TOXICOLOGICAL PROFILE FOR 

PERCHLORATES 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry

September 2008 
PERCHLORATES 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. 
PERCHLORATES iii 

UPDATE STATEMENT 

A Toxicological Profile for Perchlorates, Draft for Public Comment was released in July 2005. This 

edition supersedes any previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. ATSDR considers updating 

Toxicological profile as new research data becomes available that may significantly impact the Minimal 

Risk Levels (MRLs) or other conclusions. 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-32 

Atlanta, Georgia 30333 
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PERCHLORATES v

FOREWORD

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

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

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

and republished as necessary.

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

information for 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. 

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 
PERCHLORATES vi

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.

Director

National Center for Environmental Health/

Agency for Toxic Substances and

Disease Registry

Julie Louise Gerberding, M.D., M.P.H.

Administrator

Agency for Toxic Substances and

Disease Registry

*Legislative Background

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. 
PERCHLORATES 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. 
PERCHLORATES 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 incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (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. 
PERCHLORATES ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Sharon Wilbur, M.A. 

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

Gary Diamond, Ph.D. 

Fernando Llados, Ph.D. 

Marc Odin, M.S., D.A.B.T. 

Mario Citra, Ph.D. 

Daniel Plewak, B.S. 

Jay Tunkel, Ph.D. 

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. 
PERCHLORATES x 

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PERCHLORATES xi 

PEER REVIEW 

Peer reviewers were selected to review the ATSDR Toxicological Profile for Perchlorates. 

The post-public comment draft was reviewed on April 18, 2007 by: 

1. Dr. Jeffrey Fisher, Department Head and Professor, Department of Environmental Health 

Science, the University of Georgia, Athens, Georgia; 

2. Dr. Stephen LaFranchi, Professor, Department of Pediatrics, Head, Pediatric Endocrinology, 

Associate Chair for Education, Oregon Health Sciences University (CDRCP), Portland, Oregon; 

3. Dr. Kannan Krishnan, Professor of Occupational and Environmental Health, University of 

Montreal, Montreal, Quebec, Canada; and 

4. Dr. R. Thomas Zoeller, Professor, Department of Biology, University of Massachusetts at 

Amherst, Morrill Science Center, Amherst, Massachusetts. 

The pre-public comment draft was reviewed on June 26, 2002 by: 

1. Dr. Kannan Krishnan, Professor of Occupational and Environmental Health, University of 

Montreal, Montreal, Quebec, Canada; 

2. Dr. R. Thomas Zoeller, Professor, Department of Biology, University of Massachusetts at 

Amherst, Morrill Science Center, Amherst, Massachusetts; and 

3. Dr. Gary Williams, Professor of Pathology, Department of Pathology, New York Medical 

College, Valhalla, New York. 

These experts collectively have knowledge of perchlorates' 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 reviewers should not be understood to imply their approval of the profile's final 

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

peer reviewers on April 18, 2007 concluded that the minimal risk level (MRL) should still be based on the 

Reference Dose (RfD) as recommended by the NAS Panel Report (2005) given the research data 

available at the time of the 2007 peer review. 
PERCHLORATES xii 

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PERCHLORATES xiii 

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 PERCHLORATES?.................................................................................................1

1.2 WHAT HAPPENS TO PERCHLORATES WHEN THEY ENTER THE 

ENVIRONMENT? ........................................................................................................................3

1.3 HOW MIGHT I BE EXPOSED TO PERCHLORATES? ............................................................5

1.4 HOW CAN PERCHLORATES ENTER AND LEAVE MY BODY?..........................................6

1.5 HOW CAN PERCHLORATES AFFECT MY HEALTH?........................................................... 7

1.6 HOW CAN PERCHLORATES AFFECT CHILDREN?.............................................................. 9

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO PERCHLORATES?........10

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

PERCHLORATES?.....................................................................................................................11

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?.................................................................................................11

1.10 WHERE CAN I GET MORE INFORMATION? .......................................................................13

2. RELEVANCE TO PUBLIC HEALTH .................................................................................................15

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO PERCHLORATES IN THE 

UNITED STATES.......................................................................................................................15

2.2 SUMMARY OF HEALTH EFFECTS........................................................................................ 17

2.3 MINIMAL RISK LEVELS (MRLs)............................................................................................22

3. HEALTH EFFECTS..............................................................................................................................27

3.1 INTRODUCTION .......................................................................................................................27

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE.....................................27

3.2.1 Inhalation Exposure ..............................................................................................................28

3.2.1.1 Death ............................................................................................................................28

3.2.1.2 Systemic Effects...........................................................................................................28

3.2.1.3 Immunological and Lymphoreticular Effects...............................................................33

3.2.1.4 Neurological Effects.....................................................................................................33

3.2.1.5 Reproductive Effects....................................................................................................33

3.2.1.6 Developmental Effects .................................................................................................33

3.2.1.7 Cancer...........................................................................................................................33

3.2.2 Oral Exposure........................................................................................................................33

3.2.2.1 Death ............................................................................................................................33

3.2.2.2 Systemic Effects...........................................................................................................33

3.2.2.3 Immunological and Lymphoreticular Effects...............................................................65

3.2.2.4 Neurological Effects.....................................................................................................67

3.2.2.5 Reproductive Effects....................................................................................................67

3.2.2.6 Developmental Effects .................................................................................................69
PERCHLORATES xiv 

3.2.2.7 Cancer...........................................................................................................................79

3.2.3 Dermal Exposure...................................................................................................................80

3.2.3.1 Death ............................................................................................................................80

3.2.3.2 Systemic Effects...........................................................................................................80

3.2.3.3 Immunological and Lymphoreticular Effects...............................................................80

3.2.3.4 Neurological Effects.....................................................................................................80

3.2.3.5 Reproductive Effects....................................................................................................80

3.2.3.6 Developmental Effects .................................................................................................80

3.2.3.7 Cancer...........................................................................................................................80

3.3 GENOTOXICITY .......................................................................................................................80

3.4 TOXICOKINETICS....................................................................................................................81

3.4.1 Absorption.............................................................................................................................81

3.4.1.1 Inhalation Exposure......................................................................................................81

3.4.1.2 Oral Exposure...............................................................................................................82

3.4.1.3 Dermal Exposure ..........................................................................................................82

3.4.2 Distribution ...........................................................................................................................83

3.4.2.1 Inhalation Exposure......................................................................................................83

3.4.2.2 Oral Exposure...............................................................................................................83

3.4.2.3 Dermal Exposure ..........................................................................................................84

3.4.2.4 Other Routes of Exposure ............................................................................................84

3.4.3 Metabolism............................................................................................................................85

3.4.4 Elimination and Excretion.....................................................................................................85

3.4.4.1 Inhalation Exposure......................................................................................................85

3.4.4.2 Oral Exposure...............................................................................................................86

3.4.4.3 Dermal Exposure ..........................................................................................................86

3.4.4.4 Other Routes of Exposure ............................................................................................87

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models .............87

3.5 MECHANISMS OF ACTION ..................................................................................................108

3.5.1 Pharmacokinetic Mechanisms.............................................................................................108

3.5.2 Mechanisms of Toxicity......................................................................................................110

3.5.3 Animal-to-Human Extrapolations.......................................................................................120

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ..........................123

3.7 CHILDREN’S SUSCEPTIBILITY ...........................................................................................126

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ....................................................................129

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Perchlorates...................................130

3.8.2 Biomarkers Used to Characterize Effects Caused by Perchlorates.....................................132

3.9 INTERACTIONS WITH OTHER CHEMICALS ....................................................................132

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ...............................................134

3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................... 135

3.11.1 Reducing Peak Absorption Following Exposure ............................................................136

3.11.2 Reducing Body Burden................................................................................................... 136

3.11.3 Interfering with the Mechanism of Action for Toxic Effects .........................................136

3.12 ADEQUACY OF THE DATABASE........................................................................................ 136

3.12.1 Existing Information on Health Effects of Perchlorates.................................................137

3.12.2 Identification of Data Needs ...........................................................................................137

3.12.3 Ongoing Studies..............................................................................................................146

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................149

4.1 CHEMICAL IDENTITY...........................................................................................................149

4.2 PHYSICAL AND CHEMICAL PROPERTIES........................................................................149
PERCHLORATES xv 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................153

5.1 PRODUCTION..........................................................................................................................153

5.2 IMPORT/EXPORT....................................................................................................................156

5.3 USE............................................................................................................................................157

5.4 DISPOSAL ................................................................................................................................161

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................165

6.1 OVERVIEW..............................................................................................................................165

6.2 RELEASES TO THE ENVIRONMENT ..................................................................................169

6.2.1 Air .......................................................................................................................................169

6.2.2 Water...................................................................................................................................171

6.2.3 Soil ......................................................................................................................................172

6.3 ENVIRONMENTAL FATE......................................................................................................173

6.3.1 Transport and Partitioning...................................................................................................174

6.3.2 Transformation and Degradation ........................................................................................176

6.3.2.1 Air...............................................................................................................................176

6.3.2.2 Water ..........................................................................................................................177

6.3.2.3 Sediment and Soil.......................................................................................................179

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT .................................179

6.4.1 Air .......................................................................................................................................180

6.4.2 Water...................................................................................................................................180

6.4.3 Sediment and Soil ...............................................................................................................184

6.4.4 Other Media ........................................................................................................................185

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .......................................191

6.6 EXPOSURES OF CHILDREN ................................................................................................. 194

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES..............................................196

6.8 ADEQUACY OF THE DATABASE........................................................................................ 197

6.8.1 Identification of Data Needs ...............................................................................................197

6.8.2 Ongoing Studies ..................................................................................................................202

7. ANALYTICAL METHODS ...............................................................................................................205

7.1 BIOLOGICAL MATERIALS...................................................................................................206

7.2 ENVIRONMENTAL SAMPLES..............................................................................................207

7.3 ADEQUACY OF THE DATABASE........................................................................................ 208

7.3.1 Identification of Data Needs ...............................................................................................208

7.3.2 Ongoing Studies ..................................................................................................................209

8. REGULATIONS AND ADVISORIES ...............................................................................................211

9. REFERENCES ....................................................................................................................................217

10. GLOSSARY ......................................................................................................................................251

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 
PERCHLORATES xvi 

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PERCHLORATES xvii 

LIST OF FIGURES 

3-1. Levels of Significant Exposure to Perchlorates – Inhalation.............................................................. 31 

3-2. Levels of Significant Exposure to Perchlorates – Oral....................................................................... 49 

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

Hypothetical Chemical Substance...................................................................................................... 89

3-4. Structure of PBPK Model of Perchlorate in Typical Adult Humans and Male Rats..........................93

3-5. Structure of PBPK Models of Perchlorate in the Pregnant and Lactating Woman ............................94

3-6. Pathways Uptake and Metabolism of Iodide in the Thyroid Gland..................................................111

3-7. Hypothalamic-pituitary-thyroid (HPT) Feedback Pathways for Regulation of Thyroid 

Hormone Production and Secretion .................................................................................................113

3-8. Comparison of Dose-Response Relationships for the Inhibitory Effect of Perchlorate on 

24-hour Thyroid Iodide Uptake in Humans and Rats ......................................................................122

3-9. Changes in Serum Thyroid Hormone Levels in Rats Exposed to Perchlorate in Drinking Water 

for 14 Days.......................................................................................................................................124

3-10. Existing Information on Health Effects of Perchlorate ..................................................................138

6-1. Frequency of NPL Sites with Perchlorate Contamination................................................................166
PERCHLORATES xviii 

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PERCHLORATES xix 

LIST OF TABLES 

3-1. Levels of Significant Exposure to Perchlorates – Inhalation.............................................................. 30 

3-2. Levels of Significant Exposure to Perchlorates – Oral....................................................................... 34 

3-3. Perchlorate and Radioiodide Parameter Values for the Adult Male Rat and Human PBPK

Models................................................................................................................................................ 91

3-4. Perchlorate Chemical-specific Parameters for Human Gestation and Lactation Models...................96

3-5. Radioiodide Chemical-specific Parameters for Human Gestation and Lactation Models..................98

3-6. Perchlorate Chemical-specific Parameters for Rat Gestation and Lactation Models.......................100

3-7. Iodide Chemical-specific Parameters for Rat Gestation and Lactation Models...............................102

3-8. Model-predicted Serum ClO4

-

 Area Under the Curve (AUC) Across Lifestages............................. 106

3-9. Model-predicted Inhibition of Thyroid Iodide Uptake (Percent Inhibition) Across Lifestages ......107

3-10. Typical Reference Ranges for Serum Thyroid Hormones and TSH in Humans............................116

4-1. Chemical Identity of Perchlorates ....................................................................................................150

4-2. Physical and Chemical Properties of Perchlorates ...........................................................................151

5-1. U.S. Manufacturers of Perchlorates.................................................................................................154

5-2. Import and Export Data for Products that may Contain Perchlorate ................................................158

6-1. Measurements of Perchlorate in Samples of 27 Types of Food and Beverages Collected From

Various Locations in the United States............................................................................................187

6-2. Percent Contribution Organized by Food Group to the Total Estimated Daily Intake for 

Perchlorate for 2005–2006...............................................................................................................188

6-3. Range of Estimated Lower and Upper Bound Average Perchlorate Intake for 2005–2006.............189

6-4. Ongoing Studies on the Potential for Human Exposure to Perchlorates (Including Studies on 

Fate and Occurrence) .......................................................................................................................203

8-1. Regulations and Guidelines Applicable to Perchlorates...................................................................213
PERCHLORATES xx 

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PERCHLORATES 1 

1. PUBLIC HEALTH STATEMENT 

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

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in 

the nation. These sites are then placed on the National Priorities List (NPL) and are targeted for 

long-term federal clean-up activities. Perchlorates have been found in at least 49 of the 

1,581 current or former NPL sites. The possibility exists that the number of sites at which 

perchlorates are found may increase in the future as more sites are evaluated. In addition, 

perchlorate exposure has been found to be more widespread, so that waste sites are only a part of 

the potential perchlorate sources. Other potential sources of exposure include food, some water 

supplies, fireworks, road flares, consumer products such as bleach and matches, and natural 

sources. 

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. 

If you are exposed to perchlorates, many factors will determine whether or not you will be 

affected. These factors include the physical form of the chemical, the dose (how much), the 

duration (how long), and how you come in contact with them. You must also consider any other 

chemicals to which you are exposed and your age, sex, diet, family traits, lifestyle, and state of 

health. 

1.1 WHAT ARE PERCHLORATES? 

The terms perchlorate or perchlorate anion refer to a negatively charged group of atoms 

consisting of a central chlorine atom bonded to four oxygen atoms. Perchlorate has the 

molecular formula ClO4

-

. The terms perchlorates or perchlorate salts refer to the inorganic 

compounds that contain the perchlorate anion bonded to a positively charged group such as 

ammonium or an alkali or alkaline earth metal. 
PERCHLORATES 2 

1. PUBLIC HEALTH STATEMENT 

Perchlorates can form naturally in the atmosphere, leading to trace levels of perchlorate in 

precipitation. High levels of perchlorates occur naturally in some locations, such as regions of 

west Texas and northern Chile. 

Perchlorates are colorless and have no odor. Five perchlorates are manufactured in large 

amounts: magnesium perchlorate, potassium perchlorate, ammonium perchlorate, sodium 

perchlorate, and lithium perchlorate. Perchlorates are found in the environment in two forms, 

either as a solid or dissolved in water. If no water is present, as in a drum or on top of dry 

ground, then they will exist as solids. If water is present, then they will quickly dissolve. When 

perchlorates dissolve, they separate into two parts. One part has a positive charge, and the other 

part has a negative charge. The part with the negative charge is called the perchlorate anion or 

just perchlorate. This is the part of the chemical that people look for in the environment or in 

your body. 

Perchlorates are stable at normal temperatures, but when they are heated to a high temperature, 

they begin to react. Once they begin to react, they produce a large amount of heat. This causes 

more of the perchlorates to begin reacting, which makes even more heat. This chain reaction 

process repeats itself over and over until an explosion occurs. Because perchlorates react this 

way, they are used in rocket motors, fireworks, flares, gunpowder, and explosives. 

Because perchlorates can react quickly at high temperatures, people did not expect to find them 

in the environment. But at normal Earth temperatures, perchlorates react much more slowly. 

We have learned only recently that perchlorates may last in the environment unreacted for 

several years. 

One of the perchlorate salts, ammonium perchlorate, is produced in large amounts because it is 

used in rocket fuels. The solid booster rocket on the space shuttle is almost 70% ammonium 

perchlorate. Perchlorates are also used in explosives. Because perchlorates are used for some 

military applications, many countries consider the amounts that they make confidential. This is 

one reason why we do not know the exact amount of perchlorates produced or used in the United 
PERCHLORATES 3 

1. PUBLIC HEALTH STATEMENT 

States or around the world. As with most chemicals, private companies in the United States are 

not required to provide information on the amount of perchlorates that they make or use. We 

also do not know the exact amount of perchlorates brought into the United States from other 

countries, although the largest amount probably comes from fireworks. It is important to note 

that production figures for a limited set of the larger profile of perchlorate applications do not 

readily translate into environmental release data or accurately characterize the universe of 

perchlorate uses and potential for release. 

Other uses of perchlorates include temporary adhesives, electrolysis baths, batteries, air bags, 

drying agents, etching agents, cleaning agents and bleach, and oxygen generating systems. Little 

data are available on the nature, amount, and potential for release of these possible sources of 

perchlorate to the environment. Perchlorates are also used for making other chemicals. Many 

years ago, perchlorates were used as a medication in the United States to treat overactive thyroid 

glands, and they still have some medical uses in the United States and other parts of the world. 

Perchlorate is also used in treatment of side effects of amiodarone, a drug used in the treatment 

of cardiac arrhythmias and angina. 

You will find more information on the properties of perchlorates in Chapter 4. In Chapter 5, you 

will find more information on the uses of perchlorates and how they are made. 

1.2 WHAT HAPPENS TO PERCHLORATES WHEN THEY ENTER THE 

ENVIRONMENT? 

Perchlorates are soluble in water and generally have high mobility in soils. This characteristic 

results in their ability to move from soil surfaces into groundwater (a process called leaching) 

when they enter the environment. Perchlorates are ionic substances and therefore, do not 

volatilize from water or soil surfaces. Perchlorates are known to remain unreacted in the 

environment for long periods of time; however, there is evidence that microorganisms found in 

soil and water may eventually reduce perchlorate to other substances. If perchlorates are 

released to air, then they will eventually settle out of the air, primarily in rainfall. Perchlorates 

do not appear to accumulate in animals. Chapter 6 contains more information regarding the 

environmental fate and release of perchlorates. Our understanding of perchlorates continues to 
PERCHLORATES 4 

1. PUBLIC HEALTH STATEMENT 

evolve, and scientific understanding related to perchlorates will continue to be reviewed and reevaluated when new information becomes available. 

Before 1997, it was very hard to measure perchlorates in the environment. In 1997, a much 

better method was developed, and low levels of perchlorates in water and other media can now 

be measured. Scientists first began looking for perchlorates near sites where they had been used 

or discarded, and were surprised when they found them in many other places, including areas 

where there was no known perchlorate use. They did not think that perchlorates would last very 

long in the environment because of perchlorate’s reactivity. Since then, scientists have been 

looking for perchlorates in water at more and more places. Perchlorates have recently been 

found in environmental media such as soil, plants, and animals located in areas where 

perchlorate was used and released, and in areas where there was no known use or man made 

releases of perchlorates. 

Perchlorates can enter the environment from several sources, both human-made (called 

anthropogenic) and natural sources. Since perchlorate is used in rockets and certain military 

applications, the manufacture, use, and disposal of products like rockets and missiles has led to 

perchlorate being released into the environment. When rockets undergo successful launches, the 

intense heat leads to nearly complete reaction of the perchlorate. Therefore, release of 

perchlorate to the environment often occurs when its intended use does not occur (for example, 

dismantling and disposal of rockets, accidental release from manufacturing facilities, or 

unsuccessful rocket launches). In the past, some of these activities resulted in high levels of 

perchlorate contamination of soil and groundwater at many military installations and rocket 

manufacturing facilities. Today, great effort is made to minimize the release of perchlorates 

when rockets or missiles are dismantled or when perchlorates are manufactured. Other humanmade sources for perchlorate release into the environment include road-side safety flares and 

fireworks. Perchlorate has also been detected at low levels as an impurity in certain consumer 

products such as bleach, and the use and disposal of these products could also lead to releases. 

Perchlorate is a natural component of a nitrate fertilizer from Chile that was imported and 

regularly used in the United States for many years. Although the use of this fertilizer has 

declined in recent years, perchlorate was released directly to soil and plants in areas where this 
PERCHLORATES 5 

1. PUBLIC HEALTH STATEMENT 

fertilizer was applied. In addition, there appear to be natural sources of perchlorate in the 

environment. Perchlorates can form naturally in the atmosphere, leading to trace levels of 

perchlorate in rainfall. Higher than expected levels of perchlorates occur naturally in some 

locations such as regions of west Texas, New Mexico, and northern Chile. A combination of 

human activities and natural sources has led to the widespread presence of perchlorates in the 

environment. 

1.3 HOW MIGHT I BE EXPOSED TO PERCHLORATES? 

You may be exposed to perchlorates if you eat food or drink water that contains perchlorates. 

Perchlorates have been found in food and milk. Some plants, especially leafy green vegetables, 

have been found to have elevated levels of perchlorate. When water containing perchlorate is 

used to irrigate the plants, perchlorate is left behind when water evaporates from the leaves of the 

plants. Cows may eat fodder containing perchlorate and pass them on in their milk. The Food 

and Drug Administration (FDA) recently published the results of measurements of perchlorate 

and iodine levels in the food supply. The FDA found that 74% of the foods analyzed had at least 

one sample in which perchlorate was detected. The perchlorate dietary intake was estimated for 

14 different age/gender groups in the United States. The lowest intake range was estimated as 

0.08–0.11 μg/kg/day (micrograms/kilogram/day) for males aged 25–30 years, and the highest 

estimated intake was to be 0.35–0.39 μg/kg/day for children 2 years old. These levels are not 

expected to affect human health. The FDA did not recommend any changes in eating habits of 

Americans based upon the measured levels of perchlorate. 

Perchlorates have been found in lakes, rivers, and groundwater wells. Perchlorate has been 

identified at least once in approximately 4% of over 3,800 community water systems sampled 

throughout the United States. From 26 different states and 2 territories, the detectable levels 

averaged 9.8 μg/L (micrograms/liter) and ranged from the minimum reporting level of 4 μg/L to 

a maximum at 420 μg/L. 

Additional potential sources of perchorate may be found if you live near a rocket manufacturing 

or testing facility, if you live near or work at a factory where they are made, or if you live near a 
PERCHLORATES 6 

1. PUBLIC HEALTH STATEMENT 

factory that makes fireworks, flares, or other explosive devices. As mentioned earlier, 

perchlorate is being found in small amounts in areas where it has not been known to be 

manufactured, used, or released by humans. Exposure to perchlorates at these locations may be 

possible because natural levels of perchlorates occur in the environment. 

Perchlorate has been detected at low levels as an impurity in certain products that are commonly 

used by humans. Some of these products include bleach and cleaning products that may contain 

bleach, bottled water, and tobacco products; even some nutritional supplements (vitamins and 

minerals) have been found to contain perchlorates. However, vitamin and mineral supplements 

are typically formulated to include iodine, a factor that would provide protection against any 

possible effect of perchlorate. For more information on how you can be exposed to perchlorates, 

see Chapter 6. 

1.4 HOW CAN PERCHLORATES ENTER AND LEAVE MY BODY? 

Perchlorates can enter the body after you have swallowed food or water containing them. Since 

they easily dissolve in water, they quickly pass through the stomach and intestines and enter the 

bloodstream. If you breathe in air containing dust or droplets of perchlorate, it can pass though 

your lungs and enter the bloodstream. Perchlorates probably do not enter the body directly 

through the skin, but if present on your hands, hand-to-mouth-activity could contribute to oral 

exposure. 

The blood stream carries perchlorate to all parts of the body. Perchlorate is not changed inside 

the body. A few internal organs (for example, the thyroid, breast tissue, and salivary glands) can 

take up relatively large amounts of perchlorate from the bloodstream. Perchlorate generally 

leaves these organs in a few hours. 

When perchlorates are swallowed, a small percentage is eliminated in the feces. More than 

90% of perchlorate taken in by mouth enters the bloodstream. In the blood, perchlorate passes 

into the kidneys, which then release it into the urine. The body begins to clear itself of 

perchlorate through the kidneys within 10 minutes of exposure. Although most of the 
PERCHLORATES 7 

1. PUBLIC HEALTH STATEMENT 

perchlorate that is taken into the body is quickly eliminated, the presence of perchlorate in many 

foods and in some drinking water sources means that exposure may continue to occur on a daily 

basis. 

More information on this subject is found in Chapter 3. 

1.5 HOW CAN PERCHLORATES AFFECT MY HEALTH? 

The main target organ for perchlorate toxicity in humans is the thyroid gland. Perchlorate has 

been shown to partially inhibit the thyroid’s uptake of iodine. Iodine is required as a building 

block for the synthesis of thyroid hormone. Thyroid hormones regulate certain body functions 

after they are released into the blood. Although not demonstrated in humans, it is anticipated 

that people exposed to excessive amounts of perchlorate for a long time may develop a decreased 

production of thyroid hormones. The medical name for this condition is hypothyroidism. 

Hypothyroidism is usually caused by conditions totally unrelated to perchlorates. In 

hypothyroidism, the lower amounts of thyroid hormones in your blood cause increases in 

pituitary hormones that can lead to an increase in the size of the thyroid gland. The medical 

name for this condition is goiter. Because thyroid hormones perform important functions 

throughout the body, many normal body activities also are affected by the lower hormone levels. 

Because perchlorates were known to lower thyroid hormone levels, at one time, perchlorates 

were given as a drug (more than 400 mg per day, which is many times higher than the doses that 

people receive from environmental exposures) to treat people with overactive thyroid glands (a 

condition known as hyperthyroidism). Side effects seen in a small number of treated patients 

were skin rashes, nausea, and vomiting. A few patients developed severe shortages of blood 

cells, and some of them died. Healthy volunteers who took approximately 35 mg of perchlorate 

every day (equivalent to drinking 2 liters of water containing 17 mg/L or 17 parts per million 

[ppm] perchlorate every day) for 2 weeks or 3 mg daily for 6 months (equivalent to drinking 

2 liters of water containing 1.5 mg/L [1.5 ppm] perchlorate every day) showed no signs of 

abnormal functioning of their thyroid gland. A study of adults in Nevada found that the number 

of cases of thyroid disease in a group of people who drank water contaminated with perchlorate 

was no different than the number of cases found in a group of people who drank water without 
PERCHLORATES 8 

1. PUBLIC HEALTH STATEMENT 

perchlorate. This means that levels of perchlorate in the water were not the cause of the thyroid 

disease, and a search of the literature confirms no evidence of perchlorate inducing thyroid 

disease. Two studies of people who worked for years in the production of perchlorate found no 

evidence of alterations in the workers’ thyroids, livers, kidneys, or blood. One of these studies 

estimated that the workers may have taken up about 34 mg of perchlorate per day. A recent 

study showed that perchlorate levels to which the general population of the United States is 

exposed via food and drinking water, were associated with changes in thyroid hormone levels in 

women with low iodine intake, suggesting that the effect of perchlorate in people depends on 

gender, the length of exposure, and how much iodine the people consume. Further research is 

recommended to affirm these findings. 

As mentioned in the preceding sections, perchlorate is a naturally occurring chemical that has 

been found in some foods and in some drinking water supplies. Other naturally occuring 

chemicals, such as thiocyanate (in food and cigarette smoke) and nitrate (in some food), are also 

known to inhibit iodide uptake. Further studies are needed to completely answer all questions 

about potential toxicity of perchlorate. 

The thyroid gland is also the main target organ for perchlorate toxicity in animals. The thyroid 

changes caused by perchlorate in animals may lead to tumors in the thyroid after a long period. 

This has occurred after administering high amounts (928 to 2,573 milligrams perchlorate/kg/day) of 

perchlorate to the animals. The National Academy of Sciences (NAS) concluded that based on 

the understanding of the biology of human and rodent thyroid tumors, it is unlikely that 

perchlorate poses a risk of thyroid cancer in humans. Perchlorates have not been classified for 

carcinogenic effects by the Department of Health and Human Services (DHHS) or the 

International Agency for Research on Cancer (IARC). The EPA has determined that perchlorate 

is not likely to pose a risk of thyroid cancer in humans, at least at doses below those necessary to 

alter thyroid hormone homeostasis, based on the hormonally-mediated mode of action in rodent 

studies and species differences in thyroid function. 

Studies in animals also showed that perchlorate did not affect the reproductive organs or the 

animals’ capacity to reproduce. The NAS found that the studies in animals provided important 
PERCHLORATES 9 

1. PUBLIC HEALTH STATEMENT 

information, but their usefulness to predict whether harmful effects could occur in humans is 

small. 

1.6 HOW CAN PERCHLORATES AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 

Children and developing fetuses may be more likely to be affected by perchlorate than adults 

because thyroid hormones are essential for normal growth and development. Two studies were 

conducted of newborn babies and school-age children from an area in Chile where levels of 

perchlorate in the drinking water were much higher than those detected in some U.S. water 

supplies due to natural sources of perchlorate. No evidence of abnormal thyroid function was 

found among the babies or the children. The mothers and the children may have taken 

approximately 0.2 mg of perchlorate per day in the drinking water. Some studies of newborn 

babies in areas from Arizona, California, and Nevada, where perchlorate has been found in the 

drinking water, have not provided convincing evidence of thyroid abnormalities associated with 

perchlorate. A Centers for Disease Control and Prevention (CDC) study of people all over the 

United States showed that all of the people that were tested had detectable concentrations of 

perchlorate in their urine, thus making it difficult to find an unexposed comparison group as a 

control population. 

As indicated above, perchlorate has been found in breast milk, so that nursing mothers can 

transfer perchlorate to their babies. Nevertheless, the beneficial aspects (biological and 

psychological) of breast-feeding outweigh any risks from exposure to perchlorate from mother’s 

milk, especially if they consume adequate iodine from food and supplements. 

Animal studies have shown a low level of thyroid activity in developing animals exposed to 

perchlorates through the placenta before birth or through the mother’s milk after birth. Modern 

studies of the effects of perchlorate on developing animals have been conducted mostly in rats. 

Several studies in which pregnant rats were given relatively low amounts of perchlorate have 
PERCHLORATES 10 

1. PUBLIC HEALTH STATEMENT 

shown that perchlorate can alter the thyroid gland in the newborn animals. This has generally 

occurred when perchlorate also affected the thyroid of the mothers. In addition, a study 

suggested an alteration in an area of the brain of pups born to rats. The NAS (2005) indicated 

that rats are more sensitive to agents that disturb thyroid function than are humans, so the 

relevance of rat studies in quantitative terms to humans is limited. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO 

PERCHLORATES? 

Although perchlorate is present in food, milk, and drinking water, it is very unlikely that it will 

be present in the air of the average home or apartment. Perchlorates are found in some consumer 

products that people use. They are present in highway and marine signal flares, small fireworks, 

gunpowder, and matches. Storing these items out of the reach of children and not igniting them 

in a closed environment, such as inside the house or the garage, will decrease the potential for 

exposure. 

Although perchlorate has been detected in a few samples of bottled water, the levels have been 

very low. Therefore, if you live near a location where perchlorates have been found in drinking 

water at high levels, using bottled drinking water may reduce the risk to your family, particularly 

if you drink well water that may contain perchlorate. If you live in one of these areas, prevent 

your children from playing in dirt and from eating dirt. Make sure your children wash their 

hands frequently, and before eating. Discourage your children from putting their hands in their 

mouths or doing other hand-to-mouth activities. You may also contact local public health 

authorities and follow their advice. 

If you work in a factory that makes or uses perchlorates, it is possible to carry perchlorate dust 

from work on your clothing, skin, or hair. You may then get perchlorate dust in your car, home, 

or other locations outside of work where family members might be exposed. You should know 

about this possibility if you work with perchlorates. Taking a shower will remove any 

perchlorate dust from your skin or hair. Washing your clothes will remove any perchlorates dust 

from them. 
PERCHLORATES 11 

1. PUBLIC HEALTH STATEMENT 

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

EXPOSED TO PERCHLORATES? 

Methods to measure perchlorate in the body are not routinely available, but perchlorate can be 

measured in the urine. Because perchlorate leaves the body fairly rapidly (in a matter of hours), 

perchlorate in the urine can only indicate very recent exposure. Levels of thyroid hormones in 

the blood can be monitored. Such tests will tell you if your hormone levels are altered, but will 

not tell you the cause (exposure to perchlorate is only one of many possibilities). Medical tests 

can also measure the capacity of the thyroid gland to take iodide from the blood to manufacture 

thyroid hormones. Exposure to perchlorate can decrease this capacity, but so can exposure to 

other chemicals, as well as iodine deficiency and medical conditions unrelated to any exposure to 

chemicals. 

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 “not-to-exceed” levels, that is, levels of a 

toxic substance in air, water, soil, or food that do not exceed a critical value that is usually based 

on levels that affect animals; they are then adjusted to levels that will help protect humans. 

Sometimes these not-to-exceed 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. 
PERCHLORATES 12 

1. PUBLIC HEALTH STATEMENT 

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. Some regulations and recommendations for perchlorates include the following: 

The EPA is currently undertaking efforts to make a determination as to whether or not a national 

primary drinking water regulation is needed for perchlorate. To make this determination, EPA is 

evaluating information to more fully characterize perchlorate exposure to determine if regulation 

of perchlorate in drinking water would represent a meaningful opportunity for reducing risks to 

human health as required under the Safe Drinking Water Act (SDWA). 

The EPA has developed a Reference Dose (RfD) of 0.0007 mg/kg/day for perchlorate. The RfD 

is an estimate of a daily oral exposure to the human population (including sensitive subgroups) 

that is likely to be without appreciable risk of deleterious effects during a lifetime. This RfD 

leads to a drinking water equivalent level (DWEL) of 24.5 ppb. EPA calculates the DWEL using 

the RfD, multiplied by an adult body weight of 70 kg, and divided by a tap water consumption 

value of 2 L/day. EPA’s Office of Solid Waste and Emergency Response has provided guidance 

for perchlorate that indicates that the RfD and its corresponding DWEL of 24.5 ppb are 

respectively the recommended “to be considered” (TBC) value and the preliminary remediation 

goal (PRG) for cleanup under the Comprehensive Environmental Response, Compensation, and 

Liability Act of 1980 (CERCLA). The EPA is also responsible for developing guidelines for 

controlling hazardous waste from the time it is generated until its ultimate disposal—in effect, 

from “cradle to grave”. 

The Department of Transportation (DOT) has designated perchlorate as a hazardous material and 

limits the quantity that is transported aboard aircraft and vessels. The DOT also provides 

identification and protective guidance for an emergency response to a transportation incident 

involving a hazardous material. 

The Department of Defense (DOD) must comply with any EPA cleanup standards and processes 

under all applicable environmental laws and regulations, including CERCLA, the Resource 

Conservation and Recovery Act (RCRA), the Clean Water Act (CWA), and the SDWA. DOD 
PERCHLORATES 13 

1. PUBLIC HEALTH STATEMENT 

policy requires the testing of perchlorate when it is reasonably expected that a release has 

occurred. Specifically, the DOD’s policy states that in the absence of federal or state standards, 

if perchlorate levels in water exceed 24 ppb (current level of concern for managing perchlorate), 

a site-specific risk assessment must be conducted. When an assessment indicates that the 

perchlorate contamination could result in adverse health effects, the site must be prioritized for 

risk management. DOD will also comply with applicable state or federal promulgated standards, 

whichever is more stringent. Additionally, DOD established the Emerging Contaminants 

Directorate in 2006 to help the department proactively approach emerging contaminants to 

enable a fully informed, risk-based investment decision process that protects human health and 

DOD operations capabilities; perchlorate is one of seven emerging contaminants included on 

DOD’s Action List. 

The FDA has developed Dietary Guidelines that promote health and reduce risk for chronic diseases 

through diet and physical activity. FDA is not recommending any changes to infants’ and 

children’s diets and eating habits based on current perchlorate data. FDA continues to 

recommend a healthy eating plan, consistent with the Dietary Guidelines for Americans, that 

emphasizes fruits, vegetables, whole grains, and fat-free or low-fat milk and milk products; 

includes lean meats, poultry, fish, beans, eggs, and nuts; and is low in saturated fats, trans fats, 

cholesterol, salt (sodium), and added sugars. Additionally, adequate intake of iodine has 

previously been recognized as important for healthy thyroid function. 

See Chapter 8 for more information on regulations and advisories regarding perchlorates. 

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. 
PERCHLORATES 14 

1. PUBLIC HEALTH STATEMENT 

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-32 

 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/ 
PERCHLORATES 15 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO PERCHLORATES IN THE 

 UNITED STATES 

Perchlorates are high melting point inorganic salts that are soluble in water. There are five perchlorate 

salts that are manufactured in substantial amounts: magnesium, potassium, ammonium, sodium, and 

lithium perchlorate. Perchlorates are powerful oxidizing agents and at elevated temperatures, they can 

react explosively. The production volume of ammonium perchlorate far outpaces the other salts and it is 

used primarily as the oxidant for solid rocket boosters as well as some other industrial applications. The 

solid propellant on U.S. Space Shuttle booster rockets is approximately 70% ammonium perchlorate. The 

rockets that use perchlorates in defense and aerospace activities are engineered to utilize all of the 

perchlorate during a successful launch. Perchlorates are also used extensively in electroplating, 

fireworks, munitions, and other pyrotechnic devices. Perchlorates are also present in fertilizers that were 

made with Chilean saltpeter. 

Perchlorates are released to the environment from a combination of anthropogenic and natural sources. 

Perchlorate releases from accidents at manufacturing facilities and unsuccessful rocket launches, as well 

as activities related to the manufacture, disposal, or research of propellants, explosives, or pyrotechnics, 

are well documented. Perchlorate releases from fireworks, road safety flares, the use of certain fertilizers, 

and natural sources of perchlorate in the environment have also been documented. Perchlorate may be 

released to the environment when certain consumer products that contain perchlorate are used or disposed 

of. These potential releases are discussed in greater detail in Chapter 6. 

In water, perchlorates will rapidly dissolve and completely dissociate into the perchlorate anion and the 

corresponding cation. The cations of the solid perchlorate salts listed in Table 4-1 are naturally occurring 

and ubiquitous in the environment. It is the perchlorate anion that is responsible for the potential adverse 

health effects. In the remainder of this document, perchlorates will be used to refer to the solid salts and 

perchlorate anion (or simply perchlorate) will be used to refer to the anionic species that is monitored in 

the environment. 

The perchlorate anion is highly mobile in wet soil and it is expected to ultimately partition to surface 

water and groundwater. On dry soil, it is immobile. Perchlorate is an ionic compound and therefore, does 

not volatilize from soil or water surfaces. Few studies were located that discuss bioaccumulation of 

perchlorates. Based on existing data, bioconcentration of perchlorate appears to be low for aquatic and 
PERCHLORATES 16 

2. RELEVANCE TO PUBLIC HEALTH 

terrestrial species, although it has been detected in mammals, amphibians, fish, and insects near a site of 

known contamination. Perchlorates have been shown to accumulate in the leaves of some food crops, 

tobacco plants, and more generally in broad leaf plants. As water transpires from the leaves, perchlorate 

remains behind in the leaf due to it involatility under most environmental conditions. Although 

experimental studies detailing the environmental fate of perchlorates are limited, the current consensus 

indicates that they are persistent under most environmental conditions. The in situ degradation of the 

perchlorate anion in the environment has not yet been demonstrated, although laboratory studies indicate 

that it undergoes biodegradation by a wide variety of microorganisms under anaerobic conditions. There 

is also a growing body of evidence that the perchlorate anion may be reduced to chloride by plants. 

Human exposure to perchlorates is expected to occur primarily through the ingestion of food and water 

containing perchlorate. Efforts are being made to determine the relative contribution of perchlorate from 

food and water. Data from the recently completed FDA Total Diet Study indicate that 74% of the foods 

analyzed had at least one sample in which perchlorate was detected. The perchlorate dietary intake was 

estimated for 14 different age/gender groups in the United States. The lowest intake range was estimated 

as 0.08–0.11 μg/kg/day for males aged 25–30 years, and the highest estimated intake was 0.35– 

0.39 μg/kg/day for children 2 years old. Children had the highest estimated intake on a body weight basis 

as compared to the other age groups because they consume more food per body weight and have different 

food consumption patterns when compared to the other age groups. Perchlorate has also been detected in 

breast milk and in certain consumer products such as dietary (vitamin and mineral) supplements, bottled 

water, and tobacco products. 

The detection of perchlorate in drinking water supplies and in tap water samples indicates that members 

of the general population may be exposed by ingestion of water. Perchlorate has been identified at least 

once in approximately 4% of community water systems from 26 different states and 2 territories, with 

detectable levels averaging 9.8 μg/L and ranging from the method detection limit of 4 μg/L to a 

maximum at 420 μg/L. 

Occupational exposure to perchlorates may occur through the inhalation of the dusts formed during their 

manufacture and use. Deposition of perchlorate dust into the mouth is also possible. Section 6.5 

discusses exposures to the general population and occupational exposures in greater detail. 
PERCHLORATES 17 

2. RELEVANCE TO PUBLIC HEALTH 

2.2 SUMMARY OF HEALTH EFFECTS 

The primary and most sensitive target of the perchlorate anion (perchlorate) is the thyroid gland. 

Perchlorate inhibits the transport of iodide (I-

) from the blood into the thyroid follicle cells. The 

inhibition is thought to be accomplished by perchlorate competitively blocking iodide binding to a carrier, 

or sodium/iodide symporter (NIS), which catalyzes the simultaneous transfer of Na+

 and I- across the 

basolateral membrane of thyroid follicle cells. Perchlorate inhibition of the NIS can limit the availability 

of iodide needed for the production of the thyroid hormones thyroxine (T4) and triiodothyronine (T3), 

which in turn, may affect the circulating levels of T4 and T3. All known effects of perchlorate on the 

thyroid hormone system derive directly or secondarily from the inhibition of the NIS. 

T3 is essential for normal development of the nervous system and for the regulation of metabolism of 

cells in nearly all tissues of the body. Disruption in the availability of T3 in target tissues can result in 

adverse effects on a wide variety of organs and systems. Although some production of T3 occurs in the 

thyroid, most of the T3 that is available to extrathyroidal target tissues derives from deiodination of T4 

outside the thyroid. This reaction is catalyzed by selenium-requiring microsomal enzymes known as 

iodothyronine deiodinases. 

Because of its ability to inhibit thyroid iodide uptake, perchlorate (potassium perchlorate) was used in the 

past to treat subjects with hyperactive thyroids, including people with Graves’ disease, an autoimmune 

disorder. Perchlorate currently is used to treat amiodarone-induced thyrotoxicosis and for diagnosing 

impairments in the synthesis of thyroid hormones in the thyroid (perchlorate iodide discharge test). 

Doses for clinical uses of perchlorate have ranged from 5 to 20 mg/kg/day. Considerable information 

exists on the effects of perchlorate in patients with Graves’ disease and in subjects with hyperthyroidism 

of other etiology, and some of this information is also presented in Chapter 3 of this document. However, 

the main purpose of this review is to describe the effects of perchlorate on subjects otherwise without 

thyroid disorders. 

The main route of exposure to perchlorate for the general population and those exposed to contaminated 

media is through ingestion of food and/or water. As noted previously, efforts are being made to 

determine the relative contribution of perchlorate from food and water. Information on the effects of 

perchlorate in humans comes from occupational studies, studies of the general population (adults, 

children, and neonates), and studies of controlled exposure in volunteers. Occupational studies and 

studies in volunteers who ingested daily doses of perchlorate ≤0.05 mg/kg/day for 14 days or 
PERCHLORATES 18 

2. RELEVANCE TO PUBLIC HEALTH 

≤0.04 mg/kg/day for 6 months days showed no evidence of adverse hematological, hepatic, renal effects, 

or clinically significant thyroid effects. A study of the general population exposed to perchlorate via the 

drinking water found no significant increase in the incidence of thyroid diseases relative to a comparison 

group whose drinking water did not have perchlorate. Most studies of children and neonates in areas 

where perchlorate has been detected in the drinking water have reported no significant alterations in 

indices of thyroid function among the subjects studied. Two studies of Arizona and California residents 

found that increased levels of perchlorate in drinking water were associated with increased serum 

concentration of thyroid stimulating hormone (TSH) in neonates, but the methods used in these two 

studies have been criticized in the literature. There are no reports of exposure to perchlorate being 

associated with adverse reproductive effects or cancer in humans, or with adverse immunologic effects in 

healthy humans. 

The thyroid is also the main target of perchlorate toxicity in animals. Most experimental studies in 

animals designed to characterize the effects of perchlorate exposure have been done in rats. Rats have 

been shown to be more sensitive to agents that disturb thyroid function than are humans. Significant 

changes in serum levels of thyroid hormones at perchlorate doses as low as 0.009 mg/kg/day were 

observed in 14- and 90-day studies in adult rats. Studies in mice have reported similar findings. In 

general, morphological alterations in the thyroid become noticeable at doses higher than those that 

induced changes in serum hormone levels. There is no conclusive evidence that perchlorate is an 

immunotoxicant in animals. Perchlorate did increase the response to a known contact sensitizer in mice, 

but it is not known whether perchlorate itself is a contact sensitizer. Perchlorate has shown no evidence 

of being a neurotoxicant when administered to adult animals, although no comprehensive testing has been 

done in adult animals. A 2-generation reproductive study in rats did not observe any significant 

alterations in standard reproductive indices. Several developmental studies have shown that 

administration of low doses of perchlorate (≥0.009 mg/kg/day) to pregnant animals results in alterations 

in thyroid parameters (serum T4, T3, and TSH, and changes in morphology of the thyroid) in newborn 

and young animals. Some studies that conducted neurobehavioral testing in offspring of rats exposed to 

perchlorate during pregnancy reported no significant treatment-related effects, but the interpretation of the 

results has generated some debate among scientists. Perchlorate has produced thyroid cell hyperplasia 

and papillary and/or follicular adenomas and/or carcinomas in rats and mice exposed to relatively high 

doses. Perchlorate itself does not appear to be genotoxic. 

An expanded discussion of thyroid effects of perchlorate in healthy adults and the young exposed 

perinatally is presented below. Neurodevelopmental effects are included under the same heading of 
PERCHLORATES 19 

2. RELEVANCE TO PUBLIC HEALTH 

Endocrine (Thyroid) Effects since neurodevelopmental alterations are assumed to occur due to 

perchlorate-induced perturbation of maternal and/or fetal thyroid function. 

Endocrine (Thyroid) Effects. As mentioned above, adverse effects on a wide variety of organ 

systems can result from disruption in the availability of T3 to target tissues. Organ systems affected by 

disturbances in T3 levels include the skin, cardiovascular system, pulmonary system, kidneys, 

gastrointestinal tract, liver, blood, neuromuscular system, central nervous system, skeleton, male and 

female reproductive systems, and numerous endocrine organs, including the pituitary and adrenal glands. 

Such an array of secondary potential targets underscores the need to maintain an adequate level of 

circulating thyroid hormones. Furthermore, because thyroid hormones play a critical role in the 

neurological development of the fetus, there is concern that altered thyroid levels (maternal and/or fetal) 

during pregnancy could result in neurodevelopmental effects. 

For the most part, recent studies do not indicate that perchlorate exposure produces large changes in 

thyroid function in males or in women with adequate iodine intake. In an occupational study in which the 

investigators estimated a maximum ingested dose of 34 mg perchlorate/day, or approximately 

0.5 mg/kg/day assuming a body weight of 70 kg, no significant alterations of thyroid parameters were 

observed. Another study of adults from the general population found no significant increase in the 

prevalence of thyroid diseases in a population exposed to perchlorate in the drinking water (4–24 μg/L) 

(0.0001–0.0007 mg/kg/day) relative to a comparison population not exposed to perchlorate. With two 

exceptions, studies of neonates in areas with perchlorate contamination in the drinking water have also 

found no evidence of altered thyroid parameters among the newborns. One study found that increased 

levels of perchlorate in drinking water (6 μg/L) (0.0002 mg/kg/day) were associated with increased serum 

concentration of TSH in a study of neonates in Arizona. Another study reported similar findings of 

neonates in California. However, as indicated earlier, the methods used in the latter two studies have 

been criticized in the literature. A study also examined school-age children in Chile, and found no 

association between the concentration of perchlorate in water and altered thyroid function. In that study, 

residents from one location were exposed to perchlorate in water at a concentration of approximately 

100 μg/L. Assuming a daily intake of 1–2 L of water for the school-age children and a body weight of 

about 25 kg (measured in the study), the daily intake of perchlorate via drinking water could have been 

0.004–0.008 mg/kg/day. As often occurs with human studies, the studies mentioned above have various 

design limitations that must be considered in applying findings to health risk assessment. For example, in 

some of the occupational studies, there could have been exposure misclassification. In addition, 

occupational studies had a cross-sectional design and, thus, were unable to account for any effects of 
PERCHLORATES 20 

2. RELEVANCE TO PUBLIC HEALTH 

exposure to perchlorate that might have occurred in workers who left employment for any reason. In the 

studies that measured TSH in neonates, TSH was measured on a low T4 percentile subset without 

consideration of age at screen; since T4 distribution depends on age, births with screen ages that have 

higher T4 are less likely to be selected for TSH analysis. Explicit measures of perchlorate exposure were 

not obtained in these studies. For example, in a study, exposures were estimated from place of birth; thus, 

individual levels of exposure could not be linked to T4 levels. Regardless of these and other limitations, 

these studies collectively appear to rule out a large perchlorate-related effect on thyroid function. 

The 14-day studies of controlled exposure in volunteers showed that iodide uptake by the thyroid 

(assessed as radioiodine uptake) can be inhibited to a considerable extent in humans without a significant 

change in circulating levels of thyroid hormone and TSH. This is not unexpected given the relatively 

large storage capacity of the thyroid gland of humans. A study reported a maximum inhibition of 

approximately 70% relative to baseline in subjects who received the highest dose of perchlorate, 

0.5 mg/kg/day. No significant inhibition was observed at a dose of 0.02 mg/kg/day. Another study in 

volunteers administered up to approximately 0.04 mg perchlorate/kg/day for 6 months found no 

significant alterations in thyroid function tests, including radioiodine uptake. 

Studies in animals have shown that exposure to perchlorate can induce a wide range of effects on the 

thyroid depending on the dose and duration of exposure. Studies conducted in the past 10 years have 

used much lower doses than earlier studies and have described changes in thyroid parameters in rats 

administered doses as low as 0.009 mg perchlorate/kg/day. The effects have been observed in adults and 

also in young rats exposed in utero and via dams’ milk. A study reported a 20% decrease in serum T3 in 

male rats following 14 days of dosing with 0.009 mg perchlorate/kg/day, and a 14% decrease in T4 and 

12% decrease in T3 in males given the same dose level for 90 days. The magnitude of the effects was 

dose-related and the effects were also observed in females, although the latter appeared somewhat less 

sensitive. At higher doses (≥0.17 mg/kg/day), serum levels of TSH increased and histological alterations 

were evident in the thyroid gland (8.5 mg/kg/day). 

Administration of perchlorate to pregnant animals can result in alterations in thyroid parameters in the 

offspring. The lowest maternal dose at which this has been reported is 0.009 mg perchlorate/kg/day. This 

dose level (and higher) significantly increased TSH and decreased T4 in the dams on gestation day 21, 

and decreased T3 in newborn pups. Whether alterations in fetal thyroid parameters are due solely to an 

altered maternal thyroid, to altered fetal thyroid, or to a combined effect is not totally clear. However, 

there is sufficient information that supports the view that maternal thyroid hormones are crucial for 
PERCHLORATES 21 

2. RELEVANCE TO PUBLIC HEALTH 

normal development. Rat fetal tissues have been shown to contain both T4 and T3 prior to the onset of 

hormone production by the fetal thyroid on approximately day 17 of gestation. Furthermore, thyroid 

hormone-responsive genes that are important in early development of the brain are expressed in the rat 

fetus prior to fetal thyroid hormone production, and expression of these genes is sensitive to the maternal 

thyroid hormone status. Disruption of the maternal thyroid hormone system of rats by removal of the 

maternal thyroid or maternal iodide deficiency results in decreased levels of thyroid hormones in the fetus 

and congenital hypothyroidism. In studies with perchlorate, there is only one published report of thyroid 

effects in the offspring in the absence of apparent maternal thyroid effects. This was reported in a study 

in guinea pigs administered doses as high as 531 mg/kg/day of perchlorate during pregnancy. Overall, the 

available information in animals suggests that as long as serum maternal levels of thyroid hormones are 

maintained within normal levels during pregnancy, there is no apparent developmental risk. Observations 

in humans show that placental transfer of maternal thyroid hormones results in cord blood levels that are 

just below the lower range of normal in newborn infants, suggesting that transfer during fetal life is at 

least partially protective in cases where the fetus cannot produce adequate amounts of T4, providing that 

the maternal thyroid hormone production is not compromised. If this is the case, then inhibition of fetal 

thyroid iodide uptake by perchlorate would not be expected to be sufficient, in itself, to produce 

hypothyroidism in utero, and any effects of perchlorate on fetal hormone status are likely to be caused by 

the combined effects of limiting iodide uptake in the maternal and fetal thyroids. PBPK models predict 

that pregnant women and the fetus will have higher blood concentrations of perchlorate and greater iodide 

uptake inhibition at a given concentration of perchlorate in drinking water than either nonpregnant adults 

or older children. 

As discussed in detail in Section 3.5.3, Animal-to-Human Extrapolations, the response of human adults to 

short-term oral dosages (mg/kg/day) of perchlorate is quantitatively different from the response observed 

in rats given comparable dosages. Similar doses of perchlorate result in a more pronounced 

hypothalamic-pituitary-thyroid (HPT) response in rats, which serves to regulate thyroid iodide transport 

and hormone production in response to a decrease in serum thyroid hormones and iodide levels. 

Differences in the perchlorate dose-response relationships between human and rats are thought to be 

related to a smaller and more rapid turnover of the hormone pool in the rat thyroid and to a more rapid 

clearance of secreted hormone in the rat (serum half-life for T4 is shorter in rats than in humans). The 

NAS recommended that animal studies did not adequately serve as a surrogate for human studies due to 

specific species differences with humans, as demonstrated in the studies discussed above. 
PERCHLORATES 22 

2. RELEVANCE TO PUBLIC HEALTH 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for perchlorates. 

An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. 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 within a given route of exposure. MRLs are based on 

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for 

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. In addition, no dermal exposure risk 

from perchlorate has been documented in the literature. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

No MRLs were derived for inhalation exposure to perchlorate since adequate experimental data were not 

available by this route of exposure. No inhalation studies in animals were located. The inhalation 

database in human is limited to three studies of workers at ammonium perchlorate production facilities 

exposed during an unusual schedule of three 12-hour shifts followed by 3 days without exposure (longtime, intermittent exposure) (Braverman et al. 2005; Gibbs et al. 1998; Lamm et al. 1999). 

Oral MRLs 

ATSDR adopts the National Academy of Sciences (NAS 2005, Health Implications of Perchlorate 

Ingestion) recommended chronic reference dose (RfD) of 0.0007 mg/kg/day for the chronic oral MRL for 

the perchlorate anion (rather than for individual salts). EPA has also adopted this value and the 

perchlorate Integrated Risk Information System (IRIS) (Perchlorate and Perchlorate Salts Summary) 
PERCHLORATES 23 

2. RELEVANCE TO PUBLIC HEALTH 

summary was first posted on 02/18/2005. ATSDR’s decision was made after a careful evaluation of the 

NAS report and of studies that have been published after the NAS (2005) report. The results from newer 

studies do not change the bottom-line recommendation. 

NAS based its derivation of the RfD on the findings of a study by Greer et al. (2002). The RfD was based 

on a no-observed-effect level (NOEL) of 0.007 mg perchlorate/kg/day for thyroidal uptake of radioactive 

iodine (RAIU) in 37 healthy (euthyroid) volunteers (16 males, 21 females) who consumed potassium 

perchlorate in drinking water in doses of 0.007, 0.02, 0.1, or 0.5 mg perchlorate/kg/day for 14 days. In 

24 subjects, thyroidal uptake of RAIU was measured 8 and 24 hours after administration of radioactive 

iodine on exposure days 2 and 14 and also 15 days after exposure. To estimate daily iodine intake, 

24-hour urine samples were collected. Free and total T4, T3, and TSH were sampled 16 times throughout 

the study. Serum antibodies to thyroglobulin and thyroid peroxidase were also measured. Hematological 

and clinical chemistry tests were also conducted throughout the study. Baseline thyroid iodide uptake 

varied greatly among the subjects: 5.6–25.4% for the 8-hour uptake and 9.8–33.7% for the 24-hour 

uptake. Perchlorate inhibited RAIU in a dose-related manner. As a percentage of baseline RAIU, 

inhibition in the 0.007, 0.02, 0.1, and 0.5 mg/kg/day dose groups was 1.8, 16.4, 44.7, and 67.1%, 

respectively. The small decrease in RAIU at 0.007 mg/kg/day was not statistically significant and is well 

within the variation of repeated measurements in normal subjects. The dose is considered the NOEL. No 

significant differences were seen between the 8- and 24-hour measurements or between the 2- and 14-day 

measurements. On post exposure day 15, RAIU rebounded to values slightly over but not significantly 

>100%. Consumption of perchlorate did not significantly alter serum TSH, free T4, or total T4 and 

T3 levels. Serum anti-thyroglobulin levels were below detection levels in all samples tested. Serum antithyroid peroxidase levels were elevated in two subjects at the screening visit and thus, were not related to 

treatment with perchlorate. Hematology and clinical chemistry tests to assess liver and kidney function 

revealed no significant deviations from normal ranges. No difference was observed between the response 

of male and female subjects. The RfD was calculated by dividing the NOEL of 0.007 mg/kg/day for 

inhibition of radioiodide uptake and serum hormone levels by an uncertainty factor of 10 (see below). As 

indicated by the NAS (2005), iodide uptake inhibition is a key biochemical event that precedes all 

potential thyroid-mediated effects of perchlorate exposure. Using a nonadverse effect that is upstream of 

adverse effects is a conservative approach to perchlorate hazard assessment. 

