TOXICOLOGICAL PROFILE FOR 

FLUORIDES, HYDROGEN FLUORIDE, 

AND FLUORINE 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry
 

September 2003 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 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. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE iii 

UPDATE STATEMENT 

A Toxicological Profile for Hydrogen Fluoride, and Fluorine, Draft for Public Comment was released in 

September 2001. This edition supersedes any previously released draft or final profile. 

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

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology/Toxicology Information Branch 

1600 Clifton Road NE, 

Mailstop E-29 

Atlanta, Georgia 30333 



 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 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: 1-888-42-ATSDR or (404) 498-0110 Fax: (404) 498-0093 

E-mail: atsdric@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. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 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, 55 West Seegers Road, Arlington Heights, IL 

60005 • Phone: 847-818-1800 • FAX: 847-818-9266. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Carolyn A. Tylenda, D.M.D., Ph.D. 

ATSDR, Division of Toxicology, Atlanta, GA 

Dennis Jones, D.V.M. 

ATSDR, Division of Toxicology, Atlanta, GA 

Lisa Ingerman, Ph.D. 

Gloria Sage, Ph.D. 

Lara Chappell, 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 Research Implementation Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE xi 

PEER REVIEW 

A peer review panel was assembled for fluorides, hydrogen fluoride, and fluorine. The panel consisted of 

the following members: 

1. Jan Ekstrand, Professor & Vice Dean, Board of Research and Postgraduate Education, Nobels 

väg 5, Karolinska Institutet, Stockholm, Sweden; 

2.	 Julie Glowacki, Ph.D., Department of Orthopedic Surgery, Brigham and Women's Hospital, 

Harvard Medical School, Boston, MA; 

3.	 Michael Kleerekoper, M.B., B.S., F.A.C.P., F.A.C.E., Departments of Internal Medicine, 

Obstetrics & Gynecology, and Pathology Wayne State University School of Medicine, Detroit, 

MI; 

4.	 Gary Whitford, Ph.D., D.M.D., School of Dentistry, Medical College of Georgia, Augusta, GA. 

These experts collectively have knowledge of fluorides, hydrogen fluoride, and fluorine's 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. A list of databases reviewed and 

a list of unpublished documents cited are also included in the administrative record. 

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

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

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 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 FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE? ...........................1 

1.2 WHAT HAPPENS TO FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 

WHEN THEY ENTER THE ENVIRONMENT?.......................................................................3 

1.3 HOW MIGHT I BE EXPOSED TO FLUORIDES, HYDROGEN FLUORIDE, AND 

FLUORINE?................................................................................................................................4 

1.4 HOW CAN FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE ENTER AND 

 LEAVE MY BODY? ..................................................................................................................6 

1.5 HOW CAN FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE AFFECT MY 

HEALTH? ...................................................................................................................................7 

1.6 HOW CAN FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE AFFECT 

 CHILDREN? ...............................................................................................................................9 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO FLUORIDES, 

 HYDROGEN FLUORIDE, AND FLUORINE?.......................................................................10 

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

EXPOSED TO FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE?......................11 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?...............................................................................................12 

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

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

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO FLUORIDES, 

HYDROGEN FLUORIDE, AND FLUORINE IN THE UNITED STATES ...........................15 

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

2.3 MINIMAL RISK LEVELS .......................................................................................................22 

3. HEALTH EFFECTS..............................................................................................................................29 

3.1 INTRODUCTION.....................................................................................................................29 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ..................................31 

3.2.1 Inhalation Exposure ..............................................................................................................32 

3.2.1.1 Death.................................................................................................................................33 

3.2.1.2 Systemic Effects ...............................................................................................................36 

3.2.1.3 Immunological and Lymphoreticular Effects...................................................................69 

3.2.1.4 Neurological Effects .........................................................................................................70 

3.2.1.5 Reproductive Effects.........................................................................................................70 

3.2.1.6 Developmental Effects......................................................................................................71 

3.2.1.7 Cancer...............................................................................................................................71 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE	 xiv 

3.2.2 Oral Exposure........................................................................................................................72 

3.2.2.1 Death.................................................................................................................................74 

3.2.2.2 Systemic Effects ...............................................................................................................75 

3.2.2.3 Immunological and Lymphoreticular Effects.................................................................110 

3.2.2.4 Neurological Effects.......................................................................................................110 

3.2.2.5 Reproductive Effects.......................................................................................................111 

3.2.2.6 Developmental Effects....................................................................................................114 

3.2.2.7 Cancer.............................................................................................................................117 

3.2.3 Dermal Exposure.................................................................................................................125 

3.2.3.1 Death...............................................................................................................................126 

3.2.3.2 Systemic Effects .............................................................................................................127 

3.2.3.3 Immunological and Lymphoreticular Effects.................................................................132 

3.2.3.4 Neurological Effects.......................................................................................................132 

3.2.3.5 Reproductive Effects.......................................................................................................132 

3.2.3.6 Developmental Effects....................................................................................................132 

3.2.3.7 Cancer.............................................................................................................................132 

3.3 GENOTOXICITY ...................................................................................................................132 

3.4 TOXICOKINETICS................................................................................................................136 

3.4.1 Absorption...........................................................................................................................136 

3.4.1.1 Inhalation Exposure ........................................................................................................136 

3.4.1.2 Oral Exposure .................................................................................................................138 

3.4.1.3 Dermal Exposure ............................................................................................................139 

3.4.2 Distribution .........................................................................................................................140 

3.4.2.1 Inhalation Exposure ........................................................................................................140 

3.4.2.2 Oral Exposure .................................................................................................................141 

3.4.2.3 Dermal Exposure ............................................................................................................144 

3.4.2.4 Other Routes of Exposure............................................................................................... 144 

3.4.3 Metabolism..........................................................................................................................145 

3.4.4 Elimination and Excretion...................................................................................................145 

3.4.4.1 Inhalation Exposure ........................................................................................................145 

3.4.4.2 Oral Exposure .................................................................................................................146 

3.4.4.3 Dermal Exposure ............................................................................................................147 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ...........147 

3.5 MECHANISMS OF ACTION ................................................................................................151 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................153 

3.7 CHILDREN’S SUSCEPTIBILITY.........................................................................................154 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT ..................................................................157 

3.8.1	 Biomarkers Used to Identify or Quantify Exposure to Fluorides, Hydrogen Fluoride, 

 and Fluorine ........................................................................................................................158 

3.8.2	 Biomarkers Used to Characterize Effects Caused by Fluorides, Hydrogen Fluoride, 

 and Fluorine ........................................................................................................................160 

3.9 INTERACTIONS WITH OTHER CHEMICALS ..................................................................162 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE............................................162 

3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................164 

3.11.1 Reducing Peak Absorption Following Exposure ................................................................165 

3.11.2 Reducing Body Burden .......................................................................................................166 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects..............................................167 

3.12 ADEQUACY OF THE DATABASE.....................................................................................168 

3.12.1	 Existing Information on Health Effects of Fluorides, Hydrogen Fluoride, and 

Fluorine ...............................................................................................................................169 

3.12.2 Identification of Data Needs ...............................................................................................173 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE xv 

3.12.3 Ongoing Studies ..................................................................................................................185 

4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................187 

4.1 CHEMICAL IDENTITY......................................................................................................... 187 

4.2 PHYSICAL AND CHEMICAL PROPERTIES......................................................................187 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................193 

5.1 PRODUCTION .......................................................................................................................193 

5.2 IMPORT/EXPORT .................................................................................................................194 

5.3 USE..........................................................................................................................................199 

5.4 DISPOSAL..............................................................................................................................200 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................203 

6.1 OVERVIEW............................................................................................................................203 

6.2 RELEASES TO THE ENVIRONMENT................................................................................206 

6.2.1 Air .......................................................................................................................................209 

6.2.2 Water...................................................................................................................................213 

6.2.3 Soil ......................................................................................................................................214 

6.3 ENVIRONMENTAL FATE....................................................................................................215 

6.3.1 Transport and Partitioning...................................................................................................215 

6.3.2 Transformation and Degradation ........................................................................................216
 

6.3.2.1 Air...................................................................................................................................216 

6.3.2.2 Water...............................................................................................................................217 

6.3.2.3 Sediment and Soil ...........................................................................................................218 

6.3.2.4 Other Media ....................................................................................................................218 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT...............................218 

6.4.1 Air .......................................................................................................................................218 

6.4.2 Water...................................................................................................................................219 

6.4.3 Sediment and Soil ...............................................................................................................222 

6.4.4 Other Environmental Media................................................................................................223 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .....................................225 

6.6 EXPOSURES OF CHILDREN...............................................................................................230 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...........................................234 

6.8 ADEQUACY OF THE DATABASE......................................................................................237 

6.8.1 Identification of Data Needs ...............................................................................................237 

6.8.2 Ongoing Studies ..................................................................................................................241 

7. ANALYTICAL METHODS ...............................................................................................................243 

7.1 BIOLOGICAL MATERIALS.................................................................................................243 

7.2 ENVIRONMENTAL SAMPLES............................................................................................246 

7.3 ADEQUACY OF THE DATABASE......................................................................................251 

7.3.1 Identification of Data Needs ...............................................................................................252 

7.3.2 Ongoing Studies ..................................................................................................................253 

8. REGULATIONS AND ADVISORIES ...............................................................................................255 

9. REFERENCES ....................................................................................................................................265 

10. GLOSSARY ......................................................................................................................................351 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE xvi 

APPENDICES 

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

B. USER'S GUIDE ..................................................................................................................................B-1 

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

D. FLUORIDE AND DENTAL CARIES ...............................................................................................D-1 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE xvii 

LIST OF FIGURES 

3-1. Levels of Significant Exposure to Hydrogen Fluoride – Inhalation................................................... 41 

3-2. Levels of Significant Exposure to Fluorine – Inhalation.................................................................... 50 

3-3. Levels of Significant Exposure to Fluoride – Inhalation.................................................................... 54 

3-4. Levels of Significant Exposure to Fluoride – Oral............................................................................. 87 

3-5. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance ....................................................................................................150
 

3-6. Existing Information on Health Effects of Fluoride .........................................................................170
 

3-7. Existing Information on Health Effects of Hydrogen Fluoride/Hydrofluoric Acid..........................171
 

3-8. Existing Information on Health Effects of Fluorine .........................................................................172
 

6-1. Frequency of NPL Sites with Fluoride, Hydrogen Fluoride, and Fluorine Contamination..............204
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE xix 

LIST OF TABLES 

2-1. Adequate Intake Levels for Fluoride .................................................................................................. 16 

3-1. Levels of Significant Exposure to Hydrogen Fluoride – Inhalation................................................... 37 

3-2. Levels of Significant Exposure to Fluorine – Inhalation.................................................................... 43 

3-3. Levels of Significant Exposure to Fluoride – Inhalation.................................................................... 53 

3-4. Levels of Significant Exposure to Fluoride – Oral............................................................................. 76 

3-5. Levels of Significant Exposure to Hydrogen Fluoride – Dermal ..................................................... 128 

3-6. Levels of Significant Exposure to Fluoride – Dermal ...................................................................... 129 

3-7. Genotoxicity of Fluoride In Vitro .....................................................................................................133 

3-8. Genotoxicity of Fluoride In Vivo......................................................................................................135 

3-9. Ongoing Studies on the Health Effects of Fluoride, Hydrogen Fluoride, or Fluorine......................186 

4-1. Chemical Identity of Fluorine, Hydrogen Fluoride, Sodium Fluoride, Fluosilicic Acid, 

 and Sodium Silicofluoride ................................................................................................................188 

4-2. Physical and Chemical Properties of Fluorine, Hydrogen Fluoride, Sodium Fluoride, 

Fluosilicic Acid, and Sodium Silicofluoride.....................................................................................190 

5-1. U.S. Manufacturers of Hydrogen Fluoride, Fluorine, Sodium Fluoride, Fluosilicic Acid, 

 and Sodium Silicofluoride ................................................................................................................195 

5-2. Facilities that Produce, Process, or Use Hydrogen Fluoride ............................................................196
 

5-3. Facilities that Produce, Process, or Use Fluorine .............................................................................198 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Hydrogen 

Fluoride.............................................................................................................................................207 

6-2. Releases to the Environment from Facilities that Produce, Process, or Use Fluorine......................210 

6-3. Mean Daily Dietary Intake of Fluoride for Selected Canadian Population Groups.........................227 

6-4. Comparison of Fluoride Levels (μg/g) in Cow Milk and Infant Formulas.......................................232 

6-5. Levels of Fluoride in Human Tissue and Urine—Selected Studies .................................................235 

7-1. Analytical Methods for Determining Fluoride in Biological Materials............................................245 

7-2. Analytical Methods for Determining Fluoride in Environmental Samples......................................247 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE xx 

7-3. Analytical Methods for Determining Hydrogen Fluoride in Environmental Samples.....................249 

8-1. Regulations and Guidelines Applicable to Fluoride, Sodium Fluoride, Hydrogen Fluoride, 

 and Fluorine ......................................................................................................................................256 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about fluorides, hydrogen fluoride, and fluorine and the 

effects of exposure presented in the toxicological profile. These profiles were specifically 

prepared by ATSDR for hazardous substances which are most commonly found at facilities on 

the CERCLA National Priorities List (Superfund sites) and are intended to describe the effects of 

exposure from chemicals at these sites. 

