei et al. 

2007b). 

Overall, the in vivo gene profiling experiments summarized above confirm that PPARα plays an 

important role in the mechanism of action of PFOA and PFOS, indicate that there are similarities and 

differences in gene modulation between PFOA and PFOS, and provide confirmatory evidence for the 

existence of PPARα-independent mechanisms. Given the wide range of gene groups affected by PFOA 

and PFOS, there is the potential for a wide range of biological effects following exposure to these 

compounds. The results of these studies, however, should not be over interpreted since, as stated by 

Guruge et al. (2006), alteration of the expression of a particular gene does not necessarily mean that a 

particular protein or biochemical pathway would be affected in vivo. However, alteration of a group of 

genes involved in a particular biochemical pathway would provide strong evidence that a compound may 

affect that particular pathway. 

3.5.3 Animal-to-Human Extrapolations 

Based on information currently available, extrapolation of animal data to exposure of humans is highly 

uncertain in part because: (1) large interspecies differences in the toxicokinetics of perfluoroalkyls, 

(2) general lack of adverse health effects reported by limited research done to date in populations exposed 

chronically to elevated amounts of perfluoroalkyls, and (3) some mechanisms of toxicity in animals may 

not be operant in humans. These issues are strongly interrelated. 

Toxicokinetics Differences. The elimination rate for PFOA in female rats is approximately 40 times 

faster than in male rats, 120 times faster than in Cynomolgus monkeys, and approximately 6,000 times 

faster than in humans. Elimination of PFOS in male rats is approximately 20 times faster than in 

Cynomolgus monkeys, and approximately 240 times faster than in humans (Hundley et al. 2006). These 

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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 an elimination half-life of 1,000 days for PFOA in humans, a constant rate 

of intake for 12 years would be required to achieve 95% of steady state. Steady state (i.e., 95%) would be 

achieved in approximately 90 days in monkeys, 30 days in male rats, and in 1 day in female rats. As a 

result of these large differences in kinetics, internal doses (i.e., serum concentrations of PFOA) achieved 

during intermediate-duration exposures in rats or monkeys would not represent steady-state internal doses 

that might be achieved in humans over longer exposure durations. 

Lack of Reported Effects in Humans. Health evaluations of humans exposed occupationally or 

environmentally to elevated amounts of perfluoroalkyl compounds for long periods of time have not 

provided evidence of significant adverse effects have, although sporadic deviations in clinical tests 

associate with serum levels of perfluoroalkyl compounds have been reported (Emmett et al. 2006b; 

Gilliland and Mandel 1996; Mundt et al. 2007; Olsen and Zobel 2007; Olsen et al. 1998, 1999, 2003a; 

Sakr et al. 2007a, 2007b). Thus, the lack of reported health effects at the reported body burdens precludes 

identifying the animal model that would be most appropriate for human risk assessment based on similar 

toxic effects. 

Mode(s) of Action. As previously mentioned, many PFOA- or PFOS-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 (Klaunig et al. 2003; 

Maloney and Waxman 1999). However, 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 were reported to be PPARα-independent (Yang et 

al. 2002b). Therefore, further studies in PPARα-null mice are needed to expand the knowledge regarding 

PPARα-dependent and independent effects that would allow selection of an appropriate animal model for 

perfluoroalkyls toxicity. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

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with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

The evidence that perfluoroalkyl compounds are endocrine disruptors in humans is inconclusive based on 

a limited number of studies. A study on male workers at a PFOS production plant found no significant 

association between PFOA exposure and the levels of 11 hormones (cortisol, dehydroepiandrosterone 

sulfate, estradiol, FHS, 17α-hydroxyprogesterone, free testosterone, total testosterone, LH, prolactin, 

TSH, and sex hormone-binding globulin) in serum (Olsen et al. 1998). Workers who had PFOA serum 

levels ≥30 μg/mL had mean estradiol levels 10% higher than workers in other groups, but there were too 

few subjects in this group to draw any meaningful conclusion. In the cross-sectional study of workers 

conducted by Sakr et al. (2007b), serum estradiol and testosterone were significantly associated with 

serum PFOA in linear regression models. Other assessments of workers exposed to perfluoroalkyls did 

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not find associations between serum levels of PFOS and PFOA and thyroid hormones (Olsen and Zobel 

2007; Olsen et al. 2003a; Sakr et al. 2007b). Mean levels of PFOA and PFOS in these studies were 

≤2.5 μg/mL. An additional occupational study did not find alterations in thyroid hormones levels in 

workers exposed to PFNA (Mundt et al. 2007); serum levels of PFNA were not available in this study. A 

study of a population environmentally exposed to PFOA reported no association between serum PFOA 

and serum levels of TSH; the median serum PFOA concentration in the study subjects was 354 ng/mL 

(Emmett et al. 2006b). While mostly negative results are reported in these studies, it is worth pointing out 

that, in general, they did not account for factors that are known to affect hormonal levels such as time of 

day, seasonal variation, stress, and in the case of women, menopausal status. 

Studies in animals have reported sporadic alterations in serum levels of thyroid hormones, but for the 

most part serum levels of TSH did not change significantly, thus suggesting that a hypothyroid response 

was not induced (Butenhoff et al. 2002; Chang et al. 2008b; Luebker et al. 2005b; Seacat et al. 2002; 

Thibodeaux et al. 2003; Thomford 2001). Transient reductions in serum TT4 reported in various studies 

have been attributed to a perfluoroalkyl-induced transient increase in tissue availability of thyroid 

hormones and increased turnover of T4, with a resulting reduction in serum TT4 (Chang et al. 2008b). 

Reduced serum TT4 were also reported in rats treated with PFDeA by intraperitoneal injection (Gutshall 

et al. 1988, 1989; Van Rafelghem et al. 1987a). 

In general, studies with PFBA, PFBuS, PFOA, PFOS, and PFHxS have not reported morphological 

alterations in endocrine glands or in reproductive organs of experimental animals (3M 2001; Butenhoff et 

al. 2002; Griffith and Long 1980; Hoberman and York 2003; Perkins et al. 2004; Seacat et al. 2002, 2003; 

van Otterdiijk 2007a, 2007b). However, a single intraperitoneal dose of 50 mg/kg PFDeA induced signs 

of atrophy and degeneration of the seminiferous tubules in the testes from rats (George and Andersen 

1986). These signs were first seen 16 days after dosing and were still evident 30 days after dosing. 

In multi-generation studies, neither PFOA nor PFOS have altered fertility parameters (Butenhoff et al. 

2004b; Luebker et al. 2005a, 2005b) and the same was observed in a reproductive study with PFHxS 

(Hoberman and York 2003). However, alterations in estrous cycling was reported in a study in rats 

treated with 1 or 10 mg/kg/day PFOS intraperitoneally for 2 weeks (Austin et al. 2003). Serum PFOS 

levels in these rats at termination were 10,500 and 45,500 ng/mL, respectively. This finding is in 

disagreement with the results of Luebker et al. (2005a) who did not observe alterations in estrous cycling 

in rats dosed by gavage with up to 3.2 mg/kg/day before mating and continuing during gestation, and that 

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achieved mean serum levels of PFOS of 82,000 ng/mL. No explanation could be found for these 

apparently conflicting results. 

While there have not been significant effects on fertility in animals exposed to PFOA, PFOS, or PFHxS, 

several studies have reported alterations in sex hormone levels. Studies in male rats reported that oral 

dosing with PFOA reduced serum and testicular testosterone while significantly increasing serum 

estradiol (Cook et al. 1992). The decrease in serum testosterone was thought to be due to a decrease in 

the conversion of 17α-hydroxyprogesterone to androstenedione, which could be attributed to the elevated 

serum levels of estradiol since elevated serum estradiol are known to depress steroidogenesis at the 

Leydig cell level by negative feed-back influences on the hypothalamus and adenohypophysis. Treatment 

with PFOA was also reported to increase the activity of aromatase in the liver, but not in other sites, 

including the testes, and suggested that this was probably the mechanism by which PFOA increased 

serum estradiol (Biegel et al. 1995). PFOA also was shown to increase testicular interstitial fluid 

transforming growth factor α, which was consistent with the hypothesis that estradiol may modulate 

growth factor expression within the testis. These events beginning with the increase in serum estradiol 

have been thought to be responsible for the induction of Leydig cell tumors in rats treated with PFOA 

(Biegel et al. 2001). 

Treatment of male rats with PFDoA by gavage (5–10 mg/kg/day) for 14 days significantly decreased 

serum LH, testosterone, and estradiol (Shi et al. 2007). Assessment of 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. The results suggested that the decrease in testosterone synthesis probably resulted from 

decreased steroidogenesis gene expression. 

A study with PFDeA administered by intraperitoneal injection to male rats reported decreased serum 

testosterone and 5α-dihydrotestosterone and decreases in the weights of accessory sex organs (Bookstaff 

et al. 1990). Experiments in castrated rats implanted with testosterone-containing capsules showed that 

the androgenic deficiency caused by PFDeA was the result of decreased secretion of testosterone from the 

testis rather than increased clearance from blood. Since LH levels in blood were unaffected, the 

decreased secretion of testosterone from the testis appeared to be due to decreased testicular 

responsiveness to LH stimulation. Bookstaff et al. (1990) suggested that PFDeA disrupts the normal 

feedback relationships that exists between plasma androgen and LH concentrations. 

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Studies in vitro of PFOA, PFOA, and PFNA using a combination of the E-screen assay, cell cycle 

analysis, and gene expression analysis of estrogen-responsive biomarker genes showed that these 

chemicals did not have estrogen-like properties in MCF-7 human Caucasian breast adenocarcinoma cells 

(Maras et al. 2006). Both PFOA and PFOS showed estrogenic activity in primary cultured hepatocytes 

from fish (male tilapia), as assessed by induction of vitellogenin (Liu et al. 2007). 

While the available data in experimental animals indicate that some perfluoroalkyl compounds can alter 

the levels of some hormones in blood, it does not appear that these compounds can mimic or block the 

action of natural hormones by binding to their receptors, but additional studies are needed before more 

definite conclusions can be drawn. 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. 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. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

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infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

There are no studies that specifically address the health effects of exposure to perfluoroalkyl compounds 

in children; therefore, it is unknown whether children differ from adults in their susceptibility to health 

effects from these compounds. It is known, however, that children can absorb these compounds, that 

perfluoroalkyl compounds can cross the placenta (i.e., Midasch et al. 2007), and that can be transferred to 

newborn babies via maternal milk (i.e., Kärrman et al. 2007a). 

A health evaluation was conducted of 371 residents, including 43 children under the age of 18, in the 

Little Hocking water district in southeastern Ohio where significant environmental exposure to PFOA via 

the water occurred (Emmett et al. 2006b). The population median serum PFOA was 354 ng/mL and the 

interquartile range was 184–571 ng/mL. The study found no significant associations between serum 

PFOA levels and hematology parameters, total cholesterol and liver enzymes, indices of kidney function, 

and serum TSH levels whether the analysis included all the individuals as a group or separate analyses 

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were done for adults or children. In a study of self-reported health outcomes in relation to occupational 

exposures to PFOS at a PFOS-based fluorochemical manufacturing facility that included 263 women, 

birth weight of singleton births, adjusted for maternal age at birth, gravidity, and smoking status, did not 

vary between exposure groups (Grice et al. 2007). PFOS serum concentrations ranged from 110 to 

1,970 ng/mL). Information regarding gestational length, the most important predictor of birth weight, 

was not available. 

In a study of children born in Baltimore, both PFOA and PFOS in cord blood (respective medians were 

1.6 and 5 ng/mL) were negatively associated with birth weight, ponderal index, and head circumference 

(Apelberg et al. 2007b). No significant associations were observed between either PFOS or PFOA 

concentrations and newborn length or gestational age. Similar studies of Danish women reported that 

birth weight, birth weight, and abdominal circumference were inversely associated with plasma levels of 

PFOA collected during the first trimester (mean 35.3 ng/mL) (Fei et al. 2007, 2008a). Neither PFOA nor 

PFOS was statistically associated with length of gestation. An additional study by Fei et al. (2008b) 

found no convincing associations between developmental milestones in early childhood and levels of 

PFOA and PFOS measured in maternal blood early during pregnancy. A study of 428 Japanese women 

and their infants reported a marginally significant negative correlation between birth weight and maternal 

blood PFOS, but not PFOA levels (Washino et al. 2009). It is worth noting that the blood levels of PFOA 

and PFOS in these studies of the general population are significantly lower than those reported in the 

workers studied by Grice et al. (2007) and in animal studies. Other, much smaller studies of Japanese and 

Chinese women did not find correlations between PFOS in maternal blood and TSH and T4 in cord blood 

(Inoue et al. 2004b) or between PFOA and PFOS in breast milk and infant weight (So et al. 2006b), but 

their small sample size severely limits the conclusions that can be drawn from them. In contrast with the 

findings of some of the studies mentioned above, Nolan et al. (2009) found that mean birth weights, 

incidence of low birth weight, incidence of preterm birth, and mean gestational age of singleton neonates 

born to mother residing in an area with high levels of PFOA in the drinking water did not differ 

significantly from those born to mothers living in areas with significantly lower PFOA levels in the water. 

Mean serum PFOA levels from a random sample of individuals residing in the high PFOA area was 

354 ng/mL. 

Exposure of rodents to PFOA and PFOS during gestation has produced developmental toxicity. Studies 

with PFOA reported prenatal loss, reduced neonate weight and viability, and delays in mammary gland 

differentiation, eye opening, vaginal opening, and first estrus (Abbott et al. 2007; Lau et al. 2006; White 

et al. 2007; Wolf et al. 2007). These effects occurred generally in the absence of maternal toxicity. These 

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studies also showed that gestational exposure was sufficient to induce postnatal deficits in body weight 

and developmental delays and that PPARα was required for PFOA-induced postnatal lethality. Exposure 

to PFOS also increased neonatal mortality (Lau et al. 2003) and dosing rats late during gestation (gds 17– 

20) caused significantly more lethality than dosing early (gds 2–5) (Grasty et al. 2003). In contrast to 

PFOA and PFOS, PFBA exhibited considerably less developmental toxicity, possibly due to a much 

faster elimination rate and lower biochemical potency (Das et al. 2008). PFHxS in doses of up to 

10 mg/kg/day was not a developmental toxicant in rats exposed from premating until PND 21 (Hoberman 

and York 2003). 

Unchanged 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. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers 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. However, several 

factors can confound the use and interpretation of biomarkers of exposure. The body burden of a 

substance may be the result of exposures from more than one source. The substance being measured may 

be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from 

exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., 

biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and 

all of its metabolites may have left the body by the time samples can be taken. It may be difficult to 

identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids 

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(e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to 

perfluoroalkyls are discussed in Section 3.8.1. 

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 

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 effects caused 

by perfluoroalkyls are discussed in Section 3.8.2. 

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 3.10, Populations That Are Unusually Susceptible. 

The National Report on Human Exposure to Environmental Chemicals provides and ongoing assessment 

of the exposure of the U.S. population to environmental chemicals using biomonitoring. This report is 

available at http://www.cdc.gov/exposurereport/. The biomonitoring data for perfluoroalkyls (Calafat et 

al. 2007a, 2007b) is discussed in Section 6.5. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Perfluoroalkyls 

Both PFOA and PFOS are biomarkers of exposure to themselves, but based on studies in animals, 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-PFOSA-AcOH 

and Me-PFOSA-AcOH are metabolized fairly rapidly and have relatively short serum half-lives, their 

presence in serum should indicate only recent non-occupational exposure in the general population (Olsen 

et al. 2005). 

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3.8.2 Biomarkers Used to Characterize Effects Caused by Perfluoroalkyls 

There are no specific biomarkers of effects caused by perfluoroalkyl compounds. Health evaluations of 

workers exposed to perfluoroalkyl compounds or of subjects environmentally exposed via their drinking 

water have not provided evidence of adverse health effects in the groups studied (Emmett et al. 2006a; 

Mundt et al. 2007; Olsen and Zobel 2007; Olsen et al. 1999, 2003a; Sakr et al. 2007a, 2007b). Based on 

the existing information regarding the effects of perfluoroalkyl compounds in animals, it is difficult to 

envision a health condition that could be attributed solely to exposure to perfluoroalkyls. Even if one had 

been identified in animal studies, extrapolation to what might occur in humans is problematic based on 

the fact that studies in animals have used doses that resulted in serum levels of perfluoroalkyl 

considerably higher than those found in humans and on the differences in toxicokinetics between animals 

and humans. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

No studies were 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 and 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. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to perfluoroalkyls than will most 

persons exposed to the same level of perfluoroalkyls in the environment. Reasons may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters may result in compromised function of organs affected by perfluoroalkyls. Populations 

who are at greater risk due to their unusually high exposure to perfluoroalkyls are discussed in 

Section 6.7, Populations with Potentially High Exposures. 

A specific target for perfluoroalkyl compounds toxicity in humans exposed to the substances has not been 

identified, but it is reasonable to assume that the liver could be a main target, based on studies in animals 

and the therapeutic use of hypolipidemic substances (i.e., clofibrate, gemfibrozil) with similar 

mechanisms of action. Therefore, individuals with compromised liver function may represent a 

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susceptible population. Obese people also may represent a susceptible population based on limited data 

from a study of occupationally exposed men (Gilliland and Mandel 1996). In that study, in obese subjects 

only, serum ALT and AST activities increased with increasing PFOA concentrations, which according to 

the investigators, has biological plausibility because obesity has been associated with elevation of 

transaminases through fatty infiltration. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to perfluoroalkyls. However, because some of the treatments discussed may be experimental 

and unproven, this section should not be used as a guide for treatment of exposures to perfluoroalkyls. 

When specific exposures have occurred, poison control centers and medical toxicologists should be 

consulted for medical advice. No texts were identified that provide specific information about treatment 

following exposures to perfluoroalkyl compounds. 

3.11.1 Reducing Peak Absorption Following Exposure 

There are no established methods to reduce absorption of perfluoroalkyl compounds in humans. No 

relevant information was located from studies in animals. 

3.11.2 Reducing Body Burden 

No studies were located regarding methods to reduce body burden of perfluoroalkyl compounds in 

humans. However, Emmett et al. (2006a) described two interventions that resulted in reduced PFOA in 

residents with a contaminated public water source. One intervention was the use of a residential carbon 

filter, which resulted in a statistically significant reduction in serum PFOA in a best-fit model. The other 

intervention was the substitution of bottled water for public water, which resulted in a much greater serum 

PFOA reduction. 

In a study in rats, cholestyramine, a bile acid sequestrant which binds bile in the gastrointestinal tract to 

prevent its reabsorption, was effective in increasing total 14C eliminated in the feces following 

administration of a single intravenous dose of 14C-APFO or 14C-PFOS (Johnson et al. 1984). Mean 

cumulative 14C elimination in the feces was increased 9.8-fold for rats administered APFO and 9.5-fold 

for rats administered PFOS. 

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3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

There are no established methods for interfering with the mechanism of toxicity of perfluoroalkyl 

compounds. This is largely because health evaluations of workers exposed to perfluoroalkyl compounds 

(i.e., Olsen and Zobel 2007; Olsen et al. 1999, 2003a; Sakr et al. 2007a, 2007b) and of members of the 

general population exposed to elevated amounts of PFOA via the drinking water (Emmett et al. 2006b) 

have not shown associations between surrogates of exposure, such as blood levels of perfluoroalkyl 

compounds, and adverse health conditions. 

A main effect observed in animals exposed to perfluoroalkyl compounds is liver toxicity. The only 

relevant information located regarding mitigating liver effects is that pretreatment of mice with fish oil 

prevented the PFOA-induced increase in hepatic triglyceride content by depressing the formation of 

triglycerides by docosahexaenoic acid in fish oil (Kudo and Kawashima 1997). The relevance of this 

finding to occupational or environmental exposures of humans to perfluoroalkyl compounds is unknown. 

3.12 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 the National Toxicology Program (NTP), is required to assure 

the initiation of a program of research designed to determine the health effects (and techniques for 

developing methods to determine such health effects) of perfluoroalkyls. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health 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. 

3.12.1 Existing Information on Health Effects of Perfluoroalkyls 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

PFOA and PFOS are summarized in Figures 3-10 and 3-11. Figures for the remaining perfluoroalkyls 

discussed in this profile are not presented due to the paucity of data for these chemicals, especially data in 

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Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Animal 

Existing Studies 

PERFLUOROALKYLS 210 

3. HEALTH EFFECTS 

Figure 3-10. Existing Information on Health Effects of PFOA 

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Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Animal 

Existing Studies 

PERFLUOROALKYLS 211 

3. HEALTH EFFECTS 

Figure 3-11. Existing Information on Health Effects of PFOS 

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humans. The purpose of Figures 3-10 and 3-11 is to illustrate the existing information concerning the 

health effects of perfluoroalkyls. Each dot in the figure indicates that one or more studies provide 

information associated with that particular effect. The dot does not necessarily imply anything about the 

quality of the study or studies, nor should missing information in this figure 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 (Agency for Toxic Substances and Disease Registry 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. 

Information regarding the effects of exposure to perfluoroalkyl compounds in humans is derived mainly 

from health evaluations of subjects exposed in occupational settings and from much more limited data 

regarding exposures of the general population. Exposure levels are not available, but the concentrations 

of several perfluoroalkyl compounds have been measured in blood, thus facilitating comparisons with 

levels measured in studies with experimental animals. Most of the health evaluations have focused on 

detecting possible hepatic effects and alterations in lipid metabolism based on the extensive data available 

from studies in animals. 

Most of the information regarding the effects of perfluoroalkyl compounds in animals is derived from oral 

studies; considerable less information is available from inhalation and dermal exposure studies. It is 

important to note that the effects of perfluoroalkyl compounds in laboratory animals do not appear to be 

route-specific. 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. Acute- and 

intermediate-duration oral studies in animals have described primarily effects on the liver, body weight, 

developmental effects, and effects on the immuno/lymphoreticular system. Alterations in liver and 

kidneys weight as well as increased incidence on tumors in the liver, pancreas, and testes were reported in 

chronic studies with PFOA in rats. Information regarding other perfluoroalkyls covered in this profile is 

limited to acute-duration oral studies with PFBA, PFDeA, PFNA, PFDoA, and PFOSA, and intermediateduration oral studies with PFBA, PFHxS, and PFBuS. An acute-duration-inhalation study with PFNA is 

also available. 

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3.12.2 Identification of Data Needs 

MRLs were not derived for perfluoroalkyl compounds due to the fact that human studies to date are 

insufficient to determine with a sufficient degree of certainty that the effects are either exposure-related or 

adverse. In addition, there are large interspecies differences in the toxicokinetics of perfluoroalkyls for 

which mechanisms are not completely understood. Thus, extrapolation of external dose-response 

relationships from animals to humans would be highly uncertain (see Section 2.3 for a detailed 

explanation; see also the toxicokinetics sections below). 

Acute-Duration Exposure. There are no studies of humans exposed acutely to perfluoroalkyl 

compounds, although humans are exposed on a daily basis to small amounts of perfluoroalkyls in 

consumer products and in food and drinking water (Trudel et al. 2008). This also applies to intermediateduration exposure. Few acute-duration inhalation studies have been conducted in animals. A 2-week 

inhalation study with PFOA in rats reported mainly liver and body weight effects (Kennedy et al. 1986) 

and similar findings were reported in a 4-hour study with PFNA also in rats (Kinney et al. 1989). A need 

to conduct additional acute-duration inhalation studies in animals with other perfluoroalkyl compounds in 

animals is not apparent since the main route of exposure for the general population and for 

environmentally exposed populations is the oral route (Emmett et al. 2006a, 2006b; Trudel et al. 2008). 

The same can be said for acute dermal exposures, but it should be noted that inhalation of perfluoroalkyl 

dusts and dermal contact with dusts and or solutions of these compounds can be significant in 

occupational settings. Extensive information is available from acute-duration oral studies of PFOA and 

PFOS in animals; however, much fewer studies are available of PFBA, PFDeA and other perfluoroalkyls. 

The available studies indicate that the liver is main target (i.e., Fuentes et al. 2006; Haughom and 

Spydevold 1992; Kennedy 1987; Liu et al. 1996; Yang et al. 2001) and also that developmental effects 

can occur in mice at relatively low PFOA doses (i.e., Wolf et al. 2007). Additional oral studies of the 

comparative potency of perfluoroalkyl compounds of different chain length and functional groups would 

be useful to try to determine whether a class-risk assessment could be feasible. In addition, further 

studies with PPARα-null mice can help determine the role of the PPARα in the various toxicities of these 

compounds. Also, further information on the role of receptors other than PPARα (i.e., PPARβ, PPARγ) 

in the biological effects induced by perfluoroalkyls would be valuable (Takacs and Abbott 2007; 

Vanden Heuvel et al. 2006). Studies of simultaneous exposure to mixtures of perfluoroalkyls would be 

useful to elucidate mechanisms of interaction between these compounds. Toxicity studies should monitor 

the concentration of perfluoroalkyls in blood and/or in target organs to provide a better basis for 

interspecies comparisons. Further studies using microarray techniques of gene expression are expected to 

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continue to provide information on genes responsive to perfluoroalkyls that can be used to identify critical 

target pathways for the biological effects of perfluoroalkyl compounds and provide a basis for 

understanding similarities and differences in toxicities between compounds and between species (Guruge 

et al. 2006; Hu et al. 2005). In general, further research with shorter chain perfluoroalkyls, such as PFBA, 

should be encouraged since data in animals indicate that some effects such as hepatotoxicity and 

biochemical alterations are less pronounced the shorter the carbon chain (i.e., 3M 2007a; Kudo et al. 

2000, 2006; Permadi et al. 1992, 1993). These research recommendations apply to all the specific end 

points discussed below. 

Intermediate-Duration Exposure. Intermediate-duration oral studies have been conducted with 

PFOA, PFOS, PFBuS, and PFBA. The liver was a main target (3M 2001; Butenhoff et al. 2002; Kennedy 

1987; Perkins et al. 2004; Seacat et al. 2002, 2003; Son et al. 2008; Thomford 2001, 2002a; van Otterdiijk 

2007a, 2007b). Pup survival was also established as a sensitive end point in intermediate-duration oral 

studies with PFOA (Abbott et al. 2007) and PFOS (Lau et al. 2003; Luebker et al. 2005b). The same 

general types of studies suggested above under Acute-Duration Exposure can be designed for longer 

exposure durations. Intermediate-duration oral studies with perfluoroalkyls other than PFOA and PFOS 

are needed to construct dose-response relationships for these compounds. However, if future monitoring 

studies suggest that a specific perfluoroalkyl compound is no longer being detected in the body, 

conducting further studies on this compound may be unnecessary. Toxicity studies should focus on 

perfluoroalkyls that are being detected in humans and in the environment with increasing frequency and 

concentration. 

Chronic-Duration Exposure and Cancer. There is information regarding the effects of exposure 

to perfluoroalkyl compounds in humans derived from health evaluations of subjects exposed in 

occupational settings (Gilliland and Mandel 1996; Leonard 2006; Mundt et al. 2007; Olsen and Zobel 

2007; Olsen et al. 1998, 1999, 2003a; Sakr et al. 2007a, 2007b) and from subjects exposed 

environmentally (Emmett et al. 2006b). In most of these health assessments the concentrations of 

perfluoroalkyl compounds (mostly PFOA and PFOS) have been measured in blood, thus facilitating 

comparisons with levels measured in studies with experimental animals. For the most part, no significant 

adverse effects have been identified in these populations, but sporadic deviations in clinical tests associate 

with serum levels of perfluoroalkyl compounds have been reported. Most of the health evaluations have 

focused on detecting possible hepatic effects and alterations in lipid metabolism based on the extensive 

data available from studies in animals. It is assumed that health assessments will continue to be 

conducted in these cohorts and in any newly identified cohort exposed to perfluoroalkyl compounds. 

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Two chronic-duration oral studies in rats are available for PFOA (3M 1983; Biegel et al. 2001). The 

study by Biegel et al. (2001) investigated the role of peroxisome proliferation on hepatic, Leydig cell, and 

pancreatic acinar cells tumorigenesis. The study conducted by 3M (1983) was a standard 2-year bioassay 

in male and female rats dosed with 0, 1.5, or 15 mg/kg/day PFOA. Additional chronic-duration studies 

with PFOA do not seem necessary at this time. A 2-year dietary study of PFOS in rats that identified the 

liver as a main target is available (Thomford 2002b); additional chronic studies with PFOS are not 

necessary at this time. The need to conduct chronic-duration studies for other perfluoroalkyl compounds 

should depend on the results of 90-day studies as they become available. If specific targets are identified 

in intermediate-duration studies, conduction of longer-term studies with lower doses may be warranted. 

A few epidemiological studies have examined the potential association between cancer and perfluoroalkyl 

compounds. In a retrospective cohort mortality of workers at a plant that produced PFOA, among male 

workers categorized as exposed for at least 10 years there was a 3.3-fold increase in prostate cancer 

mortality compared to no employment in PFOA production (Gilliland and Mandel 1993). Due to the 

small number of cases involved, the investigators cautioned that the results should not be over interpreted. 

In another retrospective mortality study of workers exposed to PFOS, the most significant finding was an 

increased risk of death from bladder cancer for the entire cohort, three cases were observed and 0.62 were 

expected and all of them worked in a high-exposure group (Alexander et al. 2003). A reanalysis of this 

cohort identified a total of 11 cases of bladder cancer, 6 from surveys and 5 from death certificates 

(Alexander and Olsen 2007). Compared with those in the lowest cumulative exposure category, the highexposure workers had a small 1.5–2.0-fold increased risk. While the results did indicate an excess risk of 

bladder cancer among the cohort studied, study limitations such as uncertainty in case ascertainment and 

the size of the cohort did not allow for a conclusive exposure response analysis. An additional 

retrospective cohort mortality study of workers at a polymer production plant did not find increased 

mortality rates due to cancer among the workers (Leonard 2006). Follow-up assessments of 

perfluoroalkyl workers and of groups of the general population exposed to higher than background levels 

of perfluoroalkyls seems logical. In a 2-year bioassay, PFOA induced a “tumor triad” in rats, that is, liver 

tumors, Leydig cell tumors, and tumors in pancreatic acinar cells, characteristic of PPARα-agonist 

activation in rats (3M 1983; Biegel et al. 2001). The relevance of these findings to humans has been 

questioned by some since humans are considered refractory to most, but not all PPARα-activation effects 

(Klaunig et al. 2003). However, it is possible that PPARα agonism may not be the only mode of action 

for PFOA and further studies are needed to investigate this possibility and the potential involvement of 

the estrogen receptor or other nuclear receptors. PFOA also increased the incidence of mammary gland 

fibroadenomas (3M 1983) and of mammary gland adenocarcinomas (mid-dose only). It has been 

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suggested that an independent, appropriately designed histopathology reanalysis of the male rat livers and 

the female mammary glands be conducted (EPA 2006c). In a 2-year dietary bioassay of PFOS in rats, 

there was an increased incidence of liver hepatocellular adenoma and thyroid follicular cell adenoma 

(Thomford 2002b). No cancer studies were located for the remaining perfluoroalky compounds covered 

in this profile. PFDeA, PFOA, PFHxS, and PFBuS are listed as chemicals nominated to the NTP for indepth toxicological evaluation for carcinogenesis testing in fiscal years 1988–2003 (NTP 2005). 

Genotoxicity. Both PFOA and PFOS have been tested for mutagenic activity in standard tests and, for 

the most part, both chemicals gave negative results (EPA 2005a; Griffith and Long 1980; Oda et al. 2007; 

OECD 2002). A study in rats suggested that PFOA and PFDeA induced oxidative damage in liver DNA, 

but not in kidney DNA; PFBA had no significant effect on DNA from either tissue (Takagi et al. 1991). 