Based on the known mechanism of action of perchlorate as a competitive inhibitor of NIS and on the 

elimination half-time of perchlorate of approximately 8 hours (perchlorate is not expected to accumulate 

in the body), the NAS concluded that a dose that produced minimal inhibition of thyroid iodide uptake 
PERCHLORATES 24 

2. RELEVANCE TO PUBLIC HEALTH 

after 14 days of continuous exposure would also have no appreciable effects on thyroid iodide uptake 

with more prolonged (i.e., intermediate or chronic) exposure. On this basis, the 14-day study was used as 

the basis for adopting the RfD for the chronic MRL. This is supported by another 14-day study 

(Lawrence et al. 2000), long-term studies of workers (Braverman et al. 2005; Gibbs et al. 1998; Lamm et 

al. 1999), and studies of the general population (Li et al. 2001; Téllez et al. 2005) exposed to perchlorate 

that found no significant alterations in thyroid function in the populations examined. A study by 

Braverman et al. (2006) in which 13 volunteers dosed with perchlorate in capsules for 6 months at doses 

of 0, 0.5, and 3 mg/day exhibited no changes in iodine uptake or thyroid hormone level was considered 

for derivation of the MRL. However, this study was limited by a small number of subjects per group (4– 

5), dosing by capsule rather than intermittent exposure in drinking water, and lack of information on 

RAIU during the first 3 months of the study. 

An uncertainty factor of 10 was applied to the NOEL of 0.007 mg/kg/day. The uncertainty factor of 10 is 

intended to protect the most sensitive population—the fetuses of pregnant women who might have 

hypothyroidism or iodide deficiency. Other sensitive populations include preterm infants and nursing 

infants. As discussed by NAS (2005), preterm infants are more sensitive than term infants. The fetus is 

dependent on maternal thyroid hormones at least until the fetal thyroid begins to produce T4 and 

T3 (Zoeller and Crofton 2000). In humans, this occurs at approximately 16–20 weeks of gestation. 

Thyroid hormones are present in human amniotic fluid at 8 weeks of gestation prior to the onset of fetal 

thyroid hormone production (Contempre et al. 1993; Thorpe-Beeston et al. 1991). Thyroid hormone 

receptors are present and occupied by hormone at this time as well, suggesting that the fetus is capable of 

responding to maternal thyroid hormones (Bernal and Pekonen 1984; Ferreiro et al. 1988). The 

contribution of maternal thyroid hormones to the fetal thyroid hormone status is also evident from infants 

who have an inherited disorder that abolishes T4 production but are born, nevertheless, with normal 

serum thyroid hormone levels (i.e., euthyroid) and become hypothyroid after birth if not administered 

thyroid hormones within the first 2 weeks after birth (Larsen 1989; van Vliet 1999; Vulsma et al. 1989). 

This suggests that in the complete absence of fetal thyroid function, the maternal thyroid is able to 

maintain at least partially protective levels of thyroid hormone in the fetus at late term. Uncorrected 

maternal hypothyroidism, on the other hand, may result in impaired neurodevelopment of the fetus 

(Haddow et al. 1999; Pop et al. 1999). By inhibiting NIS in breast tissue (Levy et al. 1997; Smanik et al. 

1997; Spitzweg et al. 1998), perchlorate may also limit the availability of iodide to nursing infants, who 

depend entirely on breast milk for the iodide needed to produce thyroid hormone (Agency for Toxic 

Substances and Disease Registry 2004). No information is available on the doses in humans that might 

decrease iodide uptake into breast milk. A recent study of 57 women in the Boston area found that 47% 
PERCHLORATES 25 

2. RELEVANCE TO PUBLIC HEALTH 

of the women sampled may have been providing breast milk with insufficient iodine to meet the infants’ 

requirements (Pearce et al. 2007); however, the breast milk iodine concentrations were not correlated with 

perchlorate exposure. Radioiodine uptake into mammary milk was decreased in rats exposed to 1 or 

10 mg/kg/day perchlorate in drinking water (Yu et al. 2002). Studies conducted in cows and goats have 

also shown that perchlorate can decrease radioiodine uptake into mammary milk (Howard et al. 1996). 

As discussed by Ginsberg et al. (2007), additional factors that make neonates a sensitive group include 

their shorter serum half-life for T4 of approximately 3 days compared to approximately 7–10 days in 

adults, a lower storage capacity of the thyroid for T4, and possibly slower urinary clearance of perchlorate 

due to immature renal function. Another potential susceptible population is women with urinary iodine 

levels <100 μg/L, as regression analysis of a population study by Blount et al. (2006) indicated that 

perchlorate exposure was correlated with decreased T4 and increased TSH. Limitations of the study 

acknowledged by the investigators include those common to cross-sectional analyses, the assumption that 

urinary perchlorate correlate with levels in the thyroid stroma and tissue, and the measurement of total T4 

rather than free T4. According to the World Health Organization (WHO 2004), median urinary iodine 

levels ≥100 μg/L indicate sufficient iodine intake for the non-pregnant population, whereas pregnant 

women should maintain urinary levels of iodine >150 μg/L. The American Thyroid Association (2006) 

recommends that women generally consume iodine from dairy products, bread, seafood, meat, and some 

iodized salt, but pregnant and lactating women may require additional supplements and vitamins. 

Recently, Blount et al. (2007) assessed perchlorate exposure in a representative sample of the U.S. 

population and compared the results with the NAS-recommended RfD (NAS 2005). The study comprised 

2,820 participants of National Health and Nutrition Survey (NHANES) (2001–2002), 6 years and older. 

The investigators assessed perchlorate exposure based on urinary perchlorate, urinary creatinine 

concentration, and physiological parameters predictive of creatinine excretion rate. By measuring 

perchlorate in urine, the investigators assessed combined exposure to perchlorate from all sources. In 

adults, the estimated median dose of perchlorate was 0.066 μg/kg/day and the 95th percentile of the 

distribution of estimated daily dose was 0.234 μg/kg/day (CI, 0.202–0.268 μg/kg/day), both values lower 

than the MRL of 0.0007 mg/kg/day (0.7 μg/kg/day) that ATSDR adopted from the NAS. Only 11 out of 

1,532 adults aged 20 years and older had estimated perchlorate exposure that exceeded the NASrecommended RfD. Since the study included participants 6-year-old and older, the investigators did not 

have exposure information for infants. In women of reproductive age, which Blount et al. (2007) 

suggested can be used as surrogate population for assessment of fetal exposure, the median estimated 

perchlorate dose was 0.057 μg/kg/day and the 95th percentile 0.214 μg/kg/day. For a subset of 

110 pregnant women, the estimated median perchlorate dose was 0.066 μg/kg/day. The median dose of 
PERCHLORATES 26 

2. RELEVANCE TO PUBLIC HEALTH 

0.066 μg/kg/day for adults estimated by Blount et al. (2007) is in the same range of the lower-bound 

range of average perchlorate food intakes for men and women over 20 years of age of 0.08– 

0.11 μg/kg/day recently estimated by the FDA in the Total Diet Study (Murray et al. 2008). 

The MRL has been reviewed by experts in the field of perchlorate toxicology in 2007 after publication of 

the NAS (2005) report and the publication of the results of the Centers for Disease Control and 

Prevention (CDC) National Health and Nutrition Examination Survey (NHANES) data (Blount et al. 

2007). The expert peer reviewers concluded that the MRL should still be based on the RfD as 

recommended by the NAS Panel Report (2005) given the research data available at the time of the 2007 

peer review. 
PERCHLORATES 27 

3. HEALTH EFFECTS 

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 perchlorates. 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. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

The perchlorate anion forms salts with a wide variety of cations. There are five perchlorate salts that are 

manufactured in substantial amounts: magnesium, potassium, ammonium, sodium, and lithium 

perchlorate (see Section 4.1). The potassium, sodium, and ammonium salts are the ones most commonly 

encountered in the toxicology literature. Therefore, data on potassium, sodium, ammonium, and other 

perchlorate salts were considered pertinent to the assessment of the perchlorate anion. Perchloric acid 

was not included because it is a strong acid and its toxicity is dominated by the irritating effects of the 

hydrogen cation. In the absence of water, the five commercial perchlorates listed above will exist as a 

solid. In water, perchlorate salts (perchlorates) will rapidly dissolve and completely dissociate into the 

perchlorate anion, also referred to as perchlorate, and the corresponding metal cation. Potassium, 

ammonium, and sodium cations are ubiquitous in the environment and are considered spectator ions. 

Therefore, the species of concern in this document is the perchlorate anion. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons potentially exposed to 

perchlorate, 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 
PERCHLORATES 28 

3. HEALTH EFFECTS 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an 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 and the MRLs. 

3.2.1 Inhalation Exposure 

3.2.1.1 Death 

No studies were located regarding lethality in humans or animals after inhalation exposure to perchlorate. 

3.2.1.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, musculoskeletal, dermal, 

or ocular effects in humans or animals after inhalation exposure to perchlorate. 
PERCHLORATES 29 

3. HEALTH EFFECTS 

The highest NOAEL values for systemic effects from the two occupational studies available are recorded 

in Table 3-1 and plotted in Figure 3-1. 

Hematological Effects. No hematological effects were found in ammonium perchlorate workers 

(22–31 high-dose and 18–27 low-dose versus 72–150 controls) exposed for 1–27 years (mean=8.3 years) 

to average perchlorate concentrations of up to 0.63 mg/m3

 (Gibbs et al. 1998). The researchers estimated 

an average cumulative lifetime perchlorate absorbed dose of 38 mg/kg in the high-dose workers in this 

study, which corresponds to a daily dose of 0.01 mg/kg/day based on the approximate average exposure 

duration of 9 years for high-dose workers. Oral exposure due to deposition in the mouth and throat was 

also likely to have occurred. The accuracy of dose estimates from this study is questionable; however, 

because the researchers estimated the fraction absorbed using a study on an unrelated chemical and did 

not consider the size of the inhaled ammonium particles in their calculations. Particle size (mean and 

distribution) is an important determinant of inhaled dose for particulates (EPA 1994). A similar study of 

37 ammonium perchlorate workers also found no evidence of hematological effects among the workers 

(Lamm et al. 1999). The workers were assigned to one of three categories of presumptive exposure based 

on visible dust generated. The average airborne exposure for the high-exposure group was 8.6 mg/day 

(respirable fraction; particle size 0.1–10 μm) or 59.4 mg/day (total particulate perchlorate). Dividing by 

the default inhalation volume of 10 m3

/day results in a respirable concentration of 0.86 mg/m3. The 

absorbed oral dose per shift was calculated using urinary perchlorate measurements and the assumption 

that the absorbed dose that is excreted is 95%. In the low-, medium-, and high-exposure categories, the 

absorbed doses were estimated to be 4, 11, and 34 mg perchlorate/day, respectively. Assuming a body 

weight of 70 kg, the 34 mg/kg oral dose corresponds to about 0.5 mg perchlorate/kg/day. Measures of 

cumulative exposure were not considered in this study. It should be noted that workers exposed to 

perchlorate have an unusual work schedule consisting of three 12-hour day shifts followed by 3 days 

unexposed. 

No studies were located regarding hematological effects in animals after inhalation exposure to 

perchlorate. 

Hepatic Effects. No effects on serum enzymes indicative of liver toxicity were found in the 

ammonium perchlorate workers studied by Gibbs et al. (1998) or among those studied by Lamm et al. 

(1999) (see Hematological Effects above for further details on these studies). No further relevant 

information was located. 
126

0.630.630.630.63

211

0.860.860.860.86

Table 3-1 Levels of Significant Exposure to Perchlorates - Inhalation 

Exposure/ LOAEL 

Duration/ 

Key to

a 

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/m3) (mg/m3) (mg/m3) Chemical Form 

CHRONIC EXPOSURE Systemic 

1 Human 1-27 yr Hemato 0.63 Gibbs et al. 1998 (avg=8.3 yr) 

(occup) NH4ClO4 

Hepatic 0.63

Renal 0.63

Endocr 0.63

2 Human 40% over 5 yr Hemato 0.86 Lamm et al. 1999 (occup) NH4ClO4 

Hepatic 0.86 Renal 0.86 Endocr 0.86 

a The number corresponds to entries in Figure 3-1. avg = average; Endocr = endocrine; Hemato = hematological; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; occup = year(s) 
l a ic golot ameH 

citape H 

l ane R 

e ir n codnE 

Figure 3-1. Levels of Significant Exposure to Perchlorates - Inhalation

Chronic (≤365 days) 

Systemic 

mg/m3

1 

2 2 2 2 

1 1 1 1 

0.1 

C-c at

goD-d

taR-r

P-p gi

oC-q w

snamuHyeknoM-k

esuoM-m

tibbaR-h

hS-a ee p

erreF-f t

egiP-j no

libreG-e

retsmaH-s

niuG-g ae giP

kniM-n

o- htO re

fErecnaC Ltcef slaminA-leve

AOL E SeroM,L ire o slaminA-su

L EAO L slaminA-suoireSsseL,

slaminA-LEAON

ecnaC r Ef tcef L muH-leve a sn

snamuH-suoireSeroM,LEAOL

snamuH-suoireSsseL,LEAOL

amuH-LEAON sn

05DL L/ C50

leveLksiRlaminiM

efferof stc

trehto nah

recnaC
PERCHLORATES 32 

3. HEALTH EFFECTS 

No studies were located regarding hepatic effects in animals after inhalation exposure to perchlorate. 

Renal Effects. No effects on serum enzymes indicative of kidney toxicity or in serum creatinine and 

blood urea nitrogen (BUN) were found in the ammonium perchlorate workers evaluated by Gibbs et al. 

(1998) or Lamm et al. (1999) (see Hematological Effects above for further details on these studies). 

No studies were located regarding renal effects in animals after inhalation exposure to perchlorate. 

Endocrine Effects. No significant effects on serum levels of TSH, total serum thyroxine (TT4), T3, 

or free thyroxine index (FTI) were found among the ammonium perchlorate workers studied by Gibbs et 

al. (1998). The mean airborne concentration of perchlorate to which the workers were exposed ranged 

from 0.02 to 0.63 mg/m3

. The researchers estimated that exposure to airborne perchlorate provided an 

average cumulative lifetime absorbed dose of up to 0.01 mg perchlorate/kg/day for high-exposure 

workers. Comparison of pre- and post-shift serum thyroid hormone measurements for individual workers 

failed to find any evidence of a transient effect associated with daily exposure. In the occupationalexposure study conducted by Lamm et al. (1999), there were also no significant alterations in serum TSH, 

T3, T4, FTI, thyroid hormone binding ratio, or thyroid peroxidase antibody concentrations among the 

workers. In this study, it was estimated that the high-exposure workers, who were exposed to an average 

of 0.86 mg of respirable airborne perchlorate particles/m3

, absorbed doses of approximately 0.5 mg 

perchlorate/kg/day (see above under Hematological Effects for further details on these studies). A study 

conducted in the same manufacturing facility studied by Lamm et al. (1999) found that intermittent, high 

exposure to perchlorate for many years did not induce goiter or any evidence of hypothyroidism among 

the workers as judged by no significant alterations in serum TSH or thyroglobulin even though iodine 

uptakes were decreased during the work shift (Braverman et al. 2005). The median estimated absorbed 

dose was 0.167 mg/kg/day, equivalent to drinking approximately 2 L of water containing 5 mg 

perchlorate/L. It should be mentioned that perchlorate workers are exposed during an unusual schedule of 

three 12-hour shifts followed by 3 days without exposure (long-time, intermittent exposure). Given the 

relatively short elimination half-life of chlorine in workers of approximately 8 hours (Lamm et al. 1999), 

perchlorate would not be expected to accumulate to levels that would cause thyroid problems. 

No studies were located regarding endocrine effects in animals after inhalation exposure to perchlorate. 
PERCHLORATES 33 

3. HEALTH EFFECTS 

No studies were located regarding the following effects in humans or animals after inhalation exposure to 

perchlorate: 

3.2.1.3 Immunological and Lymphoreticular Effects 

3.2.1.4 Neurological Effects 

3.2.1.5 Reproductive Effects 

3.2.1.6 Developmental Effects 

3.2.1.7 Cancer 

3.2.2 Oral Exposure 

NOAEL and LOAEL values in Table 3-2 and Figure 3-2 represent amounts of the perchlorate anion, not 

of the perchlorate salt. 

3.2.2.1 Death 

Several cases of human deaths were reported among hyperthyroid patients treated with potassium 

perchlorate (Barzilai and Sheinfeld 1966; Fawcett and Clarke 1961; Gjemdal 1963; Hobson 1961; 

Johnson and Moore 1961; Krevans et al. 1962). Deaths were due to aplastic anemia or severe 

agranulocytosis and were considered to be causally related to potassium perchlorate. The lethal doses in 

these patients were in the low-to-moderate range of doses employed in thyrotoxicosis therapy: 600– 

1,000 mg potassium perchlorate/day, or roughly 5–12 mg perchlorate/kg/day. The patients had received 

treatment for anywhere between 2 and 8 months. All of the deaths were females (Graves’ disease, the 

most common cause of hyperthyroidism, is far more common in women than in men) and their ages 

ranged from 24 to 82 years. 

Gauss (1972) reported an LD50 dietary concentration of 3.55% (approximately 3,621 mg 

perchlorate/kg/day) for potassium perchlorate in mice exposed for up to 30 days. The first deaths 

occurred within 4 days of the start of treatment. The LD50 value for mice is recorded in Table 3-2 and 

plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

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 3-2 and plotted in Figure 3-2. 
36

3621

227

0.50.50.50.007

0.1

213

0.140.140.140.14

214

0.04

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral 

Exposure/ 

Duration/ 

Key to

a 

Species Frequency 

Figure (Strain) (Route) 

ACUTE EXPOSURE Death 

1 Mouse 6 d 

(NMRI) ad lib 

(F) 

Systemic 

2 Human 14 d 

(W) 

3 Human 14 d 

(W) 

4 Human 14 d 

(W) 

System 

Hemato HepaticRenal

EndocrHematoHepaticRenalEndocrEndocr

LOAEL 

NOAEL Less Serious Serious Reference 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

3621 F (LD50) Gauss 1972 

KClO4 

0.5 Greer et al. 2002

KClO4

0.5 0.5 

b

 c 

0.007 0.1 (42% inhibition of

radioiodine uptake by thethyroid)

0.14 Lawrence et al. 2000

KClO4

0.14 0.14 0.14 0.04 Lawrence et al. 2001

KClO4
226

0.1

39.939.9

9

1.4

7.2

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

5 Rat 

(SpragueDawley) 

6 Rat 

(SpragueDawley) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

14 d ad lib Endocr 0.1 (increased serum TSH in Caldwell et al. 1995 females, decreased T4 in NH4ClO4 (W) males and females, and

decrease T3 in females)

Bd Wt 39.9 Other 39.9 

4 d ad lib Endocr 1.4 M 7.2 M (approximately 20% Mannisto et al. 1979 decrease in T3 and 37% KClO4 (W) decrease inT4) 
200

8.58.58.58.58.58.58.5

0.009

8.58.58.58.5

229

0.09

224

0.05

0.2

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species (Route) NOAEL Less Serious Serious Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

7 Rat 14 d 

ad lib Resp 8.5 Siglin et al. 2000 (SpragueDawley) (W) NH4ClO4

Cardio 8.5

Gastro 8.5

Hemato 8.5Musc/skel 8.5Hepatic 8.5Renal 8.5Endocr 0.009 M (approximately 20%

decreased serum T3 in males) 

Dermal 8.5

Ocular 8.5Bd Wt 8.5Other 8.5

8 Rat 14 d Endocr 0.09 M (increased TSH and Yu et al. 2002 (Sprague- ad lib decreased serum T3) NH4ClO4 Dawley) (W) 9 Mouse 14 d Endocr 0.05 F 0.2 F (significant decrease in BRT 2000 (B6C3F1) ad lib serum T4 levels; NH4ClO4 (W) non-significant increase

in TSH)
218

25.525.525.5

2.6

25.525.5

222

0.05

219

25.5

202

8.5

21

532

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

Exposure/ LOAEL

Duration/

Key to

a

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

10 Mouse 14 d 

(B6C3F1) ad lib Hemato 25.5 F DOD 1999 

(W) NH4ClO4 

Hepatic 25.5 F Renal 25.5 F Endocr 2.6 F (15% decrease serum

T4)

Bd Wt 25.5 F Other 25.5 F 

Immuno/ Lymphoret 

11 Mouse 14 d

(B6C3F1) ad lib 0.05 F (increased response to BRT 2000 sensitizer NH4ClO4 (W) 2,4-dinitrochlorobenzene) 

12 Mouse 14 d 25.5 F DOD 1999 

(B6C3F1) ad lib 

(W) NH4ClO4 

Neurological 

13 Rat 14 d 8.5 Siglin et al. 2000 (Sprague- ad lib NH4ClO4 Dawley) (W) 

Reproductive 

14 Rat Gd 2-8 532 F Brown-Grant 1966 ad lib (Wistar) 

(W) KClO4 
20

1752

203

8.5

124

9

314

0.04

34

64

64

64

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a 

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

15 Rat Gd 1-13 

(Wistar) ad lib 1752 F 

(W) 

16 Rat 14 d 

(Sprague- ad lib 8.5 Dawley) (W) 

INTERMEDIATE EXPOSURE Systemic 

17 Human 4 wk Endocr 9 M (decreased thyroid I and (IN) serum TSH) 

18 Human 6 mo 

1 x/d Endocr 0.04 (C) 

19 Rat 19 wk 

(Wistar) ad lib Hepatic 64 M 

(F) 

Endocr 64 M (thyroid weight doubled; 

24% decrease in serum T4; 100% increase in TSH) 

Bd Wt 64 M 

Brown-Grant and Sherw1971 KClO4 Siglin et al. 2000 NH4ClO4 Brabant et al. 1992 KClO4 Braverman et al. 2006 KClO4 Hiasa et al. 1987 KClO4 
50

23272327

23272327

15

175175

175

307

359

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

20 Rat 

(Wistar) 

21 Rat 

(Wistar) 

22 Rat 

(Wistar) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

6 wk ad lib (W) 25 d ad lib (W) 45 d 1 x/d (G) 

LOAEL 

NOAEL Less Serious Serious Reference 

System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Cardio 2327 M (decreased heart weight) MacDermott 1992 

KClO4 

Musc/skel 2327 M (decreased membrane 

potential and intracellular K+ activity) 

Endocr 2327 M (thyroid weight more than 

doubled; 71% decrease in serum T4) 

Bd Wt 2327 M (27% reduced weight at 6 

weeks) 

Endocr 175 M (thyroid weight tripled; Ortiz-Caro et al. 1983 

undetectable levels of T3 KClO4 and T4 in serum; 50% increase in TSH) 

Bd Wt 175 M (40% reduction in weight 

gain) 

Metab 175 M (decreased alpha-GPD 

activity) 

Metab 359 (decreased glucose and Sangan and Motlag 198

increased urea in serum: KClO4 increased activity of aldolase, LDH, arginase; decreased G-6-Pase) 
53

1059

204

8.58.58.58.58.58.58.5

0.009

8.58.58.58.5

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a 

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

23 Rat 3 mo Shevtsova et al. 1994 ad lib Hemato 1059 M (decreased (Wistar) 

(W) hematopoeisis) KClO4

24 Rat 90 d 

ad lib Resp 8.5 Siglin et al. 2000 (SpragueDawley) (W) NH4ClO4

Cardio 8.5

Gastro 8.5

Hemato 8.5Musc/skel 8.5Hepatic 8.5Renal 8.5Endocr 0.009 (significant decreases in

T4 and T3 in both males and females) 

Dermal 8.5Ocular 8.5Bd Wt 8.5Other 8.5
45

406

228

0.26

2.6

25.525.5

238

0.26

2.6

25.5

0.26

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

25 Rat 

(Wistar) 

26 Rat 

(SpragueDawley) 

27 Rat 

(SpragueDawley) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

45 d 1 x/d Metab 406 M (decreased activity of Vijayalakshmi and Motla

lipase, phospholipase A; 1989a (G) decreased free fatty NaClO4

acids; increasedcholesterol, triglycerides,phospholipids)

>19 wk ad lib Endocr 0.26 2.6 (increased absolute and York et al. 2001a relative thyroid weight in NH4ClO4 (W) both sexes; hypertrophy

and hyperplasia in males;

increased TSH)

Bd Wt 25.5 Other 25.5 

16 wk ad lib Endocr 0.26 2.6 (hypertrophy/hyperplasia York et al. 2001a of the thyroid) NH4ClO4 (W) 

Bd Wt 25.5 Other 0.26 M (decreased water

consumption)
320

0.009

0.09

25.525.5

311

0.009

25.5

225

0.02

0.05

220

25.525.525.50.09

0.85

25.5

25.525.5

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

28 Rat 

(SpragueDawley) 

29 Rat 

(SpragueDawley) 

30 Mouse 

(B6C3F1) 

31 Mouse 

(B6C3F1) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

14 pmd Gd 1-21 pnd 1-10 pnd 1-22 ad lib (W) 45 d (W) 90 d ad lib (W) 90 d ad lib (W) 

System 

Endocr Bd WtOther

Endocr Bd Wt Endocr Hemato Hepatic Renal Endocr Bd Wt Other 

LOAEL 

NOAEL Less Serious Serious Reference 

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

0.009 0.09 (17% increase in serum York et al. 2003

TSH) NH4ClO4

25.5 25.5 

0.009 F (increase serum TSH York et al. 2005a

and decrease T4) NH4ClO4

25.5 F 0.02 F 0.05 F (17% increase in serum BRT 2000

TSH) NH4ClO4

25.5 F DOD 1999

NH4ClO4

25.5 F 25.5 F 0.09 F 0.85 F (significant decrease in 25.5 F (colloid depletion; 

serum T4 levels) intrafollicular capillary

congestion)

25.5 F 25.5 F 
52

1750

23

531

19

3811

38113811

205

8.5

223

0.02

0.05

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

Exposure/ LOAEL

Duration/

Key to

a

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

32 Mouse 3 mo Shevtsova et al. 1994 

(BALB/c) ad lib Hemato 1750 M (decreased hematopoiesis) KClO4 (W) 

33 Gn Pig 30, 60, or 90 d Endocr 531 F (thyroid weight almost Postel 1957 (NS) ad lib tripled; thyroid (W) hyperplasia and colloid KClO4 

depletion) 

34 Dog 3 wk Gastro 3811 (mucosal irritation) Selivanova and Vorobie

(NS) 1 x/d 1969 

(G) NH4ClO4 

Hemato 3811 (inhibition of 

hematopoeisis in bone marrrow) 

Endocr 3811 (inhibited thyroid 

function) 

Immuno/ Lymphoret 

35 Rat 90 d Siglin et al. 2000 (Sprague- ad lib 8.5 

Dawley) (W) NH4ClO4 

36 Mouse 90 d

(B6C3F1) ad lib 0.02 F 0.05 F (increased sensitization BRT 2000 response to NH4ClO4 (W) 2,4-dinitrochlorobenzene) 
221

25.5

206

8.5

207

8.5

209

25.5

310

25.5

215

8.5

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

37 Mouse 

(B6C3F1) 

Neurological 

38 Rat 

(SpragueDawley) 

Reproductive 

39 Rat 

(SpragueDawley) 

40 Rat 

(SpragueDawley) 

41 Rat 

(SpragueDawley) 

Developmental 

42 Rat 

(SpragueDawley) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

90 d DOD 1999 ad lib 25.5 F (W) NH4ClO4 90 d 8.5 Siglin et al. 2000 ad lib (W) NH4ClO4 90 d 8.5 Siglin et al. 2000 ad lib (W) NH4ClO4 16 wk 25.5 York et al. 2001a ad lib (W) NH4ClO4 45 d 25.5 F York et al. 2005a 

(W) 

NH4ClO4 

2 wk pmd Bekkedal et al. 2000 Gd 1-21 8.5pnd 1-10 NH4ClO4

ad lib(W) 
241

1

210

0.26

2.6

216

0.85

25.5

319

0.009

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

a 

Key to Species 

Figure (Strain) 

43 Rat 

(SpragueDawley) 

44 Rat 

(SpragueDawley) 

45 Rat 

(SpragueDawley) 

46 Rat 

(SpragueDawley) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

31 d Gd 2-21 1 (increased TSH and Mahle et al. 2003

pnd 1-10 decreased T4 in pups NH4ClO4

ad lib exposed via maternal milk) (W) 16 wk York et al. 2001a ad lib 0.26 2.6 (thyroid hypertrophy and hyperplasia in F1 NH4ClO4 (W) females and in F2 males

and females)

15 pmd 0.85 25.5 (delayed sternal and York et al. 2003 Gd 1-21 

ad lib phalanges ossification) NH4ClO4 

(W) 14 pmd 0.009 (decreased T3 in fetuses; York et al. 2003 Gd 1-21 

pnd 1-10 increased absolute NH4ClO4

pnd 1-22 thyroid weight inad lib 10-day-old pups; increased TSH and (W) decreased T4 in

22-day-old pups;

increased cerebellumthickness in 22-day-oldpups)
212

2.6

8.5

312

0.009

313

25.5

22

531

54

72

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

Exposure/ LOAEL

Duration/

Key to

a

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

47 Rat 31 d 2.6 8.5 (hypertrophy/hyperplasia York et al. 2004 

Dawley) Ld 1-10 NH4ClO4 (Sprague- Gd 1-21 of follicular epithelium ad lib and decrease in follicle size in pups on pnd 5) (W) 

48 Rat 45 d 0.009 (increased TSH and York et al. 2005a (Sprague- (W) decreased T4 in pups; NH4ClO4 Dawley) decreased T3 in fetuses) 

49 Rat 31-45 d 25.5 York et al. 2005b 

(Sprague- (W) 

Dawley) NH4ClO4 

50 Gn Pig Gd 21-48 Postel 1957 ad lib 531 (increased weight of fetal (NS) thyroid and hyperplasia KClO4 (W) in fetal thyroid) 

51 Rabbit Gd 1-28 

ad lib 72 (significantly enlarged Lampe et al. 1967 (NS) (F) fetal thyroid and KClO4 histological changes in

fetal thyroid )
208

85

31

928

64

1020

25

2573

315

0.0014

24

956

956

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

Exposure/ LOAEL

Duration/

a Frequency Key to Species (Route) NOAEL Less Serious Serious Reference Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

52 Rabbit 22 d 85 York et al. 2001b 

(New Gd 6-28Zealand)� ad lib NH4ClO4

(W) 

Cancer 

53 Rat 12 mo 

ad lib 928 (CEL: thyroid follicular Florencio Vicente 1990 (Wistar) 

(W) adenoma) KClO4

54 Mouse 160 d Gauss 1972 

(NMRI) ad lib 1020 F (CEL: thyroid adenoma) 

(F) KClO4 

55 Mouse 46 wk

(BALB/c) ad lib 2573 F (CEL: thyroid follicular Pajer and Kalisnik 1991 cell carcinoma in 5/6) NaClO4 (W) 

CHRONIC EXPOSURE Systemic 

56 Human lifetime Endocr 0.0014 F Tellez et al. 2005 

(W) 

NH4ClO4 

57 Rat 24 mo 

ad lib Endocr 956 M (thyroid fibrosis) Kessler and Kruskempe

(Wistar) 

(W) KClO4 

Bd Wt 956 M 
28

928

928

316

0.0014

63

956928

Table 3-2 Levels of Significant Exposure to Perchlorates - Oral (continued) 

Exposure/ LOAEL

Duration/

a Frequency Reference Key to Species (Route) NOAEL Less Serious Serious Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

58 Rat 15 mo Toro Guillen 1991 ad lib Endocr 928 (thyroid hypertrophy and (Wistar) 

(W) hyperplasia) KClO4

Bd Wt 928 (unspecified decreased

weight gain)

Developmental 

59 Human gestational 0.0014 Tellez et al. 2005 (W) NH4ClO4 

Cancer 

60 Rat 24 mo Kessler and Kruskempe

(Wistar) ad lib 956 M (CEL: increased papillary and/or follicular KClO4 (W) adenomas in thyroid) 

61 

Rat 15 mo (Wistar) ad lib 928 (CEL: follicular and Toro Guillen 1991 papillary carcinoma of KClO4 (W) thyroid) 

29 

a The number corresponds to entries in Figure 3-2. b ATSDR has adopted the NAS chronic RfD of 0.0007 mg/kg/day for the chronic oral MRL. The RfD was calculated by dividing the NOEL of 0.007 mg/kg/day by an of 10 (for the protection of sensitive populations). c Although inhibition of iodide uptake is not considered adverse, this dose is shown to illustrate the dose at which the effect became statistically significant. ad lib = ad libitum; Bd Wt = body weight; (C) = capsule; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; (F) = food; F = female; Gastro = gastrointestinal; Gd = gestation day; GPD = glycerophosphate dehydrogenase; (GW) = gavage in water; (IN) = ingestion; Hemato = hematological; Ld = la= lethal dose, 50% kill; LDH = lactate dehydrogenase; LOAEL = lowest-observable-adverse-effect level; M = male; Metab = metabolic; mo = month; Musc/skel = muNOAEL = no-observed-adverse-effect level; pmd = pre-mating day; pnd = post-natal day; Resp = respiratory; TSH = thyroid-stimulating hormone; (W) = drinking wax = times; yr = year(s) 
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Ocular Body Weight Other Immuno/Lymphor Neurological Reproductive 

Figure 3-2 Levels of Significant Exposure to Perchlorates - Oral

Acute (≤14 days) 

Systemic 

mg/kg/day

10000 

1m 

1000

100 

10m 10m 10m

10 7r 7r 7r 7r 7r 7r 7r 7r 6r

10m

6r 

1

2 2 2

9m 

3 3 3 3

0.1 2 5r 8r 

9m 4 

0.01 7r 2 

0.001 

15r

14r 

5r 5r

10m 10m 12m 

7r 7r 7r 13r 16r

11m 

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 Level

for effects

other than

Cancer 
Respiratory 

Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Dermal Ocular Body Weight Metabolic 

Figure 3-2 Levels of Significant Exposure to Perchlorates - Oral (Continued)

Intermediate (15-364 days)

Systemic 

mg/kg/day

10000

34d 34d 34d

c-Cat

d-Dog

r-Rat

p-Pig

 -Humans

k-Monkey

m-Mouse

h-Rabbit

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

n-Mink

o-Other

 LOAEL, Less Serious-Animals

NOAEL - Animals

 LOAEL, Less Serious-Humans for effects

 Cancer Effect Level-Animals

LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level

Cancer Effect Level-Humans

NOAEL - Humans

 LD50/LC50

other than

Cancer 

20r 20r 20r 20r

32m

1000 23r

33g 25r 22r 

21r 21r 21r

100

19r 19r 19r

31m 31m 31m 31m 31m 26r 27r 28r 29r

10 24r 24r 24r 24r 24r 24r 24r 17 24r 24r 24r 

26r 27r

1 31m

26r 27r 

0.1 31m 28r 

30m 18

30m 

0.01 24r 28r 29r 

0.001 

q-Cow a-Sheep g-Guinea Pig 
Other 

Immuno/Lymphor Neurological Reproductive Developmental Cancer * 

Figure 3-2 Levels of Significant Exposure to Perchlorates - Oral (Continued)

Intermediate (15-364 days)

Systemic 

mg/kg/day

10000 

55m

1000

c-Cat

d-Dog

r-Rat

p-Pig

 -Humans

k-Monkey

m-Mouse

h-Rabbit

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

n-Mink

o-Other

 LOAEL, Less Serious-Animals

NOAEL - Animals

 LOAEL, Less Serious-Humans for effects

 Cancer Effect Level-Animals

LOAEL, More Serious-Animals LOAEL, More Serious-Humans Minimal Risk Level

Cancer Effect Level-Humans

NOAEL - Humans

 LD50/LC50

other than

Cancer 

54m 53r 

50g

100 52h 51h

31m 26r 28r 37m 40r 41r 45r 49r

10 24r 35r 38r 39r 42r 47r 

44r 47r

1 43r 45r 

27r 44r 

0.1 

36m

36m

0.01 46r 48r

*Doses represent the lowest dose tested per study that produced a tumorigenic

0.001 response and do not imply the existence of a threshold for the cancer endpoint. 

q-Cow a-Sheep g-Guinea Pig 
Endocrine 

Body Weight DevelopmentalCancer * 

Figure 3-2 Levels of Significant Exposure to Perchlorates - Oral (Continued)

Chronic (≥365 days)

Systemic 

mg/kg/day

1000 57r 58r 57r 58r 60r 61r 

100

10

1

0.1

0.01 

2 

56 59 

0.001 

*Doses represent the lowest dose tested per study that produced a tumorigenic

0.0001 response and do not imply the existence of a threshold for the cancer endpoint. 

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 
PERCHLORATES 53 

3. HEALTH EFFECTS 

Respiratory Effects. No studies were located regarding respiratory effects in humans after oral 

exposure to perchlorate. The only relevant information in animals is that from a study by Siglin et al. 

(2000) in which no significant effects on lung weight and no gross or microscopic alterations were found 

in the lungs from rats administered up to 8.5 mg perchlorate/kg/day (as ammonium perchlorate) in the 

drinking water for up to 90 days. 

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after 

oral exposure to perchlorate. 

Absolute and relative heart weights were significantly decreased in rats treated with 2% potassium 

perchlorate (approximately 2,327 mg perchlorate/kg/day) in the drinking water for 6 weeks (MacDermott 

1992). No gross or microscopical alterations were observed in the heart of rats administered ammonium 

perchlorate in the drinking water at doses of up to 8.5 mg perchlorate/kg/day for up to 90 days (Siglin et 

al. 2000); the weight of the heart was also not affected by exposure to perchlorate. 

Gastrointestinal Effects. No information was located regarding gastrointestinal effects of 

perchlorate in healthy humans. Symptoms of gastrointestinal distress, including nausea and vomiting, 

have been reported in a small percentage of cases of hyperthyroid patients treated with potassium 

perchlorate (Crooks and Wayne 1960; Godley and Stanbury 1954). In a review of 250 cases, the 

incidence of nausea was 1.5% (3/200) among patients given 600 or 1,000 mg potassium perchlorate/day 

(approximately 6 or 10 mg perchlorate/kg/day) and 4% (2/50) among patients given 1,500 or 2,000 mg 

potassium perchlorate/day (approximately 15 or 20 mg perchlorate/kg/day) (Crooks and Wayne 1960). 

Although gastrointestinal distress was limited to nausea in most cases, there was one case of a 22-year-old 

anorectic female Graves’ disease patient who experienced burning epigastric discomfort and frequent 

vomiting within days of starting perchlorate treatment (600 mg potassium perchlorate/day or 6 mg 

perchlorate/kg/day), and developed a ruptured duodenal ulcer a week later (Godley and Stanbury 1954). 

Irritation of the gastric mucosa was reported in dogs given 3,811 mg perchlorate/kg/day as ammonium 

perchlorate by gavage for 3 weeks (Selivanova and Vorobieva 1969). In rats administered up to 8.5 mg 

perchlorate/kg/day as ammonium perchlorate in the drinking water for up to 90 days, there was no 

evidence of gross or histological alterations of any section of the gastrointestinal tract (Siglin et al. 2000). 

Hematological Effects. Two recent controlled acute exposure studies in euthyroid volunteers 

provide information of hematological effects of perchlorate in humans. No alterations in hematological 
PERCHLORATES 54 

3. HEALTH EFFECTS 

parameters (complete blood count and routine chemistries) were observed in a group of nine male 

subjects who consumed once a day for 14 consecutive days a solution of potassium perchlorate that 

provided 10 mg of perchlorate/day (Lawrence et al. 2000). Blood tests were repeated on days 7 and 14 of 

dosing and 14 days after perchlorate was discontinued. Assuming a body weight of 70 kg, the perchlorate 

intake was approximately 0.14 mg/kg/day. Similar lack of hematological alterations was reported among 

a group of 37 volunteers who ingested up to 0.5 mg of perchlorate/kg/day for 14 days (Greer et al. 2002). 

Hematological parameters were evaluated in an epidemiological study of school-age children from three 

cities with different concentrations of perchlorate in drinking water in northern Chile (Crump et al. 2000). 

The city with the highest perchlorate concentration was Taltal, 100–120 μg perchlorate/L (ppb); water 

from the city of Chañaral had 5–7 μg/L. Perchlorate was not detected in water from the city of 

Antofagasta. Assuming a default consumption of 1–2 L of water/day and a measured body weight of 

approximately 25 kg, the children in Taltal may have consumed up to 0.004–0.008 mg perchlorate/kg/day 

via the drinking water only, but the Chilean population also has large dietary sources of perchlorate. The 

study comprised 162 children 6–8 years of age of which 127 had resided continuously in their respective 

city since conception. There was nearly an equal number of boys and girls. Analysis of complete blood 

counts showed no significant differences between the three groups of children whether the analysis 

included all of the children or only the lifelong residents. 

Severe hematological effects were found in several cases of hyperthyroid patients treated with potassium 

perchlorate. Some patients developed aplastic anemia, characterized by drastic reductions in circulating 

granulocytes, erythrocytes, and thrombocytes, and a lack of erythropoietic and granulopoietic cells in the 

bone marrow (Barzilai and Sheinfeld 1966; Fawcett and Clarke 1961; Gjemdal 1963; Hobson 1961; 

Johnson and Moore 1961; Krevans et al. 1962). Aplastic anemia was the cause of death in most of the 

documented fatalities associated with potassium perchlorate treatment of thyrotoxicosis. In other patients, 

the decrease in formed blood elements was limited to the granulocytes (agranulocytosis) and/or 

thrombocytes (thrombocytopenia). Agranulocytosis was fatal in at least one case (Barzilai and Sheinfeld 

1966), although other patients survived this condition (Barzilai and Sheinfeld 1966; Crooks and Wayne 

1960; Southwell and Randall 1960; Sunar 1963). The doses in patients who developed agranulocytosis 

and aplastic anemia were mostly in the low-to-moderate range of doses employed in thyrotoxicosis 

therapy: 600–1,000 mg potassium perchlorate/day, or roughly 5–12 mg perchlorate/kg/day. Cases of 

agranulocytosis were found within 14 days to 3 months of the start of potassium perchlorate treatment. 

Although aplastic anemia was found after 2 months of treatment in one case, in most cases, it was only 

found after 4–8 months. All of the documented cases of aplastic anemia and agranulocytosis were 
PERCHLORATES 55 

3. HEALTH EFFECTS 

females (Graves’ disease, the most common cause of hyperthyroidism, is far more common in women 

than in men), with ages ranging from 24 to 82 years. 

Inhibition of hematopoiesis in the bone marrow has also been reported in dogs given 3,811 mg 

perchlorate/kg/day as ammonium perchlorate by gavage for 3 weeks (Selivanova and Vorobieva 1969), 

and in rats and mice exposed to 1% potassium perchlorate in the drinking water for 3 months 

(approximate doses of 1,059 and 1,750 mg perchlorate/kg/day, respectively) (Shevtsova et al. 1994). No 

significant alterations in hematological parameters were reported following administration of ammonium 

perchlorate in a drinking water study in mice at doses up to 25.5 mg perchlorate/kg/day for 14 or 90 days 

(DOD 1999). Similarly, a recent study in rats found no evidence of hematotoxicity after administration of 

up to 8.5 mg perchlorate/kg/day in the drinking water for 90 days (Siglin et al. 2000). The investigators 

evaluated routine hematology and clinical chemistry parameters. 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after 

oral exposure to perchlorate. 

MacDermott (1992) observed a decrease in membrane potential and in intracellular potassium ion activity 

in skeletal muscle from rats treated with 2% potassium perchlorate (approximately 2,327 mg 

perchlorate/kg/day) in the drinking water for 6 weeks. The observed changes are consistent with a 

decrease in the number of sodium-potassium pump units in the muscle. No alterations in gross or 

microscopic appearance of skeletal muscle were reported in rats exposed to doses up to 8.5 mg 

perchlorate/kg/day as ammonium perchlorate in the drinking water for 90 days (Siglin et al. 2000). 

Hepatic Effects. No evidence of liver toxicity, as judged by blood chemistry tests, was observed in a 

group of nine volunteers who ingested approximately 0.14 mg of perchlorate/kg/day as potassium 

perchlorate for 14 consecutive days (Lawrence et al. 2000). Similar results were reported by Greer et al. 

(2002) in a study of 37 volunteers who consumed up to 0.5 mg of perchlorate/kg/day also for 14 days. In 

the study by Crump et al. (2000) of 162 school-age children from three cities in northern Chile with 

different perchlorate concentration in the drinking water (up to 100–120 μg/L), there were no indications 

of altered liver function among the children as measured by serum aspartate aminotransferase (AST), 

alkaline phosphatase (AP), and lactate dehydrogenase (LDH) activities. 

Godley and Stanbury (1954) reported no evidence of liver toxicity in a series of 24 hyperthyroid patients 

treated with potassium perchlorate (600 mg, or approximately 6 mg perchlorate/kg/day) for up to 
PERCHLORATES 56 

3. HEALTH EFFECTS 

52 weeks. However, it is not clear what tests were conducted to monitor effects on the liver or how 

frequently such tests may have been conducted. 

A 0.1% concentration of potassium perchlorate in the diet (about 64 mg perchlorate/day) for 19 weeks 

had no effect on liver weight in rats (Hiasa et al. 1987). A more recent study in rats found that 

administration of ammonium perchlorate in the drinking water at doses up to 8.5 mg perchlorate/kg/day 

for up to 90 days caused no significant alterations in liver weight, in the gross or microscopic appearance 

of the liver, or in serum transaminase activities (Siglin et al. 2000). No effects on liver weight were 

reported in 14- and 90-day studies in mice administered up to 25.5 mg perchlorate/kg/day in the drinking 

water as the ammonium salt (DOD 1999). 

Renal Effects. Limited information exists regarding renal effects of perchlorate in humans. Two 

studies in euthyroid volunteers who ingested up to 0.5 mg of perchlorate/kg/day as the potassium salt for 

14 days found no evidence of renal effects as judged by standard clinical chemistry tests (Greer et al. 

2002; Lawrence et al. 2000). Also, no alterations in BUN or in serum creatinine levels were observed in a 

group of 60 school-age children from northern Chile exposed to perchlorate in their drinking water at 

concentrations up to 100–120 μg/L (Crump et al. 2000). 

In a case report, a patient with severe hyperthyroidism who was treated with an average of 1,068 mg 

sodium perchlorate/day (approximately 12 mg perchlorate/kg/day) for 3.5 months developed nephrotic 

syndrome, as diagnosed by albuminuria, decreased serum albumin, and increased serum cholesterol. The 

effects subsided after treatment was stopped, and were considered by the researchers to probably have 

been treatment-related (Weber and Wolf 1969). 

There is also limited information on the renal effects of perchlorate in animals. In 14- and 90-day 

drinking water studies in rats, doses of up to 8.5 mg/kg/day produced no significant alterations in kidney 

weight or in gross or microscopical appearance of the kidneys (Siglin et al. 2000). In addition, kidney 

function, monitored by measurements of BUN and serum creatinine, was not affected by exposure to 

perchlorate (Siglin et al. 2000). A similar study in mice also found no effects of ammonium perchlorate 

on kidney weight following 14 or 90 days of exposure to up to 25.5 mg perchlorate/kg/day, but kidney 

function tests were not performed (DOD 1999). 

Endocrine Effects. The findings of groundwater contamination with perchlorate in western areas of 

the United States has triggered considerable research on the effects of this anion on the thyroid gland, its 
PERCHLORATES 57 

3. HEALTH EFFECTS 

main target organ, in efforts to describe dose-response relationships at low doses and to define no-effectlevel of exposure. For example, Lawrence et al. (2000) evaluated serum TSH, FTI, total serum 

triiodothyronine (TT3), and RAIU; serum and 24-hour urine perchlorate; and 24-hour urinary iodide 

excretion in volunteers who ingested approximately 0.14 mg perchlorate/kg/day in drinking water for 

14 days. Tests were conducted pre-dosing, on day 7 and 14, and 14 days after perchlorate ingestion was 

discontinued. The only significant finding was a significant decrease in 4-, 8-, and 24-hour RAIU values 

by a mean of about 38% relative to baseline on day 14 of dosing. Fourteen days later, RAIU had 

recovered to a mean of 25% above baseline values. Greer et al. (2002) conducted a similar study in 

volunteers administered 0.007, 0.02, 0.1, or 0.5 mg perchlorate/kg/day in drinking water for 14 days. 

RAIU was measured on exposure days 2 and 14, and 15 days after dosing ceased. To estimate daily 

iodine intake, 24-hour urine samples were collected. As a percentage of baseline RAIU, inhibition in the 

0.007, 0.02, 0.1, and 0.5 mg/kg/day dose groups was 1.8, 16.4, 44.7, and 67.1%, respectively. There were 

no significant differences between the RAIU values measured on day 2 and 14. Fifteen days after 

perchlorate treatment was discontinued, RAIU values were slightly higher than baseline values. Greer et 

al. (2002) also found no significant effects of perchlorate treatment on serum TSH, free T4, TT4, and 

TT3, and on serum antithyroid peroxidase levels; serum antiglobulin levels were below detection levels in 

all samples tested. The National Academy of Sciences (NAS 2005) recommended a chronic RfD of 

0.0007 mg/kg/day for perchlorate based of the findings of Greer et al. (2002). ATSDR has adopted the 

RfD recommended by NAS for the chronic oral MRL. 

A study similar to Greer et al. (2002) was conducted by Braverman et al. (2006) who administered 

capsules containing potassium perchlorate to 13 volunteers (4 males, 9 females) once a day for 6 months. 

The estimated doses were 0 (placebo), 0.5, and 3.0 mg perchlorate/day (approximately 0.04 and 0.007 mg 

perchlorate/kg/day). The outcomes measured were serum thyroid function tests, 24-hour RAIU, serum 

thyroglobulin (Tg), urinary iodine and perchlorate, and serum perchlorate. RAIU, measured at baseline, 

3 and 6 months, and 1 month after termination, was not significantly affected by administration of 

perchlorate, and there were no significant changes in serum total T3, FTI, TSH, or Tg levels during or 

after perchlorate exposure compared to baseline values. The small number of subjects per group (4–5), 

the dosing by capsule rather than intermittent exposure in drinking water, and the lack of information on 

RAIU during the first 3 months of the study weaken the conclusions of this study. 

Other earlier studies in healthy human subjects also showed that perchlorate administered in doses 

between 7 and 10 mg/kg/day reduced thyroid iodide uptake, increased serum iodide levels, and increased 

urinary iodide excretion (Brabant et al. 1992; Bürgi et al. 1974; DeGroot and Buhler 1971; Faure and 
PERCHLORATES 58 

3. HEALTH EFFECTS 

Dussault 1975). Higher doses of perchlorate were used in the past to treat subjects with hyperactive 

thyroids. For example, Stanbury and Wyngaarden (1952) found that a single oral dose of 100 mg of 

potassium perchlorate (approximately 1 mg perchlorate/kg) dramatically reduced uptake of iodide by the 

thyroid gland in Graves’ disease patients. Subsequent to this finding, potassium perchlorate became an 

accepted treatment for hyperthyroidism, and was widely used for this purpose for several years (Connell 

1981; Crooks and Wayne 1960; Godley and Stanbury 1954; Morgans and Trotter 1960). The use of 

perchlorate for the treatment of hyperthyroidism came to a virtual stop due to the appearance of cases of 

aplastic anemia (see Hematological Effects). 

Epidemiological studies evaluating adults, children, and newborns have also been conducted (studies of 

children and newborns are summarized in Section 3.2.2.6, Developmental Effects). However, caution 

should be exercised in the interpretation of the results from the ecological studies due to the ubiquitous 

nature of perchlorate exposure and because the effects of perchlorate are dependent upon iodine uptake, 

so that differences in iodine levels will be important. 

In a study of the general population, Li et al. (2001) examined the prevalence of thyroid diseases in 

Nevada Counties with respect to perchlorate in drinking water. The cohort consisted of all users of the 

Nevada Medicaid program during the period of January 1, 1997 to December 31, 1998. Disease 

prevalence in residents from Clark County (Las Vegas), whose drinking water had 4–24 μg/L of 

perchlorate (0.0001–0.0007 mg perchlorate/kg/day), were compared with those from another urban area 

of similar size (Reno, Washoe County), but with no perchlorate in the water, and also with those from all 

other counties, also with no perchlorate exposure. Patients were defined as those having one or more of 

the following diagnoses of thyroid disease: simple and unspecified goiter, nontoxic nodular goiter, 

thyrotoxicosis with or without goiter, congenital hypothyroidism, acquired hypothyroidism, thyroiditis, 

other disorders of the thyroid, or malignant neoplasm of the thyroid gland. Analysis of the data showed 

no statistically significant period-prevalence rate difference between Clark County and Washoe County. 

For acquired hypothyroidism, the prevalence was lower in Clark County than in other counties (opposite 

to what would be expected). Li et al. (2001) acknowledged that their analysis was a crude analysis since 

age- and sex-adjusted prevalence could not be calculated because of lack of information on age and sex 

distributions of the Medicaid-eligible population in each county. 

A study of 184 pregnant women from three cities (Antofagasta, Chañaral, and Taltal) in northern Chile 

found no significant association between levels of perchlorate in the drinking water and serum levels of 

TSH, T4, or thyroglobulin measured early (16.1 weeks) or late (32.4 weeks) during pregnancy (Téllez et 
PERCHLORATES 59 

3. HEALTH EFFECTS 

al. 2005). The mean concentrations of perchlorate in the drinking water from Chañaral and Taltal were 

5.8 and 113.9 μg/L, respectively; drinking water from Antofagasta had 0.46 μg/L of perchlorate. The 

doses of perchlorate estimated by the investigators for subjects in Antofagasta, Chañaral, and Taltal were 

0.42, 6.1, and 93.5 μg perchlorate/day, respectively. Using a mean measured body weight of 66.8 kg, the 

women from Taltal took doses of approximately 0.0014 mg perchlorate/kg/day. Because of the high 

iodide intake and high background perchlorate in the Chilean diet, the studied women may not be 

representative of the U.S. population. Furthermore, such high iodide intake may effectively compete with 

perchlorate binding sites on the NIS. 

A recent study of 2,299 male and female participants in NHANES (2001–2002) found that, for women 

(n=1,111) but not men, urinary perchlorate was a significant predictor of both serum TT4 and TSH 

concentrations (Blount et al. 2006). Blood and spot urine samples were collected from the subjects. 

Separate analysis of women with urinary iodine <100 μg/L showed that urinary perchlorate was a 

significant negative predictor of TT4 (p<0.0001) and a positive predictor of TSH (p<0.001). For women 

with urinary iodine ≥100 μg/L, urinary perchlorate was a significant positive predictor of TSH (p=0.025), 

but not of TT4 (p=0.550). These associations of perchlorate exposure with TT4 and TSH are coherent in 

direction and independent of other variables known to affect thyroid function, but are present at 

perchlorate exposure levels found in the general population (median estimated dose 0.059 μg/kg bw/day). 

Covariates included in the analyses were: age, race/ethnicity, body mass index, estrogen use, menopausal 

status, pregnancy status, premenarche status, serum C-reactive protein, serum albumin, serum cotinine, 

hours of fasting, urinary thiocyanate, urinary nitrate, and selected medication groups. Of these, several 

were also predictors of thyroid hormones with various degrees of significance. For example, for women 

with urinary iodine <100 μg/L, estrogen use, menopause, pregnancy, premenarche, C-reactive protein, 

and total kilocalorie intake were also predictors of TT4 levels. In the low-iodine group of females, 

urinary perchlorate accounted for 24% of the variance in serum TT4. Limitations acknowledged by the 

investigators include those common to cross-sectional analyses, the assumption that urinary perchlorate 

correlate with levels in the thyroid stroma and tissue, and the measurement of total T4 rather than free T4. 

In addition, not all variables that may impact thyroid function, such as some dietary factors, were 

accounted for. Also, the study does not address a logical temporal association or biologic plausibility. 

The investigators also stated that further research is needed to affirm these findings. 

Studies in laboratory animals have described the thyroid effects of perchlorate in great detail. Reported 

findings have included reduced thyroid iodide uptake, increased levels of iodide in serum, decreased 

serum T4 and T3, increased serum TSH, increased thyroid size and weight, and hypertrophy and 
PERCHLORATES 60 

3. HEALTH EFFECTS 

hyperplasia of thyroid cells, eventually leading to fibrosis and tumor development (see Cancer section), 

(Fernandez-Rodriguez et al. 1991; Florencio Vicente 1990; Gauss 1972; Hartmann et al. 1971; Hiasa et 

al. 1987; Kapitola et al. 1971; Kessler and Kruskemper 1966; Logonder-Mlinsek et al. 1985; MacDermott 

1992; Mannisto et al. 1979; Matsuzaki and Suzuki 1981; Ortiz-Caro et al. 1983; Pajer and Kalisnik 1991; 

Postel 1957; Schonbaum et al. 1965; Selivanova and Vorobieva 1969; Spreca and Musy 1974; TarinRemohi and Jolin 1972; Toro Guillen 1991; Wyngaarden et al. 1952). In general, many studies 

conducted in the early 1990s and before used relatively high doses of perchlorate, and/or only one dose 

level was tested, thus precluding establishing dose-response relationships that defined no-effect dose 

levels. Perchlorate doses reported to produce the effects mentioned above ranged from 7 to 

3,811 mg/kg/day after durations ranging from 1 day to 2 years. 

Studies conducted within the past 10 years in adult nonpregnant animals have used much lower doses of 

perchlorate. For example, Caldwell et al. (1995) conducted a pilot 14-day drinking water study in rats. 

The animals were exposed to one of seven doses of perchlorate ranging from 0.1 to 39.9 mg 

perchlorate/kg/day. Perchlorate administration induced dose-related increases in TSH and decreases in 

T4 and T3 in both males and females, but females appeared to be more sensitive than males. The lowest 

administered dose, 0.1 mg/kg/day, increased TSH and decreased T4 and T3 in females roughly by 15, 12, 

and 34%, respectively, relative to controls. An additional 14-day study in rats reported a significant 

increase in serum TSH and a nonsignificant decrease in T3 at perchlorate doses 0.09 mg/kg/day, the 

lowest level tested (Yu et al. 2002). A more comprehensive 14-day study in rats was conducted by Siglin 

et al. (2000). Perchlorate was administered in the drinking water as the ammonium salt in doses of 0, 

0.009, 0.04, 0.17, 0.85, or 8.5 mg perchlorate/kg/day. At the end of the exposure period, blood TSH was 

significantly increased in males at ≥0.17 mg/kg/day (23%) and in females at ≥0.04 mg/kg/day (17%). 

Blood T4 showed a decreasing trend with increasing perchlorate doses, the differences relative to controls 

achieved statistical significance in both males (23% decrease) and females (18% decrease) only at the 

highest dose level. Blood T3 was significantly decreased (dose-related) in all male groups (21% at the 

lowest dose), but was not significantly affected in any female group. Both absolute and relative thyroid 

weights were significantly increased in males from the highest dose group, no significant effects were 

seen in females. Histological alterations in the thyroid were observed only at the high dose ranging in 

severity classified as minimal, mild, or moderate. Minimal or mild lesions were seen in 7/10 high-dose 

females and 3/10 high-dose males. Moderate lesions were seen in 7/10 males at 8.5 mg/kg/day and 

consisted of follicular cell hypertrophy with microfollicle formation and colloid depletion. There was no 

evidence of focal hyperplasia. 
PERCHLORATES 61 

3. HEALTH EFFECTS 

In a 14-day study in mice exposed to 0, 0.09, 0.85, 2.6, or 25.5 mg perchlorate/kg/day, serum T4 was 

significantly decreased at 2.6 and 25.5 mg/kg/day (14 and 22%, respectively) (DOD 1999). T3 was lower 

than controls, although not significantly, in all treated groups except the 0.85 mg/kg/day group. There 

was no clear pattern of change in TSH levels. Morphological evaluation of the thyroid showed colloid 

depletion, intrafollicular capillary congestion, and mildly hypertrophied follicular epithelium in mice 

from the highest dose group. An additional 14-day study in mice reported a significant decrease in serum 

T4 levels at ≥0.2 mg perchlorate/kg/day and a significant increase in TSH at ≥1.7 mg/kg/day; serum 

T3 was not measured (BRT 2000). Microscopical examination of the thyroid revealed colloid depletion 

and hypertrophy in 5 out of 5 mice dosed with 42.5 mg/kg/day, but no significant alterations at the next 

lower dose level, 1.7 mg/kg/day. 