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

the nation. These sites make up the National Priorities List (NPL) and are the sites targeted for 

long-term federal cleanup activities. Fluorides, hydrogen fluoride, and fluorine have been found 

in at least 188 of the 1,636 current or former NPL sites. However, the total number of NPL sites 

evaluated for these substances is not known. As more sites are evaluated, the sites at which 

fluorides, hydrogen fluoride, and fluorine is found may increase. This information is important 

because exposure to these substances may harm you and because these sites may be sources of 

exposure. 

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

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

exposure. You are 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 fluorides, hydrogen fluoride, and fluorine, many factors determine whether 

you'll be harmed. These factors include the dose (how much), the duration (how long), and how 

you come in contact with it/them. You must also consider the other chemicals you're exposed to 

and your age, sex, diet, family traits, lifestyle, and state of health. 

1.1 WHAT ARE FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE? 

Fluorides are properly defined as binary compounds or salts of fluorine and another element. 

Examples of fluorides include sodium fluoride and calcium fluoride. Both are white solids. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 2 

1. PUBLIC HEALTH STATEMENT 

Sodium fluoride readily dissolves in water, but calcium fluoride does not. Sodium fluoride is 

often added to drinking water supplies and to a variety of dental products, including toothpastes 

and mouth rinses to prevent dental cavities. Other fluoride compounds that are commonly used 

for water fluoridation are fluorosilicic acid and sodium fluorosilicate. Calcium fluoride is the 

compound in the common minerals fluorite and fluorspar. Fluorspar is the mineral from which 

hydrogen fluoride is produced. It is also used in the production of glass and enamel and in the 

steel industry. In this profile, we will often use the term “fluoride” to include substances that 

contain the element fluorine. The reason for this is that we generally measure the amount of 

fluorine in a substance rather than the amount of a particular fluorine compound. 

Fluorine is a naturally occurring, widely distributed element and a member of the halogen 

family, which includes chlorine, bromine, and iodine. However, the elemental form of fluorine, 

a pale yellow-green, irritating gas with a sharp odor, is so chemically reactive that it rarely 

occurs naturally in the elemental state. Fluorine occurs in ionic forms, or combined with other 

chemicals in minerals like fluorspar, fluorapatite, and cryolite, and other compounds. (Ions are 

atoms, collections of atoms, or molecules containing a positive or negative electric charge.) 

Fluorine gas reacts with most organic and inorganic substances; with metals, it forms fluorides 

and with water, it forms hydrofluoric acid. Fluorine gas is primarily used to make certain 

chemical compounds, the most important of which is uranium hexafluoride, used in separating 

isotopes of uranium for use in nuclear reactors and nuclear weapons. 

Hydrogen fluoride is a colorless, corrosive gas or liquid (it boils at 19.5 °C) that is made up of a 

hydrogen atom and a fluorine atom. It fumes strongly, readily dissolves in water, and both the 

liquid and vapor will cause severe burns upon contact. The dissolved form is called hydrofluoric 

acid. It is known for its ability to etch glass. Commercially, hydrogen fluoride is the most 

important fluorine compound. Its largest use is in the manufacture of fluorocarbons, which are 

used as refrigerants, solvents, and aerosols. 

For more information on the chemical properties of fluorides, hydrogen fluoride, and fluorine, 

and their production and use, see Chapters 4 and 5. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 3 

1. PUBLIC HEALTH STATEMENT 

1.2 WHAT HAPPENS TO FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 

WHEN THEY ENTER THE ENVIRONMENT? 

Fluorides occur naturally in the earth’s crust where they are found in rocks, coal, clay, and soil. 

They are released into the air in wind-blown soil. Hydrogen fluoride is released to the air from 

fluoride-containing substances, including coal, minerals, and clays, when they are heated to high 

temperatures. This may occur in coal-fired power plants; aluminum smelters; phosphate 

fertilizer plants; glass, brick, and tile works; and plastics factories. These facilities may also 

release fluorides attached to particles. The biggest natural source of hydrogen fluoride and other 

fluorides released to the air is volcanic eruptions. 

Fluorine cannot be destroyed in the environment; it can only change its form. Fluorides released 

into the atmosphere from volcanoes, power plants, and other high temperature processes are 

usually hydrogen fluoride gas or attached to very small particles. Fluorides contained in windblown soil are generally found in larger particles. These particles settle to the ground or are 

washed out of the air by rain. Fluorides that are attached to very small particles may stay in the 

air for many days. Hydrogen fluoride gas will be absorbed by rain and into clouds and fog to 

form aqueous hydrofluoric acid, which will fall to the ground mainly in precipitation. The 

fluorides released into air will eventually fall on land or water. 

In water, fluorides associate with various elements present in the water, mainly with aluminum in 

freshwater and calcium and magnesium in seawater, and settle into the sediment where they are 

strongly attached to sediment particles. When deposited on land, fluorides are strongly retained 

by soil, forming strong associations with soil components. Leaching removes only a small 

amount of fluorides from soils. Fluorides may be taken up from soil and accumulate in plants, or 

they may be deposited on the upper parts of the plants in dust. The amount of fluoride taken up 

by plants depends on the type of plant, the nature of the soil, and the amount and form of fluoride 

in the soil. Tea plants are known to accumulate fluoride in their leaves. Animals that eat 

fluoride-containing plants may accumulate fluoride. However, the fluoride accumulates 

primarily in the bones or shell rather than in edible meat. 

For more information about what happens to fluorides in the environment, see Chapter 6. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 4 

1. PUBLIC HEALTH STATEMENT 

1.3 HOW MIGHT I BE EXPOSED TO FLUORIDES, HYDROGEN FLUORIDE, AND 

FLUORINE? 

Fluoride is a natural component of the earth’s crust and soil. Small amounts of fluorides are 

present in water, air, plants, and animals. You may be exposed to small amounts of fluoride by 

breathing air, drinking water, and eating food. In particular, fluorides are frequently added to 

drinking water supplies at approximately 1 part of fluoride per million parts of water (ppm) and 

to toothpaste and mouth rinses to prevent dental decay. Analytical methods used by scientists to 

determine the levels of fluoride in the environment generally do not determine the specific form 

of fluoride present. Therefore, we do not always know the form of fluoride that a person may be 

exposed to. Similarly, we do not know what forms of fluoride are present at hazardous waste 

sites. Some forms of fluoride may be insoluble or so tightly attached to particles or embedded in 

minerals that they are not taken up by plants or animals. 

Fluorides are normally found in very small amounts in the air. Levels measured in areas around 

cities are usually less than 1 microgram (one millionth of a gram) of fluoride per cubic meter 

(μg/m3) of air. Rural areas have even lower levels. The amount of fluoride that you breathe in a 

day is much less than what you consume in food and water. You may breathe in higher levels of 

fluoride in areas near coal-fired power plants or fluoride-related industries (e.g., aluminum 

smelters, phosphorus fertilizer plants) or near hazardous waste sites. 

Levels of fluorides in surface water average about 0.2 parts of fluoride per million parts of water 

(ppm). Levels of fluorides in well water generally range from 0.02 to 1.5 ppm, but often exceed 

1.5 ppm in parts of the southwest United States. Many communities fluoridate their water 

supplies; the recommended level of fluoride is around 1 ppm. In the United States, 

approximately 15,000 water systems serving about 162 million people are fluoridated in the 

optimal range of 0.7–1.2 ppm, either occurring naturally or through adjustment. Persons living 

in non-fluoridated areas may receive water exposure through beverages and foods processed in 

fluoridated areas. You will be exposed to fluorides in the water that you drink or in beverages 

prepared with fluoridated water. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 5 

1. PUBLIC HEALTH STATEMENT 

The concentration of fluorides in soils is usually between 200 and 300 ppm. However, levels 

may be higher in areas containing fluoride-containing mineral deposits. Higher levels may also 

occur where phosphate fertilizers are used, where coal-fired power plants or fluoride-releasing 

industries are located, or in the vicinity of hazardous waste sites. You may be exposed to 

fluorides through dermal contact with these soils. 

You may also be exposed to fluorides in your diet. While food generally contains low levels of 

fluoride, food grown in areas where soils have high amounts of fluorides or where phosphate 

fertilizers are used may have higher levels of fluorides. Tea and some seafoods have been found 

to have high levels of fluorides. The average daily fluoride intake by adults from food and water 

is estimated to be 1 milligram (mg) if you live in a community with <0.7 ppm in your water, and 

about 2.7 mg if you have fluoridated water. You can contact your local water system to 

determine the level of fluoride in your drinking water or refer to the annual Consumer 

Confidence Report furnished by your water system operators. You may also be exposed to 

fluoride in dental products, such as toothpastes, fluoride gels, and fluoride rinses. Dental 

products used in the home such as toothpastes, rinses, and topically applied gels contain high 

concentrations of fluoride (range 230–12,300 ppm) and are not intended to be ingested. The 

most commonly used dental products, toothpastes, contain 900–1,100 ppm fluoride (ca. 0.10%), 

most often as sodium fluoride. If you swallow these products, you will be exposed to higher 

levels of fluoride. Swallowing toothpaste can account for a large percentage of the fluoride to 

which a child <8 years of age might be exposed The Food and Drug Administration requires that 

toothpaste tubes be labeled with instructions to minimize ingestion of fluoride by children 

including the use of a “pea-sized” amount of paste and parental supervision of brushing. 

You may also be exposed to higher levels of fluoride if you work in industries where fluoridecontaining substances are used, most notably in the electronics industry where hydrogen fluoride 

may be used to etch glass in TV picture tubes or to clean silicon chips and in aluminum and 

phosphate fertilizer plants. Exposure will primarily result from breathing in hydrogen fluoride or 

fluoride-containing dust. Exposure will be reduced if exhaust systems or protective masks are 

used in the workplace. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 6 

1. PUBLIC HEALTH STATEMENT 

For more information on how you can be exposed to fluorides, hydrogen fluoride, or fluorine, 

see Chapter 6. 

1.4 HOW CAN FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE ENTER 

AND LEAVE MY BODY? 

Generally, most of the fluoride in food or water that you swallow enters your bloodstream 

quickly through the digestive tract. However, the amount that enters your bloodstream also 

depends on factors such as how much of the fluoride you swallowed, how well the fluoride 

dissolves in water, whether you ate or drank recently, and what you ate or drank. Factors such as 

age and health status affect what happens to the fluoride ion once it is in your body. After 

entering your body, about half of the fluoride leaves the body quickly in urine, usually within 

24 hours unless large amounts (20 mg or more, which is the amount in 20 or more liters of 

optimally fluoridated water) are ingested. Most of the fluoride ion that stays in your body is 

stored in your bones and teeth. 

When you breathe in air containing hydrogen fluoride or fluoride dusts, it enters your 

bloodstream quickly through your lungs. When hydrofluoric acid touches skin, most of it can 

quickly pass through the skin into the blood. How much of it enters your bloodstream depends 

on how concentrated the hydrofluoric acid is and how long it stays on your skin. Almost all of 

the fluoride that enters the body in these ways is quickly removed from the body in the urine, but 

some is stored in your bones and teeth. 

When you breathe in air containing fluorine, fluoride can enter your bloodstream through your 

lungs, but it is not known how quickly this happens. Much of the fluoride leaves your body in 

urine, but some is stored in your bones and teeth. Exposure to fluorine gas is uncommon, except 

in industrial settings. 

For more information on how fluorides, hydrogen fluoride, and fluorine enter and leave your 

body, see Chapter 3. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 7 

1. PUBLIC HEALTH STATEMENT 

1.5 HOW CAN FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE AFFECT 

MY HEALTH? 

To protect the public from the harmful effects of toxic chemicals and to find ways to treat people 

who have been harmed, scientists use many tests. 

One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, and 

released by the body; for some chemicals, animal testing may be necessary. Animal testing may 

also be used to identify health effects such as cancer or birth defects. Without laboratory 

animals, scientists would lose a basic method to get information needed to make wise decisions 

to protect public health. Scientists have the responsibility to treat research animals with care and 

compassion. Laws today protect the welfare of research animals, and scientists must comply 

with strict animal care guidelines and must be recertified regularly with training in updated and 

new guidelines. 

Fluorides. Several medicines that contain fluoride are used for treating skin diseases (e.g., 

flucytosine, an antifungal) and some cancers (e.g., fluorouracil, an antimetabolite). 

Small amounts of fluoride are added to toothpaste or drinking water to help prevent dental decay. 

However, exposure to higher levels of fluoride may harm your health. Skeletal fluorosis can be 

caused by eating, drinking, or breathing very large amounts of fluorides. This disease only 

occurs after long-term exposures and can cause denser bones, joint pain, and a limited range of 

joint movement. In the most severe cases, the spine is completely rigid. Skeletal fluorosis is 

extremely rare in the United States; it has occurred in some people consuming greater than 

30 times the amount of fluoride typically found in fluoridated water. It is more common in 

places where people do not get proper nutrition. At fluoride levels 5 times greater than levels 

typically found in fluoridated water, fluoride can result in denser bones. However, these bones 

are often more brittle or fragile than normal bone and there is an increased risk of older men and 

women breaking a bone. Some studies have also found a higher risk of bone fractures in older 

men and women at fluoride levels typically found in fluoridated water. However, other studies 

have not found an effect at this fluoride dose. If you eat large amounts of sodium fluoride at one 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 8 

1. PUBLIC HEALTH STATEMENT 

time, it can cause stomachaches, vomiting, and diarrhea. Extremely large amounts can cause 

death by affecting your heart. 