PFOA was also reported to cause DNA strand breaks and the incidence of micronuclei in human 

hepatoma HepG2 cells (Yao and Zhong 2005). Further studies on the mechanism of DNA damage 

caused by PFOA and possibly by other perfluoroalkyl compounds seem warranted. No information was 

located regarding the mutagenicity of the perfluoroalkyls covered in this profile other than PFOA and 

PFOS. Although these chemicals have been detected in much smaller concentrations than PFOA and 

PFOS in serum samples from the general population (Calafat et al. 2007b), a screening battery of 

genotoxicity tests would provide useful additional information. 

Reproductive Toxicity. The only relevant information regarding reproductive effects in humans 

following exposure to perfluoroalkyl compounds is that of a positive association between PFOA levels in 

serum and levels of estradiol and testosterone in serum from male workers (Sakr et al. 2007b). In another 

occupational study, serum estradiol but not other sex hormones was elevated in a small group of male 

workers who had the highest serum PFOA levels (Olsen et al. 1998). Further studies of workers and of 

members of the general population environmentally exposed to perfluoroalkyl compounds could evaluate 

end points related to fertility such as sperm characteristic and time to pregnancy. Studies with PFOA in 

rats have reported increased levels of estradiol in serum (Biegel et al. 1995, 2001; Cook et al. 1992; Liu et 

al. 1996). Acute treatment of male rats with PFDoA also resulted in elevated serum estradiol (Shi et al. 

2007). Multi-generation studies have been conducted in rats dosed with PFOA, PFOS, and PFHxS; these 

studies have not provided evidence of alterations in fertility parameters or of histopathology of the 

reproductive organs (Butenhoff et al. 2004b; Hoberman and York 2003; Luebker et al. 2005a, 2005b), but 

a single intraperitoneal dose of 50 mg/kg PFDeA caused atrophy and degeneration of the seminiferous 

tubules in the testes from rats (George and Andersen 1986). Thus, further studies with lower doses 

PFDeA administered orally that evaluate reproductive parameters may be warranted. In general, acute­

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and intermediate-duration studies with PFOA or PFOS did not find morphological alterations in the sex 

organs from rats or monkeys (Butenhoff et al. 2002; Griffith and Long 1980; Seacat et al. 2002, 2003). In 

a 2-year-dietary study, PFOA significantly increased the incidences of Leydig cell hyperplasia, vascular 

mineralization in the testes, and tubular hyperplasia in the ovaries in rats in 2-year dietary studies (3M 

1983; Biegel et al. 2001). Little is known regarding reproductive effects of other perfluoroalkyl 

compounds; therefore studies that examine the effects of these compounds on the microscopic 

morphology of the reproductive organs and serum levels of sex hormones, as well as in in vitro tests that 

evaluate effects on the estrogen and androgen receptors would be valuable. 

Developmental Toxicity. Limited information is available regarding developmental effects in 

humans exposed to perfluoroalkyl compounds. A study of children in Baltimore reported negative 

associations between both PFOA and PFOS in cord blood and birth weight, ponderal index, and head 

circumference (Apelberg et al. 2007b). Similar studies of Danish women reported that plasma levels of 

PFOA during the first trimester of pregnancy were inversely associated with birth weight, birth length, 

and abdominal circumference (Fei et al. 2007, 2008a), but had no significant influence on the 

achievement of developmental milestones in early childhood (Fei et al. 2008b). A study of Japanese 

women found a negative correlation between birth weight and serum PFOS levels in maternal blood 

collected during the second trimester of pregnancy (Washino et al. 2009). An additional study of 

Japanese women did not find correlations between PFOS in maternal blood and TST and T4 in cord blood 

(Inoue et al. 2004b) and a study of Chinese women found no association between PFOA and PFOS in 

breast milk and infant weight (So et al. 2006b), but the small sample size in these two studies severily 

limits their conclusions, and need to be repeated. Future studies of this type need to incorporate into the 

analysis all covariates known to influence fetal growth indicators. One of these factors is plasma volume, 

which expands with maternal weight gain during pregnancy and can affect the distribution of proteinbound PFOA and PFOS that are found primarily in extracellular space. A different type of study found 

that birth weight and gestational age of neonates born to women residing in an area in with high levels of 

PFOA in the drinking water were not significantly different than those from neonates born to women who 

resided in areas with significantly lower levels of PFOA in the water (Nolan et al. 2009). 

Prospective evaluation of women with elevated levels of perfluoroalkyl compounds in serum such as 

female perfluoroalkyl workers or of women that are environmentally exposed to perfluoroalkyls (as in 

Nolan et al. [2009], mentioned above) who became pregnant would provide valuable information 

regarding the pharmacokinetics of these chemicals during pregnancy, placental transfer to the fetus, and 

transfer to neonates via maternal milk. Some data are available from studies of the general population in 

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which serum levels of PFOA and PFOS were significantly lower than in perfluoroalkyl workers (Inoue et 

al. 2004b; Kärrman et al. 2007a; Midasch et al. 2007; So et al. 2006b). Prospective evaluation of children 

born to women with higher body burden of perfluoroalkyls during pregnancy would also provide valuable 

information on potential delayed developmental effects or other effects. 

Studies in animals have provided information mostly on developmental effects of PFOS and PFOA in 

rodents, but a study with PFHxS is also available. Recently, a study with PFBA also became available. 

Standard gestational exposure studies with other perfluoroalkyl compounds would be valuable. Specific 

effects reported in studies with PFOA and PFOS include prenatal loss, reduced neonate weight and 

viability, and delays in mammary gland differentiation, eye opening, vaginal opening, and first estrus and 

generally occurred in the absence of maternal toxicity (Abbott et al. 2007; Lau et al. 2006; Luebker et al. 

2005a; White et al. 2007; Wolf et al. 2007). PFHxS had no significant effects on a wide range of 

developmental parameters evaluated in rats (Hoberman and York 2003). In the study with PFBA, the 

chemical had no significant effect on neonatal weight gain or viability (Das et al. 2008). A recent study 

reported that gestational exposure of mice to PFOS resulted in alterations in some immune parameters in 

the offspring (Keil et al. 2008). Further studies on immunological effects in animals exposed in utero 

would be valuable. Studies are also available that examined periods of special susceptibility during 

gestation. Wolf et al. (2007) reported that developmental effects (i.e., delayed eye opening) were more 

severe in mice as the exposure began earlier, but could not determine whether this was due to a higher 

cumulative dose of PFOA or to a developmentally sensitive period. A study with PFOS reported that 

dosing late during gestation caused significantly more lethality than dosing early (Grasty et al. 2003). 

Studies have also shown that gestational exposure alone is sufficient to induce postnatal deficits in body 

weight and developmental delays (Wolf et al. 2007) and that in mice, PPARα is required for PFOAinduced increased postnatal lethality (Abbott et al. 2007). The mechanism(s) by which PFOA and PFOS 

induce developmental effects is not known. A study in rats suggested that lung immaturity could be the 

cause of early pup death following maternal exposure to PFOS (Grasty et al. 2003, 2005). Other research 

suggested that delayed maternal mammary gland differentiation could, in part, explain the growth 

retardation seen mice offspring following maternal exposure to PFOA (White et al. 2007). This study 

also reported alterations in milk protein gene expression. Recently, Rosen et al. (2007) reported that 

exposure to PFOA during gestation altered the expression of genes related to fatty acid catabolism in both 

the fetal liver and lung. Further studies of gene expression analysis following exposure to other 

perfluoroalkyl compounds and gene expression analysis in organs other than the liver and lungs may 

provide additional insight into the mechanisms of developmental effects of perfluoroalkyls. Also, 

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additional studies are needed to examine the role of PPARα and other nuclear receptors on developmental 

toxicity induced by perfluoroalkyl compounds. 

The effects of perinatal exposure on neurological end points have also been studied. Fuentes et al. 

(2007a, 2007b) reported no significant alterations in neurobehavioral tests in offspring from mice exposed 

to PFOS in utero and tested during the first weeks of life. In contrast, Johansson et al. (2008) reported 

that administration of a single, relatively low, gavage dose of PFOS or PFOA, but not PFDeA, at the age 

of 10 days resulted in altered spontaneous behavior when tested at the age of 2 or 4 months old. 

Replication of these studies by other research groups would be useful. 

Immunotoxicity. No studies were located that examined immunological effects in humans exposed to 

perfluoroalkyl compounds. A study in mice reported increased airway reactivity following dermal 

exposure to PFOA and suggested that PFOA might increase the IgE response to environmental allergens 

(Fairley et al. 2007). Thus, examination of possible associations between exposure to perfluoroalkyls and 

health conditions such as asthma, particularly in children, could be conducted. Acute oral studies in mice 

exposed to PFOA have reported immunological alterations characterized by thymus and spleen atrophy, 

alterations in thymocytes and splenocytes and in parameters of humoral immunity (Dewitt et al. 2008; 

Yang et al. 2000, 2002a). The mechanism of these effects is unknown and further research in this area is 

needed. Information on levels of perfluoroalkyls in lymphoreticular organs would be valuable. 

Experiments in PPARα-null mice showed that the effects of PFOA on the spleen were PPARα-dependent, 

whereas those in the thymus were only partially dependent (Yang et al. 2002b). This line of research 

should be extended to examine the role of PPARα on other immunological end points and the role of 

other PPARs. Very little information is available regarding immunological effects of other perfluoroalkyl 

compounds. Single lethal (160 and 320 mg/kg) gavage doses of PFDeA induced atrophy and lymphoid 

depletion in the thymus and spleen of female C57BL/6N mice (Harris et al. 1989). Also, a single 

intraperitoneal injection of 50 mg/kg PFDeA caused thymic atrophy in male rats (George and Andersen 

1986). Dietary studies with lower doses and of various durations are necessary to establish dose-response 

relationships for immunological effects of perfluoroalkyls other than PFOA. 

Neurotoxicity. Neurological examinations were not conducted (or at least it was not explicitly 

indicated) in the studies of perfluoroalkyl workers (Gilliland and Mandel 1996; Mundt et al. 2007; Olsen 

and Zobel 2007; Olsen et al. 1998, 1999, 2003a; Sakr et al. 2007a, 2007b) or of subjects environmentally 

exposed to elevated amounts of PFOA through their drinking water (Emmett et al. 2006b). However, it is 

reasonable to assume that no frank clinical signs were detected in the groups examined. Studies in 

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animals have not provided evidence that the nervous system is a sensitive target for perfluoroalkyl 

compounds based on observations of demeanor and morphological examinations of the nervous system; 

however, no comprehensive neurological testing has been conducted except for a study with PFHxS in 

rats in which a functional observation battery and tests for motor activity provided no indication of 

adverse neurological effects (Hoberman and York 2003) and one with PFBuS, also in rats, that reported a 

decrease in tail flick latency test in males of unknown toxicological significance (3M 2001). Some 

neurological testing should be conducted as part of routine testing of workers and of groups identified as 

having had high exposure in the past or currently undergoing high exposure to perfluoroalkyl compounds. 

Epidemiological 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 (Gilliland and Mandel 1996; Leonard 2006; 

Mundt et al. 2007; Olsen and Zobel 2007; Olsen et al. 1998, 1999, 2003a; Sakr et al. 2007a, 2007b) and 

from subjects exposed environmentally (Emmett et al. 2006b). No significant health conditions have 

been associated with the serum levels of perfluoroalkyls measured in these studies, but the main focus has 

been the liver. Evaluations of other end points seem warranted. Two studies have provided suggestive 

evidence of effects on sex hormones and lipids (Olsen et al. 1998; Sakr et al. 2007b) and there are also 

reports of increased risk of death from prostate and bladder cancer (Alexander and Olsen 2007; Alexander 

et al. 2003; Gilliland and Mandel 1993). Clarification of the details, significance, and dose-response 

relationships of the observed changes is needed. When possible, health assessments should include 

subjects of different race/ethnicity and age to determine potential race/ethnicity-based and age-based 

susceptibilities. 

Biomarkers of Exposure and Effect. 

Exposure. Data are available regarding levels of perfluoroalkyl compounds in serum from the general 

population (Calafat et al. 2007a, 2007b; Emmett et al. 2006a, 2006b; Olsen et al. 2003c, 2003b, 2004b, 

2007b) and perfluoroalkyl workers (Gilliland and Mandel 1996; Olsen and Zobel 2007; Olsen et al. 1999, 

2003b, 2003c; Sakr et al. 2007a, 2007b). 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. Data on serum levels in young children are lacking, but 

presumably will be available in future NHANES reports (Calafat et al. 2007b). 

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Effect. Health evaluations of perfluoroalkyl workers (i.e., Olsen and Zobel 2007; Olsen et al. 1999, 

2003a; Sakr et al. 2007a, 2007b) or of people undergoing high environmental exposure (Emmett et al. 

2006b) have provided little evidence of adverse effects, although there has been suggestive evidence of 

changes in sex hormones levels and lipids in some studies of perfluroalkyl workers (Olsen et al. 1998; 

Sakr et al. 2007b). Although no specific studies to identify effects unique to perfluoroalkyls can be 

suggested at this time, as indicated above, clarification of the details, significance, and dose-response 

relationships of the observed changes is needed. 

Absorption, Distribution, Metabolism, and Excretion. Very limited information is available 

regarding toxicokinetics of perfluoroalkyl compounds in humans; therefore, studies on all aspects of 

toxicokinetics in humans are needed. 

A single study was located that provides direct evidence for absorption of PFOA in rats following 

exposure to an aerosol (MMAD=1.9–2.1 μm) of 1–25 mg ammonium PFOA/m3 and some information on 

the rate of absorption (i.e., time to highest plasma concentration, Hinderliter et al. 2006a). Studies of 

inhalation absorption of other perfluoroalkyls were not located, although a study in rats exposed to PFNA 

provided indirect evidence of absorption of this compound (Kinney et al. 1989). Toxicokinetics studies 

conducted in rodents provide estimates of absorption fractions and absorption rates for ingested PFOA, 

PFOS, and PFBA (see Section 3.4.1.2 for discussion of Chang et al. 2008a; Hinderliter et al. 2006b; 

Hundley et al. 2006; Johnson and Ober 1979, 1999a; Kemper 2003). Mechanisms of pulmonary and 

gastrointestinal absorption have not been elucidated; therefore, appropriate studies are needed. 

Studies of perfluoroalkyl levels in tissues from human cadavers have provided information on serum and 

liver concentrations of PFOS (Olsen et al. 2003c). Detection limits precluded reliable estimates of serum 

and liver levels of PFOA, PFOSA, or PFHxA. Toxicokinetics studies have provided information on the 

tissue distribution of PFOA and PFOS in rodents (Griffith and Long 1980; Hundley et al. 2006; Johnson 

and Ober 1980, 1999b; Kemper 2003; Seacat and Luebker 2000; Vanden Heuvel et al. 1991b, 1991c; 

Ylinen et al. 1990) and PFOA in nonhuman primates (Butenhoff et al. 2004c). These studies have 

identified the liver as a site of relatively high concentrations of PFOA and PFOS and have found marked 

species and gender differences as well as dose dependencies of tissue distribution (e.g., tissue levels that 

change disproportionately with dose). These differences have been attributed, in part, to species and 

gender differences in elimination kinetics of absorbed perfluoroalkyls and dose dependence of elimination 

kinetics (see Section 3.4.2). Toxicokinetics studies have found gender- and dose-dependent subcellular 

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distribution of PFOA in rats (Han et al. 2005; Kudo et al. 2007). 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 is greatly influenced by binding interactions with albumin and 

other high molecular weight plasma proteins. Interactions with albumin have been partially characterized 

to the extent that binding capacity and affinity constants have been estimated (Han et al. 2003). However, 

attempts to simulate plasma and excretion kinetics of PFOA and PFOS with PBPK models suggest that 

binding to plasma proteins as well as the volume of distribution may exhibit time-dependencies that may 

be gender- and species-specific (Andersen et al. 2006; Tan et al. 2008). Mechanisms underlying these 

time dependencies have not been elucidated. 

Rates of elimination of perfluoroalkyls vary substantially across chemical species and animal species, and 

show gender differences and age dependencies within certain species (see Section 3.4.4.2). Slower 

elimination of PFOA in male rats compared to female rats has been attributed to sex hormone-modulated 

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). These differences appear to be less relevant to nonhuman 

primates; studies conducted in Cynomolgus monkeys have not found differences in elimination rate. The 

influence of gender on elimination rates of perfluoroalkyls in humans has not been thoroughly examined. 

Although the few studies that have estimated elimination half-times or renal clearances in male and 

female humans have not found significant gender differences (Harada et al. 2005a; Olsen et al. 2007a), 

these outcomes may reflect the relatively low serum concentrations in these subjects compared with 

studies that have been conducted in rodents and nonhuman primates (i.e., gender influence may vary with 

dose and/or plasma concentration). 

Comparative Toxicokinetics. Toxicokinetics studies conducted in various rodent species (mice, 

rats, hamsters, rabbits) and in Cynomolgus monkeys have revealed profound species and gender 

differences as well as dose dependencies in the tissue distribution and elimination kinetics of PFOA and 

PFOS (see Sections 3.4.2 and 3.4.4.2). Studies conducted in rats have revealed contributing mechanisms 

for gender differences in elimination of PFOA; slower elimination of PFOA in male rats compared to 

female rats has been attributed to sex hormone modulated 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). 

Gender differences in elimination of PFOA have also been observed in hamsters; however, unlike the rat, 

male hamsters excreted absorbed PFOA more rapidly than female hamsters. Gender differences in 

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elimination of PFOA have not been observed in other rodent species, in Cynomolgus monkeys, or in 

limited observations made in humans. A mechanistic explanation for the species differences in genderspecificity of elimination kinetics of PFOA has not been established. 

Methods for Reducing Toxic Effects. As previously mentioned, health evaluations of workers 

exposed to perfluoroalkyl compounds or of members of the general population exposed to elevated 

amounts of PFOA via the drinking water have not shown, with few exceptions, consistent associations 

between exposure and adverse health effects. Therefore, it is difficult to design studies or methods for 

reducing toxic effects if no significant health effects have been reported to date. However, studies that 

examine the issue of how to reduce body burden by increasing the lengthy elimination rate of some 

perfluoroalkyls would be valuable. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

It is not known whether children are more or less susceptible to the effects of exposure to perfluoroalkyl 

compounds because there are no studies that specifically addressed this question. The only health 

evaluation done in children exposed to perfluoroalkyls is that conducted by Emmett et al. (2006b) of 

residents in the Little Hocking water district in southeastern Ohio that included 43 children under the age 

of 18. The cohort was exposed to elevated levels of PFOA via the drinking water. The study did not find 

significant associations between serum PFOA levels and hematology parameters, total cholesterol and 

liver enzymes, indices of kidney function, and serum TSH levels whether the analysis included all the 

individuals as a group or separate analyses were done for adults or children. Similar evaluations should 

be made in any group identified as having high exposure to perfluoroalkyls and should include children of 

all ages. Toxicokinetics information in children is needed. Half-life studies have been conducted in 

elderly retired workers; there is the need to understand if these are applicable to children. The 

significance to children, if any, of the endocrine disturbances reported in some studies of perfluoroalkyl 

workers needs to be better understood. 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. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

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3.12.3 Ongoing Studies 

The following ongoing studies pertaining to perfluoroalkyls have been identified in the FEDRIP (2008) 

database. 

Dr. M. Peden-Adams, at the Medical University of South Carolina, Charleston, South Carolina, is 

conducting research to determine the role of PPARα in the suppression of T-dependent antibody 

production by PFOS by assessing antibody responses in wild (control) type mice and PPARα-null mice. 

She also aims to elucidate the mode of action of PFOS on T-dependent antibody production. The 

research is sponsored by the National Institute of Environmental Health Sciences. 

Drs. F. Rubio, W. Shelver, and associates, at ABBRAXIS LLC, Warminster, Pennsylvania, intend to 

produce polyclonal antibodies and hybridoma cell lines that provide monoclonal antibodies suitable for a 

commercial PFOA immunoassay, and to document the production method. The research is sponsored by 

the Department of Agriculture. 

The C8 Science Panel (2008) lists the following proposed research to be conducted on the roughly 

70,000 participants in the C8 Health Project: 

Cardiovascular Risk Factors Measured in the Blood. Researchers will look at the data already collected 

from approximately 55,000 participants in the C8 Health Project over age 20 to determine whether the 

results of some tests related to heart disease, such as total cholesterol, triglycerides, uric acid, red blood 

cell counts, glucose, and others, are associated with C8 blood level. Kyle Steenland is listed as 

investigator. 

The Immune Function, Liver, Hormone Disorders, and Cancer Prevalence Study. This study will look 

in depth at this information. The participant also filled out a questionnaire, and researchers will look at 

the self-reported disease the participants listed in the questionnaire on cancers and diseases related to 

problems with the immune system, the liver, and the endocrine or hormone regulation system. Using this 

information, the investigators will look at the relationships between C8 blood levels and the above 

outcomes taking into consideration factors such as age, sex, smoking, and obesity for each participant. 

Tony Fletcher is listed as investigator. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 225 

3. HEALTH EFFECTS 

The Community Follow-up Study. Investigators will look at new diseases occurring for such end points 

as cancer, heart disease, and diabetes, among adults who participated in the C8 Health Study. They will 

follow approximately 37,000 adults (a subset of the original 70,000 participants residing in the six water 

districts) for 4 years to see whether health effects develop overtime. Kyle Steenland is listed as 

investigator. 

The Worker Follow-up Study. Investigators will follow-up a study of 6,000 Washington Works plant 

workers (who worked anytime between January 1, 1952 and December 31, 2001) for about 4 years to 

determine what diseases they have had, with special interest in cancer, heart disease, and diabetes. Kyle 

Steenland is listed as investigator. 

The Study of Birth Outcomes in the Mid-Ohio Valley. This study will determine whether birth 

outcomes, including stillbirth, preterm birth (early delivery), and birth weight, are related to C8 exposure. 

David Savitz is listed as investigator. 

The Study of Birth Outcomes Among the C8 Health Project Participants. In addition to the birth 

outcomes examined in the Mid-Ohio Valley Community Study (stillbirth, preterm birth, birth weight), in 

this study, the investigators propose to look at miscarriage, pregnancy complications like preeclampsia 

(high blood pressure during pregnancy), and birth defects among newborn babies. David Savitz is listed 

as investigator. 

The Geographic Patterns of Cancer Study. Investigators will use state cancer registries, census tract and 

zip codes, water district records and other records in West Virginia and Ohio to study whether rates of 

cancer incidence and cancer deaths differ in relation to levels of exposure to C8. Rates in the affected 

water districts will be compared to unexposed counties nearby and within the exposed areas to assess how 

cancer rates vary depending on exposure to C8 in the different water districts. Tony Fletcher is listed as 

investigator. 

Follow-up Study on Immune Function, Liver, and Hormone Disorders. A subset of 1,000 subjects 

from the 70,000 participants in the C8 Health Projects will be re-contacted to participate in this study. 

Researchers will conduct interviews and collect further blood samples to help better understand the 

relationships between C8 blood levels and outcomes with the immune, liver, and endocrine systems. 

Using the new blood samples, the researchers will do a much more complete set of tests of the immune 

system and relate these to C8 levels. Tony Fletcher is listed as investigator. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

PERFLUOROALKYLS 226 

3. HEALTH EFFECTS 

The Half-life Study. To better understand the relationship between past C8 exposures and current 

C8 blood levels, investigators will invite 200 adults from the C8 Health Project to participate in a longer 

study to determine the elimination half-life of C8 from the body. Participants will provide up to eight 

blood samples. Kyle Steenland and Barry Ryan are listed as investigators. 

NTP (2008) has initiated a long-term carcinogenicity study of PFOA in Sprague-Dawley rats. Female 

rats will receive 0, 300, or 1,000 ppm PFOA in the diet, whereas males will receive 0, 150, or 300 ppm. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

PERFLUOROALKYLS 227 

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. 

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, reaction with acids, bases, oxidants, and reductants (3M 2000; 

EPA 2008f; OECD 2002, 2006a, 2007; Schultz et al. 2003). Perfluoroalkanecarboxylic acids decompose 

when heated to temperatures >550 °C forming an olefin, HF, and CO2 (Kissa 2001). 

Perfluoroalkyl carboxylates and sulfonates are made of a long 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 character 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 below 20 mN/m has resulted in their use as wetting agents (Kissa 2001). Based on 

the behavior of some perfluoroalkanes, perfluoroalkyls are expected to form separate layers when mixed 

with hydrocarbons and water; therefore, measurement of the n-octanol water partition coefficient is not 

practical (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 pH. 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 

ammonium perfluorooctanoate (APFO), will form the corresponding anions when dissolved in water. 

Prevedouros et al. (2006) report a Krafft point of 22 °C and critical micelle concentration of 3.7x103 mg/L 

***DRAFT FOR PUBLIC COMMENT*** 
o data No data No data 

8HF15O2 C4HF7O2 C7HF13O2 

F 

F 

F 

F 

F F F 

F 

F 

F 

OH 

F F 

F 

F 

F 

F 

F 

OH 

F 

F F F 

F 

F F F 

OH 

35-67-1 375-22-4 375-85-9 

F 

F F 

F 

O 

F F F 

F F 

O O

F 

PERFLUOROALKYLS 228 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Perfluoroalkyls 

Characteristic Information 

Chemical name Perfluorooctanoic acid Perfluorobutyric acid Perfluoroheptanoic acid 

Synonym(s) PFOA; pentadecafluoro1-octanoic acid; 

pentadecafluoro-n-octanoic 

acid; pentadecaflurooctanoic 

acid; perfluorocaprylic acid; 

perfluoroctanoic acid; 

perfluoroheptanecarboxylic 

acid; octanoic acid, 

2,2,3,3,4,4,5,5,6,6,7,7,8,8, 

8-pentadecafluoroPFBA; heptafluoro1-butanoic acid; 

heptafluorobutanoic acid; 

heptafluorobutyric acid; 

perfluorobutanoic acid; 

perfluorobutyric acid; 

perfluoropropanecarboxylic 

acid 

PFHpA; perfluoron-heptanoic acid; 

tridecafluoro-1-heptanoic 

acid; heptanoic acid, 

2,2,3,3,4,4,5,5,6,6,7,7, 

7-tridecafluoroRegistered trade 

name(s) 

N

Chemical formula C

Chemical structure 

Identification 

numbers: 

CAS registry 3

NIOSH RTECS RH0781000 ET4025000 No data 

EPA hazardous No data No data No data 

waste 

OHM/TADS No data No data No data 

DOT/UN/NA/IMDG 

shipping 

UN3261 No data No data 

HSDB 7137 No data No data 

NCI No data No data No data 

***DRAFT FOR PUBLIC COMMENT*** 
mula 

ucture 

C9HF17O2 

F 

F F F F

O

F 

F F OH 

F F 

F F F

F F
 

F F 

C10HF19O2 

O 

F F OH 

F F 

F F F F F F F F F F F F 

F F F 

C11HF21O2 

O

F 

F F OH 

F F 

F F F F F F F F F F F F F F F F 

 

PERFLUOROALKYLS 229 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Perfluoroalkyls 

Characteristic Information 

Chemical name 

Synonym(s) 

Registered trade 

name(s) 

Chemical for

Chemical str

Identification

numbers: 

CAS registry 

NIOSH RTECS 

EPA hazardous 

waste 

OHM/TADS 

DOT/UN/NA/IMDG 

shipping 

HSDB 

NCI 

Perfluorononanoic acid 

PFNA; perfluoron-nonanoic acid; 

perfluorononan-1-oic acid; 

heptadecafluoro-nonanoic 

acid; nonanoic acid, 

2,2,3,3,4,4,5,5,6,6,7,7,8,8, 

9,9,9-heptadecafluoroNo data 

375-95-1 

No data 

No data 

No data 

No data 

No data 

No data 

Perfluorodecanoic acid 

PFDA; PFDeA; Ndfda; 

nonadecafluoro-n-decanoic 

acid; nonadecafluorodecanoic acid; perfluoro-ndecanoic acid; decanoic 

acid, 

2,2,3,3,4,4,5,5,6,6,7,7,8,8,9, 

9,10,10,10-nonadecafluoroNo data 

335-76-2 

HD9900000 

No data 

No data 

No data 

No data 

No data 

Perfluoroundecanoic acid 

PFUA; perfluoron-undecanoic acid; 

henicosafluoroundecanoic 

acid 

No data 

2058-94-8 

No data 

No data 

No data 

No data 

No data 

No data 

***DRAFT FOR PUBLIC COMMENT*** 
No data No data No data 

C12HF23O2 C8HF17O3S	 C6HF13O3S 

F

F 

F

F 

F

F 

F

F 

F

F 

F

F

F 

O 

F

F 

F F

F F

F

F 

O

F

F 

S

O

F

F OH S

O

O

F 

F OH 

F F OH F F

F F F F F F F F F F F F F F F F F F

F F

F F 

307-55-1 1763-23-1 355-46-4 

PERFLUOROALKYLS 230 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Perfluoroalkyls 

Characteristic	 Information 

Chemical name Perfluorododecanoic acid Perfluorooctane sulfonic acid	 Perfluorohexane sulfonic 

acid 

Synonym(s)	 PFDoA; PFOS; PFHxS; perfluorohexanetricosafluorododecanoic 1-perfluorooctanesulfonic 1-sulphonic acid; 

acid; dodecanoic acid, acid; heptadecafluoro- 1-hexanesulfonic acid, 

2,2,3,3,4,4,5,5,6,6,7,7,8, 1-octanesulfonic acid; 1,1,2,2,3,3,4,4,5,5,6,6, 

8,9,9,10,10,11,11,12,12, heptadecafluorooctan- 6-tridecafluoro-; 

12-tricosafluoro- 1-sulphonic acid; 1,1,2,2,3,3,4,4,5,5,6,6, 

perfluorooctane sulfonate; 6-tridecafluorohexaneperfluorooctylsulfonic acid; 1-sulfonic 

1-Octanesulfonic acid, 

1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8, 

8-heptadecafluoroRegistered trade 

name(s) 

Chemical formula 

Chemical structure

Identification 

numbers: 

CAS registry 

NIOSH RTECS No data RG9701600 No data
 

EPA hazardous No data No data No data
 

waste
 

OHM/TADS No data No data	 No data 

DOT/UN/NA/IMDG No data No data No data
 

shipping
 

HSDB No data 7099 No data
 

NCI No data No data No data
 

***DRAFT FOR PUBLIC COMMENT*** 
F9O3S 

F 

F

S

O 

O

F 

F OH 

F F F 

F 

F 

73-5 

C8H2F17NO2S
 

F 

S

O

O

F 

F NH2 F F F F F F F F F F F F F F 

754-91-6 

C11H6F17NO4S 

S N

F 

CH O 3 O F OH F F O F F F F F F F F F F F F F 

2355-31-9 

PERFLUOROALKYLS 231 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Perfluoroalkyls 

Characteristic	 Information 

Chemical name	 Perfluorobutane sulfonic 

acid 

Synonym(s)	 PFBuS; 

1-perfluorobutanesulfonic 

acid; nonafluoro1-butanesulfonic acid; 

nonafluorobutanesulfonic 

acid; pentyl 

perfluorobutanoate; 

1,1,2,2,3,3,4,4, 

4-nonafluoro1-butanesulfonic acid; 

1,1,2,2,3,3,4,4, 

4-nonafluorobutane1-sulphonic acid; 

1-butanesulfonic acid, 

nonafluoro- (6Cl,7Cl,8Cl) 

Registered trade No data 

name(s) 

Chemical formula C4H

Chemical structure 

Identification 

numbers: 