A 90-day study was conducted in rats exposed to 0, 0.009, 0.04, 0.17, 0.85, or 8.5 mg perchlorate/kg/day 

in the drinking water (Siglin et al. 2000). Following the exposure period, the rats were provided 

uncontaminated drinking water for an additional 30-day period. After the 90 days of exposure to 

perchlorate, relative to controls TSH was significantly increased in males at ≥0.17 mg/kg/day (17% 

increase) and in females at 8.5 mg/kg/day (21% increase). Blood T4 was significantly decreased in both 

males and females from all treated groups (dose-related) (decreases ranged from 14 to 43% in males). 

The effect of perchlorate on blood T3 was similar to that on T4 (12–35% decrease in males). At 

120 days, hormone levels approached control levels except for T4 in males and TSH in females. Both 

absolute and relative thyroid weights were significantly increased in males and females at 8.5 mg/kg/day 

at 90 days but returned to near control values at 120 days. Histological alterations in the thyroid ranged in 

severity from minimal to mild and were seen only at the 8.5 mg/kg/day dose level in both male and 

female rats. The lesions consisted of follicular cell hypertrophy with microfollicle formation and colloid 

depletion. There was no evidence of focal hyperplasia. No abnormal pathology was seen in the thyroid 

after 120 days. 

In a 2-generation reproductive study in rats, the F1 generation was exposed directly to perchlorate (0.26, 

2.6, or 25.5 mg/kg/day) from weaning to 19 weeks of age, at which time, the animals were killed (York et 

al. 2001a). In these adult rats, a significant increase in absolute and relative thyroid weight was seen in 

males at 2.6 and 25.5 mg/kg/day and in all female groups (dose-related). Hypertrophy and hyperplasia of 

the thyroid also occurred at 2.6 and 25.5 mg/kg/day in males and in high-dose females. TSH increased 

only in high-dose males and females and T4 decreased in high-dose males (26% decrease); T3 levels were 

not significantly affected. Hypertrophy and hyperplasia of the thyroid was reported at ≥2.6 mg 

perchlorate/kg/day in the paternal generation of rats in the 2-generation study mentioned above in which 
PERCHLORATES 62 

3. HEALTH EFFECTS 

the rats were exposed for a period that included premating, pregnancy, and lactation (York et al. 2001a); 

the NOAEL was 0.26 mg/kg/day. The highest dose tested, 25.5 mg/kg/day, induced a significant increase 

in TSH and a decrease in T4 in males. 

In developmental studies in rats in which dosing with ammonium perchlorate at doses of 0, 0.009, 0.09, 

0.85, and 25.5 mg perchlorate/kg/day began 14 days premating and continued to gestation day 10 or 21, 

TSH and T4 were significantly increased and decreased, respectively, in a dose-related manner in all 

dosed groups of dams (York et al. 2003, 2005a). In an additional developmental study in rats in which 

exposure started 14 days before mating and continued until postnatal day (PND) 10, treatment with up to 

8.5 mg perchlorate/kg/day caused no maternal toxicity as judged by clinical observations, body and 

thyroid weights, and thyroid histology (York et al. 2004). 

BRT (2000) evaluated serum TSH and T4 levels and thyroid histology in mice in a 90-day study. The 

exposure levels were 0, 0.02, 0.05, 0.2, 1.7, or 42.5 mg perchlorate/kg/day. Treatment with ammonium 

perchlorate decreased serum T4 levels, and the magnitude of the difference relative to controls achieved 

statistical significance at the 1.7 mg/kg/day dose level (18% decrease). The decrease in T4 was doserelated at ≥0.2 mg/kg/day and higher. Serum TSH was significantly elevated at ≥0.05 mg/kg/day relative 

to controls (17% increase at the 0.05 mg/kg/day dose level). Microscopical examination of the thyroid 

revealed hypertrophy in 3 out of 15 mice at 1.7 mg/kg/day, and in 4 out of 5 high-dose mice. Colloid 

depletion was present in 5 out of 5 mice dosed with 42.5 mg/kg/day. No significant treatment-related 

differences were observed between the other groups and controls. 

In a developmental study in New Zealand rabbits, exposure to up to 85 mg perchlorate/kg/day on 

gestation days 6–28 did not significantly alter absolute or relative thyroid weight (York et al. 2001b). 

However, hypertrophy of the follicular epithelium was seen in the does at ≥8.5 mg/kg/day, and the 

incidence was dose-related. Neither serum TSH nor T3 levels were significantly affected by treatment 

with perchlorate. Serum T4 was significantly reduced at 25.5 and 85 mg/kg/day; T4 was also reduced at 

0.85 and 8.5 mg/kg/day, but not significantly. 

Other endocrine effects reported in perchlorate-treated animals included pituitary hypertrophy and 

hyperplasia (Pajer and Kalisnik 1991), reduced serum growth hormone levels (Ortiz-Caro et al. 1983), 

and reduced serum insulin (Tarin-Remohi and Jolin 1972). All of these effects were accompanied by 

thyroid effects in the same studies. Direct correlation of these diverse animal studies to human endocrine 
PERCHLORATES 63 

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systems is not provided, reflecting the NAS (2005) recommendation that such animal studies were not 

indicative or representative of humans. 

Dermal Effects. No reports were found of adverse dermal effects of perchlorate in healthy humans. 

Skin rash was the most frequent side effect of potassium perchlorate therapy in thyrotoxicosis patients, 

occurring primarily in patients receiving doses at the high end of the therapeutic range. Rash was 

observed in 10% (5/50) of patients treated with 1,500 or 2,000 mg (approximately 15 or 20 mg 

perchlorate/kg/day) by Crooks and Wayne (1960), and in 15% (10/67) of patients treated with 1,200 or 

1,600 mg (approximately 12 or 16 mg perchlorate/kg/day) by Morgans and Trotter (1960). However, 

rash was seen in only 0.5% (1/200) patients treated with 600 or 1,000 mg (approximately 6 or 10 mg 

perchlorate/kg/day) by Crooks and Wayne (1960), and in none of the 24 patients treated with 600 mg 

(approximately 6 mg perchlorate/kg/day) by Godley and Stanbury (1954). The observed rash was 

characterized as maculopapular by Crooks and Wayne (1960), and was attributed by these authors to a 

hypersensitivity reaction. Hemorrhagic skin lesions were frequently noted in cases with severe 

hematological effects (Barzilai and Sheinfeld 1966; Fawcett and Clarke 1961; Gjemdal 1963; Hobson 

1961; Johnson and Moore 1961; Krevans et al. 1962; Southwell and Randall 1960). The lesions, which 

were described as punctate erythema, hemorrhagic pustulae, purpuric rash, skin hemorrhage, bleeding 

into the skin, and petecchiae, apparently occurred secondary to the hematological effects. 

In rats administered up to 8.5 mg perchlorate/kg/day as ammonium perchlorate in the drinking water for 

90 days, no significant gross or microscopical alterations in the skin were found throughout the study 

(Siglin et al. 2000). 

Ocular Effects. No studies were located regarding ocular effects in humans after oral exposure to 

perchlorate. Opthalmological examinations on rats dosed with up to 8.5 mg of perchlorate/kg/day for up 

to 90 days revealed no treatment-related effects (Siglin et al. 2000). 

Body Weight Effects. No studies were located regarding body weight effects in humans after oral 

exposure to perchlorate. 

In acute-duration rat studies, reduced growth was reported at an estimated dose of 1,830 mg 

perchlorate/kg/day (Arieli and Chinet 1985), but not at doses of 1,500 mg perchlorate/kg/day or below 

(Caldwell et al. 1995; Kapitola et al. 1971; Matsuzaki and Suzuki 1981; Schonbaum et al. 1965; Siglin et 

al. 2000). In longer-term studies, there are reports of reduced body weight gain in rats at doses of 175 mg 
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perchlorate/kg/day for 25 days (Ortiz-Caro et al. 1983), 1,362 mg/kg/day for 18 days (Tarin-Remohi and 

Jolin 1972), 928 mg/kg/day for 12 months (Florencio Vicente 1990), 2,327 mg/kg/day for 6 weeks 

(MacDermott 1992), and 928 mg/kg/day for 15 months (Toro Guillen 1991). Treatment of rats for 

90 days with up to 8.5 mg of perchlorate/kg/day in the drinking water did not result in significant effects 

on growth (Siglin et al. 2000), nor did treatment with 64 mg/kg/day for 19 weeks (Hiasa et al. 1987). 

Also, in a 2-generation reproduction study in rats, no significant effects on body weight were seen in 

F1 animals treated directly with up to 25.5 mg perchlorate/kg/day from weaning to 19 weeks of age in 

addition to being exposed perinatally (York et al. 2001a); no significant effects on body weight were seen 

in the paternal generation also in that study. A study in mice also found no alterations in body weight or 

weight gain following 14 or 90 days of exposure to ammonium perchlorate in the drinking water in doses 

up to 25.5 mg perchlorate/kg/day (DOD 1999). Where present, reduced growth is considered secondary 

to hypothyroidism produced by perchlorate. 

Metabolic Effects. No studies were located regarding metabolic effects in humans after oral exposure 

to perchlorate. 

Researchers in India conducted a number of studies investigating the metabolic effects of perchlorate in 

rats given 500 mg/kg/day of potassium, sodium, or ammonium perchlorate by daily gavage for 45 days 

(Sangan and Motlag 1986, 1987; Vijayalakshmi and Motlag 1989a, 1989b, 1990, 1992). They found that 

perchlorate increased protein metabolism (increased liver arginase activity and serum urea levels), altered 

carbohydrate metabolism (decreased serum glucose and increased liver and kidney glycogen levels, 

reflecting increased activity of aldolase, lactate dehydrogenase, and glycogen synthase, and decreased 

activity of glucose-6-phosphatase and glycogen phosphorylase), and modified lipid metabolism 

(increased cholesterol, triglyceride, and phospholipid, and decreased free fatty acid levels, reflecting 

decreased activity of lipase and phospholipase). They also found that perchlorate reduced the activities of 

mitochondrial enzymes involved in cellular respiration, apparently due to changes in lipid composition of 

mitochondrial membranes (increased cholesterol and decreased phospholipid) reducing membrane 

fluidity. 

Other studies reported only a small (11%), nonsignificant decrease in serum glucose levels in rats exposed 

to potassium perchlorate (1,362 mg perchlorate/kg/day) in the drinking water for 18 days (Tarin-Remohi 

and Jolin 1972), and no effect on serum glucose in rats exposed to 0.1% potassium perchlorate 

(approximately 175 mg perchlorate/kg/day) in the drinking water for 25 days (Ortiz-Caro et al. 1983). No 
PERCHLORATES 65 

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effects were observed on serum glucose levels in rats exposed to up to 8.5 mg of perchlorate/kg/day as 

ammonium perchlorate in the drinking water for up to 90 days (Siglin et al. 2000). 

Ortiz-Caro et al. (1983) observed a significant decrease in the activity of α-glycerophosphate 

dehydrogenase (α-GPD) in hepatic mitochondria in their study that was considered secondary to 

hypothyroidism produced by perchlorate. However, Arieli and Chinet (1985) found no effect on 

cytoplasmic α-GPD in brown fat in rats that received 2% potassium perchlorate (1,830 mg 

perchlorate/kg/day) in the drinking water for 2 weeks. 

Other Systemic Effects. No studies were located regarding other systemic effects in humans after 

oral exposure to perchlorate. 

Eskin et al. (1975) observed reduced iodide uptake, decreased weight, and dysplastic histopathological 

lesions in the mammary gland of rats treated with 459 mg perchlorate/kg/day as sodium perchlorate in the 

drinking water for 8 weeks. Mammary gland dysplasia was also seen in ovariectomized rats given 

estrogen replacement and then dosed with 494 mg perchlorate/kg/day for 8 weeks (Eskin et al. 1976). 

Water consumption was not significantly altered in rats administered up to 40 mg of perchlorate/kg/day 

for 14 days in the drinking water (Caldwell et al. 1995). Neither food or water consumption were affected 

in rats exposed to perchlorate via drinking water in doses up to 8.5 mg/kg/day for up to 90 days (Siglin et 

al. 2000). In a 2-generation reproduction study in rats, paternal males exposed for 16 weeks showed a 

reduction in absolute and relative water consumption at 0.26 and 25.5 mg perchlorate/kg/day, but not at 

2.6 mg/kg/day (York et al. 2001a). In that same study, no significant effects were seen on water 

consumption in the F1 generation exposed directly to up to 25.5 mg perchlorate/kg/day in the drinking 

water from weaning to 19 weeks of age. No significant effects on water consumption were also reported 

in 14- and 90-day studies in mice given ammonium perchlorate in the drinking water in doses of up to 

25.5 mg perchlorate/kg/day (DOD 1999). 

3.2.2.3 Immunological and Lymphoreticular Effects 

No reports were found of perchlorate-induced alterations in immune system parameters in healthy 

humans. Two cases of lymphadenopathy (not further described) were reported among a series of 

247 hyperthyroid patients treated with potassium perchlorate (Morgans and Trotter 1960). Both cases 
PERCHLORATES 66 

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occurred in patients treated with 1,200 or 1,600 mg potassium perchlorate/day (roughly 12 or 16 mg 

perchlorate/kg/day). Lymphoreticular effects were not reported in other case studies. 

Spreca and Musy (1974) found increases in the proportion of degranulated mast cells in the thyroid, skin, 

liver, and lungs of rats treated with potassium perchlorate (approximately 323 mg perchlorate/kg/day) for 

1 day. The effect was greatest in the thyroid (27% decrease) and skin (21% decrease). Degranulation of 

mast cells is typically associated with exposure to an allergen; degranulation releases pharmacological 

mediators of immediate hypersensitivity responses (histamine, heparin, etc.), leading to allergy 

symptoms. Clinical signs of hypersensitivity response were not monitored in this study. There was also 

an increase in the number of mast cells in the thyroid and small decreases in mast cell numbers in the 

skin, liver, and lung. The researchers suggested that the increase in the thyroid was associated with 

hyperplasia in this tissue, and that the decrease in the other tissues may reflect loss of cells by 

degranulation. An increase in mast cell numbers in the thyroid of mice treated with sodium perchlorate 

(1.2% in drinking water, or roughly 2,622 mg perchlorate/kg/day) for 64 days was also reported by 

Logonder-Mlinsek et al. (1985). The extent of mast cell degranulation was not reported in this study. 

More recent studies in animals have tested much lower doses of perchlorate and conducted a more 

complete evaluation of the immune system. For example, 14- and 90-day studies in rats administered 

ammonium perchlorate in the drinking water in doses up to 8.5 mg perchlorate/kg/day reported no 

significant effects on spleen weight and no gross or microscopic alterations in lymph nodes, spleen, and 

thymus; no tests of immunocompetence were conducted in these studies (Siglin et al. 2000). DOD (1999) 

evaluated a series of immunological end points in 14- and 90-day studies in mice exposed to ammonium 

perchlorate in the drinking water in doses of 0, 0.09, 0.9, 2.6, and 25.5 mg perchlorate/kg/day. End points 

evaluated included thymus and spleen weight and cellularity, CD4/CD8 splenocyte and thymocyte 

subpopulations, stem cell progenitors (90-day), melanoma tumor incidence (90-day), natural killer (NK) 

cell activity, delayed-type hypersensitivity (DTH), cytotoxic T cell activity, response to challenge with 

Listeria monocytogenes (90-day), peritoneal macrophage phagocytosis and nitrite production, and specific 

IgM and IgG response to cell dependent sheep red blood cell (SRBC) challenge. Significant findings in 

the 14-day study included an increase in the percent of CD4-/CD8+ thymic lymphocytes at 0.09 and 

0.9 mg/kg/day, decreased macrophage phagocytosis at 0.9 and 25.5 mg/kg/day, and increased DTH 

response at 25.5 mg/kg/day. In the 90-day study, NK cell activity was increased in the highest-dose 

group, macrophage phagocytosis was decreased in all treated groups, the DTH response was also 

increased at 25.5 mg/kg/day, and increased resistance to the challenge with Listeria in the high-dose 

group when challenged only with high immunization levels. Overall, because only a few immunological 
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parameters were affected and resistance to the challenge with Listeria was not decreased, the results of 

this study do not suggest an immunosuppressive function for perchlorate at the doses tested. 

Additional 14- and 90-day drinking water studies exposed mice to 0, 0.02, 0.05, 0.2, 1.7, or 42.5 mg 

perchlorate/kg/day examined the plaque forming cell (PFC) response following sheep red blood cells 

(SRBC) immunization and the ability of mice to generate a hypersensitivity response (local lymph node 

assay [LLNA]) to 2,4-dinitrochlorobenzene (DNCB), a known sensitizing chemical (BRT 2000). No 

significant effects were seen on the PFC response after 14 days of treatment, but an increased response 

was seen after 90 days in the 1.7 and 42.5 mg/kg/day dose groups when the results were expressed as 

number of response per spleen and only at 42.5 mg/kg/day when the responses were expressed per 

number of spleen cells. In the LLNA assay, perchlorate increased the sensitizing potential of DNCB at all 

doses except 1.7 mg/kg/day in the 14-day experiment, whereas in the 90-day experiment, perchlorate 

increased the sensitizing potential of DNCB at 0.05 and 0.2 mg/kg/day, had no effect at 0.02 or 

1.7 mg/kg/day, and decreased it at 42.5 mg/kg/day. It should be mentioned, however, that 

cyclophosphamide, the positive control, did not abolish the sensitizing effect of DNCB alone, calling into 

question the reliability of the experiment. The physiological relevancy of the enhancement of the LLNA 

is unclear. Further research in this area is needed to determine whether perchlorate is a contact sensitizer. 

NOAEL and LOAEL values for immune system effects from the rodent studies are shown in 

Table 3-2 and Figure 3-2. 

3.2.2.4 Neurological Effects 

No studies were located regarding neurological effects in humans after oral exposure to perchlorate and 

limited information is available in animals. No gross or microscopic alterations were observed in the 

brain from rats treated with ammonium perchlorate in drinking water in doses up to 8.5 mg 

perchlorate/kg/day for 14 or 90 days (Siglin et al. 2000). Brain weight was also not significantly altered 

by exposure to perchlorate. 

Neurodevelopmental effects resulting from perinatal exposure to perchlorate are discussed in 

Section 3.2.2.6, Developmental Effects. 

3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after oral exposure to perchlorate. 
PERCHLORATES 68 

3. HEALTH EFFECTS 

Exposure to 1% potassium perchlorate (roughly 532 mg perchlorate/kg/day) in the drinking water on 

days 2 through 8 of gestation had no effect on the number of live litters produced, mean litter size, or 

duration of pregnancy in rats (Brown-Grant 1966). Nor was there any effect on the number or weight of 

implantation sites in lactating pregnant female rats that received approximately 1,752 mg 

perchlorate/kg/day in the drinking water on days 1 through 13 of gestation (Brown-Grant and Sherwood 

1971). 

A more recent 14-day study in male and female rats administered ammonium perchlorate in the drinking 

water at doses up to 8.5 mg perchlorate/kg/day found no alterations in absolute weight of the uterus, 

testes, or ovaries (Siglin et al. 2000). Also, there were no gross or microscopic alterations in the testes, 

prostate, epididymis, uterus, ovaries, or mammary glands. Examination of these end points following 

90 days of exposure to the same doses also revealed no significant effects (Siglin et al. 2000). In addition, 

the 90-day study showed no significant effects on sperm motility, concentration, count, or morphology. 

In a 2-generation reproductive study, male and female rats (P generation) were exposed to ammonium 

perchlorate in the drinking water at target doses of 0, 0.26, 2.6, or 25.5 mg perchlorate/kg/day for 

10 weeks before mating and during pregnancy and lactation (York et al. 2001a). Males were sacrificed 

after 13 weeks of exposure and females were sacrificed on postpartum day (PPD) 21. Offspring (F1) 

were dosed from weaning to 19 weeks of age. Mating of F1 generation females and males produced the 

F2 generation. Male and female mating and fertility parameters were not affected by perchlorate; estrous 

cycling (before cohabitation) was also not altered by exposure to perchlorate. No significant effects were 

seen on number of dams delivering litters, duration of gestation, implantations, any litter parameter, 

lactation index, or sex ratios. In the F1 generation, there were no effects on mating and fertility or in 

sperm parameters; in F1 females, there were no effects on estrous cycling, fertility, sexual maturation, or 

in delivery and litter observations. The NOAEL for reproductive effects of perchlorate in this study was 

25.5 mg/kg/day. Exposure of female rats to up to 25.5 mg perchlorate/kg/day beginning 2 weeks before 

cohabitation with untreated males and continuing during gestation did not result in any significant 

alterations in numbers of corpora lutea and implantations, percent implantation loss, litter size, early or 

late resorptions, or sex ratio (York et al. 2005a). 

The NOAEL values for reproductive effects in these studies are shown in Table 3-2 and Figure 3-2. 
PERCHLORATES 69 

3. HEALTH EFFECTS 

3.2.2.6 Developmental Effects 

Several developmental studies of perchlorate in humans have focused on the evaluation of neonatal 

thyroid parameters. Lamm and Doemland (1999) examined rates of congenital hypothyroidism in seven 

counties of Nevada and California with perchlorate contamination in the drinking water (4–16 μg/L 

[ppb]) (0.0001–0.0005 mg/kg/day). The investigators analyzed data from the neonatal screening 

programs of the two states for any increased incidence of congenital hypothyroidism in those counties. 

The rates for the California births were adjusted for Hispanic ethnicity, which was known to be a risk 

factor for congenital hypothyroidism. During 1996 and 1997, nearly 700,000 newborns were screened. 

The risk ratio in the seven counties was 1.0 (95% confidence interval [CI] 0.9–1.2) (249 cases 

observed/243 expected). The risk ratios for the individual counties relative to statewide expected rates 

ranged from 0.6 to 1.1. While the results showed no increase in rates of congenital hypothyroidism, it is 

known that congenital hypothyroidism is caused by developmental events that are not suspected of being 

affected by perchlorate exposure. 

Kelsh et al. (2003) also found no relationship between congenital hypothyroidism and exposure to 

perchlorate through the drinking water in a study of newborns (n=15,348) whose mothers resided in the 

community of Redlands, California, during the period 1983 through 1997 and who were screened by the 

California Newborn Screening Program. Perchlorate was detected in the water system serving the 

community at a concentration of up to 9 μg/L (mean, <1 μg/L). Two adjacent communities with no 

detectable perchlorate in their water systems, San Bernardino and Riverside (n=695,967), served as 

comparison groups. The majority of the newborns had blood collected for TSH assay 18 hours or more 

after birth. Cases were defined as infants diagnosed with congenital hypothyroidism or whose TSH 

screening concentrations were >25 μU/mL or sometimes >16 μU/mL. Covariates included in the model 

were age at specimen collection, sex, race, ethnicity, birth weight, multiple birth status, and calendar year 

of birth. Analysis of the results showed an adjusted prevalence ratio for congenital hypothyroidism 

of 0.45 (95% CI, 0.06–1.64) and an odds ratio for elevated TSH of 1.24 (95% CI, 0.89–1.68) among all 

newborns screened and 0.69 (95% CI, 0.27–1.45) for newborns whose age at screening was ≥18 hours. 

Limitations of the study include the fact that data from a single year were used to characterize exposures 

over the entire 15 years of the study. 

Li et al. (2000b) compared mean monthly neonatal T4 levels for days 1–4 of life for newborns from the 

city of Las Vegas and Reno, both in Nevada. Las Vegas has perchlorate in its drinking water, whereas 

Reno does not. The cohorts consisted of 17,308 newborns in Las Vegas and 5,882 newborns in Reno 
PERCHLORATES 70 

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evaluated during the period of April 1998 through June 1999; the analysis was restricted to newborns 

whose birth weights were between 2,500 and 4,000 grams. Perchlorate was detected in the drinking water 

from Las Vegas during 7 of the 15 months of the study period at levels of 9–15 μg/L (0.0003– 

0.0004 mg/kg/day). Analyses were performed comparing serum T4 levels of children born during the 

7 months in which perchlorate was detected in the drinking water (period A) and children born during the 

months in which perchlorate was not detected in the drinking water (period B). The mean T4 levels were 

compared in a univariate analysis both crude and stratified by time period. In a multivariate analysis, 

T4 was the outcome variable, city and time period were the main effect variables, and gender, birth 

weight, and age and time of blood collection were the covariates. There was no significant difference in 

mean T4 level between Las Vegas and Reno in the crude analysis or when data were stratified by time 

period (period A or B). Gender, birth weight, and age and time of blood collection were significant 

covariates. 

The same group of investigators also evaluated blood TSH levels in newborns in their first month of life 

from Las Vegas (n=4,070) and Reno (n=133) from December 1998 to October 1999 (Li et al. 2000a). 

TSH levels were measured on screening samples that were below the 10th percentile of T4 daily 

measurements in blood samples collected throughout the state. The analysis was restricted to birth 

weights between 2,500 and 4,500 grams, adjusted for gender and age at screen (days 2–7 vs. 8–30). The 

mean TSH levels of the two cities did not differ significantly, whether crude or stratified by age or sex. 

Multiple linear regression analysis showed that the TSH level was significantly affected by age at which 

the sample was collected (higher at earlier age) and by sex (higher for males), but not by location. These 

findings suggested that neonatal TSH levels were not affected by living in areas where drinking water 

contained up to 15 μg/L of perchlorate (0.0004 mg/kg/day). 

A similar study of newborn TSH levels was conducted by Brechner et al. (2000). TSH levels were 

compared between two cities in Arizona, Yuma and Flagstaff, representing areas of exposure and 

nonexposure, respectively. The study covered a 3-year period between October 1994 and December 

1997. Exposure data for the study period were not available. However, measurements done by EPA in 

1999 showed perchlorate at 6 μg/L (0.0002 mg/kg/day) in Yuma and nondetectable levels in Flagstaff. 

Since the water processing facilities had not changed, and perchlorate persists in water for a long time, 

Brechner et al. (2000) assumed that comparable differences in perchlorate levels existed during the study 

period. The final analysis comprised 1,099 newborns from Yuma and 443 from Flagstaff. The study 

controlled for age at screen and Hispanic ethnicity, but not for gender, gestational age, or birth weight. 

The median first TSH level in Yuma was significantly higher than in Flagstaff (19.9 mU/L vs. 
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13.4 mU/L); this difference occurred in both non-Hispanics and Hispanics. A residual confounding by 

age may have persisted in the analysis due to the higher percentage of newborns screened in the first 

24 hours (when TSH levels peak) in Yuma (11%) compared with Flagstaff (3.1%). Lamm (2003) 

reanalyzed the study and compared TSH neonatal values of Yuma and two cities near Yuma, Somerton 

and San Luis, which get their water from a different source than the city of Yuma. The water from 

Somerton and San Luis is assumed to have no perchlorate contamination. Lamm’s analysis showed no 

significant difference in TSH values between newborns from Yuma and Somerton/San Luis, suggesting 

that the results of Brechner et al. (2000) reflected regional differences, possibly related to the difference in 

altitude (7,000 feet) between Yuma and Flagstaff. 

In an additional, unpublished, study of newborns, Schwartz (2001) evaluated T4 and TSH levels for all 

newborns in California during 1996. All infants were screened for serum T4 and TSH levels, and the 

samples with a low T4 (≤9 mg/dL and the next lowest 5% of the values in each tray of samples) were 

further analyzed for TSH levels. Information on the concentration of perchlorate in tap water was not 

available for this study. Therefore, perchlorate exposure was estimated using the mother’s postal zip 

code, concentration of perchlorate in underground water sources measured between February 1997 and 

June 2000, water source production, water purchases and sales, and characteristics of the water 

distribution system. Ultimately, four categories of exposure were made: 0 (n=255,382), 1–2 μg/L 

(n=127,041), 3–12 μg/L (n=131,483), and ≥13 μg/L (n=1,945). Using default values for daily water 

consumption and for body weight, a concentration of 13 μg of perchlorate/L would provide doses of 

approximately 0.0004 mg perchlorate/kg/day. This study used an analysis of the covariance model. After 

controlling for age at screening, gender, single versus multiple birth, and ethnicity, a statistically 

significant declining trend for T4 was observed with increasing perchlorate exposure. Infants in the low, 

medium, and high exposure groups had 0.97, 1.12, and 1.82 μg/dL lower T4 levels, respectively, than 

unexposed infants. Log transformed TSH values showed a significant increase trend with perchlorate 

exposure (0.029, 0.03, and 0.128 ln μU/mL, in the low, medium, and high exposure groups, respectively). 

Although significant associations were found, Schwartz (2001) noted that 90% of the variability in the 

infants’ hormone levels remained unexplained by perchlorate exposure, gender, multiple birth, birth 

weight, and blood sample age. Schwartz (2001) also noted that no adjustment was made in the study for 

gestational age and laboratory measurement variability, two strong predictors of T4 and TSH. 

As previously mentioned, Crump et al. (2000) conducted a study of school-age children from three cities 

with different concentrations of perchlorate in drinking water in northern Chile. The city with the highest 

perchlorate concentration was Taltal, 100–120 μg perchlorate/L (ppb), water from the city of Chañaral 
PERCHLORATES 72 

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had 5–7 μg/L, and perchlorate was not detected in water from the city of Antofagasta. The study 

comprised 162 children 6–8 years of age, of which 127 had resided continuously in their respective city 

since conception. The children underwent examination of the thyroid gland and a blood sample was 

taken for analysis of TSH, T4, FTI, T3, and antiperoxidase antibody. After adjusting for sex, age, and 

urinary iodide excretion, the children from Taltal and Chañaral had slightly lower TSH levels than 

children from Antofagasta (opposite to expected), but the differences were not statistically significant. 

Serum T4 levels in the city with the highest perchlorate levels were significantly higher than in the city 

with no perchlorate (opposite to expected). Analysis of all of the children included in the study revealed a 

small nonsignificant increase risk of goiter in the cities with perchlorate compared with the city without 

perchlorate, however, there was virtually no difference in risk when only lifelong residents were 

analyzed. The study also found that lifelong residents of Taltal (high perchlorate) were >5 times more 

likely to report a family history of thyroid disease compared with lifelong residents of Antofagasta (no 

perchlorate). Assuming a reference daily consumption of water of 1–2 L and using a body weight for the 

children of approximately 25 kg (measured in the study), a concentration of perchlorate in the drinking 

water of 100 μg/L would provide doses of approximately 0.004–0.008 mg perchlorate/kg/day via drinking 

water alone, but the Chilean population also has large dietary sources of perchlorate. 

Crump et al. (2000) also evaluated TSH levels in neonates from the three cities in northern Chile 

mentioned above. A total of 9,784 neonatal records were analyzed for TSH levels, sex, and date of 

screening for infants born between February 1996 and January 1999. The study did not control for iodine 

intake, ethnicity, or birth weight. The rate of congenital hypothyroidism detected in Chile from 1992 to 

1999 was 1 per 3,484 cases (based on 773,440 newborns screened). In their study, Crump et al. (2000) 

detected seven cases of presumptive congenital hypothyroidism corresponding to a rate of 1 per 

1,270 newborns. All of these cases originated in the city with no detectable levels of perchlorate. Linear 

regression comparisons of TSH by city showed a statistically significant decline in TSH with increasing 

perchlorate concentration in the drinking water, opposite to the known effect of perchlorate. The 

magnitude of the differences in TSH concentrations did not seem to be clinically significant. 

In the Téllez et al. (2005) study of 184 pregnant women in northern Chile mentioned earlier, end points 

evaluated included neonatal weight, length, head circumference, gestational length, and FT4, T3, 

thyroglobulin, and perchlorate in cord serum. The evaluation showed no significant differences between 

the three cities regarding indicators of fetal development or in FT4 or TSH. T3 and thyroglobulin were 

significantly lower among neonates from Chañaral (low perchlorate, 5.8 μg/L) than in the other two cities. 
PERCHLORATES 73 

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T3 and thyroglobulin were not significantly different between newborns from Antofagasta (no 

perchlorate) and Taltal (high perchlorate, 114 μg/L). 

A study conducted in Israel evaluated T4 levels (not specified whether TT4 or FT4) in newborns from 

mothers living in areas with very high (≤340 μg/L, n=97), high (42–94 μg/L, n=216), and low (<3 μg/L, 

n=843) levels of perchlorate (Amitai et al. 2007). Levels of perchlorate in blood from donors living in the 

three areas were used as proxy indicators of exposure. Respective blood perchlorate levels in the very 

high, high, and low exposure proxy groups were 5.99, 1.19, and 0.44 μg/L; these donors had similar blood 

levels of thiocyanate and nitrate. Blood samples from the newborns collected at the age of 36–48 hours 

did not reveal significant differences in T4 levels among the three groups. Mean T4 values in the very 

high, high, and low exposure groups were 13.9, 13.9, and 14.0 μg/L, respectively. In addition, neither 

birth weight nor gestational age was significantly different among the three groups. Although individual 

iodine measures were not conducted, the investigators stated that the study was conducted in iodinesufficient areas. 

Chang et al. (2003) evaluated the potential association between exposure to perchlorate via the drinking 

water and the incidence of attention-deficit-hyperactivity disorder (ADHD) and autism among children 

less than 18 years of age who were recipients of Medicaid in Nevada. The study included subjects from 

Clark County, which includes Las Vegas and in which the concentration of perchlorate in the public water 

supply ranged from undetected to 23.8 μg/L (mean, 10.9 μg/L), as measured in 1997–2001; subjects from 

Washoe County, which includes Reno, with no detectable perchlorate in the water supply served as an 

unexposed comparison group, and the remainder of Nevada served as a rural control. No perchlorate was 

detected in public water supplies from the rural areas. Analysis of the data from the Nevada Medicaid 

program showed that the rates for ADHD and for autism in the area with perchlorate in the drinking water 

did not exceed the rates in the areas without perchlorate in the drinking water. Furthermore, there was no 

difference between the three groups regarding overall fourth-grade school performance. No control was 

made in the analysis for age, sex, race, or ethnicity. 

Studies in laboratory animals have shown that maternal exposure to relatively high doses of perchlorate 

during pregnancy and/or lactation leads to reduced thyroid function. Pups of rats exposed to 1% sodium 

perchlorate in the drinking water (about 1,300 mg perchlorate/kg/day) throughout gestation and lactation 

had reduced growth, increased thyroid weight, drastically decreased serum T4 and T3 levels, and 

markedly increased serum TSH levels compared with controls (Golstein et al. 1988). These effects are 

the typical indicators of hypothyroidism in juvenile and adult rats treated with perchlorate directly. In a 
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study in guinea pigs, near-term fetuses from dams treated with 1% potassium perchlorate (about 531 mg 

perchlorate/kg/day) in the drinking water during the latter half of gestation had thyroid hyperplasia and a 

dramatic 15-fold increase in relative thyroid weight compared with controls, while maternal thyroids were 

unaffected (Postel 1957). This suggests that perchlorate may have entered the fetal circulation and 

directly affected the fetal thyroid gland. Similar fetal effects were seen in rabbits dosed with 72 mg 

perchlorate/kg/day in the diet throughout gestation, but in this study, effects on the maternal thyroid, 

although considerably less intense than in the fetuses, were observed (Lampe et al. 1967). Rat pups 

exposed to perchlorate only for 10 days during lactation had body weights similar to controls, but 

significantly increased relative thyroid weights (Brown-Grant and Sherwood 1971). The dams in this 

study, which were pregnant with a new litter while nursing these pups, had received an approximate dose 

of 1,752 mg perchlorate/kg/day, and showed an increase in relative thyroid weight of similar magnitude 

to the pups. 

Several developmental studies in animals have focused on the effects of perchlorate on the thyroid and 

also on neurodevelopmental effects following perinatal exposure to relatively low doses of perchlorate. 

Information on developmental effects of perchlorate is available in the 2-generation reproduction study in 

rats by York et al. (2001a) previously described in Section 3.2.2.5, Reproductive Effects. Perchlorate 

doses were 0, 0.26, 2.6, and 25.5 mg perchlorate/kg/day, and exposure started 10 weeks before mating 

and continued during pregnancy and lactation. The F1 generation was dosed from weaning (21 days old) 

to 19 weeks of age, but some pups were sacrificed on PND 21. The second generation (F2) was 

sacrificed at 3 weeks of age. F1 and F2 generations were exposed in utero, via maternal milk, and 

through maternal water. Exposure to perchlorate had no significant effect on pup weight. High-dose 

F1 pups killed on PND 21 showed a significant increase in thyroid weight (males and females) and in 

spleen weight (females). Significant hypertrophy and hyperplasia of the thyroid was seen in high-dose 

males and females and in mid-dose females. Also, there was a significant reduction in serum T3 in highdose females, TSH was reduced in low- and mid-dose males, and serum T4 was increased in low-dose 

females. Thyroid weight from high-dose F2 female pups was significantly increased, and both male and 

female from the mid- and high-dose group exhibited hyperplasia and hypertrophy of the thyroid. TSH, 

T3, and T4 levels were not significantly altered in F2 pups, although T3 was somewhat lower in highdose females. On the basis of morphological alterations in the thyroid observed in mid- and high-dose 

pups, the 0.26 mg/kg/day dose level is considered a developmental NOAEL. Parental (F0) effects were 

restricted to the thyroid and consisted mainly in hypertrophy and hyperplasia of the thyroid in the midand high-dose groups and significantly increased serum TSH levels in high-dose males. 
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A subsequent study in rats by York et al. (2003) examined the developmental effects of ammonium 

perchlorate in doses of 0, 0.009, 0.09, 0.85, and 25.5 mg perchlorate/kg/day. Dosing began 14 days 

premating and continued to gestation day (GD) 21, at which time, all rats were sacrificed. Satellite 

groups of rats were treated similarly and were used for collection of blood and thyroid tissues. The rats 

were observed for clinical signs, abortions, premature deliveries, and deaths. Body weights and food and 

water consumption were also monitored. At sacrifice, gravid uterine weights were recorded, and the 

uterus was examined for pregnancy, number and distribution of implantations, live and dead fetuses, and 

early and late resorptions. In addition, the number of corpora lutea in each ovary was recorded; the 

placenta was also examined. The fetuses were weighed and examined for gross alterations; one-half was 

examined for soft tissues alterations and the other half was examined for skeletal alterations and cartilage 

development. There were no maternal deaths and all clinical observations were considered unrelated to 

the test material. There were no significant effects on body weights, weight gains, and gravid uterine 

weights. There were no treatment-related effects on absolute or relative food or water consumption 

values. Cesarean sectioning and litter parameters were not affected by exposure to perchlorate. 

Evaluation of the fetuses showed that the average number of ossification sites per litter for sternal centers 

and for forelimb phalanges was significantly reduced in the 25.5 mg/kg/day exposure group. 

Examination of the satellite group of pups showed a statistically significant and dose-related decrease in 

T3 in all dosed groups. No developmental NOAEL is identified in this study and the 0.009 mg/kg/day 

dose level is a developmental LOAEL. T3 levels also were reduced in pooled serum samples from 

fetuses exposed through gestation and examined on GD 21 (York et al. 2005a). The lowest dose tested, 

0.009 mg/kg/day, induced a 17% decrease in T3 relative to controls, whereas at the highest dose tested, 

25.5 mg/kg/day, T3 was decreased by 33%. In this study, perchlorate also induced a dose-related increase 

in TSH (15% at 0.009 mg/kg/day) and decrease in T4 (16% at 0.009 mg/kg/day) in male pups sacrificed 

on PND 22. 

An additional study was conducted in rats given ammonium perchlorate via the drinking water that 

provided doses of 0, 0.09, 0.9, 2.6, and 8.5 mg perchlorate/kg/day (York et al. 2004). Exposure began on 

GD 1 and continued for additional 10 days postpartum. Dams were sacrificed on PND 10 or 22 (12-day 

recovery period). Four subsets of pups were formed: subset 1 was sacrificed on PND 12 for 

neurohistological examination; subset 2 was used for neurobehavioral testing (avoidance testing on 

PND 23–32, water maze on PND 59–70) and sacrificed on PND 90–92, at which time blood was 

collected for TSH, T4, and T3 determinations; subset 3 was tested for motor activity on PND 14, 18, 22, 

and 59, and for auditory startle habituation on PND 23 and 60 and sacrificed on PND 67–69; and subset 

4 was sacrificed on PND 80–86 and used for thyroid pathology and neurohistological examination and 
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morphology. In addition, on PND 5, litters were culled to eight pups, blood was collected for hormone 

analysis, and the thyroid was processed for histopathology. 

Treatment with perchlorate caused no maternal toxicity as judged by clinical observations, body and 

thyroid weights, and thyroid histology. Perchlorate did not significantly affect gestation length, litter size, 

number of stillborn, gestation index, pup viability index, or pup’s weight. In the pups, there were no 

significant changes in body weight, absolute and relative food consumption, or exposure to perchlorate 

did not affect the day of vaginal latency or the day of preputial separation. Microscopic examination of 

the thyroid from pups culled on PND 5 revealed changes restricted mainly to high-dose males consisting 

of hypertrophy/hyperplasia of the follicular epithelium and decrease in follicle size. TSH was elevated 

only in pups born to dams treated with 8.5 mg/kg/day, but T3 levels were significantly reduced at 

0.9 mg/kg/day and higher doses. T4 was significantly reduced at 2.6 mg/kg/day and higher doses. In 

pups sacrificed on PND 12 (subset 1), a significant increase in thickness of the corpus callosum was seen 

in high-dose females; this also was observed in high-dose males but the difference with controls was not 

statistically significant. Evaluation of the next lower dose group (2.6 mg/kg/day) revealed a significant 

decrease in the hippocampal gyrus size in males, increase in the anterior to posterior cerebellum size and 

decrease in the caudate putamen in females, but no significant difference in the corpus callosum. 

Evaluations of subsets 2 and 3 revealed no behavioral effects in the offspring of dams exposed up to 

8.5 mg perchlorate/kg/day (passive avoidance, swimming water maze, motor activity, and auditory 

startle). Also in subsets 2 and 3, there were no necropsy observations that seemed perchlorate-related, 

and terminal body weights and absolute and relative thyroid weights were comparable among the groups. 

In subset 4, there were no necropsy observations related to treatment, no significant effect on final body 

weight or thyroid weight, and no treatment-related neuropathological changes in the brain. However, 

morphometry evaluation of eight specific brain areas revealed a significant increase in mean thickness of 

the frontal cortex, caudate putamen, and corpus callosum from high-dose males. Based on the thyroid 

effects on pups culled on PND 5, the dose of 0.09 mg/kg/day can be considered a developmental NOAEL. 

The highest dose tested, 8.5 mg/kg/day is a maternal NOAEL. It should be mentioned that questions and 

concerns have been raised regarding the brain morphology findings. A more recent refinement of the 

study from the same group of investigators in which rats were exposed to perchlorate during gestation (0, 

0.009, 0.09, 0.9, or 25.5 mg perchlorate/kg/day) and via maternal milk through lactation day 10 showed 

no treatment-related neuropathological alterations at sacrifice on PND 10 or 22 (York et al. 2005b). The 

most significant finding was an increased thickness of the corpus callosum in male pups in the 0.09 and 

0.9 mg/kg/day dose groups, but not in the 25.5 mg/kg/day dose group. Differences in other brain 

structures were not statistically significant and/or were present in only one dose group (i.e., thickness of 
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the right and left frontal cortex, right and left parietal cortex, left striatum, and right hippocampal gyrus 

were increased only at 0.9 mg/kg/day). Issues that were raised by NAS (2005) include: “(1) apparent 

systematic differences in the plane of section among treatment groups, (2) lack of a clear and consistent 

dose-response relationship, (3) doubts about the biological plausibility of the changes that were observed, 

and (4) concerns that the measures that were used were relatively insensitive and would be unlikely to 

pick up subtle differences in neurodevelopment.” 

In a study of similar design, exposure began 2 weeks before mating and was terminated on PND 10 

(Bekkedal et al. 2000, 2004). On PND 5, all of the pups were weighed and the litter culled to four males 

and four females. Tests of motor activity were conducted on one male and one female selected randomly 

on PND 14, 18, and 22. Nine measures of motor activity were monitored: frequency and time of 

ambulatory movements, frequency and time of stereotypic movements, frequency of movements in the 

horizontal plane, distance traveled in the horizontal plane, frequency of rears, total number of horizontal 

movements made while in rearing position, and time spent resting. Each measure of activity was 

recorded for 90 consecutive minutes on each test day. Data were divided into nine 10-minute blocks. 

The results showed that the main effect for perchlorate dose was not significant for any of the nine 

dependent variables, and there were no reliable interactions for treatment. The highest dose tested, 

8.5 mg perchlorate/kg/day, is considered a NOAEL for neurodevelopmental effects in this study. 

Replication of this study by York et al. (2005b) showed that there were no significant alterations in test 

results due to consumption of perchlorate relative to controls. However, there was a pattern of response 

suggesting that exposed pups may have had a lower rate of habituation, and thus maintained a higher level 

of activity than untreated pups. 

Because of EPA’s concerns that the changes in motor activity in the rats in the two studies summarized 

above had biological significance, the results of both studies were re-analyzed (Dunson 2001). Each 

study was re-analyzed separately and combined using a Bayesian Hierarchical Modeling Approach. 

According to Dunson (2001), the re-analysis showed evidence of an increasing dose-response trend in 

motor activity in both studies, though the effect in the York et al. (2004) study was less pronounced. 

After reviewing the two studies in question and the re-analysis by Dunson, NAS (2005) concluded that: 

“general motor activity is not necessarily the most relevant or most sensitive aspect of motor function to 

assess if neonatal hypothyroidism is the suspected mechanism of action”. 

A cross-fostering study in rats was conducted by Mahle et al. (2003). Pregnant Sprague-Dawley rats were 

administered ammonium perchlorate in the drinking water at doses of 0 or 1 mg perchlorate/kg/day from 
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GD 2 to PND 21. Cross-fostering was done on PND 1 such that four groups of pups were formed: never 

exposed, exposed in utero and via maternal milk, exposed only in utero, and exposed only via maternal 

milk. Dams and pups were sacrificed on PND 10. There was no indication of maternal toxicity during 

the study. However, serum T4 was significantly decreased and TSH was significantly increased in 

exposed dams that nursed their own pups; TSH was also increased in dams that nursed unexposed pups. 

The two cross-fostered litters (exposed only in utero and exposed only via nursing) had significantly 

lower weight than control pups and than pups exposed both in utero and via milk. T3 was not 

significantly affected in any pup group (male or female). T4 was significantly reduced in female pups 

exposed only via milk and in females exposed in utero plus via milk; the decrease was more marked in 

the latter group. T4 was not significantly affected in male pups. TSH was increased significantly in male 

and female pups (more pronounced in females) from groups that received double exposure and in groups 

exposed only via milk; there was no significant difference between these two groups. The results suggest 

that: (1) exposure in utero to perchlorate at the dose tested had little or no impact on serum levels of 

thyroid hormone and TSH measured in pups on PND 10, (2) the changes in serum thyroid hormone and 

TSH levels seen in PND 10 pups exposed both in utero and via maternal milk appear to be completely 

due to postnatal exposure to perchlorate through lactation, and (3) perchlorate could be acting directly on 

the pups’ thyroid and/or may be limiting the availability of iodide to nursing pups by inhibiting NIS in 

breast tissue. 

The developmental effects of perchlorate were also examined in rabbits administered 0, 0.09, 0.85, 8.5, 

25.5, or 85 mg perchlorate/kg/day in the drinking water on GD 6–28 (York et al. 2001b). Sacrifices were 

conducted on GD 29. There were no deaths attributed to treatment with the test material or chemicalrelated clinical signs, or effects on body weight or uterine weight. There were no compound-related 

effects on any of the litter parameters studied including litter averages for corpora lutea, implantations, 

litter sizes, live and dead fetuses, percent dead or resorbed fetuses, and fetal body weights. All placentae 

appeared normal. There were no treatment-related increases in gross alterations or in skeletal and soft 

tissue anomalies. This study defined a maternal NOAEL of 0.85 mg/kg/day (see Endocrine Effects 

section for summary of maternal effects) and a developmental NOAEL of 85 mg/kg/day. 

Developmental NOAEL and LOAEL values from these studies are shown in Table 3-2 and Figure 3-2. 
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3.2.2.7 Cancer 

Limited information was located regarding exposure to perchlorate and cancer in humans. In the ecologic 

study by Li et al. (2001) described earlier, the prevalence of thyroid cancer was not significantly higher 

among residents from Clark County (Las Vegas), whose drinking water had 4–24 μg/L of perchlorate 

(0.0001–0.0007 mg perchlorate/kg/day) than in residents from another urban area of similar size (Reno, 

Washoe County), but with no perchlorate in the water, or than those from all other counties, also with no 

perchlorate exposure. 

Morgan and Cassady (2002) conducted an ecologic study among residents of 13 contiguous census tracts 

in Redlands, California, San Bernardino County. Residents had been exposed to various concentrations 

of trichloroethylene (TCE) and ammonium perchlorate. Testing for TCE began in 1980, whereas, testing 

for perchlorate began in 1997. The concentration of perchlorate in the wells in 2001 was reported to be in 

the range 5–98 ppb, with drinking water concentrations not exceeding 18 ppb. The concentration of TCE 

in the wells initially ranged from 0.09 to 97 ppb, but did not exceed 5 ppb in the drinking water since 

1991 after the water underwent treatment or the highly contaminated wells were removed from service. 

The standardized incidence ratios (SIRs, observed/expected) for all cancers combined or for any specific 

cancer site was not significantly different than 1.00, except for colon and rectum (SIR, 0.86; 99% CI, 

0.74–0.99) and lung and bronchus (SIR, 0.71; 99% CI, 0.61–0.81), which were lower than expected, and 

melanoma of the skin (SIR, 1.42; 99% CI, 1.13–1.77) and uterine cancer (SIR, 1.35; 99% CI, 1.06–1.70), 

which were higher than expected. The SIR for thyroid cancer was 1.0 (99% CI, 0.63–1.47) based on 

40 observed cases. When the analysis was restricted to children, no cancers were observed more often 

than expected. NAS (2005) notes that limitations of the study include the fact that timing and duration of 

exposure to perchlorate is unclear, that there also was exposure to TCE, and that there was no adjustment 

for other potential confounding variables. NAS (2005) further notes that the expected numbers were 

derived from the four-county region as a whole, which included the exposed community, not from an 

unexposed area. The latter could have resulted in an underestimate of the SIR. 

Potassium and sodium perchlorates have been shown to produce thyroid tumors (papillary and/or 

follicular adenomas and/or carcinomas) in rats and mice with long-term exposure (1–24 months) to 1– 

1.2% concentrations in the feed or drinking water (Fernandez-Rodriguez et al. 1991; Florencio Vicente 

1990; Gauss 1972; Kessler and Kruskemper 1966; Pajer and Kalisnik 1991; Toro Guillen 1991). 

Estimated doses in these studies ranged from 928 to 2,573 mg perchlorate/kg/day. The cancer effect 

levels from these studies are shown in Table 3-2 and Figure 3-2. In a related study in rats, Fernández-
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Santos et al. (2004) determined the incidence of Ki-ras oncogene mutations in follicular cell carcinomas 

of the thyroid induced by administration of radioactive iodine and potassium perchlorate (1% in drinking 

water) for up to 18 months. Direct sequencing showed no mutations in the amplified gene segment of any 

of the induced thyroid tumors. The results suggested that Ki-ras activation via mutations at codons 12 

and 13 is neither a constant event nor an early event in the development of rat thyroid follicular cell 

carcinoma. An additional study found that low level exposure to potassium perchlorate (0.1% in the feed, 

corresponding to a dose of 64 mg perchlorate/kg/day) for 19 weeks promoted the development of thyroid 

tumors initiated by N-bis(2-hydroxypropyl)nitrosamine (Hiasa et al. 1987). 

NAS (2005) noted that: “on the basis of the understanding of the biology of human and rodent thyroid 

tumors, it is unlikely that perchlorate poses a risk of thyroid cancer in humans”. The EPA has concluded 

that perchlorate is not likely to pose a risk of thyroid cancer in humans, at least at doses below those 

necessary to alter thyroid hormone homeostasis, based on the hormonally-mediated mode of action in 

rodent studies and species differences in thyroid function (IRIS 2007). 

3.2.3 Dermal Exposure 

No studies were located regarding the following effects in humans or animals after dermal exposure to 

perchlorate: 

3.2.3.1 Death 

3.2.3.2 Systemic Effects 

3.2.3.3 Immunological and Lymphoreticular Effects 

3.2.3.4 Neurological Effects 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

No studies were located regarding genotoxic effects in humans after inhalation, oral, or dermal exposure 

to perchlorates. Limited information is available from studies in animals. Siglin et al. (2000) found no 

evidence of bone marrow erythrocyte micronucleus formation in male and female rats as a result of 

exposure to 8.5 mg perchlorate/kg/day as ammonium perchlorate in the drinking water for 90 days. 

Zeiger et al. (1998b) also reported no increase in micronucleus formation in bone marrow from mice 
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injected intraperitoneally with 500 mg of ammonium perchlorate/kg/day for 3 consecutive days; higher 

doses were lethal to the mice. Cyclophosphamide was used as positive control in both studies. 

Magnesium perchlorate was negative in a test for SOS-inducing activity in Salmonella typhimurium strain 

1535 (Nakamura and Kosaka 1989) and in a test for production of deoxyribonucleic acid (DNA)-protein 

cross links in cultured human lymphocytes (Costa et al. 1996). Zeiger et al. (1998a) found no evidence of 

mutagenicity for ammonium perchlorate with or without metabolic activation in six different Salmonella 

strains. Ammonium perchlorate was not mutagenic in the mouse lymphoma assay with or without 

metabolic activation (San and Clarke 1999). 

The available data suggest that perchlorate is not a mutagenic or clastogenic agent. 

3.4 TOXICOKINETICS 

Overview. Short-term studies on humans and animals demonstrate that perchlorate appears to be readily 

absorbed by the digestive system after oral exposure. Maximum blood levels appear within a few hours 

after ingestion. Perchlorate is rapidly taken up into the thyroid gland, by an active transport mechanism, 

and reaches a maximum level in the thyroid in approximately 4 hours in rats. Elimination of perchlorate 

from the thyroid is also rapid; half-lives of 10–20 hours have been estimated in rats. Perchlorate does not 

appear to be modified in the body, either by degradation or covalent binding. Perchlorate is rapidly 

eliminated from the body in the urine with half-lives of approximately 8–12 hours in humans and 10– 

20 hours in rats. No studies on the kinetics of long-term administration of perchlorate in humans or 

animals have been reported. 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

No studies were found regarding quantitative absorption of perchlorate after inhalation exposure. 

Occupational studies have measured urinary perchlorate in workers, suggesting that pulmonary absorption 

may occur (Lamm et al. 1999), although swallowing of particles may have also occurred. Under normal 

ambient temperatures, the vapor pressure of a perchlorate salt solution is expected to be low, which would 

reduce the likelihood of exposure to perchlorate fumes or vapors from that source. However, if 

perchlorate particles were suspended in air, absorption by inhalation would be possible, depending on the 

particle size. It is also possible that a portion of perchlorate particles suspended in the air could be 
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swallowed and absorbed orally. Given the aqueous solubility of perchlorate salts, it is likely that small 

particles reaching the alveoli would dissolve and readily enter the systemic circulation. 

3.4.1.2 Oral Exposure 

Perchlorate has been shown, in both human and animal studies, to be readily absorbed after oral exposure. 

In human subjects who ingested 10 mg/day perchlorate as potassium perchlorate in drinking water for 

14 days (0.14 mg/kg/day), urinary excretion rate of perchlorate was 77% of the dose/day, after 7 days of 

exposure, indicating that at least 77% of the ingested dosage had been absorbed (Lawrence et al. 2000). 

Evidence for rapid absorption in humans is provided by studies of elimination patterns. Anbar et al. 

(1959) detected potassium perchlorate in urine samples collected from four subjects 3 hours after 

ingestion of 200 mg perchlorate. Durand (1938) gave sodium perchlorate in a single oral dose (784 mg 

perchlorate per person) to two individuals and found perchlorate in the urine as early as 10 minutes after 

ingestion. Approximately 30% of the ingested dose had been eliminated in the urine within 3 hours after 

the dose, and 95% was eliminated within 48 hours. In a study of 13 subjects given 0.5 or 3 mg 

perchlorate/day for 6 months, serum perchlorate increased from undetected at baseline to an average of 

24.5 μg/L in the low-dose group and 77.9 μg/L in the high-dose group over the 6 months (Braverman et 

al. 2006). The investigators estimated that approximately 65–70% of the daily dose was excreted during a 

24-hour period. These results suggest rapid and near complete absorption of perchlorate through the 

digestive system. 

Selivanova et al. (1986) examined the absorption of ammonium perchlorate in rats, rabbits, and calves 

after a single oral dose (2, 20, 200, or 600 mg perchlorate/kg). In rats, a maximum concentration of 

perchlorate in blood was noted between 30 and 60 minutes after administration (suggesting entrance into 

the systemic circulation before 30 minutes); in cattle, the maximum blood concentration of perchlorate 

occurred at 5 hours. In this study, only 8.5% of the administered dose was excreted in feces, and the rest 

was excreted in the urine, suggesting that >90% of the administered oral dose was absorbed. 

3.4.1.3 Dermal Exposure 

No studies were found regarding absorption of perchlorate after dermal exposure. As a general rule, 

electrolytes applied from aqueous solutions do not readily penetrate the skin (Scheuplein and Bronaugh 

1983). On this basis, dermal absorption of perchlorate is expected to be low. 
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3.4.2 Distribution 

Perchlorate binds to bovine and human serum albumin (Carr 1952; Scatchard and Black 1949). 

Perchlorate binds only weakly to either of the two binding sites of transferrin (association constants 7 and 

35 M) (Harris et al. 1998). 

Studies conducted in rabbits and rats indicate that perchlorate concentrations in most soft tissues (e.g., 

kidney, liver, skeletal muscle) are similar to the serum concentrations; tissue:serum concentration ratios 

>1 have been found in thyroid (5–10) and skin (1–2) (Durand 1938; Yu et al. 2002). Accumulation of 

perchlorate in the thyroid occurs by a saturable, active transport process (see Section 3.5.1). As a result, 

thyroid serum concentrations and the amount of perchlorate in the thyroid as a fraction of the absorbed 

dose decrease with increasing dose (Chow and Woodbury 1970). Elimination of perchlorate from the 

thyroid gland is relatively rapid, with half-times in rats estimated to be approximately 10–20 hours 

(Fisher et al. 2000; Goldman and Stanbury 1973; Yu et al. 2002). 