We do not know if eating, drinking, or breathing fluoride can cause reproductive effects in 

humans. Reproductive effects, such as decreased fertility and sperm and testes damage, have 

been seen in laboratory animals at extremely high doses (more than 100 times higher than levels 

found in fluoridated water). However, other studies have not found any reproductive effects in 

laboratory animals. 

A number of studies have been done to assess whether there is an association between fluoride 

and cancer in people who live in areas with fluoridated water or naturally high levels of fluoride 

in drinking water, or people who work in jobs where they may be exposed to fluorides. Most 

studies have not found any association between fluoride and cancer in people. A study in rats 

and mice found that a small number of male rats developed bone cancer after drinking water with 

high levels of fluoride in it throughout their lives. This was considered equivocal evidence that 

fluoride causes cancer in male rats. Fluoride did not cause cancer in mice or female rats. 

Another study found no evidence that even higher doses of fluoride caused cancer in rats. Both 

animal studies had problems that limited their usefulness in showing whether fluoride can cause 

cancer in humans. The International Agency for Research on Cancer (IARC) has determined 

that the carcinogenicity of fluoride to humans is not classifiable. 

Hydrogen Fluoride. Hydrogen fluoride is also a very irritating gas. Hydrogen fluoride is not as 

dangerous as fluorine, but large amounts of it can also cause death. People breathing hydrogen 

fluoride have complained of eye, nose, and skin irritation. Breathing in a large amount of 

hydrogen fluoride with air can also harm the lungs and heart. Kidney and testes damage have 

been observed in animals breathing hydrogen fluoride. 

Hydrofluoric acid is dangerous to humans because it can burn the eyes and skin. The initial 

exposure to hydrofluoric acid may not look like a typical acid burn. Skin may only appear red 

and may not be painful at first. Damage to skin may happen over several hours or days, and 

deep, painful wounds may develop. When not treated properly, serious skin damage and tissue 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 9 

1. PUBLIC HEALTH STATEMENT 

loss can occur. In the worst cases, getting a large amount of hydrofluoric acid on your skin can 

lead to death caused by the fluoride affecting your lungs or heart. 

Fluorine. Fluorine gas is very irritating and very dangerous to the eyes, skin, and lungs. Fluorine 

gas at low concentrations makes your eyes and nose hurt. At higher concentrations, it becomes 

hard to breathe. Exposure to high concentrations of fluorine can cause death due to lung 

damage. 

For more information on the health effects of fluorides, hydrogen fluoride, and fluorine, see 

Chapter 3. For more information on fluoride and dental caries, see Appendix D. 

1.6 HOW CAN FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE AFFECT 

CHILDREN? 

This section discusses potential health effects from exposures during the period from conception 

to maturity at 18 years of age in humans. 

When used appropriately, fluoride is effective in preventing and controlling dental caries. 

Drinking or eating excessive fluoride during the time teeth are being formed can cause visible 

changes in teeth. The condition is called dental fluorosis. The changes increase in severity with 

increasing levels of fluoride. Dental fluorosis develops only while the teeth are forming in the 

jaw and before they erupt into the mouth (age <8 years). After the teeth have developed and 

erupted, they cannot become fluorosed. Most enamel fluorosis seen today is of the mildest form, 

in which there are a few almost invisible white spots on the teeth. In moderate cases, there are 

large white spots on the teeth (mottled teeth), and some brown spots. In severe cases, the teeth 

are pitted and are fragile, and sometimes the teeth can break. The appearance of affected teeth is 

not identical for all children exposed to the same level of fluoride in the drinking water. 

Exposure to fluoride from other sources, such as fluoride tablets or rinses, may account for these 

differences. In general, some children who drink water with 1 ppm fluoride may get a few small 

spots or slight discolorations on their teeth. Some children who drink water with 4 ppm fluoride 

in it for long periods before their permanent teeth are in place may develop a more severe form 

of dental fluorosis. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 10 

1. PUBLIC HEALTH STATEMENT 

Fluoride can cross the placenta from the mother’s blood to the developing fetus. Only a very 

small portion of fluoride ingested by women is transferred to a child through breast milk. 

Several human studies found an increase in birth defects or lower IQ scores in children living in 

areas with very high levels of fluoride in the drinking water. Those studies did not adequately 

access other factors that could have contributed to the effects. Another study did not find birth 

defects in children living in areas with low levels of fluoride. Birth defects have not been found 

in most studies of laboratory animals. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO FLUORIDES, 

HYDROGEN FLUORIDE, AND FLUORINE? 

If your doctor finds that you have been exposed to significant amounts of fluorides, hydrogen 

fluoride, and fluorine, ask whether your children might also be exposed. Your doctor might need 

to ask your state health department to investigate. 

It is unlikely that the general population would be exposed to fluorine gas or hydrogen fluoride. 

Because fluorides are found naturally in the environment, we cannot avoid being exposed to 

them. Some areas of the United States, such as the Southwest, naturally have high levels of 

fluorides in well water. There has been an increase in the cosmetic condition of tooth enamel 

fluorosis in children in both fluoridated and non-fluoridated communities. Ask your health 

department whether your area has naturally high levels of fluorides in the drinking water. If you 

live in such an area, you should use bottled drinking water and consult your dentist for guidance 

on the need for appropriate alternative fluoride supplements. 

These areas may also contain high levels of fluorides in soil. A few hazardous waste sites may 

contain high levels of fluorides in soil. By limiting your contact with such soil (for example, 

reducing recreational activities that raise dust), you would reduce your family’s exposure to 

fluoride. Some children eat a lot of dirt. You should prevent your children from eating dirt. 

You should discourage your children from putting their hands or objects in their mouths or 

engaging in other hand-to-mouth activity. Make sure they wash their hands frequently and 

always before eating. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 11 

1. PUBLIC HEALTH STATEMENT 

If you work in a phosphate fertilizer plant or other industry that uses minerals high in fluorides, it 

is sometimes possible to carry fluorides home from work on your clothing, skin, hair, tools, or 

other objects removed from the workplace. You may contaminate your car, home, or other 

locations outside work where children might be exposed to fluoride-containing dust. Your 

occupational health and safety officer at work can and should tell you whether the chemicals that 

you work with are likely to be carried home on your clothes, body, or tools as well as whether 

you should be showering and changing clothes before you leave work, storing your street clothes 

in a separate area of the workplace, or laundering your work clothes at home separately from 

other clothes. 

Children may be exposed to high levels of fluorides if they swallow dental products containing 

fluoridated toothpaste, gels, or rinses. Swallowing toothpaste can account for a large percentage 

of the fluoride to which a small child might be exposed. You should teach your children not to 

swallow these products. For children under age 8, parents should supervise brushing and place, 

at most, a small pea size dab of toothpaste on the brush. 

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

EXPOSED TO FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE? 

Urine and blood samples can be analyzed to find out if you have been exposed to fluorides. The 

fluoride level in the sample is compared with the level of fluoride usually found in urine or 

blood. This will show if a person has been exposed recently to higher-than-normal levels of 

fluorides. However, this test cannot be used to predict any specific health effects that may occur 

after fluoride exposure. The test must be performed soon after exposure because fluoride that is 

not stored in the bones leaves the body within a few days. This test can be done at most 

laboratories that test for chemical exposure. Bone sampling can be done in special cases to 

measure long-term exposure to fluorides. Because fluorides, hydrogen fluoride, and fluorine all 

enter the body as fluoride, these tests cannot distinguish among exposure to these different 

chemicals. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 12 

1. PUBLIC HEALTH STATEMENT 

For more information on medical tests to determine exposure to fluorides, hydrogen fluoride, and 

fluorine, see Chapters 3 and 6. 

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. Federal agencies that develop regulations for toxic 

substances include the Environmental Protection Agency (EPA), the Occupational Safety and 

Health Administration (OSHA), and the Food and Drug Administration (FDA). 

Recommendations provide valuable guidelines to protect public health but cannot be enforced by 

law. Federal organizations that develop recommendations for toxic substances include the 

Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institute for 

Occupational Safety and Health (NIOSH). 

Regulations and recommendations can be expressed in not-to-exceed levels in air, water, soil, or 

food that are usually based on levels that affect animals; then they are adjusted to help protect 

people. Sometimes these not-to-exceed levels differ among federal organizations because of 

different exposure times (an 8-hour workday or a 24-hour day), the use of different animal 

studies, or other factors. 

Recommendations and regulations are also periodically updated 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 fluorides, hydrogen fluoride, and 

fluorine include the following: 

Sodium fluoride, hydrogen fluoride, and fluorine have been named hazardous substances by the 

EPA. The federal government has set regulatory standards and guidelines to protect workers 

from the possible health effects of fluorides, hydrogen fluoride, and fluorine in air. OSHA has 

set a legally enforceable limit of 0.2 milligrams per cubic meter (mg/m3

) for fluorine, 2.0 mg/m3 

for hydrogen fluoride, and 2.5 mg/m3 for fluoride in workroom air to protect workers during an 

8-hour shift over a 40-hour work week. NIOSH recommends air levels of 0.2 mg/m3 for 
 

 

 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 13 

1. PUBLIC HEALTH STATEMENT 

fluorine, 2.5 mg/m3 for hydrogen fluoride, and 2.5 mg/m3 for sodium fluoride in workroom air to 

protect workers during an 8-hour shift over a 40-hour work week. 

The federal government has also set regulatory standards and guidelines to protect the public 

from the possible health effects of fluoride in drinking water. EPA determined that the 

maximum amount of fluoride allowed in drinking water is 4.0 milligrams per liter (mg/L). 

For the prevention of dental decay, the Public Health Service (PHS) has, since 1962, 

recommended that public water supplies contain fluoride at concentrations between 0.7 and 

1.2 mg/L. PHS scientists representing the National Institutes of Health, the Centers for Disease 

Control and Prevention, the FDA, ATSDR, and other government agencies conducted an 

extensive examination of the worldwide biomedical literature on the public health risks and 

benefits of fluoride in 1991. The PHS report stated that fluoride in the drinking water 

substantially reduces tooth decay. 

For more information on recommendations regarding exposure to fluorides, hydrogen fluoride, 

and fluorine, see Chapter 8. 

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 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology 

1600 Clifton Road NE 

Mailstop E-29 

Atlanta, GA 30333 

* Information line and technical assistance 

Phone: 1-888-42-ATSDR (1-888-422-8737) 

Fax: 1-404-498-0057 
 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 14 

1. PUBLIC HEALTH STATEMENT 

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

clinics specialize in recognizing, evaluating, and treating illnesses resulting from exposure to 

hazardous substances. 

* To order toxicological profiles, contact 

National Technical Information Service 

5285 Port Royal Road 

 Springfield, VA 22161 

Phone: (800) 553-6847 or (703) 605-6000 

 Web site: http://www.ntis.gov/ 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 15 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO FLUORIDES, 

HYDROGEN FLUORIDE, AND FLUORINE IN THE UNITED STATES 

Fluorine is the most electronegative and reactive of all elements; fluoride is the ionic form of fluorine. 

Fluorine and anhydrous hydrogen fluoride are naturally occurring gases that have a variety of industrial 

uses including the production of fluorine-containing chemicals, pharmaceuticals, high octane gasoline, 

and fluorescent light bulbs; aqueous hydrofluoric acid is a liquid used for stainless steel pickling, glass 

etching, and metal coatings. The general population is typically exposed to very low levels of gaseous 

fluoride (primarily as hydrogen fluoride); in the United States and Canada, the levels ranged from 0.01 to 

1.65 μg/m3

. Populations living near industrial sources of hydrogen fluoride, including coal burning 

facilities, may be exposed to higher levels of hydrogen fluoride in the air. Additionally, vegetables and 

fruits grown near these sources may contain higher levels of fluoride, particularly from fluoridecontaining dust settling on the plants. 

Fluoride salts, generically referred to as fluorides, are naturally occurring components of rocks and soil. 

One of the more commonly used fluoride salt is sodium fluoride; its principal use is for the prevention of 

dental caries. Sodium fluoride and other fluoride compounds, such as fluorosilicic acid and sodium 

hexafluorisilicate, are used in the fluoridation of public water. Sodium monofluorophosphate and 

stanneous fluoride are commonly used in dentifrices such as toothpaste. The general population can be 

exposed to fluoride through the consumption of fluoridated drinking water, food, and dentifrices. The 

average dietary intake (including water) of fluoride ranges between 1.4 and 3.4 mg/day (0.02– 

0.048 mg/kg/day) for adults living in areas with 1.0 mg/L fluoride in the water. In areas with <0.3 mg/L 

fluoride in water, the adult dietary intakes ranged from 0.3 to 1.0 mg/day (0.004–0.014 mg/kg/day). In 

children, the dietary intakes ranged from 0.03 to 0.06 mg/kg/day in areas with fluoridated water and from 

0.01 to 0.04 mg/kg/day in areas without fluoridated water. The Food and Nutrition Board of the Institute 

of Medicine has developed adequate intakes (AIs) for fluoride. The AI is the “estimated fluoride intake 

that has been shown to reduce the occurrence of dental caries maximally in a population without causing 

unwanted side effects including moderate dental fluorosis.” The AIs for each age group are presented in 

Table 2-1. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 16 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. Adequate Intake Levels for Fluoridea 

Age range Adequate intake level (mg/day) Adequate intake level (mg/kg/day)b 

0–6 months 0.01 0.0014 

6–12 months 0.5 0.056 

1–3 years 0.7 0.054 

4–8 years 1 0.045 

9–13 years (males and females) 2 0.05 

14–18 years (males) 3 0.046 

14–18 years (females) 3 0.053 

>18 years (males) 4 0.052 

>18 years (females) 3 0.049 

a

Source: IOM 1997 

b

mg/kg/day doses were calculated by using reference body weights reported by IOM (1997) 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 17 

2. RELEVANCE TO PUBLIC HEALTH 

2.2 SUMMARY OF HEALTH EFFECTS 

Fluoride. The main health concern regarding fluoride is likely to be from excessive chronic oral 

exposure in drinking water. Due to the deposition of significant amounts of fluoride in bone, the primary 

target system for intermediate and chronic exposures of both humans and several laboratory animal 

species is the skeletal system (including teeth). Both beneficial and detrimental dental and skeletal effects 

have been observed in humans. Fluoride has been shown to decrease the prevalence of dental caries and, 

under certain conditions, has been used for the treatment of osteoporosis. However, excess fluoride can 

also result in dental fluorosis and can result in an increased prevalence of bone fractures in the elderly or 

skeletal fluorosis. Both the beneficial and detrimental effects of fluoride appear to be related to fluorideinduced alterations in tooth and bone mineralization. 