CAS registry 375-

NIOSH RTECS EK5930000
 

EPA hazardous No data
 

waste
 

OHM/TADS No data 

DOT/UN/NA/IMDG No data
 

shipping
 

HSDB No data
 

NCI No data
 

Perfluroroocatanesulfona
 

mide
 

PFOSA;
 

perfluoroctylsulfonamide;
 

perfluorooctanesulfonic
 

acid amide;
 

heptadecafluorooctanesul
 

phonamide;
 

1-octanesulfonamide,
 

1,1,2,2,3,3,4,4,5,5,6,6,7,7,
 

8,8,8-heptadecafluoroNo data
 

RG9701400 

No data 

No data 

No data 

No data 

No data 

2-(N-methyl-perfluorooctane 

sulfonamido) acetic acid 

Me-PFOSA-AcOH 

No data 

No data 

No data 

No data 

No data 

No data 

No data 

***DRAFT FOR PUBLIC COMMENT*** 
 

S N

F 

H3C O

O F OH F F O F F F F F F F F F F F F F 

2991-50-6 

No data 

PERFLUOROALKYLS 232 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Perfluoroalkyls 

Characteristic	 Information 

Chemical name	 2-(N-ethyl-perfluorooctane 

sulfonamido) acetic acid 

Synonym(s)	 Et-PFOSA-AcOH 

Registered trade name(s)	 No data 

Chemical formula	 C12H8F17NO4S 

Chemical structure 

Identification numbers: 

CAS registry 

NIOSH RTECS 

EPA hazardous waste No data 

OHM/TADS No data 

DOT/UN/NA/IMDG shipping No data 

HSDB No data 

NCI No data 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; HSDB =Hazardous 

Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; 

OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of 

Chemical Substances 

Source: Calafat et al. 2007a, 2007b; CAS 2008; ChemIDplus 2008; RTECS 2008 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

PERFLUOROALKYLS 233 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls 

Property PFOA PFBA PFHpA PFNA 

Molecular 414.069a 214.039a 364.06b 464.08b 

weight 

Color No data No data No data No data 

Physical state Solidc Liquida No data No data 

Melting point 54.3 °Ca -17.5 °Ca No data No data 

Boiling point 188 °Ca 121 °Ca No data No data 

Density at 20 °C 1.8 g/cm3 d 1.651 g/cm3 a 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 9.5x103 mg/L at 25 °Ce No data No data No data 

Organic No data Soluble in ethanol No data No data 

solvents and toluene; 

insoluble in 

petroleum ethera 

Partition 

coefficients: 

Log Kow Not applicablef Not applicablef Not applicablef Not applicablef 

Koc 17–230g No data No data No data 

pKa 2.8h 0.08 (estimated)i -0.15 (estimated)i -0.17 (estimated)i 

Vapor pressure 0.017 mm Hg at 20 °C No data No data No data 

(extrapolated); 

0.962 mm Hg at 59.25 

°C (measured)j 

Henry's law Not applicablek Not applicablek Not applicablek Not applicablek 

constant 

Autoignition Not applicablel Not applicablel Not applicablel Not applicablel 

temperature 

Flashpoint Not applicablel Not applicablel Not applicablel Not applicablel 

Flammability Not applicablel Not applicablel Not applicablel Not applicablel 

limits 

Conversion 

factors 

1 ppm= 

17.21 mg/m3 

1 mg/m3

= 

1 ppm= 

8.90 mg/m3

; 

1 mg/m3

= 

1 ppm= 

15.14 mg/m3

; 

1 mg/m3

= 

1 ppm= 

19.29 mg/m3

; 

1 mg/m3

= 

0.058 ppmc 0.11 ppm 0.07 ppm 0.05 ppm 

(calculated using (calculated using (calculated using 

molecular weight) molecular weight) molecular weight) 

Explosive limits Not applicablel Not applicablel Not applicablel Not applicablel 

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PERFLUOROALKYLS 234 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls 

Property PFDeA PFUA PFDoA PFOS 

Molecular 514.084a 564.085 (ChemID 614.1b 500.03b 

weight Plus 2008) 

Color No data No data No data No data 

Physical state No data No data No data No data 

Melting point No data No data No data ≥400 °C (potassium 

salt) (3M 2000) 

Boiling point 219 °C No data No data No data 

Density at No data No data No data No data 

20 °C 

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 No data No data 570 mg/L (potassium 

salt in pure water) 

(3M 2000) 

Organic No data No data No data No data 

solvents 

Partition 

coefficients: 

Log Kow Not applicablef Not applicablef Not applicablef Not applicablef 

Koc No data No data No data No data 

pKa -0.17 (estimated)i -0.17 (estimated)i -0.17 (estimated)i 0.14 (estimated)i 

Vapor pressure No data No data No data 2.48x10-6 mm Hg at 

20 °C (potassium 

salt)c 

Henry's law Not applicablek Not applicablek Not applicablek Not applicablek 

constant at 

25 °C 

Autoignition Not applicablel Not applicablel Not applicablel Not applicablel 

temperature 

Flashpoint Not applicablel Not applicablel Not applicablel Not applicablel 

Flammability Not applicablel Not applicablel Not applicablel Not applicablel 

limits 

Conversion 

factors 

1 ppm= 

21.37 mg/m3

; 

1 mg/m3

= 

1 ppm= 

23.45 mg/m3

; 

1 mg/m3

= 

1 ppm= 

25.53 mg/m3

; 

1 mg/m3 

1 ppm= 

20.79 mg/m3

; 

1 mg/m3 

0.05 ppm 0.04 ppm =0.04 ppm =0.05 ppm 

(calculated using (calculated using (calculated using (calculated using 

molecular weight) molecular weight) molecular weight) molecular weight) 

Explosive limits Not applicablel Not applicablel Not applicablel Not applicablel 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

PERFLUOROALKYLS 235 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls 

Property 

Molecular 

weight 

PFHxS 

400.12b 

PFBuS 

300.1b 

PFOSA 

499.15b 

Me-PFOSAAcOH 

571.21 (from 

structure) 

Et-PFOSA-AcOH 

585.24b 

Color No data No data No data No data No data 

Physical state No data No data No data No data No data 

Melting point No data No data No data No data No data 

Boiling point No data No data No data No data No data 

Density at 

20 °C 

No data No data No data No data No data 

Odor No data No data No data No data No data 

Odor 

threshold: 

Water No data No data No data No data No data 

Air No data No data No data No data No data 

Solubility: 

Water No data No data No data No data No data 

Organic 

solvents 

No data No data No data No data No data 

Partition 

coefficients: 

Log Kow Not applicablef Not applicablef Not applicablef Not applicablef Not applicablef 

Koc 

pKa 

Vapor 

pressure 

Henry's law 

constant 

No data 

0.14 (estimated)i 

No data 

Not applicablek 

No data 

0.14 (estimated)i 

No data 

Not applicablek 

No data 

6.24 (estimated)i 

No data 

Not applicablek 

No data 

3.92 (estimated)i 

No data 

Not applicablek 

No data 

3.92 (estimated)i 

No data 

Not applicablek 

Autoignition 

temperature 

Flashpoint 

Flammability 

limits 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

Not applicablel 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

PERFLUOROALKYLS 236 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Perfluoroalkyls 

Me-PFOSAProperty PFHxS PFBuS PFOSA AcOH Et-PFOSA-AcOH 

Conversion 1 ppm= 

factors 16.63 mg/m3

; 

1 mg/m3

= 

0.06 ppm 

(calculated using 

molecular weight) 

Explosive limits Not applicablel 

1 ppm= 

12.48 mg/m3; 

1 mg/m3 

=0.08 ppm 

(calculated using 

molecular weight) 

Not applicablel 

1 ppm= 

20.75 mg/m3; 

1 mg/m3 

=0.05 ppm 

(calculated using 

molecular weight) 

Not applicablel 

1 ppm= 

23.75 mg/m3; 

1 mg/m3

= 

0.04 ppm 

(calculated using 

molecular weight) 

Not applicablel 

1 ppm= 

24.33 mg/m3; 

1 mg/m3

= 

0.04 ppm 

(calculated using 

molecular weight) 

Not applicablel 

a

Lide 2005
 b

EPA 2008h
 c

3M 2008c
 d

Kroschwitz and Howe-Grant 1994
 e

Kauck and Diesslin 1951
 f

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).
 g

Prevedouros et al. 2006)

h

Kissa 2001
 i

SPARC 2008
 j

Washburn et al. 2005
 k

Henry's law constant is not applicable for these substance since they are dissociated in the environment.
 l

Perfluoroalkyls are nonflammable and chemically stable even at high temperatures (3M 1999; Kissa 2001; OECD
 

2007).
 

Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; Me-PFOSA-AcOH = 2-(M-methylperfluorooctane sulfonamide) acetic acid; 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; PFOSA = perfluorooctane sulfonamide; PFUA = perfluoroundecanoic acid
 

***DRAFT FOR PUBLIC COMMENT*** 
PERFLUOROALKYLS 237 

4. CHEMICAL AND PHYSICAL INFORMATION 

for the perfluorooctanoate anion (PFO). Above these values, the solubility of PFO is expected to increase 

abruptly due to the formation of micelles. 

***DRAFT FOR PUBLIC COMMENT*** 
PERFLUOROALKYLS 238 

4. CHEMICAL AND PHYSICAL INFORMATION 

This page is intentionally blank. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PERFLUOROALKYLS 239 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

No information is available in the TRI database on facilities that manufacture or process perfluoroalkyls 

because this chemical 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 1998). 

Perfluoroalkyls have been manufactured for their direct use in commercial products as well as for their 

use in industrial process streams. The most important perfluoroalkyl compounds in terms of production 

and use have been PFOS and PFOA; however, these substances and related perfluoroalkyl compounds are 

currently being phased out as a joint effort by EPA and industry. 

The 3M Company, which was the principal worldwide manufacturer of PFOS and related chemicals, 

completed the phase-out of its PFOS production in 2002 (3M 2008a; EPA 2008f). During the same year, 

EPA finalized the significant new use rule for 88 perfluoroalkyl sulfonate compounds, which requires 

manufacturers to notify EPA 90 days prior to commencing manufacture or importing these substances for 

a significant new use to allow time for evaluation (EPA 2002, 2007c, 2008f). The purpose of this rule 

was to limit future manufacturing and importation of these substances. According to EPA, the rule allows 

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 significant new use 

rule was amended in 2007 to include 183 additional perfluoroalkyl sulfonate compounds (EPA 2007c, 

2008f). Included on the current list are PFOS, PFHxS, PFOSA, and Et-PFOSA-AcOH. EPA believed 

that the perfluoroalkyl sulfonate compounds listed under the significant new use rule were no longer 

manufactured; 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 2007c). EPA has since excluded this from the list of significant uses. 

In 2006, the eight major companies of the perfluoropolymer/perfluorotelomer industry agreed to 

participate in EPA's PFOA Stewardship Program (EPA 2008f). 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. 

Progress reports were provided in 2007. 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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

PERFLUOROALKYLS 240 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Content (ppm) and Percent Reduction of PFOA, PFOA Homologues, or
 

PFOA Precursors in Products from the 2006 U.S. Operations of
 

Fluoropolymer/Fluorotelomer Companies
 

Dispersions Other fluoropolymers Telomers 

Percent Percent Percent 

Company Chemicals Content reductiona Content reductiona Content reductiona 

Arkema, Inc.	 PFOA and >500– 0% >70–150 30 Not Not 

higher 1,000 applicable applicable 

homologues 

Precursors Not Not Not Not Not Not 

applicable applicable applicable applicable applicable applicable 

Asahi Glass PFOA, PFOA 500–1,570 12% 0.12 Not Not Not 

Company salts, and higher applicable applicable applicable 

homologues 

Precursors Not Not Not Not Not Not 

applicable applicable applicable applicable applicable applicable 

Ciba Specialty PFOA 0.05 kg >99% 0.05 kg >99% 0.05 kg >99% 

Chemicals Higher 0.05 kg >99% 0.05 kg >99% 0.05 kg >99% Corporation homologues
 

Precursors 0 >99% 0 >99% 0 >99%
 

Clariant Not applicable Not Not Not Not Not Not 

International applicable applicable applicable applicable applicable applicable 

Ltd. 

Daikin PFOA 280 34% 2; 300 0% 0.28 72% 

America, Inc. Precursors and Not Not Not Not 2,500 78% 

higher applicable applicable applicable applicable 

homologues 

E.I. DuPont PFOA, PFOA 547 44% 69 80% 246 kg 50% 

de Nemours salts 

and Company Direct Not Not Not Not 57 kg 14% 

precursors applicable applicable applicable applicable 

3M/Dyneon PFOA 0 100% Not Not Not Not 

reported reported applicable applicable 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Content (ppm) and Percent Reduction of PFOA, PFOA Homologues, or
 

PFOA Precursors in Products from the 2006 U.S. Operations of
 

Fluoropolymer/Fluorotelomer Companies
 

Dispersions Other fluoropolymers Telomers 

Company 

Solvay 

Solexis 

Chemicals 

PFOA and 

PFOA salts 

Higher 

homologues 

Precursors 

Content 

600–700 

Not 

applicable 

0 

Percent 

reductiona Content 

59% Not 

applicable 

Not 

applicable 

170–200 

Not 

applicable 

Not 

applicable 

Percent 

reductiona Content 

Not 

applicable 

Not 

applicable 

0% Not 

applicable 

Not 

applicable 

Not 

applicable 

Percent 

reductiona 

Not 

applicable 

Not 

applicable 

Not 

applicable 

a

Percent 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 = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid 

Source: EPA 2008f 

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PERFLUOROALKYLS 242 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

According to DuPont, PFOA is produced at trace levels as a byproduct during the manufacture of 

fluorotelomer products; however, DuPont specifies that PFOA is not used to manufacture its 

fluorotelomer products (DuPont 2008). DuPont has announced that a new manufacturing process has 

been developed for its fluorotelomer products that are based on short-chain chemistry. The company 

claims that this new process will remove >97% of trace levels of PFOA, its homologues, and direct 

precursors from DuPont fluorotelomer products. The chemicals that will be involved in DuPont’s new 

manufacturing process are not identified. Based on statements made by the 3M Chemical Company, the 

short chain perfluoroalkyl, PFBuS, may play a role in new technologies that will be used to reformulate 

products affected by the phase out of PFOA and related perfluoroalkyls (3M 2008a). 

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, ammonium perfluorooctanoate (APFO), are also listed. During the reporting year 2002, 

manufacturers reported that the production volumes were within the range of 15,000–500,000 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 2008g). PFBA was reported as having a production volume within the 

range of 15,000–500,000 pounds (6–227 metric tons) during 1986; however, PFBA production volumes 

were not reported for subsequent years (EPA 2008g). None of the other perfluoroalkyl compounds were 

listed in EPA’s IUR database. Current U.S. production volume data for perfluoroalkyl compounds are 

not available; however, the production volume of PFBA and the production volumes of PFOS and related 

perfluoroalkyl sulfonate compounds are expected to be zero since 3M ceased production of these 

substances in 1998 and 2002, respectively (3M 2008a; Agency for Toxic Substances and Disease Registry 

2008; EPA 2007c). Similarly, the current production volumes of PFOA and APFO are expected to be 

much less as a result of efforts by companies to reduce PFOA emissions and develop alternatives for this 

chemical so that it can be completely removed from process streams (EPA 2008f). 

Perfluoroalkyls have been manufactured industrially through two methods, the electrochemical 

fluorination (ECF) process and the telomerization process (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 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. U.S. Production Volume Ranges for Perfluoroalkyls (1986–2002)
 

Reported under the EPA Inventory Update Rule
 

Perfluoro- Reporting year production volume range (pounds) 

alkyl 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; PFBA = perfluorobutyric acid; PFOA = perfluorooctanoic acid; 

PFOS = perfluorooctane sulfonic acid 

Source: EPA 2008g 

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catalyst

4 + IF5 + 2I2 → 5C2F5I 

5I + nC2F4  → C2F5(C2F4)nI 

SO3 )nI → C2F5(C2F4)n-1CF2COOH 

 

hSO2F + HF  → RfSO2F + H2
 

O2F + KOH  → RfSO3K + HF
 

K + H2SO4  → RfSO3H + KHSO4
 

RhCOF + HF  → RfCOF + H2 + byproducts
 

RfCOF + H2O  → RfCOOH + HF
 

PERFLUOROALKYLS 244 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

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). 

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. 

R

RfS

RfSO3

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 telomerization process was developed by DuPont and has served as the basis for their fluoropolymer 

production chemistry (Hekster et al. 2003; Savu 1994a; Siegemund et al. 2005). It begins with the 

preparation of pentafluoroiodoethane from tetrafluoroethane. Tetrafluoroethane is then added to this 

product at a molar ratio that gives a product of desired chain length. Finally, the product is oxidized to 

form the carboxylic acid. The telomerization process produces linear perfluorocarboxylic acids of even 

carbon numbers. An example of telomerization is shown below. 

5C2F

C2F

C2F5(C2F4

Ammonium perfluorooctanoate is currently manufactured in Japan through oxidation of a mixture of 

linear fluorotelomer olefins (Prevedouros et al. 2006). Fluorotelomer iodide carboxylation has also been 

described; however, it does not appear that this production method has been used commercially 

(Prevedouros et al. 2006). 

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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.2 IMPORT/EXPORT 

Information regarding the import and export of perfluoroalkyl compounds were not located. 

5.3 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, 

electrical wire casing, fire and chemical resistant tubing, and plumbing thread seal tape (DuPont 2008; 

EPA 2008f). 

5.4 DISPOSAL 

Recommended disposal methods specific to perfluoroalkyl compounds have not been located. DuPont 

(2008) stated that it had developed proprietary technologies for the safe disposal, recovery, and/or 

recycling of PFOA extracted during fluoropolymer production processes; however, this company has 

since committed to the phase-out of PFOA from their fluoropolymer production streams. The 

Fluoropolymers Division has outlined two preferred disposal options for fluoropolymer dispersions, 

which may contain <1% fluoropolymer polymerization aids such as PFOA. 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 while the liquid waste is discharged to a waste water 

treatment facility. The second method involves incineration at temperatures >800 °C using a scrubber to 

remove hydrogen fluoride. Currently, several companies under the direction of EPA are performing 

incineration testing on commercially available fluoropolymers and fluorotelomers to determine whether 

these disposal processes result in the formation and release of perfluoroalkyl compounds into the 

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PERFLUOROALKYLS 246 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

environment (EPA 2008f). According to perfluorochemical facility assessment reports, historical 

disposal of perfluoroalkyl containing waste has been through onsite and offsite landfills, through sludge 

incorporation (subsurface injection), and through incineration (3M 2007b, 2008a; Agency for Toxic 

Substances and Disease Registry 2005). 

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PERFLUOROALKYLS 247 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Perfluoroalkyls have not been reported at EPA National Priorities List (NPL) sites, however, it's unknown 

how many of the 1,467 current or former NPL sites have been evaluated for the presence of 

perfluoroalkyls (HazDat 2008). 

Since the early 2000s, companies in the fluorochemical industry have been working with EPA to phaseout the production and use of several perfluoroalkyl compounds (3M 2008a; DuPont 2008; EPA 2007c, 

2008f). 3M ceased production of PFOS and related chemicals in 2002 (3M 2008a; EPA 2007c). PFOA, 

PFOA precursors, and higher homologues are currently being phased out by DuPont and other members 

of EPA's PFOA Stewardship Program (DuPont 2008; EPA 2008f). Industrial releases of these 

perfluoroalkyls in the United States are declining based on company reports submitted to EPA (EPA 

2008f). In the past, large amounts of perfluoroalkyls were released to the air, water, and soil in and 

around fluorochemical facilities (3M 2007b, 2008a, 2008b; Barton et al. 2007; Davis et al. 2007; DuPont 

2008; EPA 2008f). 

Other sources of perfluoroalkyls in the environment have also been considered. Perfluorocarboxylates 

and sulfonates may be formed from the oxidation of precursors such as fluorotelomer alcohols and 

perfluoroalkyl sulfonamides in air, water, and soil (D'eon et al. 2006; Ellis et al. 2004; Gauthier and 

Mabury 2005; Liu et al. 2007; Martin et al. 2006; Wallington et al. 2006; Wang et al. 2005a, 2005b; 

Wania 2007). The use of perfluoroalkyls in surface protectants such as treatments for carpets and textiles 

is expected to result in the release of these substances to the air (Barber et al. 2007; Jahnke et al. 2007a; 

Kubwabo et al. 2005; Moriwaki et al. 2003; Prevedouros et al. 2006; Shoeib et al. 2004). The former use 

of perfluoroalkyls in aqueous fire-fighting foams has resulted in the release of these substances to soil and 

groundwater (Moody and Field 1999; Moody et al. 2003). 

Perfluoroalkyl carboxylic acids and sulfonic acids are expected to dissociate in the environment based on 

measured and estimated pKa values of <3 (Kissa 2001; SPARC 2008). Perfluoroalkyl 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 highly 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 

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PERFLUOROALKYLS 248 

6. POTENTIAL FOR HUMAN EXPOSURE 

particulates (Kim and Kannan 2007). Perfluoroalkyl sulfonamides may partially dissociate in the 

environment, especially under acidic conditions and are therefore expected to have a higher rate of 

volatilization compared to the carboxylic acids and sulfonic acids (Martin et al. 2006; SPARC 2008). 

Perfluoroalkyls are very stable compounds and are resistant to biodegradation, direct photolysis, 

atmospheric photooxidation, and hydrolysis (3M 2000; EPA 2008f; OECD 2002, 2007; Schultz et al. 

2003). Atmospheric photooxidation half-lives determined for representative perfluoroalkyl sulfonamides 

ranging from 20 to 50 days indicate that this may be an important degradation mechanism for this group 

of perfluoroalkyls (D'eon et al. 2006; Martin et al. 2006). 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). 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). 

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; Yamashita et al. 

2005, 2008; Wei et al. 2007a). Proposed source pathways include long-range atmospheric transport of 

precursor compounds followed by photooxidation to form perfluoroalkyls, direct long-range transport of 

perfluoroalkyls via oceanic currents, and transport of perfluoroalkyls in the 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 

were recently 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. 

PFOA and PFOS have been measured in outdoor urban air samples at concentrations as high as 46 and 

919 pg/m3

, respectively (Barber et al. 2007; Harada et al. 2005b, 2006; Kim and Kannan 2007). 

Concentrations of other perfluoroalkyls measured in outdoor air are generally <1 pg/m3

. Reported 

concentrations of perfluoroalkyls measured in four indoor air samples were <5 pg/m3 (Barber et al. 2007). 

PFOA, PFOS, and PFHxS have been detected in indoor dust samples at concentrations ranging from 

<2.29–3,700, <4.56–5,065, and <4.56–4,305 ng/g, respectively (Kubwabo et al. 2005; Moriwaki et al. 

2003). Reported concentrations of perfluoroalkyls measured in surface water samples are generally 

below 50 ng/L (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). Background concentrations of perfluoroalkyls in 

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PERFLUOROALKYLS 249 

6. POTENTIAL FOR HUMAN EXPOSURE 

groundwater, drinking water, soil, and sediment have not been located. Perfluoroalkyls have been 

detected in different types of foods at reported concentrations ranging from 0.05 to 10,000 ng/g fresh 

weight (3M 2001; Food Standards Agency 2006; Fromme et al. 2007b; Tittlemier et al. 2007). 

Perfluoroalkyls have also been detected in consumer products such as treated carpeting, treated apparel, 

and paper food packaging (Begley et al. 2005; Washburn et al. 2005). 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). 

The highest concentrations of perfluoroalkyls 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; 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). 

Mean PFOA, PFOS, and PFHxS serum concentrations reported in various studies from the United States 

were 2.1–9.6, 14.7–55.8, and 1.5–3.9 ng/mL, respectively (Calafat et al. 2006b, 2007a, 2007b; De Silva 

and Mabury 2006; Kuklenyik et al. 2004; Olsen et al. 2003a, 2003b, 2004c, 2005, 2007a). Mean 

concentrations of PFHpA, PFNA, PFDeA, PFUA, PFDoA, PFBuS, PFBA, PFOSA, Me-PFOSA-AcOH, 

and Et-PFOSA-AcOH are generally <1 ng/mL in these studies. Major PFOS exposure pathways 

proposed for the general population are food and water ingestion, dust ingestion, and hand-to-mouth 

transfer from mill-treated carpets (Trudel et al. 2008). For PFOA, the major exposure pathways are 

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. Based on 

these proposed exposure pathways, adult uptake doses estimated for high exposure scenarios were 

approximately 30 and 47 ng/kg body weight/day for PFOS and PFOA, respectively (Trudel et al. 2008). 

The proposed PFOS and PFOA exposure pathways are expected to be similar for children except that 

exposure from hand-to-mouth transfer from treated carpets would be much larger. 

PFOS and PFOA doses determined for children under the age of 12 under high exposure scenarios were 

101–219 and 65.2–128 ng/kg body weight/day, respectively (Trudel et al. 2008). Perfluoroalkyls have 

been detected in human breast milk and umbilical cord blood. The reported maximum concentrations of 

PFOS and PFOA measured in human breast milk samples were 0.360–0.639 and 0.210–0.490 ng/mL, 

respectively (Kärrman et al. 2007a; So et al. 2006b; Völkel et al. 2008). Maximum concentrations of 

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PERFLUOROALKYLS 250 

6. POTENTIAL FOR HUMAN EXPOSURE 

other perfluoroalkyl compounds were <0.18 ng/mL. 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. 2004b; Midasch et al. 2007). Other 

perfluoroalkyls have been detected less frequently, with maximum concentrations of <2.6 ng/mL. 

Estimated on-site exposure of individuals to PFOA while working at a fluorochemical facility ranged 

from 3.2x10-6 to 2.4 ng/kg/day (3M 2008c). Individuals who perform jobs that require frequent contact 

with perfluoroalkyl-containing products, such as individuals who install and treat carpets, are expected to 

have occupational exposure to these substances. Individuals who work at fluorochemical facilities 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). 

Studies of individuals living near fluorochemical facilities suggest that drinking water is the major 

exposure pathway (Emmett et al. 2006a; Holzer et al. 2008; Wilhelm et al. 2008b). Estimated off-site 

exposure of local residents that live near a fluorochemical facility to PFOA from contaminated 

environmental media ranged from 0.011 to 260 ng/kg/day (3M 2008c). 

6.2 RELEASES TO THE ENVIRONMENT 

There is no information listed in EPA’s Toxic Release Inventory (TRI) on releases of perfluoroalkyls to 

the environment from manufacturing and processing facilities because these releases are not required to 

be reported within this program (EPA 1998). 

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 consumer 

products (Hekster et al. 2003; Schultz et al. 2003). These substances are now 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; De Silva and Mabury 2006; Kuklenyik et al. 

2004; Olsen et al. 2003b, 2003c, 2004b, 2004c, 2005, 2007a; Prevedouros et al. 2006). These findings 

have prompted efforts to reduce and even eliminate emissions of these substances from industrial process 

streams. 

In 2006, the eight major companies of the perfluoropolymer/perfluorotelomer industry agreed to 

participate in EPA's PFOA Stewardship Program (EPA 2008f). This included voluntary commitments 

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6. POTENTIAL FOR HUMAN EXPOSURE 

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 2008f). Progress reports were provided in 2007. Data from these 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 6-1. Total releases of these substances by these companies are uncertain since 

some of the data are listed as confidential business information. 

Prevedouros et al. (2006) estimated the total global historical emissions of perfluoroalkyl carboxylates 

into the environment from both direct and indirect sources. These data are provided in Table 6-2. 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), fluoropolymer manufacture (2,200– 

5,400 metric tons), and fluoropolymer processing (210–320 metric tons). Direct release of perfluoroalkyl 

carboxylates from use of aqueous fire fighting foams and consumer and industrial products were 

estimated to be 20–100 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). 

3M ceased production of PFOS and related chemicals in 2002 (3M 2008a; EPA 2008f). EPA has since 

established the significant new use rule to limit future manufacturing and importation of these substances 

(EPA 2002, 2007c, 2008f). Included on the current list are PFOS, PFHxS, PFOSA, and Et-PFOSAAcOH. Therefore, current industrial releases of these perfluoroalkyl sulfonates in the United States are 

expected to be negligible. Information regarding current releases of shorter-chain perfluoroalkyls that are 

not included under phase-out regulations, such as PFBA and PFBuS, have not been located. Production 

of PFBA in the United States appears to have ceased, although some is reportedly imported for 

commercial use (3M 2008a; Agency for Toxic Substances and Disease Registry 2008). 

6.2.1 Air 

There is no information listed in the TRI on releases of perfluoroalkyls to the atmosphere from 

manufacturing and processing facilities because these releases are not required to be reported within this 

program (EPA 1998). 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Reported Emissions of PFOA, PFOA Homologues, or PFOA
 

Precursors in Products from the 2006 U.S. Operations of
 

Fluoropolymer/Fluorotelomer Companies
 

Percent reduction 

in emissionsa 

Releases to all media Percent 

Releases to all from fluorotelomer reductions in total 

Company Chemicals 

media from 

fluorotelomer and 

telomer 

manufacturing (kg) 

and telomer 

manufacturing (kg of 

release/kg of product 

produced) 

quantity of 

chemical(s) 

released from 

baseline year 

Arkema, Inc. PFOA and higher >1,000–10,000 For fluorotelomer 22% 

homologues production: >0.1– 

1 kg/100 kg 

Precursors Not applicable Not applicable Not applicable 

Asahi Glass PFOA, PFOA salts, 4,922 For fluorotelomer 6% 

Company and higher production: 

homologues <1 kg/100 kg 

Precursors Not applicable Not applicable Not applicable 

Ciba Specialty PFOA 0.05 0.05 kg >99% 

Chemicals Higher 0.05	 0.05 kg >99% Corporation homologues
 

Precursors 0 kg 0 >99%
 

Clariant Not applicable Not applicable Not applicable Not applicable 

International 

Ltd. 

Daikin America, PFOA Confidential business	 For fluorotelomer 94% for FP 

Inc. information	 production: 8.0x10-3 production; 92% for 

kg/100 kg; for telomer telomer production 

production: 6.4x10-7 

kg/100 kg 

Precursors and Confidential business For telomer production: 22% for telomere 

higher homologues information 6.4x10-7 kg/100 kg production 

E.I. DuPont de PFOA, PFOA salts 1,100 Not reported 98% 

Nemours and Direct precursors Confidential business Not reported Confidential Company information business 

information 

3M/Dyneon PFOA 0 0 100% 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Reported Emissions of PFOA, PFOA Homologues, or PFOA
 

Precursors in Products from the 2006 U.S. Operations of
 

Fluoropolymer/Fluorotelomer Companies
 

Percent reduction 

in emissionsa 

Releases to all media Percent 

Releases to all from fluorotelomer reductions in total 

media from and telomer quantity of 

fluorotelomer and manufacturing (kg of chemical(s) 

telomer release/kg of product released from 

Company Chemicals manufacturing (kg) produced) baseline year 

Solvay Solexis PFOA and PFOA Not applicable Not applicable Not applicable 

salts
 

Higher >1,000–10,000 For fluorotelomer 28%
 

homologues production:
 

0.161 kg/100 kg 

Precursors Not applicable Not applicable Not applicable 

a

Percent 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 = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid 

Source: EPA 2008f 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Global Historical PFCA Production and Emissions Summarya 

Historical time Estimated total global 

Environmental input source period (years) historical PFCA emissions (t) 

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 fire fighting 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 impurities 1960–2002 20–130 

POSF-based precursor degradation 1960–2002 1–30 

POSF-based AFFF 1970–2002 3–30 

Fluorotelomer-based products 

PFCA residual impurities 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 

a

Low 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. 