Studies conducted in rats administered intravenous injections of perchlorate indicate that perchlorate is 

secreted into the gastric lumen (Yu et al. 2002). Perchlorate secreted into the gastric lumen may be 

absorbed in the small intestine. 

3.4.2.1 Inhalation Exposure 

No studies were found in humans or in animals regarding distribution of perchlorate after inhalation 

exposure. 

3.4.2.2 Oral Exposure 

In a survey of 36 healthy lactating volunteers, perchlorate was detected in breast milk at a mean 

concentration of 10.5 μg/L (range, 0.6–92. μg/L) (Kirk et al. 2005). Exposure of the lactating women 

was presumed to have occurred mainly from perchlorate in food and drinking water. No correlation was 

apparent between the concentration of perchlorate in the breast milk and the water that the respective 

mothers consumed. Serial collection of breast milk from 10 lactating women over a 3-day period 

revealed that the concentrations of perchlorate, iodide, and thiocyanate varied significantly over time 

(Kirk et al. 2007). For perchlorate, the range, mean and median in 147 samples were 0.5–39.5, 5.8, and 

4.0 μg/L, respectively. A study of women from three different cities in Chile also detected perchlorate in 

breast milk at mean concentrations ranging from 17.7 to 95.6 μg/L (Téllez et al. 2005). This study also 
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found no significant correlations between breast milk perchlorate and either urine perchlorate or breast 

milk iodine concentrations. A study of 57 lactating women in Boston reported a median concentration of 

perchlorate in milk of 9.1 μg/L (range 1.3–411 μg/L) (Pearce et al. 2007). 

Perchlorate also has been detected in dairy milk. A survey of 12 U.S. states showed a mean milk 

perchlorate level of 5.81 μg/L in 125 samples (FDA 2007a, 2007b), which was lower than a reported 

mean of 9.39 μg/L for Japanese samples (Dyke et al. 2007). The recent Total Diet Study (TDS) study 

conducted by the FDA reported a mean concentration of perchlorate of 7 μg/L in eight samples of milk 

(Murray et al. 2008). 

Studies conducted in rabbits and rats indicate that perchlorate concentrations in most soft tissues (e.g., 

kidney, liver, skeletal muscle) are similar to the serum concentrations; tissue:serum concentration ratios 

>1 have been found in thyroid (5–10) and skin (1–2) (Durand 1938; Yu et al. 2002). Accumulation of 

perchlorate in the thyroid occurs by a saturable, active transport process (see Section 3.5.1). 

Perchlorate has been shown to cross the placenta of rats. In rats exposed to perchlorate in drinking water, 

fetal:maternal serum concentration ratios were approximately 1 when the maternal dosage was 

1 mg/kg/day or lower, and were <1 when the maternal dosage was 10 mg/kg/day, suggesting the 

possibility of a dose-dependent limitation in the capacity of transplacental transfer (Clewell et al. 2003a). 

3.4.2.3 Dermal Exposure 

No studies were found regarding distribution of perchlorate after dermal exposure. 

3.4.2.4 Other Routes of Exposure 

Several studies have examined the distribution of perchlorate in animals after intravenous, intramuscular, 

or peritoneal injection (Anbar et al. 1959; Chow and Woodbury 1970; Chow et al. 1969; Durand 1938; 

Goldman and Stanbury 1973; Yu et al. 2002). These studies have shown that absorbed perchlorate, 

regardless of the route of exposure, will distribute to soft tissues, including adrenal, brain, kidney, liver, 

mammary gland, skeletal muscle, spleen, testes, and thyroid. The highest concentrations occur in the 

thyroid, where tissue:serum concentration ratios of 5–10 have been observed (Chow and Woodbury 

1970). The elimination half-time for the thyroid was estimated in rats to be approximately 10–20 hours 

(Fisher et al. 2000; Goldman and Stanbury 1973; Yu et al. 2002). 
PERCHLORATES 85 

3. HEALTH EFFECTS 

Other tissues that appear to concentrate perchlorate are the salivary gland and skin, although not to the 

same degree as the thyroid (Anbar et al. 1959; Lazarus et al. 1974; Yu et al. 2002). Tissue:blood 

concentration ratios of 1.5–2 have been observed for the salivary gland (Anbar et al. 1959) and 1–2 for 

the skin (Yu et al. 2002). 

3.4.3 Metabolism 

There is no evidence that perchlorate is metabolized in the body. Anbar et al. (1959) assayed for potential 

metabolites of potassium perchlorate (radiolabeled with 36Cl and 18O4) in the urine of patients 3 hours 

after a single oral dose (200 mg perchlorate per person). They did not detect any isotopic exchange of the 

oxygen atoms in excreted perchlorate; furthermore, although they found that 1–3% of the excreted 36Cl 

was chloride ion, this value was within experimental error. They concluded that the perchlorate excreted 

after 3 hours was unmodified. There has been no investigation as to whether perchlorate that is 

eliminated at later time points would exhibit the same isotopic pattern. 

Goldman and Stanbury (1973) found that perchlorate reached a maximum concentration (>3% of the 

administered dose/g tissue) in the thyroid gland of rats 4 hours after an intraperitoneal injection of 

radiolabeled potassium perchlorate (K 36ClO4; 18 or 24 mg perchlorate/kg). However, trichloroacetic acid 

precipitates of thyroid homogenates contained only background levels of radioactivity, indicating that 

perchlorate is not covalently bound to thyroid protein. 

3.4.4 Elimination and Excretion 

The few studies of the elimination and excretion of perchlorate, described in the sections that follow, 

suggest that it is rapidly eliminated from the body through the urinary tract. Similar results have been 

obtained after oral exposure or after intravenous or intraperitoneal injection; the specific cation appears 

not to influence the pattern of excretion. 

3.4.4.1 Inhalation Exposure 

A study in two workers occupationally exposed to perchlorate found that the urinary perchlorate 

concentration increased over 3 days of perchlorate exposure, but there was a decrease between the 

12-hour work shifts (Lamm et al. 1999). Excretion after the last exposure appeared to follow a first-order 

kinetics pattern, particularly when the urinary perchlorate concentration was between 0.1 and 10 mg/L. 
PERCHLORATES 86 

3. HEALTH EFFECTS 

The average elimination half-life for the two workers was approximately 8 hours. No information was 

located regarding excretion of perchlorate in animals following inhalation exposure. 

3.4.4.2 Oral Exposure 

In adult human subjects who ingested potassium perchlorate in drinking water (0.14 mg/kg/day) for 

14 days, urinary excretion rate of perchlorate was 77% of the dose/day after 7 days of exposure, 

indicating that urine is the main excretory pathway for absorbed perchlorate (Lawrence et al. 2000). The 

urinary excretion rate of perchlorate returned to control levels (<0.5 mg/day) within 14 days after 

exposure to perchlorate was terminated (Lawrence et al. 2000). Perchlorate was detected in the urine of 

two adults at 10 minutes after a single oral dose of sodium perchlorate (784 mg perchlorate per person); 

urinary excretion as a percentage of the dose was 30% at 3 hours, 50% in at 5 hours, 85% at 24 hours, and 

95% at 48 hours (Durand 1938). This suggests an excretion half-time of approximately 12 hours. The 

latter estimate is consistent with the elimination kinetics of perchlorate from serum. The elimination halftime for perchlorate in serum was estimated to be approximately 8 hours in adult human subjects who 

ingested potassium perchlorate in drinking water (0.5 mg/kg/day) for 14 days (Greer et al. 2002). In 

another study in adult humans, it was estimated that approximately 65–70% of a daily dose of 0.5–3 mg 

perchlorate/day was excreted over a 24-hour period (Braverman et al. 2006). Thus, in humans, 

perchlorate is rapidly eliminated and would not be expected to accumulate in the body with prolonged 

exposure. Based on an elimination half-time of approximately 8–12 hours, a steady state would be 

achieved within 3–4 days of continuous exposure. The detection of perchlorate in breast milk from 

lactating women (Kirk et al. 2005; Pearce et al. 2007; Téllez et al. 2005) also indicates breast milk as an 

excretion route in humans. 

Studies conducted in a variety of experimental animals, including rats, rabbits, and calves, have shown 

that absorbed perchlorate is rapidly and nearly completely excreted in the urine (Fisher et al. 2000; 

Selivanova et al. 1986; Yu et al. 2002). 

Studies conducted in rats have shown that perchlorate is excreted in mammary milk (Clewell et al. 

2003b). Perchlorate has also been detected in dairy milk (Howard et al. 1996; Kirk et al. 2005). 

3.4.4.3 Dermal Exposure 

No studies were found regarding elimination or excretion of perchlorates after dermal exposure. 
PERCHLORATES 87 

3. HEALTH EFFECTS 

3.4.4.4 Other Routes of Exposure 

Studies in which rats received intravenous or intraperitoneal injections of perchlorate provide additional 

support for the rapid excretion of perchlorate in urine. Rats that received a single intravenous injection of 

0.01, 0.1, 1.0, or 3.0 mg/kg perchlorate (as ammonium perchlorate) excreted 85, 86, 80, or 79% of the 

administered dose, respectively, in urine (Fisher et al. 2000). The elimination half-time for intravenously 

injected perchlorate (approximately 0.04 mg, 0.18–0.25 mg/kg, as potassium perchlorate) from serum, 

and the urinary excretion half-time were estimated in rats to be approximately 20 hours (Goldman and 

Stanbury 1973). Similarly, rats injected with sodium perchlorate (2, 8, or 49 mg perchlorate/kg) excreted 

50% of the administered dose in urine during the first 6 hours and had excreted 93–97% of the dose by 

60 hours (Eichler and Hackenthal 1962); in this study, higher doses of perchlorate were eliminated at a 

faster rate than lower doses. Similar results were obtained in rats that received a single intravenous dose 

of 3.3 mg/kg perchlorate as ammonium perchlorate; urinary excretion of perchlorate was essentially 

complete within 12 hours (Yu et al. 2002). Possible contributors to the relatively longer elimination halflife of perchlorate in rats than in humans include differences in serum protein binding or perhaps the NIS 

protein in the gastrointestinal tract may sequester perchlorate temporarily to a greater degree in the rat 

than human. 

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 
PERCHLORATES 88 

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 3-3 shows a conceptualized representation of a PBPK model. 

If PBPK models for perchlorates 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. 
3. HEALTH EFFECTS 

PERCHLORATES 89 

Figure 3-3. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a Hypothetical 

Chemical Substance 

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 urine, feces, or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 
PERCHLORATES 90 

3. HEALTH EFFECTS 

Perchlorate PBPK Models 

Description of the models. PBPK models of the kinetics of ingested or injected perchlorate in rats 

and humans have been developed (Fisher et al. 2000; Merrill et al. 2003, 2005). The models were 

developed simultaneously with models of radioiodide biokinetics. When combined, the perchlorate and 

radioiodide models simulate the competitive inhibition of radioiodide transport by perchlorate in thyroid 

and other tissues that have NIS activity. The adult rat model was extended to include pregnancy and 

maternal-fetal transfer of perchlorate, and lactation and maternal-pup perchlorate transfer through milk 

(Clewell et al. 2003a, 2003b). Corresponding human models of pregnancy, maternal-fetal transfer, and 

maternal-infant transfer of perchlorate were developed (Clewell et al. 2007). 

The adult rat and human models have the same structure and differ only in values for physiological and 

some of perchlorate parameters (Table 3-3, Figure 3-4). Both models simulate nine tissue compartments: 

blood, kidney, liver, skin, stomach, thyroid, fat, other slowly perfused tissues, and other richly perfused 

tissues. Uptakes from blood into the tissue vascular compartments are simulated as flow-limited 

processes. Distributions within blood, skin, stomach, and thyroid are simulated as diffusion limited 

processes with first-order clearance terms. Excretion is described with a first-order clearance term for 

transfer of perchlorate from the kidney into urine. Uptake of perchlorate into tissues that have NIS 

activity are simulated using a Michaelis-Menten approach with tissue- and species-specific maximum 

velocities and affinity constants that are conserved across tissues and species. This includes uptake of 

perchlorate into thyroid follicle cells. Secretion of perchlorate into the follicle lumen, thought to be 

mediated by the pendrin anion transporter, is simulated using a Michaelis-Menten approach. 

Upregulation of NIS (i.e., induction in response to TSH) is simulated by fitting increased maximum 

velocities of perchlorate and radioiodide transport into the thyroid gland. The model does not explicitly 

include TSH-dependence of NIS levels or other aspects of the metabolism of iodide within the thyroid 

(e.g., hormone production and secretion), and does not simulate changes in TSH levels resulting from NIS 

inhibition. Active transport of perchlorate into the stomach lumen and in skin is also simulated in the 

models. 

Extensions of the adult models to simulate perchlorate (and radioiodide) kinetics during pregnancy in rats 

and humans include the addition of two additional compartments representing the mammary gland and 

placenta (Clewell et al. 2003a, 2003b, 2007). The structure of the human pregnancy and lactation models 

for perchlorate (which are identical to the corresponding rat models) are shown in Figure 3-5. Parameter 
PERCHLORATES 91 

3. HEALTH EFFECTS 

Table 3-3. Perchlorate and Radioiodide Parameter Values for the Adult Male Rat 

and Human PBPK Models 

Male rat Human 

Parameter Perchlorate Radioiodide Perchlorate Radioiodide 

Partition coefficients (unitless) 

 Slowly perfused/plasma 0.31 0.21 0.31 0.21 

 Richly perfused/plasma 0.56 0.40 0.56 0.40 

 Fat/plasma 0.05 0.05 0.05 0.05 

 Kidney/plasma 0.99 1.00 0.99 1.09 

 Liver/plasma 0.56 0.44 0.56 0.44 

Gastric tissue/gastric blood 0.70 1.0 1.80 0.50 

Gastric juice/gastric tissue 1.70 3.50 2.30 3.50 

Skin tissue/skin blood 1.0 0.70 1.15 0.70 

Thyroid follicle/thyroid stroma 0.15 0.15 0.13 0.15 

Thyroid lumen/thyroid follicle 8.00 8.00 7.00 7.00 

 Red blood cells/plasma 0.73 1.00 0.80 1.00 

Max capacity (ng/hour/kg) 

 Thyroid follicle 1.0x103

 5.4x104 5.0x105 ~1.5x105 

± 8.2x104

 Thyroid lumen 2.0x104

 4.0x106 2.5x104 7.0x107

 Skin 5.0x105

 5.0x105 1.0x106 6.0x105

 Gastric 2.0x104

 2.0x106 1.0x105 9.0x105

 Plasma binding 3.4x103

 1.0x102 5.0x102 2.0x102 

Affinity constants (ng/L) 

 Thyroid lumen 1.0x108

 1.0x109 1.0x108 1.0x109

 Thyroid follicle 1.8x105

 4.0x106 1.6x105 4.0x106

 Skin 1.8x105

 4.0x106 2.0x105 4.0x106

 Gastric 1.7x105

 4.0x106 2.0x105 4.0x106

 Plasma binding 1.1x104

 NA 1.8x104 7.8x105 

Permeability area cross products (L/hour/kg) 

Gastric blood to gastric tissue 1.00 1.00 0.6 0.2 

Gastric tissue to gastric juice 0.80 0.10 0.8 2.0 

Skin blood to skin tissue 0.80 0.10 1.0 0.01 

Plasma to red blood cells 1.00 1.00 1.0 1.0 

Thyroid follicle to thyroid stroma 6.0x10-5 1.0x10-4 1.0x10-4 6.0x10-4 

Thyroid lumen to thyroid follicle 0.01 4.0x10-7 0.01 1.0x10-4 
PERCHLORATES 92 

3. HEALTH EFFECTS 

Table 3-3. Perchlorate and Radioiodide Parameter Values for the Adult Male Rat 

and Human PBPK Models 

Male rat Human 

Parameter Perchlorate Radioiodide Perchlorate Radioiodide 

Clearance values (L/hour/kg) 

 Urinary excretion 0.07 0.05 0.13±0.05 0.11 

Plasma unbinding 0.032 NA 0.025 No data 

 Hormone production NA 0.10 NA 0.01 

 Hormone secretion NA 1.2x10-6 NA 1.2x10-6 

 Hormone deiodination NA NA NA 9.0x10-4 

NA = not applicable; PBPK = physiologically based pharmacokinetic 

Sources: Merrill et al. 2003, 2005 
3. HEALTH EFFECTS 

Figure 3-4. Structure of PBPK Model of Perchlorate in Typical Adult Humans and 

Male Rats* 

i.v. Dose

Oral DoseOral Dose

bound free

Plasma

RBC’sQC

Stomac h 

Conten ts

Stomac h 

Tissue

Stomach Stomach 

Bl ood

QG QG

QL

Liver

Richly

Pe rfused erfused

Kidney

Colloid

Thyroid 

FollicleFollicle

Stroma

Skin

Skin Blood

Fat

Slowl y

Perfused

QR

Urine

QK

QT

QSK

QF

QS

PERCHLORATES 93 

*Bold arrows within tissue compartments indicate active transport (i.e., Michaelis-Menten), thin arrows represent firstorder rate transfers, and double arrows represent passive diffusion. Q indicates blood flow. 

PBPK = physiologically based pharmacokinetic 
3. HEALTH EFFECTS 

Figure 3-5. Structure of PBPK Models of Perchlorate in the Pregnant and 

Lactating Woman 

i.v. Dosei.v. Dose

Neonatal GI

Contents

Fetal Plasma

Oral DoseOral Dose

boun d free

Plasma

RBC’sQC

Colloid

Thyroid 

FollicleFollicle

Stroma

QT

Ktrans Milk

Mammar y

Tissue

QM Mamamary

Blood

Cltrans 1 

PlacentaPlacenta

Cltrans 2Cltr Placenta QP

Blood

QG

QG QL

QR

Richly 

Perfused 

Richly

Perfused

Urine

Kidney QK

Skin

Skin Blood

QSK

QF

Fat

Slowly 

Perfused 

Slowly

Perfused QS

GI Contents 

GI Tissue 

GI Blood 

Liver 

GI Contents

GI Tissue

GI Blood

Liver

PERCHLORATES 94 

Differences between fetal, neonatal, and adult models are described in the text. Bold arrows within tissue 

compartments indicate active transport (i.e., Michaelis-Menten), thin arrows represent first-order rate transfers, and 

double arrows represent passive diffusion. Q indicates blood flow. A PBPK model for radioiodide has the same 

structure with addition of radioiodide incorporation into thyroid hormones within the thyroid and subsequent secretion 

into the plasma and further estimate for whole-body deiodination (release of iodide from thyroid hormones). 

Parameter values for the perchlorate and radioiodide models are presented in Tables 3-4 and 3-5. 

Source: Clewell et al. 2007 
PERCHLORATES 95 

3. HEALTH EFFECTS 

values for the perchlorate and radioiodide human models are presented in Tables 3-4 and 3-5, 

respectively. Corresponding rat model parameter values are presented in Tables 3-6 and 3-7. 

Uptake of perchlorate into the mammary gland tissue from the mammary tissue vascular space is 

simulated as a capacity-limited transport process, representing the activities of NIS and pendrin in this 

tissue. Uptake of perchlorate into the placenta from blood into placental blood is simulated as a diffusionlimited process with capacity-limited transport from placenta blood to placental tissue via NIS. 

Exchanges of perchlorate between the placenta and fetus are simulated with first-order clearance terms. 

The fetal model is identical in structure to the adult (nonpregnant) model, with adjustments in the 

physiological and perchlorate parameters to reflect the fetus, and the following exceptions: (1) fetal 

exposure is described as a first-order transfer from the placenta to the serum of the fetus; (2) clearance in 

the fetus is described as first-order loss from the fetal serum to the placenta; and (3) binding of iodine is 

not represented in the fetal thyroid and plasma. 

The lactating rat and human models include a milk compartment in mammary tissue and a first-order 

clearance term for describing secretion of perchlorate from mammary tissue into milk (Clewell et al. 

2003b, 2007). Transfer of perchlorate from milk to the neonate is simulated as a first-order clearance 

process. The neonate model is identical in structure to the adult (nonpregnant) model, with adjustments to 

the physiological and perchlorate parameter values to reflect the neonate (Clewell et al. 2003a). 

Parameter values for perchlorate and radioiodide in children were allometrically scaled from adult values. 

Validation of the models. The rat adult perchlorate model has been evaluated for predicting kidney, 

serum, gastric lumen, tissue (including thyroid), and urine perchlorate concentrations in adult rats that 

received acute intravenous injection of radiolabeled perchlorate (36ClO4

-

), (Merrill et al. 2003; Yu et al. 

2002). In general, model predictions were within 1–2 standard deviations of observed values. When the 

same parameter values were used to predict perchlorate concentrations in the thyroid in rats that were 

exposed to repeated doses of perchlorate in drinking water for 14 days, the model predicted lower levels 

of perchlorate in thyroid than were observed for dosages ≥3 mg/kg/day. At doses of perchlorate 

>1 mg/kg/day, only slight inhibition of thyroid radioiodide uptake was observed (Yu et al. 2002); 

presumably, a result of upregulation of NIS by TSH, whereas the model predicted greater inhibition. 

However, good correspondence with observations was achieved by adjusting the parameters for 

maximum velocity of transport of perchlorate and radioiodide into the thyroid gland. This adjustment 

mimics induction of NIS that occurs in response to elevations in serum TSH, which was observed in the 

rats exposed to perchlorate in drinking water (Uyttersprot et al. 1997; Yu et al. 2002). TSH stimulates 
PERCHLORATES 96 

3. HEALTH EFFECTS 

Table 3-4. Perchlorate Chemical-specific Parameters for Human Gestation and 

Lactation Models 

Gestation Lactation 

Parameters Woman Fetus Woman Neonate 

Gastric tissue/gastric blood PG 1.29a 1.79a 4.6a 8.25a 

Gastric juice/gastric tissue PGJ 1.76a 2.3a 3.1a 7.63a 

Skin tissue/skin blood PSk 1.32a

 1.32a 1.32a 1.32a 

Mammary tissue/mammary blood PM 0.66b

 NA 0.66b NA 

Mammary/milk PMk NA NA 2.39b

 NA 

Placenta/placental blood 0.56b

 NA NA NA 

Maximum capacity (ng/hour/kg) 

 Thyroid follicle VmaxcTF 6.0x103a 0–2x105e 9.0x103a 0.6–2.4x105e/6x103c

 Thyroid colloid (luman)VmaxcTL 1.7x104a 1.7x104a 8.4x103a 1.7x104a

 Skin VmaxcS 1.2x106a 8.0x105a 1.6x106a 1.6x106a

 Gastrointestinal VmaxcG 3.2x107a 4.0x106a 5.0x106a 5.0x106a

 Mammary VmaxcM 2.2x104b NA 2.0x104b NA 

Milk VmaxcMk NA NA 2.0x104b NA 

Placenta VmaxcP 6.0x104b NA NA NA 

Affinity constants (ng/L) 

Mammary KmM 2.0x105c NA 2.0x105c NA 

Milk KmMk NA NA 1.0x106b N A 

Placenta KmP 2.0x105c NA NA NA 

Permeability area cross products (L/hour/kg) 

Gastric blood to gastric tissue PAGc 0.6a

 0.6 0.6 0.6a 

Gastric tissue to gastric juice PAGJc 1.0a

 1.0 1.0 1.0a 

Thyroid stroma to thyroid follicle PATFc 1.0x10-4a 1.0x10-2f 6.7x10-5 6.7x10-5a 

Thyroid follicle to thyroid colloid (lumen) 0.01a

 0.01a 0.01 0.01a 

PATLc

Skin blood to skin tissue PASkc 1.25a

 1.25a 0.63 1.25a

Mammary blood to mammary tissue PAMc 0.04a

 NA 0.01 NA 

Mammary tissue to milk PAMkc NA NA 0.1 NA 

Placenta blood to placenta PAPCc 0.1b

 NA NA NA 

Clearance values (L/hour/kg) 

 Urinary excretion CLUc 0.05d

 NA 0.05d 0.13c 

Placenta to fetal blood Cltrans1c 0.12f

 NA NA 

Fetal blood to placenta Cltrans2c 0.12b

 NA NA 
PERCHLORATES 97 

3. HEALTH EFFECTS 

Table 3-4. Perchlorate Chemical-specific Parameters for Human Gestation and 

Lactation Models 

Gestation Lactation 

Parameters Woman Fetus Woman Neonate 

Binding constants (ng/hour/kg) 

Plasma binding VmaxcB 5.9x102a 5.0x102c 1.32x103a 5.0x102c 

Note: Partition coefficients for perfusion limited compartments (i.e., fat, liver, kidney, rapidly and slowly perfused 

tissues) were the same across species and life stages. 

a

Calculated using parallelogram approach (Clewell 2008). 

b

Set to rat value (in absence of equivalent human parameter). 

c

Set to adult human value. 

d

Adjusted to fit data set. 

e

Calculated from human perinatal iodide parameter and ClO4

-

:I- ratio in adult. f

Set to human perinatal iodide value (in absence of equivalent perchlorate data). 

NA = not applicable 

Source: Clewell 2008; Clewell et al. 2007) 
PERCHLORATES 98 

3. HEALTH EFFECTS 

Table 3-5. Radioiodide Chemical-specific Parameters for Human Gestation and 

Lactation Models 

Gestation Lactation 

Parameters Woman Fetus Woman Neonate 

Gastric tissue/gastric blood PG 1.0a 1.0a 0.5a 0.6a 

Gastric juice/gastric tissue PGJ 2.0a 2.0a 1.0a 1.0a 

Skin tissue/skin blood PSk 1.0a

 1.0a 1.0a 1.0a 

Mammary tissue/mammary blood PM 0.66b

 NA 0.8b NA 

Mammary/milk PMk N A NA 1.0b

 NA 

Placenta/placental blood 0.40b

 NA NA NA 

Maximum capacity (ng/hour/kg) 

 Thyroid follicle VmaxcTF 1.22x105a 0–5.0x106d 1.4x105a 1.5–6x106d/1.5x105c

 Thyroid colloid (lumen) VmaxcTL 1.0x108a 1.0x108a 1.0x108a 1.0x108a

 Skin VmaxcS 7.2x104a 8.4x105a 5.6x105a 3.5x105a

 Gastrointestinal VmaxcG 4.6x105a 9.0x105a 9.0x105a 9.0x105a

 Mammary VmaxcM 4.0x104a NA 8.0x105b NA 

Milk VmaxcMk NA NA 5.0x105b NA 

Placenta VmaxcP 5.5x104b NA NA NA 

Affinity constants (ng/L) 

Mammary KmM 4.0x106b NA 4.0x106b NA 

Milk KmMk NA NA 1.0x107b NA 

Placenta KmP 4.0x106b NA NA NA 

Permeability area cross products, (L/hour/kg) 

Gastric blood to gastric tissue PAGc 0.16a

 0.12a 0.16a 0.01a 

Gastric tissue to gastric juice PAGJc 12.0a

 0.3a 12.0a 1.8a 

Thyroid stroma to thyroid follicle PATFc 1.0x10-4a 1.0x10-2d 1x10-4a 1.0x10-4a 

Thyroid follicle to thyroid colloid (lumen) 1.5x10-5a 1.0x10-4a 2.0x10-3a 1.25x10-3a 

PATLc 

Skin blood to skin tissue PASkc 0.06a

 0.06a 0.12a 0.012a 

Mammary blood to mammary tissue PAMc 0.01b

 NA 0.02b NA 

 Mammary tissue/milk PAMkc NA NA 0.02b

 NA 

Placenta blood to placenta PAPCc 0.005b

 NA NA NA 
PERCHLORATES 99 

3. HEALTH EFFECTS 

Table 3-5. Radioiodide Chemical-specific Parameters for Human Gestation and 

Lactation Models 

Gestation Lactation 

Parameters Woman Fetus Woman Neonate 

Clearance values, (L/hour/kg) 

 Urinary excretion CLUc 0.05a

 NA 0.1a 0.1c 

Placenta to fetal blood Cltrans1c 0.12d

 NA NA 

Fetal blood to placenta Cltrans2c 0.12b

 NA NA 

Note: Partition coefficients for perfusion limited compartments (i.e., fat, liver, kidney, rapidly and slowly perfused 

tissues) were the same across species and life stages. 

a

Calculated using parallelogram approach. 

b

Set to rat value (in absence of equivalent human parameter). 

c

Set to adult human value. 

d

Adjusted to fit data set. 

NA = not applicable 

Source: Clewell et al. 2007 
PERCHLORATES 100 

3. HEALTH EFFECTS 

Table 3-6. Perchlorate Chemical-specific Parameters for Rat Gestation and 

Lactation Models 

Gestation Lactation 

Parameters Dam Fetus Dam Pup 

Partition coefficients (unitless) 

Slowly perfused/plasma PS 0.31 0.31 0.31 0.31 

Rapidly perfused/plasma PR 0.56 0.56 0.5 0.5 

Fat/plasma PF 0.05 NA 0.05 0.05 

Kidney/plasma PK 0.99 0.99 0.99 0.99 

Liver/plasma PL 0.56 0.56 0.56 0.56 

Gastric tissue/gastric blood PGI 0.50 1.80 1.8 3.21 

Gastric juice/gastric tissue PGIJ 1.30 2.30 2.3 5.64 

Skin tissue/skin blood PSk 1.15 1.15 1.15 1.15 

Thyroid tissue/thyroid blood PTF 0.15 0.15a

 0.13 0.13 

Thyroid lumen/thyroid tissue PTL 7.0 7.0 7.0 7.0 

Red blood cells/plasma PRBC 0.73 0.73 0.73 0.73 

Placenta/plasma PPl 0.56 NA NA NA 

Mammary/plasma PM 0.66 NA NA NA 

Mammary tissue/mammary blood PM NA NA 0.66 NA 

Mammary/plasma PMk NA NA 2.39 NA 

Max capacity, Vmaxc (ng/hour/kg) 

Thyroid follicle VmaxcTF 2.6x103

 0–2.25x103 1.5x103 1.5x103 

Thyroid colloid VmaxcTL 1.0x104

 1.0x104b 1.0x104 1.0x104 

Skin VmaxcSk 6.0x105

 4.0x105 8.0x105 8.0x105 

Gut VmaxcGI 8.0x105

 1.0x105 1.0x106 1.0x106 

Placenta VmaxcP 6.0x104

 NA NA NA 

Mammary VmaxcM 2.2x104

 NA 2.0x104 NA 

Milk VmaxcMk NA NA 2.0x104

 NA 

Affinity constants, Km (ng/L) 

Thyroid follicle KmTF 1.0x105

 1.0x105 1.5x105 1.5x105 

Thyroid colloid KmTL 1.0x108

 1.0x108 1.0x108 1.0x108 

Skin KmSk 1.0x105

 1.0x105 1.5x105 1.5x105 

Gut KmGI 1.0x105

 1.0x105 1.5x105 NA 

Placenta KmP 1.0x105

 NA NA NA 

Mammary KmM 1.0x105

 NA 1.5x105 NA 

Milk KmMk NA NA 1.0x106

 NA 

Permeability area cross-products (L/hour/kg) 

Gastric blood to gastric tissue PAGIc 1.00 1.00 1.00 1.00 

Gastric tissue to gastric juice PAGIJc 1.00 1.00 1.00 1.00 

Thyroid stroma to follicle PATFc 6.0x10–5 6.0x10-5 4.0x10–5 4.0x10-5 

Thyroid follicle to colloid (lumen) PATLc 0.01 0.01b

 0.01 0.01 

Skin blood to skin tissue PASkc 1.00 1.00 0.50 1.00 
PERCHLORATES 101 

3. HEALTH EFFECTS 

Table 3-6. Perchlorate Chemical-specific Parameters for Rat Gestation and 

Lactation Models 

Gestation Lactation 

Parameters Dam Fetus Dam Pup 

Placenta blood to placenta tissue PAPc 0.1 NA NA NA

Plasma to red blood cells PARBCc 1.00 1.00 1.00 1.00 

Mammary blood to mammary tissue PAMc 0.04 NA 0.01 NA 

Mammary tissue/milk PAMkc NA NA 0.10 NA 

Clearance values (L/hour/kg) 

Urinary excretion ClUc 0.07 NA 0.07 0.0075 

Fraction of pup urine ingested by dam NA NA 0.80 NA 

Transfer from placenta to fetus ClTrans1c 0.065 NA NA NA 

Transfer from fetus to placenta ClTrans2c 0.12 NA NA NA 

Binding constants 

Association to binding sites VmaxcB (ng/hour/kg) 4.0x103

 1.5x103 9.0x103 2.0x103 

Affinity for binding sites KmB (ng/L) 1.0x104

 1.5x104 1.0x104 1.0x104 

Dissociation from plasma binding sites ClUnbc 0.034 0.01 0.034 0.01 

(hour-1) 

a

Parameters with two values indicate acute and drinking water parameters, respectively. 

b

Fetus was given maternal values for Vmax (scaled by fetal body weight) in the absence of data. 

NA = not applicable 

Source: Clewell et al. 2003a 
PERCHLORATES 102 

3. HEALTH EFFECTS 

Table 3-7. Iodide Chemical-specific Parameters for Rat Gestation and Lactation 

Models 

Gestation Lactation 

Parameters Dam Fetus Dam Pup 

Partition coefficients (unitless) 

Slowly perfused/plasma PS 0.21 0.21 0.21 0.21 

Rapidly perfused/plasma PR 0.40 0.40 0.40 0.40 

Fat/plasma PF 0.05 NA 0.05 0.05 

Kidney/plasma PK 1.09 1.09 1.09 1.09 

Liver/plasma PL 0.44 0.44 0.44 0.44 

Gastric tissue/gastric blood PGI 1.00 1.00 1.00 1.20 

Gastric juice/gastric tissue PGIJ 2.00 2.00 1.00 1.00 

Skin tissue/skin blood PSk 0.70 0.70 0.70 1.00 

Thyroid tissue/thyroid blood PTF 0.15 0.15 0.15 0.15 

Thyroid lumen/thyroid tissue PTL 7.0 7.0 7.0 7.0 

Red blood cells/plasma PRBC 1.00 1.00 1.00 1.00 

Placenta/plasma PPl 0.40 NA NA NA 

Mammary/plasma PM 0.66 NA NA NA 

Mammary tissue/mammary blood PM NA NA 0.80 NA 

Mammary/plasma PMk NA NA 1.0 NA 

Max capacity, Vmaxc (ng/hour/kg) 

Thyroid follicle VmaxcTF 4.4x104

 0–5.0x104 5.0x104 1.3x104 

Thyroid colloid VmaxcTL 4.0x106

 4.0x106b 6.0x107 6.0x107 

Skin VmaxcSk 6.0x104

 7.0x105 4.0x105 2.5x105 

Gut VmaxcGI 1.0x106

 2.0x106 2.0x106 2.0x106 

Placenta VmaxcP 5.5x104

 NA NA NA 

Mammary VmaxcM 4.0x104

 NA 8.0x105 NA 

Milk VmaxcMk NA NA 4.0x105

 NA 

Affinity constants, Km (ng/L) 

Thyroid follicle KmTF 4.0x106

 4.0x106 1.5x105 1.5x105 

Thyroid colloid KmTL 1.0x109

 1.0x109 1.0x108 1.0x108 

Skin KmSk 4.0x106

 4.0x106 1.5x105 1.5x105 

Gut KmGI 4.0x106

 4.0x106 1.5x105 NA 

Placenta KmP 4.0x106

 NA NA NA 

Mammary KmM 4.0x106

 NA 4.0x106 NA 

Milk KmMk NA NA 1.0x107

 NA 

Permeability area cross-products (L/hour/kg) 

Gastric blood to gastric tissue PAGIc 0.80 0.10 0.80 0.04 

Gastric tissue to gastric juice PAGIJc 0.60 0.30 0.60 0.09 

Thyroid stroma to follicle PATFc 1.0x10-4 1.0x10-4 1.0x10-4 1.0x10-4 

Thyroid follicle to colloid (lumen) PATLc 4.0x10-7 4.0x10-4 1.0x10-4 1.0x10-4 

Skin blood to skin tissue PASkc 0.10 0.02 0.20 0.02 
PERCHLORATES 103 

3. HEALTH EFFECTS 

Table 3-7. Iodide Chemical-specific Parameters for Rat Gestation and Lactation 

Models 

Gestation Lactation 

Parameters Dam Fetus Dam Pup 

Placenta blood to placenta tissue PAPc 0.005 NA NA NA 

Plasma to red blood cells PARBCc 1.00 1.00 1.00 1.00 

Mammary blood to mammary tissue PAMc 0.01 NA 0.02 NA 

Mammary tissue/milk PAMkc NA NA 0.02 NA 

Clearance values (L/hour/kg) 

Urinary excretion ClUc 0.03 NA 0.06 0.012 

Fraction of pup urine ingested by dam NA NA 0.80 NA 

Incorporation of iodide into hormones ClProdc 0.03 NA 0.10 0.06 

Incorporated iodine secretion to serum CSecrC 1.0x10-6 NA 7.0x10-7 1.0x10-6 

Deiodination NA NA 0.02 0.025 

Transfer from placenta to fetus ClTrans1c 0.06 NA NA NA 

Transfer from fetus to placenta ClTrans2c 0.12 NA NA NA 

Binding constants 

Association to binding sites VmaxcB (ng/hour/kg) NA NA 1.5x103

 500 

Affinity for binding sites KmB (ng/L) NA NA 1.0x105

 1.0x105 

Dissociation from plasma binding sites ClUnbc 

(hour-1) 

NA NA 0.09 0.05 

a

Parameters with two values indicate acute and drinking water parameters, respectively. 

b

Fetus was given maternal values for Vmax (scaled by fetal body weight) in the absence of data. 

NA = not applicable 

Source: Clewell et al. 2003a 
PERCHLORATES 104 

3. HEALTH EFFECTS 

other changes in radioiodide metabolism in the thyroid (e.g., hormone production and secretion) that are 

not simulated by the model. 

The adult human model (nonpregnant, non-lactating) also predicted reasonably well (i.e., within 1– 

2 standard deviations of observations) perchlorate concentrations in plasma and urine in subjects who 

received oral doses of perchlorate (Durand 1938; Eichler 1929; Greer et al. 2002; Kamm and Drescher 

1973; Merrill et al. 2005). Model predictions of radioiodide in gastric juice, serum, thyroid, and urine 

following an intravenous dose of radioiodide also corresponded with observations made in healthy adults 

(Hays and Solomon 1965). Model predictions of thyroid radioiodine uptake in subjects who received oral 

doses of perchlorate agreed with observations when the kinetic parameters for iodide in the thyroid (i.e., 

maximum transport into the thyroid follicle) were adjusted to achieve good correspondence to the 

observations (Greer et al. 2002; Merrill et al. 2005). When the model was calibrated by adjusting the 

maximum transport rate for iodide into the thyroid follicle, it accurately predicted the observed time 

course for radioiodine uptake in a Graves’ disease patient who received a single tracer dose of radioiodine 

(Stanbury and Wyngaarden 1952); however, the model substantially overpredicted iodide uptake after the 

same patient received a dose of perchlorate. The error in predictions of the effect of perchlorate on iodide 

uptake may reflect humoral regulation of iodide transport and organification mechanisms or a response to 

perchlorate in Graves’ disease patients that is not simulated in the model. 

The rat maternal/fetal model was evaluated by comparing predictions of perchlorate concentrations in 

maternal and fetal serum and maternal thyroid in rats exposed to perchlorate in drinking water (Clewell et 

al. 2001, 2003a). Model predictions agreed well (within 1–2 standard deviations of observations) with 

observations. Predictions of maternal and fetal radioiodine uptakes in thyroid were also in reasonable 

agreement with observations in rats that received single injections of iodine with or without single 

injections or oral gavage doses of perchlorate, or at the conclusion of 18 days of exposures to perchlorate 

in drinking water (Brown-Grant 1966; Clewell et al. 2001, 2003a; Sztanyik and Turai 1988). 

Similar outcomes occurred in evaluations of the lactating dam/neonate model (Clewell et al. 2003b). The 

model accurately predicted serum and thyroid iodide concentrations in the dam and neonate following 

single intravenous injections of radioactive iodine, with or without concurrent injection of perchlorate, 

and in maternal thyroid following an 18-day exposure to perchlorate in drinking water (Clewell et al. 

2003b). Model predictions of radioiodide levels in mammary gland and milk, in rats that did or did not 

receive single doses of perchlorate, corresponded with observations (Clewell et al. 2003b). 
PERCHLORATES 105 

3. HEALTH EFFECTS 

The human pregnancy and lactation models were evaluated by comparing model predictions of 

perchlorate concentrations in serum with observations made in pregnant women (15 and 33 weeks of 

gestation) and their infants at birth (from cord blood), and in a group of children (mean age 7.4 years) 

(Téllez et al. 2005). Exposures simulated in the model were the continuous perchlorate intake 

corresponding to the mean ±1 standard deviation drinking water exposure concentrations (114±13 ppm) 

for a cohort in the Téllez et al. (2005) study. Model predictions for maternal, fetal, and child serum 

perchlorate concentrations agreed well (within ±1 standard deviation of observed means) with 

observations. Téllez et al. (2005) also reported perchlorate concentrations in breast milk measured at 5– 

6 weeks postpartum. Simulation of the continuous perchlorate intake corresponding to the group means 

(± standard deviation) of drinking water exposure concentrations (5.8±0.6 ppm or 114±13 ppm) yielded 

predictions of breast milk perchlorate concentrations that were within ±1 standard deviation of the 

observed means. 

Risk assessment. The rat (Clewell et al. 2003a, 2003b; Merrill et al. 2003) and human models 

(Clewell et al. 2007; Merrill et al. 2005) can be used to estimate the human equivalent exposure level for 

perchlorate that would give rise to a given percent inhibition of thyroidal radioiodide uptake. The models 

do not include downstream effects on the thyroid axis, such as decreases in serum thyroid hormones. The 

Clewell et al. and Merrill et al. model estimates have been used to extrapolate dose-response relationships 

for perchlorate observed in rats to humans, and across various human lifestages (e.g., fetus, neonate, 

child, adult, pregnancy, lactation). External dose–internal dose relationships for various human lifestages predicted from the human models are presented in Tables 3-8 and 3-9 (Clewell et al. 2007). The 

models predict a relatively high vulnerability of the fetus, pregnant woman, and lactating woman to 

perchlorate-induced thyroid iodine uptake, compared to other lifestages (i.e., greater inhibition of thyroid 

iodide uptake occurs in these lifestages in association with lower external doses), compared to neonates, 

child or nonpregnant or nonlactating adult). The potential impact of external exposures to perchlorate on 

inhibition on thyroidal radioiodide uptake is sensitive to assumptions about urinary clearance of 

perchlorate, especially in neonates and young infants. The estimates based on external exposures from 

consumption of drinking water are also dependent on assumptions regarding age-related changes in 

contribution of drinking water to liquid consumption across lifestages (e.g., milk in children). 

Target tissues. Tissues simulated in the perchlorate models are shown in Figures 3-4 and 3-5. The 

models were designed to calculate perchlorate concentrations in serum and thyroid and inhibition of 

radioiodide uptake into the thyroid resulting from exposures to perchlorate for various lifestages (e.g., 

fetus, neonate, child, adult, pregnancy, lactation). 
PERCHLORATES 106 

3. HEALTH EFFECTS 

Table 3-8. Model-predicted Serum ClO4

-

 Area Under the Curve (AUC) Across 

Lifestages 

External Pregnanta Lactatingc 

dose Fetusa Neonateb Child Adult woman woman 

(mg/kg/day) (mg/L) (mg/L) (mg/L) (mg/L) (mg/L) (mg/L) 

0.001 0.010 0.008 0.001 0.002 0.005 0.008 

0.01 0.06 0.05 0.01 0.01 0.04 0.05 

0.1 0.2 0.2 0.1 0.1 0.3 0.3 

1.0 1.2 0.5 0.8 1.0 2.5 2.5 

a

Fetus and pregnant woman shown in gestation week 38. 

b

Neonate shown at postnatal month 1.5. c

Lactating woman shown at postnatal day 7. 

Source: Clewell et al. 2007 
PERCHLORATES 107 

3. HEALTH EFFECTS 

Table 3-9. Model-predicted Inhibition of Thyroid Iodide Uptake 

(Percent Inhibition) Across Lifestages 

 Percent Inhibition 

External 

dose 

(mg/kg/day) Fetusa

 Neonateb Child Adult 

Pregnanta 

woman 

Lactatingc 

woman 

0.001 1.1 0.9 0.3 0.6 1.0 1.1 

0.01 10 8 3 4 9 10 

0.1 49 34 21 31 50 54 

1.0 84 63 72 81 91 92 

a

Fetus and pregnant woman shown in gestation week 38 (birth). 

b

Neonate shown at postnatal month 1.5. c

Lactating woman shown at postnatal day 7. 

Source: Clewell et al. 2007 
PERCHLORATES 108 

3. HEALTH EFFECTS 

Species extrapolation. The models are designed for applications to rat or human dosimetry and 

cannot be applied to other species without modification and validation. 

Interroute extrapolation. The models are designed to simulate intravenous or oral exposures to 

perchlorate and cannot be applied to other routes of exposure without modification and validation. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Perchlorate is readily soluble in water and is quickly absorbed through the digestive tract. The 

mechanism by which perchlorate is transferred from the digestive system to the blood has not been 

investigated. Since Durand (1938) detected perchlorate in the urine of subjects 10 minutes after oral 

administration, it seems likely that absorption of perchlorate may begin in the stomach and continue in the 

small intestine. Anbar et al. (1959) determined that perchlorate eliminated in the urine 3 hours after an 

oral dose had not been metabolized (see Section 3.4.1). Whether microflora of the gut or intestinal 

enzymes modify perchlorate that is finally eliminated in the feces has not been investigated. 

Whatever the mechanism of absorption, perchlorate is distributed throughout the body via the circulation 

(see Section 3.4.2). It apparently is not metabolized (Anbar et al. 1959) and it binds only weakly to 

cations. Concentrations of perchlorate rise above serum levels only for those tissues that are equipped 

with the anion transporter mechanism that normally takes up iodide. The effects of perchlorate on the 

thyroid gland are known from studies on humans and animals (see Section 3.2); perchlorate levels in the 

thyroid reach a maximum several hours after administration. Chow and co-workers (Chow and 

Woodbury 1970; Chow et al. 1969) determined that perchlorate is taken up from interstitial fluid by 

active transport at the base of thyroid follicular cells, which then actively transport it out into the follicular 

lumen. The effects of perchlorate on the transfer of maternal iodide in milk have been studied in rats and 

cattle (Clewell et al. 2003b; Dobian et al. 2007; Howard et al. 1996; Kirk et al. 2005). The accumulation 

of perchlorate in ducts of the salivary gland has been described in mice (Lazarus et al. 1974). Studies on 

rodents have demonstrated that perchlorate can cross the placental barrier and affect the thyroid gland of 

the fetus (see Section 3.2). 

Perchlorate transport in the thyroid gland and in other tissues that express NIS (e.g., mammary 

epithelium) appears to be mediated by NIS. Perchlorate is accumulated in thyroid follicle cells and lumen 
PERCHLORATES 109 

3. HEALTH EFFECTS 

against an electrochemical gradient, indicating an active transport mechanism, and possibly different 

mechanisms at the basolateral and luminal membranes (Chow and Woodbury 1970; Chow et al. 1969; 

Clewell et al. 2004; Goldman and Stanbury 1973). Thyroid uptake of perchlorate in hypophysectomized 

rats is stimulated by administration of TSH (Chow et al. 1969). Perchlorate competitively inhibits iodide 

transport in thyroid slices, cultured thyrocytes, cultured cells transformed to express thyroid NIS, and 

thyrocyte membrane vesicles (Dohán et al. 2007; Eskandari et al. 1997; O'Neill et al. 1987; Tran et al. 

2008; Wolff and Maurey 1962, 1963; Yoshida et al. 1997). The above observations suggest that 

perchlorate transport into thyroid follicle cells, and possibly into other tissues where NIS is expressed, is 

mediated by NIS (Wolff 1998). Perchlorate uptake into thyroid cells is stimulated by TSH (Tran et. al. 

2008). Unlike the NIS-mediated transport of iodide, transport of perchlorate by NIS appears to be 

electroneutral (Dohán et al. 2007; Eskandari et al. 1997; Yoshida et al. 1997). Chinese hamster ovary 

(CHO) cells transfected with the rat thyroid NIS gene and Xenopus oocytes transfected with rat thyroid 

NIS mRNA express active NIS that exhibits a Na(2):I(1) stoichiometry, is electrogenic (inward directed 

current), occurs against an electrochemical gradient for iodide in the presence of an inward 

electrochemical gradient for sodium, and is inhibited by perchlorate (Eskandari et al. 1997; Yoshida et al. 

1997). Both systems, when clamped at an interior negative potential (40–50 mV), exhibit sodiumdependent inward currents in the presence of I-

 and SCN-; the transfected oocyte exhibits sodiumdependent inward currents in the presence of a variety of anions, including I-

, ClO3

-

, SCN-, SeCN-, NO3

-

, 

Br-

, BF4

-

, IO4

-

, BrO3

-

, SO4

-2, F-

, and HPO4

-2. However, these systems do not show perchlorate-stimulated 

currents in the presence or absence of a favorable inward-directed Na gradient. FRTL5 cells and other 

cell types that have been transfected to express NIS transport the structural tetrahedral oxyanion analogs 

of perchlorate, perrhenate (ReO4

-

), and pertechnetate (TcO4

-

), providing further support for NIS-mediated 

perchlorate transport. Furthermore, in MDCK cells transfected to express NIS-mediated electrogenic 

transport of iodide, transport of perchlorate, perrhenate (ReO4

-

), and pertechnetate (ReO4

-

) was also 

electroneutral (Dohán et al. 2007). 

Studies of the kinetics of excretion and elimination of perchlorate from serum in humans indicate that 

absorbed perchlorate is excreted in urine with an elimination half-time of 8–14 hours (Durand 1938; 

Greer et al. 2002; Lawrence et al. 2000). Thus, in humans, perchlorate would not be expected to 

accumulate in the body with prolonged exposure. Based on an elimination half-time of approximately 8– 

12 hours, a steady state would be achieved within 3–4 days of continuous exposure. Rapid elimination of 

perchlorate (half-time of 20 hours) has also been observed in rats (Eichler and Hackenthal 1962; Fisher et 

al. 2000; Goldman and Stanbury 1973; Yu et al. 2002). The mechanisms of renal excretion of perchlorate 

are not understood. 
PERCHLORATES 110 

3. HEALTH EFFECTS 

3.5.2 Mechanisms of Toxicity 

Perchlorate is an inhibitor of NIS, the primary mechanism by which iodide enters thyroid follicle cells 

from the blood, and the first step in the uptake of iodide into the thyroid and formation of thyroid 

hormones (Figure 3-6; Carrasco 1993; Taurog 2000; Wolff 1998). All toxic effects of perchlorate on the 

thyroid hormone system derive directly or secondarily from this mechanism. Because the primary and 

most sensitive target of the perchlorate anion is the thyroid gland, only toxicities related to the thyroid 

hormone system are addressed below. 

Thyroid Hormone. The thyroid hormone, T3, is essential for normal development of the nervous system 

and for the regulation of metabolism of cells in nearly all tissues of the body. Adverse effects on a wide 

variety of organ systems can result from disruption in the availability of T3 to target tissues. Organ systems 

affected by disturbances in T3 levels include the skin, cardiovascular system, pulmonary system, kidneys, 

gastrointestinal tract, liver, blood, neuromuscular system, central nervous system, skeleton, male and female 

reproductive systems, and numerous endocrine organs, including the pituitary and adrenal glands. 

T3 exerts its wide range of actions by binding to thyroid hormone receptors (TRs) in the cell nucleus, 

which, when bound with hormone, modulate the transcription of a variety of genes (Anderson et al. 

2000). TRs consist of a family of structurally similar proteins within the so-called steroid receptor 

superfamily that includes receptors for steroid hormones, vitamin D, retinoic acid, and peroxisomal 

proliferator activators (Lazar 1993). Each receptor has DNA binding domains capable of forming two 

zinc fingers; the sequence of the latter determine hormone receptor specificity to response elements on 

DNA that modulate gene transcription of hormone-sensitive genes. A ligand binding domain is 

responsible for conferring specificity for hormone binding. 

Modulation of gene expression occurs when the T3–TR complex binds to a region of DNA associated 

with a thyroid hormone response element (TRE). Studies in humans and experimental animals have 

identified TREs associated with a variety of genes, including growth hormone, myelin basic protein, 

α-myosin heavy chain, malic enzyme and protein S14 (important in lipogenesis), sarcoplasmic reticulum 

Ca2_ ATPase, Pcp-2 (in Purkinje cells), Na+

/K+-ATPase, and TSH (Anderson et al. 2000; Klein and Levey 

2000; Schwartz et al. 1994). 
111

I- Na+ ATP ADP 

Na+ K+ 

Figure 3-6. Pathways Uptake and Metabolism of Iodide in the Thyroid Gland* 

Plasma Cell Follicle Lumen

ClO -

4 TPO + 

H2O2 I

+ H , HOI 2O2 I+, HOI

or EOI Tg

(b) (c)

(inhibition)(inhibition)

I

- I-

(a) -DITNIS (g) -MIT- ITDH

(j) MIT -DIT- TSH TPO + H TPO + H 2O2

DIT (e) -MIT-

--T4-- (d) (f) --T3-­-

Apical Membrane

T4 T4

(i)

(h)5’-DI T3 T3

Basolateral Membrane

METABOLIC STEP 

a. Iodine uptake (inhibited by ClO 4) 

b. Iodine efflux 

c. Iodination 

d. Coupling 

e. Colloidresorption 

f. Proteolysis 

g. Deiodination of DIT 

h. Deiodination of T 4 

i. Secretion of T 3 and T 4 

j. TSH receptor binding 

PERCHLORATES 

3. HEALTH EFFECTS 

­

­

­

­

*The diagram depicts a single thyroid follicle cell, with the plasma side of the follicle on the left and the follicle lumen 

on the right. Iodide uptake (a) occurs through a Na+/I- symporter (NIS) in the basolateral membrane; the perchlorate 

ion competitively inhibits the NIS, preventing uptake of iodide into the follicle cell. Efflux into the follicle lumen (b) is 

thought to occur through an I- channel in the apical membrane. Iodination occurs in the follicle lumen (c). The 

enzyme thyroid peroxidase (TPO), depicted in the follicle lumen, is actually located in the apical membrane. 

Deiodination of iodotyrosines (g) is catalyzed by a microsomal enzyme, iodotyrosine dehalogenase (ITDH); 

monodeiodination of T4 (h) is catalyzed by the microsomal enzyme, 5’-diodinase. All steps in the uptake of iodine 

and synthesis of thyroid hormones (a–h) are stimulated by binding of thyroid stimulating hormone (TSH) to a receptor 

in the basolateral membrane. 

DIT = diiodotyrosine; EOI = enzyme-linked species; HOI = hypoidous acid; ITDH = iodotyrosine dehalogenase; 

MMI = methimazole; MIT = monoiodotyrosine; PTU = propylthiouracil; T3 = triiodothyronine; T4 = thyronine; 

Tg = thyroglobulin; TPO = thyroid peroxidase; TSH = thyroid stimulating hormone 

Source: adapted from Taurog 2000 
PERCHLORATES 112 

3. HEALTH EFFECTS 

Adverse effects on cell metabolism and growth can result from either understimulation or overstimulation 

of target tissues by T3. The amount of T3 available to target tissues is highly controlled by feedback 

regulation of the production, secretion, and elimination of both T3 and its metabolic precursor, 

T4 (Figure 3-7). Major components of this mechanism include negative feedback control mediated by 

T4 and T3 of the synthesis and release of thyrotropin-releasing hormone (TRH) in the hypothalamus and 

of TSH in the pituitary. TRH stimulates the synthesis and secretion of TSH in the pituitary and modulates 

the biologic potency of TSH. The latter is thought to result from effects of TRH on posttranslational 

glycosylation of TSH (Cohen et al. 2000; Scanlon and Toft 2000). TSH promotes growth of the thyroid 

gland follicle cells and stimulates thyroid iodide uptake and synthesis and secretion of T4 and 

T3 (Spaulding 2000). 

The metabolism of T4 and T3 is also regulated by feedback control mechanisms (Darras et al. 1999). 

T3 is synthesized from the deiodination of T4 in a reaction catalyzed by selenium requiring, microsomal 

enzymes known as iodothyronine deiodinases. Although some production of T3 occurs in the thyroid, 

most of the T3 that is available to extrathyroidal target tissues derives from deiodination of T4 that occurs 

outside of the thyroid (Figure 3-7). The liver and kidney are thought to be major sites of production of 

T3 in the circulation; however, local tissue production of T3 from T4 is thought to be the predominant 

source of T3 in the brain and pituitary. Iodothyronine deoidinases also catalyze the inactivation of T4 and 

T3. The activities of deiodinases are under feedback control, mediated by T3, T4, and reverseT3 (rT3) an 

inactive deiodination product of T4 (Darras et al. 1999). 

Mechanism of Uptake of Iodide into the Thyroid. Synthesis of T4 and T3 in the thyroid is dependent on 

delivery of iodide into the thyroid follicle where the iodination of thyroglobulin occurs in the first steps of 

hormone synthesis (Figure 3-6). Uptake of iodide into the thyroid is facilitated by a membrane carrier in 

the basolateral membrane of the thyroid follicle cell (Carrasco 1993; Levy et al. 1998a; Shen et al. 2001). 

The carrier, or NIS, catalyzes the simultaneous transfer of Na+

 and I- across the basolateral membrane 

(Chambard et al. 1983; Iff and Wilbrandt 1963; Nilsson et al. 1990). The NIS enables the follicle cell to 

achieve intracellular/extracellular concentration ratios of 10–50 for iodide (Andros and Wollman 1991; 

Bagchi and Fawcett 1973; Shimura et al. 1997; Vroye et al. 1998; Weiss et al. 1984b; Wolff 1964). 