Direct contact with fluoride can result in tissue damage. At high concentrations, fluoride can cause 

irritation and damage to the respiratory tract, stomach, and skin following inhalation, oral, and dermal 

exposure, respectively. At very high fluoride doses, fluoride can bind with serum calcium resulting in 

hypocalcemia and possibly hyperkalcemia; the severe cardiac effects (e.g., tetany, decreased myocardial 

contractility, cardiovascular collapse, ventricular fibrillation) observed at or near lethal doses are probably 

due to this electrolyte imbalance. 

The available data on the potential of fluoride to induce reproductive and/or developmental effects is 

inconclusive. A study of birth records found a significant association between high levels of fluoride in 

municipal drinking water (3 ppm and greater) and decreases in fertility rates; another study found 

decreases in serum testosterone levels in men with skeletal fluorosis (fluoride concentration in water was 

3.9 ppm). However, design limitations of these studies, particularly the use of poorly matched controls, 

limits the usefulness of these studies. Some animal studies have found alterations in reproductive 

hormone levels, histology of the testes, spermatogenesis, and fertility following exposure to relatively 

high oral doses of sodium fluoride, roughly equivalent to a human exposure level of >150 ppm in 

drinking water. However, other animal studies, including two-generation studies, have not found 

alterations in serum hormone levels in male rats, testicular histopathology, sperm morphology, or fertility. 

None of the available laboratory animal studies examined reproductive toxicity at low fluoride doses. 

The inadequate human studies and conflicting animal studies do not allow for an assessment of the 

potential of fluoride to induce reproductive effects in humans. Available human studies provide 

suggestive evidence that exposure to elevated levels of fluoride in drinking water may decrease IQ in 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 18 

2. RELEVANCE TO PUBLIC HEALTH 

children; however, neither study controlled for other confounding variables. Animal studies have not 

found increases in the incidences of birth defects in the absence of maternal toxicity; at doses that caused 

maternal toxicity (decreases in body weight gain and food consumption), increases in abnormalities were 

found. 

Numerous community-based studies have examined the possible association between fluoridated water 

and cancer. Most of these studies did not find significant associations between water fluoridation and 

cancer mortality or site-specific cancer incidence. Some studies have found associations between water 

fluoridation and cancer mortality/incidence or site-specific cancer incidence (osteosarcoma or bone 

cancer). The lack of control for potential confounding variables (i.e., age, race) limits the interpretation 

of the total cancer study results. The weight of the evidence indicates that fluoridation of water does not 

increase the risk of developing cancer. A 2-year study in rats found a weak, equivocal fluoride-related 

increase in the occurrence of osteosarcomas in male rats, and no evidence of carcinogenicity in female 

rats or male or female mice. IARC has determined that the carcinogenicity of fluoride to humans is not 

classifiable. 

Hydrogen Fluoride. Hydrogen fluoride is highly corrosive, the primary effects are tissue damage 

resulting from direct contact. Acute inhalation exposure can result in irritation, inflammation, bronchiolar 

ulceration, pulmonary hemorrhage and edema, and death. Gastrointestinal irritation has also been 

observed in humans exposed to low levels of hydrogen fluoride. Direct contact of hydrogen 

fluoride/hydrofluoric acid with the eyes or skin can produce skin burns, “burning sensation”, and 

lacrimation. In addition to these direct contact effects, exposure to hydrogen fluoride can result in 

skeletal and cardiac effects. Some evidence of early skeletal fluorosis has been observed in workers 

exposed to hydrogen fluoride and fluoride dusts. These studies did not adequately characterize fluoride 

exposure levels and, in most of the studies, there is some uncertainty regarding the diagnosis of skeletal 

fibrosis. Exposure to very high levels of hydrogen fluoride/hydrofluoric acid can result in severe 

cardiovascular effects, which are attributed to a combination of hypocalcemia and hyperkalemia; cardiac 

arrhythmias have been seen in humans following hydrofluoric acid splashes in the face region, and 

myocardial necrosis and congestion were observed in rabbits. Hepatic (fatty degeneration and necrosis) 

and renal effects (tubular degeneration and necrosis) have also been observed in animal studies. 

Although elevated cancer rates have been reported in some occupational groups exposed to hydrogen 

fluoride and fluoride dusts, these studies were not controlled for the multiple substance exposures to 

which industrial workers are generally exposed. Because of these multiple exposures and the problems 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 19 

2. RELEVANCE TO PUBLIC HEALTH 

inherent in all occupational studies in identifying appropriate reference populations, only limited evidence 

from such studies is specifically relevant to the investigation of possible carcinogenic effects of long-term 

dermal exposure to hydrofluoric acid and inhalation exposure to hydrogen fluoride and/or fluoride dusts 

in human beings. As noted previously, IARC has determined that the carcinogenicity of fluoride to 

humans is not classifiable. 

Fluorine. Limited data exist on the toxicity of fluorine; the two possible routes of exposure to fluorine 

are inhalation or dermal contact with the gas. Fluorine gas is extremely irritating; human and animal data 

suggest that the primary health effects of acute fluorine inhalation are nasal and eye irritation (at low 

levels), and death due to pulmonary edema (at high levels). In animals, renal and hepatic damage have 

also been observed. 

A greater detailed discussion of fluoride-induced skeletal effects and portal of entry effects following 

exposure to fluorides, hydrogen fluoride, hydrofluoric acid, or fluorine follows. The reader is referred to 

Section 3.2, Discussion of Health Effects by Route of Exposure, for additional information on other 

health effects. 

Dental and Skeletal Effects. Human and animal data clearly indicate that fluoride accumulates in 

the teeth and bone resulting in beneficial and detrimental alterations in the structure. There is strong 

evidence that oral exposure to fluoride can reduce the risk of dental caries. However, elevated fluoride 

levels during enamel maturation can also result in dental fluorosis, which is characterized by hypomineralization of subsurface layers of enamel. In the mildest forms of dental fluorosis, the tooth is fully 

functional but has cosmetic alterations, almost invisible opaque white spots. In more severely fluorosed 

teeth, the enamel is pitted and discolored and is prone to fracture and wear. Several studies have found 

significant increases in the number of decayed, missing, or filled tooth surfaces in children with severe 

dental fluorosis. The prevalence and severity of dental fluorosis is strongly associated with fluoride 

exposure levels. Dose-response relationships cannot be established from most of these studies because all 

sources of fluoride were not considered and most studies used fluoride levels in drinking water as the 

dosimetric. A recent meta-analysis estimated that 48% of children living in communities with 1 ppm 

fluoride in the water would have evidence of dental fluorosis, most of it considered very mild. The 

predicted incidence of dental fluorosis of aesthetic concern was 12.5%. Although the exact mechanism of 

dental fluorosis is not known, it is generally believed to result in a fluoride-induced delay in the 

hydrolysis of the enamel matrix protein amelogenin during the early enamel maturation phase of tooth 

development. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 20 

2. RELEVANCE TO PUBLIC HEALTH 

In bone, fluoride replaces the hydroxyl ion in hydroxyapatite to form fluorapatite, thus changing the 

physicochemical properties of the bone. Ingestion (and inhalation) of large doses of fluoride for an 

extended period of time can result in thickened bones and exostoses (skeletal fluorosis). Signs of skeletal 

fluorosis range from increased bone density to severe deformity, known as crippling skeletal fluorosis. In 

the more severe cases of crippling fluorosis, complete rigidity of the spine can occur. Reported cases are 

found almost exclusively in developing countries, particularly India and China, and are often associated 

with malnutrition. It is generally stated that a dose of 10–20 mg/day (equivalent to 5–10 ppm in the 

water, for a person who ingests 2 L/day) for at least 10 years is necessary for the development of crippling 

skeletal fluorosis, but individual variation, variation in nutritional status, and the difficulty of determining 

water fluoride levels in such situations make it difficult to determine the critical dose. 

At lower doses, fluoride can cause an increase in bone density and fragility. A large number of 

epidemiology studies have attempted to examine the relationship between fluoride in drinking water and 

the risk of bone fracture. The results of these predominantly ecological studies are inconsistent. Studies 

have found increases and decreases in hip fracture rates among older women living in areas with fluoride 

in the drinking water (typically about 1 ppm), as compared to women living in areas with very low levels 

of fluoride in the drinking water (<0.3 ppm). Other studies have not found an effect of fluoride on 

fracture risk. A relationship between exposure to 1 ppm fluoride in drinking water and the risk of bone 

fractures cannot be established from these studies. Studies involving exposure to higher doses of fluoride 

have consistently found significant increases in the risk of nonvertebral fractures, particularly hip 

fractures. A study involving lifetime exposure to 4.3–8 ppm fluoride in drinking water found an elevated 

risk of hip fractures among elderly men and women; this elevated risk of hip fracture was also observed in 

a community with very low fluoride (0.25–0.34 ppm) in the water. Studies of individuals using sodium 

fluoride for the treatment of osteoporosis also found significant increases in bone mineral density. 

Studies in laboratory animals have found defects in bone growth, fracture healing, and bone strength. 

Respiratory, Gastrointestinal, Dermal, and Ocular Effects. Fluoride, hydrogen fluoride, 

hydrofluoric acid, and fluorine are extremely irritating chemicals and can cause tissue damage after direct 

contact. The respiratory tract is the primary target of toxicity following inhalation exposure to hydrogen 

fluoride or fluorine. Single exposures to relatively low concentrations of hydrogen fluoride (≥0.5 ppm) or 

fluorine (≥10 ppm) can result in upper respiratory tract irritation in humans. At higher concentrations 

pulmonary congestion, necrosis and/or edema have been observed in laboratory animals; pulmonary 

edema has also been observed in humans exposed to lethal concentrations of hydrogen fluoride. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 21 

2. RELEVANCE TO PUBLIC HEALTH 

Pulmonary and nasal irritations have also been reported following repeated exposures for about 30 days. 

Chronic exposure to hydrogen fluoride and cryolite dust has resulted in impaired lung function in 

workers. The observed respiratory effects are attributed to its highly corrosive properties. Human and 

animal data suggest that preexposure to lower levels can reduce the respiratory effects. 

Acute and chronic oral exposure to high doses of sodium fluoride, typically >1 mg fluoride/kg, can result 

in nausea, vomiting, and gastric pain. Nausea, loss of appetite, and vomiting has also been reported by 

workers exposed to cryolite dust for >2 years. The effects occur shortly after ingestion and are likely due 

to the formation of hydrofluoric acid in the stomach. There is some evidence to suggest that these overt 

signs of gastric irritation may not be sensitive indicators of gastric mucosa damage. Petechiae and/or 

erosions were observed in most subjects exposed to sodium fluoride or a dental gel; however, nausea was 

only reported by 33% of the subjects. Similar findings were reported in animal studies; thickening of the 

glandular stomach mucosa and punctate hemorrhages were observed in rats ingesting high doses of 

sodium fluoride in drinking water for an intermediate duration. Gastrointestinal effects have been 

observed following inhalation and oral exposure to hydrogen fluoride. Populations living near a smelter 

emitting hydrogen fluoride or exposed during an accidental release of hydrogen fluoride have reported 

gastrointestinal effects, including nausea, gastrointestinal distress, and vomiting. 

Fluorine and hydrogen fluoride are highly reactive chemicals; direct contact can result in severe damage 

to the skin or eyes. The severity of the damage is directly related to the concentration and duration of 

exposure. Humans exposed to hydrogen fluoride gas for an acute duration have reported symptoms of 

skin irritation (itching and burning sensation) and eye irritation. Most of these human data are inadequate 

for establishing concentration-response relationships; the data on ocular irritation do provide some 

information of the threshold of toxicity. Very mild eye irritation was observed in subjects exposed to 

0.5–4.5 ppm hydrogen fluoride for 1 hour, mild eye irritation was reported during a 15–50-day, 

6-hour/day exposure to 3 ppm. Aqueous hydrofluoric acid applied directly to the skin can cause 

extensive damage; it is quickly absorbed through the epidermis causing necrosis in underlying tissues 

(Chela et al. 1989). In rabbits, a 1-minute exposure to 2% hydrofluoric acid did not produce skin lesions; 

however, necrotic lesions were observed after a 1–4-hour exposure to this concentration. 