AFFF = aqueous fire fighting foams; APFN = ammonium perfluorononanoate; APFO = ammonium 

perfluorooctanoate; PFCA = perfluorinated carboxylic acid; PFO = perfluorooctanoate; 

POSF = perfluorooctanesulfonyl fluoride 

Source: Prevedouros et al. 2006 

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PERFLUOROALKYLS 255 

6. POTENTIAL FOR HUMAN EXPOSURE 

According to 3M, PFOA was 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 air emissions of PFOA at this facility (3M 2008b). PFOA concentrations (75,000– 

900,000 pg/m3

) measured at the fence line of the DuPont Washington Works facility near Parkersburg, 

West Virginia in 2004 correlated with values modeled from wind speeds and trajectories surrounding this 

facility (Barton et al. 2006; Davis et al. 2007; Prevedouros et al. 2006). Based on current EPA regulations 

and information submitted by companies under EPA's PFOA Stewardship Program, industrial emissions 

of perfluoroalkyls to air are expected to be decreasing (EPA 2008f). 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 

2007d). 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 are 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. 

2004; Strynar and Lindstrom 2008). 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 may be 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. 

6.2.2 Water 

There is no information listed in the TRI on releases of perfluoroalkyls to water from manufacturing and 

processing facilities because these releases are not required to be reported within this program (EPA 

1998). 

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PERFLUOROALKYLS 256 

6. POTENTIAL FOR HUMAN EXPOSURE 

Waste water discharge is also indicated as a release pathway for ammonium perfluorooctanoate (APFO) 

from the DuPont Washington Works facility (Davis et al. 2007). The average monthly concentrations of 

APFO measured in surface water from three outlets at the Washington Works facility during 2007 and 

early 2008 ranged from 3.65 to 377 μg/L (EPA 2008i). 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. 

Discharge into Bakers Creek from the wastewater treatment plant at the 3M Decatur facility was 

considered to be a principal source of PFOA release from this facility (3M 2008b). Based on current EPA 

regulations and information submitted by companies under EPA's PFOA Stewardship Program, industrial 

emissions of perfluoroalkyls to water are expected to be decreasing (EPA 2008f). 

Levels of perfluoroalkyls measured in groundwater near fire-training areas are attributed to the use of 

these substances in aqueous fire-fighting foams (Moody and Field 1999; Moody et al. 2003). Use and 

disposal of perfluoroalkyl-containing consumer products is expected to be a source of release to water 

(Prevedouros et al. 2006). 

Both PFOA and PFNA were among the identified products of the aqueous photooxidation of 

8:2 fluorotelomer alcohol (Gauthier and Mabury 2005). Wang et al. (2005a, 2005b) measured PFOA as a 

product of the biodegradation of 8:2 fluorotelomer alcohol in an activated sludge inoculum. These results 

indicate that both aqueous photooxidation and biodegradation of fluorotelomer alcohols may result in the 

formation of perfluoroalkyl carboxylic acids in water. 

6.2.3 Soil 

There is no information listed in the TRI on releases of perfluoroalkyls to soil from manufacturing and 

processing facilities because these releases are not required to be reported within this program (EPA 

1998). 

Amounts of perfluoroalkyl compounds released to soil from industrial facilities were not located. 

Between 1978 and 1998, 3M disposed of PFOA-containing sludge from its waste water treatment plant at 

the Decatur Facility in Alabama through subsurface injection in on-site area fields (3M 2008b). The total 

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PERFLUOROALKYLS 257 

6. POTENTIAL FOR HUMAN EXPOSURE 

amount of sludge applied to the former sludge incorporation area during this time period was 

43,149 metric tons, dry weight. Sludge from the Decatur facility has also been disposed of at off-site 

landfills. During fluorochemical operations at its Cottage Grove facility in Minnesota, 3M disposed of 

perfluoroalkyl-containing waste at both on- and off-site locations (3M 2007b). Off-site disposal locations 

included the Washington County Landfill, the Oakdale Dump, and the Woodbury Disposal Site (3M 

2008a). Based on current EPA regulations and information submitted by companies under EPA's PFOA 

Stewardship Program, industrial emissions of perfluoroalkyls to soil are expected to be decreasing (EPA 

2008f). 

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; Wang et al. 2005a, 2005b). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Based on the low pKa values (<3) for the perfluoroalkyl carboxylic acids and sulfonic acids, these 

compounds are expected to exist primarily as anions in the environment (Kissa 2001; SPARC 2008). 

Volatilization of perfluoroalkyl anions such as perfluorooctanoate (PFO) from water surfaces is expected 

to be negligible since ions do not volatilize (Prevedouros et al. 2006). However, due to the surfactant 

nature of the perfluoroalkyl compounds, some of the amount released to water may form micelles and 

exist in the associated form despite the low pKa values of these substances (EPA 2005a; Prevedouros et 

al. 2006). Perfluoroalkyl compounds that associate on water and soil surfaces may volatilize into the 

atmosphere (EPA 2005a; Kim and Kannan 2007). The extrapolated vapor pressure of PFOA is 0.017 mm 

Hg at 20 °C, indicating that the neutral form of this substance is highly volatile (Barton et al. 2007). 

Barton et al. (2007) explored 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

. 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– 

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PERFLUOROALKYLS 258 

6. POTENTIAL FOR HUMAN EXPOSURE 

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). 

Estimated pKa values of 3.92 for Me- and Et-PFOSA-AcOH and 6.24 for PFOSA indicate that these 

compounds may exist partially in the undissociated form in the environment, especially under acidic 

conditions (SPARC 2008). Volatilization information are not available for these substances; however, a 

vapor pressure of 0.05 mm Hg at 25 °C for n-ethylperfluorooctane sulfonamide (Et-PFOSA) indicates 

that undissociated perfluoroalkyl sulfonamides may volatilize into the atmosphere (Martin et al. 2006). 

Assuming that wet and dry deposition is not important for gas-phase perfluoroalkyl sulfonamides and an 

atmospheric photooxidation lifetime of 20–50 days, Martin et al. (2006) concluded that perfluoroalkyl 

sulfonamides could possibly undergo long-range transport in the atmosphere. 

Koc values of 17–230 measured for perfluorooctanoate 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). Measurements of PFOA in soil and groundwater near a 

perfluoropolymer manufacturing facility indicate migration of air deposited ammonium 

perfluorooctanoate from surface soil to unsaturated subsurface soil to the aquifer (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 carboxylic acids and sulfonic acids have been widely detected in both environmental 

media and biota of the Arctic region (see Table 6-3) and other remote locations. The source of the 

perfluoroalkyl compounds at these locations is not clear. A number of source pathways for perfluoroalkyl 

compounds in these remote areas have been proposed and it is likely that the actual source is a 

combination of these (Barber et al. 2007; Prevedouros et al. 2006). 

One hypothesis is the long-range atmospheric transport of precursor compounds such as fluorotelomer 

alcohols and perfluoroalkyl sulfonamides followed by the atmospheric photooxidation of these substances 

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PERFLUOROALKYLS 259 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Biological Monitoring of PFOA and PFOS in the Arctic 

Concentration (ng/g) 

Location and organism PFOA PFOS Reference 

Northeastern Canada, 1996–2002; Tomy et al. 2004 

wet weight 

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 

Northern Canada, 1992–2002 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 weight Verreault et al. 2005, 2007 

Herring gull eggs <91–652 21,400–42,200 

Glaucous gulls 

Eggs (n=10) <0.70 104 

Plasma (n=20) <0.70–0.74 134 

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PERFLUOROALKYLS 260 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Biological Monitoring of PFOA and PFOS in the Arctic 

Concentration (ng/g) 

Location and organism PFOA PFOS Reference 

Nanavut, Canada Butt et al. 2007a, 2007b 

Thick-billed murres <MDLa–0.16 <0.40–0.76 

Northern fulmars <MDLa–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, Smithwick et al. 2005a 

1999–2002 

Polar bears (n>72) <2.3–57.1 263–3,770 

Greenland, 1999–2001 Smithwick et al. 2005b 

Polar bears (n=29) 10 2,470 

Greenland, 1972–2002 Smithwick et al. 2006 

Polar bears 1.6–4.4 120–1,400 

a

Minimum 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 = maximum detection limit; ND = not detected; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane 

sulfonic acid 

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PERFLUOROALKYLS 261 

6. POTENTIAL FOR HUMAN EXPOSURE 

to form perfluoroalkyl carboxylic acids and perfluoroalkyl sulfonic acids (Barber et al. 2007; D'eon et al. 

2006; Dinglasan-Panlilio and Mabury 2006; Ellis et al. 2004; Martin et al. 2006; Simcik 2005; Wallington 

et al. 2006; Wania 2007). Proponents of this hypothesis state that fluorotelomer alcohols and 

perfluoroalkyl sulfonamides are volatile enough and have long enough atmospheric residence times for 

long-range transport to be possible (Barber et al. 2007; Yarwood et al. 2007). The presence of 

fluorotelomer alcohols and perfluoroalkyl sulfonamides in urban and Arctic air offers evidence of longrange 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 (see Section 6.2.1). According to Young et al. (2007), the presence of perfluorodecanoic acid 

and perfluoroundecanoic acid in an Arctic ice cap indicate atmospheric oxidation as a source. 

A second hypothesis for the source of perfluoroalkyls in remote areas is direct oceanic transport of these 

substances (Armitage et al. 2006; Barber et al. 2007; Simcik 2005; Wania 2007; Yamashita et al. 2005, 

2008). This hypothesis is supported by the presence of perfluoroalkyl compounds measured in ocean 

water, analysis of ocean currents directed toward the Arctic Ocean, and elevated perfluoroalkyl 

concentrations measured in coastal waters near industrial regions (Armitage et al. 2006; Barber et al. 

2007; Prevedouros et al. 2006; Saito et al. 2003, 2004; Wania 2007; Wei et al. 2007a; Yamashita et al. 

2004, 2005, 2008). A third hypothesis is the transport of perfluoroalkyls in the form of marine aerosols 

(Barber et al. 2007; CEMN 2008; Prevedouros et al. 2006). This mechanism may be especially relevant 

for perfluoroalkyl compounds since surfactants have been shown to accumulate in upper sea layers and at 

water surfaces (Prevedouros et al. 2006). Although direct atmospheric transport of perfluoroalkyl 

carboxylic acids and sulfonic acids was initially discounted, some researchers are suggesting that this may 

be a contributing source pathway based on recent atmospheric measurements of these compounds in both 

the vapor phase and as particulates (Barber et al. 2007; Prevedouros et al. 2006). 

Perfluoroalkyls 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 

perfluoroalkyls in animals are measured in apex predators, such as polar bears (Table 6-3), 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). 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 

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PERFLUOROALKYLS 262 

6. POTENTIAL FOR HUMAN EXPOSURE 

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). 

6.3.2 Transformation and Degradation 

Perfluoroalkyl compounds are considered to be environmentally persistent chemicals (EPA 2008f; 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). 

6.3.2.1 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) 

reports a weak absorption band for PFOA that ranges 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. 

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 

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PERFLUOROALKYLS 263 

6. POTENTIAL FOR HUMAN EXPOSURE 

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. 

6.3.2.2 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 over pH 5, 7, and 

9 (OECD 2002, 2006b). Based on the data for PFOS and PFOA, hydrolysis is not expected to be an 

important degradation process for perfluorinated carboxylates and sulfonates in the environment. 

Hydrolysis data were not located for perfluoroalkyl sulfonamides. 

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PERFLUOROALKYLS 264 

6. POTENTIAL FOR HUMAN EXPOSURE 

Available information indicates that perfluoroalkyl compounds are resistant to aerobic biodegradation. 

PFOA and PFNA were not biodegraded during an OECD guideline 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. 

6.3.2.3 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 2008f; Hekster 

et al. 2003; OECD 2002, 2007; Prevedouros et al. 2006; Schultz et al. 2003). 

6.3.2.4 Other Media 

Data are not available regarding the transformation and degradation of perfluoroalkyl compounds in other 

media. 

6.4 LEVELS MONITORED OR ESTIMATED 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 

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. The analytical methods 

available for monitoring perfluoroalkyls in a variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Perfluoroalkyl levels have been measured in outdoor air at a few 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 6-4. 

***DRAFT FOR PUBLIC COMMENT*** 
 

)
 

)
 


 

/g in
 

n dust
 

)
 

,c 

0.26 0.21 

(0.13–0.42) (0.16–0.31) 

0.37 0.13 

(<0.12–0.81) (<0.12–0.40) 

— — 

— — 

— — 

8.2, 0.2 <26.6, 0.8 

0.87 0.12 

<0.001 <3.3 

1.6, 14.4b 0.9 

<0.6 0.3 

(ND–<0.6) (ND–0.5) 

ND <0.2 

(ND–0.3) 

— — 

Ki

20

Ki

20

Har

20

Har

20

Har

20

Bar

20

Bar

20

Bar

20

Bar

20

Ja

20

Ja

20

Bar

20

 

 

 

 

 

 

PERFLUOROALKYLS 265 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Concentrations of Perfluoroalkyl in Outdoor Air 

Mean (range) concentration (pg/m3) 

Location PFOA PFHpA PFNA Reference 

Urban 

Albany, New York 

Gas phase (n=8) 

Particulate phase (n=8) 

Oyamazaki, Japan (n=12) 

Fukuchiyama, Japan 

Morioka, Japan (n=8) 

Manchester, United 

Kingdom (n=2,1)a
 

Rural 

Kjeller, Norway (n=2) 

Mace Head, Ireland (n=4) 

Hazelrigg, United Kingdom 

(semi-rural) (n=10) 

Marine air 

Near Europe (northwest) 

(n=3) 

Near Africa (east coast) 

(n=5) 

Source dominated 

DuPont Washington 

Works Facility; 

Parkersburg, West Virginia 

(n=28) 

DuPont Washington 

Works Facility; 

Parkersburg, West Virginia 

(n=90) 

3.16 

(1.89–6.53

2.03
 

(0.76–4.19

262.7
 

(72–919);

3,412.8 ng

dust
 

15.2;
 

314 ng/g i

2.0
 

(1.59–2.58

341, 15.7

1.54
 

8.9
 

101, 552b

1.22 

(0.5–2.0) 

<0.5 

(ND–0.7) 

430,000 

(75,000– 

900,000)d

55,260 

(10–75,900) 

— — 

m and Kannan 

07 

m and Kannan 

07 

ada et al. 

05b 

ada et al. 

06 

ada et al. 

05b 

ber et al. 

07 

ber et al. 

07 

ber et al. 

07 

ber et al. 

07 

hnke et al. 

07a 

hnke et al. 

07a 

ton et al. 

06 

EPA 2007d 

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PERFLUOROALKYLS 266 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Concentrations of Perfluoroalkyl in Outdoor Air 

Mean (range) concentration (pg/m3) 

Location PFDeA PFUA PFDoA Reference 

Urban 

Albany, New York 

Gas phase (n=8) 0.63 <0.12 0.27 Kim and Kannan 

(0.24–1.56) (ND–0.16) (0.14–0.43) 2007 

Particulate phase 0.27 ND 0.12 Kim and Kannan 

(n=8) (0.13–0.49) (<0.12–0.38) 2007 

Oyamazaki, Japan (n=12) — — — Harada et al. 

2005b 

Fukuchiyama, Japan — — — Harada et al. 

2006 

Morioka, Japan (n=8) — — — Harada et al. 

2005b 

Manchester, UK (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 1.0, 8.3b 0.7 <0.01 Barber et al. 

(semi-rural) (n=10) 2007 

Marine air 

Near Europe (northwest) <0.6 ND <0.14 Jahnke et al. 

(n=3) (ND–0.6) (ND–0.17) 2007a 

Near Africa (east coast) ND 0.03 ND Jahnke et al. 

(n=5) (ND–0.2) 2007a 

Source dominated 

DuPont Washington — — — Barton et al. 

Works Facility – 2006 

Parkersburg, West Virginia 

(n=28) 

DuPont Washington — — — EPA 2007d 

Works Facility;
 

Parkersburg, West Virginia 

(n=90)
 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Concentrations of Perfluoroalkyl in Outdoor Air 

Mean (range) concentration (pg/m3) 

Location PFOS PFBuS PFHxS PFOSA Reference 

Urban 

Albany, New York 

Gas phase (n=8) 1.70 — 0.31 0.67 Kim and Kannan 

(0.94–3.0) (0.13–0.44) (0.22–2.26) 2007 

Particulate phase (n=8) 0.64 — <0.12 0.29 Kim and Kannan 

(0.35–1.16) (<0.12–0.79) 2007 

Oyamazaki, Japan (n=12) 5.2 — — — Harada et al. 

(2.51–-9.80); 2005b 

72.2 ng/g in 

dust 

Fukuchiyama, Japan 2.2; — — — Harada et al. 

46.0 ng/g in 2006 

dust 

Morioka, Japan (n=8) 0.7 — — — Harada et al. 

(0.46–1.19) 2005b 

Manchester, United 46, 7.1 2.2, <1.6 1.0, 0.1 <1.6, <0.2 Barber et al. 

Kingdom (n=2,1)a 2007 

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 1.6 2.6 0.04 0.2 Barber et al. 

(semi-rural) (n=10) 2007 

Marine air 

Near Europe (north west) 1.36 ND 0.12 ND Jahnke et al. 

(n=3) (0.4–2.5) (0.02–0.3) 2007a 

Near Africa (east coast) 0.544 ND 0.013 ND Jahnke et al. 

(n=5) (0.05–1.9) (ND–0.05) 2007a 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Concentrations of Perfluoroalkyl in Outdoor Air 

Mean (range) concentration (pg/m3) 

Location PFOS PFBuS PFHxS PFOSA Reference 

Source dominated 

DuPont Washington Works — — — — Barton et al. 

Facility, Parkersburg, West 2006 

Virginia (n=28) 

DuPont Washington — — — — EPA 2007d 

Works Facility; 

Parkersburg, West Virginia 

(n=90) 

a

Mean values were reported for separate sampling sessions.

b

The second concentration reported was measured during an earlier sampling session (n=2).
 c

A maximum PFOA concentration of 828 pg/m3 was measured in air at Hazelrigg, United Kingdom.
 d

Average and range of concentrations in 6 out of 28 samples that contained PFOA above the quantitation limit
 

(70,000–170,000 pg/m3

).
 

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
 

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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. 

PFOA concentrations were above the method quantitation limit (70,000–170,000 pg/m3

) in 6 out of 28 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). 

The reported concentrations in these six 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 2007d). 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. 

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 ng/L 

for PFNA, <8–22 pg/L for PFDeA, and <6–27 pg/L for PFUnA. 

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The concentration of PFOS measured in rainwater collected during a rain event in Winnipeg, Manitoba 

was 0.59 ng/L (Loewen et al. 2005). PFOA, PFNA, PFDA, 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. 

Very few studies of perfluoroalkyl concentrations in indoor environments are available (Table 6-5). 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 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 ng/m3 for PFNA, 3.4 ng/m3 in PFDeA, <1.3 ng/m3 

for PFUnA, and 1.2 ng/m3 for PFDoA (Barber et al. 2007). 

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, 

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. 

Atmospheric monitoring data were not located for PFBA, Me-PFOSA-AcOH, and Et-PFOSA-AcOH. 

***DRAFT FOR PUBLIC COMMENT*** 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Concentrations of Perfluoroalkyl in Indoor Air 

Mean (range) concentration 

Location 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 — — Kubwabo et al. 2005 

(<2.29–1,234); 

19.72 (median)a 

Japan (n=16) 380 — — Moriwaki et al. 2003 

(70–3,700); 

165 (median) 

North Carolina and 296 109 22.1 Strynar and 

Ohio (n=112) (<10.2–1960); 

142 (median)b 

(<12.5–1150); 

50.2 (median)b 

(<11.3–263); 

7.99 (median)b 

Lindstrom 2008 

Mean (range) concentration (pg/m3) 

Location 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 15.5 30.4 18.0 Strynar and 

Ohio (n=112) (<9.40–267); (<10.7–588); (<11.0–520); Lindstrom 2008 

6.65 (median)b 7.57 (median)b 7.78 (median)b 

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PERFLUOROALKYLS 272 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Concentrations of Perfluoroalkyl in Indoor Air 

Mean (range) concentration (pg/m3) 

Location	 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 NDa 391.96 <1.38a Kubwabo et al. 2005 

(<4.56–5,065); (<4.56– 

37.8 (median)a	 4,305); 

23.1 

(median)a 

Japan (n=16)	 200 — — — Moriwaki et al. 2003 

(11–2,500); 

24.5 (median)
 

North Carolina and 761 41.7 874 — Strynar and 

Ohio (n=112)	 (<8.93–12,100); (<12.5– (<12.9– Lindstrom 2008
 

201 (median)b 1150); 35,700);
 

9.11 45.5 

(median)b (median)b 

a

Method 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%).

b

Limit 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.
 

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
 

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6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.2 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; Kannan et al. 2005; Kim and Kannan 2007; 

Nakayama et al. 2007; Simcik and Dorweiler 2005; Sinclair et al. 2004, 2006). 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 (Kim and 

Kannan 2007; Nakayama et al. 2007; Simcik and Dorweiler 2005). Concentrations of perfluoroalkyls 

measured in surface water are listed in Tables 6-6 and 6-7. Reported concentrations of perfluoroalkyls in 

surface water samples are generally below 50 ng/L. 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. 

Levels of some perfluoroalkyl compounds measured in surface water and groundwater surrounding 

perfluorochemical industrial facilities are listed in Table 6-8. Maximum PFOS and PFOA concentrations 

measured in surface water downstream of the 3M Decatur, Alabama facility were 144 and 598 ng/L, 

respectively (Hansen et al. 2002). The average monthly concentrations of APFO measured in surface 

water from three outlets at the Washington Works facility during 2007 and early 2008 ranged from 

3.65 to 377 μg/L (EPA 2008i). 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. 

Levels of APFO and PFOA measured in groundwater samples collected from three wells at the 

Washington Works facility during 2007 and early 2008 were 2.9–100 and 2.8–100 μg/L, respectively 

(EPA 2008i). Information regarding background concentrations of perfluoroalkyls in groundwater in the 

United States has not been located. 

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 6-9. 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, 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Concentrations of PFOA and PFOS in Surface Water (ng/L) 

Concentration 

Location 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 1.5–3.4 

(median=35) 

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 ND–9.30 

(median=7.20) (median=2.88) 

Surface water runoff (n=14) 0.51–29.3 <0.25–14.6 

(median=3.80) (median=0.81) 

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 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Concentrations of PFOA and PFOS in Surface Water (ng/L) 

Concentration 

Location 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 

a

Detection limit is 0.05 ng/L 

ND = not detected; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid 

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Table 6-7. Concentrations of Other Perfluoroalkyls in Surface Water 

Concentration (ng/L) 

EtLocation PFOSA­

(reference)a PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA AcOH 

Great Lakes (Boulanger et al. 2004) 

Lake Ontario — — — — — — — — <0.3–10 

(n=8) 

Lake Erie (n=8) — — — — — — — — 3–11 

New York State waters (Sinclair et al. 2006) 

Onondaga — — — — — — 4.2–8.5 — —
 

Lake (n=3)
 

Erie Canal — — — — — — 2.5–5.6 — —
 

(n=3) 

Other lakes — — — — — — 0.9–2.8 — — 

and rivers 

Albany, New York (Kim and Kannan 2007) 

Lake water 1.15– ND– 0.25– ND– ND– — <0.25– <0.25 —
 

(n=11) 12.7 3.51 3.58 1.45 <0.25 4.05
 

Surface water <0.25– <0.25– ND–8.39 ND– ND–1.60 — ND– ND–2.14 —
 

runoff (n=14) 6.44 5.90 1.99 13.5 

Minnesota waters and Lake Michigan (Simcik and Dorweiler 2005) 

Remote (n=4)
 

Loiten 10 ND ND — — — — — —
 

Little Trout 4.8 ND ND — — — — — —
 

Nipisiquit 0.9 <0.3 ND — — — — — —
 

Tettegouche 3.1 ND ND — — — — — —
 

Urban (n=4) — — — — —
 

Calhoun 11 0.6 0.5 — — — — — —
 

Lake Harriet 2.6 ND ND — — — — — —
 

Lake of the 0.4 ND ND — — — — — —
 

Isles 

Minnesota 0.7 1.9 ND — — — — — — 

River 

Lake Michigan <0.6–4.1 <0.6– ND – — — — — — 

(n=4) 3.1 

Cape Fear Basin, North Carolina (Nakayama et al. 2007) 

80 Sites 

(n=100)
 

Mean 38.7 33.6 22.1 10.4 2.17 2.58 7.29 — —
 

Median 14.8 5.70 13.2 5.67 1.95 2.46 5.66 — —
 

Maximum 329 194 120 52.1 4.46 9.41 35.1 — —
 

Percent not 32.9 10.1 15.2 17.7 53.2 38.0 45.6 — —
 

detectedb 

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Table 6-7. Concentrations of Other Perfluoroalkyls in Surface Water 

Concentration (ng/L) 

EtLocation PFOSA­

(reference)a PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA AcOH 

Raisin and St. Clair Rivers, Michigan (Kannan et al. 2005) 

Raisin River — — — — — — <1 <10 — 

St. Clair River — — — — — — <1 <10 — 

(n=3) 

a

See Table 6-5 for numbers of samples collected at these locations. b

Detection limit = 0.05 ng/L
 

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
 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-8. Concentrations of Perfluoroalkyls in Surface Water and Groundwater at
 

Fluorochemical Industrial Facilities
 

Percent detection and concentration (μg/L) 

Location 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 2008i 

Percent detected 100% — — — — 

Minimum 2.8 — — — — 

Maximum 100 — — — — 

Surface water 

Outlets (n=4) EPA 2008i 

Percent detected 100% — — — — 

Minimum 2.3 — — — — 

Maximum 61 — — — — 

3M Cottage Grove Facility, Minnesota 

Groundwater 

Wells (n=1–7) 3M 2007 

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 2007 

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 2007 

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 2007 

Percent detected 14% 12% 0% 0% 0% 

Maximum 0.0501 0.0530 ND ND ND 

3M Decatur Facility, Alabama 

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Table 6-8. Concentrations of Perfluoroalkyls in Surface Water and Groundwater at
 

Fluorochemical Industrial Facilities
 

Percent detection and concentration (μg/L) 

Location PFOA PFBA PFOS PFHxS PFBuS Reference 

Groundwater 

Off-site groundwater (n=18) 3M 2008c 

Percent detected 94% — — — — 

Mean 1.87 — — — — 

Range 0.083–19.8 — — — — 

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 — — — — 

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 — — 

a

Analyte was reported as APFO. 

APFO = ammonium perfluorooctanoate; ND = not detected; PFBA = perfluorobutyric acid; PFBuS = perfluorobutane 

sulfonic acid; PFHxS = perfluorohexane sulfonic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic 

acid 

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PERFLUOROALKYLS 280 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-9. Concentrations of PFOA and PFOS in Ocean Water 

Concentration (pg/L) 

Location 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 

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) 673–5450 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 

PFHxS = perfluorohexane sulfonic acid; PFNA = perfluorononanoic acid; PFOA = perfluorooctanoic acid; 

PFOS = perfluorooctane sulfonic acid 

Source: Yamashita et al. 2005 

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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. 

Little information is available regarding the concentrations of perfluoroalkyl compounds in drinking 

water. The widespread presence of PFOA and PFOS detected in surface water in the United States 

indicates that drinking water taken from these sources may contain 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 range 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). Emmett et 

al. (2006a) reported an average PFOA concentration of 3.55 ng/mL in residential drinking water from the 

Little Hocking community, which is located across the Ohio River from the DuPont Washington Works 

Facility. According to the Agency for Toxic Substances and Disease Registry (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 were generally <2 ng/L at these locations. PFOS concentrations ranging from 0.1 to 4 ng/L were 

measured in tap water samples collected from the areas of Morioka City, Iwate, Tokyo, and Kyoto in 

Japan (Harada et al. 2003). Concentrations of 43.7 and 50.9 ng/L were measured in samples of tap water 

originating from the PFOS-contaminated Tama River. 

6.4.3 Sediment and Soil 

Background environmental levels of perfluoroalkyl compounds in sediment and soil were not located. 

Levels of some perfluoroalkyl compounds measured in soil and sediment surrounding perfluorochemical 

industrial facilities are listed in Table 6-10. PFOA was detected in most soil and sediment samples 

collected on- and off-site at the 3M Decatur facility in Alabama. 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 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 injected with PFOA-containing sludge. 

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 

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Table 6-10. Concentrations of Perfluoroalkyls in Soil and Sediment at
 

Fluorochemical Industrial Facilities
 

Percent detection and concentration (ng/g) 

Location 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 2007 

Percent detected 100% — 95% 90% 60% 

Maximum 21,800 — 104,000 3,470 139 

Fire training area (n=8–11) 3M 2007 

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 2007 

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 2007 

Percent detected 70% 44% 80% 28% 29% 

Maximum 341 124 79.0 11.5 29.4 

Mississippi River transect (n=38–40) 3M 2007 

Percent detected 18% 0% 82% 0% 0% 

Maximum 1.09 ND 3.16 ND ND 

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 — — — — 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-10. Concentrations of Perfluoroalkyls in Soil and Sediment at
 

Fluorochemical Industrial Facilities
 

Percent detection and concentration (ng/g) 

Location PFOA PFBA PFOS PFHxS PFBuS Reference 

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 — — — — 

a

Analyte was reported as APFO. 

APFO = ammonium perfluorooctanoate; ND = not detected; PFBA = perfluorobutyric acid; PFBuS = perfluorobutane 

sulfonic acid; PFHxS = perfluorohexane sulfonic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane 

sulfonic acid 

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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 PFBuA were only reported for soil in 

the fire training area; it was detected in 9 out of 11 samples from this location at 0.306–9.07 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 for 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, PFBuA, 

PFOS, PFHxS, and PFBuS were 341, 124, 79.0, 11.5, and 29.4 ng/g, respectively. PFHxS, PFBuS, and 

PFBuA 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. 

Limited monitoring data are available for the DuPont Washington Works Facility in West Virginia. 

Davis et al. (2007) reported that APFO was detected in 8 out of 22 boring samples collected at a site 

along the Ohio River opposite from the Washington Works Facility. Reported APFO concentrations 

ranged from <0.17 to 170 ng/g in these samples. 

6.4.4 Other Environmental Media 

Limited data are available regarding the concentrations of perfluoroalkyl compounds in food. One study 

has been located that analyzed foods in the United States for PFOS, PFOA, and PFOSA (3M 2001). 

During this study, over 200 food items were collected from grocery stores in three U.S. test cities having 

commercial perfluoroalkyl manufacturing or use and from grocery stores in three U.S. control cities that 

do not have this type of activity. Twelve samples contained perfluoroalkyls above the limit of 

quantification. Eight of the positive detections were collected in test cities. PFOSA was not detected in 

any of the food samples. PFOS was detected in four whole milk samples (0.573–0.852 ng/g) and 

3 ground beef samples (0.570–0.587 ng/g). PFOA was detected in two ground beef samples (0.504, 

1.09 ng/g), two bread samples (0.524, 14.7 ng/g), two apple samples (1.13, 2.35 ng/g), and one green 

bean sample (0.543 ng/g). The author’s state that concentration of 14.7 ng/g measured for PFOA in the 

one bread sample may have resulted from contamination. 

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 

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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 

0.98–2.7 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% 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). 

Limited data are available regarding the levels of perfluoroalkyls in food packaging; however, some 

measurement have been performed. 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, a sandwich wrapper, a French fry box, and soak-proof paper 

plates and did not find PFOA above the detection limit in these products. These paper products were not 

necessarily coated with fluorochemicals. The concentration of PFOA measured in undiluted perfluoro 

paper coating formulations ranged from 88,000 to 160,000 μg/kg (Begley et al. 2005). 