The NIS has been studied extensively in several in vitro preparations, including isolated plasma 

membrane vesicles of mammalian thyroid (O’Neill et al. 1987), FRTL-5 cells, a cell line derived from 

normal rat thyroid (Weiss et al. 1984b), Xenopus lavis oocytes transformed by intracellular injection of 

FRTL-5 RNA to express NIS (Eskandari et al. 1997), and other mammalian cells cultures transformed to 
PERCHLORATES 113 

3. HEALTH EFFECTS 

Figure 3-7. Hypothalamic-pituitary-thyroid (HPT) Feedback Pathways for 

Regulation of Thyroid Hormone Production and Secretion* 

*T3 inhibits the synthesis and secretion of thyroid releasing hormone (TRH) in the paraventricular nuclei of the 

hypothalamus and the synthesis and secretion of thyroid stimulating hormone (TSH) in the thyrotrophs of the anterior 

pituitary. Most of the T3 in these tissues derives from local deiodination of T4; as a result, TRH and TSH synthesis 

and secretion are sensitive to circulating levels of both T3 and T4. Doses of perchlorate that decrease circulating 

levels of T3 or T4 can trigger the HPT feedback mechanism to stimulate thyroid growth, including hypertrophy and 

hyperplasia of follicle cells. Chronic stimulation of thyroid growth is thought to be contributor to the development of 

thyroid tumors in rats exposed to perchlorate. 
PERCHLORATES 114 

3. HEALTH EFFECTS 

express NIS (Levy et al. 1997; Nakamura et al. 1990; Smanik et al. 1996; Yoshida et al. 1997). Iodide 

transport by the NIS is inhibited by other anions, most notably, thiocyanate (SCN-

) and perchlorate 

(ClO4

-

) (Carrasco 1993; Wolff 1964). Thiocyanate is one of several anions other than I- that can be 

transported by the NIS, including SeCN-

, NO3

-

, ClO3

-

, Br-, BF4

-

, IO4

-

, BrO3

-

, ReO4

-

, and TcO4

- (Eskandari 

et al. 1997; Van Sande et al. 2003). Direct evidence for perchlorate transport by NIS (i.e., measurement 

of radioperchlorate flux through the NIS) is lacking; however, transport activity is likely given that the 

NIS transports the structural analogs, perrhenate and pertechnetate. Perchlorate transport by NIS may be 

electroneutral, preventing its detection from measurements of ion currents or electrochemical gradients 

(Dohán et al. 2007; Eskandari et al. 1997; Yoshida et al. 1997). 

The NIS is expressed in a variety of other tissues, including breast tissue where it is thought to function in 

the transport of iodide into breast milk (Levy et al. 1997; Smanik et al. 1997; Spitzweg et al. 1998). In 

the rat, expression of the NIS, or a structurally similar membrane protein, increases during nursing and 

decreases after weaning (Levy et al. 1998a). In the mouse, expression of NIS in mammary tissue appears 

to be stimulated by prolactin (Perron et al. 2001; Rillema and Rowady 1997; Rillema et al. 2000). 

Inhibition of Thyroid NIS and Thyroid Hormone Production by Perchlorate. Perchlorate inhibition of 

NIS can limit the availability of iodide needed for the production of T4 and T3 in the thyroid. The degree 

of perchlorate-induced iodide uptake inhibition required to impair T4 or T3 synthesis has not been 

studied, but the duration of exposure required to produce a reduction in circulating levels of thyroid 

hormones appears to vary with species. In this regard, the duration of perchlorate exposure required to 

cause a reduction in circulating levels of thyroid hormones appears to be shorter in rats than in humans 

(see Section 3.5.3). This difference is thought to derive from the rat thyroid gland having a smaller store 

of iodinated thyroglobulin that is more quickly depleted when the availability of iodide is limited, and 

from the rat having a shorter T4 half-life (about 1 day) compared to humans (about 7 days). In humans, 

THBG functions as an important storage depot for circulating T4 and a buffer for homeostatic regulation 

of free T4 levels in serum (Robbins 2000). If the production of T4 and T3 is impaired sufficiently to 

deplete the thyroid of stored iodinated thyroglobulin, the thyroid cannot produce or secrete amounts of 

T4 and T3 needed to support physiological demands, circulating levels of T4 (fT4) and T3 decrease, and a 

state of thyroid hormone insufficiency ensues. A decrease in the levels of circulating thyroid hormones 

triggers HPT feedback control mechanisms that serve to adjust thyroidal iodide transport and hormone 

production in response to changes in circulating levels of T4, T3, and iodide. Major components of this 

mechanism include inhibition of the secretion of TRH from the hypothalamus, TRH-stimulated secretion 

of TSH from the pituitary, TSH-stimulated induction of thyroid follicle cell NIS (i.e., upregulation) and 
PERCHLORATES 115 

3. HEALTH EFFECTS 

other thyroid cell proteins, increased capacity for transport of iodide into thyroid follicle cells, and 

increased synthesis and secretion of T4 and T3 from the thyroid. This system normally maintains 

circulating levels of T4 and T3 within narrow individual limits (Andersen et al. 2002). Doses of 

perchlorate that are sufficient to decrease circulating levels of thyroid hormones outside of these 

individual limits will result in increased secretion of TSH. Thus, an increase in the circulating levels of 

TSH is a sign that perchlorate has perturbed circulating levels of thyroid hormones. In humans, intraindividual variation in T4 levels is less than inter-individual variation, suggesting that the HPT feedback 

mechanism can detect relatively small changes in thyroid hormone levels that are well within the range of 

variation expected in populations (Andersen et al. 2002). Triggering of the HPT feedback response in 

profound iodide deficiency can affect the response of the thyroid to perchlorate. Rats maintained on an 

iodine-deficient diet for sufficient periods to lower serum T4 levels, exhibited higher 24-hour thyroid 

radioiodide uptake when exposed to perchlorate in drinking water (1.1–28 mg/L) for 5 weeks than iodinereplete rats (Paulus et al. 2007). The increased resistance to perchlorate-induced inhibition of thyroid 

iodide uptake in iodine deficiency has been attributed, at least in part, to induction of NIS in the thyroid, 

which partially overcomes the competitive inhibition of NIS resulting from a given dosage of perchlorate. 

Perchlorate-induced Hypothyroidism. Inhibition of thyroid iodide uptake can potentially deplete stores 

of T4 and T3 in the thyroid and lower serum T4 and T3 levels. Thus, perchlorate has the potential for 

producing hypothyroidism or for aggravating an ongoing hypothyroid condition. The term 

hypothyroidism refers to a state of suppressed production and/or secretion of thyroid hormones. The term 

clinical hypothyroidism refers to a condition in which the circulating levels of T4 and/or T3 are depressed 

below their normal ranges (usually accompanied with elevated serum TSH levels above the normal range) 

and in which there are clinical symptoms of thyroid hormone insufficiency (Ladenson 2000). Typical 

normal ranges for hormone levels are shown in Table 3-10. Subclinical hypothyroidism refers to an 

increase in serum TSH (usually mild) with serum T4 and T3 remaining in their respective normal ranges 

for age. An important question is whether small changes in circulating levels of thyroid hormones that 

trigger the HPT feedback mechanism, but do not fall outside of the normal population range, are detected 

as thyroid hormone insufficiency in tissues other than the hypothalamus or pituitary, including the 

embryo or fetal brain. 

In humans, relatively large doses of perchlorate (600–900 mg/day, 8–13 mg/kg/day) are required to 

deplete thyroidal iodine stores sufficiently to decrease serum levels of T4 (Brabant et al. 1992; Bürgi et al. 

1974). A 4-week oral exposure to 900 mg/day (approximately 13 mg/kg/day) did not produce clinical 

hypothyroidism in healthy adults (Brabant et al. 1992); however, a dosage considerably lower, 
PERCHLORATES 116 

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Table 3-10. Typical Reference Ranges for Serum Thyroid Hormones and TSH in 

Humans 

Hormone Metric 

Reference range 

SI unit 

Total T4 

Free T4 

Total T3 

4–11 μg/dL 

0.7–2.1 ng/dL 

75–175 ng/dL 

60–140 nMa 

10–25 pMa 

1.1–2.7 nMa 

Free T3 0.2–0.5 ng/dL 3–8 pM 

Reverse T3 

TSH 

15–45 ng/dL 

0.3–4.0 mU/Lb,c 

0.2–0.7 nM 

1–15 pM 

a

Children may have higher levels b

Assumes a biologic potency of 7–15 mU/mg c

Higher in neonates (de Zegher et al. 1994) 

SI = Systems Integration; T3 = 3,5,3’-triiodo-L-thyronine; T4 = 3,5,3',5’-tetraiodo-L-thyronine (thyroxine); 

TSH = thyroid stimulating hormone 

Sources: Stockigt 2000; Vanderpump and Tunbridge 1996 
PERCHLORATES 117 

3. HEALTH EFFECTS 

0.5 mg/kg/day for 14 days, produced a 70% inhibition of thyroid iodide uptake with no effects on the 

levels of circulating T4, T3, or TSH in serum, at least over the 14-day dosing period (Greer et al. 2002). 

In these short-term studies, it is possible that thyroid hormone production could have been suppressed by 

perchlorate inhibition of thyroid NIS without changing serum thyroid hormone levels. This could occur 

because the human adult thyroid contains a surplus of T4 to support normal levels of serum levels for 

several months (Greer et al. 2002). The ability of high dosages of perchlorate to lower T4 and T3 levels 

in serum is the basis for use of perchlorate in the pharmacological management of thyrotoxicosis, the 

clinical manifestation of abnormally elevated circulating levels of T4 and/or T3 (Soldin et al. 2001). 

Perchlorate-induced Thyroid Enlargement and Cancer. Although there is no direct evidence of 

perchlorate causing cancer in humans, perchlorate has produced thyroid cell hyperplasia and papillary 

and/or follicular adenomas and/or carcinomas in rats and mice (see Section 3.2.2.7). Perchlorate itself 

does not appear to be genotoxic (see Section 3.3). Production of thyroid tumors in rodents appears to be 

related to perchlorate-induced inhibition of thyroid iodide uptake and the resulting triggering of the HPT 

feedback control mechanism that elevates serum TSH levels. Persistent stimulation of the thyroid by 

TSH results in hypertrophy and hyperplasia of thyroid follicle cells, which are reflected in an increase in 

the size and weight of the thyroid (goiter). Tumors appear to be a progression of this hyperplasia. The 

mechanism by which gland enlargement leads to thyroid tumors is not completely understood. Thyroid 

gland proliferation may increase the fixation of mutations in the thyroid and promote the development of 

autonomous nodules, regions of thyroid follicle tissue that are less responsive or unresponsive to serum 

TSH concentrations (Corvilain et al. 2000; Fagin 2000). Consistent with the concept that TSHstimulation and the resulting thyroid cell hypertrophy and hyperplasia are contributing factors to thyroid 

tumorigenesis are the observations that thyroid tumors can be produced in rats by a variety of different 

treatments that chronically elevate serum TSH levels, including maintaining the animals on a diet 

deficient in iodide, or by exposing the animals to chemical agents (e.g., thiouracil compounds, 

sulfonamides) that disrupt thyroid hormone production (Capen 1997). 

Developmental Effects of Perchlorate. Thyroid hormones are essential for normal development of the 

nervous system, lung, skeletal muscle, and possibly other organ systems (Forhead et al. 2002; Hume et al. 

2001; Porterfield and Hendrich 1993). The fetus is dependent on maternal thyroid hormones at least until 

the fetal thyroid begins to produce T4 and T3 (Zoeller and Crofton 2000). In humans, this occurs at 

approximately 16–20 weeks of gestation. Brain development begins in humans prior to the onset of fetal 

thyroid hormone production, with a major growth spurt occurring between 12 and 18 weeks of gestation 

with the beginning of neuron multiplication (Pintar 2000). This is followed by glial cell multiplication, 
PERCHLORATES 118 

3. HEALTH EFFECTS 

myelination, and formation of dendritic extensions and synapses, which begin at approximately 18 weeks, 

reaching their peak near the end of gestation and continuing through postnatal years 1 and 2 (Boyages 

2000; Fisher and Brown 2000; Oppenheimer and Schwartz 1997). Thyroid hormones are present in 

human amniotic fluid at 8 weeks of gestation prior to the onset of fetal thyroid hormone production 

(Contempre et al. 1993; Thorpe-Beeston et al. 1991). Thyroid hormone receptors are present and 

occupied by hormone at this time as well, suggesting that the fetus is capable of responding to maternal 

thyroid hormones (Bernal and Pekonen 1984; Ferreiro et al. 1988). Calvo et al. (2002) showed that first 

trimester fetal tissues are exposed to concentrations of free T4 (FT4) that depend ultimately on the 

circulating maternal levels of T4 or FT4. Thus, a decrease in the maternal supply results in lower 

concentrations of FT4 in fetal fluids and, consequently, of T4 available to the developing brain. The 

contribution of maternal thyroid hormones to the fetal thyroid hormone status is also evident from infants 

who have an inherited disorder that abolishes T4 production but are born, nevertheless, with normal 

serum thyroid hormone levels (i.e., euthyroid) and become hypothyroid after birth if not administered 

thyroid hormones within 2 weeks after birth (Larsen 1989; Vulsma et al. 1989). This suggests that 

transfer during fetal life is at least partially protective in cases where the fetus cannot produce adequate 

amounts of T4, providing that the maternal thyroid hormone production is not compromised. However, 

athyrotic babies, although born euthyroid, show retarded skeletal maturation at birth, suggesting that fetal 

thyroid function during earlier phases of gestation may be necessary for normal skeletal development 

(Rovet et al. 1987; Wolter et al. 1979). Uncorrected maternal hypothyroidism, on the other hand, may 

result in impaired neurodevelopment of the fetus with severe long-lasting implications. For example, Pop 

et al. (1999) studied a cohort of 220 healthy children and found that children of women with FT4 levels 

below the 5th and 10th percentiles at 12 weeks of gestation showed impaired psychomotor development at 

10 months of age. In women with the lowest 10th percentile FT4 concentrations at 12 weeks of gestation, 

maternal FT4 concentration was positively correlated with the children’s psychomotor development. 

Haddow et al. (1999) measured TSH levels in serum collected from 25,216 women and found that the 7– 

9-year-old children of the 62 women with high TSH levels performed less well in 15 tests relating to 

intelligence, attention, language, reading ability, school performance, and visual-motor performance than 

children of women with normal TSH values. Their full-scale IQ scores on the Wechsler Intelligence 

Scale for Children averaged 4 points lower than those of the children of matched control women. 

Studies in rats provide further support for the importance of maternal thyroid hormones in development. 

Both T4 and T3 are present in rat fetal tissues prior to the onset of hormone production by the fetal 

thyroid on approximately day 17 of gestation, and maternal hormones appear to make a significant 

contribution to hormone levels in the fetus in late gestation as well (Calvo et al. 1990; Escobar del Rey et 
PERCHLORATES 119 

3. HEALTH EFFECTS 

al. 1986; Morreale de Escobar et al. 1990; Zoeller and Crofton 2000). Furthermore, thyroid hormoneresponsive genes that are important in early development of the brain are expressed in the rat fetus prior 

to fetal thyroid hormone production, and expression of these genes is sensitive to the maternal thyroid 

hormone status (Dowling and Zoeller 2000; Dowling et al. 2001). Disruption of the maternal thyroid 

hormone system of rats by removal of the maternal thyroid or maternal iodide deficiency results in 

decreased levels of thyroid hormones in the fetus, and maternal iodide deficiency will result in fetal 

iodide deficiency and congenital hypothyroidism (Escobar del Rey et al. 1986; Morreale de Escobar et al. 

1985). These observations suggest an important role of maternal thyroid hormones in development of the 

rat fetus and that, by limiting the availability of thyroid hormones to the early fetus, suppression of 

maternal thyroid hormone production by perchlorate could translate into disruptions of fetal development. 

The availability of maternal T4 to the fetus appears to be particularly important for maintenance of 

T3 levels in the fetal rat brain. Treatment of pregnant rats with methimazole, an inhibitor of thyroid 

hormone synthesis, resulted in decreased levels of both T4 and T3 in fetal tissues, including fetal brain 

(Calvo et al. 1990). Maternal infusions of T4 restored brain T3 levels; however, maternal infusion of 

T3 had little restorative effect on brain T3 levels, although it was able to restore T3 levels in other fetal 

tissues. Studies in which radiolabelled T4 was administered to neonatal rats made hypothyroid by 

maternal or neonatal treatment with methimazole provide direct evidence for the enhanced production of 

brain T3 from T4 (Silva and Matthews 1984). These observations are consistent with an important role of 

local generation of T3 from T4 in the brain by the action of brain iodothyronine deiodinases in 

maintaining brain T3 levels (Darras et al. 1999; Zoeller and Crofton 2000). From a toxicological 

perspective, these observations also suggest that in the rat, a decrease in maternal serum T4 levels, even in 

the absence of changes in maternal serum T3 levels may have adverse consequences on fetal brain 

development. Zoeller and Rovet (2004), and others cited therein, have reviewed the issue of the role of 

thyroid hormones in brain development and concluded that studies of models of maternal 

hypothyroidism, hypothyroxinemia and congenital hypothyroidism suggest that the timing and severity of 

thyroid hormone insufficiency predicts the type and severity of the neurological deficits. 

Perchlorate could potentially disrupt fetal thyroid hormone status by three mechanisms. Perchlorate 

inhibition of maternal thyroid iodide uptake, and the resulting suppression in production and levels of 

maternal thyroid hormones, could limit the availability of thyroid hormones needed for normal fetal 

development prior to the onset of fetal thyroid hormone production if thyroid function in the mother is 

compromised. Perchlorate can also cross the placenta and may directly inhibit fetal thyroid iodide uptake 

and, secondarily, fetal thyroid hormone production. By inhibiting NIS in breast tissue, perchlorate may 

also limit the availability of iodide to nursing infants, who depend entirely on breast milk for the iodide 
PERCHLORATES 120 

3. HEALTH EFFECTS 

needed to produce thyroid hormone (Agency for Toxic Substances and Disease Registry 2004). No 

information is available on the doses in humans that might decrease iodide uptake into breast milk. 

Radioiodine uptake into mammary milk was decreased in rats exposed to 1 or 10 mg/kg/day perchlorate 

in drinking water (Clewell et al. 2003b). Studies conducted in cows and goats have also shown that 

perchlorate can decrease radioiodine uptake into mammary milk (Howard et al. 1996). 

Thyroid suppression at birth has been observed in infants born to mothers who received potassium 

perchlorate during pregnancy for treatment of hyperthyroidism (Crooks and Wayne 1960; Fisher et al. 

1962). Direct evidence of maternal-fetal transfer of perchlorate and suppression of fetal thyroid iodide 

uptake and hormone production has been provided from studies of rats and guinea pigs (Clewell et al. 

2003a; Postel 1957; Schröder-van der Elst et al. 2001; York et al. 2001b). Several epidemiological 

studies have explored the strength of possible associations between perchlorate exposures and neonatal 

thyroid hormone status. Although some of these studies are suggestive of a possible association between 

perchlorate exposures and elevated serum TSH levels in infants, the findings of the currently available 

epidemiological literature, taken in toto, is inconclusive regarding effects of perchlorate on neonatal 

thyroid hormone status (Brechner et al. 2000; Crump et al. 2000; Lamm and Doemland 1999; Li et al. 

2000a, 2000b; Schwartz 2001). Furthermore, these studies were likely to be confounded because they did 

not obtain individual estimates of perchlorate exposure. Without this information, it is likely that these 

studies were comparing T4 levels, on average, among groups of people that were not, on average, 

exposed to different levels of perchlorate. Studies conducted in rats provide direct evidence that 

perchlorate exposures during pregnancy or lactation can disturb thyroid hormone status in the neonate 

(Brown-Grant 1966; Brown-Grant and Sherwood 1971; Clewell et al. 2003a, 2003b; Golstein et al. 1988; 

Lampe et al. 1967; Mahle et al. 2003; York et al. 2001a, 2003, 2004). The mechanisms for these effects 

have not been elucidated. 

3.5.3 Animal-to-Human Extrapolations 

The ability of perchlorate to inhibit thyroid uptake of iodide in both humans (Bürgi et al. 1974; DeGroot 

and Buhler 1971; Faure and Dussault 1975; Greer et al. 2002; Lawrence et al. 2000, 2001; Stanbury and 

Wyngaarden 1952) and animals (Kapitola et al. 1971; Ortiz-Caro et al. 1983; Schonbaum et al. 1965; 

Wyngaarden et al. 1952) is well established. Based on this ability, potassium perchlorate was widely 

used for a time as treatment to restore normal thyroid activity in patients with hyperactive thyroids (e.g., 

Crooks and Wayne 1960; Morgans and Trotter 1960). Therapeutically effective doses in humans were in 

the range of 5–20 mg perchlorate/kg/day. 
PERCHLORATES 121 

3. HEALTH EFFECTS 

Although abundant evidence exists to show that perchlorate can inhibit thyroid iodide uptake in humans, 

direct evidence that perchlorate can disrupt thyroid hormone levels and produce changes in thyroid 

morphology (in the absence of underlying thyroid disorder, such as Graves’ disease or other causes such 

as thyrotoxicosis) derives largely from animal studies. Changes in serum levels of thyroid hormones, 

indicative of suppressed hormone production, and thyroid hypertrophy, indicative of stimulation of the 

thyroid gland by TSH, have been shown to occur in rats and mice exposed to perchlorate by the oral route 

(see Section 3.2.2.2, Endocrine Effects). Evidence that perchlorate can produce thyroid tumors also 

derives from the results of studies conducted in mice and rats (see Section 3.2.2.7). In humans and other 

mammals, a limitation in the availability of iodide for thyroid hormone production, regardless of the 

cause of the limitation, triggers an HPT feedback mechanism, which serves to maintain serum hormones 

at sufficient levels to satisfy physiological requirements. Extrapolation of dose levels that disrupt thyroid 

hormone status in animals to pharmacodynamically equivalent doses in humans must take into account 

not only potential species differences in perchlorate biokinetics, but also potential species differences in 

the compensatory response to a limitation in iodide availability to the thyroid. 

Few studies have been reported that allow direct comparisons of the dose-response relationships for the 

effects of perchlorate on thyroid hormone status in humans and experimental animals. However, these 

studies indicate that the response of human adults to short-term oral dosages (mg/kg/day) of perchlorate is 

quantitatively different from the response observed in rats given comparable dosages. Inhibition of 

thyroid iodide uptake has been observed in healthy euthyroid adults who were exposed to dosages 

exceeding 0.007 mg/kg/day in drinking water (Greer et al. 2002; Lawrence et al. 2000). The dosage that 

produced a 50% inhibition of 24-hour thyroid iodide uptake was approximately 0.15 mg/kg/day when the 

exposure duration was either for 2 or 14 days (Figure 3-8; Greer et al. 2002). Oral doses that ranged from 

0.007 to 0.5 mg/kg/day for 14 days had no observable effect on serum TSH or thyroid hormone levels in 

healthy adults (Greer et al. 2002; Lawrence et al. 2000). Oral doses of perchlorate that produced the same 

magnitude of inhibition of 24-hour thyroid iodide were higher in rats compared to humans. For example, 

in rats, 1 mg/kg/day in drinking water for 1 or 14 days produced a 0 or 15% inhibition, respectively 

(Figure 3-8; Yu et al. 2002). However, this same study observed inhibition of thyroid iodide uptake (10– 

30%) that was similar in magnitude to that observed in humans when iodide was administered to rats 

2 hours following a single intravenous dose of 0.01 or 0.1 mg perchlorate/kg/day and thyroid iodide 

uptake was determined 2–9 hours following the radioiodide dose (Yu et al. 2002). Rats also exhibited 

elevated plasma levels of TSH when exposed to perchlorate for 14 days, and a pronounced attenuation of 

the inhibition in thyroid iodide uptake compared to the response observed following 2 days of exposure to 
PERCHLORATES 122 

3. HEALTH EFFECTS 

Figure 3-8. Comparison of Dose-Response Relationships for the Inhibitory Effect 

of Perchlorate on 24-hour Thyroid Iodide Uptake in Humans and Rats 

y = 15.57Ln(x) + 78.702 

R2 = 0.9976 

0 

10 

20 

30 

40 

50 

60 

70 

80 

0.001 0.01 0.1 1 10 100 

Dose (mg/kg/day) 

Greer et al. 2002 (human, 14d) Greer et al. 2002 (human, 2d) 

Lawrence et al. 2000, 2001 (human, 14d) Yu et al. 2002 (rat, 14d) 

Yu et al 2002 (rat, 1d) Fitted line to Greer et al 2002 (14d) 

% Inhibtion of Thyroid Iodide 

Uptake 

Greer et al. (2002) administered perchlorate in drinking water to adult humans for 14 days and measured RAIU on 

exposure days 2 or 14. Lawrence et al. (2000, 2001) administered perchlorate in drinking water to adult humans for 

14 days and measured RAIU on exposure day 14. Yu et al. (2002) exposed rats to perchlorate in drinking water for 

1 day (24 hours) and measured RAIU on day 2 (day following cessation of exposure); rats were also exposed to 

perchlorate for 14 days and RAIU was measured on day 15. 
PERCHLORATES 123 

3. HEALTH EFFECTS 

perchlorate (Yu et al. 2002). Differences in the perchlorate dose-response relationships for thyroid iodide 

uptake between humans and rats may reflect the triggering of HPT feedback control mechanisms and 

induction of NIS, which serve to regulate thyroid iodide transport and hormone production in response to 

a decrease in serum thyroid hormones and iodide levels. The involvement of the HPT control mechanism 

in the response to perchlorate in the rat is consistent with the observed dose-response relationship for 

changes in serum T3, T4, and TSH levels (Figure 3-9). Perchlorate dosages of 1–5 mg/kg/day for 14 days 

in drinking water depressed serum levels of T3 and T4 and increased levels of TSH (Caldwell et al. 1995; 

Siglin et al. 2000; Yu et al. 2002). By contrast, serum hormone levels were unchanged in human adults 

who received dosages of up to 0.5 mg/kg/day for the same duration and who exhibited as much as a 70% 

inhibition of thyroid iodide uptake (Greer et al. 2002; Lawrence et al. 2000). These observations suggest 

that dosages of perchlorate that inhibit thyroid iodide uptake must occur over a longer duration to produce 

effects on circulating levels of thyroid hormones in healthy, euthyroid adult humans than in healthy, 

euthyroid adult rats (see Lewandowski et al. 2004 for review on interspecies differences). This is thought 

to be related to a smaller and more rapid turnover of the hormone pool in the rat thyroid, and to a more 

rapid clearance of secreted hormone in the rat (serum half-life for T4 is shorter in rats than in humans). 

Less is known about the relative sensitivities of humans and experimental animals to developmental 

effects of perchlorate. Outstanding uncertainties include potential differences in kinetics of maternal-fetal 

and maternal-infant transfer of perchlorate, as well as potential differences in the degree to which the 

fetus of the human, in comparison to experimental animals, is dependent on maternal thyroid hormone for 

development, particularly during the period of gestation prior to the onset of fetal hormone production. 

NAS (2005) reviewed the human and animal data and concluded that the human data provided a more 

reliable point of departure for the risk assessment than the animal data. In agreement with the above 

discussion, NAS (2005) further noted that: “the rat is a good quantitative model for assessing inhibition 

of iodide uptake by the thyroid caused by perchlorate exposure, but it is only a good qualitative model for 

the effects of that inhibition.” 

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 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 
PERCHLORATES 124 

3. HEALTH EFFECTS 

Figure 3-9. Changes in Serum Thyroid Hormone Levels in Rats Exposed to 

Perchlorate in Drinking Water for 14 Days 

1.E-03 1.E-02 1.E-01 1.E+00 1.E+01 1.E+02 

1.E-03 1.E-02 1.E-01 1.E+00 1.E+01 1.E+02 

1.E-03 1.E-02 1.E-01 1.E+00 1.E+01 1.E+02 

Dose (mg/kg/day) 

Caldwell et al. 1995 (m) Caldwell et al. 1995 (f) Siglin et al. 2000 (m) 

Siglin et al. 2000 (f) Yu et al. 2002 

-60 

-50 

-40 

-30 

-20 

-10 

0 

10 

Seru

m T3 (% Change) -50 

-40 

-30 

-20 

-10 

0 

Seru

m T4 (% 

Change) 

0 

40 

80 

120 

160 

200 

Seru

m T

S

H (% Increase) 
PERCHLORATES 125 

3. HEALTH EFFECTS 

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 1997a). 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). 

Perchlorate can impair thyroid hormone production and, therefore, can be classified as an endocrine 

disruptor. As discussed in Sections 3.2.2.2 (Systemic-Endocrine Effects) and 3.5.2 (Mechanisms of 

Toxicity), at sufficiently high dosages, perchlorate can limit the availability of iodide needed for the 

production of the hormones in the thyroid and can depress serum levels of the thyroid hormones, T4 and 

T3. The latter effect triggers HPT feedback control mechanisms to produce TSH, which stimulates 

growth of the thyroid and induces NIS, the primary mechanism by which iodide enters thyroid follicle 

cells from the blood and the first step in the uptake of iodide into the thyroid and formation of thyroid 

hormones. Thus, perchlorate exposure at sufficiently high doses has the potential for producing all of the 

adverse consequences of hypothyroidism including impairments in the development of the nervous 

systems and other organ systems, thyroid gland enlargement, and follicular cell hyperplasia and neoplasia. 
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However, studies discussed earlier indicate that at perchlorate levels routinely found in the environment, 

no evidence of such adverse effects have been observed or documented. 

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 most biological systems have fully developed. However, the 

brain continues to develop until about 25 years of age. 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, 

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 
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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). 

Fetuses, infants and children may be especially susceptible to the thyroid effects of perchlorate. Thyroid 

hormones regulate cell proliferation, migration, and differentiation during development, therefore, 

maintenance of normal levels is essential to normal growth and development. Disruption of circulating 

hormone levels can have markedly different effects, depending on the stage of development. Effects can 

include mental retardation, impaired motor skills, and hearing and speech impediments (Boyages 2000; 

Fisher and Brown 2000; Haddow et al. 1999; Pop et al. 1999). Several factors may contribute to a high 

vulnerability of the fetus and neonate to perchlorate (see Section 3.10, Susceptible Populations, for further 

details). In addition, as discussed by NAS (2005), preterm infants are more sensitive to thyroid hormone 

perturbations than term infants. 

Thus far, there is no conclusive evidence that exposure to perchlorate produces developmental effects in 

humans. Two studies of newborns in Arizona and California reported that neonates from women whose 

drinking water contained perchlorate had higher TSH values than those from women with no exposure to 

perchlorate (Brechner et al. 2000; Schwartz 2001). However, the methods used in the two latter studies 

have been questioned. Other similar studies in the United States have found no significant associations 

between maternal exposure to perchlorate via the drinking water and T4 levels (Li et al. 2000a), TSH 

levels (Li et al. 2000b), and incidence of congenital hypothyroidism (Kelsh et al. 2003; Lamm and 

Doemland 1999). Two studies of Chilean neonates whose mothers may have been chronically exposed to 

up to 100–120 μg/L (ppb) of perchlorate in the drinking water found no evidence of adverse thyroid 
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effects among the neonates (Crump et al. 2000; Téllez et al. 2005). Studies in experimental animals have 

shown that exposure of the mother to perchlorate during gestation, or even during lactation, can lead to 

reduced thyroid hormone levels and associated thyroid effects in the offspring (Brown-Grant and 

Sherwood 1971; Golstein et al. 1988; Lampe et al. 1967; Postel 1957; York et al. 2001a, 2003, 2004). 

Evaluation of a series of neurobehavioral parameters in rat pups exposed to perchlorate in utero (maternal 

exposure up to 8.5 mg perchlorate/kg/day) and through maternal milk revealed no significant treatmentrelated effects (Bekkedal et al. 2000; York et al. 2004). Microscopic examination of the brain from 

12-day-old pups showed a significant increase in the thickness of the corpus callosum from females in the 

highest dose group, 8.5 mg/kg/day (York et al. 2004), but a subsequent study by the same group of 

investigators reported a similar effect at 0.09 and 0.9 mg/kg/day, but not at highest dose tested, 

25.5 mg/kg/day (York et al. 2005b). The toxicological significance of this finding is controversial and its 

biological significance has been questioned (NAS 2005). High-dose male offspring sacrificed at about 

80 days of age had a significant increase in brain weight and in the weight of the prefrontal cortex and 

corpus callosum (York et al. 2004). Exposure to perchlorate has not caused teratogenic effects in 

animals. 

Perchlorate has been shown to cross the placenta of rats (Clewell et al. 2003a; Schröeder-van der Elst et 

al. 2001). Thus, in addition to the potential for perchlorate to exert effects on fetal development by 

depressing levels of maternal thyroid hormones, perchlorate may exert direct effects on the fetal thyroid. 

Thyroid suppression at birth has been observed in infants born to mothers who received potassium 

perchlorate during pregnancy for treatment of hyperthyroidism (Crooks and Wayne 1960; Fisher et al. 

1962). Direct evidence of maternal-fetal transfer of perchlorate and suppression of fetal thyroid hormone 

production has been provided from studies of rats and guinea pigs (Postel 1957; York et al. 2001b; Yu et 

al. 2002). 

Studies conducted in experimental animals have shown that perchlorate enters mammary milk (Clewell et 

al. 2003b). Perchlorate has also been detected in human breast milk at a mean concentration of 10 ppb 

(Kirk et al. 2005). Whereas this indicates that nursing infants may be exposed to perchlorate in breast 

milk, whether the amount of perchlorate in the breast milk is great enough to affect thyroid function of the 

infant has not been demonstrated. However, a recent study in rats showed that the NIS actively 

concentrates perchlorate in the milk and suggested that exposure of newborns to high levels of perchlorate 

may pose a greater health risk than previously thought because it could directly inhibit the newborn 

thyroidal iodide uptake (Dohán et al. 2007). Nevertheless, the beneficial aspects (biological and 
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psychological) of breast-feeding outweigh any risks from exposure to perchlorate from mother’s milk, 

especially if they consume adequate iodine from food and supplements. 

Models of the biokinetics of perchlorate in adult humans and rats have been developed (Fisher et al. 2000; 

Merrill et al. 2003, 2005). An adult rat model has been extended to include pregnancy and maternal-fetal 

transfer of perchlorate, and lactation and maternal-pup perchlorate transfer through milk (Clewell et al. 

2003a, 2003b). These models have been used to develop predictive models for the human gestation and 

postnatal period (Clewell et al. 2007). In the latter study, pregnant and lactating women, the fetus, and 

nursing infants were predicted to have higher concentrations of perchlorate in blood and greater thyroid 

iodide uptake inhibition at a given concentration of perchlorate in drinking water than either nonpregnant 

adults or older children. Although the fetus was predicted to receive the greatest dose, the predicted 

extent of iodide inhibition was not significant (approximately 1%) at the NAS-recommended reference 

dose of 0.7 μg/kg/day for perchlorate. 

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). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. 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 (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to perchlorates are discussed in Section 3.8.1. 
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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 perchlorates 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. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Perchlorates 

Studies in workers exposed to perchlorate (Lamm et al. 1999) and in volunteers who ingested daily doses 

of perchlorate for 14 days (Lawrence et al. 2000) indicate that perchlorate is rapidly eliminated 

unchanged in the urine (see Section 3.4.4). Urine, therefore, is a convenient testing medium for 

perchlorate. However, the excretion of perchlorate is so rapid that an acute exposure might be detectable 

for only a few days after exposure. Both occupational studies and studies with volunteers have estimated 

an elimination half-life for perchlorate of approximately 8–12 hours (Greer et al. 2002; Lamm et al. 1999; 

Lawrence et al. 2000). The methods used for measuring perchlorate in urine have not been standardized 

(see also Section 7.1). 

Using a highly selective analytical method of coupled ion chromatography and electrospray tandem mass 

spectrometry, Valentín-Blasini et al. (2005) found an association between urinary levels of perchlorate 

with the concentrations of perchlorate in drinking water in a population of women from Chile. In a 

population with no known perchlorate drinking water contamination, concentrations of perchlorate 

adjusted for urinary creatinine showed a median level of 7.8 μg perchlorate/g creatinine, with a range of 

1–35 μg perchlorate/g creatinine. Although the intake of perchlorate through food had not been measured 

in this population, this population probably has a high background dietary intake of perchlorate because 
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Chilean soil is a natural source of of perchlorate. When the urine samples of the pregnant women in three 

cities in the study in Chile (Crump et al. 2000) were analyzed by this method, the women in the city with 

a drinking water concentration of perchlorate of about 0.4 ng/mL had a median urinary concentration of 

21 μg perchlorate/g creatinine, those with a drinking water concentration of about 5.8 ng/mL had a 

median urinary concentration of 37 μg perchlorate/g creatinine, and those with a drinking water 

concentration of about 114 ng/mL had a median urinary concentration of 120 μg perchlorate/g creatinine 

(Valentín-Blasini et al. 2005). Recently, Gibbs (2006) demonstrated a highly significant linear correlation 

between the concentration of perchlorate in serum and dose over a dose range covering almost four orders 

of magnitude. The studies that contributed data for Gibbs’ analysis included Brabant et al. (1992), Crump 

et al. (2000), Lawrence et al. (2000), and Merrill et al. (2005). 

Perchlorate has also been detected in human breast milk, but the concentrations were not correlated with 

the water consumed by the lactating women. As perchlorate is fairly rapidly cleared when exposure 

ceases, the presence of perchlorate in breast milk may be highly variable with time and recent dietary 

history (Kirk et al. 2005; Pearce et al. 2007). 

Other potential biomarkers of exposure to perchlorate relate to their effect on the thyroid gland. As 

described in Section 3.5.2, Mechanisms of Toxicity, perchlorate blocks uptake of iodide into the thyroid, 

leading to an increase in the serum level of free iodine (i.e., not bound to T4), which is then excreted in 

urine. No study has developed a correlation between exposure to particular dose levels of perchlorate and 

specific relative increases of free iodine in serum or urine. In serum, the normal level of free iodine 

ranges from 1.0 to 5.2 μg/L and the level of protein-bound iodine ranges from 32 to 72 μg/L. Iodine is 

excreted in urine at a rate that is nearly equal to the rate of intake, or approximately 100–200 μg/24 hours 

(Agency for Toxic Substances and Disease Registry 2004). Saliva also has potential as a source of 

noninvasive biomarker because anions such as perchlorate are actively sequestered into the salivary gland 

by the NIS. Perchlorate produces a decrease in the levels of T3 and T4 in serum, while increasing the 

serum level of TSH in rats, but this has not been shown in humans at doses below those used in clinical 

medicine to treat thyrotoxicosis. Specific correlations between levels and duration of exposure to 

perchlorate and alterations in serum levels of T3, T4, or TSH in humans have not been developed. 

Furthermore, these potential biomarkers are not specific to perchlorate; other antithyroid agents, such as 

carbimazole, can have similar effects. 
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3.8.2 Biomarkers Used to Characterize Effects Caused by Perchlorates 

The thyroid is the critical target for perchlorate. Perchlorate blocks uptake of iodide into the thyroid, 

leading to an increase in the serum level of free iodine (i.e., not bound to T4), which is then excreted in 

urine. If the dosage is sufficient to limit the availability of iodide for the production of thyroid hormones, 

then perchlorate can also produce a decrease in the levels of T3 and T4 in serum, while increasing the 

serum level of TSH. Therefore, levels of iodide in serum or urine, and levels of T3, T4, and TSH in 

serum, can all be considered to be biomarkers of effect for perchlorate. A recent study showed that in 

women with urinary iodine <100 μg/L, urinary perchlorate (which is a measure of perchlorate intake) was 

a significant negative predictor of TT4 and a positive predictor of TSH (Blount et al. 2006). It should be 

noted that none of these biomarkers is specific to perchlorate; other antithyroid agents such as 

carbimazole can have similar effects. It should also be noted that TT4 is not routinely measured for 

clinical significance as it is too impacted by other biological variables. Although the specific amount of 

change in these biomarkers associated with a demonstrably adverse effect has not been established, 

changes in these parameters can be considered to indicate potential impairment of health. Typical normal 

ranges for hormone levels are shown in Table 3-4. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

No studies were located regarding health effects in humans exposed to perchlorate in combination with 

other chemicals that are likely to be found with perchlorate in the environment, in the workplace, or at 

hazardous waste sites. 

Limited information was found in studies in animals. Administration of a single dose of 7.5 or 75 μg/kg 

of 3,3’,4,4’5-pentachlorobiphenyl (PCB 126) to rats followed 9 days later by doses of up to 1 mg 

perchlorate/kg/day in the drinking water for additional 14 days showed less than additive effects on serum 

TSH, TT4, FT4, and hepatic T4-glucuronide (McLanahan et al. 2007). Exposure to lower doses of each 

chemical (NOEL doses), resulted in no interaction between the chemicals for the thyroid indices 

measured. In another study, simultaneous exposure of rats to various concentrations of ammonium 

perchlorate and sodium chlorate for 7 days reduced serum total T4 to a greater extent than either chemical 

alone (Khan et al. 2005). 

Tonacchera et al. (2004) investigated the simultaneous joint effects of perchlorate and other competitive 

inhibitors of iodide uptake (thiocyanate, nitrate, and non-radioactive iodide) in inhibiting RAIU in an 

in vitro test system in which human NIS was stably transfected into a Chinese hamster ovary (CHO) cell 
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line. The relative potency of perchlorate to inhibit 125I⎯ uptake at the NIS was 15, 30, and 240 times that 

of thiocyanate, non-radioactive iodide, and nitrate, respectively, on a molar concentration basis. The 

results showed that the anions interact in a simple additive fashion and that the concentration response for 

each inhibitor was indistinguishable from that of each of the others after adjusting for differences in 

inhibition potencies. 

Nitrate and thiocyanate are widely distributed in nature and, because both anions also inhibit RAIU, as 

demonstrated by Tonacchera et al. (2004), should also be included in the discussion of the effects of 

inhibition of the NIS by anions. Nitrate is a natural constituent of green leafy vegetables and is also used 

as a preservative. Administration of a diet containing 3% potassium nitrate to rats for 4 weeks resulted in 

a significant increase in thyroid weight and serum TSH levels and in reductions in serum T3 and T4 

(Mukhopadhyay et al. 2005). Thiocyanate can be derived from thioglucosides present in foods such as 

cabbage, cauliflower, and broccoli, and is also found in tobacco. The effects of thiocyanate on thyroidal 

function of humans have been known for a long time. Gibbs (2006) reviewed the literature and reported 

that no adverse or non-adverse thyroidal effects of thiocyanate occur at serum concentrations of 

thiocyanate <50 μmol/L. This concentration of thiocyanate is equivalent to approximately 3.3 μmol 

perchlorate/L in terms of iodine uptake inhibition (Tonacchera et al. 2004). To achieve such 

concentration of perchlorate in serum, the daily dose of perchlorate would have to be 0.27 mg/kg/day, or a 

70-kg adult would have to drink 2 L of water daily containing 9 mg perchlorate (Gibbs 2006). However, 

extrapolating data from the in vitro studies such as the Tonacchera et al. (2004) study to situations in vivo 

may not be appropriate because the in vitro studies cannot account for the relative human half-lives of 

perchlorate, thiocyanate, and nitrate or other factors such as protein binding and chronicity. In a related 

study, De Groef et al. (2006) examined the possible contribution of nitrate and thiocyanate to NIS 

inhibition. Using EPA’s current Maximum Contaminant Level (MCL) for nitrate in drinking water, 

De Groef et al. (2006) showed that the concentration of nitrate allowed in water would cause an inhibition 

of iodine uptake by the NIS equivalent to 300 ppb perchlorate, 12 times greater than the concentration of 

about 25 ppb that corresponds to the RfD for perchlorate proposed by the NAS (assuming a 70-kg adult 

consuming 2 L of water per day). The same exercise with thiocyanate showed that the MCL for 

thiocyanate is equivalent to approximately 23 ppb perchlorate. The conclusion reached by the 

investigators was that “when considering the potential thyroid-related health risks posed by monovalent 

anions, perchlorate only accounts for a small fraction (<10%) of the exposure from drinking water.” 
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3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to perchlorates than will most 

persons exposed to the same level of perchlorates 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 result in reduced detoxification or excretion of perchlorates or compromised function of 

organs affected by perchlorates. Populations who are at greater risk due to their unusually high exposure 

to perchlorates are discussed in Section 6.7, Populations with Potentially High Exposures. 

Any condition affecting processes by which circulating iodide ultimately becomes part of a functional 

thyroid hormone will increase the susceptibility to substances that affect thyroid function such as 

perchlorate. Among these conditions are genetic factors. This topic has been reviewed by Scinicariello et 

al. (2005) and original citations can be obtained therein. For example, people with congenital iodide 

transport deficit (ITD), an infrequent autosomic recessive condition that has been linked to mutations of 

the perchlorate-sensitive NIS gene, may exhibit a defective transport of iodide from circulation into the 

thyroid cell. People who suffer from Pendred Syndrome (PDS), an autosomal recessive disorder 

characterized by deafness and goiter, may have a diminished iodide transport over the apical membrane, 

which causes iodide to remain in the thyrocyte. The PDS gene product pendrin is a protein that transports 

chloride and iodide and mediates the exchange of chloride and formate. Increased susceptibility to 

perchlorate can also result from defects in iodide organification, a process by which iodide is oxidized 

and bound to thyrosine residue in thyroglobulin. Mutations identified in proteins involved in the 

iodination of the thyrosine residue may result in accumulation of iodide in the thyrocyte. 

As discussed in NAS (2005), fetuses and preterm newborns constitute the most sensitive populations, 

although infants and developing children are also considered sensitive populations. The expected high 

sensitivity of developing organisms is due to the important role played by thyroid hormones during 

development (Zoeller 2006; see also Section 3.5.2). Perchlorate may reduce the level of circulating 

thyroid hormones in the blood, and low thyroid hormone levels during embryonic or fetal development 

can lead to effects such as mental retardation, impaired motor skills, and hearing and speech impediments 

(Haddow et al. 1999; Pop et al. 1999; Soldin et al. 2001). This is because the fetus is dependent on 

maternal thyroid hormones at least until the fetal thyroid begins to produce T4 and T3 (Zoeller and 

Crofton 2000). In humans, this occurs at approximately 16–20 weeks of gestation. Perchlorate also can 

inhibit the NIS in breast tissue (Levy et al. 1997; Smanik et al. 1997; Spitzweg et al. 1998), and therefore 

may limit the availability of iodide to nursing infants, who depend entirely on breast milk for the iodide 
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needed to produce thyroid hormone (Agency for Toxic Substances and Disease Registry 2004). 

However, in a study of 57 lactating women in Boston, Massachusetts, no correlation was found between 

perchlorate concentrations in breast milk and concentrations of iodide in breast milk (Pearce et al. 2007). 

As discussed by Ginsberg et al. (2007), additional factors that make neonates a sensitive group include 

their shorter serum half-life for T4 of approximately 3 days compared to approximately 7–10 days in 

adults, a lower storage capacity of the thyroid for T4, and possibly slower urinary clearance of perchlorate 

due to immature renal function. Hypothyroid pregnant women also constitute a susceptible group who 

may also put the fetus at higher risk if maternal hypothyroidism is present before the onset of fetal thyroid 

function at 10–12 weeks of gestation (Zoeller and Crofton 2000). Human models of pregnancy, maternalfetal transfer, and maternal-infant transfer of perchlorate have also been developed (Clewell et al. 2007, 

see Section 3.4.5). These models have yielded predictions of external dose–internal dose relationships for 

various human lifestages (Clewell et al. 2007; see Tables 3-6 and 3-7). The models predict a relatively 

high vulnerability of the fetus, pregnant women, and lactating women to perchlorate-induced thyroid 

iodine uptake, compared to other lifestages (e.g., greater inhibition of thyroid iodide uptake occurs in the 

fetus in association with lower external doses). Women with low iodine intake may also constitute a 

susceptible group, as suggested by a recent study in which urinary perchlorate was reported to be a 

significant negative predictor of serum TT4 and a significant positive predictor of serum TSH in women 

with urinary iodine <100 μg/L (Blount et al. 2006). 

People with reduced thyroid activity from other causes may also be an unusually susceptible population. 

This includes people living in endemic goiter areas with low iodine intake, people with exposure to other 

anti-thyroid drugs (e.g., lithium) (Green 1996; Spaulding et al. 1972), and people with Hashimoto’s 

disease (autoimmune hypothyroidism [Weetman 2000]) or other diseases that reduce thyroid hormone 

levels. Exposure to perchlorate may produce additional deficiencies in these people beyond those due to 

their pre-existing conditions, potentially increasing the severity of their conditions. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to perchlorates. 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 perchlorates. When 

specific exposures have occurred, physicians who specialize in thyroid disorders should be consulted for 

medical advice. 
PERCHLORATES 136 

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No texts were located that provided specific information about treatment following exposures to 

perchlorate. 

3.11.1 Reducing Peak Absorption Following Exposure 

There are no established methods for managing initial exposure to perchlorate or for reducing peak 

absorption 

Since perchlorate is readily excreted in the urine, it is reasonable to assume that increasing the water 

uptake would help the body eliminate perchlorate. No studies have investigated this issue. 

3.11.2 Reducing Body Burden 

Perchlorate is readily eliminated from the body and does not bioaccumulate or result in a body burden. 

The elimination half-life for perchlorate has been estimated to be 8–12 hours (Durand 1938; Greer et al. 

2002; Lamm et al. 1999). 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

There are no published studies on the treatment of perchlorate exposure by interfering with its mechanism 

of toxicity. Since the inhibition of the NIS by perchlorate can limit the availability of iodide needed for 

the production of T4 and T3 in the thyroid, it is important to maintain an adequate intake of iodine. 

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 perchlorates 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 perchlorates. 

The following categories of possible data needs have been identified. They are defined as substancespecific 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 
PERCHLORATES 137 

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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 Perchlorates 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

perchlorates are summarized in Figure 3-10. The purpose of this figure is to illustrate the existing 

information concerning the health effects of perchlorates. 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. 

Human studies on perchlorate include cross-sectional epidemiology studies of perchlorate workers with 

inhalation exposure, short-term oral experimental studies on healthy and hyperthyroid subjects, general 

population studies of adults, school-age children, and neonates, and case reports of hyperthyroid patients 

with intermediate- or chronic-duration oral treatment with perchlorate. 

Animal studies for perchlorate are available only by the oral route. The available studies have included 

investigation of systemic effects by acute, intermediate, and chronic exposure, as well as immunological, 

reproductive, and developmental effects, lethality, and cancer. Limited information is available regarding 

effects of perchlorate on the nervous system in adult animals. No experimental studies have been 

conducted that examine the interactions of perchlorate exposure and dietary iodine levels. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. Acute-duration studies are available for healthy humans (Bürgi et al. 

1974; DeGroot and Buhler 1971; Faure and Dussault 1975; Greer et al. 2002; Lawrence et al. 2000, 2001) 

and animals (Arieli and Chinet 1985; BRT 2000; Caldwell et al. 1995; DOD 1999; Kapitola et al. 1971; 

Mannisto et al. 1979; Matsuzaki and Suzuki 1981; Schonbaum et al. 1965; Siglin et al. 2000; Spreca and 

Musy 1974) orally exposed to perchlorate. These studies suggest that the thyroid is the main target for 

acute exposure to perchlorate. The study by Greer et al. (2002) identified a NOEL for radioactive iodine 
3. HEALTH EFFECTS 

Figure 3-10. Existing Information on Health Effects of Perchlorate 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate 

Chronic 

Immunologic/Ly

e ro g

e ro u

e elo m

e

oto i

a ce

m

h r

p o etic 

N u

lo ic 

R p

d ctive 

D v

p

ental 

G n

x c 

C n

r 

Systemic 

Animal 

Existing Studies 

PERCHLORATES 138 
PERCHLORATES 139 

3. HEALTH EFFECTS 

uptake by the thyroid of 0.007 mg/kg/day. NAS (2005) recently completed an evaluation of the literature 

on perchlorate and derived an RfD of 0.0007 mg/kg/day based on the findings of Greer et al. (2002). 

ATSDR has adopted the EPA’s chronic RfD recommended by NAS (2005) for the chronic oral MRL. 

Acute and intermediate MRL values will need to be assessed as relevant data from new studies are 

published. Conducting acute studies by the inhalation route does not seem warranted since this route of 

exposure does not play a significant role in environmental exposures to perchlorate. Although dermal 

absorption of perchlorate should be negligible, information on dermal absorption and dermal toxicity 

studies could be useful because skin contact with perchlorate in water supplies is likely when water 

contains perchlorate. In its review of perchlorate toxicity, NAS (2005) notes that further studies of 

perchlorate in rats would be of limited utility for clarifying the health effects of perchlorate in humans. 

Instead, NAS recommends conducting a series of in vitro studies using human tissues and animal studies 

to determine the role of NIS in placental iodide transport, the susceptibility of breast NIS to perchlorate 

inhibition, the role of iodide status in these effects, and the effects of perchlorate on development 

independently of effects on iodide transport. NAS (2005) further notes studies on the effects of 

perchlorate on other tissues that contain NIS could be conducted. 

Intermediate-Duration. Intermediate-duration studies are available for humans (Brabant et al. 1992; 

Braverman et al. 2006) and animals (Bekkedal et al. 2000; BRT 2000; DOD 1999; Eskin et al. 1975; 

Gauss 1972; Hiasa et al. 1987; Logonder-Mlinsek et al. 1985; MacDermott 1992; Ortiz-Caro et al. 1983; 

Pajer and Kalisnik 1991; Postel 1957; Sangan and Motlag 1986, 1987; Selivanova and Vorobieva 1969; 

Shevtsova et al. 1994; Siglin et al. 2000; Tarin-Remohi and Jolin 1972; Vijayalakshmi and Motlag 1989a, 

1989b, 1990, 1992; York et al. 2001a, 2001b, 2003, 2004, 2005a, 2005b) orally exposed to perchlorates. 

Brabant et al. (1992) studied the effect of administration of perchlorate for 4 weeks on thyroid hormone 

levels in healthy volunteers and their findings suggested that a period of iodide deficiency may increase 

the sensitivity of the thyroid to TSH. Braverman et al. (2006) reported that administration of up to 

approximately 0.04 mg perchlorate/kg/day to volunteers for 6 months caused no significant alterations in 

thyroid function tests, including radioiodine uptake. The studies in animals provided information on 

systemic, immunologic, reproductive, and developmental effects of perchlorate. The thyroid gland was 

shown to be the most sensitive target. Almost all of the earlier studies used only one dose level, usually 

quite high. Studies conducted in the past few years have used much lower doses, which allow the 

construction of dose-response relationships and the identification of NOAELs and LOAELs. In three of 

these studies (Siglin et al. 2000; York et al. 2003, 2005a), ATSDR identified LOAELs of 

0.009 mg/kg/day. Additional studies in animals would be useful to clarify some controversial findings of 

the studies recently available. These findings concern effects of perchlorate on neurobehavioral effects 
PERCHLORATES 140 

3. HEALTH EFFECTS 

and brain morphometry in young animals exposed in utero. As indicated above, additional studies in rats 

for the purpose of clarifying the health effects of perchlorate in humans seem unnecessary given the 

difference in the manner rats and humans handle the inhibition of iodide uptake by the thyroid. As 

mentioned above, studies by inhalation and dermal exposure do not seem necessary at this time since the 

most relevant route of exposure for perchlorate is the oral route, specifically drinking water. 

Chronic-Duration Exposure and Cancer. Humans with chronic inhalation exposure to 

perchlorate at work were the subject of cross-sectional epidemiology studies (Braverman et al. 2005; 

Gibbs et al. 1998; Lamm et al. 1999). These studies found no significant effects associated with 

perchlorate exposure. Cancer has not been reported in humans with exposure to perchlorate. A study by 

Li et al. (2001) found no significant association between perchlorate in drinking water and the prevalence 

of thyroid diseases or thyroid cancer residents in Nevada counties. However, no information was 

available on age, gender, ethnicity, iodine intake, and other risk factors. An additional study of cancer 

among residents of San Bernardino County, California, was limited by mixed exposures and lack of 

adjustment for potential confounding variables (Morgan and Cassady 2002). A few chronic-duration 

studies of toxicity and carcinogenicity are available in animals exposed to perchlorate orally (Kessler and 

Kruskemper 1966; Toro Guillen 1991). A few intermediate-duration carcinogenicity studies by the oral 

route are also available (Florencio Vicente 1990; Gauss 1972; Pajer and Kalisnik 1991). The data from 

these studies are limited for assessment of toxicity or carcinogenicity, however, because only a high dose 

level was used. Still, it was evident that the main target of toxicity was the thyroid gland, as thyroid 

adenomas and/or carcinomas were observed in the animals. It is unclear whether additional studies would 

provide new key information. As noted above, ATSDR has adopted the NAS (2005) recommended RfD 

for the chronic oral MRL. EPA adopted this chronic RfD based on the NAS (2005) recommendation. 

NAS (2005) recommended a clinical study designed to provide information on the potential chronic 

effects of low-dose perchlorate exposure on thyroid function, with a special focus on the ability and 

mechanisms of thyroid compensation. If for ethical or other reasons it is not possible to conduct studies 

in humans, NAS (2005) suggested that chronic studies in nonhuman primates could provide useful 

information. However, baseline thyroid studies would have to be conducted first to compare strains of 

monkeys to humans. 

Genotoxicity. No genotoxicity studies were located for perchlorate in humans, but two studies were 

located in animals in vivo. Siglin et al. (2000) found no evidence of bone marrow micronucleus 

formation in male and female rats exposed to perchlorate in the drinking water for 90 days. Similar 

negative results were reported by Zeiger et al. (1998b) in mice treated with perchlorate intraperitoneally 
PERCHLORATES 141 

3. HEALTH EFFECTS 

for 3 days. In vitro studies were limited to a test for SOS-inducing activity in S. typhimurium (Nakamura 

and Kosaka 1989), a test for production of DNA-protein cross links in cultured human lymphocytes 

(Costa et al. 1996), tests for mutagenicity in various Salmonella strains (Zeiger et al. 1998a), and a mouse 

lymphoma assay (San and Clarke 1999). Perchlorate gave negative results in all tests. Additional testing 

does not seem necessary at this time. 

Reproductive Toxicity. No data on reproductive effects of perchlorate in humans were located. 

Earlier reproductive toxicity studies available for perchlorate in animals (Brown-Grant 1966; BrownGrant and Sherwood 1971) were of limited utility for assessing reproductive toxicity because they 

included only brief exposure of females during gestation, limited investigation of reproductive end points, 

and single dose levels. In a two-generation reproduction study, exposure of rats to up to 25.5 mg 

perchlorate/kg/day did not affect any reproductive index (York et al. 2001b). In another study, exposure 

of rats to up to 25.5 mg perchlorate/kg/day beginning 2 weeks before cohabitation with untreated males 

and continuing during gestation did not result in any significant alterations in numbers of corpora lutea 

and implantations, percent implantation loss, litter size, early or late resorptions, or sex ratio (York et al. 

2005a). In addition, a 90-day drinking water in rats did not find gross or microscopic alterations in the 

testes, prostate, epididymis, uterus, ovaries, or mammary glands (Siglin et al. 2000). That study also 

reported no significant effects on sperm motility, concentration, count, or morphology. Further studies do 

not appear to be necessary at this time. 