There are limited data on the dermal and ocular toxicity of fluorine. A human study reported slight eye 

irritation following a repeated exposure to 10 ppm fluorine (no irritation was reported a during 15-minute 

exposure to this concentration), mild eye irritation during a 3-minute exposure to 30–50 ppm, and marked 

irritation during a <1-minute exposure to 100 ppm. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 22 

2. RELEVANCE TO PUBLIC HEALTH 

2.3 MINIMAL RISK LEVELS 

Fluorides 

Inhalation MRLs 

No inhalation MRLs were derived for fluoride. Several occupational exposure studies examined fluoride 

toxicity in aluminum potroom workers (Carnow and Conibear 1981; Chan-Yeung et al. 1983b; 

Czerwinski et al. 1988; Dinman et al. 1976c; Kaltreider et al. 1972). Interpretation of these studies is 

limited by co-exposure to hydrogen fluoride and other chemicals including aluminum. There are limited 

data on the inhaled toxicity of fluoride. Significant increases in lung weight and pulmonary edema have 

been observed in mice exposed to 10 mg fluoride/m3 as sodium fluoride 4 hours/day, for 10–14 days 

(Chen et al. 1999; Yamamoto et al. 2001). Impaired pulmonary bactericidal activity has also been 

observed in mice exposed to 5 mg fluoride/m3

 as sodium fluoride (Yamamoto et al. 2001). These studies 

cannot be used for MRL derivation because none of the studies examined the skeletal system, which has 

been shown to be a sensitive target following oral exposure. 

Oral MRLs 

A limited number of end points have been examined in humans and animals following acute oral 

exposure to fluorides. Most of the available data involved exposure to lethal doses of fluoride; other 

examined potential targets of toxicity include the gastrointestinal tract, bone, sperm morphology, and the 

developing organism. Symptoms of gastric irritation, such as nausea, vomiting, and gastric pain, have 

been observed shortly after exposure to fluoride in drinking water (Hoffman et al. 1980; Spak et al. 1989, 

1990; Spoerke et al. 1980). Spak et al. (1989) reported macroscopic and microscopic signs of gastric 

irritation in subjects ingesting 20 mg fluoride (1,000 ppm) as sodium fluoride; other studies have not 

reliably identified exposure concentrations. A decrease in modulus of elasticity was observed in the 

bones of weanling rats exposed to 9.5 mg fluoride/kg/day as sodium fluoride in drinking water for 

2 weeks (Guggenheim et al. 1976). No alterations in sperm morphology were observed in mice exposed 

to 32 mg fluoride/kg/day as sodium fluoride (Li et al. 1987a). In the absence of maternal toxicity, no 

adverse effects in rat or rabbit offsprings were observed (Heindel et al. 1996); skeletal and visceral 

alterations were observed in the offspring of rat dams with decreases in body weight and feed 

consumption (Guna Sherlin and Verma 2001). From the available data, it appears that the stomach is a 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 23 

2. RELEVANCE TO PUBLIC HEALTH 

sensitive target of fluoride toxicity following consumption of a bolus dose of fluoride. However, the 

observed effect (gastric irritation) is likely due to the fluoride concentration rather than a daily dose 

(expressed as mg/kg/day). It is not known whether the gastric mucosa would adapt to repeated exposure 

to this concentration of fluoride. An acute-duration oral MRL for fluorides was not derived due to the 

previously mentioned uncertainties in basing the MRL on a study that administered a single bolus dose of 

sodium fluoride and because the resultant MRL would be lower than the chronic-duration oral MRL. 

Several studies have examined the toxicity of sodium fluoride following intermediate-duration exposure 

in laboratory animals. These studies have identified a number of potentially sensitive targets of fluoride 

toxicity. The lowest identified lowest-observed-adverse-effect levels (LOAELs) are 0.5 mg 

fluoride/kg/day for thyroid effects in rats exposed to sodium fluoride in drinking water for 2 months 

(Bobek et al. 1976) and 0.80 mg fluoride/kg/day for increased bone formation in mice exposed to sodium 

fluoride in drinking water for 4 weeks (Marie and Hott 1986). Neither study identified a no-observedadverse-effect level (NOAEL). Derivation of an intermediate-duration MRL from either study would 

result in an MRL that is lower than the chronic-duration oral MRL. 

• A chronic-duration oral MRL of 0.05 mg fluoride/kg/day was derived for fluoride. 

A number of studies have examined the possible association between exposure to fluoridated water and 

the risk of increased bone fractures, particularly hip fractures. In general, the studies involved comparing 

the incidence of hip fractures among residents aged 55 years and older living in a community with 

fluoridated water (around 1 ppm) with the incidence in a comparable community with lower levels of 

fluoride in the water. Inconsistent results have been found, with studies finding decreases (Lehmann et al. 

1998; Phipps et al. 2000; Simonen and Laittinen 1985), increases (Cooper et al. 1990, 1991; Danielson et 

al. 1992; Jacobsen et al. 1990, 1992; Kurttio et al. 1999), or no effect (Arnala et al. 1986; Cauley et al. 

1995; Goggin et al. 1965; Jacobsen et al. 1993; Karagas et al. 1996; Kröger et al 1994; Suarez-Almazor et 

al. 1993) on hip fracture risk. Studies by Li et al. (2001) and Sowers et al. (1986) have examined 

communities with higher levels of naturally occurring fluoride in the water. Both studies found increases 

in the incidence of hip fractures in residents exposed to 4 ppm fluoride and higher (Li et al. 2001; Sowers 

et al. 1986, 1991); the hip fracture incidence in the highly exposed community was compared to the rates 

in communities with approximately 1 ppm fluoride in the water. Significant increases in the occurrence 

of nonvertebral fractures were also observed in postmenopausal women ingesting sodium fluoride (34 mg 

fluoride/day; 0.56 mg fluoride/kg/day) for the treatment of osteoporosis (Riggs et al. 1990, 1994). This 

result was not found in another study of postmenopausal women with spinal osteoporosis treated with 

34 mg fluoride/day as sodium fluoride (Kleerekoper et al. 1991). A meta-analysis of these data, as well 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 24 

2. RELEVANCE TO PUBLIC HEALTH 

as other clinical studies, found a significant correlation between exposure to high levels of fluoride and an 

increased relative risk of nonvertebral fractures (Haguenauer et al. 2000). The Li et al. (2001) study was 

selected as the basis for the chronic-duration oral MRL. This study was selected because other potential 

sources of fluoride were considered (the Riggs et al. [1990] study did not provide information on the level 

of fluoride in the drinking water or other sources of fluoride) and calcium levels were similar among the 

different communities (the Sowers et al. [1986] study did not control for calcium intake). The Li et al. 

(2001) study identified a NOAEL of 2.62–3.56 ppm (0.15 mg fluoride/kg/day) and LOAEL of 4.32– 

7.97 ppm (0.25 mg fluoride/kg/day). An MRL of 0.05 mg fluoride/kg/day is calculated by dividing the 

NOAEL of 0.15 mg/kg/day by an uncertainty factor of 3 to account for human variability; a partial 

uncertainty factor was used because the most sensitive subpopulation, elderly men and women, was 

examined. 

Hydrogen Fluoride/Hydrofluoric Acid 

Inhalation MRLs 

• An acute-duration inhalation MRL of 0.02 ppm fluoride was derived for hydrogen fluoride. 

The respiratory tract appears to be the primary target of hydrogen fluoride toxicity. Upper respiratory 

tract irritation and inflammation and lower respiratory tract inflammation have been observed in several 

human studies. Nasal irritation was reported by one subject exposed to 3.22 ppm fluoride as hydrogen 

fluoride 6 hours/day for 10 days (Largent 1960). Very mild to moderate upper respiratory symptoms 

were reported by healthy men exposed to 0.5 ppm fluoride as hydrogen fluoride for 1 hour (Lund et al. 

1997). At higher concentrations, 4.2–4.5 ppm fluoride as hydrogen fluoride for 1 hour, more severe 

symptoms of upper respiratory irritation were noted (Lund et al. 1997, 2002). In subjects exposed to 

4.2 ppm for 1 hour, analysis of nasal lavage fluid provided suggestive evidence that hydrogen fluoride 

induces an inflammatory response in the nasal cavity (Lund et al. 2002). Similarly, bronchoalveolar 

lavage fluid analysis revealed suggestive evidence of bronchial inflammation in another study of subjects 

exposed to 1.9 ppm fluoride as hydrogen fluoride for 1 hour (Lund et al. 1999); no alterations were 

observed at 0.5 ppm. Respiratory effects have also been reported in rats acutely exposed to hydrogen 

fluoride. Mild nasal irritation was observed during a 60-minute exposure to 120 ppm fluoride 

(Rosenholtz et al. 1963), and respiratory distress was observed at 2,310, 1,339, 1,308, and 465 ppm 

fluoride for 5, 15, 30, or 60 minutes, respectively (Rosenholtz et al. 1963). Midtracheal necrosis was 

reported in rats exposed to 902 or 1,509 ppm fluoride as hydrogen fluoride for 2 or 10 minutes using a 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 25 

2. RELEVANCE TO PUBLIC HEALTH 

mouth breathing model with a tracheal cannula (Dalbey et al. 1998a, 1998b). These effects were not 

observed when the tracheal cannula was not used. 

The Lund et al. (1997, 1999) study was selected as the basis of the acute-duration inhalation MRL for 

hydrogen fluoride. As reported in the 1997 publication, a trend (p=0.06) toward increased upper 

respiratory tract symptom score, as compared to pre-exposure symptom scores, was observed at the 

lowest concentration tested (0.5 ppm). A significant increase in the total symptom score was also 

observed at this concentration. No significant alterations in symptom scores were observed at the mid 

concentration (1.9 ppm), and increases in upper respiratory and total symptom scores were observed at 

the high concentration (4.5 ppm). Suggestive evidence of bronchial inflammation was also observed at 

≥1.9 ppm fluoride (Lund et al. 1999), although no alterations in lower respiratory tract symptoms (Lund 

et al. 1997) or lung function (Lund et al. 1997) were observed at any of the tested concentrations. The 

MRL is based on the minimal LOAEL of 0.5 ppm fluoride for upper respiratory tract irritation. Data on 

nasal irritation from the Largent (1960) report, the Lund et al. (2002) study, and the intermediate-duration 

study by Largent (1960) provide suggestive evidence that the severity of nasal irritation does not increase 

with increasing exposure duration. These three studies identified similar LOAEL values for different 

exposure durations: 3.22 ppm 6 hours/day for 10 days (Largent 1960), 3.8 ppm 1 hour/day for 1 day 

(Lund et al. 2002), and 2.98 ppm 6 hours/day, 6 days/week for 15–50 days (Largent 1960). Thus, time 

scaling was not used to derive the acute MRL. The MRL of 0.02 ppm was calculated by dividing the 

minimal LOAEL of 0.5 ppm by an uncertainty factor of 30 (3 for the use of a minimal LOAEL and 10 to 

account for human variability). 

There are limited data on the long-term toxicity of hydrogen fluoride. Slight nasal irritation was reported 

by volunteers exposed to an average concentration of 2.98 ppm fluoride, 6 hours/day for 15–50 days 

(Largent 1960). In rats, rabbits, and dogs, pulmonary hemorrhages were observed after exposure to 

31 ppm fluoride for 6 hours/day, 6 days/week for 5 weeks (Stokinger 1949). An intermediate-duration 

inhalation MRL was not derived for hydrogen fluoride because an MRL based on the Largent (1960) 

study is higher than the acute-duration inhalation MRL derived from the Lund et al. (1997, 1999) study. 

No chronic-duration studies were located for hydrogen fluoride; thus, a chronic-duration inhalation MRL 

was not derived. 

Oral MRLs 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 26 

2. RELEVANCE TO PUBLIC HEALTH 

No oral MRLs were derived for hydrogen fluoride/hydrofluoric acid. Only lethality studies were 

identified for hydrogen fluoride/hydrofluoric acid, precluding derivation of oral MRLs for this chemical. 

Fluorine 

Inhalation MRLs 

• An acute-duration inhalation MRL of 0.01 ppm fluorine was derived for fluorine. 

Irritation appears to be the primary effect following acute inhalation exposure to fluorine. The observed 

effects include eye, skin, and nasal irritation in humans intermittently exposed to ≥10 ppm for 0.5– 

15 minutes (Keplinger and Suissa 1968) and dyspnea and lung congestion in rats and mice exposed to 47– 

175 ppm fluorine for 5–60 minutes (Keplinger and Suissa 1968). The threshold for the respiratory effects 

appears to be duration-related. Necrosis was also observed in the liver parenchymal tissue and in the 

renal tubules of rodents acutely exposed to fluorine. In general, the liver and kidney effects occurred at 

higher concentrations than the respiratory effects. 

The NOAEL and LOAEL values for nasal irritation identified in the human study by Keplinger and 

Suissa (1968) were selected as the basis of an acute-duration inhalation MRL for fluorine. Subjects did 

not report nasal or eye irritation following a 3-, 5-, or 15-minute exposure to 10 ppm. Eye irritation was 

observed at ≥23 ppm; nose irritation at ≥50 ppm, and skin irritation at ≥78 ppm. The severity of the 

irritation was concentration related. Exposure to 100 ppm was considered very irritating and the subjects 

did not inhale during the exposure period. The NOAEL of 10 ppm was adjusted for intermittent exposure 

(0.25 hour/24 hours) and divided by an uncertainty factor of 10 to account for human variability to derive 

an acute-duration inhalation MRL of 0.01 ppm fluorine. 