Washburn et al. (2005) measured the concentration of the perfluorooctanoate anion in fluorotelomer 

treated 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 

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6. POTENTIAL FOR HUMAN EXPOSURE 

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). 

PTFE is a fluoropolymer used in applications such as nonstick cookware coatings and plumbing sealant 

tape; PFOA has been used as a processing aid in the manufacture of PTFE (DuPont 2008). DuPont states 

that PFOA is removed from the fluoropolymer material during the baking and curing step of nonstick 

cookware coatings in a high temperature oven and that there may be trace amounts of residual PFOA in 

the final coatings (DuPont 2008). Begley et al. (2005) has 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 19–287 pg/cm2 measured using 

four 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). 

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 

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). 

6.5 GENERAL POPULATION AND OCCUPATIONAL 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 6-11 and 6-12 list concentrations of perfluoroalkyl compounds measured in serum 

samples collected from the general population in the United States. Mean PFOA, PFOS, and PFHxS 

serum concentrations reported in various studies from the United States were 2.1–9.6, 14.7–55.8, and 1.5– 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-11. Concentrations of PFOA and PFOS in Human Serum Collected in the
 

United States
 

Detection and concentration (ng/mL [ppb])a 

Location PFOA PFOS Reference 

U.S. residents—NHANES 

1999–2000 (n=1,562) Calafat et al. 2007a
 

Percent >LOD 100% 100%
 

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%
 

Geometric mean 3.9 20.7
 

95th percentile 9.8 54.6
 

U.S. residents	 Calafat et al. 2006b 

1990–2002 (n=23) 

Percent >LOD 100% 100%
 

Geometric mean 9.6 30.0
 

95th percentile 23.0 52.3
 

U.S. blood donors	 Olsen et al. 2003b 

2000–2001 (n=645)
 

Percent >LLOQ 100% 92.5%
 

Geometric mean 4.6 34.9
 

95th percentileb 12.1 88.5
 

Maximum 52.3 1,656.0
 

U.S. residents	 Olsen et al. 2003c 

(n=24)
 

Percent >LLOQ Not reported 98%
 

Geometric mean 2.5 14.7
 

Minimum <3.0 <6.1
 

Maximum 7.0 58.3
 

Midwestern United States	 De Silva and Mabury 2006 

2004–2005 (n=16)c
 

Percent detected 100% Not detected
 

Mean 4.4
 

Maximum 8.6
 

Minneapolis-St. Paul blood donors (plasma)	 Olsen et al. 2007b 

2005 (n=40)
 

Percent >LLOQ 95% 100%
 

Geometric mean 2.2 15.1
 

75th percentile 3.5 20.2
 

Maximum 4.7 36.9
 

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Table 6-11. Concentrations of PFOA and PFOS in Human Serum Collected in the
 

United States
 

Detection and concentration (ng/mL [ppb])a 

Location PFOA PFOS Reference 

Atlanta, Georgia Kuklenyik et al. 2004 

2003 (n=20)
 

Percent >LOD 100% 100%
 

Mean 4.9 55.8
 

Minimum 0.2 3.6
 

Maximum 10.4 164.0
 

Seattle, Washington elderly individuals Olsen et al. 2004c 

(n=238)
 

Percent >LLOQ 99.2% 99.5%
 

Geometric mean 4.2 31.0
 

95th percentileb 9.7 84.1
 

Maximum 16.7 175.0
 

Washington County, Maryland Olsen et al. 2005 

1974 (n=178)
 

Percent >LLOQ 71% 100%
 

Geometric mean 2.1 30.1
 

75th percentile 3.0 40.2
 

1989 (n=178)
 

Percent >LLOQ 99% 100%
 

Geometric mean 5.5 33.3
 

75th percentile 6.7 44.0
 

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.

b

Reported as bias-corrected estimates.
 c

One sample purchased separately with no origin information supplied.
 

LLOQ = lower limit of quanitification; LOD = limit of detection; PFOA = perfluorooctanoic acid;
 

PFOS = perfluorooctane sulfonic acid
 

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Table 6-12. Concentrations of Other Perfluoroalkyls in Human Serum Collected 

in the United States 

Detection and concentration (ng/mL [ppb])a 

Me- EtSample PFOSA PFOSA 

population PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA -AcOH -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% 

Geometric <0.4 0.5 <0.2 <0.2 <0.2 2.1 0.4 1.0 0.6 

mean 

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% 

Geometric <0.3 1.0 <0.3 <0.3 <1.0 <0.4 1.9 <0.2 <0.6 <0.4 

mean 

95th percentile 0.4 3.2 0.8 0.6 <1.0 <0.4 8.3 0.2 1.3 <0.4 

U.S. residents (Calafat et al. 2006b) 

1990–2002 

(n=23) 

Percent >LOD 0% 8.7% 0% 13% 0% — 91.3% 26.1% 13% 56.5% 

Geometric NA <0.3 NA <0.3 NA 1.6 <0.4 <0.6 <0.4 

mean 

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 >LLOQ — — — — — — 64% 2% 49% 58% 

Geometric 1.9 NR <1.8 <2.8 

mean 

95th percentileb 9.5 NR 5.0 7.6 

Maximum 66.3 NR 16.4 60.1 

U.S. residents (Olsen et al. 2003c) 

(n=24) 

Geometric — — — — — — 1.8 3.0 — — 

mean 

Minimum <1.2 <1.3 

Maximum 5.9 22.1 

Midwestern United States (De Silva and Mabury 2006) 

2004–2005 

(n=16) 

Percent — 100% 100% 13% 0% — — — — — 

detected 

Mean 0.77 0.17 NR NA 

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Table 6-12. Concentrations of Other Perfluoroalkyls in Human Serum Collected 

in the United States 

Detection and concentration (ng/mL [ppb])a 

Me- EtSample PFOSA PFOSA 

population PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA -AcOH -AcOH 

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% 

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 >LLOQ — — — — — — 76% "Few" 65% 52% 

Geometric 2.2 NR 1.2 <1.6 

mean 

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% 

Geometric 1.5 NA 0.5 1.2 

mean 

75th percentile 2.5 NA <1.0 1.8 

1989 (n=178) 

Percent >LLOQ — — — — — — 82% 0% 38% 93% 

Geometric 2.5 NA 0.8 3.6 

mean 

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 limit of detection or lower limit of quantification, a value between zero and the 

LOD or LLOQ was assigned when calculating the mean concentration.

b

Reported as bias-corrected estimates c

Arithmetic mean of positive concentrations 

Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; LLOQ = lower limit of quanitification; 

LOD = limit of detection; Me-PFOSA-AcOH = 2-(M-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 

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3.9 ng/mL, respectively. Mean concentrations of PFHpA, PFNA, PFDeA, PFUA, PFDoA, PFBuS, 

PFOSA, Me-PFOSA-AcOH, and Et-PFOSA-AcOH are generally <1 ng/mL in these studies. 

Biomonitoring data for PFBA in the general population have not been located. 

The widespread presence of perfluoroalkyl compounds in blood is well illustrated in studies by Calafat et 

al. (2007a, 2007b). These authors reported perfluoroalkyl levels in human serum collected during the 

1999–2000 and 2003–2004 periods of the National Health and Nutrition Examination Survey 

(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. Mean concentrations were slightly lower in the 2003–2004 survey 

for PFOA, PFOS, and PFHxS while PFNA levels were slightly higher. A more dramatic difference 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 widespread detection of perfluoroalkyl compounds in the blood of U.S. residents demonstrates that 

exposure of the general population to these substances is common. 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). 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 

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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 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 

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. (2008) assessed human exposure to perfluoroalkyls for adults in the general population of 

western countries. These authors determined 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. These authors 

concluded that the oral route, especially diet, was the primary route of exposure to perfluoroalkyls. 

Limited information has been located regarding pathways of human exposure to PFBA, PFHpA, PFNA, 

PFUnA, PFDoA, PFBuS, PFHxS, PFOSA, Me-PFOSA-AcOH, and Et-PFOSA-AcOH. 

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 (Agency for Toxic Substances 

and Disease Registry 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 

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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. 

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-per-fluorooctane sulfonamido) 

ethanol and 2-(N-ethyl-per-fluorooctane sulfonamido) ethanol, which have been 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 6-13. 3M has 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 ranges from 

3.2x10-6 to 2.4 ng/kg/day, with the highest estimated exposure corresponding to construction/utility 

workers engaged in projects that involve contact with soil from an onsite field. Individuals who perform 

jobs that require frequent contact with perfluoroalkyl containing products, such as fire fighters, waste 

handlers, and individuals who install and treat carpets, are 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). 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

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Table 6-13. Concentrations of PFOA, PFOS, and PFHxS in Human Serum for
 

Perfluoroalkyl Workers
 

Concentration (μg/mL [ppm]) 

Location PFOA PFOS PFHxS Reference 

Decatur, Alabama 

1993 (n=111) 0.00–80.00; — — Olsen et al. 1998 

89% <8.92 

1995 (n=80) 0.00–114.10; — — Olsen et al. 1998 

81% <8.20 

1995 (n=90) — 96% <6.00 — Olsen et al. 1999 

1997 (n=84) — 94% <6.00 — Olsen et al. 1999 

2000 (n=263) 1.78; 0.04–12.70 1.32; 0.06–10.06 — Olsen et al. 2003a 

1999–2004 (n=26)a Olsen et al. 2007a 

Initial 0.691 (0.072–5.1) 0.799 (0.145–3.49) 0.290 (0.016– 

1.30) 

Final 0.262 (0.017–2.44) 0.403 (0.037–1.74) 1.85 (0.01– 

0.791) 

Cottage Grove, Minnesota 

1993 (n=111) 0.00–80.00; — — Olsen et al. 2000 

88% <8.92 

1995 (n=80) 0.00–114.1; — — Olsen et al. 2000 

81% <8.20 

1997 (n=74) 0.05–81.35; — — Olsen et al. 2000 

85% <7.66 

2000 (n=122) 4.63 (0.01–92.03) 0.86 (0.03–4.79) — Olsen and Zobel 

2007 

Washington Works, Parkersburg, West Virginia 

2004–2005 Emmett et al. 

2006a 

No occupational 0.423 (0.175– — — 

exposure (n=312) 0.537)b 

Potential occupational 0.406 (0.168– — —
 

exposure (n=48) 0.623)b
 

Substantial 0.824 (0.422– — —
 

occupational exposure 0.999)b
 

(n=18)
 

Antwerp, Belgium 

1995 (n=88) — 75% <6.00 — Olsen et al. 1999 

1997 (n=65) — 86% <6.00 — Olsen et al. 1999 

2000 (n=255) 0.84 (0.01–7.04) 0.80 (0.04–6.24) — Olsen et al. 2003a 

a

Data include results from three retirees from the 3M plant in Cottage Grove, Minnesota.

b

Reported as the interquartile range. 

PFHxS = perfluorohexane sulfonic acid; PFOA = perfluorooctanoic acid; PFOS = perfluorooctane sulfonic acid 

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or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Perfluoroalkyl compounds have been detected in childhood serum samples, human breast milk, and 

umbilical cord blood; reported concentrations are listed in Tables 6-14 and 6-15. Measurements of 

perfluoroalkyl compounds in amniotic fluid, meconium, neonatal blood, or other tissues have not been 

located. 

A few studies are available that report serum levels of perfluoroalkyls measured in children. Calafat et al. 

(2007a, 2007b) reported perfluoroalkyl serum concentrations measured in 543–640 adolescents who make 

up the 12–19 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 from various locations in the United States who have been 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. 

Although mean serum concentrations of perfluoroalkyl compounds are reported to be similar for children 

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. This value is higher than biascorrected 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-PFOSAAcOH 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). 

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Table 6-14. Percent Detection and Levels of PFOA and PFOS in Children’s
 

Serum, Umbilical Cord Blood, and Breast Milk
 

Detection and concentration (ng/mL [ppb]) 

Location PFOA PFOS Reference 

Serum 

U.S. adolescents—NHANES (ages 12–19) 

1999–2000 (n=543) Calafat et al. 2007a 

Percent >LOD 100% 100% 

Geometric mean 5.5 29.1 

95th percentile 11.2 56.8 

2003–2004 (n=640) Calafat et al. 2007b 

Percent >LOD 99.7%a 99.9%a 

Geometric mean 3.9 19.3
 

95th percentile 8.6 42.2
 

U.S. children (ages 2–12) 

1994–1995 (n=598) Olsen et al. 2004b 

Percent >LLOQ 97–99% 100% 

Geometric mean 4.9 37.5 

95th percentileb 10 89 

Umbilical cord blood 

Baltimore THREE Study Apelberg et al. 2007a, 

2007b 

Cord serum (n=299)
 

Percent >LOD 100% 99%
 

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%
 

Median 3.4 7.3
 

Maternal plasma (n=11)
 

Percent detected 100% 100%
 

Median 2.6 13.0
 

Danish National Birth Cohort Fei et al. 2007 

Cord blood (n=50) 

Mean 3.7 11.0 

Maternal blood (n=200) 

Mean 4.5 29.9 

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Table 6-14. Percent Detection and Levels of PFOA and PFOS in Children’s
 

Serum, Umbilical Cord Blood, and Breast Milk
 

Detection and concentration (ng/mL [ppb]) 

Location PFOA PFOS Reference 

Japan Inoue et al. 2004b 

Cord serum (n=15)
 

Percent detected 0% 100%
 

Minimum <0.5 1.6
 

Maximum No data 5.3
 

Maternal serum (n=15)
 

Percent detected 20% 100%
 

Minimum <0.5 4.9
 

Maximum 2.3 17.6
 

Breast milk 

Massachusetts (n=45) Tao et al. 2008 

Milk
 

Percent >LOQ 89% 96%
 

Median 0.0361 0.106
 

Minimum <0.0301 <0.032
 

Maximum 0.161 0.617
 

Sweden (n=12) Kärrman et al. 2007a 

Milk
 

Percent >LOD 8%c 100%
 

Minimum <0.209 0.060
 

Maximum 0.492 0.470
 

Maternal serum
 

Percent >LOD 100% 100%
 

Minimum 2.4 8.2
 

Maximum 5.3 48.0
 

China (n=19) So et al. 2006b 

Percent >LOD 100% 100% 

Minimum 0.047 0.045 

Maximum 0.210 0.360 

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Table 6-14. Percent Detection and Levels of PFOA and PFOS in Children’s
 

Serum, Umbilical Cord Blood, and Breast Milk
 

Detection and concentration (ng/mL [ppb]) 

Location PFOA PFOS Reference 

Germany/Hungary (n=70) Völkel et al. 2008 

Percent >LOQ 16% 100% 

Minimum <0.200 0.028 

Maximum 0.460 0.639 

a

Percent detection for the adolescent age group was not specified for the 2003–2004 NHANES samples.
 

Percentages listed here are for the total sample population.

b

Reported as bias-corrected estimates.
 c

All 12 samples were above the detection limit (0.01 ng/mL); however, levels were only reported for one sample due 

to a high blank level for this substance (0.209 ng/mL).
 

LLOQ = lower limit of quantification; LOD = limit of detection; LOQ = limit of quantification; PFOA = perfluorooctanoic
 

acid; PFOS = perfluorooctane sulfonic acid
 

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Table 6-15. Percent Detection and Levels of Other Perfluoroalkyls in Children’s
 

Serum, Umbilical Cord Blood, and Breast Milk
 

Detection and concentration (ng/mL [ppb])a 

Me- EtPFOSA PFOSA 

Sample population PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA -AcOH -AcOH 

Serum 

U.S. NHANES (ages 12–19)
 

1999–2000 (n=543) (Calafat et al. 2007a)
 

Percent >LOD 10%a 96% 15% 12%a <1%a — 100% 100% 100% 98% 

Geometric — 0.5 <0.2 — — — 2.7 0.4 1.3 0.8 

mean 

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%a 98.8%a 31.3%a 9.7%a <0.1%a <0.4%a 98.3%a 22.2%a 27.5%a 3.4%a 

Geometric <0.3 0.9 <0.3 <0.3 <1.0 <0.4 2.4 <0.2 <0.6 <0.4 

mean 

95th percentile 0.5 2.7 0.7 <0.3 <1.0 <0.4 13.1 0.3 1.4 <0.4 

U.S. children (ages 2–12)
 

1994–1995 (n=598) (Olsen et al. 2004b)
 

Percent — — — — — — 85% 14% 77% 92% 

>LLOQ 

Geometric — — — — — — 4.5 <2.0 1.9 3.3 

mean 

95th — — — — — — 65 <2.0 12 10 

percentileb 

Umbilical cord blood 

Baltimore THREE Study (Apelberg et al. 2007a, 2007b) 

Cord serum (n=299) 

Percent >LOD 2% — 24% 34% 5% 3% — 26% 40% 1% 

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 

Japan (Inoue et al. 2004b) 

Cord serum 

(n=15) 

Percent — — — — — — — 0% — — 

detected 

Maternal serum (n=15) 

Percent — — — — — — — 0% — — 

detected 

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Table 6-15. Percent Detection and Levels of Other Perfluoroalkyls in Children’s
 

Serum, Umbilical Cord Blood, and Breast Milk
 

Detection and concentration (ng/mL [ppb])a 

Me- EtPFOSA PFOSA 

Sample population PFHpA PFNA PFDeA PFUA PFDoA PFBuS PFHxS PFOSA -AcOH -AcOH 

Breast milk 

Massachusetts (n=45) (Tao et al. 2008) 

Milk 

Percent >LOQ <1% 64% <1% <1% <1% <1% 51% — — — 

Minimum <0.010 <0.005 <0.007 <0.004 <0.004 <0.010 <0.012 — — — 

2 72 99 40 0 0 

Maximum 0.0234 0.0184 0.0111 0.0088 0.0097 0.0198 63.8 — — — 

4 4 

Sweden (n=12) (Karrman et al. 2007a) 

Milk 

Percent >LOD — 17% 0% 0% — — 100% 67% — — 

Minimum — <0.005 <0.008 <0.005 — — 0.031 <0.007 — — 

Maximum — 0.020 <0.008 <0.005 — — 0.172 0.030 — — 

Maternal serum — — — — 

Percent >LOD — 100% 100% 100% — — 100% 75% — — 

Minimum — 0.43 0.27 0.20 — — 1.8 <0.10 — — 

Maximum — 2.5 1.8 1.5 — — 11.8 0.49 — — 

China (n=19) (So et al. 2006b) 

Percent >LOD 37% 100% 100% 100% — 11% 100% — — — 

Minimum <0.005 0.01 0.0038 0.0091 — <0.001 0.004 — — — 

Maximum 0.0067 0.062 0.011 0.056 — 0.0025 0.10 — — — 

a

Percent detection for the adolescent age group was not specified for these samples. Percentages listed here are 

for the total sample population.

b

Reported as bias-corrected estimates.
 

Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid; LLOQ = lower limit of quantification;
 

LOD = limit of detection; Me-PFOSA-AcOH = 2-(M-methyl-perfluorooctane sulfonamide) acetic acid; ND = no data;
 

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
 

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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) states 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 postmarket carpet 

cleaning 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) assumes the same 

exposure pathways for children as were proposed for adults, but considers 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; 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 with the estimates for children under age 12, relative exposure 

pathways and uptake doses estimated for teenagers (12–20 years) were approximately the same as for 

adults. 

Tao et al. (2008) 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 PFBS were each detected in <1% of the samples. Perfluoroalkyls 

have also been measured in the human breast milk of individuals from Sweden, China, and Germany/ 

Hungary (Kärrman et al. 2007a; So et al. 2006b; Völkel et al. 2008). PFOS was detected in all samples 

while detection of PFOA ranged from 8–100% 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. 2007a; 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. 

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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. 2004b; 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. 2004b; Midasch et 

al. 2007). Inoue et al. (2004b) 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-PFOSAAcOH were detected most frequently (24, 34, 26, and 40%, respectively). Maximum concentrations in 

these samples ranged from 1.1 to 1.8 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. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Individuals who work at or are located near fluorochemical facilities 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). PFOA, PFOS, PFBA, PFBuS, 

and PFHxS have been detected in the municipal drinking water of some communities located near 

fluorochemical facilities (3M 2008c; Emmett et al. 2006a; Holzer et al. 2008; Agency for Toxic 

Substances and Disease Registry 2008; Wilhelm et al. 2008b). 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 the level in residential drinking water. 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 those over 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). 

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, may have higher 

levels of exposure to perfluoroalkyl compounds than the general population (Calafat et al. 2006a). 

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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 ranges from 0.011 to 260 ng/kg/day with the highest estimated exposure 

corresponding to children whose source of drinking water is groundwater adjacent to the southern side of 

the facility. 

6.8 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 health effects (and techniques for developing methods to determine 

such health effects) of perfluoroalkyls. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health 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. 

6.8.1 Identification of Data Needs 

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 end points are needed. Where determination of a particular 

end point is not possible, a thorough description of the physical and chemical properties as they relate to 

that end point would be helpful. 

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Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2006, became available in May of 2008. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

United States production volume ranges as of 2002 are available for PFOA, APFO (PFOA salt), PFBA, 

and PFOS (EPA 2008g). Production volume information for other perfluoroalkyls has not been located. 

Perfluoroalkyl production is expected to be declining since companies have begun phasing out these 

substances (EPA 2008f). Continued reporting on perfluoroalkyl production is expected to provide 

evidence of this decline. 

No information has been located regarding the import and export of perfluoroalkyl compounds. Uses of 

perfluoroalkyls are well described in the literature; no further information is needed (3M 1999; DuPont 

2008; EPA 2008f; Hekster et al. 2003; Schultz et al. 2003). 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; Agency for Toxic Substances and Disease Registry 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. 

Environmental Fate. Perfluoroalkyls are very stable compounds and are resistant to biodegradation, 

direct photolysis, atmospheric photooxidation, and hydrolysis (3M 2000; EPA 2008f; 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). Further study of the transport and fate of 

perfluoroalkyl compounds in the environment would be helpful in verifying these assumptions. 

Bioavailability from Environmental Media. Perfluoroalkyls are widely detected in humans and 

animals indicating that 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 

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6. POTENTIAL FOR HUMAN EXPOSURE 

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 study would be helpful (de Vos et al. 

2008). 

Food Chain Bioaccumulation. The highest concentrations of perfluoroalkyls 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. 2006a; Kannan et al. 2005; Smithwick et al. 2005a, 2005b, 2006). 

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. 

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. Limited 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; 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. Background concentrations of perfluoroalkyls in groundwater, drinking water, soil, and 

sediment have not been located and therefore are a data need. 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. 

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 

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6. POTENTIAL FOR HUMAN EXPOSURE 

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. Concentrations 

of perfluoroalkyls measured in urine have not been located. 

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. Limited data are available regarding the levels of 

perfluoroalkyls in young children (Olsen et al. 2004b). The recent NHANES surveys did not include 

perfluoroalkyl serum levels for children below 12 years of age (Calafat et al. 2007a, 2007b). Future 

NHANES efforts are scheduled to include children of ages 3–11 in the sample population (Calafat et al. 

2007a). 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. 2004b; Kärrman et al. 2007a; Midasch et al. 2007; So et al. 

2006b; Völkel et al. 2008). Additional monitoring for perfluoroalkyls in these media would be useful. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for perfluoroalkyls were located. This substance is not 

currently one of the compounds for which a sub-registry has been established in the National Exposure 

Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates 

the epidemiological research needed to assess adverse health outcomes that may be related to exposure to 

this substance. 

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6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2008) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. These 

studies are summarized in Table 6-16. 

As part of the EPA PFOA Stewardship Program, member companies have agreed 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. These companies have also agreed to 

provide progress reports to EPA on a regular basis. DuPont and 3M are currently working with EPA to 

develop thorough assessments of perfluoroalkyl environmental contamination and human exposure to 

these substances surrounding major fluorochemical facilities such as the Decatur, Alabama facility and 

the Washington Works facility (3M 2008a, 2008b, 2008c, 2008d; DuPont 2008; EPA 2008f). 

As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental 

Health Laboratory Sciences Division of the National Center for Environmental Health, Centers for 

Disease Control and Prevention, will be analyzing human blood samples for perfluoroalkyls. These data 

will give an indication of the frequency of occurrence and background levels of these compounds in the 

general population. 

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Table 6-16. Ongoing Studies on Perfluoroalkyls 

 

 

 

Investigator Affiliation Research description Sponsor 

Emmett EA University of 

Pennsylvania 

Assessment of exposure of residents in the 

Little Hocking Water Association district to 

perfluorooctanoate (C8). The area is near the 

DuPont Washington Works facility in 

Parkersburg, WV. The study will involve 

measurement of perfluorooctanoate in a 

sample of residents and identification of the 

relative importance of potential exposure 

National Institute of 

Environmental 

Health Sciences 

sources. 

Lee LS et al. Purdue 

University, 

Agronomy 

This study will include research on 

environmental degradation of fluorotelomer 

alcohols resulting in formation of 

perfluorocarboxylates. 

U.S. Department of 

Agriculture, HATCH 

Source: FEDRIP 2008 

PERFLUOROALKYLS 308 

6. POTENTIAL FOR HUMAN EXPOSURE 

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The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring perfluoroalkyls, their metabolites, and other biomarkers of exposure and 

effect to perfluoroalkyls. The intent is not to provide an exhaustive list of analytical methods. Rather, the 

intention is to identify well-established methods that are used as the standard methods of analysis. Many 

of the analytical methods used for environmental samples are the methods approved by federal agencies 

and organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). 

Other methods presented in this chapter are those that are approved by groups such as the Association of 

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower 

detection limits and/or to improve accuracy and precision. 

Although analytical methods sensitive to ppt/ppb levels have been developed for detecting perfluoroalkyls 

in biological and environmental media, these methods have not yet been standardized (Longnecker et al. 

2008; van Leeuwen et al. 2006). No methods approved by federal agencies and organizations were 

located for perfluoroalkyl compounds. As part of EPA's PFOA Stewardship Program, member 

companies have agreed to "work with EPA, other PFOA Stewardship Program participants, and others in 

order to establish scientifically credible analytical standards and laboratory methods for measuring the 

chemicals in the program by 2010" (EPA 2008f). This effort will be useful for ensuring accuracy and 

reproducibility across studies monitoring for perfluoroalkyls. Analytical techniques currently in use are 

summarized in the following sections (Longnecker et al. 2008; van Leeuwen et al. 2006). 

7.1 BIOLOGICAL MATERIALS 

Detection of individual perfluoroalkyls in biological materials was not possible until the 1980s, when 

methods were developed based on gas chromatographic (GC) techniques (Belisle and Hagen 1980; 

Kärrman et al. 2005). These techniques, however, required derivitization of the analytes to methyl esters 

or other moieties (Belisle and Hagen 1980; Flaherty et al. 2005; Kärrman et al. 2005; Kudo et al. 1998). 

This involved complex and tedious sample preparation and resulted in low sensitivity. The introduction 

of high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (MS/MS) 

allowed for more sensitive determination of individual perfluoroalkyls in biological materials and much 

simpler sample preparation (Flaherty et al. 2005; Hansen et al. 2001; Kärrman et al. 2005; Ohya et al. 

1998). Most perfluoroalkyl detection methods currently in use are forms of HPLC-MS/MS (van Leeuwen 

et al. 2006). Methods of sample preparation used for perfluoroalkyls have included solvent extraction, 

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7. ANALYTICAL METHODS 

ion-pair extraction, solid-phase extraction, and column-switching extraction (Flaherty et al. 2005). 

Analytical methods for detecting perfluoroalkyls in biological materials are listed in Table 7-1. 

Calafat et al. (2007a, 2007b) reported a summary of the method that was developed to measure 

perfluoroalkyls in NHANES serum samples. Serum samples were stored at -70 °C prior to analysis. 

Serum samples (1 mL) were then analyzed using automated solid phase extaction coupled to reversedphase HPLC-MS/MS. The limits of detection, accuracy, and precision determined for the perfluoroalkyl 

analytes were 0.1–1.0 μg/L, 84–135%, and 10–26%, respectively. 

Kuklenyik et al. (2004) described a method for measuring perfluoroalkyls in human breast milk samples. 

The milk samples were stored at -40 °C. Sample preparation included combining 3 mL of 0.1 M formic 

acid, 50 μL of internal standard solution, and 1 mL of milk. This solution was then analyzed using 

automated solid-phase extraction followed by HPLC-MS/MS. Limits of detection, recovery, and 

accuracy reported for the perfluoroalkyl analytes ranged from 0.1–1.0 μg/L, 26–102%, and 70–118%, 

respectively. 

One of the greatest challenges with regard to trace-level analysis of perfluoroalkyl compounds is avoiding 

sample contamination (Flaherty et al. 2005; Longnecker et al. 2008; Van Leeuwen et al. 2006; Yamashita 

et al. 2004). Perfluoroalkyl compounds may be present at trace levels in reagents, labware, sample 

collection implements, and instrumentation; therefore, these items must be carefully screened prior to 

analysis to avoid contamination. 

7.2 ENVIRONMENTAL SAMPLES 

As with biological matrices, methods developed for analysis of perfluoroalkyls in environmental samples 

such as air, water, and soil are primarily based on HPLC-MS/MS technology (Harada et al. 2006; Jahnke 

et al. 2007b; Kubwabo et al. 2005; Schroder 2003; Schultz et al. 2006; Taniyasu et al. 2005; Tseng et al. 

2006; Washington et al. 2008; Yamashita et al. 2004). Some studies have measured perfluoroalkyls in air 

samples using GC-MS (Barber et al. 2007; Barton et al. 2006; Martin et al. 2002). Available methods 

report sensitivities of low pg/m3 levels in air, high pg/L to low ng/L levels in water, and high pg/g to low 

ng/g levels in soil (Jahnke et al. 2007b; Martin et al. 2002; Schultz et al. 2006; Taniyasu et al. 2005; 

Washington et al. 2008) 

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Samples

Sample 

matrix Preparation method 

Detection 

method Analytes 

Sample 

detection 

limit 

Percent 

recovery Reference 

Human 

Plasma 

Solvent extraction, 

derivatization with 

diazomethane 

GC-ECD PFOA 15 ng/mL 97–113% Belisle and 

Hagen 1980 

Human 

Urine 

Solvent extraction, 

derivatization with 

diazomethane 

GC-ECD PFOA 1.5 ng/mL 100% Belisle and 

Hagen 1980 

Rat and 

monkey 

liver 

Homogenization, 

solvent extraction, 

derivatization with 

diazomethane 

GC-ECD PFOA 0.145 uM/5 

g liver 

(60 ppb) 

98% Belisle and 

Hagen 1980 

Rat liver Homogenization, 

solvent extraction, 

derivatization with 

GC-ECD PFOA, PFNA, 

PFDeA 

40–60 μg/g 

liver 

30–60% Kudo et al. 

1998 

diazomethane 

Rat liver Homogenization, ion 

pair extraction using 

tetrabutylammonium 

ion, derivatization with 

3-bromoacetyl-7­

methoxycoumarin 

HPLC-FD PFHpA, PFOA, 

PFNA, PFDeA 

50 pmol/50 

mg liver 

92–98% Ohya et al. 

1998 

Human 

serum 

Ion pair extraction 

using 

tetrabutylammonium 

hydrogen sulfate 

HPLCESMSMS PFOS, PFOA, 

PFHxS, 

PFOSA 

1–3 ng/mL 85–101% Hansen et al. 

2001 

Human 

serum, milk 

Automated solidphase extraction HPLCMS/MS PFOSA, MePFOSA-AcOH, 

Et-PFOSAAcOH, PFHxS, 

PFOS, PFHpA, 

PFOA, PFNA, 

PFDeA, PFUA, 

PFDoA 

0.1– 

1.0 ng/mL 

(serum); 

0.1– 

1.0 ng/mL 

(milk) 

30–91% 

(serum); 

26–89% 

(milk) 

Kuklenyik et al. 