Developmental Toxicity. There are several oral studies available that evaluated the effects of 

perchlorate on thyroid parameters in human newborns (Amitai et al. 2007; Brechner et al. 2000; Crump et 

al. 2000; Kelsh et al. 2003; Lamm and Doemland 1999; Li et al. 2000a, 2000b; Schwartz 2001; Téllez et 

al. 2005). Crump et al. (2000) also examined the effects of perchlorate on thyroid function in school-age 

children. For the most part, no significant alterations were reported, although Brechner et al. (2000) and 

Schwartz (2001) reported an association between high levels of perchlorate in the drinking water and 

elevated serum levels of TSH, but the methods used in the two latter studies have been criticized. The 

neurodevelopmental progress of children presumed to have been exposed to perchlorate in utero could be 

followed in longitudinal studies in search of possible long-term effects. Developmental toxicity studies 

are available for perchlorate in animals (Bekkedal et al. 2000; Brown-Grant and Sherwood 1971; Golstein 

et al. 1988; Lampe et al. 1967; Mahle et al. 2003; Postel 1957; York et al. 2001a, 2001b, 2003, 2004, 

2005a, 2005b). Although the earlier studies were of limited utility because standard developmental 

toxicity end points were not monitored and only single high dose levels were administered, the studies 

conducted in the past few years have been able to establish dose-response relationships using relatively 
PERCHLORATES 142 

3. HEALTH EFFECTS 

low exposure levels of perchlorate. Exposure of pregnant rats to perchlorate has resulted in thyroid 

alterations in the pups at maternal doses as low as 0.009 mg/kg/day (York et al. 2003, 2005a). In addition 

to evaluating thyroid effects in the offspring, some recent studies have conducted neurobehavioral testing 

in the offspring at various ages and have also conducted histological and morphometric evaluations of 

pups’ brains (Bekkedal et al. 2000; York et al. 2003, 2004, 2005b). However, these studies have not 

evaluated known thyroid hormone-responsive end points in brain; for example, expression of genes that 

are known to respond to thyroid hormone or maturation specific brain structures (i.e., Purkinje cells) that 

respond to thyroid hormone (Porterfield and Hendrich 1993; Zoeller and Crofton 2000). Furthermore, 

there is no evidence that the linear measures of specific brain areas that have been evaluated in animal 

studies are responsive to changes in circulating levels of thyroid hormone. Studies directed at 

characterizing the reaction of thyroid hormone responsive end points in brain to small changes in thyroid 

hormone have not been conducted. NAS (2005) noted that studies of pregnant monkeys could provide 

useful information on the effects of perchlorate on fetal and neonatal development. Continued research is 

necessary to help improve our understanding of the potential mechanistic steps resulting in thyroid 

hormone level changes from exposure to low levels of perchlorate and other environmental contaminants 

such as thyocyanate and nitrate that can inhibit iodide uptake and potentially result in prenatal and 

infant/early childhood effects. In addition, metabolic differences between perchlorate and other 

goitrogens, such as nitrate and thiocyanate (availability in the body) need to be further explored. 

Immunotoxicity. Immune system and lymphoreticular effects due to perchlorate have not been 

systematically studied in healthy humans. Lymphoreticular effects were reported in one case series of 

human thyrotoxicosis patients treated with potassium perchlorate (Morgans and Trotter 1960). Immune 

effects in animals treated with very high doses of perchlorate (300–2,600 mg/kg/day) were reported as 

increases in the number and degranulation of mast cells in the thyroid and other tissues (LogonderMlinsek et al. 1985; Spreca and Musy 1974). More recent acute- and intermediate-duration studies 

assessed indices of humoral- and cell-mediated immunocompetence in mice (0.1–50 mg/kg/day), but 

there were deficiencies in the studies (BRT 2000; DOD 1999). It would be helpful if some other end 

points were studied, such as the determination of whether perchlorate increases the sensitizing response to 

other chemicals or whether perchlorate is a sensitizer itself. 

Neurotoxicity. No data were located regarding neurological effects in humans or animals exposed to 

perchlorate. Neither 14-day nor 90-day studies in animals observed any signs indicative of neurotoxicant 

in adult animals. However, since thyroid hormone insufficiency is known to affect brain function in adult 

humans, and perchlorate can produce decreased circulating levels of thyroid hormone, it is likely that 
PERCHLORATES 143 

3. HEALTH EFFECTS 

perchlorate can, at some dose, impair brain function in adults. The dose-response relationship for these 

effects has not been characterized. As mentioned above under Developmental Effects, some studies in 

rats have suggested that exposure to perchlorate during pregnancy can cause neurodevelopmental 

alterations in the offspring (York et al. 2004, 2005b). The biological significance of some of the 

neurodevelopmental alterations, particularly the changes in thickness of the corpus callosum (York et al. 

2004, 2005b), has been questioned (NAS 2005). 

Epidemiological and Human Dosimetry Studies. Information on effects of exposure to 

perchlorate in healthy humans is derived from occupational studies (Braverman et al. 2005; Gibbs et al. 

1998; Lamm et al. 1999), studies of the general population, including adults, children, and neonates 

(Brechner et al. 2000; Chang et al. 2003; Crump et al. 2000; Kelsh et al. 2003; Li et al. 2000a, 2000b, 

2001; Schwartz 2001; Téllez et al. 2005) and controlled exposures in volunteers (Braverman et al. 2006; 

Greer et al. 2002; Lawrence et al. 2000, 2001). All of these studies provide information on the effects of 

perchlorate on thyroid parameters, but a few of them provide additional information on hematological, 

hepatic, and renal effects. Although it is well known that the thyroid is the target organ for perchlorate, 

the existing studies of the general population have had design limitations that preclude establishing with 

confidence the levels of environmental exposure that may induce clinically significant alterations in 

thyroid function and, therefore, represent a health risk. Well-designed epidemiological studies of 

environmentally exposed populations could provide valuable information and decrease the uncertainty of 

using data collected in acute studies in volunteers to establish long-term safe exposure levels. NAS 

(2005) identified pregnant women, their fetuses, and newborns as populations at greatest risk of the 

adverse effects of iodide deficiency and recommended that epidemiologic research should focus on 

assessing possible health effects of perchlorate exposure in these populations. These studies should use 

direct methods of exposure to perchlorate in individuals and methods more suitable for examining 

potentially causal associations. NAS (2005) further suggested that future research could be organized 

into additional analysis of existing data, new studies of health effects in selected populations, and 

monitoring of the frequencies of specific conditions in communities affected by the continuing efforts to 

reduce perchlorate in drinking water. Regarding a study in Chile (Téllez et al. 2005), NAS (2005) 

recommended incorporating more extensive neurodevelopmental assessments of the children beginning in 

infancy and continuing through school age. Specific end points that should be assessed in follow-up 

studies include auditory function, including measures of otoacoustic emissions; visual attention; cognitive 

function, including tests for executive function and memory; and tests of motor function, particularly 

balance, coordination, and rapid finger movements (NAS 2005). Increasing the sample sizes of the birth 

cohorts from the cities studied in Chile would be desirable to achieve appropriate statistical power for 
PERCHLORATES 144 

3. HEALTH EFFECTS 

detecting possible differences among exposure groups on the developmental assessments. NAS (2005) 

also suggested that the question of whether or not exposures to perchlorate at concentrations present in 

municipal drinking water are related to an increased incidence of maternal hypothyroidism during 

gestation could be addressed in the study of pregnant women in Chile (Téllez et al. 2005) and that using 

larger samples would improve the precision of the estimates. 

Biomarkers of Exposure and Effect. 

Exposure. Potential biomarkers of exposure include perchlorate in urine, breast milk, iodide in blood and 

urine, thyroid (T4, T3) and pituitary (TSH) hormones in blood, and radioactive iodine uptake. 

Perchlorate in urine is a biomarker that is specific for exposure to perchlorate; however, the biomarkers 

for iodine and thyroid hormones are not exclusive to perchlorate (changes may be produced by other antithyroid compounds and may be influenced by diet). One study of women from Chile found an 

association between urinary levels of perchlorate and drinking water concentrations of perchlorate 

(Valentín-Blasini et al. 2005). Further studies designed to correlate levels of one or more of these 

potential biomarkers with exposure levels would be useful to facilitate medical surveillance that can lead 

to early detection of exposure to perchlorate. 

Effect. Biomarkers of effect for perchlorate also include levels of iodine in blood and urine, and thyroid 

(T4, T3) and pituitary (TSH) hormones in blood. Dosimetry has not been established to relate specific 

degrees of change in these markers to demonstrably adverse effects. Studies designed to perform this 

dosimetry would be useful to determine whether exposed populations may be experiencing adverse health 

effects due to perchlorate exposure. 

Absorption, Distribution, Metabolism, and Excretion. Existing studies of absorption, 

distribution, metabolism, and excretion of perchlorate in humans provide information about the extent of 

absorption of ingested perchlorate and the extent and kinetics of urinary excretion of absorbed perchlorate 

(Anbar et al. 1959; Durand 1938; Greer et al. 2002; Lawrence et al. 2000). These studies lend support to 

estimates of elimination half-time of absorbed perchlorate of approximately 8–12 hours. Studies in 

animals provide support for the above estimates as well as information about the tissue distribution and 

kinetics of elimination of perchlorate from various tissues after intravenous or oral exposures (Chow and 

Woodbury 1970; Chow et al. 1969; Clewell et al. 2003a, 2003b; Durand 1938; Fisher et al. 2000; 

Goldman and Stanbury 1973; Lazarus et al. 1974; Selivanova et al. 1986; Yu et al. 2002). The above 

information has been used to support the development of PBPK models of perchlorate in adult humans, 
PERCHLORATES 145 

3. HEALTH EFFECTS 

adult rats, pregnant rats and rat fetus, and lactating rats and rat pups (Clewell et al. 2003a, 2003b, 2007; 

Fisher et al. 2000; Merrill et al. 2003, 2005). 

All of the above studies were by the oral or parenteral routes; no information is available regarding 

absorption following inhalation or dermal exposure. Inhalation is a potential route of exposure for 

perchlorate workers, but may not be relevant for the general population; however, dermal absorption is 

expected to be negligible, but experimental information could confirm this expectation as dermal contact 

with water is likely when water contains perchlorate. 

Comparative Toxicokinetics. Existing studies in humans and rats provide comparative information 

on the extent of absorption of ingested perchlorate, the routes of excretion of absorbed perchlorate, and 

the kinetics of excretion of absorbed perchlorate. PBPK models have been developed for the adult human 

and rat for the purpose of species extrapolation of oral or intravenous dosages of perchlorate (Clewell et 

al. 2003a, 2003b, 2007; Merrill et al. 2003, 2005). However, further research is necessary to determine 

how differences in thyroid physiology between humans and rats may affect the use of these models for 

human risk characterization and risk assessment. NAS (2005) identified a number of issues as potential 

data gaps with existing rat PBPK models including the need to: “(1) develop a more biologically-based 

description of placental transfer of perchlorate and iodide in rats, (2) determine whether perchlorate is 

transported by thyroid NIS if analytic methods of sufficient sensitivity can be developed or radiolabeled 

perchlorate with high radiochemical purity can be synthesized, (3) modify the adult human model to 

include the physiology of pregnancy and lactation to incorporate data from the recommended human 

clinical studies (if they are conducted), and (4) modify models to incorporate dietary iodide measurements 

from biomonitoring studies in pregnant or lactating women.” Issue (2) has been partially addressed by a 

study that showed that the NIS actively transports perchlorate (Dohán et al. 2007). Issue (3) also has been 

partially addressed by a recent study that described a model that is able to predict iodide and perchlorate 

kinetics in the human from fetal life through adulthood, thus allowing the quantitative estimation of dose 

in the target tissue, the developing thyroid (Clewell et al. 2007). 

Methods of Reducing Toxic Effects. There are no established methods for reducing the toxic 

effects of perchlorate. Removal of the individual from exposure would also be effective since perchlorate 

is rapidly eliminated from the body (elimination half-time 8–12 hours) (Greer et al. 2002). Research into 

methods for reducing the toxic effects of perchlorate would enable treatment for individuals experiencing 

adverse health effects due to perchlorate exposure. 
PERCHLORATES 146 

3. HEALTH EFFECTS 

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. 

Children, infants, and the developing embryo and fetus may be especially susceptible to the thyroid 

effects of perchlorate because thyroid hormones are essential to normal growth and development. The 

embryo and fetus is dependent on maternal thyroid hormones prior to the onset of fetal thyroid hormone 

production at mid-gestation. Perchlorate studies in animals have shown that exposure of the mother to 

perchlorate during gestation, or even during lactation, can lead to reduced thyroid hormone levels and 

associated thyroid effects in the offspring (Brown-Grant and Sherwood 1971; Golstein et al. 1988; Lampe 

et al. 1967; Postel 1957; York et al. 2001b, 2003, 2004). Human models of pregnancy, maternal-fetal 

transfer, and maternal-infant transfer of perchlorate have also been developed (Clewell et al. 2007, see 

Section 3.4.5). These models have yielded predictions of external dose–internal dose relationships for 

various human lifestages (Clewell et al. 2007; see Tables 3-6 and 3-7). The models predict a relatively 

high vulnerability of the fetus, pregnant women, and lactating women to perchlorate-induced thyroid 

iodine uptake, compared to other lifestages (e.g., greater inhibition of thyroid iodide uptake occurs in the 

fetus in association with lower external doses). Further characterization of the toxicokinetics of 

perchlorate during pregnancy and lactation as well as comparisons of neurobehavioral tests between 

young animals exposed only in utero with animals exposed solely through lactation would provide 

valuable information. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

The following ongoing research has been identified in the Federal Research in Progress database 

(FEDRIP 2008). 

Dr. J. Hershman from the Department of Veterans Affairs, Medical Center West Los Angeles, California, 

has proposed research to test the hypothesis that increasing iodide intake will prevent the deleterious 

effects of perchlorate on thyroid function; perchlorate does not alter thyroid cell growth; and perchlorate 

does not impair neural development through a direct effect on the brain. The research is sponsored by the 

Department of Veterans Affairs, Research and Development. 
PERCHLORATES 147 

3. HEALTH EFFECTS 

Drs. J. Fisher, F. Duncan, and J. Wagner from the University of Georgia are conducting research to 

develop biologically based pharmacokinetic (BBPK) maternal and fetal/neonatal models of the HPT axis 

in the rat by conducting experimental and computational research. The BBPK models of the HPT will 

describe the highly nonlinear relationships between the administered dose of thyroid active chemicals, 

mode-of-action, specific perturbations in the HPT axis, and developmental neurotoxicity. The research is 

sponsored by EPA’s National Center for Environmental Research. 

Dr. T. Zoeller from the University of Massachusetts is conducting research to test the hypothesis that 

thyroid hormone produces nonlinear, dose-dependent effects on end points within the developing brain, 

heart, and liver and to determine if some end points are more sensitive than others to thyroid hormones. 

Dr. Zoeller proposes that thyroid toxicants disrupting the HPT axis by different mechanisms will produce 

different dose-response curves on these end points. Dr. Zoeller suggests that a principle mechanism 

shaping the dose-response curve to thyroid hormone or by extension, thyroid disrupters, is a change in 

tissue metabolism of thyroid hormone in response to perturbations in the HPT axis. The research is 

sponsored by EPA’s National Center for Environmental Research. 
PERCHLORATES 148 

3. HEALTH EFFECTS 

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PERCHLORATES 149 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of the most widely used perchlorates is located in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Perchlorates are high melting point inorganic salts that are soluble in water at environmentally significant 

concentrations. There are five perchlorate salts that are manufactured in substantial amounts: 

magnesium, potassium, ammonium, sodium, and lithium perchlorate. Perchlorates are powerful 

oxidizing agents and at elevated temperatures can react explosively (Schilt 1979). The activation energy 

of ammonium perchlorate is 123.8 kJ/mol below 240 °C, 79.1 kJ/mol above 240 °C, and 307.1 kJ/mol 

between 400 and 440 °C (Mendiratta et al. 1996). The production volume of ammonium perchlorate far 

outpaces the other salts (Mendiratta et al. 1996). 

Information regarding the physical and chemical properties of these five perchlorate salts is located in 

Table 4-2. 
PERCHLORATES 150 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Perchloratesa 

Magnesium Potassium Ammonium Sodium Lithium 

Characteristic perchlorate perchlorate perchlorate perchlorate perchlorate 

Synonym(s) Anhydrous Potassium hyper- Perchloric acid, Perchloric acid, No data 

magnesium per- chloride; per- ammonium salt sodium salt 

chlorate; per- chloric acid, (1:1) PKHA, (1:1) 

chloric acid, potassium salt APCb 

magnesium salt (1:1) 

(1:1) 

Registered trade Anhydrone, Peroidin, No data Irenat No data 

name(s) Dehydrite Astrumal, Irenal, 

Irenat 

Chemical formula Mg(ClO4)2 KClO4 NH4ClO4 NaClO4 LiClO4

c 

Chemical structure [Mg2+][ClO4

-

]2 [K+][ClO4

-

] [NH4

+

][ClO4

-

] [Na+][ClO4

-

] [Li+][ClO4

-

] 

Identification 

numbers: 

CAS Registry 10034-81-8 7778-74-7 7790-98-9 7601-89-0 7791-03-9c 

NIOSH RTECS SC8925000 SC9700000 SC7520000 SC9800000 No data

EPA Hazardous D003 D003 D003 D003 D003

Wasted

OHM/TADS No data No data 7216589 No data No data 

DOT/UN/NA/ UN1475, IMO 5.1 UN 1489, IMO 5.1 UN1442, UN1502, UN1481e 

IMDG IMO 5.1 IMO 5.1 

HSDB 661 1222 474 5038 No data 

NCI No data No data No data No data 0106672f 

a

All information was obtained from HSDB 2006 unless otherwise noted. Perchlorate ion was not included in this 

table since it is never found independent of a corresponding cation. b

Ashford 1994 c

O'Neil 2001 d

EPA 1992a e

ERG 2004 

f

ChemIDplus 2007 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substance 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 
PERCHLORATES 151 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Perchloratesa 

Magnesium Potassium Ammonium Sodium Lithium 

Property perchlorate perchlorate perchlorate perchlorate perchlorate 

Molecular weight 223.21 138.55 117.49 122.44 106.39 

Color White Colorless or 

white 

White crystalsb White Colorless 

crystalsc 

Physical state Solid granular or Solid crystals Solid orthombic Solid deliquesce Solid crystals 

flaky powder crystals crystals 

Melting point ~250 °C dec. 400 °C dec. 130 °C dec.d 471 °C dec.d

 236 °Ce 

Boiling point N/A N/A N/A N/A ~400 °C dec.

c 

Density at -20 °C 2.21 g/mLf 2.52 g/mL 1.95 g/mL 2.02 g/mLg 2.43 g/mL 

Odorb No odor No odor No odor No odor No odor 

Odor threshold: 

Water N/A N/A N/A N/A N/A 

Air N/A N/A N/A N/A N/A 

Taste No data No data Imparts a bitter No data No data 

and salty taste 

to waterc 

Solubility: 

 Freshwater at 

25 °Cf 

9.96x105

 mg/L 2.06x104 mg/L 2.49x105 mg/L 2.10x106 mg/L 5.97x105 mg/L 

Organic 

solvent(s)d

 Methanol 5.18x105

 mg/L 1.05x103 mg/L 6.86x104 mg/L 5.14x105 mg/L 1.82x106 mg/L

 Ethanol 2.40x105

 mg/L 1.20x102 mg/L 1.91x104 mg/L 1.47x105 mg/L 1.52x106 mg/L

 n-Propanol 7.34x105

 mg/L 1.00x102 mg/L 3.87x103 mg/L 4.89x104 mg/L 1.05x106 mg/L

 Acetone 4.29x105

 mg/L 1.55x103 mg/L 2.26x104 mg/L 5.17x105 mg/L 1.37x106 mg/L

 Ethyl acetate 7.09x105

 mg/L 1.00x101 mg/L 3.20x102 mg/L 9.65x104 mg/L 9.51x105 mg/L

 Ethyl ether 2.91x103

 mg/L No data No data No data 1.14x106 mg/L 

Vapor pressure at 

25 °Ca 

Very low Very low Very low Very low Very low 

Polymerization N/A N/A N/A N/A N/A 
PERCHLORATES 152 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Perchloratesa 

Property 

Magnesium 

perchlorate 

Potassium 

perchlorate 

Ammonium 

perchlorate 

Sodium 

perchlorate 

Lithium 

perchlorate 

Incompatibilities Oil, grease, 

benzene, calcium 

hydride, charcoal, 

olefins, ethanol, 

strontium hydride, 

sulfur, sulfuric 

acid, and 

carbonaceous 

materialb,f 

Charcoal, 

magnesium, 

reducing agents, 

sulfur, oil, 

grease, benzene, calcium 

hydride, olefins, 

ethanol, strontium hydride, 

sulfuric acid, 

carbonaceous 

materialb,f 

Nitryl perchlorate, potassium 

iodate, potassium permanganate, metals, 

powdered 

carbon, ferrocene, sulfur, 

organic matter, 

charcoal, 

copperb,f 

Organic material, oil, grease, 

benzene, 

calcium hydride, 

charcoal, 

olefins, ethanol, 

strontium 

hydride, sulfur, 

sulfuric acid, 

carbonaceous 

materialb,f,g 

Sulfur, sulfuric 

acid, 

powdered 

magnesium, 

aluminum, 

benzene, 

calcium hydride, charcoal, 

olefins, 

ethanol, 

strontium 

hydride, 

carbonaceous 

materialb,f 

Other Sensitive to Sensitive to Sensitive to Sensitive to Sensitive to 

rubbing, shock, 

percussion, 

sparks, and 

heating.c 

Dissolves in 

water with 

rubbing, shock, 

percussion, 

sparks, and 

heating.c 

rubbing, shock, 

percussion, 

sparks, and 

heating.c 

rubbing, shock, 

percussion, 

sparks, and 

heating.c 

Hygroscopic.d 

rubbing, 

shock, 

percussion, 

sparks, and 

heating.c 

evolution of a 

considerable 

amount of heat. 

a

Perchlorate ion was not included in this table since it is never found independent of a corresponding cation. All 

information was taken from O'Neil 2001 unless otherwise noted. Measured data were not available for the following 

end points: log Kow, Koc, Henry's law constant. Conversion factors were also not available. Autoignition 

temperature, flashpoint, flammability limits, and explosive limits are not applicable. b

Lewis 2000 c

Von Burg 1995 d

Schilt 1979 e

Bauer 1990 f

Vogt et al. 1986 

g

Lewis 2001 

dec. = decomposes; N/A = not applicable 
PERCHLORATES 153 

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

5.1 PRODUCTION 

No information is available in the TRI database on facilities that manufacture or process perchlorates 

because these chemicals are 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 1997a). 

Commercial interest in perchlorates began in the late 1890s/early 1900s in Europe and the United States 

as a direct result of the pioneering efforts in rockets and their propulsion systems (Mendiratta et al. 1996). 

The production of ammonium perchlorate, the largest component of solid rocket propellants, far outpaced 

that of the other perchlorates listed in Table 4-1. Their commercial manufacture began later, and it was 

not until 1928 when GFS Chemicals began producing magnesium perchlorate for use as a dessicant (GFS 

1997) that these salts became available on the U.S. market. Up until 1940, the total worldwide production 

of perchlorates had not exceeded 3.6 million pounds. An abrupt change in production was realized with 

the onset of World War II and the resulting increase in demand for rocket and missile propellants. 

Annual perchlorate production quickly increased to 36 million pounds because of this demand and 

remained at a high level thereafter (Mendiratta et al. 1996). By 1974, U.S. perchlorate production had 

reached 50 million pounds (Vogt et al. 2005). 

Recent production data for ammonium perchlorate as well as for the other salts listed in Table 4-1 are 

lacking. In 1994, U.S. production of ammonium perchlorate was estimated at 22 million pounds or just 

36% of capacity (Mendiratta et al. 1996). Actual production volumes for ammonium perchlorate have 

been historically dependent on the demand of aerospace and military applications due to its predominant 

use in propellants (Mendiratta et al. 1996). This use has resulted in defining ammonium perchlorate as a 

strategic chemical (Mendiratta et al. 1996; Vogt et al. 2005), and current worldwide production figures 

are not readily available. 

Approximately 900,000 pounds of ammonium perchlorate in aqueous solution serve as the feedstock for 

the production of magnesium and lithium salts for use in batteries (Mendiratta et al. 1996). The wide 

variety of uses for perchlorates (see Section 5.3) suggests that the combined production of the salts listed 

in Table 4-1 would be significantly higher. U.S. facilities listed in the SRI Directory of Chemical 

Producers that currently manufacture perchlorates are provided in Table 5-1. According to data listed on 
PERCHLORATES 154 

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

Table 5-1. U.S. Manufacturers of Perchlorates 

Aluminum Magnesium Potassium Ammonium Sodium Lithium 

Producer perchlorate perchlorate perchlorate perchlorate perchlorate perchlorate 

GFS Chemicals, 

Inc. √ √ √ √ √

Columbus, Ohio 

Western 

Electrochemical 

Co.a √ √ √

Cedar City, Utah 

Barium and 

Chemicals, Inc. 

Steubenville, √

Ohio 

a

Western Electrochemical is a subsidiary of the AMPAC Corporation. 

Source: SRI 2007 
PERCHLORATES 155 

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

EPA’s website, there were 63 Federal agency facilities and 168 non-Federal facilities in the United States 

that were either known or suspected perchlorate manufacturers/users as of April, 2003 (EPA 2005c). 

Potential source contributions of perchlorate from its intended uses and from its content as an impurity in 

various non-military products have been analyzed (Aziz et al. 2006; Dasgupta et al. 2006). Dasgupta et 

al. (2006) used data from the U.S. Government Accountability Office (GAO) and production capacities of 

individual plants to estimate ammonium perchlorate production and use within the United States. Based 

upon their analysis, an average annual perchlorate production rate of approximately 1.06x107

 kg per year 

had been estimated from 1951 to 1997 (Dasgupta et al. 2006). Potassium perchlorate is an important 

ingredient in fireworks and road safety flares. Using statistical data regarding total flare sales, average 

cost per flare and an assumed concentration of 3.6 g of perchlorate per flare, a perchlorate source 

contribution of 1.4x105 kg per year was estimated (Dasgupta et al. 2006). No quantitative estimates were 

made for firework usage since the amounts of perchlorate in fireworks vary greatly. The perchlorate 

composition by weight percentage has been estimated to range from 4 to 70%, depending upon the type of 

firework (Aziz et al. 2006; SERDP 2005). Perchlorate is recognized as an impurity in the production of 

electrochemically produced chlorine products, including sodium chlorate. The pulp and paper industry 

uses most of the sodium chlorate consumed in the United States for on-site production of chlorine dioxide 

to bleach cellulose fibers (Aziz et al. 2006; SERDP 2005). Sodium chlorate has also been used as a nonselective contact herbicide and a defoliant for cotton, sunflowers, sundangrass, safflower, rice, and chili 

peppers (Aziz et al. 2006; SERDP 2005). Using a sodium chlorate consumption rate of approximately 

109

 kg per year and a 0.01% perchlorate content, a source strength of roughly 105 kg per year was 

calculated (Dasgupta et al. 2006). Perchlorate is also found as an impurity in other common consumer 

products that may ultimately lead to human exposure and release to the environment. The occurrence of 

perchlorates in these products as well as natural sources of perchlorate in the environment are discussed in 

Chapter 6. 

The predominant commercial method for the manufacture of perchlorates begins with the production of 

the most soluble salt, sodium perchlorate. Electrochemical oxidation of an aqueous solution of sodium 

chloride is the most common method of producing sodium perchlorate (Schilt 1979; Vogt et al. 2005). 

Many variations for this process have been described over the years. They differ in the amount of current 

used, electrode composition, ionic strength of the bath, or temperature, although they all proceed via the 

following series of two-electron oxidations: 

Cl- → ClO2

- → ClO3- → ClO4-
PERCHLORATES 156 

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

The manufacture of all other perchlorate salts, including those listed in Table 4-1, is accomplished by 

selectively re-crystalizing the perchlorate salts that are less soluble than sodium perchlorate. Thus, adding 

common salts to a solution of sodium perchlorate leads to a metathesis (ion exchange) process that is 

driven to the right as the desired product precipitates out of solution: 

- Na+

 (aq) + ClO4 (aq) + M+(aq) + X-(aq) » MClO4(s) ↓ + Na+(aq) + X-(aq) 

where M is magnesium, potassium, lithium, or ammonium; X is chloride, sulfate, or carbonate; and 

MClO4(s) is the desired perchlorate. The majority of sodium perchlorate produced in the United States is 

converted to ammonium perchlorate using this process (Grotheer 1994). 

Given that the manufacture of perchlorates is typically accomplished in aqueous solution, the resulting 

perchlorate is produced as a hydrate. The anhydrous salt is required for pyrotechnic applications, and 

water molecules are removed from the hydrate by a number of methods including controlled heating, 

displacement of the water molecules by volatile amines (which are subsequently removed at reduced 

pressure or elevated temperatures), or through the use of a strong desiccant (Kamienski et al. 1995). High 

purity perchlorate salts are produced by a wide variety of methods. For example, lithium perchlorate may 

be prepared by direct electrochemical oxidation of lithium chloride or by reaction of 70% perchloric acid 

with lithium carbonate (Kamienski et al. 1995; Schilt 1979). A more recent approach in the production of 

high purity ammonium perchlorate involves the electrolytic conversion of chloric acid to perchloric acid, 

which is then neutralized by ammonia gas (Mendiratta et al. 1996). The ammonium perchlorate is spray 

dried to the desired crystal size at air temperatures below 150 °C. 

5.2 IMPORT/EXPORT 

The U.S. Census bureau does not list perchlorates as a separate, reportable item on its schedule B book on 

imports or exports. Instead, perchlorates are listed under the general category of perchlorates; bromates 

and perbromates; iodates and periodates. The total amount of imports for this category were 1.867x106

, 

1.881x106

, and 1.281x106 kg for 2005, 2006, and 2007, respectively (USITC 2008). Exports totaled 

1.349x106

, 2.067x106, and 1.927x106 kg in 2005, 2006, and 2007, respectively (USITC 2008). 

Using import/export volumes of substances in which perchlorates are contained may yield an indirect 

estimate of how much perchlorate is imported into the United States either from its intentional use in a 
PERCHLORATES 157 

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

specific product or unintentionally as an impurity of a product or commodity. For example, the import of 

Chilean nitrate fertilizer, which contains perchlorate as a natural component, peaked around 1920 and has 

dropped significantly since the 1960s. The total amount of Chilean nitrate fertilizer imported into the 

United States from 1930 to 1993 was estimated as 2.4x1010 kg (Dasgupta et al. 2006). Assuming an 

average perchlorate content of approximately 0.2%, the total amount of perchlorates imported over this 

time was approximately 4.8x107 kg. Perchlorates are used in fireworks (see Section 5.3) and in 1997, 

U.S. imports of these pyrotechnic devices totaled $93 million (U.S. Census Bureau 1999). U.S. exports 

of fireworks in 1997 totaled $6.2 million. In 2003, 221 million pounds (approximately 1x108

 kg) of 

fireworks were consumed in the United States, with an estimated 3% produced domestically and the 

remainder (214 million pounds) imported from China (Aziz et al. 2006; SERDP 2005). Using data from 

the U.S. Trade Commission (USITC 2008), the import/export volumes for fireworks, signal flares, and 

propellant powders from 2005 to 2007 are provided in Table 5-2. The actual volume of perchlorates 

represented by these figures is difficult to estimate since the content of perchlorate in these commodities 

is not known or is highly variable. 

5.3 USE 

The predominant uses of perchlorates take advantage of their strong oxidizing power and relative stability 

at moderate temperatures (Conkling 1996; Mendiratta et al. 1996; Schilt 1979; Vogt et al. 2005). On 

heating, perchlorates decompose into chlorine, chlorides, and oxygen. As the reaction proceeds and 

temperatures increase, decomposition becomes self-propagating. In the presence of organics and other 

oxidizable materials (the fuel), large amounts of energy are released. The decomposition of ammonium 

perchlorate differs from that of the metal salts listed in Table 4-1 because it produces only the neutral 

products chlorine, water, oxygen, and nitrous oxide (or nitrogen oxide at high temperatures) and leaves no 

solid residue (e.g., sodium chloride residue is produced by the decomposition of sodium perchlorate). 

Ammonium perchlorate is the largest volume perchlorate used in the United States (Mendiratta et al. 

1996). Its primary use is as an oxidant for solid rocket boosters. The solid propellent used in the booster 

rockets on the U.S. Space Shuttle is approximately 70% ammonium perchlorate by weight (Conkling 

1996). According the the Interstate Technology and Regulatory Council (ITRC) (2008), “Solid rocket 

products developed and manufactured by Aerojet consisted primarily of jet-assisted take-off motors; 

tactical rockets such as Falcon, Hawk, Harpoon, Sidewinder, Maverick, Bullpup, Genie, Sparrow, 

AMRAAM, Tartar, and Navy Standard Missile; ballistic missiles Minuteman I, II, and III, Polaris, 

Midgetman, Peacekeeper, and space boosters; and sounding rockets.” DOD’s use of perchlorates in 
PERCHLORATES 158 

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

Table 5-2. Import and Export Data for Products that may Contain Perchlorate 

Product or commodity 2005 2006 2007 

Imports (amount in kg) 

Fireworks 1.248x108 1.234x108 1.082x108 

Signal flares 3.152x106 2.333x106

 1.885x106 

Propellant powders 3.755x106

 4.755x106 3.150x106 

Exports (amount in kg) 

Fireworks 2.39x105 3.98x105 3.07x105 

Signal flares 4.36x105

 3.35x105 3.54x105 

Propellant powders 1.824x106

 2.446x106 2.210x106 

Source: USITC 2008 
PERCHLORATES 159 

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

weapon systems over the last 5 years was 6–8 million pounds per year, much of which is recovered and 

recycled (DOD 2007) (see Section 5.4) 

The other perchlorates listed in Table 4-1, most notably potassium perchlorate, also find use as oxidants 

in solid booster rockets (Lindner 1993). Oxidant mixtures developed using metal perchlorate salts are 

less powerful than those using ammonium perchlorate (Schilt 1979). 

Perchlorates are used extensively in pyrotechnic devices such as fireworks, safety flares, and blasting 

explosives (Aziz et al. 2006; SERDP 2005). Ammonium perchlorate is used in small amounts in gun 

powder (Lindner 1993). Ammonium perchlorate is used in a mixture with sulfamic acid to produce a 

dense smoke or fog for military applications. Perchlorates are also used in civilian explosives. 

It has been widely published in the scientific literature that perchlorates are used in airbag inflator systems 

(see, for example, Cowan 2000; Lamm et al. 1999; Logan 2001; Smith et al. 2001; Von Burg 1995). 

When used in this application, a chlorine scavenger would be required to prevent this gas from entering 

the passenger compartment (Mausteller 1996). Encyclopedic sources limit their discussion of airbag 

inflator systems to sodium azide (Antonsen 1996; Conkling 1996; Jansen 1992; Jobelius and Scharff 

1989; Stiefel 1995), although potassium perchlorate has been used in compositions described as suitable 

for this purpose (Schilt 1979). Airbag inflators containing perchlorate have been described in the patent 

literature (see, for example, Scheffee and Wheatley 1999). According to the Automotive Occupant 

Restraint Council, perchlorate-containing airbag initiators are sealed from the environment prior to 

deployment and during an accident in which they are deployed, and the perchlorate is destroyed through 

the combustion process, essentially resulting in little or no release of perchlorate (CADTSC 2005). 

Perchlorates have also found use in a wide variety of other applications. They are used as oxygen 

generating systems (oxygen candles) for enclosed environments, such as submarines, spacecraft, and 

civilian and military aircraft (Vogt et al. 2005). Anhydrous perchlorates, most notably the magnesium 

salt, are used as a highly efficient drying agent for gases as well as for scrubbing the last traces of polar 

compounds from inert gases (Schilt 1979). Lithium and magnesium perchlorate have been used in 

batteries due to their low weight and high energy density. Potassium perchlorate, mixed with a reactive 

metal such as iron or zirconium, has been used in heat pellets for the activation of reserve battery cells 

(Cohen 1993). Perchlorate salts are being investigated as additives for conducting polymers although 

they have been problematic due to their explosive nature (Druy 1986). 
PERCHLORATES 160 

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

A novel use of ammonium perchlorate is as a component of temporary adhesives for steel or other 

metallic plates (Vogt et al. 2005). Ammonium perchlorate is mixed with an epoxy resin, which, after 

curing, forms the adhesive bond between the plates. When separation of the plates is required, they are 

heated to initiate the self-propagating perchlorate decomposition, which, in turn, decomposes the epoxy 

adhesive (Vogt et al. 2005). 

Perchlorates find frequent use to adjust the ionic strength of electroplating baths (Schilt 1979; Vogt et al. 

2005). Metals that have been used in this process include aluminum and its alloys, iron, steel, nickel and 

its alloys, tin and lead alloys, and zirconium and its alloys. Perchlorate electrolysis baths are specifically 

used in plating razor blades. Perchlorates are also routinely used to adjust the ionic strength of aqueous 

solutions of analytical and investigative procedures of metal solutions (Nair et al. 1997; Papini and 

Majone 1997; Puls and Powell 1992; Sposito and Traina 1987). They are used in this application because 

of the tendency of perchlorates not to form metal complexes in solution and, therefore, not to interfere 

with the chemical dynamics of the investigation (Cotton and Wilkinson 1980). 

Perchlorates were widely used in the treatment of hyperthyroidism during the 1950s and early 1960s 

especially for people with Graves’ disease (Von Burg 1995). Perchlorate is also available in the United 

States for administration (200–400 mg orally) to block radioactive technetium (

99TcO4

-

) uptake in the 

thyroid, choroid plexus, and salivary glands during medical imaging of the brain, blood, and placenta 

(Gibbs et al. 1998). Potassium perchlorate is currently used as part of a treatment to counter the thyroid 

effects of the drug amiodarone (Martino et al. 2001). 

Other uses for perchlorates include matches, etching and engraving agents, photography, and synthetic 

reagents (Lewis 2001). Lithium perchlorate has been described as a catalyst that should be used with 

caution for synthetic organic chemistry using the Diels-Alder reaction (Kamienski et al. 1995). Potassium 

perchlorate was used as an ignition ingredient in flash bulbs (Vogt et al. 2005) and has been approved for 

use as an additive in rubber gaskets for food containers (FDA 1998). Perchlorates have also been used in 

weed killers and as growth promoters in leguminous plants. Ammonium, sodium, and potassium 

perchlorates have also been used as stimulants for increasing the weight of farm animals and poultry 

(Von Burg 1995). 

Chilean saltpeter, a naturally occurring material proven to contain perchlorates (Schilt 1979), has been 

marketed mainly as a granular product for fertilizers (Laue et al. 1991). Chilean researchers initiated a 

study in 1967 to establish why soybeans were exhibiting stunted growth, rugose, and crumpled leaves as a 
PERCHLORATES 161 

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

result of domestic fertilizer application and to determine what levels of perchlorate these plants could 

tolerate (Tollenaar and Martin 1972). The saltpeter used to produce the fertilizer at that time contained 

0.12–0.26% perchlorate (by weight) as a contaminant. The United States first began importing Chilean 

saltpeter in 1830 (Hoffmeister 1993). U.S. importers of the refined Chilean nitrate reached historic highs 

prior to 1980 (Bortle 1996), and current annual imports are at 2 million pounds (Laue et al. 1991). 

However, this amount represents <0.1% of the total amount of nitrogen fertilizer usage in the United 

States (Hoffmeister 1993). Fertilizer derived from Chilean saltpeter has been traditionally applied mainly 

to tobacco plants, but is also marketed for citrus fruits, cotton, and some vegetable crops (Urbansky et al. 

2001). The amount of perchlorate present in recent samples of these fertilizers was found to range from 

0.7 to 2.0 mg/g, although steps have been taken to reformulate these products to remove perchlorate. 

In 1999, perchlorate was also detected in nine different brands of synthetic fertilizer products (Susarla et 

al. 1999), raising concern for the potential widespread contamination from this source. The results of this 

study were questioned (Urbansky et al. 2000b) and a reinvestigation of many of the same products 

purchased at a later date found perchlorate in only one sample at a concentration two orders of magnitude 

lower than typically found in the original publication (Susarla et al. 2000). Nevertheless, it raised 

important questions as to why perchlorate would be present in synthetic fertilizers and how frequently it 

appeared. It also highlighted the difficulty in analyzing for perchlorate in solid samples and other 

complex matrices. Urbansky and Collette (2001) conducted a survey of approximately 40 fertilizer 

products comparing the results of six different laboratories. After an evaluation phase to determine the 

ability of each laboratory to quantify perchlorate in a fertilizer matrix, their results indicated that 

perchlorate was not detectable in any real-world fertilizer products (including synthetic fertilizers) that 

were not derived from Chilean caliche. During a survey of 48 fertilizer products collected from 

representative sites across the United States, perchlorate was detected in only 5 of the products 

(concentrations ranging from 1,800 to 4,200 μg/g) (EPA 2001a). 

5.4 DISPOSAL 

In 1998, perchlorate was listed in the Drinking Water Contaminant Candidate List. The Safe Drinking 

Water Act, as amended in 1996, required EPA to publish a list of contaminants that were not subject to 

other primary drinking water regulation (EPA 1998a). In 1999, perchlorate was subsequently added to 

the Unregulated Contaminant Monitoring List that required public water systems that serve 

>10,000 persons, and other representative systems, to monitor for perchlorate and other substances 
PERCHLORATES 162 

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

beginning January, 2001 (EPA 1999b). The following year, EPA published a final rule indicating that 

standard method 314.0 should be used to monitor for perchlorate in drinking water (EPA 2000). 

EPA would consider discarded perchlorate to be a solid waste and depending on the fact-specific 

circumstances, EPA believes that discarded perchlorate could be a hazardous waste under the Solid Waste 

Disposal Act (EPA 2006b). Specifically, because perchlorates are oxidizing chemicals, waste discarded 

chemical formulations of perchlorate and its salts are likely to be classified as D001 Resource 

Conservation and Recovery Act (RCRA) hazardous waste under 40 CFR 261.23, which regulates wastes 

that meet the reactivity characteristic. Such a determination is generally based on the nature of the waste 

at the point of generation; however, characteristic hazardous waste, such as D001, ceases to be hazardous 

waste once it no longer exhibits a hazardous waste characteristic. In addition, Comprehensive 

Environmental Response, Compensation, and Liability Act (CERCLA) 101(14) defines “hazardous 

substance.” According to that section, “the term hazardous substance means . . . .any hazardous waste 

having the characteristics identified under or listed pursuant to Section 3001 of the Solid Waste Disposal 

Act. . . . .” Therefore, depending on the fact-specific circumstances, discarded perchlorate could be 

classified as a D001 hazardous waste and therefore, under certain circumstances, EPA would consider 

perchlorate a CERCLA hazardous substance. 

As noted in Section 5.3, of the 6–8 million pounds of perchlorates used annually by DOD in weapon 

systems, approximately 4 million pounds of ammonium perchlorate is recovered and returned to the 

manufacturer for use in commercial applications, such as, blasting agents or perchloric acid for glass 

etching (DOD 2007). 

Water treatment technologies, including air stripping, activated carbon adsorption, chemical oxidation, 

and aerobic biodegradation are not efficient at removing perchlorate from water (Logan 1998; Urbansky 

1998). Granular activated carbon columns do not economically remove the perchlorate anion from water. 

The useful lifetime of these columns was reduced from approximately 18 months to one month while 

treating tap water at the Texas Street Well facility in Redlands, California (Logan 2001). 

The most promising physical removal process for treating perchlorate-contaminated water uses ion 

exchange technology (DOD 2005c, 2005d; EPA 2005e; Urbansky 2002). Perchlorate can be removed 

from water using ion exchange columns, although the resulting brine contains 7–12% perchlorate (Logan 

et al. 2001a). Currently, scientists are finding ways to improve this technology as well as to make it more 

cost efficient (Logan 2001). An ion exchange treatment facility has been installed at Edwards Air Force 
PERCHLORATES 163 

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

Base in California (DOE 2003). The DOD (2005c, 2005d) has reported that more than 9 million gallons 

of perchlorate contaminated groundwater have been successfully treated (perchlorate <4 ppb) since its 

implementation. 

Perchlorate removal using anaerobic bioreactors has been proven for onsite applications and at the pilotplant level (Urbansky 1998). Research in this area is active (Bardiya and Bae 2005; Brown et al. 2003; 

Cramer et al. 2004; Logan and LaPoint 2002; Min et al. 2004). Suspended growth, fixed bed, and 

fluidized bed bioreactors have been used to degrade perchlorate at influent concentrations ranging from 

0.13 to 7,750 ppb (Logan et al. 2001b). Abatement and remediation of perchlorate in soil and 

groundwater was achieved using a biological permeable reactive barrier system at the McGregor, Texas 

Naval Weapons Industrial Reserve Plant (Cowan 2000). A biological fluidized bed reactor installed at the 

Longhorn Army Ammunition Plant in Karnack, Texas has successfully reduced perchlorate levels in 

groundwater at the site to below the detection limit (<4 ppb) (DOD 2005c, 2005d). Biological fluidized 

bed reactors are being used to remove perchlorate, with a 99.99% efficiency from contaminated 

groundwater at the Kerr-McGee site in Henderson, Nevada (EPA 2006a). 

Phytoremediation is another method being explored as a possible treatment process for perchloratecontaminated soil, sediment, and water (Nzengung et al. 1999, 2004; Tan et al. 2004b; Urbansky 2002; 

van Aken and Schnoor 2002). Plantings of lettuce and willow trees have been shown to reduce the 

concentration of perchlorate in contaminated soil (EPA 2004b; Nzengung et al. 1999, 2004; Yu et al. 

2004). Uptake followed by accumulation was indicated as the main phytoremediation process in lettuce, 

whereas both uptake and rhizodegradation appear to be an important removal processes associated with 

woody plants. 
PERCHLORATES 164 

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

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PERCHLORATES 165 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Perchlorates have been identified in at least 49 of the 1,581 hazardous waste sites that have been proposed 

for inclusion on the EPA National Priorities List (NPL) (EPA 2008b, 2008c). However, the number of 

sites evaluated for perchlorates is not known. The frequency of these sites can be seen in Figure 6-1. 

Perchlorates are high melting inorganic salts that are soluble in water at environmentally significant 

concentrations. They are found in or released to the environment in two forms. In the absence of water, 

the perchlorate salts listed in Table 4-1 will be found (or released) as a solid. In water, perchlorates will 

rapidly dissolve and completely dissociate into the perchlorate anion and the corresponding cation (e.g., 

for potassium perchlorate, the corresponding cation would be K+

). The cations of the perchlorates listed 

in Table 4-1, magnesium, potassium, ammonium, sodium, and lithium, are ubiquitous in the environment. 

Given that perchlorates completely dissociate at environmentally significant concentrations, their cations 

are, for all practical purposes, spectators in the aqueous fate of perchlorates. Therefore, the 

environmental fate of the perchlorate salts listed in Table 4-1 is dominated by the perchlorate anion. 

Perchlorates are known to be highly reactive thermodynamically and therefore, they may react vigorously 

under the proper conditions. The activation energy of ammonium perchlorate is 123.8 kJ/mol below 

240 °C, 79.1 kJ/mol above 240 °C, and 307.1 kJ/mol between 400 and 440 °C (Mendiratta et al. 1996). 

The decomposition of perchlorates is usually initiated using a high temperature source, such as a glow 

wire, to overcome the thermodynamic barrier. Once decomposition of some perchlorate molecules is 

initiated, the resulting reaction produces a large amount of heat. Between 200 and 300 °C, ammonium 

perchlorate undergoes an autocatalytic decomposition (Singh et al. 2000). At about 400 °C, ammonium 

perchlorate decomposes very fast and suddenly explodes. The reactivity is a function of the reaction 

pathway. Different reaction pathways for perchlorates would have different barriers than the thermal 

decomposition discussed above. Nevertheless, the existence of a large thermodynamic barrier for the 

decomposition of a reactive compound such as perchlorate is important in understanding its persistence in 

the environment. 
PERCHLORATES 166 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Perchlorate Contamination 
PERCHLORATES 167 

6. POTENTIAL FOR HUMAN EXPOSURE 

When the perchlorate anion is detected in water, it is not always possible to determine the perchlorate salt 

that represents the original source of the contamination. That is, potassium perchlorate may be the 

compound that was released to the environment, yet some other perchlorate salt, such as sodium 

perchlorate, may be the "charge neutral" species present in the analyzed sample. For ammonium 

perchlorate, this is of particular relevance as the ammonium ion biodegrades in the environment and, 

therefore, must be replaced with some other cation to maintain the overall neutrality of the solution. 

From a practical standpoint, however, the concentration of the perchlorate ion is the most important factor 

when determining the potential for adverse effects to the perchlorates. It is the perchlorate ion that is 

analyzed for in environmental samples. 

In Chapter 5 of this profile, the uses of the perchlorates listed in Table 4-1 were provided. Many of these 

uses result from the high reactivity and strong oxidizing power of perchlorates. The environmental fate of 

perchlorate is also dominated by this reactivity, yet its persistence is much longer than might be expected 

for a strong oxidizing agent. This apparent discrepancy can, in part, be explained by differences in its 

high energy of activation. 

When released to the environment, perchlorates are expected to be highly mobile in soil and to partition to 

surface water or groundwater. They are not expected to significantly adsorb to sediment or suspended 

organic matter. They are also expected to readily settle from the atmosphere by wet and dry deposition. 

No degradation process for perchlorates in the environment has been unambiguously established. 

Laboratory experiments suggest that they may be reduced by anaerobic microbes in soil and water, 

although the presence of sulfates and nitrates in the environment attenuates this process. Laboratory 

experiments also suggest that perchlorates may undergo uptake by some plants and may be subsequently 

reduced to chloride. Neither the types of plants that take up perchlorate nor the types capable of reducing 

it have been well categorized. The mechanism for uptake by plants has not been established. 

The potential for contamination resulting from discharges at facilities that manufacture and use 

perchlorate was studied following the accidental fire and subsequent explosion at the PEPCON rocket 

fuel plant, located in Henderson, Nevada in May 1988 (Urbansky 1998). This plant was one of the 

principal manufacturing facilities for ammonium perchlorate in the United States. Perchlorate 

concentrations as high as 630,000 μg/L were observed in nearby surface water samples following the 

accident (Urbansky 1998). Nearby groundwater samples were also contaminated with perchlorate at 

concentrations ranging from 51,400 to 630,000 μg/L. Monitoring data from 50 wells obtained near the 
PERCHLORATES 168 

6. POTENTIAL FOR HUMAN EXPOSURE 

Kerr-McGee ammonium perchlorate producing facility, also located in Henderson, Nevada, had 

perchlorate levels as high as 3.7 g/L (Urbansky 1998). The EPA has published a list of federal and 

private facilities in the United States from 25 states with known perchlorate releases to environmental 

media such as surface water, groundwater, and soil (EPA 2003, 2005c). 

Perchlorate can also be released to the environment from the use of other commodities such as safety 

flares and fireworks. For example, following a July 4th fireworks display near a small lake in Oklahoma, 

a maximum perchlorate concentration of 44.2 μg/L was measured in the lake (Wilkin et al. 2007). This 

maximum level was roughly 1,000 times greater than the mean perchlorate concentration (0.043 μg/L) 

that was observed in the lake prior to the fireworks display. 

In addition to the potential anthropogenic sources of perchlorate discussed in Chapter 5 and the use of 

products for which perchlorate is found as an impurity, there are natural sources of perchlorate in the 

environment (Dasgupta et al. 2006; Rajagopalan et al. 2006). Traces of perchlorate found in rain and 

snow may be caused by a series of reactions that result in the formation of atmospheric perchlorate 

(Dasgupta et al. 2006). In addition, perchlorate has been detected in laboratory experiments upon passage 

of sodium chloride aerosols through an electrical discharge that simulates lightening. Kang et al. (2006) 

demonstrated that perchlorate can be generated as an end-product of chlorine precursors such as aqueous 

salt solutions of hypochlorite, chlorite, and chlorate, following exposure to UV radiation. Using 

perchlorate levels observed in rainfall samples and estimated rainfall rates in the United States, the rate of 

natural atmospheric perchlorate deposition was estimated to range from 1.3x105 to 6.4x105 kg per year 

(Dasgupta et al. 2006). Further evidence of natural sources of perchlorate is the widespread occurrence in 

the arid Southwestern United States in places where no anthropogenic sources of perchlorate exist 

(Dasgupta et al. 2006; Rajagopalan et al. 2006). Perchlorate was detected in groundwater from several 

counties located in western Texas and eastern New Mexico at relatively low concentrations (<4 μg/L); 

however, some samples had levels of nearly 200 μg/L (Rajagopalan et al. 2006). The primary source of 

perchlorate in this area was postulated as deposition of naturally occurring atmospheric perchlorate. 

Humans are primarily exposed to perchlorate through the ingestion of food items and also through the 

consumption of drinking water that contains perchlorate. Efforts are being made to determine the relative 

contribution of perchlorates from food and water. There are also consumer products that are widely 

available to the general population that also contain perchlorate. For example, household bleach has been 

shown to contain perchlorate, with concentrations ranging from 89 to 8,000 ppb (MassDEP 2006a). A 

correlation was observed between storage time of the bleach and higher levels of perchlorate. Perchlorate 
PERCHLORATES 169 

6. POTENTIAL FOR HUMAN EXPOSURE 

has also been detected in tobacco products (Ellington et al. 2001) and nutritional supplements (Snyder et 

al. 2006). General population and occupational exposure to perchlorate is discussed in greater detail in 

Section 6.5. 

6.2 RELEASES TO THE ENVIRONMENT 

6.2.1 Air 

There is no information in the TRI database on releases of perchlorates to the atmosphere from 

manufacturing and processing facilities because these releases are not required to be reported (EPA 

1997a). 

The perchlorates listed in Table 4-1 are high melting inorganic salts that have very low vapor pressures. 

Therefore, solid perchlorates are not expected to directly volatilize to air as fugitive emissions during their 

manufacture, processing, transport, disposal, or use. Release to the air through volatilization from water 

is also not expected for perchlorates as dissociated inorganic ions are known to not be stripped from water 

(Bodek et al. 1988). 

Solid perchlorate aerosols may be released to the atmosphere as fugitive emissions in dust-forming 

operations during manufacture, processing, and use. Gibbs et al. (1998) reported an occupational 

exposure investigation where they noted that dust was generated in an ammonium perchlorate production 

facility. Lamm et al. (1999) classified dust-forming manipulations at an ammonium perchlorate 

production facility as low for perchlorate solutions or slurries, moderate for limited quantities for dry 

perchlorates, and high when large quantities of dry perchlorates were used. 

One documented major use of perchlorates is as a component of solid rocket boosters (Vogt et al. 1986). 

Solid rocket boosters rapidly release gases to provide propulsion through the atmosphere, and the release 

of unspent perchlorates may occur during this process. However, engineered design of rocket boosters 

target efficient and complete reaction of the perchlorate as a fundamental requirement to ensure 

successful launches. Studies on particulate emissions from propulsion systems have been performed 

(Hindman and Finnegan 1980), although it is not known if perchlorate was a targeted analyte. 

Perchlorates may be released to the environment from booster rockets during a catastrophic failure 

(Merrill and O’Drobinak 1998) or aborted flight. Following the Delta II flight failure that occurred at 

Cape Canaveral in January 1997, it was estimated that 200,000 pounds of perchlorate-containing 

hydroxyl-terminated polybutadiene (HTPB) solid propellant was released (Merrill and O’Drobinak 1998). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Release of perchlorates to the atmosphere may also occur during open-burn decommissioning of rocket 

booster propellants or munitions (Chan et al. 2000). Emissions of regulated substances have been 

measured during tests of this disposal process (DOD 1995), although perchlorate was not one of the 

targeted analytes. 

Perchlorates also find extensive use in fireworks and other pyrotechnic devices (Conkling 1996; Dasgupta 

et al. 2005; Lindner 1993; Schilt 1979). Release of unspent perchlorate may occur during the detonation 

of fireworks, flares, oxygen generators, flash-pots, smoke bombs, and other pyrotechnic devices, although 

very little information on the amounts, if any, was located in the available literature. Dasgupta et al. 

(2005) calculated an annual source strength of 1.4x105

 kg/year for perchlorate in road flares used in the 

United States, which is estimated as 1.4% of the production of total oxidizer perchlorate. These authors 

were not able to estimate perchlorate released from fireworks, since fireworks vary greatly in their type 

and composition. Release of perchlorate may also occur during catastrophic explosions at firework 

facilities (CSB 1999) or at facilities that manufacture other pyrotechnic devices based on this oxidant. 

It has been postulated that perchlorate may be formed naturally in the atmosphere during photochemical 

transformation reactions involving chlorine precursors. Some possible mechanisms include the reaction 

of ClO radicals with sulfuric acid aerosols, electrical discharge through chloride aerosol, reaction of 

aqueous chloride with high concentrations of ozone, and direct photolysis of aqueous chlorite (Dasgupta 

et al. 2005; Jaegle et al. 1996; Kang et al. 2006). Accordingly, perchlorate may be produced in the 

atmosphere after volcanic eruptions. The authors suggest that perchlorate produced in volcanic eruptions 

similar to Mt. Pinatubo may represent a significant reservoir of chlorine in the lower stratosphere. 

In an effort to locate the source of perchlorate contamination in the southern high plains desert in the 

Texas panhandle where there has been no known anthropogenic release of perchlorates nearby, Dasgupta 

et al. (2005) explored the possibility of perchlorate generation through atmospheric processes. The 

authors reported that perchlorate was formed during experiments where chloride aerosol was exposed to 

electrical discharge (lightning simulation) and where aqueous chloride was exposed to high amounts of 

ozone. Natural atmospheric perchlorate deposition was estimated to range from 1.3x105 to 6.4x105 kg per 

year in the United States (Dasgupta et al. 2006). However, additional testing is needed to determine 

whether these atmospheric processes are indeed natural pathways by which perchlorates enter the 

environment (Dasgupta et al. 2005; Erickson 2004; Renner 2005a). 
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6. POTENTIAL FOR HUMAN EXPOSURE 

6.2.2 Water 

There are no data in the TRI database on releases of perchlorates to the water from manufacturing and 

processing facilities because these releases are not required to be reported (EPA 1997a). 

Perchlorates may be released to water in emissions from their manufacture, processing, or use. Waste 

water treatment processes used by POTWs and onsite treatment facilities, including stripping, 

precipitation, filtration, oxidation, or aerobic biodegradation, do not effectively remove perchlorates from 

waste streams (Urbansky 1998). Therefore, perchlorate in waste water may eventually be released to 

surface water. 

EPA published a list of facilities from 25 states with perchlorate releases related to the manufacture, 

disposal, or research of explosives, propellants, or pyrotechnics (EPA 2003, 2005c). Maximum 

perchlorate concentrations observed in monitoring wells for several of these facilities exceeded 

1,000 μg/L, with some observed concentrations in excess of 100,000 μg/L (EPA 2003, 2005c). Propellant 

removal during decommissioning or maintenance (reloading with new propellant) of solid rockets is 

known to have been accomplished using high pressure water sprays (Chan et al. 2000). The amount of 

ammonium perchlorate-laden washout from decommissioning rockets was expected to reach 8.5 million 

pounds in the first decade of the twenty-first century (Buckley et al. 1999), but since this estimate was 

made, significant changes in decommissioning and maintenance practices of rocket motors have 

substantially reduced the potential for future releases of perchlorate to the environment. According to the 

ITRC (2008), “There are times when rocket propellant must be removed from the rocket motor casing. 