Longer-duration exposure studies are limited to a multi-species intermediate-duration study (Stokinger 

1949) and an occupational exposure study (Lyon 1962). As with acute-duration exposure, the primary 

effect of intermediate-duration exposure to fluorine was eye, nose, and mouth irritation, which was 

observed in rats and dogs (Stokinger 1949). Evidence of pulmonary damage (bronchitis, hemorrhage, and 

edema) was also observed in rats, rabbits, and dogs. The study author noted that there was some 

difficulty in measuring the exposure concentrations and considered the measurements of exposure 

concentrations to be questionable. The chronic-duration study of workers exposed to fluorine (Lyon 

1962) was not considered for MRL derivation because it used a relatively insensitive measure of 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 27 

2. RELEVANCE TO PUBLIC HEALTH 

respiratory effects (absences from work and visits to the medical department with respiratory complaints) 

and the workers and the controls were exposed to uranium hexafluoride and hydrogen fluoride. 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 29 

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 fluorides, 

hydrogen fluoride, and fluorine. 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 term fluoride properly refers to numerous natural and synthesized compounds that are derived from 

hydrofluoric acid. This class of chemicals is commonly referred to as fluorides. Some of these 

compounds, such as oxygen difluoride, are very reactive and highly toxic. Because of their reactivity, 

these compounds would not migrate unchanged from a hazardous waste site. Fluoride salts, such as 

sodium fluoride and calcium fluoride, are much less reactive and much less toxic. Since the fluoride ion 

is the toxicologically active agent, and discussion of water fluoridation uses the term fluoride, the term 

fluoride is used generically in this profile to refer to toxicology of fluoride salts. Because numerous 

different fluoride compounds exist naturally in the environment and have varying chemical properties, the 

term fluorides is used in the discussion of environmental media. Most of the available literature on 

fluoride toxicity concerns sodium fluoride. Additional toxicity literature is available on some other forms 

of fluoride, such as stannous fluoride. Other forms of fluoride are discussed only if exposure is likely to 

occur at a hazardous waste site. (Such exposure to stannous fluoride is not likely.) Wherever the form of 

fluoride exposure is known, that salt is identified in the profile. 

Hydrogen fluoride is also a gas and is very water soluble. It dissolves readily in any water present in the 

air or other media. When hydrogen fluoride is dissolved in water, it is called hydrofluoric acid. Although 

hydrofluoric acid is very corrosive and can etch glass, it is a weak acid, meaning that it can be present in 

water as an undissociated molecule. However, in dilute solutions, it is almost completely ionized; salts 

are formed if cations are available. Due to formation of complexes, very concentrated solutions of 

hydrofluoric acid are also largely ionic in nature. Therefore, a hydrogen fluoride or hydrofluoric acid 

spill would result in contamination with fluoride ion, but hydrogen fluoride or hydrofluoric acid would 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 30 

3. HEALTH EFFECTS 

not be of concern outside the immediate vicinity of the spill. However, while members of the public are 

only likely to come into contact with fluoride contamination, clean-up workers could be exposed to 

hydrogen fluoride/hydrofluoric acid. In this profile, hydrogen fluoride is used to refer to the gas, while 

hydrofluoric acid is used to refer to the liquid form. When both forms are included, the term hydrogen 

fluoride is used. 

Fluorine is a gaseous element that occurs only in very low concentrations in the environment in the 

absence of anthropogenic sources (see Chapter 6 for further discussion). Because it is strongly 

electronegative, it is rarely found in the environment in the elemental state, nor is it likely to be found in 

the environment near toxic waste sites as molecular fluorine. 

Limited information also exists concerning occupational exposure to the mineral cryolite (Na3AlF6), 

sometimes with concomitant exposure to hydrogen fluoride. Because these exposures usually involve 

exposure to both hydrogen fluoride and cryolite, sometimes along with exposure to other fluoride dusts, 

they are discussed separately in the profile. 

This profile will discuss data, or the absence of data, concerning the toxicity of inorganic compounds of 

fluorine that people could be exposed to at a hazardous waste site. Exposure and toxicity are discussed 

separately for fluoride, hydrogen fluoride/hydrofluoric acid, and fluorine. Toxic effects of occupational 

exposure in aluminum reduction plants, where exposures to hydrogen fluoride, fluoride dusts, and cryolite 

all occur, are also discussed separately. Because the toxic effects of fluorine are largely due to the action 

of the fluorine molecule on the respiratory tract or other exposed surfaces, fluorine exposure is reported as 

exposure to a level of diatomic fluorine. By contrast, systemic effects of hydrogen fluoride are due to the 

fluoride ion, so concentrations of hydrogen fluoride are converted to fluoride equivalents. All doses of 

fluoride are reported as the amount of fluoride ion. 

The primary routes and durations of concern vary with the different fluorine compounds. In general, the 

more soluble the fluoride, the more that can be absorbed by oral ingestion, and the more toxic it is. The 

primary exposure routes and duration for hydrofluoric acid are the inhalation or dermal routes, related to 

acute occupational exposure, while the primary exposure route and duration for fluoride is chronic oral 

exposure to fluoride in the drinking water, food, and fluoride-containing dental products. Therefore, most 

of the information for the inhalation and dermal routes comes from studies of acute exposure to fluorine 

or hydrofluoric acid, while most of the information regarding the oral route is based on sodium fluoride. 

The toxicity following inhalation or dermal exposure to other inorganic fluorine compounds differs from 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 31 

3. HEALTH EFFECTS 

that of hydrofluoric acid. Similarly, oral exposure to various fluorides other than sodium fluoride may 

result in different toxic effects. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

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

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

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

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

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 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 32 

3. HEALTH EFFECTS 

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. 

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been 

made for fluorides, hydrogen fluoride, and fluorine. 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. 

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. 

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 

Inhalation exposure most commonly occurs in an occupational setting. As discussed above, most of the 

available information concerning toxic effects of fluorine and its compounds following inhalation 

exposure comes from studies of exposure to hydrogen fluoride or hydrofluoric acid. There are also a 

limited number of useful studies concerning inhalation exposure to fluorine or particulates of inorganic 

fluoride compounds. However, no animal studies were located regarding toxic effects of exposure to the 

particulate fluoride compounds. Toxic effects of hydrogen fluoride are discussed in all of the following 

sections. Where toxicity data exist for fluoride or fluorine, these substances are also discussed. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 33 

3. HEALTH EFFECTS 

Acute inhalation of hydrogen fluoride following facial splashes with hydrofluoric acid can cause 

bronchiolar ulceration, pulmonary hemorrhage and edema, and death. In addition, renal and hepatic 

damage have been observed in animal studies. Many of the human studies regarding inhalation of 

hydrogen fluoride fumes also involved dermal exposure; in such cases, it is difficult to determine which 

effects are specific to the inhalation route. However, the respiratory effects of hydrogen fluoride appear 

to be inhalation-specific, because they have not been reported in cases where there was clearly no 

inhalation exposure. The effects of combined inhalation and dermal exposure to hydrofluoric acid are 

also discussed in Section 3.2.3. 

Fluorine gas is extremely irritating. The primary health effects of acute fluorine inhalation are nasal and 

eye irritation (at low levels), and death due to pulmonary edema (at high levels). In animals, renal and 

hepatic damage have also been observed. 

The major health effect of chronic inhalation exposure to fluoride is skeletal fluorosis, which has been 

reported in cases of exposure to fluoride dusts and hydrogen fluoride, either individually or in 

combination. 

3.2.1.1 Death 

Both hydrogen fluoride and fluorine can cause lethal pulmonary edema, although cardiac effects also 

contribute to the toxicity of hydrogen fluoride. The reported LC50 values for hydrogen fluoride in rats for 

a given duration are generally at least 3.5 times higher than the value for fluorine (as diatomic fluorine) in 

rats for the same duration. Although strain differences could account for some of this difference, the 

LC50 values of hydrogen fluoride in Crl:CD®BR and Wistar-derived rats were very similar. 

Hydrogen Fluoride. Acute inhalation of hydrogen fluoride fumes in combination with dermal exposure 

to hydrofluoric acid has been reported to cause death in humans. Actual exposure concentrations are not 

known in any of these cases. Death was generally due to pulmonary edema (resulting from irritation and 

constriction of the airways) or to cardiac arrhythmias with pronounced hyperkalemia, hypocalcemia, and 

hypomagnesemia. 

The death of a chemist who sustained first- and second-degree burns of the face, hands, and arms when a 

vat containing hydrofluoric acid accidentally ruptured has been described (Kleinfeld 1965). This 29-yearold male died 10 hours after admission to the hospital. Postmortem examination revealed severe 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 34 

3. HEALTH EFFECTS 

tracheobronchitis and hemorrhagic pulmonary edema. A petroleum refinery worker was splashed in the 

face with 100% anhydrous hydrofluoric acid (Tepperman 1980). The absorption of fluoride produced 

acute systemic fluoride poisoning with profound hypocalcemia and hypomagnesemia and cardiac 

arrhythmias. The patient died <24 hours after exposure; autopsy revealed pulmonary edema. A young 

woman splashed in the face with hydrofluoric acid died of respiratory insufficiency a few hours after 

exposure (Chela et al. 1989). The autopsy revealed severe burns of the skin and lungs, with hemorrhagic 

pulmonary edema produced by hydrofluoric acid and its vapor. 

The lethal concentration of hydrogen fluoride has been investigated in rats, mice, and guinea pigs. It 

appears that mice are more sensitive to the acute effects of hydrogen fluoride than rats, and rats are more 

sensitive than guinea pigs. The 15-minute LC50 values for hydrogen fluoride were 4,327 ppm fluoride for 

guinea pigs and 2,555 ppm fluoride for Wistar-derived rats (Rosenholtz et al. 1963). The 60-minute 

LC50 values for hydrogen fluoride were 325 ppm fluoride in ICR-derived mice (Wohlslagel et al. 1976), 

1,325 ppm fluoride in Sprague-Dawley-derived rats (Wohlslagel et al. 1976), and 1,242 ppm fluoride in 

Wistar-derived rats (Rosenholtz et al. 1963). In a study (Dalbey et al. 1998a) comparing the toxicity of 

hydrogen fluoride in rats using mouth-breathing (rats fitted with a tracheal cannula) and nose-breathing 

models, dramatic differences in lethality were observed. In the mouth-breathing rats, 50 and 80% of the 

animals died within 2 weeks of a 10-minute mouth breathing exposure to 3,655 or 6,663 ppm fluoride, 

respectively. In contrast, no deaths were noted following exposure to these concentrations using the nosebreathing model. The difference in lethality between the two models is probably due to the higher dose of 

hydrogen fluoride reaching the lower airways in the mouth-breathing model. 

The LC50 values reported by Haskell Laboratory (1988) for Crl:CD®BR rats were much higher than the 

values reported by the above investigators, although the size of the discrepancy decreased with longer 

exposure durations. For example, the 15-minute LC50 was reported as 6,620 ppm, while the 60-minute 

LC50 was 1,610 ppm. Although the concentration of hydrogen fluoride that produced death was reported 

to be lower when it was administered to rats in humid air (Haskell Laboratory 1988), the method for 

measuring fluoride in humid air may not have given accurate results. This limitation was recognized by 

the authors, who stated that the collection efficiency of the sampling train for aerosols was not evaluated. 

Longer-term effects of hydrogen fluoride were investigated by exposing various species to 8.2 or 31 ppm 

fluoride as hydrogen fluoride for 6 hours/day, 6 days/week for 5 weeks (Stokinger 1949). Humidity was 

47–97% at the lower concentration and 48–66% at the higher concentration. Marked species differences 

were observed. All rats and mice exposed to 31 ppm died, but no guinea pigs, rabbits, or dogs exposed at 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 35 

3. HEALTH EFFECTS 

this level died. No animal of any species died following exposure to 8.2 ppm. In an experiment where 

five rabbits, three guinea pigs, and two Rhesus monkeys were exposed to 18 ppm for 6–7 hours/day, 

5 days/week for 50 days (309 hours total), the only deaths observed were two guinea pigs (Machle and 

Kitzmiller 1935). Exposure of one of these animals stopped after 134 hours of exposure, and exposure of 

the other one stopped after 160 hours, when marked weight loss was observed. Nevertheless, the animals 

died about 2 weeks later. 

Fluorine. No information was located on death in humans caused by fluorine. Fluorine toxicity has been 

investigated in Osborne-Mendel rats, Swiss-Webster mice, New England guinea pigs, and New Zealand 

rabbits (Keplinger and Suissa 1968). Similar values for the LC50 were calculated for the different species. 

In the rats, the LC50 values for exposures of 5, 15, 30, and 60 minutes were 700, 390, 270, and 185 ppm, 

respectively. At concentrations near the LC50, few signs of intoxication were observed immediately after 

exposure, except for irritation of the eyes and nose. Several hours after exposure, the animals exhibited 

lethargy, dyspnea, and general weakness. Except at concentrations above the LC90, death generally 

occurred 12–18 hours after exposure. Animals that survived for 48 hours generally survived for the 

duration of the observation period. Loss of body weight was also observed, but was considered 

nonspecific and was attributed to anorexia. 

Toxic effects of inhalation exposure to fluorine and hydrogen fluoride were compared in rats, mice, 

rabbits, and guinea pigs (Stokinger 1949). Lethal doses from fluorine exposure determined by this group 

are about 3–4 times those determined by Keplinger and Suissa (1968), but quantitative exposure level 

data from these experiments are not reliable due to technical problems in monitoring fluorine gas levels. 

However, qualitative results from these experiments are useful. These experiments also found that 

fluorine was more toxic than hydrogen fluoride. 