2004 

Human 

plasma 

Centrifugation, 

Column-switching 

extraction, 

backflushing into 

analytical column 

LC-ESIMS/MS PFOS, PFOA, 

PFOSA 

0.05– 

0.25 ng/mL 

82.2– 

98.7% 

Inoue et al. 

2004a 

Human 

plasma 

Protein precipitation 

using acetonitrile, 

LC-IT-MS PFOS, PFOA, 

PFHpA 

0.2– 

0.5 ng/mL 

NR Holm et al. 

2004 

Table 7-1. Analytical Methods for Determining Perfluoroalkyls in Biological


 

extraction via large 

volume injection 

capillary column 

switching, 

backflushing into 

analytical column 

PERFLUOROALKYLS 311 

7. ANALYTICAL METHODS 

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Table 7-1. Analytical Methods for Determining Perfluoroalkyls in Biological
 

Samples
 

Sample 

Sample Detection detection Percent 

matrix Preparation method method Analytes limit recovery Reference 

Human Protein precipitation LC-MS/MS PFOA 0.5 ng/mLa 91–109% Flaherty et al. 

serum/ using acetonitrile in a 2005 

plasma column arrayed in a 

96-well plate format 

Human Treatment with formic LC-MSD PFBuS, 0.1–2 ng/mL 26–112% Kärrman et al. 

whole acid, sonication, solid PFHxS, PFOA, 2005 

blood phase extraction PFOS, PFNA, 

PFDeA, 

PFOSA, PFUA, 

PFDoA 

Human Samples collected in HPLC- PFBuS, 5–10 ng/mLa 93.2– Ehresman et 

whole heparin or EDTA, MS/MS PFHxS, PFOS, 99.7% al. 2007 

blood solid phase extraction PFOA 

a

Limit of quantitation 

GC = gas chromatography; ECD = electron capture detection; EDTA = ethylenediamine tetraacetic acid; 

ESMSMS = negative ion electrospray tandem mass spectrometry; HPLC-FD = high performance liquid 

chromatography with fluorescence detection; Et-PFOSA-AcOH = 2-(N-ethyl-perfluorooctane sulfonamide) acetic 

acid; LC-ESI-MS = liquid chromatography with electrospray mass spectrometry; LC-IT-MS = liquid chromatography 

coupled to electrospray ionization mass spectrometry; LC-MSD = liquid chromatography coupled to mass 

spectrometric detector; Me-PFOSA-AcOH = 2-(M-methyl-perfluorooctane sulfonamide) acetic acid; MS = mass 

spectrometry; 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 

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7.3 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 health effects (and techniques for developing methods to determine 

such health effects) of perfluoroalkyls. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health 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. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. The presence of perfluoroalkyls in blood and other human biological matrices are biomarkers 

of exposure to these substances. The presence of some perfluoroalkyls in the blood may also be the result 

of exposure to precursor compounds. For example, PFOSA, Me-PFOSA-AcOH, and Et-PFOSA-AcOH 

are expected to be oxidized in the body to form PFOS (Olsen et al. 2005; Seacat and Luebker 2000). 

Exposure to 8–2 fluorotelomer alcohol may result in the formation of PFOA as a metabolite within the 

body (Fasano et al. 2006; Henderson and Smith 2007; Kudo et al. 2005; Nabb et al. 2007). 

Analytical methods that identify perfluoroalkyl compounds in blood or other biological matrices are 

available; however, these have not been standardized. Two studies have been performed that assessed 

interlaboratory variability in the analysis of perfluoroalkyls. According to Longnecker et al. (2008), 

assays of identical plasma specimens from six different laboratories were relatively precise. However, 

van Leeuwen et al. (2006) stated that 38 laboratories were not able to produce consistent data when 

analyzing for perfluoroalkyls in provided samples of human plasma, whole blood, fish muscle tissue, and 

fish liver extract, although agreement was better for the human matrices than for the fish matrices. These 

authors suggested that laboratories need to address poor extraction efficiency, suitability of external 

calibration, suitability of native perfluorinated compounds as internal standards, quality of standards used, 

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7. ANALYTICAL METHODS 

matrix effects, and selectivity of MS/MS technique. Both interlaboratory studies concluded that 

standardized methods are needed for the analysis of perfluoroalkyls (Longnecker et al. 2008; 

van Leeuwen et al. 2006). 

Effect. There are no known biomarkers of effect for perfluoroalkyl compounds. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. As mentioned for analytical methods for measuring perfluoroalkyls in biological materials, 

standardization is needed for methods for measuring these substances in environmental media as well. 

According to van Leeuwen et al. (2006), 38 laboratories were not able to produce consistent data when 

analyzing for perfluoroalkyls in provided samples of water. 

7.3.2 Ongoing Studies 

As part of PFOA stewardship program, EPA and member companies have agreed to develop analytical 

standards for measured the perfluoroalkyl chemicals included within the program by 2010. Lynne 

Petterson of the U.S. EPA is leading an ongoing study to develop analytical methods to investigate human 

exposures to compounds including some perfluoroalkyls, such as PFOS and PFOA (FEDRIP 2008). No 

other ongoing studies regarding analytical methods for measuring perfluoroalkyls in biological materials 

or environmental media were located. 

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MRLs are substance specific estimates, which are intended to serve as screening levels, are used by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. 

ATSDR did not derive MRLs for perfluoroalkyl compounds based on lack of adequate human data and 

uncertainties related to the appropriateness of using animal data for human risk assessment. The EPA has 

not derived a reference dose (RfD) or reference concentration (RfC) for perfluoroalkyl compounds and 

has not classified perfluoroalkyls as to their carcinogenicity (IRIS 2008). 

Perfluoroalkyl compounds are included on the chemical imports and exports regulations (EPA 2008d) and 

significant new uses of chemical substances, whereas manufacturers are required to follow the regulations 

including: chemical substance and significant new uses subject to reporting; industrial, commercial, and 

consumer activities; protection in the workplace; hazard communication program; disposal; releases to 

water; and recordkeeping (EPA 2008d). 

OSHA has not required employers of workers who are occupationally exposed to perfluoroalkyl 

compounds to institute engineering controls and work practices to maintain employee exposure to a 

minimum. 

Perfluoroalkyl compounds are among the chemicals nominated to the National Toxicology Program 

(NTP) for in-depth toxicological evaluation for carcinogenesis testing in fiscal years 1988–2003 (NTP 

2005). 

The international and national regulations and guidelines regarding perfluoroalkyls in air, water, and other 

media are summarized in Table 8-1. 

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8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations, Advisories, And Guidelines Applicable to Perfluoroalkyls 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification No data IARC 2008 

WHO Air quality guidelines No data WHO 2000 

Drinking water quality guidelines No data WHO 2004 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) No data 

EPA AEGL-1, -2, and -3a No data EPA 2007a 

Hazardous air pollutant No data EPA 2007b 

NIOSH REL (10-hour TWA) No data 

OSHA PEL (8-hour TWA) for general No data OSHA 2007 

industry 29 CFR 1910.1000, 

Table Z-1 

b. Water 

EPA Drinking water standards and health 

advisories (provisional) 

Perfluorooctanoic acid 0.4 μg/L EPA 2009 

Perfluorooctane sulfonate 0.2 μg/L EPA 2009 

National primary and secondary No data EPA 2003 

drinking water standards 

National recommended water quality No data EPA 2006b 

criteria 

c. Food 

FDA Bottled drinking water No data FDA 2007 

21 CFR 165.110 

EAFUSb No data FDA 2008 

d. Other 

ACGIH Carcinogenicity classification No data 

EPA Carcinogenicity classification No data 

RfC No data 

RfD No data 

Chemical imports and exports Yes EPA 2008a 

regulations 40 CFR 707 

Master Testing Listc No data EPA 2008c 

Significant new uses of chemical Yesd EPA 2008d 

substances 40 CFR 721 

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8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations, Advisories, And Guidelines Applicable to Perfluoroalkyls 

Agency Description	 Information Reference 

NATIONAL (cont.) 

EPA Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous No data EPA 2008b 

substance 40 CFR 302.4 

EPA Superfund, emergency planning, and 

community right-to-know 

Effective date of toxic chemical No data EPA 2008e 

release reporting 40 CFR 372.65 

NTP	 Chemicals nominated to the NTP for NTP 2005 

in-depth toxicological evaluation for 

carcinogenesis testing in fiscal years 

1988–2003 

Perfluorobutane sulfonic acid Yes 

Pefluorodecanoic acid Yes 

Perfluorohexane sulfonic acid Yes 

Perfluorooctane sulfonic acid Yes 

Perfluorooctanoic acid Yes 

STATE 

Minnesota Groundwater regulations Minnesota Department 

Health risk limitse of Health 2007 

Perfluorooctanoic acid 0.3 μg/L 

Perfluorooctane sulfonic acid 0.3 μg/L 

Toxicologic end pointf 

Perfluorooctanoic acid Liver, hematologic 

system, developmental 

effects, and immune 

system 

Perfluorooctane sulfonic acid Liver and thyroid 

New Jersey Drinking-water guidance value New Jersey 

Department of Perfluorooctanoic acid 0.04 ppb Environmental 

Protection 2007 

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8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations, Advisories, And Guidelines Applicable to Perfluoroalkyls 

Agency Description Information Reference 

STATE (cont.) 

Washington Persistent Bioaccumulative Toxins Washington State 

rule Department of Ecology 

Perfluorooctane sulfonic acid Yes 2006 

a

AEGLs are intended to describe the risk to humans resulting from once-in-a-lifetime, or rare, exposure to airborne 

chemicals (EPA 2007a).

b

The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food 

additives or listed or affirmed as GRAS. 

c

OPPT uses a "Master Testing List" (MTL) since 1990 to establish its TSCA Existing Chemical Testing Program 

agenda. The MTL presents a consolidated listing of OPPT's Existing Chemical Testing Program priorities. The main 

purposes of the MTL are to (1) identify chemical testing needs of the Federal Government (including EPA) and 

relevant international organizations (e.g., OECD); (2) focus limited EPA resources on the highest priority chemical 

testing needs; (3) publicize the testing priorities for industrial chemicals; (4) obtain broad public input on OPPT's 

TSCA Chemical Testing Program and its priorities; and (5) encourage voluntary initiatives by the U.S. chemical 

industry to fill the priority data needs that are identified on the MTL (EPA 2008c).

d

Under Section 40 CFR 721, manufacturers are required to follow the regulations for chemical substances with 

significant new uses: Chemical substance and significant new uses subject to reporting; industrial, commercial, and 

consumer activities; protection in the workplace; hazard communication program; disposal; releases to water; and 

recordkeeping (EPA 2008d). 

e

A Health Risk Limit is an exposure value for a concentration of a groundwater contaminant, expressed in μg/L, that 

can be safely consumed daily for a lifetime.

f

The Toxicologic End point indicates the organ or organ system that is most sensitive to the contaminant. 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels; 

CERCLA = Comprehensive Environmental Response, Compensation, and Liability Act; CFR = Code of Federal 

Regulations; EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency; 

FDA = Food and Drug Administration; GRAS = Generally Recognized As Safe; IARC = International Agency for 

Research on Cancer; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology 

Program; OECD = Organisation for Economic Co-operation and Development; OPPT = Office of Pollution Prevention 

and Toxics; OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; 

REL = recommended exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose; 

TLV = threshold limit values; TSCA = Toxic Substances Control Act; TWA = time-weighted average; WHO = World 

Health Organization 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

_______________________ 

PERFLUOROALKYLS 319 

9. 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. Enviromental Protection Agency's Admistrative Record. OPPT2002-0043-0005. 

*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. 

*3M. 2007b. Remedial investigation report. Phase 2. Fluorochemical (FC) data assessment report for 

the Cottage Grove, MN site. 3M Company. 

*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. 2008d. Future data needs assessment report. 3M Decatur, Alabama Facility PFOA Site-Related 

Environmental Monitoring Program. St. Paul, MN: 3M Company. 

*3M. 2008e. U.S. locations. 3M. 

http://solutions.3m.com/wps/portal/3M/en_US/our/company/information/US-locations/. July 10, 2008. 

+*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. 

*Abdellatif A, Al-Tonsy AH, Awad ME, et al. 2004. Peroxisomal enzymes and δhydroxydeoxyguanosine 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. 

* Cited in text 

+ Cited in supplemental document 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

PERFLUOROALKYLS 320 

9. REFERENCES 

Adinehzadeh M, Reo NV. 1998. Effects of peroxisome proliferators on rat liver phospholipids: 

Sphingomyelin degradation may be involved in hepatotoxic mechanism of perfluorodecanoic acid. Chem 

Res Toxicol 11(5):428-440. 

Adinehzadeh M, Reo NV, Jarnot BM, et al. 1999. Dose-response hepatotoxicity of the peroxisome 

proliferator, perfluorodecanoic acid and the relationship to phospholipid metabolism in rats. Toxicology 

134:179-195. 

*Adinolfi M. 1985. The development of the human blood-CSF-brain barrier. Dev Med Child Neurol 

27(4):532-537. 

*Adlercreutz H. 1995. Phytoestrogens: Epidemiology and a possible role in cancer protection. Environ 

Health Perspect Suppl 103(7):103-112. 

*Agency for Toxic Substances and Disease Registry. 1989. Decision guide for identifying substancespecific data needs related to toxicological profiles; Notice. Agency for Toxic Substances and Disease 

Registry, Division of Toxicology. Fed Regist 54(174):37618-37634. 

*Agency for Toxic Substances and Disease Registry. 1990. Biomarkers of organ damage or dysfunction 

for the renal, hepatobiliary, and immune systems. Subcommittee on Biomarkers of Organ Damage and 

Dysfunction. Atlanta, GA: Agency for Toxic Substances and Disease Registry. 

*Agency for Toxic Substances and Disease Registry. 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. 

*Agency for Toxic Substances and Disease Registry. 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. 

*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. 

Alsarra IA, Brockmann WG, Cunningham ML, et al. 2006. Hepatocellular proliferation in response to 

agonists of peroxisome proliferator-activated receptor alpha: A role for kupffer cells? J Cardiogr 5:26. 

*Altman PL, Dittmer DS. 1974. Biological handbooks: Biology data book. Vol. III. 2nd ed. Bethesda, 

MD: Federation of American Societies for Experimental Biology, 1987-2008, 2041. 

*Andersen ME, Krishnan K. 1994. Relating in vitro to in vivo exposures with physiologically based 

tissue dosimetry and tissue response models. In: Salem H, ed. Animal test alternatives: Refinement, 

reduction, replacement. New York, NY: Marcel Dekker, Inc., 9-25. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PERFLUOROALKYLS 321 

9. REFERENCES 

*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, Gargas ML, et al. 1987. Physiologically based pharmacokinetics and the 

risk assessment process for methylene chloride. Toxicol Appl Pharmacol 87(2):185-205. 

*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. 

*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. 

Arand M, Coughtrie MWH, Burchell B, et al. 1991. Selective induction of bilirubin UDP-glucuronosyltransferase by perfluorodecanoic acid. Chem Biol Interact 77:97-105. 

*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. 

*Austin ME, Kasturi BS, Barber M, et al. 2003. Neuroendocrine effects of perfluorooctane sulfonate in 

rats. Environ Health Perspect 111(12):1485-1489. 

Badr MZ, Birnbaum LS. 2004. Enhanced potential for oxidative stress in livers of senescent rats by the 

peroxisome proliferator-activated receptor alpha agonist perfluorooctanoic acid. Mech Ageing Dev 

125(1):69-75. 

*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. 

*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. 

*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. 

*Belisle H, Hagen DF. 1980. A method of the determination of perfluorooctanoic acid in blood and 

other biological samples. Anal Biochem 101:369-376. 

*Berger GS, ed. 1994. Epidemiology of endometriosis. In: Endometriosis: Advanced management and 

surgical techniques. New York, NY: Springer-Verlag, 3-7. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 322 

9. REFERENCES 

Berthiaume J, Wallace KB. 2002. Perfluorooctanoate, perflourooctanesulfonate, and N-ethyl 

perfluorooctanesulfonamido ethanol; peroxisome proliferation and mitochondrial biogenesis. Toxicol 

Lett 129:23-32. 

Betts K. 2007a. PFOS and PFOA in humans: New study links prenatal exposure to lower birth weight. 

Environ Health Perspect 115(11):A550-A551. 

Betts KS. 2007b. Perfluoroalkyl acids: What is the evidence telling us? Environ Health Perspect 

115(5):A250-A256. 

+*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. 

Bojes HK, Thurman RG. 1994. Peroxisomal proliferators inhibit acyl CoA synthetase and stimulate 

protein kinase C in vivo. Toxicol Appl Pharmacol 126:233-239. 

*Bookstaff RC, Moore RW, Ingall GB, et al. 1990. Androgenic deficiency in male rats treated with 

perfluorodecanoic acid. Toxicol Appl Pharmacol 104:322-333. 

Booth B. 2006. Can drugs found in water harm humans? Environ Sci Technol 40(7):2072-2078. 

Borges T, Glauert HP, Chen L, et al. 1990. Effect of the peroxisome proliferator perfluorodecanoic acid 

on growth and lipid metabolism in Sprague Dawley rats fed three dietary levels of selenium. Arch 

Toxicol 64:26-30. 

Borges T, Glauert HP, Robertson LW. 1993a. Perfluorodecanoic acid noncompetitively inhibits the 

peroxisomal enzymes enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase. Toxicol Appl 

Pharmacol 118:8-15. 

Borges T, Peterson RE, Pitot HC, et al. 1993b. Effect of the peroxisome proliferator perfluorodecanoic 

acid on the promotion of two-stage hepatocarcinogenesis in rats. Cancer Lett 72:111-120. 

Borges T, Robertson LW, Peterson RE, et al. 1992. Dose-related effects of perfluorodecanoic acid on 

growth, feed intake and hepatic peroxisomal beta-oxidation. Arch Toxicol 66(1):18-22. 

*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. 

Boujrad N, Vidic V, Gazouli M, et al. 2000. The peroxisome proliferator perfluorodecanoic acid inhibits 

the peripheral-type benzodiazepine receptor (PBR) expression and hormone-stimulated mitochondrial 

cholesterol transport and steroid formation in Leydig cells. Endocrinology 141(9):3137-3148. 

Boulanger B, Peck AM, Schnoor JL, et al. 2005a. Additions and corrections: Mass budget of 

perfluorooctane surfactants in Lake Ontario. Environ Sci Technol 39(6):1920. 

Boulanger B, Peck AM, Schnoor JL, et al. 2005b. Mass budget of perfluorooctane surfactants in Lake 

Ontario. Environ Sci Technol 39:74-79. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PERFLUOROALKYLS 323 

9. REFERENCES 

*Boulanger B, Vargo J, Schnoor JL, et al. 2004. Detection of perfluorooctane surfactants in Great Lakes 

water. Environ Sci Technol 38:4064-4070. 

Braune BM, Outridge PM, Fisk AT, et al. 2005. Persistent organic pollutants and mercury in marine 

biota of the Canadian Arctic: An overview of spatial and temporal trends. Sci Total Environ 351-352:4­

56. 

+*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. 

+*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, Gaylor DW, Moore JA. 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, Olsen GW, Pfahles-Hutchens A. 2006. The applicability of biomonitoring data for 

perfluorooctanesulfonate to the environmentalpPublic health continuum. Environ Health Perspect 

114:1776-1782. 

*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. 

*C8 Science Panel. 2008. Community study summary. The studies at a glance. C8 Science Panel. 

http://www.c8sciencepanel.org/studies.html. August 12, 2008. 

Cai Y, Nelson BD, Li R, et al. 1996. Thyromimetic action of the peroxisome proliferators clofibrate, 

perfluorooctanoic acid, and acetylsalicylic acid includes changes in mRNA levels for certain genes 

involved in mitochondrial biogenesis. Arch Biochem Biophys 325(1):107-112. 

Cain DJ, Luoma SN, Wallace WG. 2004. Linking metal bioaccumulation of aquatic insects to their 

distribution patterns in a mining-impacted river. Environ Toxicol Chem 23(6):1463-1473. 

*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

PERFLUOROALKYLS 324 

9. REFERENCES 

*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. 

*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. 

*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. 

*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 [Epub ahead of print]. 

Chang S, Thibodeaux JR, Eastvold ML, et al. 2007. Negative bias from analog methods used in the 

analysis of free thyroxine in rat serum containing perfluorooctanesulfonate. Toxicology 234(1-2):21-33. 

+*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. 

*ChemIDplus. 2008. Perfluoroalkyls. ChemIDplus. Bethesda, MD: U.S. National Library of Medicine. 

http://sis.nlm.nih.gov/chemical.html. July 10, 2008. 

Chen H, Huang C, Wilson MW, et al. 1994. Effect of the peroxisome proliferators ciprofilbrate and 

perfluorodecanoic acid on hepatic cell Sprague-Dawley rats. Carcinogenesis 15(12):2847-2850. 

Chen L, Borges T, Glauert HP, et al. 1990. Modulation of selenium-dependent glutathione peroxidase by 

perfluorodecanoic acid in rats: Effect of dietary selenium. J Nutr 120:298-304. 

Chen L, Tatum V, Glauert HP, et al. 2001. Peroxisome proliferator perfluorodecanoic acid alters 

glutathione and related enzymes. J Biochem Mol Toxicol 15(2):107-113. 

Chinje E, Kentish P, Jarnot B, et al. 1994. Induction of the CYP4A subfamily by perfluorodecanoic acid: 

The rat and the guinea pig as susceptible and non-susceptible species. Toxicol Lett 71(1):69-75. 

*Clewell HJ, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. Toxicol 

Ind Health 1(4):111-131. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 325 

9. REFERENCES 

+*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. 

Corton CJ, Lapinskas PJ, Gonzalez FJ. 2000. Central role of PPARa in the mechanism of action of 

hepatocarcinogenic peroxisome proliferators. Mutat Res 448:139-151. 

*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. 

*Das KP, Grey BE, Zehr RD, et al. 2008. Effects of perfluorobutyrate exposure during pregnancy in the 

mouse. Toxicol Sci [Epub ahead of print] 

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 41:4799-4805. 

*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. 

*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. 

*Daikin. 2007. Elimination of PFOA in fluorochemical products. Daikin Industries, Ltd. 

http://www.daikin.com/press/2007/071221/press_20071221.pdf. May 11, 2009. 

Dauwe T, Van de Vijver K, De Coen W, et al. 2007. PFOS levels in the blood and liver of a small 

insectivorous songbird near a fluorochemical plant. Environ Int 33:357-361. 

*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. 

Davis JW, Vanden Heuvel JP, Peterson RE. 1991. Effects of perfluorodecanoic acid on de novo fatty 

acid and cholesterol synthesis in the rat. Lipids 26:857-859. 

*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. 

Derbel M, Hosokawa M, Satoh T. 1996. Differences in the induction of carboxylesterase RL4 in rat liver 

microsomes by various perfluorinated fatty acides, metabolically inert derivatives of fatty acides. Biol 

Pharm Bull 19(5):765-767. 

De Silva AO, Mabury SA. 2004. Isolating isomers of perfluorocarboxylates in polar bears (Ursus 

maritimus) from two geographical locations. Environ Sci Technol 38:6538-6545. 

*De Silva AO, Mabury SA. 2006. Isomer distribution of perfluorocarboxylates in human blood: 

Potential correlation to source. Environ Sci Technol 40:2903-2909. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 326 

9. REFERENCES 

Deubner D, Kelsh M, Shum M, et al. 2001. Beryllium sensitization, chronic beryllium disease, and 

exposures at a beryllium mining and extraction facility. Appl Occup Environ Hyg 16(5):579-592. 

*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, 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. 

Diaza MJ, Chinje E, Kentish P, et al. 1994. Induction of cytochrome P4504A by the peroxisome 

proliferator perfluoro-n-octanoic acid. Toxicology 86:109-122. 

Dillert R, Bahnemann D, Hidaka H. 2007. Light-induced degradation of perfluorocarboxylic acids in the 

presence of titanium dioxide. Chemosphere 67(4)785-792 

*Dinglasan-Panlilio MJA, Mabury SA. 2006. Significant residual fluorinated alcohols present in various 

fluorinated materials. Environ Sci Technol 40:1447-1453. 

*Dupont. 2008. Information on PFOA. http://repanet.de/PFOA2/en_US/index.html. April 07, 2008. 

*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. 

*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 27:225-3321. 

*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. 

EPA. 1990. Interim methods for development of inhalation reference concentrations. Washington, DC: 

U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Office of 

Research and Development, Environmental Criteria and Assessment Office. EPA600890066A. 

*EPA. 1997. Special report on environmental endocrine disruption: An effects assessment and analysis. 

Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum. EPA630R96012. 

*EPA. 1998. Automated Form R for Windows user’s guide (RY97). Washington, DC: U.S. 

Environmental Protection Agency, Office of Pollution Prevention and Toxics. 

*EPA. 2002. Perfluoroalkyl sulfonates; significant new use rule. U.S. Environmental Protection 

Agency. Fed Regist 67(236):72854-72867. 

*EPA. 2003. National primary drinking water standards. Washington, DC: U.S. Environmental 

Protection Agency, Office of Ground Water and Drinking Water. EPA816F03016. 

http://www.epa.gov/safewater/mcl.html. March 07, 2006. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PERFLUOROALKYLS 327 

9. REFERENCES 

*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. 2006a. 2006 edition of the drinking water standards and health advisories. Washington, DC: 

U.S. Environmental Protection Agency, Office of Water. EPA822R06013. 

http://www.epa.gov/waterscience/criteria/drinking/dwstandards.pdf. April 11, 2007. 

*EPA. 2006b. National recommended water quality criteria. Washington, DC: U.S. Environmental 

Protection Agency, Office of Water, Office of Science and Technology. 

http://www.epa.gov/waterscience/criteria/nrwqc-2006.pdf. January 08, 2008. 

*EPA. 2006c. 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.p 

df. April 24, 2008. 

*EPA. 2007a. Acute exposure guideline levels (AEGLs). Washington, DC: Office of Pollution 

Prevention and Toxics, U.S. Environmental Protection Agency. 

http://www.epa.gov/oppt/aegl/pubs/compiled.pdf. April 24, 2008. 

*EPA. 2007b. The Clean Air Act amendments of 1990 list of hazardous air pollutants. Clean Air Act. 

U.S. Environmental Protection Agency. United States Code. 42 USC 7412. 

http://www.epa.gov/ttn/atw/orig189.html. April 24, 2008. 

*EPA. 2007c. Perfluoroalkyl sulfonates; significant new use rule. U.S. Environmental Protection 

Agency. Fed Regist 72:57222-57235. 

*EPA. 2007d. 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-OPPT-2004­

0113. May 18, 2009. 

*EPA. 2008a. Chemical imports and exports. U.S. Environmental Protection Agency. Code of Federal 

Regulations. 40 CFR 707. http://www.epa.gov/lawsregs/search/40cfr.html. May 23, 2008 

*EPA. 2008b. Designation of hazardous substances. U.S. Environmental Protection Agency. Code of 

Federal Regulations. 40 CFR 302.4. 

*EPA. 2008c. Master testing list. Washington, DC: Office of Pollution Prevention and Toxics, U.S. 

Environmental Protection Agency. http://www.epa.gov/opptintr/chemtest/pubs/mtl.htm. April 24, 2008. 

*EPA. 2008d. Significant new uses of chemical substances. U.S. Environmental Protection Agency. 

Code of Federal Regulations. 40 CFR 721. http://www.epa.gov/lawsregs/search/40cfr.html. May 23, 

2008. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

PERFLUOROALKYLS 328 

9. REFERENCES 

*EPA. 2008e. Toxic chemical release reporting. Chemicals and chemical categories to which this part 

applies. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 372.65. 

http://www.epa.gov/lawsregs/search/40cfr.html. April 24, 2008. 

*EPA. 2008f. Perfluorooctanoic acid (PFOA). U.S. Environmental Protection Agency. 

http://www.epa.gov/oppt/pfoa/. May 29, 2008. 

*EPA. 2008g. 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. 2008h. Perfluoroalkyls. Substance registry system. U.S. Environmental Protection Agency. 

http://www.epa.gov/srs/. July 10, 2008. 

*EPA. 2008i. 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-OPPT-2004­

0113. May 18, 2009. 

*EPA. 2009. Provisional health advisories for perfluorooctanoic acid (PFOA) and perfluorooctane 

sulfonate (PFOS). U.S. Environmental Protection Agency. 

http://media.timesfreepress.com/docs/2009/01/EPA_provisional_health_advisory_PFOA.pdf. May 19, 

2009. 

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. 

Ericson I, Marti-Cid R, Nadal M, et al. 2008. Human exposure to perfluorinated chemicals through the 

diet: Intake of perfluorinated compounds in foods from the Catalan (Spain) market. J Agric Food Chem 

56:1787-1794. 

Fairley KJ, Kearns S, Myers LP, et al. 2005. Augmentation of ovalbumin-induced IGE and airway 

hyperreactivity response by perfluorooctanoic acid (PFOA) [Abstract]. Toxicol Sci 84:248. 

+*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. 

Falandys ZJ, Taniyasu S, Gulkowska A, et al. 2006. Is fish a major source of fluorinated surfactants and 

repellents in humans living on the Baltic Coast? Environ Sci Technol 40:748-751. 

Falandyse J, Taniyasu S, Yamashita N, et al. 2007. Perfluorinated compounds in some terrestrial and 

aquatic wildlife species from Poland. J Environ Sci Health Part A 42(6):715-719. 

*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PERFLUOROALKYLS 329 

9. REFERENCES 

*FDA. 2007. Beverages. Bottled water. U.S. Food and Drug Administration. Code of Federal 

Regulations. 21 CFR 165.110. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm. 

April 24, 2008. 

*FDA. 2008. EAFUS: A food additive database. U.S. Food and Drug Administration. 

http://vm.cfsan.fda.gov/~dms/eafus.html. April 24, 2008. 

*FEDRIP. 2008. Perfluoroalkyls. Federal Research in Progress database. Springfield, VA: National 

Technical Information Service. 

*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. 

*Flaherty JM, Connolly PD, Decker ER, et al. 2005. Quantitative determination of perfluorooctanoic 

acid in serum and plasma by liquid chromatography tandem mass spectrometry. J Chromatogr B Biomed 

Sci Appl 819:329-338. 

*Fomon SJ. 1966. Body composition of the infant: Part I: The male reference infant. In: Falkner F, ed. 

Human development. Philadelphia, PA: WB Saunders, 239-246. 

*Fomon SJ, Haschke F, Ziegler EE, et al. 1982. Body composition of reference children from birth to 

age 10 years. Am J Clin Nutr 35(Suppl 5):1169-1175. 

*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. 

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, 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. 2008. Perfluorinated compounds-exposure assessment for 

the general population in western countries. Int J Hyg Environ Health [Epub ahead of print]. 

+*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PERFLUOROALKYLS 330 

9. REFERENCES 

*Fuentes S, Vicens P, Colomina MT, et al. 2007b. Behavioral effects in adult mice exposed to 

perfluorooctane sulfonate (PFOS). Toxicology 242:123-129. 

*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. 

*Gauthier SA, Mabury SA. 2005. Aqueous photolysis of 8:2 fluorotelomer alcohol. Environ Toxicol 

Chem 24(8):1837-1846. 

*George ME, Andersen ME. 1986. Toxic effects of nonadecafluoro-n-decanoic acid in rats. Toxicol 

Appl Pharmacol 85:169-180. 

*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 enzyhmes, lipoproteins, and 

cholesterol: A study of occupationally exposed men. Am J Ind Med 29(5):560-568. 