To do so the rocket motor was taken to the ‘hog-out’ facility, where the propellant was removed using a 

water knife to avoid explosion hazards. The water containing ammonium perchlorate in both solid and 

dissolved forms was discharged to unlined and lined ponds (Aerojet Case Study)....Perchlorate is also 

found at areas where waste ammonium perchlorate rocket propellant was taken to be destroyed by 

burning and detonation (Aerojet Case Study)....Past management practices were not concerned with the 

release of perchlorate to the environment because it was not recognized or regarded as a contaminant of 

concern. Widespread perchlorate presence in the United States was observed after the spring of 1997 

when an analytical method was developed with a quantitation level of 4 parts per billion. Subsequent 

advances in analytical chemistry have proven perchlorate to be more widespread in the environment than 

previously thought.” 
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6. POTENTIAL FOR HUMAN EXPOSURE 

The catastrophic failure of a Delta II rocket in 1997 over the Atlantic Ocean resulted in unspent propellant 

falling into the ocean (Merrill and O’Drobinak 1998). Subsequent laboratory tests indicated that 

ammonium perchlorate will migrate from the propellant matrix to seawater. Similarly, perchlorates that 

have been released to the atmosphere may also enter environmental waters by deposition onto the surface 

of oceans, rivers, lakes, or ponds by either gravitational (dry settling) or wet (rain wash-out) processes. 

Perchlorates may ultimately be released to surface water from the runoff from or erosion of perchlorateladen sand or soil (Herman and Frankenberger 1998). The percolation of water through contaminated 

sand or soil is expected to bring perchlorate into underground aquifers; this is consistent with monitoring 

studies in wells sampled near known sites of its use (see Section 6.4.2). Runoff from perchlorate-laden 

soil is expected to lead to surface water contamination as determined by its detection in surface water 

samples down gradient from facilities that manufactured, maintained, decommissioned, or tested solid 

rocket boosters (Herman and Frankenberger 1998; Mendiratta et al. 1996; Urbansky 1998). The use of 

fireworks may also contaminate nearby water bodies. A small lake near Ada, Oklahoma had baseline 

perchlorate concentrations in surface water ranging from 0.005 to 0.081 μg/L, with a mean value of 

0.043 μg/L. Following the release of a fireworks display (14 hours after the fireworks), perchlorate 

concentrations spiked to values ranging from 24 to 1,028 times the mean baseline value (Wilkin et al. 

2007). A maximum perchlorate concentration of 44.2 μg/L was determined following the July 4th event 

in 2006. After the fireworks displays, perchlorate concentrations decreased toward the background level 

within 20–80 days, with the rate of attenuation correlating to surface water temperature. 

6.2.3 Soil 

There are no data in the TRI database on releases of perchlorates to the soil from manufacturing and 

processing facilities because these releases are not required to be reported (EPA 1997a). As discussed in 

Section 6.2.2, facilities that manufactured, maintained, decommissioned, or tested solid rocket boosters 

likely released perchlorates to the environment. Their detection in groundwater wells at some of these 

sites (see Section 6.4.3) suggests that the initial release was to soil, and subsequent transport led to 

contamination of the aquifer. Information on the amount of perchlorate released to soil as a result of its 

manufacture, processing, and use in aerospace and military applications could not be located in the 

available literature. 

The use of explosives that contain perchlorates in underground applications, such as mining (Vogt et al. 

1986), may result in the release of unspent oxidant to soil. The amount of perchlorate used in explosives, 
PERCHLORATES 173 

6. POTENTIAL FOR HUMAN EXPOSURE 

the frequency of use in underground applications, and the amount of unspent oxidant released are not 

available. 

Perchlorates that have been released to the atmosphere may be deposited directly on the Earth’s surface 

by either dry or wet deposition processes. The catastrophic failure of a Delta II rocket was found to 

release unspent ammonium perchlorate propellant to land (Merrill and O’Drobinak 1998). Deposition of 

perchorate to soil from the use of fireworks is also expected to be significant. 

Perchlorate has been detected in fertilizers derived from Chilean caliche (Ellington et al. 2001; Urbansky 

et al. 2001). It was also detected in other fertilizer products (Susarla et al. 1999), although follow-up 

studies failed to detect perchlorate in the 40 products tested (Urbansky and Collette 2001). Fertilizer 

derived from Chilean saltpeter has been traditionally applied mainly to tobacco plants, but is also 

marketed for citrus fruits, cotton, and some vegetable crops (Urbansky et al. 2001). Perchlorate 

containing fertilizers would result in the contamination of soil as a direct result of their intended use. 

Using a perchlorate concentration of 0.2% and a total importation volume of 2.4x1010 kg of Chilean 

nitrate fertilizer (Dasgupta et al. 2006), 4.8x107 kg of perchlorate may have been released directly to soil 

over the period from 1930 to 1993. 

6.3 ENVIRONMENTAL FATE 

Only a limited number of studies investigating the environmental fate of perchlorate were located in the 

peer-reviewed literature. Key aspects of its environmental fate have been assessed based on the analysis 

of physical and chemical properties, available monitoring data, and known sources of release. Although 

substantial research efforts are currently underway (see Section 6.8.2, Ongoing Studies), much has been 

learned concerning the behavior of perchlorates in the environment. 

In water, perchlorates are expected to readily dissolve and dissociate into their component ions. 

Thermodynamic data on the dissolution of the perchlorates (Schilt 1979) indicate that the rate of this 

process should be rapid for all of the perchlorates listed in Table 4-1. The cations of the perchlorates 

listed in Table 4-1, magnesium, potassium, ammonium, sodium, and lithium, are ubiquitous in the 

environment. Given that perchlorates completely dissociate at environmentally significant 

concentrations, their cations are, for all practical purposes, spectators in the environmental fate of 

perchlorates dissolved in water. Therefore, when in water, the cations do not participate in, nor do they 

substantially influence, the fate of the perchlorate anion in the environment. 
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6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.1 Transport and Partitioning 

Perchlorates are water soluble and the anion does not typically form insoluble metal complexes in 

solution (Cotton and Wilkinson 1980). Since the perchlorate ion is only weakly adsorbed to mineral 

surfaces in solutions of moderate ionic strength, its movement through soil is not retarded (Logan 2001; 

Urbansky and Brown 2003; Urbansky and Collette 2001). These two properties indicate that perchlorate 

will travel rapidly over soil with surface water runoff or be transported through soil with infiltration. 

Therefore, if released to soil, perchlorates are expected to be highly mobile and travel to groundwater and 

surface water receptors. This is consistent with surface water and groundwater monitoring data that 

indicate that perchlorates have been found far from known sites of their release to soil (see Section 6.4.2). 

Although data quantifying the extent of perchlorate adsorption to soil were not located in the available 

literature, a study on willow decontamination in sand bioreactors (Nzengung et al. 1999) established, 

through a mass-balance assessment, that perchlorates were not adsorbed by sand under the conditions of 

the experiment. 

Perchlorates are not expected to volatilize from soil to the atmosphere given their very low vapor 

pressure. Moreover, dissociated inorganic ions do not undergo volatilization (Bodek et al. 1988). 

Perchlorates may be transported from soil to the atmosphere by wind-borne erosion. This convective 

process may release either aerosols or particulate matter to which dry perchlorate salts are adsorbed. 

If released to water, perchlorates are not expected to volatilize to the atmosphere based on the extensive 

data set available for soluble inorganic ions that indicates this process does not occur (Bodek et al. 1988). 

The water solubility of perchlorates indicates that they will not be removed from the water column by 

physical processes and become adsorbed to sediment and suspended organic matter. Since the 

perchlorate ion is only weakly adsorbed to mineral surfaces in solutions of moderate ionic strength 

(Logan 2001; Urbansky and Brown 2003; Urbansky and Collette 2001), perchlorate is not expected to 

adsorb to sediment and organic matter. Since perchlorate does not serve as a ligand in aqueous solutions 

(Cotton and Wilkinson 1980), it is not expected to undergo removal from water through the formation of 

insoluble metal complexes. The water solubility and degree of complex formation of perchlorate do not 

change significantly as a function of acidity (Bodek et al. 1988), indicating that its fate is not expected to 

change within the pH range typically found in the environment. In cases where high concentration 

perchlorate brines enter the subsurface, the movement of perchlorate is expected to be controlled by 

gravity and the topography of confining layers (DOD 2006a). Perchlorate brines may sink through the 
PERCHLORATES 175 

6. POTENTIAL FOR HUMAN EXPOSURE 

subsurface and accumulate on or in confining layers where its release into groundwater is limited by 

diffusion. 

Limited data indicate that perchlorate may accumulate in living organisms, as it has been detected in 

vegetation, fish, amphibian, insect, and rodent samples collected near a site of known contamination 

(Smith et al. 2001). The concentrations of perchlorate in male threespine stickleback fish (Gasterosteus 

aculeatus) were 0.63, 0.54, and 4.47 μg/g, corresponding to aquarium water perchlorate concentrations of 

0, 1, and 10 ppm, respectively (U.S. Air Force Space Missile Systems Center 2002). Dean et al. (2004) 

reported bioconcentration factors of 1.854 for Asiatic clam (Corbicula fluminea) and 0.70 for bluegill 

(Lepomis macrochirus), indicating that bioconcentration of perchlorates in aquatic organisms is low. 

Theodorakis et al. (2006) analyzed fillets and heads of fish collected from Lakes Waco and Belton in 

Texas for perchlorates. These lakes are located near the Naval Weapons Industrial Reserve Plant where 

solid fuel rocket motors are manufactured. Perchlorate concentrations in positive samples ranged from 

146 to 2,740 μg/kg wet weight in fillets and from 626 to 4,560 μg/kg wet weight in heads. Perchlorates 

were not detected in water samples from these lakes except for one instance at one of the three sampling 

sites in Lake Belton (14 μg/L) indicating that food chain transfer is possible. Possible routes of exposure 

for these fish include ingestion of contaminated periphyton (algae film), ingestion of contaminated 

detritus, and ingestion of perchlorate-containing invertebrates. 

In a study on plant-mediated treatment of perchlorate-contaminated water (Nzengung et al. 1999), it was 

reported that uptake occurred in eastern cottonwoods (Populus deltoides and hybrid populus), Eucalyptus 

cineria, and willow (Salix nigra) in sand bioreactors. Willow was the only tree studied in detail. 

Perchlorate uptake was found to be initially rapid at a rate that was linear with the volume of water 

evapotranspired by the tree until a plateau was reached where perchlorate uptake ceased. At an initial 

application of 88.8 mg (at 96.4 mg/L), the total amounts of perchlorate in the root, lower stem, upper 

stem, and leaf after 26 days were 0.04, 0.18, 0.34, and 0.48 mg, respectively. In addition, 11% of the 

perchlorate was not accounted for, and was believed to be degraded to chloride in the leaves. Perchlorate 

uptake has also been established in salt cedar (Tamarix ramosissima) although the rate of uptake, 

excretion, and/or reduction was not determined (Urbansky et al. 2000c). Yu et al. (2004) observed uptake 

of perchlorate from sand in cucumber (Cucumis sativus L.), lettuce (Lactuca sativa L.), and soybean 

(Glycine max). Concentrations of perchlorate were higher in the lettuce (750 ppm) than in the cucumber 

(41 ppm) and soybean (18 ppm). It was reported that the presence of external nutrients such as nitrate 

may hinder uptake of perchlorate. The percent recovery of perchlorate in lettuce after it was applied at 
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6. POTENTIAL FOR HUMAN EXPOSURE 

500, 1,000, 5,000, and 10,000 ppb to lettuce pots in a greenhouse was 82, 74, 76, and 73%, respectively 

(EPA 2004b). 

A study on the uptake of perchlorate by tobacco plants from soil amended with Chilean-nitrate derived 

fertilizer (containing perchlorate at 36–1,544 mg/kg) found that extracts of the green and flue-cured 

leaves contained perchlorate at 12.4–164.6 mg/kg (dry weight) (Ellington et al. 2001). The authors point 

out that the available data set is not sufficient at this point in time to predict which plants undergo 

perchlorate uptake and accumulation and which ones are capable of completely reducing it to chloride, an 

important factor to consider given that food crops may be irrigated with contaminated water containing 

perchlorate. The uptake and transport of perchlorate from contaminated soil to the leaves of tobacco 

plants was also demonstrated over a wide range of initial soil concentrations (Sundberg et al. 2003). The 

results of this study indicate that perchlorates are taken up by the root system, transported up the stem via 

the xylem, and accumulate in the leaves and stems. 

If released to the atmosphere, the perchlorate salts are expected to exist as a solid aerosol or be adsorbed 

to suspended particulate matter. Removal from the atmosphere is expected to occur by both dry and wet 

deposition to the Earth’s surface. The water solubility and rapid rate of dissolution of perchlorates 

indicate that they may partition to clouds or fog, although subsequent deposition to the Earth’s surface 

would be expected. 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

No data were located on the transformation or degradation of perchlorates in air. The dominant 

mechanism for the degradative removal of chemical compounds from the atmosphere is via their reaction 

with gas-phase oxidants (Lyman et al. 1990). Gas-phase oxidants include the neutral molecules, ozone 

and singlet oxygen, as well as hydroxyl radicals during the day or nitrate radicals at night. However, 

these species are all weaker oxidants than perchlorate, and atmospheric degradation via this pathway is, 

therefore, not expected to occur. 

The other major atmospheric degradation process for chemical compounds is through direct photolysis. 

In general, this reaction is not sufficiently facile for solid phase materials for it to occur to any significant 

extent in the atmosphere. Since perchlorates are expected to exist as a solid dust in the atmosphere or be 
PERCHLORATES 177 

6. POTENTIAL FOR HUMAN EXPOSURE 

adsorbed to suspended particulate matter, direct photolysis is not expected to occur. Jaegle et al. (1996) 

estimated that the photolytic loss of perchloric acid in the atmosphere would be negligible. 

6.3.2.2 Water 

The ability of bacteria to utilize perchlorate as a terminal electron acceptor was first reported in 

1976 (Logan et al. 2001b). Reviews by Logan (1998) and Herman and Frankenberger (1998) provide an 

extensive set of examples where laboratory experiments using microorganisms biodegrade (respire) 

perchlorate under anaerobic conditions. In the environment, anaerobic degradation has been found to be 

an important process in anoxic groundwater, sediments, and some soils. Microorganisms utilize 

alternative electron acceptors such as nitrate or sulfate anions in lieu of oxygen to generate energy and 

produce carbon-based building blocks in these anaerobic environs. In laboratory studies, the perchlorate 

anion has also been found to serve as an alternative electron acceptor in anaerobic microbial respiration. 

The reduction of perchlorate by microorganisms has been found to be inhibited by the electron acceptors 

most commonly found in anaerobic environments, most notably nitrate and/or sulfate. In a few cases, 

they were found to be reduced preferentially. The initial product from the respiration of perchlorate is 

chlorate (ClO3

-

), which, in turn, is reduced by some of the isolates to chlorite (ClO2

-

) and ultimately 

chloride (Cl-

) and either oxygen or bicarbonate. A confounding aspect of the complete reduction of 

perchlorate is the production of oxygen, the absence of which defines a medium as anaerobic. For some 

microorganisms (obligate or strict anaerobes), perchlorate reduction was completely inhibited by the 

presence of oxygen. For others (facultative anerobes), perchlorate reduction would subside with the 

introduction of oxygen and reoccur once it had been removed from the system via other processes. 

Nzengung et al. (1999, 2004) studied the use of willows and other trees for the phytoremediation of 

perchlorate-contaminated water using hydroponic bioreactors. These investigators found that reduction of 

perchlorate to chloride occurred rapidly in the root zone (rhizosphere) after a relatively short acclimation 

period. Added nitrate inhibited the degradation of perchlorate indicating that reduction was occurring 

anaerobically, presumably in oxygen free micro-environments. The level of nitrate found to result in 

inhibition, 100 mg/L, is on the low end of the range typically found in soils, 0–1,200 mg/L. Tan et al. 

(2004b) reported that in the absence of nitrate, perchlorate was removed to levels below the detection 

limit (<4 μg/L) in wetland columns with perchlorate influents of 4, 8, 16, and 32 mg/L. van Aken and 

Schnoor (2002) studied poplar tree cuttings (Populus deltoide x nigra) grown in the presence of 

radiolabled perchlorate at 25 mg/L. These authors reported that 50% of the perchlorate was reduced 

30 days after perchlorate application. 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Despite the numerous observations that perchlorate is readily reduced by microorganisms in laboratory 

cultures and the perceived ubiquity of these microorganisms in the environment (Bruce et al. 1999; 

Coates et al. 1999), it has been found to be persistent in the environment (Logan et al. 1998). In situ 

removal of perchlorate has not yet been demonstrated (Coates and Anderson 2000). This is likely due to 

the ubiquitous presence of nitrate and sulfate in the environment and the preferential utilization of these 

electron acceptors by anaerobes. Nevertheless, work in this area is continuing and recent studies are 

available on the reduction of perchlorate by hydrogen utilizing bacteria (Giblin et al. 2000) in the 

presence of acetate (Bruce et al. 1999; Coates et al. 1999; Kim and Logan 2001; Logan et al. 2001b) and 

in the presence of nitrate (Giblin and Frankenberger 2001; Herman and Frankenberger 1999). 

Biodegration of perchlorate has also been demonstrated in salt solutions (11% brine) (Logan et al. 2001a). 

No other degradation processes that are likely to remove perchlorates from water were identified. Photooxidation in water by alkoxy, peroxy, or other reactive species (Mill 1982) is not expected to occur as 

these species are weaker oxidants than perchlorate. Millero (1990) studied the rates of the indirect 

photochemical oxidation of Cu(I) and Fe(II) by hydroxyl radicals in artificial seawater solutions prepared 

using sodium perchlorate. No correction for a hydroxyl radical reaction with perchlorate was included in 

the detailed kinetic analysis performed by the authors, indicating that the reaction of perchlorate with 

hydroxyl radicals did not occur to any significant extent. 

Another common removal process in the environment is biodegradation under aerobic conditions. In this 

process, the substrate is oxidized by microorganisms. Given that the perchlorate anion is at its highest 

oxidation state, this process is not expected to occur. 

No studies on the direct photochemical degradation of perchlorates in water were located in the available 

literature. One of the requirements for direct photolysis to occur is the possession of a suitable 

chromophore that absorbs light in the environmentally significant range of >290 nm (i.e., wavelengths not 

blocked by the ozone layer); it does not address to what extent, if any, a reaction will ensue after a 

quantum of light has been adsorbed. Aqueous solutions of sodium perchlorate have a broad absorption at 

605–700 nm (GMELIN 1999). This wavelength of light is on the long-wavelength (red), low energy side 

of the visible spectrum. A quantum of light at this wavelength does not typically have sufficient energy 

to result in the direct photochemical degradation of chemical compounds. 
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6. POTENTIAL FOR HUMAN EXPOSURE 

The other major removal process for chemical compounds in environmental waters is through hydrolysis. 

Hydrolysis does not occur for inorganic salts that ionize in aqueous solutions, and it will not occur for 

perchlorates. 

6.3.2.3 Sediment and Soil 

Very few studies on the degradation of perchlorates in sediment or soil have been located in the available 

literature. Microorganisms isolated from soil have been found to reduce perchlorates under anaerobic 

conditions in the laboratory (Herman and Frankenberger 1998; Logan 1998) suggesting the potential for 

removal from anoxic soils and sediments. As noted for the degradation and removal from water 

(Section 6.3.2.2), perchlorates have been found to be persistent; the importance of this process in anoxic 

sediment and soils is not known. Tipton et al. (2003) have stated that the necessary criteria for 

perchlorate degradation in soil are anaerobic conditions, an adequate carbon source, and an active 

perchlorate-degrading microbial population. Perchlorate applied to Yolo loam at 180 mg/L during an 

anaerobic flooded batch experiment was completely biodegraded after 30 days (Tipton et al. 2003). 

During an analysis of perchlorate contaminated streambed sediment located near the Naval Weapons 

Industrial Reserve Plant in McGregor, Texas, it was concluded that microbial degradation of perchlorate 

was taking place based on a sequential depletion of electron acceptors and a constant Cl- concentration in 

the sediment (Tan et al. 2005). While studying the natural biodegradation of perchlorate in the Las Vegas 

Wash area in Nevada, Zhang et al. (2002) concluded that this process is hindered by the lack of an 

electron donor, the presence of nitrate, and salinity levels in the area. 

No other degradation process can be predicted for perchlorates in soil or sediment. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to perchlorates depends in part on the reliability 

of supporting analytical data from environmental samples and biological specimens. Concentrations of 

perchlorates 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 perchlorates 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 

perchlorates in a variety of environmental media are detailed in Chapter 7. 
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6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.1 Air 

No monitoring data on the atmospheric concentration of perchlorates were located in the available 

literature. 

6.4.2 Water 

Drinking water samples from 3,858 public water systems located across the United States were collected 

from 2000 to 2004 as part of the Unregulated Contaminants Monitoring Rule (UCMR) (EPA 2005g). 

EPA found that approximately 4.1% (or 160) of these systems had at least one analytical detection of 

perchlorate (in at least one entry/sampling point) at levels greater than or equal to the minimum reporting 

level of 4 micrograms per liter (μg/L). These 160 systems are located in 26 states and 2 territories. 

Perchlorate was detected at >4 μg/L in 365 of 13,401 (2.7%) samples from 67 of 1,247 (5.4%) surface 

water systems that serve >10,000 people with a mean (range) concentration of 15.6 μg/L (4.0–420 μg/L). 

Perchlorate was detected at >4 μg/L in 29 of 1,496 (1.9%) samples from 5 of 236 (2.1%) surface water 

systems that serve <10,000 people with a mean (range) concentration of 6.4 μg/L (4.1–17 μg/L). 

Perchlorate was detected at >4 μg/L in 214 of 14,972 (1.4%) samples from 69 of 962 (7.2%) groundwater 

systems that serve >10,000 people with a mean (range) concentration of 11.3 μg/L (4.0–200 μg/L). 

Perchlorate was detected at >4 μg/L in 6 of 2,459 (0.2%) samples from 5 of 485 (1%) groundwater 

systems that serve <10,000 people with a mean (range) concentration of 7.8 μg/L (4.3–20 μg/L). Based 

on analysis of 2004 UCMR data, NAS (2005) estimated that more than 11 million people are served by 

public drinking water supplies from which samples containing at least 4 μg/L of perchlorate were 

collected. 

According to information provided by the California Department of Health Services (CADHS 2007), 

perchlorate has been detected above 4 μg/L in 267 out of approximately 7,000 drinking water sources 

located across California during monitoring conducted between March 2002 and March 2007. The 

greatest numbers of detections were in Los Angeles, Riverside, San Bernardino, and Orange Counties 

where perchlorate was found in 106, 64, 57, and 18 sources, respectively. The peak concentrations 

reported for these counties were 100, 73, 88, and 10.6 μg/L, respectively. Perchlorate was detected 

drinking water from only four sources in Sacramento County; however, the peak concentration reported 

was 95.9 μg/L. 

In drinking water wells tested in Riverside and San Bernardino Counties, California, the maximum 

perchlorate concentration measured was 216 μg/L (Herman and Frankenberger 1998). Five of six well-
PERCHLORATES 181 

6. POTENTIAL FOR HUMAN EXPOSURE 

water samples obtained near Sacramento, California, March–April 1997, contained 4–260 μg/L of 

perchlorate (Okamoto et al. 1999). The concentrations of perchlorate measured in six water supply wells 

that serve the city of Loma Linda, California during 1997–1998 ranged from <4 to 29 μg/L (Agency for 

Toxic Substances and Disease Registry 2000). Jackson et al. (2005b) detected perchlorate above 0.5 μg/L 

in 179 out of 254 public water system and private wells in nine counties in the Texas Southern High 

Plains. Perchlorate concentrations were >4 μg/L in 88 wells. The maximum concentrations were 

58.8 μg/L for private wells and 45.6 μg/L for public water system wells. The Massachusetts Department 

of Environmental Protection (MassDEP 2006a) reported that perchlorate concentrations were at or above 

the analytical reporting limit of 1 μg/L in only 9 of 600 tested public water supply systems in that state. 

Elevated perchlorate concentrations (maximum 1.5–1,300 μg/L) were measured near areas where blasting 

agents and fireworks were used. 

Snyder et al. (2005) measured perchlorate concentrations ranging from 0.06 to 6.8 μg/L in 12 of 13 waters 

from various sources (seven surfaces waters, one groundwater, one spring water, and four treated waters) 

in the United States. The level in the spring water sample was reported to be “clearly visible” but below 

the reporting limit of 0.05 μg/L. These authors also detected perchlorate in 10 of 21 bottled water 

samples from various sources at levels ranging from 0.07 to 0.74 μg/L. Eleven of these samples were 

below the method reporting limit of 0.05 μg/L. In a separate study, perchlorate was not detected in 

16 brands of imported and domestic bottled water (Urbansky et al. 2000a). 

During a 1997–1998 drinking water survey, perchlorate was not detected (reporting limit=4.0 μg/L) in 

surface water samples from 40 sites in 11 states (Gullick et al. 2001). Out of 367 groundwater wells in 

17 states tested during this survey, only 9 wells located in California and New Mexico contained 

perchlorate. Concentrations in samples from these wells ranged from <4–7 μg/L. The Southern Nevada 

Water Authority detected perchlorate at 11 μg/L in tap water samples (Urbansky 1998). Perchlorate was 

detected in the drinking water supply for Clark County, Nevada, at 4–15 μg/L (Li et al. 2000a). The 

perchlorate level in finished drinking water supplies in Yuma, Arizona, 1999, was 6 μg/L (Brechner et al. 

2000). Drinking water advisory levels for perchlorate have been set in Arizona (14 μg/L), Maryland 

(1 μg/L), Nevada (18 μg/L), New Mexico (1 μg/L), New York (5 and 18 μg/L), and Texas (17 and 

51 μg/L) (Dasgupta et al. 2005; EPA 2005c; Tikkanen 2006). Drinking water standards have been set in 

California (6 μg/L) and Massachusetts (2 μg/L). Perchlorate was generally not detected in surface water 

samples collected from 50 sites across the Great Lakes Basin (Backus et al. 2005). Concentrations were 

near the method detection limit of 0.2 μg/L in two samples from Hamilton Harbour and six creek/river 

water samples from the Mailtand Valley and the Upper Thames River watersheds in Canada. 
PERCHLORATES 182 

6. POTENTIAL FOR HUMAN EXPOSURE 

Perchlorate contamination in drinking water has been reported at 12 DOD facilities and 2 other federal 

agency facilities located in California, Illinois, Maryland, Massachusetts, New Mexico, Ohio, and Utah as 

of March, 2005 (EPA 2005c). Maximum reported perchlorate concentrations in surface water at these 

sites range from approximately 1 to 720 μg/L. Perchlorate contamination in drinking water has been 

reported at 16 private facilities located in Arizona, California, Iowa, Nebraska, New Mexico, Nevada, 

New York, and Utah as of March, 2005 (EPA 2005c). Maximum reported perchlorate concentrations in 

surface water at these sites range from approximately 5 to 811 μg/L. 

Surface water samples taken in August 1997 from the Las Vegas Wash, which feeds into Lake Mead, had 

perchlorate concentrations of 1,500–1,680 μg/L (Herman and Frankenberger 1998; Urbansky 1998). 

Smith et al. (2004) reported a mean perchlorate concentration of 450 μg/L in 24 water samples from 

3 sites at the Las Vegas Wash collected in March, 2002 near Henderson, Clark County, Nevada. The Los 

Angeles Metropolitan Water District has detected perchlorate at 8 μg/L at an intake located in Lake Mead 

(Urbansky 1998). In a separate study, perchlorate was detected in 57% of 147 surface water samples and 

50% of 10 pore water samples collected in the Lake Mead area with average (maximum) concentrations 

of 10.5 (130) and 19.6 (98.0) mg/kg, respectively (Dean et al. 2004). Reported concentrations of 

perchlorate in the Colorado River are 5–9 μg/L (Sanchez et al. 2005b, 2006). In Utah, perchlorate 

concentrations in groundwater wells at Alliant Techsystems, a rocket manufacturing site, ranged from 4 to 

200 μg/L (Urbansky 1998). According to a report issued by the EPA in December 2005, surface water 

concentrations in Las Vegas Wash, Lake Mead, and the Lower Colorado River have declined by 85, 

70, and 60%, respectively, since the inception of a seep capture and treatment program at the Kerr-McGee 

site in Henderson, Nevada began in November 1999 (EPA 2006a). 

Groundwater samples from a shallow aquifer near the Aerojet General Corporation’s solid rocket fuel 

facility near Sacramento, California had maximum perchlorate levels of 8,000 μg/L (Herman and 

Frankenberger 1998). Sampling wells at the Kennecott Utah Copper mines in Magna, Utah had 

perchlorate levels of 13 μg/L. In well water samples in California, 30% had detectable levels of 

perchlorate (detection limit presumably 4 μg/L) and the concentration of perchlorate in 9% of them was 

over 18 μg/L. 

Perchlorate has been detected in surface and groundwater samples in Texas, Arkansas, Maryland, New 

York, California, Utah, and Nevada (Coates et al. 1999). It was detected in 30 groundwater wells by the 

California Department of Health Services at concentrations >18 μg/L and in 50% of the wells test in 
PERCHLORATES 183 

6. POTENTIAL FOR HUMAN EXPOSURE 

Suffolk Country, New York at concentrations up to 40 μg/L (Kim and Logan 2001; Logan et al. 2001b). 

In 1998, a survey by the California Department of Health Services found at 144 wells were contaminated 

at levels >18 μg/L (Giblin et al. 2000). 

Perchlorate contamination in surface water has been reported at 17 DOD facilities located in Alabama, 

Arizona, Indiana, Maryland, New Mexico, Ohio, Oklahoma, Texas, and West Virginia as of March, 2005 

(EPA 2005c). Maximum reported perchlorate concentrations in surface water at these sites vary widely, 

ranging from approximately 1 to 16,000 μg/L. Maximum reported concentrations of perchlorate in 

surface water at three private locations, Aerojet Company in Arkansas, Boeing/Rocketdyne in Nevada, 

and Elf Atochem in Oregon, were 12,500, 120,000, and 14 μg/L, respectively. 

Perchlorate contamination in groundwater has been reported at 48 DOD facilities and 5 other federal 

agency facilities located in Alabama, Arizona, Arkansas, California, Colorado, Illinois, Indiana, Iowa, 

Maryland, Massachusetts, Minnesota, Missouri, New Jersey, New Mexico, Oregon, South Carolina, 

South Dakota, Tennessee, Texas, Utah, Virginia, Washington, and West Virginia as of March, 2005 (EPA 

2005c). Maximum reported perchlorate concentrations in groundwater at these sites vary widely, ranging 

from approximately 1 to 276,000 μg/L. Perchlorate contamination in groundwater has been reported at 

29 private facilities located in Arizona, Arkansas, California, Iowa, Kansas, Missouri, Nebraska, Nevada, 

New York, Oregon, and Utah as of March, 2005 (EPA 2005c). Maximum reported perchlorate 

concentrations in surface water at these sites vary widely, ranging from approximately 5 to 

3,700,000 μg/L. Similar data listing concentrations of perchlorate in surface and groundwater at both 

federal and private facilities in the United States as of April, 2003 have been reported by EPA (2003, 

2005c). The suspected source of these high levels of perchlorate in groundwater was usually related to 

the manufacture, disposal, testing, or research of explosives, rockets, or propellants (EPA 2003, 2005c). 

Perchlorate levels in 8 of 12 groundwater and surface water samples at the Longhorn Army Ammunition 

plant, Texas, 1999, ranged from 3 to 776 μg/L (Smith et al. 2001). The concentration of perchlorate near 

the McGregor, Texas Naval Weapons Industrial Reserve Plant was 5,600 μg/L in tributary surface water 

samples collected at the site boundary and <4.0–91,000 μg/L in groundwater samples taken in the area 

(Cowan 2000). In a nearby wet weather spring connected to a boundary tributary, the concentration was 

22,000 μg/L, while approximately 1 and 3 miles downstream in a creek, the concentrations were 200 and 

56 μg/L, respectively. Perchlorate was detected in 13 of 25 local groundwater samples collected in 

Livermore, California, at 1–37 μg/L (Koester et al. 2000) and in drinking water from southern Nevada at 

8–9 μg/L (Magnuson et al. 2000). Perchlorate concentrations measured in groundwater from remote 
PERCHLORATES 184 

6. POTENTIAL FOR HUMAN EXPOSURE 

locations in the Middle Rio Grande Basin in north-central New Mexico ranged from 0.12 to 1.8 μg/L 

(Plummer et al. 2006). 

A study of 54 counties in west Texas and 2 adjacent counties in New Mexico found perchlorate levels in 

several groundwater samples (Rajagopalan et al. 2006). The concentration of perchlorate was generally 

low (<4 μg/L); however, some samples had detectable levels approaching 200 μg/L. While a single 

definitive source for these perchlorate levels could not be identified, the authors concluded that the 

majority of perchlorate detected at these sites could result from atmospheric deposition. 

The U.S. Government Accountability Office listed perchlorate concentrations measured in surface water, 

groundwater, and drinking water samples from 395 sites from 35 states, the District of Columbia, and two 

commonwealths of the United States (GAO 2005). The concentrations at these locations ranged from 4 to 

3,700,000 μg/L. According to the survey, 110 sites were located near defense-related activities, 36 sites 

were located near perchlorate manufacturing and handling operations, 16 sites were located near 

fireworks and flare manufacturing, general manufacturing, and hazardous waste sites, 6 sites were located 

near agricultural operations, and 227 sites were not located near activities linked to perchlorate. 

Seawater samples collected off the coasts of Texas, Massachusetts, California, Hawaii, Oregon, Maine, 

and Mexico contained perchlorate at concentrations ranging from below the detection limit (0.07 μg/L) to 

0.345 μg/L (Martinelango et al. 2006). The concentrations of perchlorate measured in 22 rain and 4 snow 

samples collected in Lubbock, Texas ranged from <0.01 to 1.6 and from <0.01 to 0.4 μg/L, respectively 

(Dasgupta et al. 2005). 

6.4.3 Sediment and Soil 

Perchlorate contamination in soil or sediment has been reported at 27 DOD facilities and 2 other federal 

agency facilities located in Alabama, Arizona, California, Indiana, Massachusetts, Maryland, New Jersey, 

New Mexico, Texas, Utah, Washington, and West Virginia as of March, 2005 (EPA 2005c). Maximum 

reported perchlorate concentrations in soil at these sites vary widely, ranging from approximately 32 to 

2,000,000 ppb. Maximum reported concentrations of perchlorate in sediment were 17 ppb at the 

Aberdeen Proving Ground in Maryland, 230 ppb at the Naval Surface Warfare Center in Maryland, 

186 ppb at the Lone Star Army Ammunition Plant in Texas, and 190 ppb at the Allegheny Ballistics 

Laboratory in West Virginia. Perchlorate contamination in soil was also reported at two private sites in 

Arizona and one private site in Arkansas; however, concentrations were not provided. 
PERCHLORATES 185 

6. POTENTIAL FOR HUMAN EXPOSURE 

Perchlorate levels in 4 of 12 sediment samples at the Longhorn Army Ammunition plant, Texas, 1999, 

ranged from 12 to 704 μg/L (Smith et al. 2001). It was also detected in 4 of 18 soil samples near a single 

building at the facility at 50–322 μg/kg. The concentration of perchlorate in soil samples underneath the 

foundations of former propellant mixing facilities at the McGregor, Texas Naval Weapons Industrial 

Reserve Plant ranged from 23 to 1,800,000 μg/kg (Cowan 2000). Perchlorate was detected in 38% of 

113 soil samples and 93% of 93 sediment samples collected from the Lake Mead area of Nevada with 

average (maximum) concentrations of 57.7 (1,470) mg/kg and 12.8 (56.0) mg/kg, respectively (Dean et 

al. 2004). Smith et al. (2004) reported a mean perchlorate concentration of 24.7 μg/g in 51 soil samples 

from 3 sites at the Las Vegas Wash near Henderson, Clark County, Nevada. 

The concentration of perchlorate in soil samples taken from a tobacco field, December 1999, was 

340 μg/kg (Ellington et al. 2001). Tobacco plants grown in this field had been fertilized that summer 

using products derived from Chilean caliche (which contained perchlorate at 35,800 and 

1,544,000 μg/kg). The concentrations of perchlorate measured in the saturation extract of six soil samples 

from the Mission Valley Formation in San Diego, California ranged from below the detection limit 

(2 μg/L) to 40.2 μg/L (Duncan et al. 2005). 

6.4.4 Other Media 

FDA (2007b) presented measurements of perchlorate in 27 foods and beverages obtained in fiscal years 

2004–2005. Lettuce samples were collected from growers in various locations in Arizona, California, 

Texas, New Jersey, and/or Florida. Mean perchlorate levels were 10.6 ppb (μg/kg) in green leaf lettuce, 

8.06 ppb (μg/kg) in iceberg lettuce, 11.19 ppb (μg/kg) in red leaf lettuce, and 11.75 ppb (μg/kg) in 

romaine lettuce (fresh/dry weight not specified). Bottled water with location sources from Georgia, 

Missouri, California, North Carolina, Texas, Colorado, Maryland, Minnesota, Nebraska, South Carolina, 

Arkansas, Kansas, Wisconsin, and Pennsylvania generally contained no detectable perchlorate. Milk 

samples from Maryland, California, Pennsylvania, Virginia, Arizona, Georgia, Kansas, Louisiana, New 

Jersey, North Carolina, Texas, and Washington had a mean perchlorate level of 5.81 ppb. For 

comparison, Dyke et al. (2007) provide concentrations of perchlorate in dairy milk from Japan that are 

higher than the preliminary data values reported for the United States by FDA. Perchlorate 

concentrations in the Japanese samples ranged from 5.47 to 16.40 μg/L with a mean value of 9.39 μg/L 

and a median value of 9.34 μg/L. Sanchez et al. (2007) compared perchlorate levels in broccoli, 

cauliflower, and cabbage grown in fields irrigated with water from the Colorado River, which contains 
PERCHLORATES 186 

6. POTENTIAL FOR HUMAN EXPOSURE 

perchlorate, with levels of thiocyanate and nitrate, two other anions that inhibit iodide uptake. The 

authors concluded that brassica irrigated with Colorado River water do accumulate trace levels of 

perchlorate. However, the levels of perchlorate observed are much lower than the levels of nitrate and 

thiocyanate, which are naturally present in these food plants. 

Perchlorate concentrations in other foods reported by FDA (2007b) are listed in Table 6-1. 

Following the preliminary assessment on perchlorate exposure (FDA 2007b), FDA completed its Total 

Diet Study (TDS) and released estimated dietary intakes for perchlorate and iodine for 14 age and gender 

groups (Murray et al. 2008). These perchlorate intakes are based on data collected from the TDS from 

2005 to 2006. TDS sampling is conducted four times annually, once in each of the major geographical 

regions of the country (west, north central, south, and northeast). Each round of sampling is referred to as 

an individual market basket survey and for each market basket survey, samples of 285 selected food and 

beverages are obtained from three cities within the region. The TDS results found that detectable levels 

of perchlorate were observed in 59% of all samples analyzed, with 74% (211 of the 285) of the TDS 

foods having at least one positive sample. Perchlorate was not detected in 26% (74 of 285) of TDS foods. 

The contribution by food groups to the total intake of perchlorate for these age/gender groups are 

illustrated in Table 6-2. Table 6-3 provides the actual estimated dietary intake of perchlorate for these 

groups. 

During a study of perchlorate concentrations in lettuce irrigated with Colorado River water (5 mg/L 

perchlorate concentration), perchlorate concentrations ranged from below quantifiable levels to 142 μg/kg 

(fresh weight) in the total above ground plant, 195 μg/kg (fresh weight) in the frame and wrapper leaves, 

and below detection to 26 μg/kg (fresh weight) in the edible head (Sanchez et al. 2005b). Perchlorate was 

detected above 0.2 μg/L in 144 out of 438 leafy vegetable samples produced in California (outside the 

Colorado River region), Colorado, New Jersey, New Mexico, New York, Michigan, Ohio, and Quebec 

(Sanchez et al. 2005a). Quantifiable perchlorate concentrations ranged from 18 to 104 μg/kg fresh weight 

in conventionally grown vegetables and from 21 to 628 μg/kg fresh weight in organically grown 

vegetables. Sanchez et al. (2006) measured perchlorate in citrus fruit grown from trees in the Southwest 

that were irrigated with perchlorate contaminated water (mean concentration of approximately 6 μg/L). 

Mean, median, and maximum perchlorate concentrations were 2.3, 1.3, and 14.8 μg/L fresh weight, 

respectively, in 33 lemon samples, 3.3, 1.3, and 16.2 μg/L fresh weight, respectively, in 15 grapefruit 

samples, and 7.4, 4.8, and 37.6 μg/L fresh weight, respectively, in 28 orange samples. Krynitsky et al. 

(2004) detected perchlorate in 11 edible cantaloupe and 10 whole cantaloupe samples with median 
PERCHLORATES 187 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Measurements of Perchlorate in Samples of 27 Types of Food and 

Beverages Collected From Various Locations in the United States 

Type of food or beverage Mean residue (μg/kg)a Number of samples 

Lettuce (green leaf) 10.3 

4.4b 

137 

2b 

Lettuce (iceberg) 8.1 

2.1b 

43 

4b 

Milk 5.81c 125 

7b 8b 

Tomatoes 13.7 73 

78b 4b 

Carrots 15.8 59 

Spinach 115 

40b 

36 

4b 

Collards 95.1 13 

17.7b 4b 

Cantaloupes 28.6 

24.4b 

48 

4b 

Apples 0.15c

 9 

Grapes 8.58 12 

Oranges 3.47 

2.7b 

10 

4b 

Strawberries 2.14 19 

Watermelon 1.96 19 

Fruit juices (apple and orange) 2.31c

 14 

Broccoli 8.49 14 

Cabbage 8.80 13 

Greens 92.4 14 

Cucumber 6.64 20 

19.1b 4b 

Green beans 6.12 19 

Onions 0.53 12 

Potatoes 0.15d

 6 

Sweet potatoes 1.24 6 

Corn meal 1.16 22 

Oatmeal 3.96 22 

Rice (brown and white) 0.50d

 19 

Whole wheat flour 4.27 19 

Catfish 1.02 7 

Salmon 1.06 11 

Shrimp 19.83 5 

a

Mean values are reported as ppb in source. Mean values were calculated treating non-detections as equal to onehalf the detection limit. Fresh/dry weight not specified. b

Murray et al. 2008 c

Mean value is in μg/L. d

All samples were non-detects. 

Source: FDA 2007b 
PERCHLORATES 188 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Percent Contribution Organized by Food Group to the Total 

Estimated Daily Intake for Perchlorate for 2005–2006 

Intake (percent of total) 

Females Males Women 

Food Infants 6– Children Children Children 14– 14– 25– 

group 11 months 2 years 6 years 10 years 16 years 16 years 30 years 

Baby food 49 0 0 0 0 0 0 

Beverages 1 3 3 4 7 7 12 

Dairy 32 51 50 47 29 37 20 

Egg 0 0 0 0 0 0 0 

Fat/oil 0 0 0 0 0 0 0 

Fruit 4 15 11 9 11 7 8 

Grain 2 6 8 8 8 9 8 

Legume 0 0 0 0 0 0 0 

Mixture 6 8 9 10 14 12 14 

Meat, 1 4 6 5 7 7 11 

poultry, fish 

Sweets 0 1 1 1 1 1 1 

Vegetables 5 12 12 16 23 20 26 

Women Women Women 

Men 25– 40– Men 40– 60– Men 60– 70+ Men 70+ 

30 years 45 years 45 years 65 years 65 years years years 

Baby food 0 0 0 0 0 0 0 

Beverages 12 12 11 9 9 6 7 

Dairy 20 17 21 17 19 23 22 

Egg 0 0 0 0 0 0 0 

Fat/Oil 0 0 0 0 0 0 0 

Fruit 5 11 8 12 9 12 12 

Grain 8 8 9 8 8 8 9 

Legume 0 0 0 0 0 0 0 

Mixture 16 13 13 9 10 10 10 

Meat, 9 7 8 7 8 5 7 

poultry, fish 

Sweets 0 1 1 0 0 0 0 

Vegetables 30 31 29 38 37 36 33 

Source: Murray et al. 2008 
PERCHLORATES 189 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Range of Estimated Lower and Upper Bound Average Perchlorate 

Intake for 2005–2006

 Intake (μg/person/day) 

Females Males Women 

Food Infants 6– Children Children Children 14– 14– 25– 

group 11 months 2 years 6 years 10 years 16 years 16 years 30 years 

Baby food 1.1–1.3 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 

Beverages 0.0–0.1 0.0–0.3 0.0–0.4 0.0–0.5 0.02–0.8 0.0–0.1 0.2–1.2 

Dairy 0.8–0.8 2.6–2.6 2.9–2.9 3.1–3.1 1.6–1.6 3.1–3.1 1.2–1.2 

Egg 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 

Fat/oil 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 

Fruit 0.1–0.1 0.7–0.9 0.6–0.7 0.5–0.6 0.6–0.7 0.5–0.6 0.5–0.6 

Grain 0.0–0.1 0.3–0.3 0.4–0.5 0.5–0.5 0.4–0.5 0.7–0.8 0.4–0.5 

Legume 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 

Mixture 0.1–0.1 0.4–0.5 0.5–0.6 0.6–0.7 0.8–0.8 1.0–1.1 0.9–0.9 

Meat, 0.0–0.0 0.2–0.2 0.3–0.3 0.3–0.4 0.3–0.4 0.5–0.6 0.7–0.7 

poultry, fish 

Sweets 0.0–0.0 0.0–0.0 0.0–0.1 0.0–0.1 0.0–0.1 0.0–0.1 0.0–0.1 

Vegetables 0.1–0.1 0.6–0.6 0.7–0.7 1.0–1.0 1.2–1.3 1.7–1.7 1.5–1.5 

Total intake 2.4–2.7 4.9–5.5 5.4–6.1 6.1–6.9 5.1–6.1 7.7–9.1 5.4–6.8 

Total intake 0.26–0.29 0.35–0.39 0.25–0.28 0.17–0.20 0.09–0.11 0.12–0.14 0.09–0.11 

(μg/kg/day) 

Women Women Women 

Men 25– 40– Men 40– 60– Men 60– 70+ Men 70+ 

30 years 45 years 45 years 65 years 65 years years years 

Baby food 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 

Beverages 0.2–1.6 0.3–1.3 0.2–1.7 0.2–1.0 0.2–1.3 0.1–0.7 0.1–0.9 

Dairy 1.5–1.5 1.1–1.1 1.8–1.8 1.1–1.1 1.5–1.5 1.4–1.4 1.7–1.7 

Egg 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 

Fat/oil 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 

Fruit 0.3–0.4 0.7–0.8 0.6–0.7 0.7–0.8 0.6–0.8 0.7–0.8 0.8–1.0 

Grain 0.6–0.7 0.5–0.6 0.7–0.8 0.5–0.5 0.6–0.7 0.5–0.6 0.6–0.7 

Legume 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 

Mixture 1.2–1.3 0.8–0.9 1.1–1.1 0.6–0.6 0.8–0.9 0.6–0.6 0.7–0.8 

Meat, 0.7–0.7 0.5–0.5 0.6–0.7 0.4–0.5 0.6–0.7 0.3–0.4 0.5–0.6 

poultry, fish 

Sweets 0.0–0.0 0.0–0.0 0.1–0.1 0.0–0.0 0.0–0.0 0.0–0.0 0.0–0.0 

Vegetables 2.2–2.2 1.9–2.0 2.4–2.4 2.4–2.4 2.8–2.9 2.2–2.2 2.5–2.5 

Total intake 6.7–8.6 5.9–7.3 7.4–9.4 5.9–7.1 7.2–8.8 5.8–6.9 7.1–8.3 

Total intake 0.08–0.11 0.09–0.11 0.09–0.11 0.09–0.10 0.09–0.11 0.09–0.11 0.11–0.12 

(μg/kg/day) 

Source: Murray et al. 2008 
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(range) concentrations of 9.6 (<2.0–18.2) and 23.9 (<2.0–39.3) μg/kg, respectively (fresh/dry weight not 

specified). 

According to El Aribi et al. (2006), perchlorate was detected in all produce, wine, and beer samples 

purchased in grocery and liquor stores located in the greater Toronto, Ontario area between January 2005 

and February 2006. These products were harvested or produced in many parts of the world. Median 

concentrations reported for perchlorate in products from each country ranged from 0.047 to 

169.698 μg/kg in 63 produce samples, 0.013–15.54 μg/L in 77 wine samples, and 0.03–10.663 μg/L in 

144 beer samples, and below detection (5 ng/L). Perchlorate was detected above 5 ng/L in 11 out of 

12 beverage samples and in 7 out of 10 bottled water samples from around the world at reportable 

concentrations of 0.067–5.098 μg/L and 0.021–4.795 μg/L, respectively. Median, minimum, and 

maximum perchlorate concentrations in samples harvested or produced in the United States were 0.252, 

0.094, and 19.29 μg/kg, respectively, in 8 produce samples, 20.9, 0.197, and 4.593 μg/L, respectively, in 

12 wine samples, and 0.662, 0.364, and 2.014 μg/L, respectively, in 8 beer samples. 

Perchlorate was detected in 20 out of 31 dietary supplements with mean, median, and maximum 

reportable concentrations of 247, 25, and 2,420 ng/g, respectively (Snyder et al. 2006). The limits of 

detection ranged from 2 to 15 ng/g. Perchlorate was also detected in two samples of kelp granules, a 

flavor enhancing ingredient, at concentrations of 709 and 740 ng/g. 

In a survey of 10 randomly selected off-the-shelf tobacco products, perchlorate was detected in six of 

seven brands of different plug chewing tobacco at 2.3–149.3 mg/kg (dry weight), two of two brands of 

cigarettes at 15.1–71.7 mg/kg, and one of one brand of cigars at 7.1 mg/kg (Ellington et al. 2001). 

Mean perchlorate concentrations measured in the blood, milk, urine, and feces of cows with calculated 

perchlorate intakes of 0.46 mg/day from feed and 0.03 mg/day from water were 0.24, 4.37, 3.68, and 

5.84 ng/mL, respectively (Capuco et al. 2005). Perchlorate concentrations were monitored in vegetation 

and animal samples collected at various locations at the Longhorn Army Ammunition plant, Texas, 1999. 

It was detected in green tree frog samples (86–153 μg/kg), harvest mouse samples (1,120–2,328 μg/kg), 

cotton mouse samples (356 μg/kg), mosquitofish samples (83–206 μg/kg), juvenile sunfish samples 

(132 μg/kg), blackstripe minnow samples (104 μg/kg), bullfrog tadpole samples (1,130–2,567 μg/kg), 

chorus frog samples (580 μg/kg), Notropis spp. samples (77 μg/kg), weed shiner samples (100 μg/kg), 

bullrush samples (555–9,487 μg/kg dry weight), crabgrass samples (1,060,000–5,557,000 μg/kg dry 

weight), and damselfly larvae (811–2,036 μg/kg) (Smith et al. 2001). Perchlorate was not detected in 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Northern cricket frog samples, American toad sample, bullfrog samples, or largemouth bass samples. For 

most of these samples, it was not specified whether measurements were conducted on a wet- or dryweight basis. The concentrations of perchlorate were below the detection limit of 2.5 μg/L wet weight in 

most fish samples (tissue extracts) collected from lakes, rivers, and streams located near the Naval 

Weapons Industrial Reserve Plant in McLennan County, Texas (Theodorakis et al. 2006). Concentrations 

in fish with quantifiable levels ranged from 10.8 to 4,560 μg/kg wet weight. Perchlorate was detected in 

18% of 88 terrestrial mammals, 3% of 107 fish, and 12% of 42 terrestrial birds sampled in the Lake Mead 

area, Nevada with average (maximum) concentrations of 13.4 (53.0), 16.4 (44.3), and 1.5 (4.2) mg/kg, 

respectively (Dean et al. 2004). It was not specified whether these measurements were conducted on a 

wet or dry-weight basis. 

In wood samples from dormant salt cedars near the Las Vegas Wash, Nevada, date not provided, 

perchlorate concentrations ranged from 5 to 6 mg/kg in twigs extending above the water and at 300 mg/kg 

in submersed stalks (Urbansky et al. 2000c). The rate and selectivity of perchlorate uptake by the salt 

cedars was not determined. The mean concentration of perchlorate was 289.3 μg/g in 71 vegetation 

samples collected from 3 sites at the Las Vegas Wash during March, 2002 (Smith et al. 2004). 

Perchlorate has been detected in 50% of 177 terrestrial vegetation samples and 24% of 50 aquatic 

vegetation samples from the Lake Mead area in Nevada with average (maximum) concentrations of 

34.7 (428) and 38.8 (176) mg/kg, respectively (Dean et al. 2004). Tan et al. (2004b) tested several plants 

and trees (smartweed [Polygonum spp.], watercress (Nasturtium spp.), ash (Fraxinus greggii A. Gray), 

chinaberry (Melia azedarach L.), elm (Ulmus parvifolia Jacq.), willow (Salix nigra Marshall), mulberry 

(Broussonetia papyrifera [L.] Vent.), and hackberry (Celtis laevigata Willd.) that were growing beside 

streams near the Naval Weapons Industrial Reserve Plant at McGregor, Texas for perchlorate. 

Perchlorate was detected above 1 μg/L in streamwater at five out of six locations with average 

concentrations ranging from <1 to 281 μg/L. The average concentrations of perchlorate in the plants and 

trees at these locations ranged from <1 to 40,600 μg/kg dry weight. Martinelango et al. (2006) measured 

perchlorate concentrations ranging from 29 to 878 μg/kg dry weight in 13 commercially available 

seaweed species. 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The general population is likely to be exposed to perchlorate through some dietary routes, drinking water 

sources, and consumer products. 
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6. POTENTIAL FOR HUMAN EXPOSURE 

Data from the FDA TDS indicated that 74% (211 of the 285) of the foods analyzed had at least one 

sample in which perchlorate was detected (Murray et al. 2008). The perchlorate dietary intake was 

estimated to range from 0.08 to 0.11 μg/kg/day for males aged 25–30 years to 0.35–0.39 μg/kg/day for 

children 2 years old (see Table 6-3). These estimates are in good agreement with previous estimates 

based upon limited sets of data. Daily dose for perchlorate exposure via ingestion of lettuce, dietary 

supplements, and citrus fruit have been calculated (Sanchez et al. 2005a, 2005b, 2006; Snyder et al. 

2006). None of these estimates were above the EPA reference dose (0.7 μg/kg/day). Blount et al. (2007) 

estimated a daily perchlorate dose based on measured concentrations in urine, which account for the 

combined exposure from all sources. Reported geometric mean and 95th percentile urinary perchlorate 

concentrations of 3.35 and 12 μg/L, respectively, were measured in a nationally representative population 

of 1,618 U.S. residents, ages ≥20 years, during 2001 and 2002 as part of the National Health and 

Nutrition Survey (NHANES). Based on these monitoring data, the geometric mean and 95th percentile 

values of the estimated perchlorate dose in adults were 0.066 and 0.234 μg/kg/day, respectively. Only 

11 adults had estimated doses greater than the EPA reference dose. 

The detection of perchlorate in drinking water supplies (Brechner et al. 2000; Giblin et al. 2000; Herman 

and Frankenberger 1998; Li et al. 2000a; Urbansky 1998) and in tap water samples (Urbansky 1998) 

indicates that members of the general population may be exposed by ingestion of water containing 

perchlorate. Perchlorate has been identified at least once in approximately 4% of over 3800 community 

water systems from 26 different states and 2 territories, with detectable levels averaging 9.8 μg/L and 

ranging from the method detection limit of 4 μg/L to a maximum at 420 μg/L (EPA 2007). 

Contaminated groundwater sources near known ammonium perchlorate production or use sites (Giblin et 

al. 2000; Herman and Frankenberger 1998; Kim and Logan 2001; Logan et al. 2001b; Smith et al. 2001; 

Urbansky 1998) suggest that populations that obtain drinking water from down gradient wells at such 

sites may also be exposed to perchlorates. Since more sensitive analytical techniques have been 

developed, perchlorate is also being found in areas other than where it has been manufactured, used, or 

released by humans, suggesting that exposure from natural sources are possible (Dasgupta et al. 2005; 

Rajagopalan et al. 2006; Urbansky 2002; Valentín-Blasini et al. 2005). 

Valentín-Blasini et al. (2005) measured perchlorate concentrations ranging from 0.66 to 

21 (median 32) ng/mL in urine samples from 61 healthy adult donors from Atlanta, Georgia with no 

known perchlorate exposure. These authors also measured perchlorate in urine samples from 60 pregnant 

women from 3 Chilean cities (Antofagasta, Chañaral, and Taltal) where perchlorate concentrations in tap 
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water range from approximately 0.4 to 114 ng/mL. The median and range of concentrations of 

perchlorate in the samples were 35 and 0.49–1,100 ng/mL, respectively. Pearce et al. (2007) reported 

perchlorate concentrations ranging from 0.37 to 127 μg/L measured in 56 urine samples from 57 Bostonarea nursing mothers. 

Perchlorate has been detected in different types of tobacco products (Ellington et al. 2001). It is likely 

that smokeless tobacco products (chewing tobacco) will result in greater exposure than cigarettes since 

the combustion of the perchlorate upon lighting will result in a reaction before it is inhaled. Individuals 

that reload their own ammunition may also be exposed to perchlorates due to their presence in gunpowder 

(Lindner 1993). Members of the general population undergoing some types of medical imaging may be 

exposed to small amounts (200–400 mg orally) of perchlorate (Gibbs et al. 1998). Perchlorate has also 

been identified in certain common household products such as bleach. Perchlorate levels in bleach were 

reported to range from 89 to 8,000 ppb, with concentrations increasing with time of product storage 

(MassDEP 2006a). Perchlorate has also been detected in dietary (vitamin and mineral) supplements and 

flavor-enhancing ingredients collected from various commercial vendors in two large U.S. cities (Snyder 

et al. 2006). The highest level of perchlorate was found in a supplement recommended for pregnant 

women as a prenatal vitamin/mineral supplement. 

Workers at facilities where perchlorates are manufactured or used may be exposed by inhalation. 

Workers at an ammonium perchlorate facility were exposed to calculated single-shift absorbed doses of 

0.2–436 μg/kg with a 35 μg/kg average (Gibbs et al. 1998). Lifetime cumulative doses for workers over 

an average of 8.3 years ranged from 8,000 to 88,000 μg/kg. Workers may also be exposed to perchlorate 

dusts through oral routes through deposition of particles via mouth breathing (Gibbs et al. 1998). In a 

survey at an ammonium perchlorate manufacturing facility, respirable air samples had an average 

perchlorate concentration of 0.091 mg/day for workers at low dust-forming operations. The average 

perchlorate concentration for moderate and high dust-forming operations was 0.601 and 8.591 mg/day, 

respectively (Lamm et al. 1999). Exposure through inhalation or dermal contact may also occur from 

aqueous perchlorate solutions if aerosol-producing operations, such as spray drying, are used; however, 

dermal absorption of perchlorate is expected to be low since electrolytes applied from aqueous solutions 

do not readily penetrate the skin (Scheuplein and Bronaugh 1983). 