There are some indications that preexposure to low levels of fluorine may provide resistance to lethal 

effects of fluorine. Increases in survival time were observed in rabbits exposed to 50 ppm fluorine for 

30 minutes, 1 day/week for 4 weeks prior to exposure to a lethal concentration of fluorine (400 ppm for 

30 minutes) (Keplinger 1969). Survival time in the rabbits was 48 hours, as compared to 18 hours or less 

in similarly exposed rabbits not preexposed to fluorine. In mice, slight increases in LC50 values were 

found in animals receiving a single exposure to 30–45 ppm fluorine prior to exposure to lethal 

concentrations. However, slight decreases in LC50 values were seen in mice preexposed to 25 ppm 

fluorine (Keplinger 1969). No mechanism for the possible tolerance was suggested. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 36 

3. HEALTH EFFECTS 

Repeated exposures of rats, mice, guinea pigs, and rabbits to 0.5, 2, 5, or 18 ppm fluorine were conducted 

for up to 178 hours over 35 days (Stokinger 1949). The exposure regimen was not stated, but appears to 

be 6 hours/day, 6 days/week. The exposure levels at these lower concentrations were considered fairly 

reliable. Guinea pigs and rats were less sensitive to lethal effects than were rabbits or dogs. All of the 

rabbits and dogs exposed to 5 ppm and mice exposed to 18 ppm died, while only half of the rats and 

guinea pigs exposed to 18 ppm died. Most animals exposed to 2 ppm survived. 

The LC50 values for each species and duration category of exposure to hydrogen fluoride are recorded in 

Table 3-1 and plotted in Figure 3-1. The LC50 values for each species and duration category of exposure 

to fluorine are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.1.2 Systemic Effects 

The highest NOAEL values and all reliable LOAEL values for systemic effects in each species and 

duration category of exposure to hydrogen fluoride are recorded in Table 3-1 and plotted in Figure 3-1. 

The highest NOAEL values and all reliable LOAEL values for systemic effects in each species and 

duration category of exposure to fluorine are recorded in Table 3-2 and plotted in Figure 3-2. The highest 

NOAEL values and all reliable LOAEL values for systemic effects in each species and duration category 

of exposure to fluoride are recorded in Table 3-3 and plotted in Figure 3-3. 

Respiratory Effects. 

Hydrogen Fluoride. Acute inhalation of 122 ppm fluoride as hydrogen fluoride by two male volunteers 

produced marked respiratory irritation within 1 minute (Machle et al. 1934). Pulmonary edema, 

pulmonary hemorrhagic edema, and tracheobronchitis have been reported in cases of people being 

splashed in the face with hydrofluoric acid, where concurrent inhalation and dermal exposures are likely 

(Chan et al. 1987; Chela et al. 1989; Dieffenbacher and Thompson 1962; Kleinfeld 1965; Tepperman 

1980). Exposure concentrations were not known in these cases. In another case, a women developed 

herrhagic alveolitis and adult respiratory disease syndrome following exposure to a presumably high 

concentration of hydrogen fluoride from a cleaning product (Bennion and Franzblau 1997). 

Two human experimental studies have been conducted to assess the ability of hydrogen fluoride to induce 

respiratory tract inflammation. In the first study, increases in upper airway symptoms were observed in 
Table 3-1 Levels of Significant Exposure to Hydrogen Fluoride - Inhalation 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

ACUTE EXPOSURE Death 

1 Rat 1 d 

2890 (30-minute LC50) 5-60 

min/d 

6620 (15-minute LC50) 

14600 (5-minute LC50) 

1610 (60-minute LC50) 

2 Rat 1 d 

1940 (30-minute LC50) 5-60 (Wistar) min/day 

2555 (15-minute LC50) 4722 (5-minute LC50) 1242 (60-minute LC50) 

3 Rat 1 d 

1325 (60-minuteLC50) 60 min/d 

4 Mouse 1 d 

325 (60-minute LC50) 60min/d 

5 Gn Pig 1 d 

4327 (15-minute LC50) (Hartley) 5-60 min/d 

Systemic 

6 Human 1 hour 

Resp 1.9 M (lower respiratory inflammation) 

b

0.5 M (upper respiratory irritation) 
Table 3-1 Levels of Significant Exposure to Hydrogen Fluoride - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

7 Human 1 hour 

Resp 4.2 M (upper airway irritation and 

inflammation) 

8 Human 1 to sev 

minutes Dermal 122 (smarting of the skin) 

seecomments

Ocular 122 (conjunctival irritation) 

9 Rat 2 min 

Resp 563 1509 (mucosal necrosis in mid (Sprague- trachea) 

Dawley) 

Hemato 4643 8190 (incr RBC, hemoglobin, and 

hematocrit levels) 

Hepatic 563 1509 (incr asparate aminotransferase 

activity) 

10 Rat 10 min 

Resp 257 902 (minimal midtracheal necrosis) (Sprague- 

Dawley) 

Hemato 1676 (incr hemoglobin and hematocrit 

levels) 

Hepatic 1676 

11 Rat 1 d 

Resp 712 (mild nasal irritation) 2310 (temporary respiratory distres

5 min/d 

and nasal discharge) 

Ocular 712 (moderate lacrimation) 
Table 3-1 Levels of Significant Exposure to Hydrogen Fluoride - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

12 Rat 1 d 

15min/d Resp 292 357 (nasal irritation) 1339 (temporary respiratory distress 

and nasal discharge) 

Ocular 292 357 (lacrimation) 

13 Rat 1 d 

Resp 98 120 (nasal irritation) 465 (temporary respiratory distress 60min/d 

and nasal discharge) 

Ocular 98 120 (lacrimation) 

14 Rat 30 min 

Resp 1235 (fibrinonecrotic rhinitis in nose (Fischer- 344) breathing rats; tracheal and 

bronchial necrosis in mouth breathing rats) 

Bd Wt 1235 (10% body weight reduction) 

INTERMEDIATE EXPOSURE Death 

15 Rat 5 wks 

31 (100% mortality) 6d/wk (NS) 

6hr/d 

16 Mouse 5 wks 

31 (100% mortality) 6d/wk (NS) 

6hr/d 

Systemic 

17 Human 15-50 d 

6 hr/d Resp 2.98 (slight nasal irritation) 

Dermal 2.98 (stinging sensation on skin) Ocular 2.98 (stinging sensation in eyes) 
Table 3-1 Levels of Significant Exposure to Hydrogen Fluoride - Inhalation (continued) 

a 

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

(ppm) 

Serious 

18 

(NS) 

Rat 5 wks 

6hr/d Resp 

Hemato 

8.2 

31 

31 (pulmonary hemorrhage) 

Renal 8.2 31 (cortical necrosis) 

Ocular 8.2 (subcutaneous hemorrhage 

around the eyes and on the feet) 

19 

(NS) 

Mouse 5 wks 

6d/wk 6hr/d 

Dermal 8.2 (subcutaneous hemorrhage 

around the eyes and on the feet) 

20 

(NS) 

Dog 5 wks 

6d/wk 6hr/d 

Resp 31 (pulmonary hemorrhage) 

Hemato 31 

21 

(NS) 

Rabbit 5 wks 

6d/wk 6hr/d 

Resp 8.2 31 (pulmonary hemorrhage) 

22 

Neurological 

(albino) 

Rat 5mo 

24hr/d 

Hemato 31 

0.01 0.03 (disturbances in conditioned 

reflexes; lengthened latent periods) 

a The number corresponds to entries in Figure 3-1. b Used to derive an acute-duration inhalation minimal risk level (MRL) of 0.02 ppm; the concentration was divided by an uncertainty factor of 30 (3 for use of a to account for human variability). Bd = body weight; d = day(s); Hemato = hematological; hr = hour(s); incr = increase; LC50 = lethal concentration, 50% kill; LOAEL = lowest-observed-adverseminute(s); mo = month(s); NOAEL = no-observed-adverse-effect level; ppm = parts per million; RBC = red blood cell; Resp = respiratory; wk = week(s) 
10 

100 

1000 

Death Respiratory Hematological Hepatic Dermal Ocular 

Figure 3-1. Levels of Significant Exposure to Hydrogen Fluoride - Inhalation 

Acute (≤14 days) 

Systemic 

ppm 

100000 

1r 

10000 9r 1r 

5g 2r 9r 1r 2r 11r 2r 1r 9r 10r 9r 10r 2r 3r 12r 14r 

10r 11r 11r 9r 9r 13r

4m 12r 12r 12r 12r 10r 

13r 8 8 13r 13r 13

76

1 

6 

0.1 

0.01 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans h-Rabbit 

p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 
100 

Death Respiratory Hematological Renal Dermal Ocular 

Figure 3-1. Levels of Significant Exposure to Hydrogen Fluoride - Inhalation (Continued

Intermediate (15-364 days)

Systemic 

ppm 

16m 15r 20d 18r 21h 20d 18r 21h 18r 

10 

18r 21h 18r 19m 18r 

17 17 17 

1 

0.1 

0.01 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat h-Rabbit e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 
Table 3-2 Levels of Significant Exposure to Fluorine - Inhalation 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

ACUTE EXPOSURE Death 

1 Rat 1d 

270 (30-minute LC50) 5-60min/d (Osborne- 

Mendel) 390 (15-minute LC50)

700 (5-minute LC50) 185 (60-minute LC50) 

2 Mouse 1d 

225 (30-minute LC50) 15-60min/d (Swiss- 

Webster) 375 (15-minute LC50)

600 (5-minute LC50) 150 (60-minute LC50) 

3 Gn Pig 1d 

395 (15-minute LC50) 15-60min/d (New 

England) 170 (60-minute LC50)

4 Rabbit 1d 

820 (5-minute LC50) 5-30min/d (New 

Zealand) 270 (30-minute LC50)

Systemic 

5 Human 2-3 days 

3-5 minutes every 15 Dermal 10 (slight skin irritation) 

minutes 

Ocular 10 (slight eye irritation) 
a 

Key to 

figure 

Species 

(Strain) 

NOAEL Less Serious

System (ppm) (ppm)

Exposure/ 

Duration/ 

Frequency 

(Specific Route) 

Table 3-2 Levels of Significant Exposure to Fluorine 

LOAEL 

- Inhalation 

(ppm) 

Serious 

(continued) 

6 Human 15 minutes 

Resp Dermal Ocular 

10 

b

10 10 

7 Human 1d 

0.5min/d Resp 

Ocular 

100 (nasal irritation) 100 (eye irritation) 

8 Human 1d 

1min/d Resp 

Dermal Ocular 

67 

67 67 67 

(nasal irritation) (skin irritation) (eye irritation) 

9 Human 1d 

3min/d Resp 

Ocular 

10 10 

50 50 

(slight nasal irritation) (eye irritation) 

10 Human 1d 

5min/d Resp 

Dermal Ocular 

23 23 10 23 (slight eye irritation) 
Table 3-2 Levels of Significant Exposure to Fluorine - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

11 Rat 1d 

5min/d Resp 88 350 (irritation) (Osborne- 

Mendel) 175 (dyspnea; mild lung congestion) 

Ocular 88 175 (eye irritation) 

12 Rat 1d 

15min/d Resp 49 195 (irritation) (Osborne- 

Mendel) 98 (very mild lung congestion) 

Ocular 195 

13 Rat 1d 

30min/d Resp 35 140 (nasal irritation) (Osborne- 

Mendel) 70 (very mild lung congestion) 

Ocular 70 140 (eye irritation) 

14 Rat 1d 

60min/d Resp 28 93 (nasal irritation) (Osborne- 

Mendel) 47 (very mild lung congestion) 

Ocular 93 

15 Mouse 1d 

Resp 79 174 (dyspnea; nasal irritation; 5min/d (Swiss- diffuse lung congestion; alveola

Webster) necrosis) 

Hepatic 174 195 (necrosis and cloudy swelling) Renal 79 114 (necrosis) Ocular 300 467 (eye irritation) 
Table 3-2 Levels of Significant Exposure to Fluorine - Inhalation (continued) 

a 

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

(ppm) 

Serious 

16 

(SwissWebster) 

Mouse 1d 

15min/d Resp 65 188 (irritation) 

87 (very mild lung congestion) 

Ocular 188 

17 

(SwissWebster) 

Mouse 1d 

15min/d Resp 

Hepatic Renal 

65 

128 

65 

82 (alveolar necrosis and 

hemorrhage) 

144 (coagulation, necrosis, and 

cloudy swelling) 

82 (coagulation, necrosis) 

18 

(SwissWebster) 

Mouse 1d 

30min/d Resp 

Hepatic Renal 

51 82 51 

82 (alveolar necrosis and 

hemorrhage) 

116 (coagulation, necrosis, and 

cloudy swelling) 

82 (coagulation, necrosis) 

19 

(SwissWebster) 

Mouse 1d 

30min/d Resp 67 

32 

113 (irritation) 

67 (very mild lung congestion) 

Ocular 113 

20 

(SwissWebster) 

Mouse 1d 

60min/d Resp 30 150 (nasal irritation) 

50 (very mild lung congestion) 
a 

Key to 

figure 

Species 

(Strain) 

NOAEL Less Serious

System (ppm) (ppm)

Exposure/ 

Duration/ 

Frequency 

(Specific Route) 

Table 3-2 Levels of Significant Exposure to Fluorine 

LOAEL 

- Inhalation 

(ppm) 

Serious 

(continued) 

21 

(SwissWebster) 

Mouse 1d 

60min/d Resp 

Hepatic Renal 

30 55 50 

50 80 55 

(alveolar necrosis and 

hemorrhage) (necrosis and cloudy swelling) (necrosis) 

22 

(New England) 