*Giwercman A, Carlsen E, Keiding N, et al. 1993. Evidence for increasing incidence of abnormalities of 

the human testis: A review. Environ Health Perspect Suppl 101(2):65-71. 

Glauert HP, Hong JT, Leung LK, et al. 1996. Role of eicosanoid metabolism in carcinogenesis by 

peroxisome proliferators. Ann N Y Acad Sci 804:719-721. 

Glauert HP, Srinivasan S, Tatum VL, et al. 1992. Effects of the peroxisome proliferators ciprofibrate and 

perfluorodecanoic acid on hepatic cellular antioxidants and lipid peroxidation in rats. Biochem 

Pharmacol 43(6):1353-1359. 

Glaza SM. 1997. Acute oral toxicity study of T-6669 in rats (OECD guidelines). Corning Hazleton Inc. 

Godin CS, Myhr BC, Lawlor TE, et al. 1992. Assessment of the potential genotoxicity of 

perfluorodecanoic acid and chlorotrifluoroethylene trimer and tetramer acids. Fundam Appl Toxicol 

18:557-569. 

*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. 

Goecke CM, Jarnot BM, Reo NV. 1994. Effects of the peroxisome proliferator perfluoro-n-decanoic 

acid on hepatic gluconeogenesis and glycogenesis: A 13C NMR investigation. Chem Res Toxicol 7:15­

22. 

*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. 

Goecke-Flora CM, Wyman JF, Jarnot BM, et al. 1996. Effect of the peroxisome proliferator perfluoro-ndecanoic acid on glucose transport in the isolated perfused rat liver. Chem Res Toxicol 8:77-81. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

PERFLUOROALKYLS 331 

9. REFERENCES 

*Gortner EG, Lamprecht EG, Case MT. 1982. Oral teratology study of T-3141CoC in rabbits. St. Paul, 

MN: Riker Laboratories, Inc. 

Goss K. 2008. The pKa values of PFOA and other highly fluorinated carboxylic acids. Environ Sci 

Technol 42:456-458. 

+*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, Grey BE, Thibodeaux J, et al. 2002. Critical period for increased nenonatal mortality 

induced by perfluorooctane sulfonate (PFOS) in the rat [Abstract]. Toxicologist 66(Suppl 1):25. 

Grasty RC, Roberts N, Grey BE, et al. 2004. Perfluorooctane sulfonate (PFOS) alters lung development 

in the neonatal rat. Toxicologist 78(1-S):394. 

+*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. 

Griesbacher T, Pommer V, Schuligoi R, et al. 2008. Anti-inflammatory actions of perfluorooctanoic acid 

and peroxisome proliferator-activated receptors (PPAR) α and γ in experimental acute pancreatitis. Int 

Immunopharmacol 8:325-329. 

+*Griffith FD, Long JE. 1980. Animal toxicity studies with ammonium perfluorooctanoate. Am Ind 

Hyg Assoc J 41(8):576-583. 

Guruge KS, Taniyasu S, Yamashita N, et al. 2005. Perfluorinated organic compounds in human blood 

serum and seminal plasma: A study of urban and rural tea worker populations in Sri Lanka. J Environ 

Monit 7:371-377. 

*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. 

*Gutshall DM, Pilcher GD, Langley AE. 1988. Effects of thyroxine supplementation on the response to 

perfluoro-n-decanoic acid (PFDA) in rats. J Toxicol Environ Health 24(4):491-498. 

*Gutshall DM, Pilcher GD, Langley AE. 1989. Mechanism of the serum thyroid hormone lowering 

effect of perfluoro-n-decanoic acid PFDA in rats. J Toxicol Environ Health 28(1):53-66. 

*Guzelian PS, Henry CJ, Olin SS, eds. 1992. Similarities and differences between children and adults: 

Implications for risk assessment. Washington, DC: International Life Sciences Institute Press. 

*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

PERFLUOROALKYLS 332 

9. REFERENCES 

*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. 

Handler JA, Seed CB, Bradford BU, et al. 1992. Induction of peroxisomes by treatment with 

perfluorooctanoate does not increase rates of H2O2 production in intact liver. Toxicol Lett 60:61-68. 

*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, Clemen LA, Ellefson ME, et al. 2001. Compound-specific, quantitative characterization of 

organic fluorochemicals in biological matrices. Environ Sci Technol 35:766-770. 

*Hansen KJ, Johnson HO, Eldridge JS, et al. 2002. Quantitative characaterization of trace levels of 

PFOS and PFOA in the Tennessee River. Environ Sci Technol 36:1681-1685. 

*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, Koizumi A, Saito N, et al. 2007. Historical and geographical aspects of the increasing 

perfluorooctanoate and perfluorooctane sulfonate contamination in human serum in Japan. Chemosphere 

66:293-301. 

*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 K, Saito N, Inoue K, et al. 2004. The influence of time, sex and geographic factors on levels of 

perfluorooctane sulfonate and perfluorooctanoate inhuman serum over the last 25 years. J Occup Health 

46:141-147. 

*Harada K, Saito N, Sasaki K, et al. 2003. Perfluorooctane sulfonate contamination of drinking water in 

the Tama River, Japan: Estimated effects oon resident serum levels. Bull Environ Contam Toxicol 

71(1):31-36. 

Harada K, Xu F, Ono K, et al. 2005c. Effects of PFOS and PFOA on L-type Ca2+ currents in guinea-pig 

ventricular myocytes. Biochem Biophys Res Commun 329:487-494. 

+*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 Nematol 13:723-726. 

Harrison EH, Lane JS, Luking S, et al. 1988. Perfluoro-n-decanoic acid: Induction of peroxisomal poxidation by a fatty acid with dioxin-like toxicity. Lipids 23:115-119. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 333 

9. REFERENCES 

*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. 

*HazDat. 2008. Perfluoroalkyls. HazDat Database: ATSDR’s Hazardous Substance Release and Health 

Effects Database. Atlanta, GA: Agency for Toxic Substances and Disease Registry. 

http://www.atsdr.cdc.gov/hazdat.html. May 1, 2008. 

Hebert GM, Odom MA, Craig PS, et al. 2002. Method for the determination of sub-ppm concentrations 

of perfluoroalkylsulfonate anions in water. J Environ Monit 4:90-95. 

*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. 

Henderson WM, Weber EJ, Smith MA. 2005. Maternal distribution and fetal transfer of 8-2 

fluorotelomer alcohol and its oxidation metabolites. Teratology Society platform sessions abstracts. 

Conference: Fortieth Annual Meeting Teratology Society, Palm Beach, Florida, 24 June 2000 to 29 June 

2000. Teratology Society. 

Henwood SM. 1997. 5 Daily dose oral toxicity study with T-6669 in rats. [Unpublsihed study] 3M. 

Higgins CP, Field JA, Criddle CS, et al. 2005. Quantitative determination of perfluorochemicals in 

sediments and domestic sludge. Environ Sci Technol 39:3946-3956. 

Higgins CP, McLeod PB, MacManus-Spencer LA, et al. 2007. Bioaccumulation of perfluorochemicals 

in sediments by the aquatic Oligochaete lumbriculus variegatus. Environ Sci Technol 41:4600-4606. 

*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. 

*Hoberman AM, York RG. 2003. Oral (gavage) combined repeated dose toxicity study of T-7706 with 

the reproduction/developmental toxicity screening test. Argus Research. 

Hodgson MJ, Van Thiel DH, Lauschus K, et al. 1989. Liver injury tests in hazardous waste workers: 

The role of obesity. J Occup Med 31(3):238-242. 

*Hoel DG, Davis DL, Miller AB, et al. 1992. Trends in cancer mortality in 15 industrialized countries, 

1969-1986. J Natl Cancer Inst 84(5):313-320. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

PERFLUOROALKYLS 334 

9. REFERENCES 

*Holm A, Wilson SR, Molander P, et al. 2004. Determination of perfluorooctane sulfonate and 

perfluorooctanoic acid in human plasma by large volume injection capillary column switching liquid 

chromatography coupled to electrospray ionization mass spectrometry. J Sep Sci 27:1071-1079. 

Holmström KE, Järnberg U, Bignert A. 2005. Temporal trends of PFOS and PFOA in Guillemot eggs 

from the Baltic Sea, 1968-2003. Environ Sci Technol 39:80-84. 

*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. 

*Hori H, Hayakawa E, Einaga H, et al. 2004. Decomposition of environmentally persistent 

perfluorooctanoic acid in water by photochemical approaches. Environ Sci Technol 38:6118-6124. 

*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. 

House M, Balmer BC, Brandsma S, et al. 2006. Perfluoroalkyl compounds in relation to life-history and 

reproductive parameters in bottlenose dolphins (Tursiops truncatus) from Sarasota Bay, Florida, USA. 

Environ Toxicol Chem 25(9):2405-2412. 

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 Sprague-Dawley 

rats in vivo. Toxicol Sci 68(2):429-426. 

*Hu W, Jones PD, Celius T, et al. 2005. Identification of genes responsive to PFOS using gene 

expression profiling. Environ Toxicol Pharmacol 19:57-70. 

Hu Wy, Jones PD, DeCoen W, et al. 2003. Alterations in cell membrane properties caused by 

perfluorinated compounds. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 135:77-88. 

Huang C, Wilson MW, Lay LT, et al. 1994. Increased 8-hydroxydeoxyguanosine in hepatic DNA of rats 

treated with the peroxisome proliferators ciprofibrate and perfluorodecanoic acid. Cancer Lett 87:223­

228. 

*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

PERFLUOROALKYLS 335 

9. REFERENCES 

IARC. 1995. IARC technical publication no. 24. Peroxisome proliferation and its role in carcinogenesis. 

Lyon, France: International Agency for Research on Cancer. World Health Organization. 

http://monographs.iarc.fr/ENG/Publications/techrep24/IARCrep24.pdf. June 26, 2007. 

*IARC. 2008. Agents reviewed by the IARC monographs: Volumes 1-99. Lyon, France: International 

Agency for Research on Cancer. http://monographs.iarc.fr/ENG/Classification/index.php. April 24, 

2008. 

*ICRP. 1994. Human respiratory tract model for radiological protection. International Commission on 

Radiological Protection. Pergamon Press, Oxford. 

+*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. 

*Inoue K, Okada F, Ito R, et al. 2004a. Determination of perfluorooctane sulfonate, perfluorooctanoate 

and perfluorooctane sulfonylamide in human plasma by column-switching liquid chromatographyelectrospray mass spectrometry coupled with solid-phase extraction. J Chromatogr B Biomed Sci Appl 

810:49-56. 

*Inoue K, Okada F, Ito R, et al. 2004b. 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. 

Intrasuksri U, Feller DR. 1991. Comparison of the effects of selected monocarboxylic, dicarboxylic and 

perfluorinated fatty acids on peroxisome proliferation in primary cultured rat hepatocytes. Biochem 

Pharmacol 42(1):184-188. 

Intrasuksri U, Rangwah SM, O'Brien M, et al. 1998. Mechanisms of peroxisome proliferation by 

perfluorooctanoic acid and endogenous fatty acids. Gen Pharmacol 31(2):187-197. 

*IRIS. 2008. Perfluoroalkyls. Washington, DC: Integrated Risk Information System. U.S. 

Environmental Protection Agency. http://www.epa.gov/iris/subst/. May 29, 2008. 

*Issemann I, Green S. 1990. Activation of a member of a steroid hormone receptor superfamily by 

peroxisome proliferators. Nature 347:645-650. 

+*Iwai H, Yamashita K. 2006. A fourteen-day repeated dose oral toxicity study of APFO in rats. Drug 

Chem Toxicol 29:323-332. 

*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. 

*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. 

*Johanson CE. 1980. Permeability and vascularity of the developing brain: Cerebellum vs cerebral 

cortex. Brain Res 190(1):3-16. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PERFLUOROALKYLS 336 

9. REFERENCES 

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, Conard GJ. 1999. Extent and route of excretion of total carbon-14 in pregnant rats after a 

single oral dose of ammonium 14C-perfluorooctanoate. 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. 1979. Absorption of FC-95-14C in rats after a single oral dose. 3M. Submitted 

to the U.S. Environmental Protection Agency's Admistrative 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 Admistrative 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 

LTR DTD, 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 PF, Hu W, De Coen W, et al. 2003. Binding of perfluorinated fatty acids to serum proteins. 

Environ Toxicol Chem 22(11):2639-2649. 

Just WW, Gorgas K, Hartl FU, et al. 1989. Biochemical effects and zonal heterogeneity of peroxisome 

proliferation induced by perfluorocarboxylic acids in rat liver. Hepatology 9(4):570-581. 

*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, Corsolini S, Falandysz J, et al. 2004. Perfluorooctanesulfonate and related fluorochemicals in 

human blood from several countries. Environ Sci Technol 38:4489-4495. 

*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PERFLUOROALKYLS 337 

9. REFERENCES 

*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. 

*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. 

*Kärrman A, Ericson I, van Bavel B, et al. 2007a. 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, Langlois I, van Bavel B, et al. 2007b. Identification and pattern of perfluorooctane sulfonate 

(PFOS) isomers in human serum and plasma. Environ Int 33:782-788. 

*Kärrman A, Mueller JF, Van Bavel B, et al. 2006. Levels of 12 perfluorinated chemicals in pooled 

Australian serum, collected 2002-2003, in relation to age, gender, and region. Environ Sci Technol 

40:3742-3748. 

*Kärrman A, van Bavel B, Jarnberg U, et al. 2005. Development of a solid-phase extractionHPLC/single quadrupole MS method for quantification of perfluorochemicals in whole blood. Anal 

Chem 77:864-870. 

Karstadt ML. 2007. Serum PFOA levels in residents of communities near a teflon-production facility. 

Environ Health Perspect 115(10):A486-A487. 

*Kauck EA, Diesslin AR. 1951. Some properties of perfluorocarboxylic acids. Ind Eng Chem 

43(10):2332-2334.. 

Kawashima Y, Horii S, Matsumaga T, et al. 1989a. Co-induction by peroxisome proliferators of 

microsomal 1-acylglycerophosphocholine acyltransferase with peroxisomal β-oxidation in rat liver. 

Biochim Biophys Acta 1005:123-129. 

+*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. 

Kawashima Y, Matsunaga T, Hirose A, et al. 1989b. Induction of microsomal 1­

acylglycerophosphocholine acyltransferase by peroxisome proliferators in rat kidney; co-induction with 

peroxisomal (betta)-oxidatation. Biochim Biophys Acta 1006(2):214-218. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 338 

9. REFERENCES 

Kawashima Y, Matsunaga T, Uy-Yu N, et al. 1991. Induction by perfluorooctanoic acid of microsomal 

1-acylglycerophosphocholine acyltransferase in rat kidney. Sex-related difference. Biochem Pharmacol 

42(10):1921-1926. 

Kawashima Y, Suzuki S, Kozuka H, et al. 1994. Effects of prolonged administration of 

perfluorooctanoic acid on hepatic activities of enzymes which detoxify peroxide and xenobiotic in the rat. 

Toxicology 93(2-3):85-97. 

Kawashima Y, Uy-Yu N, Kozuka H. 1989c. Sex-related difference in the inductions by perfluorooctanoic acid of peroxisomal beta-oxidation, microsomal 1-acylglycerophosphocholine acyltransferase 

and cytosolic long-chain acyl-CoA hydrolase in rat liver. Biochem J 261:593-600. 

Kawashima Y, Uy-Yu N, Kozuka H. 1989d. Sex-related differences in the enhancing effects of 

perfluorooctanoic acid on stearoyl-CoA desaturase and its influence on the acyl composition of 

phospholipid in rat liver: Comparison with clofibric acid and tiadenol. Biochem J 263:897-904. 

Keil DE, Mehlam T, Butterworth L, et al. 2005. Gestational exposure to PFOS suppresses 

immunological function in F1 mice [Abstract]. Toxicol Sci 84(1-S):180. 

+*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 BJ, Yamanaka H, Thunnan RG. 1992. Inhibition of mitochondria1 respiration and oxygendependent hepatotoxicity by six structurally dissimilar peroxisomal proliferating agents. Toxicology 

71:49-61. 

*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. 

Kelling CK, Van Rafelghem MJ, Menahan LA, et al. 1987. Effects of perfluorodecanoic acid on hepatic 

indices of thyroid status in the rat. Biochem Pharmacol 25(1337):1337-1344. 

*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 Admistrative 

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. 

+*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 339 

9. REFERENCES 

*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 Admistrative Record. AR226-1354. 

*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 SC, Hong JT, Jang SJ, et al. 1998. Formation of 8-oxodeoxyguanosine in liver DNA and hepatic 

injury by peroxisome proliferator clofibrate and perfluorodecanoic acid in rats. J Toxicol Sci 23(2):113­

119. 

+*Kinney LA, Chromey NC, Kennedy Jr GL. 1989. Acute inhalation toxicity of ammonium 

perfluorononanoate. Food Chem Toxicol 21(1):46-68. 

*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. 

*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. 

Kleszczynski K, Gardzielewski P, Mulkiewicz E, et al. 2007. Analysis of structure-cytotoxicity in vitro 

relationship (SAR) for perfluorinated carboxylic acids. Toxicol In Vitro 21:1206-1211. 

Kojo A, Hanhijarvi H, Ylinen M, et al. 1986. Toxicity and kinetics of perfluoro-octanoic acid in the 

Wistar rat. Arch Toxicol Suppl 9:465-468. 

*Komori M, Nishio K, Kitada M, et al. 1990. Fetus-specific expression of a form of cytochrome P-450 

in human livers. Biochemistry 29(18):4430-4433. 

Kozuka H, Yamada J, Home S, et al. 1991. Characteristics of induction of peroxisomal liver by drugs 

fatty acid oxidation-related enzymes in rat. Biochem Pharmacol 41(4):617-623. 

*Krishnan K, Andersen ME. 1994. Physiologically based pharmacokinetic modeling in toxicology. In: 

Hayes AW, ed. Principles and methods of toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 149­

188. 

*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. 

Kropp T, Houlihan J. 2005. Human health risks from exposures to perfluorooctanoic acid: A critique of 

Butenhoff et al. 2004. Regul Toxicol Pharmacol 42:145. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

PERFLUOROALKYLS 340 

9. REFERENCES 

*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. 

*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. 

Kubwabo C, Vais N, Benoit FM. 2004. A pilot study on the determination of perfluorooctanesulfonate 

and other perfluorinated compounds in blood of Canadians. J Environ Monit 6:540-545. 

*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. 2003a. 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, Kawashima Y. 2003b. Toxicity and toxicokinetics of perfluorooctanoic acid in humans and 

animals. J Toxicol Sci 28(2):49-57. 

*Kudo N, Bandai N, Kawashima Y. 1998. Determination of perfluorocarboxylic acids by gas-liquid 

chromatography in rat tissues. Toxicol Lett 99:183-190. 

*Kudo N, Bandai N, Suzuki E, et al. 2000. Induction by perfluorinated fatty acids with different carbon 

chain length of peroxisomal b-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 beta-oxidation and microsomal 1-acylglycerophosphocholine acyltransferase. 

Biol Pharm Bull 29(9):1952-1957. 

*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

PERFLUOROALKYLS 341 

9. REFERENCES 

Lagerkvist BJ, Lundstrom NG. 2004. Lead-and cadmium levels in children living close to a copper and 

lead smelter in Sweden. Biometals 17(5):593-594. 

Lange FT, Wenz M, Schmidt CK, et al. 2007. Occurrence of perfluoroalkyl sulfonates and carboxylates 

in German drinking water sources compared to other countries. Water Sci Technol 56(11):151-158. 

Langley AE. 1990. Effects of perfluoro-n-decanoic acid on the respiratory activity of isolated rat liver 

mitochondria. J Toxicol Environ Health 29(3):329-336. 

*Langley AE, Pilcher GD. 1985. Thyroid bradycardic and hypothermic effects of perfluoro-n-decanoicacid in rats. J Toxicol Environ Health 15(3-4):485-492. 

Lau C, Anitole K, Hodes C, et al. 2007. Perfluoroalkyl acids: A review of monitoring and toxicological 

findings. Toxicol Sci 99(2):366-394. 

Lau C, Butenhoff JL, Rogers JM. 2004a. The developmental toxicity of perfluoroalkyl acids and their 

derivatives. Toxicol Appl Pharmacol 198:231-241. 

Lau C, Rogers JM, Thibodeaux JR, et al. 2002. Maternal and developmental toxicity of perfluorooctane 

sulfonate (PFOS) in the rat. Toxicologist 66(S-1):25. 

+*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. 2004b. Effects of perfluorooctanoic acid exposure during 

pregnancy in the mouse [Abstract]. Birth Defects Res A Clin Mol Teratol 70(5):312. 

+*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. 

Lau C, Thibodeaux JR, Thai L, et al. 2005. Pregnancy loss associated with exposure to perflorooctanoic 

acid in the mouse [Abstract]. Birth Defects Res A Clin Mol Teratol 73(5):358. 

Lawrence JF, Ryan JJ. 1977. Comparisonof electron-capture and electrolytic-conductivity detection for 

the gas-liquid chromoatographic analysis of heptafluorobutyryl derivatives of somae agricultural 

chemicals. J Chromatogr 130:97-102. 

*Leeder JS, Kearns GL. 1997. Pharmacogenetics in pediatrics: Implications for practice. Pediatr Clin 

North Am 44(1):55-77. 

*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. 

*Leung HW. 1993. Physiologically-based pharmacokinetic modelling. In: Ballentyne B, Marrs T, 

Turner P, eds. General and applied toxicology. Vol. 1. New York, NY: Stockton Press, 153-164. 

Levitt D, Liss A. 1986. Toxicity of perfluorinated fatty acids for human and murine B cell lines. Toxicol 

Appl Pharmacol 86:1-11. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 342 

9. REFERENCES 

*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. 

*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 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. Fundam Appl 

Toxicol 30:220-228. 

*Livingston AL. 1978. Forage plant estrogens. J Toxicol Environ Health 4(2-3):301-324. 

*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. 

Logan MN, Thibodeaux JR, Hanson RG, et al. 2004. Effects of perfluorooctane sulfonate (PFOS) on 

thyroid hormone status in adult and neonatal rats. Toxicologist 78(S-1):394-395. 

Loganathan BG, Sajwan KS, Sinclair E, et al. 2007. Perfluoroalkyl sulfonates and perfluorocarboxylates 

in two wastewater treatment facilities in Kentucky and Georgia. Water Res 41:4611-4620. 

Long A, Wang WX. 2005. Assimilation and bioconcentration of Ag and Cd by the marine black bream 

after waterborne and dietary metal exposure. Environ Toxicol Chem 24(3):709-716. 

*Longnecker MP, Smith CS, Kissling GE, et al. 2008. An interlaboratory study of perfluorinated alkyl 

compound levels in human plasma. Environ Res (In Press). 

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. 

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(2-3):203­

217. 

Luebker D, York R, Seacat A, et al. 2002a. Perfluorooctanesulfonae-induced perinatal mortality in rat 

pups is not a result of reduced serum lipids. Toxicologist 66(1-5):26. 

+*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. 2002b. Interactions of flurochemicals 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. 

MacKenzie SA, Mylchreest E, Munley S, et al. 2003. Evaluation of the subchronic, reproductive, and 

developmental toxicity of a fluoroalkylethyl ethoxylate surfactant. Toxicologist 72(S-1):388. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 343 

9. REFERENCES 

Maloney EK, Waxman DJ. 1999. trans-Activation of PPARα and PPARγ by structurally diverse 

environmental chemicals. Toxicol Appl Pharmacol 161:209-218. 

*Maras M, Vanparys C, Muylle F, et al. 2006. Estrogen-like properties of fluorotelomer alcohols as 

revealed by MCF-7 breast cancer cell proliferation. Environ Health Perspect 114:100-105. 

Maras M, Vanparys C, Muylle F, et al. 2006. Estrogen-like properties of fluorotelomer alcohols as 

revealed by MCF-7 breast cancer cell proliferation. Environ Health Perspect 114:100-105. 

*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, Mabury SA, O’Brien PJ. 2005. Metabolic products and pathways of fluorotelomer alcohols 

in isolated rat hepatocytes. Chem Biol Interact 155:165-180. 

Martin JW, Mabury SA, Solomon KR, et al. 2003a. Bioconcentration and tissue distribution of 

perfluorinated acids in rainbow trout (Oncorhynchus mykiss). Environ Toxicol Chem 22(1):196-204. 

Martin JW, Mabury SA, Solomon KR, et al. 2003b. Dietary accumulation of perfluorinated acids in 

juvenile rainbow trout (Oncorhynchus mykiss). Environ Toxicol Chem 22(1):189-195. 

*Martin JW, Muir DCG, Moody CA, et al. 2002. Collection of airborne fluorinated organics and 

analysis by gas chromatography/chemical ionization mass spectrometry. Anal Chem 74:584-590. 

*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. 

Matsubara E, Nakahari T, Yoshida H, et al. 2007. Effects of perfluorooctane sulfonate on tracheal ciliary 

beating frequency in mice. Toxicology 136:190-198. 

*Mayr U, Butsch A, Schneider S. 1992. Validation of two in vitro test systems for estrogenic activities 

with zearalenone, phytoestrogens and cereal extracts. Toxicology 74(2-3):135-149. 

McLachlan MS, Holmstrom KE, Reth M, et al. 2007. Riverine discharge of perfluorinated carboxylates 

from the European continent. Environ Sci Technol 41:7260-7265. 

McMillian M, Niea AY, Parker JB, et al. 2004. Inverse gene expression patterns for macrophage 

activating hepatotoxicants and peroxisome proliferators in rat liver. Biochem Pharmacol 67:2141-2165. 

*Meesters RJ, Schröder HF. 2004. Perfluorooctane sulfonate- a quite mobile anionic anthropogenic 

surfactant, ubiquitoously found in the environment. Water Sci Technol 50(5):235-242. 

Mehrotra K, Morgenstern R, Ahlberg MB, et al. 1999. Hypophysectomy and/or peroxisome proliferators 

strongly influence the levels of phase II xenobiotic metabolizing enzymes in rat testis. Chem Biol 

Interact 122(2):73-87. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 344 

9. REFERENCES 

Mehrotra K, Morgenstern R, Lundqvist G, et al. 1997. Effects of peroxisome proliferators and/or 

hypothyroidism on xenobiotic-metabolizing enzymes in rat testis. Chem Biol Interact 104(2-3):131-145. 

*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. 

Midasch O, Schettgen T, Angerera J. 2006. Pilot study on the perfluorooctanesulfonate and 

perfluorooctanoate exposure of the German general population. Int J Hyg Environ Health 209:489-496. 

*Minnesota Department of Health. 2007. Groundwater health risk limits. St. Paul, MN: 

http://www.health.state.mn.us/divs/eh/groundwater/hrltable.html. July 01, 2008. 

*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. 

Morikawa A, Kamei N, Harada K, et al. 2006. The bioconcentration factor of perfluorooctane sulfonate 

is significantly larger than that of perfluorooctanoate in wild turtles (Trachemys scripta elegans and 

Chinemys reevesii): An Ai River ecological study in Japan. Ecotoxicol Environ Saf 65:14-21. 

*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. 

*Morselli PL, Franco-Morselli R, Bossi L. 1980. Clinical pharmacokinetics in newborns and infants: 

Age-related differences and therapeutic implications. Clin Pharmacokin 5(6):485-527. 

*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. 

*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. 

Nakata H, Kannan K, Nasu T, et al. 2006. Perfluorinated contaminants in sediments and aquatic 

organisms collected from shallow water and tidal flat areas of the Ariake Sea, Japan: Environmenetal fate 

of perfluorooctane sulfonate in aquatic ecosystems. Environ Sci Technol 40(16):4916-4921. 

*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. 

*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. 

*New Jersey Department of Environmental Protection. 2007. Drinking-water guidance value. Trenton, 

NJ: http://www.nj.gov/dep/watersupply/pfoa.htm. July 01, 2007. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

PERFLUOROALKYLS 345 

9. REFERENCES 

*Nilsson R, Beije B, Preat V, et al. 1991. On the mechanism of the hepatocarcinogenicity of peroxisome 

proliferations. Chem Biol Interact 78:235-250. 

*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. 

*NRC. 1993. Pesticides in the diets of infants and children. Washington, DC: National Academy Press. 

National Research Council. 

*NTP. 2005. Report on carcinogens. Research Triangle Park, NC: U.S. Department of Health and 

Human Services, Public Health Service, National Toxicology Program. http://ntpserver.niehs.nih.gov/ntp/roc/toc11.html. April 24, 2008. 

*NTP. 2008. Testing status. Perfluorooctanoic acid PFOA. National Toxicology Program. 

http://ntp.niehs.nih.gov/go/TS-M910070. December 10, 2008. 

O'Brien TM, Wallace KB. 2004. Mitochondrial permeability transition as the critical target of n-acetyl 

perfluorooctane sulfonamide toxicity in vitro. Toxicol Sci 82(1):333-340. 

*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. 

*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 Cooperation 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 precursers. 

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. 

*Ohya T, Kudo N, Suzuki E, et al. 1998. Determination of perfluorinated carboxylic acids in biological 

smaples by high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 

720(1-2):1-7. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

PERFLUOROALKYLS 346 

9. REFERENCES 

*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. 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, 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. 

*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, Gilliland FD, Burlew MM, et al. 1998. 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, Logan PW, Hansen KJ, et al. 2003d. An occupational exposure assessment of 

perfluorooctanesulfonyl fluoride production site: Biomonitoring. AIHA J (Fairfax, Va) 

*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. 

*Olson CT, Andersen ME. 1983. The acute toxicity of perfluorooctanoic and perfluorodecanoic acids in 

male rats and effects on tissue fatty acids. Toxicol Appl Pharmacol 70(3):362-372. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

PERFLUOROALKYLS 347 

9. REFERENCES 

O'Malley KD, Ebbens KL. 1981. Repeat application 28 day percutaneous absorption study with T2618CoC in Albino rabbits. Riker Laboratories, Inc. 

Ophaung RH, Singer L. 1980. Metabolic handling of perfluorooctanoic acid in rats (40715). Proc Soc 

Exp Biol Med 163:19-23. 

*OSHA. 2007. Air contaminants. Occupational Safety and Health Administration. Code of Federal 

Regulations. 29 CFR 1910.1000, Table Z 1. http://www.osha.gov/comp-links.html. April 24, 2008. 

*Owen GM, Brozek J. 1966. Influence of age, sex and nutrition on body composition during childhood 

and adolescence. In: Falkner F, ed. Human development. Philadelphia, PA: WB Saunders, 222-238. 

Panaretakis T, Shabalina IG, Grande D, et al. 2001. Reactive oxygen species and mitochondria mediate 

the induction of apoptosis in human hepatoma HepG2 cells by the rodent peroxisome proliferator and 

hepatocarcinogen, perfluorooctanoic acid. Toxicol Appl Pharmacol 173:56-64. 

+*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. 

+*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. 

*Pilcher GD, Langley AE. 1986. The effects of perfluoro-n-decanoic acid in the rat heart. Toxicol Appl 

Pharmacol 85:389-397. 

*Pilcher GD, Gutshall DM, Langley AE. 1987. The effects of perfluoro-n-decanoic acid (PFDA) on rat 

heart ß-receptors, adenylate cyclase, and fatty acid composition. Toxicol Appl Pharmacol 90:198-205. 

*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. 

*Prevedouros K, Cousins I T, Buck RC, et al. 2006. Sources, fate and transport of 

perfluorocarboxylates. Environ Sci Technol 40(1):32-44. 

Renner R. 2006a. 3-D modeling substantiates perfluorinated theory. Environ Sci Technol 40(3):632­

633. 

Renner R. 2006b. Sorting out sources of perfluorinated chemicals. Environ Sci Technol 40(9):2866­

2867. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PERFLUOROALKYLS 348 

9. REFERENCES 

Renner R. 2007a. Past PFOA sources in the Arctic Ocean. Environ Sci Technol 41(13):4490. 