The National Occupational Exposure Survey (NOES), conducted from 1981 to 1983, indicates that 

2,641 total workers were exposed to potassium perchlorate, 1,452 to sodium perchlorate, 1,445 to 

ammonium perchlorate, and 1,906 to magnesium perchlorate in the United States (NIOSH 1995). No 
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values were reported for lithium perchlorate. Exposure for female workers was reported as 

1,948 (potassium), 230 (sodium), 230 (ammonium), and 713 (magnesium). It is not known why females 

represented a higher percentage of the total worker exposure for lithium and magnesium perchlorates 

relative to that for the sodium and ammonium salts. 

These NOES data suggest that the highest production volume salts, sodium and ammonium perchlorates, 

were used in operations involving fewer people than magnesium and potassium perchlorates. These data 

also suggest that magnesium and potassium perchlorates were used either in a wider range of applications, 

in processes requiring more human manipulation, or in applications that were performed at multiple sites 

in the United States. 

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 

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). 

Children are expected to undergo environmental exposure to perchlorates via the same routes predicted 

for adult members of the general population in Section 6.5, primarily through the ingestion of food and 

drinking water containing perchlorate. Blount et al. (2007) reported geometric mean and 95th percentile 

urinary perchlorate concentrations of 4.93 and 19 μg/L, respectively, measured in 374 children living in 

the United States, ages 6–11 years, during 2001 and 2002 as part of the NHANES. Geometric mean and 

95th percentile concentrations in 828 children ages 12–19 years measured during this study were 3.80 and 

12 μg/L, respectively. The authors note that the adjusted geometric mean of urinary perchlorate 

concentrations is higher for children (5.40 μg/L) than for adolescents (3.30 μg/L) and adults (3.41 μg/L). 

Possible explanations for this are differences in pharmacokinetics, the relationship of dose per body 
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6. POTENTIAL FOR HUMAN EXPOSURE 

weight, and differences in dietary habits between children and adults such as the consumption of milk and 

green leafy vegetables. 

The estimated dietary intakes for children have been calculated based upon the FDA TDS (see Table 6-3). 

These data indicate that children have the highest estimated intake on a body weight basis as compared to 

the other age groups because they consume more food per body weight and have different food 

consumption patterns when compared to the other age groups (Murray et al. 2008). Children 2 years of 

age had the highest estimated intake ranging from 0.35 to 0.39 μg/kg/day, which is roughly 50–56% of 

the EPA reference dose (RfD). Dairy products provided over 50% of the total perchlorate intake in their 

diets. Using measured urinary concentration data, Blount et al. (2007) estimated the daily dose of 

perchlorate for women of reproductive age to give an indication of possible fetal exposure to perchlorate. 

The median and 95th percentile values of the estimated perchlorate dose were 0.057 and 0.214 μg/kg/day, 

respectively, in 662 women of reproductive age. The median of the estimated dose was 0.066 μg/kg/day 

in 110 pregnant women (95th percentile value was not reported). 

Measurements of perchlorate concentration in mother’s milk, a potential route of exposure for infants, 

indicated a mean level of 10.5 μg/L and a maximum level of 92 μg/L in 35 human milk samples from 

18 states (Kirk et al. 2005). Kirk et al. (2007) reported perchlorate concentrations ranging from 0.5 to 

39.5 μg/L measured in the breast milk of 10 women (from Texas, Colorado, Florida, Missouri, New 

Mexico, and North Carolina). Mean and median concentrations were 5.8 and 4.0 μg/L, respectively. 

Téllez et al. (2005) reported mean perchlorate concentrations of 81.6, 18.3, and 85.6 μg/L measured in the 

breast milk of women from the Chilean cities of Antofagasta (14 samples), Chañaral (16 samples), and 

Taltal (25 samples), respectively. Perchlorate was detected in all 49 breast milk samples from 57 Bostonarea women ranged at concentrations ranging from 1.3 to 411 μg/L (Pearce et al. 2007). These authors 

also measured perchlorate in infant formulae; perchlorate was detected in all 17 samples measured at 

concentrations ranging from 0.22 to 4.1 μg/L. Using data from Kirk et al. (2005) for levels of perchlorate 

in human milk and exposure factors described in EPA (1997b), Baier-Anderson et al. (2006) estimated 

that infants breastfed for 6 months may have daily doses of perchlorate that exceed the NAS 

recommended RfD of 0.7 μg/kg/day. This information needs to be put in context by reiterating that the 

RfD is, by definition, an estimate spanning as much as an order of magnitude, and that the perchlorate 

RfD is based on a precursor to an adverse effect. 

Perchlorate has also been detected in dairy milk, another source of exposure of children and adults (Kirk 

et al. 2005). The mean level of perchlorate in 47 cow’s milk samples from 11 states was 2 μg/L, with a 
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6. POTENTIAL FOR HUMAN EXPOSURE 

maximum level of 11 μg/L. The FDA has reported a mean concentration of 5.81 ppb measured in 

125 dairy milk samples collected from 12 states (FDA 2007b). Data from the most recent FDA TDS 

found a mean concentration of 7 ppb measured in 8 samples of milk (Murray et al. 2008). Rice et al. 

(2007) demonstrated the transfer of perchlorate from feed to cows was a significant source of perchlorate 

in subsequent milk samples. Analysis of the ingredients of the total mixed ration (TMR) determined that 

the majority of perchlorate arose from corn silage, alfalfa, and hay. 

Perchlorates may be released to soil by a number of pathways. Because children sometimes eat 

inappropriate things and put dirt in their mouths, they may be exposed to perchlorates through ingestion 

of contaminated soil. The presence of certain household products that contain perchlorates could also 

lead to a child being exposed. Children may be exposed to perchlorates if they use or disassemble flares; 

infants may be exposed orally if they put them in their mouths. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Members of the general population who live near hazardous waste sites containing perchlorates and draw 

their drinking water from underground wells may potentially receive high exposure to perchlorates. 

Similarly, people who live near facilities that manufacture, process, use, or dispose of large amount of 

perchlorates may also receive potentially higher exposures. 

Workers in facilities that manufacture or use large amounts of solid perchlorates may receive potentially 

high inhalation exposures. Twenty-nine individuals were tested for perchlorate exposure after 

3 consecutive days of 12-hour shifts working at an ammonium perchlorate production facility near Cedar 

City, Utah (Braverman et al. 2005). The mean and median concentrations of perchlorates in serum 

samples collected from the workers were 2 and 0 μg/L, respectively, before exposure and 838.4 and 

358.9 μg/L, respectively, after exposure. The mean and median concentrations of perchlorates in urine 

samples were 0.16 and 0.11 mg/g creatinine, respectively, before exposure and 43.0 and 19.2 mg/g 

creatinine, respectively, after exposure. Gibbs et al. (1998) calculated that workers at an ammonium 

perchlorate manufacturing facility may receive doses that are 2–3 orders of magnitude greater than a 

person might receive from drinking water obtained from Lake Mead or the Colorado River and 2–3 orders 

of magnitude less than that historically prescribed for the treatment of Grave’s disease. 

Due to their presence and potential emission in signal flares, members of the population that use these 

devices on a frequent basis, such as law enforcement officers, may be exposed to higher levels of 
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6. POTENTIAL FOR HUMAN EXPOSURE 

perchlorates than the general public. Similarly, frequent users of perchlorate-based civilian explosives, 

fireworks display technicians, and related occupations may be exposed to higher levels. 

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 perchlorates 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 perchlorates. 

The following categories of possible data needs have been identified. They are defined as substancespecific 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. Perchlorates have been manufactured commercially for nearly 

100 years (Schilt 1979). Their fundamental physical and chemical properties have been well described in 

the literature. Vapor pressure data are not available for the perchlorate salts listed in Table 4-1; however, 

they are high melting ionic solids and would be expected to be nonvolatile. No further investigation of 

the physical/chemical properties of perchlorates is required to assess their potential for human and 

environmental exposure. 

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. Reliable data on the production 

of perchlorates are not available. Reasonable estimates are available for past ammonium perchlorate 

production, although current values are not available. Past or present production data for the remainder of 

the perchlorates listed in Table 4-1 are not available. Accurate production data may not become available 

because perchlorates are considered strategic chemicals due to their extensive use in military and 

aerospace applications and there are no requirements to track and report for the numerous industrial and 
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6. POTENTIAL FOR HUMAN EXPOSURE 

commercial applications for perchlorate. Accordingly, available worldwide perchlorate production data 

are unlikely to be complete. Accurate production data is one factor that is required to establish the 

foundation from which potential human and environmental exposure to perchlorates can be determined. 

The techniques used in manufacturing perchlorates have been well described in the available literature 

and there are no data needs in this area. 

Accurate import and export data on perchlorate are not readily available. Perchlorates are not listed as a 

separate, reportable item on U.S. Census Bureau’s schedule B book on imports. Production, import and 

export data are available for certain products that may contain perchlorate. For example, large amounts of 

fireworks (approximately 1x108

 kg) are imported into the United States (USITC 2008). The actual 

volume of perchlorates represented by these figures is not known since the content of perchlorate varies 

by firework type and origin. Reliable data on the importation of fireworks as well as the amount of 

perchlorate they contain are important in determining human exposure. 

The numerous uses of perchlorates have been described in the available literature. However, the amount 

of perchlorates used in these applications is not always available. Determining the amount of perchlorates 

in these products is essential in fully establishing the extent, level, and route of potential occupational 

exposures. Moreover, the amount of perchlorate contained in pyrotechnic devices, especially consumer 

products (i.e., small fireworks, flares, and gunpowder) is required to establish worker exposure as well as 

potential exposure to members of the general population. This data gap requires additional research to 

characterize and document potential significant sources of perchlorate released to the environment. 

Limited data on the release of perchlorates to the environment were located. Releases are known to be 

associated with the perchlorate production for propellants as well as rocket manufacture, testing, and 

decommissioning. The amount, frequency, and duration of these releases are not well documented. 

Researchers have speculated that the current extent of perchlorate contamination in western waters is a 

direct result of these activities. A better understanding of historical releases, used in combination with an 

extensive monitoring database, will allow the development of robust models that can be used to predict 

the potential for human and environmental exposure 

The wide variety of uses for perchlorates suggests that other releases are likely during production, 

processing, formulation, transport, use, and disposal. No data on the resulting release of perchlorates 

were located in the available literature. The water solubility of perchlorates suggests that disposal in 
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6. POTENTIAL FOR HUMAN EXPOSURE 

aqueous waste streams may occur during their production and use. Given that perchlorates are not known 

to be removed from waste water streams in POTWs or other common treatment processes, release to 

waste water represents a point source release to surface water. Since perchlorates are known to persist in 

surface water, a comprehensive understanding of point source releases to the environment is required to 

fully establish the potential for human exposure. 

Perchlorates are explosive chemicals that see extensive use in pyrotechnic devices including fireworks. 

Catastrophic accidents resulting from manufacturing of perchlorates (Urbansky 1998) and products in 

which it is contained (CSB 1999) are known to have occurred. Release of unspent perchlorates to the 

environment is a likely result of these events. Members of the general population who live near these 

facilities may therefore be exposed to perchlorates as a result of a catastrophic explosion. Similarly, 

perchlorates are known to be released during the catastrophic explosion of booster rockets (Merrill and 

O’Drobinak 1998). Determining the amount released during these events is required to estimate potential 

human and environmental exposure. 

Unspent perchlorates may be released to the environment in the effluent of propulsion systems in solid 

propellant rockets and fireworks. Unspent oxidant may also be released during the “burst” at fireworks 

displays. The amount of perchlorates released via these mechanisms, if any, is not known but may be 

significant. Given the large volume of perchlorates used in rockets and that members of the general 

population frequent firework displays, the amount released from these potential pathways is required for a 

comprehensive determination of general population exposure. 

Concern over the disposal of perchlorate has not arisen until recently (Urbansky 1998). DOD recovers 

much of the perchlorate that is used in weapon systems and returns it to the manufacturer for use in 

commcercial applications (DOD 2007). More information on the level, frequency, amount, composition, 

method, route, duration, and chronology of perchlorate disposal would be needed for a thorough 

assessment of the environmental burden of perchlorates. 

Environmental Fate. Studies of sufficient number and breadth to rigorously establish the 

environmental fate of perchlorates have not been performed, and currently, there are no regulations in 

place that restrict their use. Very few studies on the transport and partitioning of perchlorates in the 

environment were located. Moreover, current methodologies for estimating key predictors of fate 

processes, including the octanol/water partition coefficient, soil adsorption coefficient, and 
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6. POTENTIAL FOR HUMAN EXPOSURE 

bioconcentration factor are not sufficiently robust to provide accurate results for inorganic ions in general 

and perchlorates specifically. 

Some aspects of the environmental fate of perchlorates can be reliably predicted. Volatilization from 

water or soil to the atmosphere is not expected to occur to a significant extent. If released directly to the 

atmosphere, deposition through wet and dry process is expected to return perchlorates to the Earth’s 

surface (although the importance of long-range transport in air was not located in the available literature). 

Analysis of physical/chemical properties and available monitoring data indicate that perchlorates are 

unlikely to be strongly adsorbed to soil or sediment. 

There is also a paucity of data available on the degradation of perchlorate in the environment. Given that 

they are fully oxidized, perchlorates are not expected to react with the common environmental oxidants 

found in air and surface waters. Direct photolysis is also not expected to be a significant process. 

Numerous workers have demonstrated that in laboratory studies, isolated microorganisms can respire 

perchlorates, although to date, no evidence of the biodegradation of perchlorate in the environment has 

been located. The anaerobic biodegradation of perchlorates would be expected to occur in anoxic soils 

and groundwater. Because members of the general population may be exposed to perchlorates through 

the ingestion of contaminated well water, aerobic biodegradation studies that establish its potential 

removal from drinking water sources are important. Ingestion of perchlorate-contaminated drinking 

water may be a route of exposure for those members of the general population living near hazardous 

waste sites containing perchlorates. 

The available data on the fate of perchlorates in the environment do not allow an accurate prediction of 

their lifetime in soil and water. 

Bioavailability from Environmental Media. No data are available to determine the bioavailability 

of perchlorate from environmental media. It has been detected in plants (Nzengung et al. 1999) and 

tobacco products (Ellington et al. 2001) and may be present in food crops irrigated with perchlorate 

contaminated water. The bioavailability of perchlorate from environmental media would provide 

additional information to help determine potential levels of human exposure. 

Food Chain Bioaccumulation. Limited data are available on the uptake of perchlorates in biota. A 

laboratory study (Nzengung et al. 1999) provides evidence for the uptake and depuration of perchlorates 
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6. POTENTIAL FOR HUMAN EXPOSURE 

in willows. It has been detected in vegetation, fish, amphibian, insect, and rodent samples near a site of 

known contamination (Smith et al. 2001). Few studies of perchlorate bioconcentration in fish and aquatic 

organisms or food chain bioaccumulation have been identified. These data are required in order to 

determine the potential exposure of higher organisms to perchlorates. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of perchlorates 

in contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

perchlorates in the environment can be used in combination with the known body burden of perchlorates 

to assess the potential risk of adverse health effects in populations living in the vicinity of hazardous 

waste sites. 

No monitoring data are available on the concentration or frequency of detection of perchlorates in air, or 

plant materials, while there are data on the concentration of perchlorates in soil, surface water and 

groundwater at various sites where perchlorates have been used or disposed or are naturally occurring. 

Exposure Levels in Humans. Recent data are available on perchlorate exposure levels in humans 

for both age and gender groups (Blount et al. 2007; Murray et al. 2008). Continued monitoring data and 

estimates of human exposure are necessary to compare exposure levels and observed health effects in the 

population. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. Children are expected to be exposed to perchlorates primarily through the 

ingestion of food (including milk) and drinking water containing perchlorate. Infants may be exposed 

through mother’s milk. Since younger children have the propensity to place objects in their mouths, the 

levels of perchlorate in soil and consumer items needs to be determined. 

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 perchlorates 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 
PERCHLORATES 202 

6. POTENTIAL FOR HUMAN EXPOSURE 

the epidemiological research needed to assess adverse health outcomes that may be related to exposure to 

this substance. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2008) database and the Current Research and Information 

System database funded by the U.S. Department of Agriculture (CRIS 2008) provide 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 6-4. 

In addition, DOD is pursuing recycling technology to recover ammonium perchlorate from demilitarized 

rocket motors for military reuse, which should significantly reduce the amount of propellants that must be 

destroyed by open burn/open detonation (DOD 2008). 

It should be noted that additional information on the potential for human exposure to perchlorates is 

continually appearing in the scientific literature. Much of this work is being performed by both private 

and governmental laboratories and, therefore, would not be cited in FEDRIP. Interested readers who 

require the latest information on the potential for human exposure to perchlorates are urged to consult the 

scientific literature. 
PERCHLORATES 203 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Ongoing Studies on the Potential for Human Exposure to Perchlorates 

(Including Studies on Fate and Occurrence) 

Investigator Affiliation Research description 

EPA EPA, Office of Research and Survey of industrial and foodgrade chemicals for 

Development, National perchlorate content 

Exposure Research Lab 

CDC CDC, NCEH Perchlorate exposure in the US population (ages 6+ 

using NHANES data (2001–) 

CDC CDC, NCEH Maternal and perinatal fetal perchlorate exposure 

CDC CDC, NCEH Perchlorate exposure of infants consuming either 

breastmilk or infant formula 

CDC CDC. NCEH Mechanisms of active transport of perchlorate in 

cultured mammalian cells 

CDC CDC, NCEH Perchlorate exposure and thyroid hormone levels in a 

population of women with low iodine intake 

FDA FDA Ongoing FDA Total Diet Survey analysis for 

perchlorate 

Follet RF Agricultural Research Service Improving soil and nutrient management systems for 

sustained productive and environmental quality 

Mylon S Lafayette College Removal and destruction of perchlorate from aqueous 

systems using polymer ligand technology and packed 

bed reactors 

Raskin LM University of Illinois at Urbana- Process optimization, molecular microbial 

Champaign, Department of Civil characterization, and biofilm modeling of a bioreactor 

and Environmental Engineering for perchlorate removal from drinking water 

Sanchez CA University of Arizona Assessment of perchlorate content of food crops 

irrigated with water from the Colorado River 

Sanchez CA University of Arizona Study of the fate and transport of perchlorate in the soil 

of the lower Colorado River region of Arizona 

Scow KM University of California Study of microbial degradation of contaminants in soil, 

vadose, and groundwater 

Stewart VJ University of California Study of bacterial anaerobic respiration in relation to its 

use and application in environmental microbiology and 

bioremediation 

Strathmann T University of Illinois at Urbana- Development of a sustainable catalytic treatment 

Champaign process for perchlorate 

CDC = Centers for Disease Control and Prevention; EPA = Environmental Protection Agency; FDA = Food and Drug 

Administration; NCEH = National Center for Environmental Health; NHANES = National Health and Nutrition 

Examination Survey 

Source: CRIS 2008; FEDRIP 2008; SI/EPA 2008 
PERCHLORATES 204 

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PERCHLORATES 205 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring perchlorates, their metabolites, and other biomarkers of exposure and effect 

to perchlorates. 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. 

In January 1997, the California Department of Health Services (DHS) began to test for perchlorate in 

drinking water wells near the Aerojet production facility outside of Sacramento (EPA 1999a). At that 

time, the best analytical method available had sensitivities of 400 μg/L. Subsequently, it was improved to 

100 μg/L by Aerojet Corporation. Existing data indicated that a 4 μg/L detection limit was required for a 

comprehensive assessment of the Aerojet site. By March of the same year, the California DHS, in 

collaboration with an analytical equipment manufacturer, refined the methodology to achieve a method 

detection limit of approximately 1 μg/L and a reporting limit of 4 μg/L. 

With this analytical methodology in place, monitoring studies soon indicated that perchlorate 

contamination existed far beyond the boundaries of the Aerojet site. Because of concern for potential 

widespread perchlorate contamination and the importance of ammonium perchlorate in military and 

aerospace operations there has been a dramatic increase in the research on determining trace quantities of 

the perchlorate anion, especially in raw and finished drinking water supplies (Urbansky 2000). Extensive 

effort has also been expended to modify the quantitative techniques developed for water to measure 

perchlorate in other environmental matrices, such as soil, plants, blood, or sludge. 

Four standardized methods are available for quantifying perchlorate in drinking water. These include 

EPA Method 314.0 (Ion Chromatography), EPA Method 314.1 (Inline Column Concentration/Matrix 

Elimination Ion Chromatography with Suppressed Conductivity Detection), EPA Method 331.0 (Liquid 

Chromatography Electrospray Ionization Mass Spectrometry), and EPA Method 332.0 (Ion 

Chromatography with Suppressed Conductivity and Electrospray Ionization Mass Spectrometry) (EPA 
PERCHLORATES 206 

7. ANALYTICAL METHODS 

1999c, 2005h, 2005i, 2005j). High salt concentrations can cause interference when using 

Methods 314.0 and 314.1 (Tikkanen 2006). Method detection limits and minimal reporting levels are 

0.5 and 4.0 μg/L, respectively, for Method 314.0 and 0.03 and 0.13–0.14 μg/L, respectively, for 

Method 314.1 (EPA 1999c, 2005h). EPA Methods 332.0 and 331.0 require isotopically labeled internal 

standards for quantitation (Tikkanen 2006). Method 332.0 has greater sensitivity than Methods 314.0 and 

314.1 with a method detection limit of 0.02 μg/L and a minimum reporting level of 0.10 μg/L (EPA 

2005j; Tikkanen 2006). Method 331.0 offers the greatest sensitivity with a method detection limit of 

0.005–0.008 μg/L and a minimum reporting level of 0.022–0.056 μg/L (EPA 2005i; Tikkanen 2006). 

7.1 BIOLOGICAL MATERIALS 

No standardized methods for the detection of perchlorates in biological samples have been reported. Ion 

chromatography (IC) has been used to detect perchlorate in human breast milk and cow’s milk (Kirk et al. 

2005). Ells et al. (2000) describe a method for determining perchlorate in urine samples using 

electrospray ionization mass spectrometry. A method using ion chromatography (IC) and electrospray 

(ES) tandem mass spectrometry (MSMS) for determining perchlorate in urine (limit of detection 

0.025 ng/mL) showed an association between urinary levels and drinking water concentrations of 

perchlorate (Valentín-Blasini et al. 2005). Similarly, Blount et al. (2006) used IC-ES-MSMS to measure 

perchlorate in amniotic fluid. This analytical method included measurement of iodide so that the levels of 

perchlorate relative to iodide could be assessed. Because perchlorate competitively inhibits iodide 

uptake, the presence of larger quantities of iodide may minimize impact of perchlorate on thyroid 

function. A method to quantify perchlorate, thiocyanate, nitrate, and iodide in human urine, milk, serum, 

blood spots, amniotic fluid, and infant formula using IC-ES-MSMS has been published (Blount and 

Valentín-Blasini 2007). 

Methods for detecting perchlorate in food using IC-ES-MSMS have been described (El Aribi et al. 2006; 

Krynitsky et al. 2004). According to El Aribi et al. (2006), detection of perchlorate at levels as low as 

5 ng/L in food is possible. An IC-MSMS method was employed by the FDA for its Total Diet Study, 

which achieved a detection limit of 1 ppb and a quantification limit of 3 ppb (Murray et al. 2008). 

Perchlorate has also been measured in plants (Nzengung et al. 1999; Smith et al. 2001; Urbansky et al. 

2000c) and mammals, amphibians, fish, and insects (Dodds et al. 2004; Smith et al. 2001) using IC. 

Narayanan et al. (2003) described a method for measuring perchlorate in biological samples that uses IC 

coupled with conductivity detection. The detection limits determined for perchlorate in the fluids and 

tissues of rats were reported to be 3–6 ng/mL and 0.007–0.7 mg/kg, respectively. Perchlorate exposure 
PERCHLORATES 207 

7. ANALYTICAL METHODS 

was previously assessed by using IC-conductivity to measure perchlorate in urine and serum (Lamm et al. 

1999; Lawrence et al. 2000); however, the analytical methods lacked sensitivity (detection limit 

500 ng/mL). 

7.2 ENVIRONMENTAL SAMPLES 

EPA method 314.0 (EPA 1999c) was developed for the analysis of perchlorate in drinking water samples 

by IC. This method reports a minimum detection limit of 0.53 μg/L and a minimum reporting limit of 

4 μg/L. Separation of anions is accomplished on a Dionex IonPac AS5 ion chromatography column (or 

equivalent) using a 50 mM sodium hydroxide eluent. Sample detection is accomplished using a 

suppressed conductivity detector (Dionex CD20). Large concentrations of other anions, such as chloride, 

sulfate, or carbonate may interfere with the analysis. Perchlorate identification is based on retention time. 

Other variations of the IC method for determining perchlorate in water samples have also been described 

(Ellington and Evans 2000; Jackson et al. 1999, 2000; Liu and Mou 2003; Liu et al. 2002; Okamoto et al. 

1999; Polesello et al. 2001; Tian et al. 2003). According to the Department of Defense Perchlorate 

Handbook, EPA Method 331.0 (Liquid Chromatography Electrospray Ionization Mass Spectrometry), 

and EPA Method 332.0 (Ion Chromatography with Suppressed Conductivity and Electrospray Ionization 

Mass Spectrometry) (EPA 1999c, 2005h, 2005i, 2005j) are the preferred methods for drinking water 

analysis at Department of Defense sites (DOD 2006a). 

Another technique that is used to determine perchlorate in water samples is electrospray ionization mass 

spectrometry, which provides better analytical selectivity compared with conductivity detection 

(Urbansky 2000). This technique has been used to determine perchlorate in a variety of water samples 

(Ells et al. 2000; Koester et al. 2000; Magnuson et al. 2000). The detection limit of this technique is 

approximately 0.030 μg/L if microextraction using an organic solvent was employed before analysis 

(Urbansky 2000). Winkler et al. (2004) describe a method for detecting perchlorate in water and soil by 

ES liquid chromatography/MSMS. The method detection limits were 0.05 μg/L for water and 0.5 μg/kg 

for soil. U.S. Army Corp of Engineers (2004) described a calorimetric method for the field screening of 

water and soil samples. Detection limits were 1 μg/L for water and 0.3 μg/g for soil. 

IC has also been used to analyze fertilizer samples for perchlorate (Collette et al. 2003; De Borba and 

Urbansky 2002; Urbansky and Collette 2001). In addition to IC, Collette et al. (2003) analyzed fertilizer 

for perchlorate using complexation electrospray ionization mass spectrometry, and high field asymmetric 

waveform mass spectrometry in addition to IC. These authors reported that using these techniques in 
PERCHLORATES 208 

7. ANALYTICAL METHODS 

concert offers a more powerful approach since each method depends on a different property of 

perchlorate for detection. 

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 perchlorates 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 perchlorates. 

The following categories of possible data needs have been identified. They are defined as substancespecific 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. Perchlorate levels in human 

urine, milk, blood, or other tissue are biomarkers of exposure. In humans, perchlorate is primarily 

excreted in the urine; however, lactating mothers also excrete perchlorate in milk (Anbar et al. 1959; Kirk 

et al. 2005). IC-conductivity and IC-MS have been used to measure perchlorate in human milk as a 

biomarker of exposure (Kirk et al. 2005). Human exposure to perchlorate has also been assessed by using 

IC-ES-MSMS to measure perchlorate in urine (Valentín-Blasini et al. 2005). A similar analytical 

approach was used to measure perchlorate in amniotic fluid as a biomarker of exposure of the developing 

fetus (Blount et al. 2006). Serum levels of free iodine, T4, T3, and TSH hold potential as biomarkers of 

effect if they can be correlated with environmental exposures. These methods for measuring biomarkers 

of exposure and effect should improve the assessment of human exposure to perchlorate and potential 

health effects. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Surface water, groundwater, and drinking water have been monitored using EPA Method 

314.0. Derivations of this ion chromatography method have been used to determine perchlorate in a 
PERCHLORATES 209 

7. ANALYTICAL METHODS 

variety of different environmental media. Although further work to develop methods that can quantify 

perchlorate in a wider variety of matrices is required, this is currently a highly active area of research. 

These methods involve electrospray ionization mass spectrometry. 

7.3.2 Ongoing Studies 

No ongoing analytical methodology studies were located as a result of a search of Federal Research in 

Progress (FEDRIP 2008). It should be noted that new techniques are continually being applied to the IC 

method to allow a variety of different sample matrices to be analyzed. It should also be noted that 

additional information on the accuracy of other quantitative techniques that can be used to measure 

perchlorate is continually appearing in the scientific literature. Much of this work is being performed by 

both private and Governmental laboratories and, therefore, would not be cited in FEDRIP. Interested 

readers that require the latest information on analytical techniques that can be used to quantify perchlorate 

are urged to consult the scientific literature. 
PERCHLORATES 210 

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PERCHLORATES 211 

8. REGULATIONS AND ADVISORIES 

The international, national, and state regulations and guidelines regarding perchlorate compounds in air, 

water, and other media are summarized in Table 8-1. 

ATSDR has adopted the EPA’s chronic RfD of 0.0007 mg/kg/day recommended by the NAS (2005) for 

the chronic oral MRL for perchlorate. NAS based the RfD derivation on a NOEL of 0.007 mg/kg/day 

corresponding to a nonstatistical significant change in thyroidal uptake of radioactive iodine in volunteers 

exposed to potassium perchlorate in water for 14 days (Greer et al. 2002). As indicated by the NAS 

(2005), iodide uptake inhibition is a key biochemical event that precedes all potential thyroid-mediated 

effects of perchlorate exposure. Using a nonadverse effect that is upstream of adverse effects is a 

conservative approach to perchlorate hazard assessment. An uncertainty factor of 10 was applied to the 

NOEL for the protection of sensitive subpopulations. 

EPA (IRIS 2007) has developed a chronic RfD of 0.0007 mg/kg/day for perchlorate based on the NAS 

(2005) recommendation to use a NOEL of 0.007 mg/kg/day for changes in thyroid hormone and TSH in 

serum, and thyroidal uptake of radioactive iodine in volunteers exposed to potassium perchlorate in water 

for 14 days (Greer et al. 2002) as the basis for an RfD. An uncertainty factor of 10 was applied to the 

NOEL for the protection of sensitive subpopulations. This RfD leads to a drinking water equivalent level 

(DWEL) of 24.5 ppb (EPA 2006c). EPA calculates the DWEL using the RfD, multiplied by an adult 

body weight of 70 kg, and divided by a tap water consumption value of 2 L/day. EPA’s Office of Solid 

Waste and Emergency Response has provided guidance for perchlorate that indicates that the RfD and its 

corresponding DWEL of 24.5 ppb are respectively the recommended “to be considered” (TBC) value and 

the preliminary remediation goal (PRG) for cleanup under the Comprehensive Environmental Response, 

Compensation, andLiability Act of 1980 (CERCLA) (EPA 2006c). 

The federal government has set standards and guidelines to protect people from the possible harmful 

health effects of perchlorate. Specifically, EPA would consider discarded perchlorate to be a solid waste 

and depending on the fact-specific circumstances, EPA believes that discarded perchlorate could be a 

hazardous waste under the Solid Waste Disposal Act (EPA 2006b). That is, because perchlorates are 

oxidizing chemicals, waste discarded chemical formulations of perchlorate and its salts are likely to be 

classified as D001 RCRA hazardous waste under 40 CFR 261.23, which regulates wastes that meet the 

reactivity characteristic. Such a determination is generally based on the nature of the waste at the point of 

generation; however, characteristic hazardous waste, such as D001, ceases to be hazardous waste once it 
PERCHLORATES 212 

8. REGULATIONS AND ADVISORIES 

no longer exhibits the hazardous waste characteristics. In addition, CERCLA 101(14) defines “hazardous 

substances.” According to that section, “the term hazardous substance means. . . . any hazardous waste 

having the characteristics identified under or listed pursuant to Section 3001 of the Solid Waste Disposal 

Act . . . . .” Therefore, depending on the fact-specific circumstances, discarded perchlorate could be 

classified as a D001 hazardous waste and therefore, under certain circumstances, EPA would consider 

perchlorate a CERCLA hazardous substance. 

DOT has designated perchlorate as a hazardous material and limits the quantity that is transported aboard 

aircraft and vessels. DOT also provides identification and protective guidance for an emergency response 

to a transportation incident involving a hazardous material. FDA has restricted potassium perchlorate 

from coming in contact with food containers. 

DOD must comply with any EPA cleanup standards and processes under all applicable environmental 

laws and regulations, including the CERCLA, RCRA, the CWA, and the SDWA. DOD policy requires 

for the testing of perchlorate when it is reasonably expected that a release has occurred. Specifically, 

DOD policy states that in the absence of federal or state standards, if perchlorate levels exceed 24 ppb in 

water, a site-specific risk assessment must be conducted. When an assessment indicates that the 

perchlorate contamination could result in adverse health effects, the site must be prioritized for risk 

management (DOD 2006b). DOD will also comply with applicable state or federal promulgatged 

standards, whichever is more stringent. Additionally, DOD established the Emerging Contaminants 

Directorate in 2006 to help the department proactively approach emerging contaminants to enable a fully 

informed, risk-based investment decision process that protects human health and DOD operational 

capabilities (DOD 2008); perchlorate is one of seven contaminants on DOD’s action list. 
PERCHLORATES 213 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Perchlorates 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification No data IARC 2004 

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 ACGIH 2004 

DOT Hazardous Materials Table Yes DOT 2007 

Ammonium perchlorate, 49CFR172.101 

magnesium perchlorate, 

potassium perchlorate, and 

sodium perchlorate 

NIOSH REL (10-hour TWA) No data NIOSH 2005 

OSHA Threshold quantity for highly OSHA 2005d 

hazardous chemicals for general 29CFR1910.119, 

industry Appendix A 

Ammonium perchlorate 7,500 pounds 

Threshold quantity for highly OSHA 2005c 

hazardous chemicals for construction 29CFR1926.64, 

industry Appendix A 

Ammonium perchlorate 500 pounds 

b. Water 

EPA National primary drinking water EPA 2005a 

regulations; monitoring requirements 40CFR141.40 

for unregulated contaminants (a)(3) 

Perchlorate 

EPA analytical method 314.0 

Minimum reporting level 4.0 μg/La 

Sampling location EPDTSb 

Period during which monitoring 2001–2003 

be completed 

Office of Solid Waste and Emergency 

Response 

Perchlorate Preliminary 24.5 μg/L EPA 2006c 

Remediation Goal (PRG) 

DOD Policy on DOD Required 24 μg/L DOD 2006b 

Actions Related to Perchlorate 
PERCHLORATES 214 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Perchlorates 

Agency Description Information Reference 

NATIONAL (cont.) 

c. Food 

FDA Substances for use as basic com- FDA 2005 

ponent of single and repeated use 21CFR177.1210 

food contact surfaces; closures with (b)(5) 

sealing gaskets for food containers 

Potassium perchlorate Not to exceed 1% 

d. Other 

ACGIH Carcinogenicity classification No data ACGIH 2004 

EPA Carcinogenicity classification Not likely to be IRIS 2007 

carcinogenic 

RfCc Has not been derivedd

 RfDc

 7x10-4 mg/kg/day 

Standards for owners and operators of Generation of toxic EPA 2005b 

hazardous waste TSD facilities; hydrogen cyanide or 40CFR264, 

potentially incompatible waste; the hydrogen sulfide gas Appendix V 

mixing of Group 6-A (perchlorate) with 

Group 6-B may have the potential 

consequence as noted 

NTP Carcinogenicity classification No data NTP 2004 

STATE 

California Presumed hazardous wastes Yes CalEPA 2007 

Ammonium perchlorate, 22 CCR Chapter 11, 

magnesium perchlorate, Appendix X 

potassium perchlorate, and 

sodium perchlorate 

Public health goal for 6 ppb CalEPA 2004 

perchlorate in drinking water 

Massachusetts Maximum contaminant level for 2 ppb MassDEP 2006b 

perchlorate 

Right-to-Know list Yes MassDPH 2006 

Ammonium perchlorate, 105 CMR 670, 

magnesium perchlorate, Appendix A 

potassium perchlorate, and 

sodium perchlorate 
PERCHLORATES 215 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Perchlorates 

Agency Description Information Reference 

STATE (cont.) 

New Jersey List of hazardous substances Yes NJDEP 2007 

Ammonium perchlorate, lithum NJAC 7:13, Appendix 

perchlorate, potassium A 

perchlorate, and sodium 

perchlorate 

Workplace hazardous substance list Yes NJDHSS 2006 

and special health hazard substance NJAC 8:59, 

list Subchapter 9 

Ammonium perchlorate, 

magnesium perchlorate, 

potassium perchlorate, and

sodium perchlorate 

Pennsylvania Hazardous substance list Yes PADLI 2007 

Ammonium perchlorate, Title 34, Chapter 323, 

magnesium perchlorate, Appendix A 

potassium perchlorate, and 

sodium perchlorate 

Rhode Island Hazardous substance list Yes RIDLT 2007 

Ammonium perchlorate, 

magnesium perchlorate, 

potassium perchlorate, and

sodium perchlorate 

a

Minimum reporting level was established at a concentration, which is at least 1/4th the lowest known adverse health

concentration, at which acceptable precision and accuracy has been demonstrated in spiked matrix samples. b

Entry Points to the Distribution System (EPTDS), after treatment, representing each non-emergency water source in

use over the 12-month period of monitoring; this only includes entry points for sources in operation during the months 

in which sampling is to occur. Sampling must occur at the EPTDS, unless the State has specified other sampling 

points that are used for compliance monitoring under 40 CFR 141.24(f)(1), (2), and (3). See 40 CFR 

141.40(a)(5)(ii)(C) for a complete explanation of requirements, including the use of source (raw) water sampling 

points. c

IRIS record for perchlorate and perchlorate salts include ammonium perchlorate, lithium perchlorate, potassium 

perchlorate, and sodium perchlorate. d

An inhalation RfC has not been derived because the available inhalation data are insufficient to characterize doseresponse relationships or portal-of-entry modulation of internal dose. 

ACGIH = American Conference of Governmental Industrial Hygienists; CFR = Code of Federal Regulations; 

CCR = Calironia Code of Regulations; CMR = Code of Massachusetts Regulations; DOT = Department of 

Transportation; EPA = Environmental Protection Agency; EPTDS = Entry Points to the Distribution System; 

IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information System; NIOSH = National 

Institute for Occupational Safety and Health; NJAC = New Jersey Administrative Code; NTP = National Toxicology

Program; OSHA = Occupational Safety and Health Administration; REL = recommended exposure limit; 

RfC = inhalation reference concentration; RfD = oral reference dose; TLV = threshold limit values; TSD = treatment, 

storage, and disposal; TWA = time-weighted average; WHO = World Health Organization
PERCHLORATES 216 

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PERCHLORATES 217 

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PERCHLORATES 251 

10. GLOSSARY 

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. 
PERCHLORATES 252 

10. GLOSSARY 

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. 
PERCHLORATES 253 

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. 
PERCHLORATES 254 

10. GLOSSARY 

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. 
PERCHLORATES 255 

10. GLOSSARY 

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 

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. 
PERCHLORATES 256 

10. GLOSSARY 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

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. 
PERCHLORATES 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 
PERCHLORATES 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. 
PERCHLORATES A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Perchlorates 

CAS Numbers: 10034-81-8, 7778-74-7, 7790-98-9, 7601-89-0 

Date: August 2008 

Profile Status: Post-Public, Final Draft 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 2 

Species: Humans 

Minimal Risk Level: ATSDR adopts the National Academy of Sciences (NAS 2005) recommended 

chronic RfD of 0.0007 mg/kg/day for chronic oral MRL. NAS based the RfD on the findings of a human 

study by Greer et al. (2002) summarized below. 

References: Greer MA, Goodman G, Pleus RC, et al. 2002. Health effects assessment for environmental 

perchlorate contamination: The dose-response for inhibition of thyroidal radioiodine uptake in humans. 

Environ Health Perspect 110(9):927-937. 

NAS. 2005. Health implications of perchlorate ingestion. Washington, DC: National Academies Press. 

http://www.nap.edu/books/0309095689/html/. January 31, 2005. 

Experimental design: The study was conducted in 37 healthy (euthyroid) volunteers (16 males, 

21 females) who consumed potassium perchlorate in drinking water in doses of 0.007, 0.02, 0.1, or 

0.5 mg perchlorate/kg/day for 14 days. In 24 subjects, thyroidal uptake of radioactive iodine (RAIU) was 

measured 8 and 24 hours after administration of radioactive iodine on exposure days 2 and 14 and also 

15 days after exposure. To estimate daily iodine intake, 24-hour urine samples were collected. Free and 

total T4, T3, and TSH were sampled 16 times throughout the study. Serum antibodies to thyroglobulin 

and thyroid peroxidase were also measured. Hematological and clinical chemistry tests were also 

conducted throughout the study. 

Effects noted in study and corresponding doses: Baseline thyroid iodine uptake varied greatly among the 

subjects: 5.6–25.4% for the 8-hour uptake and 9.8–33.7% for the 24-hour uptake. Perchlorate inhibited 

RAIU in a dose-related manner. As a percentage of baseline RAIU, inhibition in the 0.007, 0.02, 0.1, and 

0.5 mg/kg/day dose groups was 1.8, 16.4, 44.7, and 67.1%, respectively. The small decrease in RAIU at 

0.007 mg/kg/day was not statistically significant and is well within the variation of repeated 

measurements in normal subjects. The dose is considered the study NOEL. No significant differences 

were seen between the 8- and 24-hour measurements or between the 2- and 14-day measurements. On 

post-exposure day 15, RAIU rebounded to values slightly over but not significantly greater than 100%. 

Consumption of perchlorate in drinking water did not significantly alter serum TSH, free T4 or total 

T4 and T3 levels. Serum antiglobulin levels were below detection levels in all samples tested. Serum 

anti-thyroid peroxidases were elevated in two subjects at the screening visit and thus, were not related to 

treatment with perchlorate. Hematology and clinical chemistry tests to assess liver and kidney function 

revealed no significant deviations from normal ranges. No difference was observed between the response 

of male and female subjects. 

Based on the known mechanism of action of perchlorate as a competitive inhibitor of NIS and on the 

elimination half-time of perchlorate of approximately 8 hours (perchlorate is not expected to accumulate 

in the body), the NAS concluded that a dose that produced minimal inhibition of thyroid iodide uptake 

after 14 days of continuous exposure would also have no appreciable effects on thyroid iodide uptake 

with more prolonged (i.e., intermediate or chronic) exposure. On this basis, the 14-day study was used as 
PERCHLORATES A-4 

APPENDIX A 

the basis for adopting the RfD for the chronic MRL. This is supported by another 14-day study 

(Lawrence et al. 2000), long-term studies of workers (Braverman et al. 2005; Gibbs et al. 1998; Lamm et 

al. 1999), and studies of the general population (Li et al. 2001; Téllez et al. 2005) exposed to perchlorate 

that found no significant alterations in thyroid function in the populations examined. A study by 

Braverman et al. (2006) in which 13 volunteers dosed with perchlorate in capsules for 6 months at doses 

of 0, 0.5, and 3 mg/day exhibited no changes in iodine uptake or thyroid hormone level, was considered 

for derivation of the MRL. 

An uncertainty factor of 10 was applied to the NOEL of 0.007 mg/kg/day. The uncertainty factor of 10 is 

intended to protect the most sensitive population—the fetuses of pregnant women who might have 

hypothyroidism or iodide deficiency. Other sensitive populations include preterm infants and nursing 

infants. As discussed by NAS (2005), preterm infants are more sensitive than term infants. The fetus is 

dependent on maternal thyroid hormones at least until the fetal thyroid begins to produce T4 and 

T3 (Zoeller and Crofton 2000). In humans, this occurs at approximately 16–20 weeks of gestation. 

Thyroid hormones are present in human amniotic fluid at 8 weeks of gestation prior to the onset of fetal 

thyroid hormone production (Contempre et al. 1993; Thorpe-Beeston et al. 1991). Thyroid hormone 

receptors are present and occupied by hormone at this time as well, suggesting that the fetus is capable of 

responding to maternal thyroid hormones (Bernal and Pekonen 1984; Ferreiro et al. 1988). The 

contribution of maternal thyroid hormones to the fetal thyroid hormone status is also evident from infants 

who have an inherited disorder that abolishes T4 production but are born, nevertheless, with normal 

serum thyroid hormone levels (i.e., euthyroid) and become hypothyroid after birth if not administered 

thyroid hormones within the first 2 weeks after birth (Larsen 1989; van Vliet et al. 1999; Vulsma et al. 

1989). This suggests that, in the complete absence of fetal thyroid function, the maternal thyroid is able 

to maintain at least partially protective levels of thyroid hormone in the fetus at late term. Uncorrected 

maternal hypothyroidism, on the other hand, may result in impaired neurodevelopment of the fetus 

(Haddow et al. 1999; Pop et al. 1999; Soldin et al. 2001). By inhibiting NIS in breast tissue (Levy et al. 

1997; Smanik et al. 1997; Spitzweg et al. 1998), perchlorate may also limit the availability of iodide to 

nursing infants, who depend entirely on breast milk for the iodide needed to produce thyroid hormone 

(Agency for Toxic Substances and Disease Registry 2002). No information is available on the doses in 

humans that might decrease iodide uptake into breast milk. It is important to note that a recent study of 

51 women in the Boston area found that 47% of the women sampled may have been providing breast milk 

with insufficient iodine to meet the infants’ requirements (Pearce et al. 2007). Radioiodine uptake into 

mammary milk was decreased in rats exposed to 1 or 10 mg/kg/day perchlorate in drinking water (Yu et 

al. 2002). Studies conducted in cows and goats have also shown that perchlorate can decrease radioiodine 

uptake into mammary milk (Howard et al. 1996). As discussed by Ginsberg et al. (2007), additional 

factors that make neonates a sensitive group include their shorter serum half-life for T4 of approximately 

3 days compared to approximately 7–10 days in adults, a lower storage capacity of the thyroid for T4, and 

possibly slower urinary clearance of perchlorate due to immature renal function. In addition, PBPK 

models predict that pregnant women and the fetus will have higher blood concentrations of perchlorate 

and greater iodide uptake inhibition at a given concentration of perchlorate in drinking water than either 

nonpregnant adults or older children (Clewell et al. 2007). 

Another potential susceptible population is women with urinary iodine levels <100 μg/L (Blount et al. 

2006), as regression analysis indicted that perchlorate exposure was correlated with decreased T4 and 

increased TSH. According to the World health Organization (WHO 2004), median urinary iodine levels 

≥100 μg/L indicate sufficient iodine intake for the non-pregnant population, whereas pregnant women 

should maintain urinary levels of iodine >150 μg/L. The American Thyroid Association (2006) 

recommends that women generally consume iodine from diary products, bread, seafood, meat, and some 

iodized salt, but pregnant and lactating women may require additional supplements and vitamins. 
PERCHLORATES A-5 

APPENDIX A 

Dose and end point used for MRL derivation: 0.007 mg/kg/day (NOEL for inhibition of iodide uptake 

into the thyroid). As indicated by the NAS (2005), iodide uptake inhibition is a key biochemical event 

that precedes all potential thyroid-mediated effects of perchlorate exposure. Using a nonadverse effect 

that is upstream of adverse effects is a conservative approach to perchlorate hazard assessment. 

Uncertainty Factors used in MRL derivation: 10 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to NAS’s RfD: Lawrence et al. (2000) 

evaluated serum TSH, free thyroxine index (FTI), total serum triiodothyronine (TT3), and RAIU; serum 

and 24-hour urine perchlorate; and 24-hour urinary iodide excretion in volunteers who ingested 

approximately 0.14 mg perchlorate/kg/day in drinking water for 14 days. Tests were conducted predosing, on day 7 and 14, and 14 days after perchlorate ingestion was discontinued. The only significant 

finding was a significant decrease in 4-, 8-, and 24-hour RAIU values by a mean of about 38% relative to 

baseline on day 14 of dosing. Fourteen days later, RAIU had recovered to a mean of 25% above baseline 

values. In another study, Braverman et al. (2006) administered capsules containing potassium perchlorate 

to 13 volunteers (4 males, 9 females) for 6 months. The estimated doses were 0 (placebo), 0.5 and 3.0 mg 

perchlorate/day (approximately 0.04 and 0.007 mg perchlorate/kg/day). The outcomes measured were 

serum thyroid function tests, 24-hour RAIU, serum thyroglobulin (Tg), urinary iodine and perchlorate, 

and serum perchlorate. RAIU, measured at baseline, 3, 6 months and 1 month after termination, was not 

significantly affected by administration of perchlorate and there were no significant changes in serum 

total T3, FTI, TSH, or Tg levels during or after perchlorate exposure compared to baseline values. The 

small number of subjects per group (4–5), the dosing by capsule rather than intermittent exposure in 

drinking water, and the lack of information on RAIU during the first 3 months of the study somewhat 

diminish the strengths of this study. 

Relatively large doses of perchlorate (600–900 mg/day, 8–13 mg/kg/day) are required to deplete thyroidal 

iodine stores sufficiently to decrease serum levels of T4 (Brabant et al. 1992; Bürgi et al. 1974). A 

4-week oral exposure to 900 mg/day (approximately 13 mg/kg/day) significantly decreased serum levels 

of FT4 (not out of the normal range), but not FT3 and did not significantly change serum TSH levels 

(Brabant et al. 1992). 

A study conducted in an ammonium perchlorate manufacturing facility found that intermittent, high 

exposure to perchlorate for many years did not induce goiter or any evidence of hypothyroidism among 

the workers, as judged by no significant alterations in serum TSH or thyroglobulin even though iodine 

uptakes were decreased during the work shift (Braverman et al. 2005). The median estimated absorbed 

dose was 0.167 mg/kg/day, equivalent to drinking approximately 2 L of water containing 5 mg 

perchlorate/L. 

Agency Contact (Chemical Manager): Sharon Wilbur 
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PERCHLORATES 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. 
PERCHLORATES 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 judgment, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgment 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. 
PERCHLORATES 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"). 
PERCHLORATES 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. 
PERCHLORATES 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. 
SAMPLE 

1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

Exposure LOAEL (effect) 

Key to frequency/ NOAEL Less serious Serious (ppm)

figurea Species duration System (ppm) (ppm) Re

234 

→ 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 W

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 

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). 

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PERCHLORATES 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 benchmark dose 

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 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/Intergovernmental Maritime Dangerous Goods Code 
PERCHLORATES C-2 

APPENDIX C 

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 

FT4 free T4 

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 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 
PERCHLORATES C-3 

APPENDIX C 

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 

NIS Sodium/iodide symporter 

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 

OW Office of Water 
PERCHLORATES C-4 

APPENDIX C 

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 

RAIU radioactive iodine uptake 

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 

T3 triiodothyronine 

T4 thyronine 

TT4 total T4 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRH thyrotropin-releasing hormone 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TSH thyroid-releasing hormone 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 
PERCHLORATES C-5 

APPENDIX C 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 

> greater than ≥ greater than or equal to 

= equal to 

< less than ≤ less than or equal to 

% percent α alpha β beta γ gamma δ delta μm micrometer μg microgram q1

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 
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PERCHLORATES D-1 

APPENDIX D. INDEX 

absorbed dose............................................................................................................ 19, 29, 32, 83, 123, 185 

active transport.................................................................................................................. 81, 83, 84, 94, 102 

adrenal gland....................................................................................................................................... 18, 103 

adsorbed .................................................................................................................... 166, 168, 169, 170, 192 

adsorption.................................................................................................................................. 154, 166, 192 

aerobic............................................................................................................................... 154, 163, 170, 192 

anaerobic..................................................................................................... 16, 154, 159, 169, 171, 192, 195 

anemia............................................................................................................................................. 33, 54, 58 

aspartate aminotransferase (see AST).........................................................................................................56 

AST (see aspartate aminotransferase).........................................................................................................56 

bioaccumulation.................................................................................................................................. 15, 193 

bioavailability ...........................................................................................................................................192 

bioconcentration factor ..................................................................................................................... 167, 192 

biodegradation..................................................................................................... 16, 154, 163, 170, 171, 192

biokinetics................................................................................................................................... 90, 114, 122 

biomarker .................................................................................................. 122, 123, 124, 125, 137, 197, 200 

body weight effects .....................................................................................................................................63 

breast milk..................................................... 9, 24, 83, 86, 98, 107, 113, 122, 124, 128, 137, 186, 187, 198 

cancer .......................................................................................................... 8, 18, 79, 80, 109, 120, 130, 133 

carcinogenic .............................................................................................................................. 8, 21, 27, 206 

carcinogenicity..........................................................................................................................................133 

carcinoma........................................................................................................................ 18, 79, 80, 109, 133 

cardiovascular ......................................................................................................................... 18, 28, 53, 103 

cardiovascular effects..................................................................................................................................53 

clearance ................................................................................................................... 20, 24, 90, 97, 115, 128 

cognitive function .....................................................................................................................................137 

death................................................................................................................................................ 27, 28, 54 

deoxyribonucleic acid (see DNA)...............................................................................................................81 

dermal effects..............................................................................................................................................63 

developmental effects ............................... 33, 58, 68, 69, 74, 75, 78, 80, 111, 115, 121, 130, 133, 136, 139 

DNA (see deoxyribonucleic acid)....................................................................................... 81, 105, 123, 134 

elimination half-time......................................................................................... 23, 84, 86, 87, 103, 138, 139

endocrine................................................................................................................. 18, 33, 63, 103, 118, 119 

endocrine effects ................................................................................................. 32, 33, 57, 63, 78, 114, 119

erythema......................................................................................................................................................63 

fetal tissue ................................................................................................................................... 21, 111, 112 

fetus....................................... 19, 21, 24, 25, 97, 99, 102, 111, 112, 118, 119, 121, 122, 128, 138, 139, 200 

gastrointestinal effects ................................................................................................................................53 

general population.............................................................. 7, 16, 17, 19, 23, 25, 58, 59, 122, 130, 136, 138, 

160, 183, 184, 185, 186, 188, 190, 191, 192 

genotoxic................................................................................................................................. 18, 27, 80, 109 

genotoxicity...............................................................................................................................................134 

groundwater ................................................................. 3, 4, 15, 57, 154, 159, 160, 164, 166, 167, 169, 172, 

173, 174, 175, 176, 184, 192, 193, 195, 200 

half-life................................................................................ 20, 24, 33, 86, 87, 108, 115, 123, 124, 128, 129 

hematological effects .......................................................................................................... 29, 32, 54, 58, 63

hepatic effects ....................................................................................................................................... 32, 55 

hydrolysis..................................................................................................................................................171 
PERCHLORATES D-2 

APPENDIX D 

hydroxyl radical ........................................................................................................................................170 

immune system ............................................................................................................................. 66, 67, 142 

immunological .............................................................................................................................. 27, 66, 130 

Kow ............................................................................................................................................................144 

LD50....................................................................................................................................................... 33, 53 

lymphoreticular.........................................................................................................................................135 

melanoma.............................................................................................................................................. 66, 79 

metabolic effects .........................................................................................................................................64 

milk ................................................................ 5, 9, 10, 20, 24, 74, 77, 78, 83, 84, 86, 90, 95, 96, 97, 98, 99, 

102, 113, 121, 122, 124, 177, 182, 186, 187, 193, 198, 200 

musculoskeletal effects ...............................................................................................................................55 

neonatal....................................................................... 69, 70, 71, 72, 73, 78, 94, 98, 99, 112, 113, 135, 140 

neoplasm .....................................................................................................................................................58 

neurobehavioral............................................................................................. 18, 76, 119, 121, 133, 135, 139 

neurodevelopmental.......................................................................................... 18, 19, 74, 77, 135, 136, 137

neurological effects................................................................................................................. 33, 67, 80, 136 

ocular effects......................................................................................................................................... 28, 63 

odds ratio.....................................................................................................................................................69 

pharmacodynamic .......................................................................................................................................87 

pharmacokinetic.......................................................................................... 87, 88, 89, 92, 93, 120, 140, 186 

photolysis .......................................................................................................................... 162, 168, 170, 192 

placenta ............................................................................................. 9, 75, 84, 90, 95, 96, 97, 113, 121, 152 

placental barrier ........................................................................................................................................102 

renal effects............................................................................................................................. 17, 32, 56, 136 

reproductive effects............................................................................................... 18, 33, 68, 69, 74, 80, 134 

respiratory effects........................................................................................................................................53 

retention ....................................................................................................................................................199 

sequestered................................................................................................................................................125 

solubility ............................................................................................................................. 82, 166, 168, 191 

systemic effects........................................................................................................... 28, 29, 53, 65, 80, 130 

T3..................................................................... 16, 17, 18, 20, 21, 23, 24, 30, 32, 34, 57, 60, 61, 62, 72, 73,

74, 75, 76, 78, 94, 103, 104, 105, 106, 107, 108, 109, 

110, 111, 112, 115, 119, 125, 126, 128, 129, 137, 200 

T4............................................................... 16, 17, 18, 19, 20, 23, 24, 32, 57, 59, 60, 61, 62, 70, 71, 72, 73, 

74, 75, 76, 78, 94, 104, 105, 106, 107, 108, 109, 110, 111, 

112, 114, 115, 119, 121, 124, 125, 126, 128, 129, 137, 200 

thrombocytopenia .......................................................................................................................................54 

thyroid...........3, 6, 8, 9, 10, 16, 17, 18, 19, 20, 23, 24, 25, 32, 57, 58, 59, 60, 61, 62, 63, 66, 69, 72, 74, 75, 

76, 78, 79, 80, 81, 83, 84, 85, 90, 91, 94, 95, 96, 97, 98, 99, 102, 103, 104, 105, 

106, 107, 108, 109, 110, 111, 112, 113, 114, 118, 119, 120, 121, 122, 124, 125, 

126, 127, 128, 129, 132, 133, 134, 135, 136, 137, 138, 139, 140, 152, 198, 203 

thyroid stimulating hormone............................................................................................... 17, 104, 106, 110 

thyroxine ................................................................................................................................. 16, 32, 57, 110 

toxicokinetic........................................................................................................................................ 27, 139 

triiodothyronine............................................................................................................................. 16, 57, 104 

TSH...................................................... 17, 18, 19, 20, 23, 24, 32, 57, 59, 60, 61, 62, 69, 70, 71, 72, 73, 74, 

75, 76, 78, 90, 97, 102, 104, 105, 106, 108, 109, 110, 111, 112, 

113, 114, 115, 119, 121, 125, 126, 128, 132, 135, 137, 200, 203 

tumors ............................................................................................................... 8, 79, 80, 106, 109, 111, 114

vapor pressure ............................................................................................................................. 81, 161, 166 

volatilization ..................................................................................................................................... 161, 166