Renner R. 2007b. New Jersey dives into PFOA water guidance. Environ Sci Technol 41(10):3395­

3396. 

Renner R. 2007c. PFOA in people. Environ Sci Technol 41(13):4497-4500. 

Renner R. 2008. Do perfluoropolymers biodegrade into PFOA? Environ Sci Technol 42(3):648-650. 

Reo NV, Goecke CM, Narayanan L, et al. 1994. Effects of perfluoro-n-octanoic acid, perfluoro-ndecanoic acid, and clofibrate on hepatic phosphorus metabolism in rats and guinea pigs in vivo. Toxicol 

Appl Pharmacol 124(2):165-173. 

Reo NV, Narayanan L, Kling KB, et al. 1996. Perfluorodecanoic acid, a peroxisome proliferator, 

activates phospholipase C, inhibits CTP:phosphocholine cytidylyltransferase, and elevates diacylglycerol 

in rat liver. Toxicol Lett 86:1-11. 

Rogers AM, Andersen ME, Back KC. 1982. Mutagenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 

perfluoro-n-decanoic acid in L5178Y mouse-lymphoma cells. Mutat Res 105:445-449. 

Rosen MB, Lee JS, Ren H, et al. 2008. Toxicogenomic dissection of the perfluorooctanoic acid 

transcript profile in mouse liver: Evidence for the involvement of nuclear receptors PPARa and CAR. 

Toxicol Sci 103(1):46-56. 

*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. 

*RTECS. 2008. Perfluoroalklys. Registry of Toxic Effects on Chemical Substances. National Institute 

of Occupational Safety and Health. MDL Information Systems, Inc. May 29, 2008. 

Saikia N, Kato S, Kojima T. 2006. Behavior of B, Cr, Se, As, Pb, Cd and Mo present in waste leachates 

generated from combustion residues during the formation of ettringite. Environ Toxicol Chem 

25(7):1710-1719. 

*Saito N, Harada K, Inoue K, et al. 2004. Perfluorooctanoate and perfluorooctane sulfonate 

concentrations in surface waters in Japan. J Occup Health 46:49-59. 

*Saito N, Sasaki K, Nakatome K, et al. 2003. Perfluorooctane sulfonate concentrations in surface water 

in Japan. Arch Environ Contam Toxicol 45:149-158. 

*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. 

*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. 

Sambasiva Rao M, Reddy JK. 1996. Hepatocarcinogenesis of peroxisome proliferators. Ann N Y Acad 

Sci 804(1):573-587. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PERFLUOROALKYLS 349 

9. REFERENCES 

Sasaki K, Harada K, Saito N, et al. 2003. Impact of airborne perfluorooctane sulfonate on the human 

body burden and the ecological system. Bull Environ Contam Toxicol 71(2):408-413. 

*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. 

Schnellmann RG. 1990. The cellular effects of a unique pesticide sulfuramid (N-ethylperfluorooctane 

sulphonamide) on rabbit renal proximal tubules. Toxicol In Vitro 4(1):71-74. 

Schramm H, Friedberg T, Robertson LW, et al. 1989. Perfluorodecanoic acid decreases the enzyme 

activity and the amount of glutathione stransferases proteins and mRNAs in vivo. Chem Biol Interact 

70:127-143. 

*Schroder HF. 2003. Determination of fluorinated surfactants and their metabolites in sewage sluldge 

samples by liquid chromatography with mass spectrometry and tandem mass spectrometry after 

pressurised liquid extraction and separation on fluorine-modified reversed-phase sorbents. J Chromatogr 

A 1020(1):131-151. 

*Schultz MM, Barofsky DF, Field JA. 2003. Fluorinated alkyl surfactants. Environ Eng Sci 20(5):487­

501. 

*Schultz MM, Barofsky DF, Field JA. 2006. Quantitative determination of fluorinated alkyl substances 

by large-volume-injection liquid chromatography tandem mass spectrometryscharacterization of 

municipal wastewaters. Environ Sci Technol 40:289-295. 

Schwerha JJ. 2007. Occupational medicine forum. J Environ Monit 49(8):872-879. 

Scialli AR, Iannucci A, Turim J. 2007. Combining perfluoroalkane acid exposure levels for risk 

assessment. Regul Toxicol Pharmacol 49(3):195-202. 

Scott BF, Moody CA, Spencer C, et al. 2006a. Analysis for perfluorocarboxylic acids/anions in surface 

waters and precipitation using GC-MS and analysis of PFOA from large-volume samples. Environ Sci 

Technol 40:6405-6410. 

Scott BF, Spencer C, Mabury SA, et al. 2006b. Poly and perfluorinated carboxylates in North American 

precipitation. Environ Sci Technol 40(23):7167-7174. 

+*Seacat AM, Luebker DJ. 2000. Toxicokinetic study of perfluorooctane sulfonamide (PFOS; T7132.2) in rats. 3M Strategic Toxicology Laboratory. Submitted to the U.S. Environmental Protection 

Agency's Admistrative 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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

PERFLUOROALKYLS 350 

9. REFERENCES 

+*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. 

*Setchell BP, Waites GMH. 1975. The blood-testis barrier. In: Creep RO, Astwood EB, Geiger SR, 

eds. Handbook of physiology: Endocrinology V. Washington, DC: American Physiological Society, 

143-172. 

Shabalina IG, Panaretakis T, Bergstrand A, et al. 1999. Effects of the rodent peroxisome proliferator and 

hepatocarcinogen, perfluorooctanoic acid, on apoptosis in human hepatoma HepG2 cells. Carcinogenesis 

20(12):2237-2246. 

+*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. 

*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. 

*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. 

*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. 

Singer SS, Andersen ME, George ME. 1990. Perfluoro-N-decanoic acid effects on enzymes of fatty acid 

metabolism. Toxicol Lett 54(1):39-46. 

*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PERFLUOROALKYLS 351 

9. REFERENCES 

*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, Miyake Y, Yeung WY, et al. 2007. Perfuorinated compounds in the Pearl River and Yangtze 

River of China. Chemosphere 68:2085-2095. 

*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, Taniyasu S, Yamashita N, et al. 2004. Perfluorinated compounds in coastal waters of Hong 

Kong, South China, and Korea. Environ Sci Technol 38(15):4056-4063. 

*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. 

Sohlenius AK, Andersson K, DePierre JW. 1992a. The effects of perfluoro-octanoic acid on hepatic 

peroxisome proliferation and related parameters show no sex-related differences in mice. Biochem J 

285(3):779-783. 

Sohlenius AK, Andersson K, Olsson J, et al. 1995. Peroxisome proliferation and associated effects 

caused by perfluorooctanoic acid in vitamin A-deficient mice. Chem Biol Interact 98(1):45-50. 

Sohlenius AK, Eriksson AM, Hogstrom C, et al. 1993. Perfluorooctane sulfonic acid is a potent inducer 

of peroxisomal fatty acid ß-oxidation and other activities ionom to be affected by peroxisome 

proliferators in mouse liver. Pharmacol Toxicol 72:90-93. 

Sohlenius AK, Lundgren B, DePierre JW. 1992b. Perfluorooctanoic acid has persistent effects on 

peroxisome proliferation and related parameters in mouse liver. J Biochem Toxicol 7(4):205-212. 

Sohlenius AK, Reinfeldt M, Backstrom K, et al. 1996. Hepatic peroxisome proliferation in vitamin Adeficient mice without a simultaneous increase in peroxisomal acyl-CoA oxidase activity. Biochem 

Pharmacol 51(6):821-827. 

+*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. 

*SPARC. 2008. Macroscopic pka. Sparc Performs Automated Reasoning in Chemistry. 

http://sparc.chem.ugs.edu/sparc/display/ShowMacro.cfm. May 08, 2008. 

*SRI. 2007. Perfluoroalkyls. 2007 Directory of chemical producers United States. Menlo Park, CA: 

SRI Consulting, 126-128. 

+*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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

PERFLUOROALKYLS 352 

9. REFERENCES 

Starkov AA, Wallace KB. 2002. Structural determinants of fluorochemical-induced mitochondrial 

dysfunction. Toxicol Sci 66(2):244-252. 

*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. 

*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. 

*Strynar MJ, Lindstrom AB. 2008. Perfluorinated compounds in house dust from Ohio and North 

Carolina, USA. Environ Sci Technol 42:3751-3756. 

Szostek B, Prickett KB. 2004. Determination of 8:2 fluorotelomer alcohol in animal plasma and tissues 

by gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 

813(1-2):313-321. 

*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. 

Takagi A, Sai K, Umemura T, et al. 1992. Hepatomegaly is an early biomarker for hepatocarcinogenesis 

induced by peroxisome proliferators. J Environ Pathol Toxicol Oncol 11:145-149. 

*Tan Y, Clewell HJ, Andersen ME. 2008. Time dependencies in perfluorooctylacids disposition in rat 

and monkeys: A kinetic analysis. Toxicol Lett 177:38-47. 

Taniyasu S, Kannan K, Horii Y, et al. 2003. A survey of perfluorooctane sulfonate and related 

perfluorinated organic compounds in water, fish, birds, and humans from Japan. Environ Sci Technol 

37:2634-2639. 

*Taniyasu S, Kannan K, So MK, et al. 2005. Analysis of fluorotelomer alcohols, fluorotelomer acids, 

and short- and long-chain perfluorinated acids in water and biota. J Chromatogr A 1093:89-97. 

*Tao L, Kannan K, Wong CM, et al. 2008. Perfluorinated compounds in human milk from 

Massachusetts, U.S.A. Environ Sci Technol 42(8):3096-3101. 

Thibodeaux J, Hanson RG, Rogers JM, et al. 2005. Effects of perfluorooctanoic acid exposure during 

pregnancy in the mouse. Toxicol Sci 84(1-S):58. 

+*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. 

*Thomas K, Colborn T. 1992. Organochlorine endocrine disruptors in human tissue. In: Colborn T, 

Clement C, eds. Chemically induced alterations in sexual and functional development: The 

wildlife/human connection. Princeton, NJ: Princeton Scientific Publishing, 365-394. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

PERFLUOROALKYLS 353 

9. REFERENCES 

*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. 

Thottassery J, Windberg L, Youssef J, et al. 1992. Regulation of perfluorooctanoic acid-induced 

peroxisomal enzyme activities and hepatocellular growth by adrenal hormones. Hepatology 15(2):316­

322. 

Tillett T. 2007. Research helps clean up a water supply. Environ Health Perspect 115(3):A134. 

*Tilton SC, Orner GA, Benninghoff AD, et al. 2008. Genomic profiling reveals an alternate mechanism 

for hepatic tumor promotion by perfluorooctanoic acid in rainbow trout. Environ Health Perspect 

116(8):1047-1055. 

Tittlemier SA, Pepper K, Edwards L. 2006. Concentrations of perfluorooctanesulfonamides in Canadian 

Total Diet Study composite food samples collected between 1992 and 2004. J Agric Food Chem 

54:5385-8389. 

*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. 

*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. 

*Tseng C, Liu L, Chen C, et al. 2006. Analysis of perfluorooctanesulfonate and related fluorochemicals 

in water and biological tissue samples by liquid chromatography-ion trap mass spectrometry. J 

Chromatogr A 1105:119-126. 

Ubel FA, Sorenson SD, Roach DE. 1980. Health status of plant workers exposed to fluorochemicals - a 

preliminary report. Am Ind Hyg Assoc J 41:584-589. 

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. 

USAF. 1983. Toxicity of perfluorodecanoic acid in rodents. Wright-Patterson AFB, OH: U.S. Air 

Force. ADP001980. 

Uy-Yu N, Kawashima Y, Horii S, et al. 1990a. Effects of chronic administration of perfluorooctanoic 

acid on fatty acid metabolism in rat liver: Relationship among stearoyl-coenzyme A desaturase, 1­

acylglycerophosphocholine acyltransferase, and acyl composition of microsomal phosphatidylcholine. J 

Pharmacobiodyn 13:581-590. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

PERFLUOROALKYLS 354 

9. REFERENCES 

Uy-Yu N, Kawashima Y, Kozuka H. 1990b. Comparative studies on sex-related difference in 

biochemical responses of livers to perfluorooctanoic acid between rats and mice. Biochem Pharmacol 

39(9):1492-1495. 

Vanden Heuvel JP. 1996. Perfluorodecanoic acid as a useful pharmacologic tool for the study of 

peroxisome proliferation. Gen Pharmacol 27(7):1123-1129. 

*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. 

*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 De Vijver K, Hoff PT, Das K, et al. 2003a. Perfluorinated chemicals infiltrate ocean waters: Link 

between exposure levels and stable isotope ratios in marine mammals. Environ Sci Technol 37:5545­

5550. 

Van De Vijver KI, Hoff PT, Das K, et al. 2003b. Tissue distribution of perfluorinated chemicals in 

harbor seals (Phoca vitulina) from the Dutch Wadden Sea. Environ Sci Technol 37:5545-5550. 

Van De Vijver KI, Hoff PT, Van Dongen W, et al. 2003c. Exposure patterns of perfluorooctane 

sulfonate in aquatic invertebrates from the Western Scheldt estuary and the southern North Sea. Environ 

Toxicol Chem 22(9):2037-2041. 

Van de Vijver KI, Holsbeek L, Das K, et al. 2007. Occurrence of perfluorooctane sulfonate and other 

perfluorinated alkylated substances in harbor porpoises from the Black Sea. Environ Sci Technol 41:315­

320. 

*Van Leeuwen SPJ, Karrman A, Van Bavel B, et al. 2006. Struggle for quality in determination of 

perfluorinated contaminants in environmental and human samples. Environ Sci Technol 40:7854-7860. 

Vanparys C, Maras M, Lenjou M, et al. 2006. Flow cytometric cell cycle analysis allows for rapid 

screening of estrogenicity in MCF-7 breast cancer cells. Toxicol In Vitro 20:1238-1248. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PERFLUOROALKYLS 355 

9. REFERENCES 

*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. 

*Van Rafelghem MJ, Inhorn Sl, Peterson RE. 1987a. Effects of perfluorodecanoic acid on thyroid status 

in rats. Toxicol Appl Pharmacol 87:430-439. 

*Van Rafelghem MJ, Mattie DR, Bruner RH, et al. 1987b. Pathological and hepatic ultrastructural 

effects of a single dose of perfluoro-n-decanoic acid in the rat, hamster, mouse and guinea pig. Fundam 

Appl Toxicol 9(3):522-540. 

*Van Rafelghem MJ, Noren CW, Menahan LA, et al. 1988b. Interrelationships between energy and fat 

metabolism and hypophagia in rats treated with perfluorodecanoic acid. Toxicol Lett 40(1):57-69. 

*Van Rafelghem MJ, Vanden Heuvel JP, Menahan LA, et al. 1988a. Perfluorodecanoic acid and lipid 

metabolism in the rat. Lipids 23(7):671-678. 

Veltman K, Huijbregts MA, Hamers T, et al. 2007. Cadmium accumulation in herbivorous and 

carnivorous small mammals: Meta-analysis of field data and validation of the bioaccumulation model 

optimal modeling for ecotoxicological applications. Environ Toxicol Chem 26(7):1488-1496. 

*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. 

*Vieira I, Sonnier M, Cresteil T. 1996. Developmental expression of CYP2E1 in the human liver: 

Hypermethylation control of gene expression during the neonatal period. Eur J Biochem 238(2):476-483. 

*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. 

*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. 

*Wang N, Szostek B, Buck RC, et al. 2005a. Fluorotelomer alcohol biodegradations direct evidence that 

perfluorinated carbon chains breakdown. Environ Sci Technol 39:7416-7528. 

*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, 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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

 

 

 

 

 

PERFLUOROALKYLS 356 

9. REFERENCES 

*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, Henderson WM, Ellington JJ, et al. 2008. Analysis of perfluorinated carboxylic acids 

in soils II: Optimization of chromatography and extraction. J Chromatogr A 1181:21-32. 

*Washington State Department of Ecology. 2006. Persistent Bioaccumulative Toxins rule. Olympia, 

WA: Chapter 173-333 WAC. http://www.ecy.wa.gov/biblio/wac173333.html. July 01, 2008. 

*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. 

*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. 

Wenyue H, Jones PD, Celius T, et al. 2005. Identification of genes responsive to PFOS using gene 

expression profiling. Environ Toxicol Pharmacol 19:57-70. 

*West JR, Smith HW, Chasis H. 1948. Glomerular filtration rate, effective renal blood flow, and 

maximal tubular excretory capacity in infancy. J Pediatr 32:10-18. 

+*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, Rayner JL, Hines EP, et al. 2005. Stunted mouse mammary gland development, in the 

absence of body weight effects, following prenatal exposure to PFOA [Abstract]. Biol Reprod (Special 

issue):142-143. 

*WHO. 2000. Air quality guidelines. Geneva, Switzerland: World Health Organization. 

http://www.euro.who.int/Document/AIQ/AirQualRepMtg.pdf. March 08, 2006. 

*WHO. 2004. Guidelines for drinking-water quality. Volume 1. Recommendations. Geneva, 

Switzerland: World Health Organization. http://www.who.int/water_sanitation_health/dwq/gdwq3/en/. 

March 08, 2006. 

Wiesmuller GA, Eckard R, Dobler L, et al. 2007. The environmental specimen bank for human tissues 

as part of the German environmental specimen bank. Int J Hyg Environ Health 210:299-305. 

*Widdowson EM, Dickerson JWT. 1964. Chemical composition of the body. In: Comar CL, Bronner 

F, eds. Mineral metabolism: An advanced treatise. Volume II: The elements Part A. New York, NY: 

Academic Press, 1-247. 

Wilhelm M, Angerer J, Fromme H, et al. 2007. Contribution to the evaluation of reference values for 

PFOA and PFOS in plasma of children and adults from Germany. Int J Hyg Environ Health (In Press). 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PERFLUOROALKYLS 357 

9. REFERENCES 

*Wilhelm M, Kraft M, Rauchfuss K, et al. 2008a. 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. 2008b. Preliminary observations on perfluorinated compounds in 

plasma samples (1977-2004) of young German adults from an area with perfluorooctanoate-contaminated 

drinking water. Int J Hyg Environ Health [Epub ahead of print]. 

Witzmann F, Coughtrie M, Fultz C, et al. 1996. Effect of structurally diverse peroxisome proliferators 

on rat hepatic sulfotransferase. Chem Biol Interact 99(1-3):73-84. 

Witzmann FA, Parker DN. 1991. Hepatic protein pattern alterations following perfluorodecanoic acid 

exposure in rats. Toxicol Lett 57(1):29-36. 

+*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. 

Xie Y, Yang Q, Nelson BD, et al. 2002. Characterization of the adipose tissue atrophy induced by 

peroxisome proliferators in mice. Lipids 37(2):139-146. 

+*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. 

Yamamoto A, Kawashimaã Y. 1997. Perfluorodecanoic acid enhances the formation of oleic acid in rat 

liver. Biochem J 325:429-434. 

*Yamashita N, Kannan K, Taniyasu S, et al. 2004. Analysis of perfluorinated acids at parts-perquadrillion levels in seawater using liquid chromatography-tandem mass spectrometry. Environ Sci 

Technol 38:5522-5528. 

*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 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. 

***DRAFT FOR PUBLIC COMMENT*** 
 

 

 

 

 

 

PERFLUOROALKYLS 358 

9. REFERENCES 

+*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 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. 

Yeung LW, So MK, Jiang G, et al. 2006. Perfluorooctanesulfonate and related fluorochemicals in 

human blood samples from China. Environ Sci Technol 40(3):715-720. 

*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, Hanhijarvi H, Jaakonaho J, et al. 1989. Stimulation by oestradiol of the urinary excretion of 

perfluorooctanoic acid in the male rat. Pharmacol Toxicol 65:274-277. 

*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. 

York RG, Case MT, Christian MS. 2000. Rat and rabbit developmental toxicology studies with two 

perfluorinated compounds administered orally. Int J Toxicol 19(6):35. 

*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. 

Youssef J, Badr M. 1997. Activated Kupffer cells attenuate the liver response to the peroxisome 

proliferator perfluorooctanoic acid. Mol Cell Biochem 169:143-147. 

*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. 

*Ziegler EE, Edwards BB, Jensen RL, et al. 1978. Absorption and retention of lead by infants. Pediatr 

Res 12(1):29-34. 

Zushi Y, Takeda T, Masunaga S. 2008. Existence of nonpoint source of perfluorinated compounds and 

their loads in the Tsurumi River basin, Japan. Chemosphere 71:1566-1573. 

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Absorption—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 or less, 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)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

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—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of 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-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 

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Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

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. At least one exposed group is compared to one unexposed 

group. 

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 one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health 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 adverse effects. 

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 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance 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. 

Epidemiology—Refers to 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. 

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. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

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10. GLOSSARY 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio 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. 

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. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

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Mutagen—A substance that causes mutations. A mutation is a change 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 

chemical. 

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. Effects may be produced at this dose, but 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 OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour 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. 

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 end 

points. 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. 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

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10. GLOSSARY 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood 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 the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

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 reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater 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 chemical. 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 chemical. 

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PERFLUOROALKYLS 364 

10. GLOSSARY 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

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 most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

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 chemical that is foreign to the biological system. 

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PERFLUOROALKYLS A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (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 duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. 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 no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) 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 chemical-induced end 

point 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 

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PERFLUOROALKYLS A-2 

APPENDIX A 

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. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, 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 levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-32, Atlanta, Georgia 30333. 

For reasons discussed in Section 2.3, MRLs were not derived for perfluoroalkyls. 

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PERFLUOROALKYLS B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points 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? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived 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. 

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PERFLUOROALKYLS B-2 

APPENDIX B 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical 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. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" 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 end point 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 end point 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 

(UF) 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 substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

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, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures 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 Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 

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PERFLUOROALKYLS B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(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 Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2)	 Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is 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)	 Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4)	 Key to Figure. 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 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5)	 Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "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. 

(6)	 Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7)	 System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8)	 NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

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PERFLUOROALKYLS B-4 

APPENDIX B 

(9)	 LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful 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 end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10)	 Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11)	 CEL. A 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. 

(12)	 Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

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 acute and intermediate exposure periods are illustrated. 

(14)	 Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects 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)	 NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17)	 CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 

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PERFLUOROALKYLS B-5 

APPENDIX B 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 

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12 → a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

LOAEL (effect) Exposure 

Key to frequency/ NOAEL Less serious Serious (ppm) figurea Species duration System (ppm) (ppm) Re

2 3 4 

→ INTERMEDIATE EXPOSURE 

5 6 7 8 9 10 

→ Systemic ↓ ↓ ↓ ↓ ↓ ↓

18 Rat 13 wk Resp 3b 10 (hyperplasia) 

→ 5 d/wk Nit

6 hr/d 

CHRONIC EXPOSURE 

Cancer 11 

↓

38 Rat 18 mo 20 (CEL, multiple Wo

5 d/wk organs) 7 hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumors, NT

5 d/wk nasal tumors) 6 hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumors, NT

5 d/wk hemangiosarcomas) 6 hr/d 

SAMPLE

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PERFLUOROALKYLS B-8 

APPENDIX B 

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PERFLUOROALKYLS C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

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 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

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PERFLUOROALKYLS C-2 

APPENDIX C 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMDG North America/Intergovernmental Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg 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 Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

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PERFLUOROALKYLS C-3 

APPENDIX C 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

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PERFLUOROALKYLS C-4 

APPENDIX C 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

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 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 

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PERFLUOROALKYLS C-5 

APPENDIX C 

> 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 

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PERFLUOROALKYLS C-6 

APPENDIX C 

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PERFLUOROALKYLS D-1 

APPENDIX D. INDEX
 

absorbed dose.................................................................................................................................... 165, 206
 

adenocarcinoma ................................................................................................................................ 202, 215
 

adipose tissue ............................................................................................................................................135
 

adrenal gland............................................................................................................................... 52, 126, 127
 

adrenals ............................................................................................................................... 56, 126, 127, 158
 

adsorbed............................................................................................................................................ 247, 257
 

aerobic.......................................................................................................................................................264
 

alanine aminotransferase (see ALT) ...........................................................................................................12
 

ALT (see alanine aminotransferase) ........................................... 12, 30, 47, 49, 50, 118, 119, 120, 155, 208
 

ambient air ................................................................................................................................................291
 

androgen receptor......................................................................................................................................217
 

aspartate aminotransferase (see AST).........................................................................................................12
 

AST (see aspartate aminotransferase)....................................................... 12, 47, 49, 50, 118, 119, 155, 208
 

bioaccumulation.................................................................................................................. 10, 249, 261, 304
 

bioavailability ...........................................................................................................................................167
 

biodegradation............................................................................................... 9, 248, 256, 257, 262, 264, 304
 

biomarker ........................................................................................... 37, 202, 205, 206, 207, 309, 313, 314
 

blood cell count................................................................................................................................. 115, 224
 

body weight effects....................................................................................................... 53, 57, 129, 156, 213
 

breast milk..................................... 4, 6, 11, 14, 140, 141, 171, 172, 204, 217, 249, 293, 295, 301, 306, 310
 

cancer .............................................................. 5, 6, 12, 14, 21, 35, 36, 38, 55, 148, 157, 203, 215, 220, 225
 

carcinogenic .................................................................................................................................. 20, 33, 148
 

carcinogenicity.............................................................................................................................. 5, 226, 315
 

carcinoma.................................................................................................................................... 29, 148, 149
 

cardiovascular ........................................................................................................................... 35, 38, 46, 57
 

cardiovascular effects.................................................................................................................. 46, 113, 150
 

chromosomal aberrations..........................................................................................................................161
 

clearance ............................................................................................. 24, 173, 174, 179, 190, 192, 201, 222
 

cognitive function .....................................................................................................................................140
 

death.................................................. 6, 14, 18, 33, 35, 36, 37, 38, 55, 56, 57, 145, 149, 150, 215, 218, 220
 

deoxyribonucleic acid (see DNA).............................................................................................................117
 

dermal effects.............................................................................................................................. 52, 128, 155
 

developmental effects ........................................................ 6, 13, 17, 26, 28, 30, 54, 55, 138, 144, 146, 147, 

148, 157, 212, 213, 217, 218, 223, 317
 

DNA (see deoxyribonucleic acid)..................................... 117, 119, 131, 149, 160, 161, 193, 196, 206, 216
 

elimination half-time......................................................................................................... 163, 174, 189, 222
 

elimination rate ..................................... 23, 24, 172, 174, 179, 180, 181, 189, 192, 197, 198, 205, 222, 223
 

endocrine..................................................................................... 11, 126, 135, 198, 199, 200, 223, 224, 225
 

endocrine effects ............................................................................................................. 11, 51, 54, 125, 155
 

estrogen receptor............................................................................................................................... 197, 215
 

estrogenic .......................................................................................................................................... 149, 202
 

fetus........................................................................................................................................... 171, 202, 217
 

follicle-stimulating hormone (see FSH)......................................................................................................29
 

FSH (see follicle-stimulating hormone).................................................................................. 29, 51, 54, 137
 

gastrointestinal effects .......................................................................................................... 46, 54, 113, 150
 

general population.................................................... 5, 6, 7, 10, 11, 13, 14, 15, 21, 34, 35, 36, 37, 138, 140, 

161, 162, 174, 179, 204, 206, 209, 212, 213, 215, 216, 

217, 220, 223, 249, 250, 286, 291, 292, 302, 305, 307
 

genotoxic.....................................................................................................................................................33
 

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PERFLUOROALKYLS D-2 

APPENDIX D 

genotoxicity....................................................................................................................................... 160, 216
 

groundwater .................. 3, 9, 10, 11, 247, 248, 249, 250, 256, 258, 273, 279, 292, 302, 303, 304, 305, 318
 

growth retardation.....................................................................................................................................218
 

half-life.............................................................................................. 10, 15, 17, 23, 121, 198, 205, 226, 263
 

hematological effects .......................................................................................................... 47, 114, 115, 155
 

hematopoietic..............................................................................................................................................36
 

hepatic effects ............................................................................. 16, 17, 37, 47, 52, 116, 123, 155, 212, 214
 

hydrolysis...................................................................................................................... 9, 248, 262, 263, 304
 

hydroxyl radical ................................................................................................................................ 262, 263
 

immune system ......................................................................................................................... 224, 225, 317
 

immunological ............................................................ 18, 19, 22, 33, 53, 131, 133, 146, 156, 198, 218, 219
 

immunological effects............................................................................................................... 198, 218, 219
 

Kow .................................................................................................................................... 233, 234, 235, 236
 

LD50............................................................................................................................... 55, 56, 146, 150, 158
 

lymphatic ....................................................................................................................................................36
 

lymphoreticular............................................................................................. 28, 53, 131, 133, 156, 212, 219
 

melanoma.............................................................................................................................................. 36, 55
 

micronuclei ............................................................................................................................... 160, 161, 216
 

milk ........................4, 6, 11, 18, 136, 141, 171, 172, 203, 217, 218, 249, 284, 285, 297, 300, 301, 310, 311
 

musculoskeletal effects ............................................................................................................... 47, 116, 155
 

neonatal..................................................................................................... 14, 18, 28, 55, 145, 205, 218, 295
 

neoplastic ..................................................................................................................................................148
 

neurobehavioral........................................................................................................... 26, 134, 145, 199, 219
 

neurodevelopmental............................................................................................................................ 28, 140
 

neurological effects................................................................................. 22, 53, 54, 129, 133, 135, 157, 220
 

norepinephrine ..........................................................................................................................................159
 

nuclear......................................................................................................... 15, 116, 170, 193, 197, 215, 219
 

ocular effects............................................................................................................................... 52, 128, 156
 

pharmacodynamic.....................................................................................................................................181
 

pharmacokinetic.................................................................................. 22, 181, 182, 183, 189, 190, 202, 217
 

photolysis...................................................................................................................... 9, 227, 248, 262, 304
 

placenta ............................................................................................................................................. 171, 203
 

placental barrier ........................................................................................................................................302
 

rate constant ...................................................................................................... 184, 186, 187, 188, 262, 263
 

renal effects................................................................................................................................. 51, 124, 155
 

reproductive effects............................................................................................. 54, 125, 135, 138, 157, 216
 

respiratory effects.......................................................................................................................... 39, 57, 150
 

salivation.....................................................................................................................................................53
 

solubility ................................................................................................................................... 237, 258, 303
 

systemic effects....................................................................................................................... 28, 39, 57, 150
 

T3.................................................................................................... 40, 52, 58, 126, 127, 128, 145, 151, 159
 

T4............................................................................ 13, 20, 52, 126, 127, 128, 141, 145, 159, 200, 204, 217
 

thyroid................................................. 12, 20, 21, 26, 52, 125, 126, 127, 128, 149, 155, 159, 200, 216, 317
 

thyroid stimulating hormone (see TSH)......................................................................................................12
 

thyroxine ....................................................................................................................... 20, 52, 126, 127, 128
 

toxicokinetic........................................................................ 15, 23, 25, 27, 33, 195, 197, 207, 213, 220, 221
 

triiodothyronine................................................................................................................................... 52, 126
 

TSH (see thyroid stimulating hormone)............................................. 12, 13, 20, 51, 52, 125, 126, 127, 128, 

141, 145, 199, 200, 203, 204, 223 

tumors ....................................................................................................... 5, 20, 21, 135, 149, 201, 212, 215 

vapor phase ............................................................................................................... 247, 248, 257, 261, 262 

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PERFLUOROALKYLS D-3 

APPENDIX D 

vapor pressure ........................................................................................................................... 257, 258, 303
 

volatility................................................................................................................................ 9, 248, 258, 304
 

volatilization .............................................................................................................................................247
 

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