Gn Pig 1d 

15min/d Resp 70 198 (irritation) 

100 (very mild lung congestion) 

23 

(New England) 

Gn Pig 1d 

60min/d Resp 73 135 (mild lung congestion, irritation, 

dyspnea) 

24 

(NS) 

Dog 1d 

15min/d Resp 39 93 (slight lung congestion) 

Ocular 39 93 (eye irritation) 

25 

(NS) 

Dog 1d 

60min/d Resp 

Ocular 

68 38 

93 68 

(irritation, cough, and slight 

dyspnea) (eye irritation) 

26 

(New Zealand) 

Rabbit 1d 

5min/d Resp 79 410 (irritation) 

134 (slight dyspnea) 
Table 3-2 Levels of Significant Exposure to Fluorine - Inhalation (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (ppm) (ppm) (ppm) 

27 Rabbit 1d 

30min/d Resp 32 135 (irritation) (New 

Zealand) 71 (very mild lung congestion) 

INTERMEDIATE EXPOSURE Death 

28 Rat 5 wks 

18 (100% mortality) 6d/wk (NS) 

6hr/d 

29 Dog 5 wks 

5 (100% mortality) 6d/wk (NS) 

6hr/d 

30 Rabbit 5 wks 

5 (100% mortality) 6d/wk (NS) 

6hr/d 

Systemic 

31 Rat 5 wks 

6d/wk Resp 5 18 (severe pulmonary irritation) (NS) 

6hr/d 

Bd Wt 18 (weight loss) 

32 Dog 5 wks 

6d/wk Resp 0.5 2 (pulmonary hemorrhage and (NS) edema) 

6hr/d 

Hepatic 5 18 (liver congestion) 

33 Rabbit 5 wks 

6d/wk Resp 0.5 2 (mild bronchial inflammation) 18 (hemorrhage in the lungs) (NS) 

6hr/d 

Hepatic 2 5 (hyperemia of the liver) 
Table 3-2 Levels of Significant Exposure to Fluorine - Inhalation (continued) 

a 

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

(ppm) 

Serious 

Reproductive 

34 Rat 5 wks 

5 18 (testicular degeneration) 6d/wk (NS) 

6hr/d 

a The number corresponds to entries in Figure 3-2. b Used to derive an acute inhalation minimal risk level of 0.01 ppm; the concentration was adjusted for intermittent exposure (0.25 hours/24 hours) and divided factor of 10 to account for human variability. d = day(s); Gn Pig = Guinea pig; LC50 = lethal concentration, 50% kill; LOAEL; lowest-observed-adverse-effect-level; min = minute(s); NOAEL = no-observedppm = parts per million; Resp = respiratory 
100 

1000 

Death Respiratory 

Figure 3-2. Levels of Significant Exposure to Fluorine - Inhalation

Acute (≤14 days)

Systemic 

ppm 

24d 25d 22g 7

4h 1r 2m 

3g 1r 

2m 11r 

1r 4h 2m 

1r 22g 16m 

3g 15m 11r 2m 23g 20m 

19m 

16m 17m 18m 11r 15m 25d 22g 23g 8 19m 19m 

16m 17m 

9 18m 20m 21m 

24d 

19m 20m 21m 

10 

10 6 9 

1 

0.1 

0.01 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat e-Gerbil LOAEL, Less Serious-Animals h-Rabbit LOAEL, Less Serious-Humans 

p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 
1000 

Hepatic Renal Dermal Ocular 

Figure 3-2. Levels of Significant Exposure to Fluorine - Inhalation (Continued) 

Acute (≤14 days) 

Systemic 

ppm 

15m 15m

15m 16m 

15m 1

17m 

17m 18m 15m 19m 100 24d 7 1

18m 21m 15m 17m 18m

17m 8 8 25d 8 

21m 18m 21m 21m 9

24d 25d 

10 10

10 5 6 5 6 9 

1

0.1 

0.01 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat h-Rabbit e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 
100 

Death Respiratory Hepatic Body Weight Reproductive 

Figure 3-2. Levels of Significant Exposure to Fluorine - Inhalation (Continued) 

Intermediate (15-364 days) 

Systemic 

ppm 

28r 31r 33h 32d 31r 34r 

10 

29d 30h 31r 32d 33h 34r 

32d 33h 33h 

1 

32d 33h 

0.1 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat h-Rabbit e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 
Table 3-3 Levels of Significant Exposure to Fluoride - Inhalation 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (mg/m3) (mg/m3) (mg/m3) 

ACUTE EXPOSURE Systemic 

1 Mouse 4 hours/day 

10 days Resp 13.3 M (increased relative lung weight) (ICR) 

2 Mouse 4 hour/day 

Resp 2 M 10 M (pulmonary edema) 14 days (BALB/c) 

Immuno/ Lymphoret 

3 Mouse 4 hour/day 

14 days 2M 5 M (decreased pulmonary (BALB/c) bactericidal activity) 

INTERMEDIATE EXPOSURE Systemic 

4 Mouse 4 hours/day 

20-30 days Resp 13.3 M (increased relative lung weight) (ICR) 

a The number corresponds to entries in Figure 3-3. LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; Resp = respiratory 
100 

Respiratory Immuno/Lymphor 

Systemic 

Figure 3-3. Levels of Significant Exposure to Fluoride - Inhalation 

Acute (≤14 days) 

1m 

10 2m 

3m 

2m 3m 

1 

mg/m3 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 

h-Rabbit 
100 

Respiratory 

Systemic 

Figure 3-3. Levels of Significant Exposure to Fluoride - Inhalation (Continued) 

Intermediate (15-364 days) 

4m 

mg/m3 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat e-Gerbil LOAEL, Less Serious-Animals h-Rabbit LOAEL, Less Serious-Humans p-Pig s-Hamster NOAEL - Animals NOAEL - Humans a-Sheep q-Cow 

g-Guinea Pig 

10 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 56 

3. HEALTH EFFECTS 

individuals exposed to 0.5 or 4.5 ppm hydrogen fluoride for 1 hour (Lund et al. 1997). Significant 

increases in the percentage of CD3-positive cells and lymphocytes in the bronchial portion of the lower 

respiratory tract, as assessed via bronchoalveolar lavage performed 3 weeks prior to exposure and 

24 hours after exposure, was also observed at 4.5 ppm, but not at 0.5 ppm (Lund et al. 1999). However, 

no significant alterations in lung function or lower airway symptoms were observed (Lund et al. 1997). 

The second study with a similar study design assessed upper airway inflammation via nasal lavage (Lund 

et al. 2002). An inflammatory response in the nasal mucosa was observed following a 1-hour exposure to 

3.8–4.5 ppm hydrogen fluoride. Seven of the 10 tested subjects also reported upper airway symptoms 

(specific symptoms were not presented); most of the subjects scored the severity of the symptoms as very 

mild to mild. 

A number of residents of Texas City, Texas, reported respiratory symptoms following the accidental 

release of hydrogen fluoride. It was estimated that most of the hydrogen fluoride was released in the first 

2 hours after the accident, and evacuation of residents within 0.5 miles of the facility began within 

20 minutes of the accident. Many of the 939 people who went to the emergency room within 24 hours of 

the accident reported signs of respiratory irritation: throat burning (21.0%), shortness of breath (19.4%), 

sore throat (17.5%), and cough (16.4%) (Wing et al. 1991). Forced expiratory volume in 1 second 

(FEV1) was <80% of predicted values in 42.3% of the 130 individuals who underwent pulmonary 

function testing. In another study of the Texas City residents, health effects within 1 month of the 

accident and 2 years after the accident were assessed in 1,994 residents who were asked to complete 

health questionnaires 2 years after the accident (Dayal et al. 1992). A large number of highly exposed 

residents reported severe symptoms of breathing problems (e.g., coughing, difficulty breathing, shortness 

of breath), throat problems (e.g., difficulty swallowing, burning irritation, phlegm, voice changes), and 

nose problems (e.g., sneezing, runny nose, problems smelling food); the prevalence of severe symptoms 

were 60.2, 51.9, and 40.7% for breathing, throat, and nose problems, respectively, within the first month 

of the accident. High prevalence of these effects was still reported 2 years after the accident; 38.5, 22.1, 

and 26.5% for severe breathing, throat, and nose problems, respectively. The prevalence of severe 

breathing, throat, and nose problems in the nonexposed population were 11.3, 6.2, and 6.4%, respectively, 

within 1 month of the accident and 8.2, 3.3, and 4.1%, respectively, 2 years after the accident. The 

prevalence of the breathing problems were higher in a subgroup of the high exposure group that had preexisting respiratory problems or smoked more than two packs of cigarettes per day. Although this study 

(Dayal et al. 1992) provides suggestive evidence that acute exposure to hydrogen fluoride can result in 

long-term damage to the respiratory tract, the study results should be interpreted with caution. The 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 57 

3. HEALTH EFFECTS 

symptom survey was administered 2 years after the accident, there was no medical confirmation of the 

effects, and the study authors did not provide a definition for severe symptoms. 

Lethality studies in animals have also reported respiratory effects in rats, mice, and guinea pigs from 

acute inhalation exposure to hydrogen fluoride. True respiratory effects, such as respiratory distress, 

pulmonary congestion, and intra-alveolar edema were generally observed at levels of at least ~50% of the 

LC50 (Haskell Laboratory 1988; Rosenholtz et al. 1963; Wohlslagel et al. 1976). These effects appear to 

be reversible within a week upon cessation of exposure. 

A series of experiments by Dalbey et al. (1998a, 1998b) examined the acute toxicity of nonlethal 

concentrations of hydrogen fluoride in rats following a 2- or 10-minute exposure. In most of the 

experiments, a mouth-breathing model with a tracheal cannula was used to maximize delivery of 

hydrogen fluoride to the lower respiratory tract. A number of respiratory tract effects were found in the 

mouth-breathing rats, including alterations in bronchioalveolar lavage (BAL) parameters (increased total 

protein, myeloperoxidase, lactate dehydrogenase, β-glucuronidase, and glucose-6-phosphate 

dehydrogenase), impaired lung function (decreased total lung capacity, vital capacity, peak expiratory 

flow, forced expiratory flow at 50 and 25% of the forced vital capacity, forced expiratory volume at 

0.1 second, forced vital capacity, and diffusing capacity and increased pulmonary resistance), and 

histological damage (necrosis and acute inflammation in trachea and acute alveolitis and perivascular/ 

peribronchial edema and inflammation in the lung). Rats exposed for 2 minutes manifested histological 

damage and BAL parameter alterations at 1,509 ppm fluoride and impaired lung function at 4,643 ppm. 

No adverse respiratory effects were observed at 563 ppm fluoride. In the rats exposed for 10 minutes, 

histopathological alterations (necrosis of the trachea only) and BAL parameters (polymorphonuclear 

leukocytes and myeloperoxidase levels only) were observed at 903 ppm fluoride; impaired respiratory 

function was observed at 1,676 ppm fluoride. No adverse effects were observed at 257 ppm fluoride. 

The respiratory effects were consistently more severe in the rats exposed for 2 minutes as compared to 

10 minutes, when exposure was expressed as the product of concentration x time. In other experiments, 

rats were exposed for 60 minutes to hydrogen fluoride. No adverse respiratory effects were observed at 

19 or 46 ppm. Respiratory effects observed in nose-breathing rats were limited to the nose. Necrosis and 

acute inflammation of the ventral meatus, nasal septum, and nasoturbinates were observed in rats exposed 

to 6,072 ppm for 2 minutes and 1,586 ppm for 10 minutes. A dramatic decrease in breathing frequency 

was also observed in the nose-breathing rats; within the first minute of exposure, breathing frequency was 

32–35% of the preexposure levels. The decrease in breathing frequency, which is a component of reflex 

apnea, is a response to sensory irritation. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 58 

3. HEALTH EFFECTS 

Similar results were observed in rats exposed to 1,235 ppm fluoride for 30 minutes. Moderate to severe 

fibronecrotic rhinitis and large fibrin thrombi in the submucosa and hemorrhage were observed in the 

nasal cavity of nose-breathing rats; no nasal lesions were observed in similarly exposed rats fitted with a 

tracheal cannula to simulate mouth-breathing. Epithelial, submucusal, and cartilage necrosis in the 

trachea, trace levels of neutrophils in the alveoli, and necrosis of the bronchi were observed in the mouthbreathing rats, but not in the nose-breathing rats, suggesting that the toxicity of hydrogen fluoride occurs 

at the point of entry. Reflex apnea, as evidenced by a marked decrease in breathing frequency, was 

observed in the nose-breathing rats. Based on differences in minute ventilation rates, the study authors 

estimated that the mouth-breathing rats inhaled 27% more hydrogen fluoride than the nose-breathing rats. 

Pulmonary hemorrhage was noted in dogs, rabbits, and rats exposed to 31 ppm fluoride as hydrogen 

fluoride for 6 hours/day, 6 days/week for 5 weeks (Stokinger 1949). At 8.2 ppm fluoride, no effect was 

seen in rats or rabbits, and localized hemorrhages were seen in only 1/5 dogs. 

Pulmonary hemorrhage, alveolar inflammation, and hyperplasia of the bronchial epithelium were 

observed in guinea pigs that died due to exposure to 18 ppm fluoride as hydrogen fluoride for 6– 

7 hours/day, 5 days/week for about 35 days (Machle and Kitzmiller 1935). This effect was not readily 

reversible. The one surviving guinea pig had alveolar exudates, thickening of the alveolar walls, and 

hemorrhages of the lungs when necropsied 9 months after the conclusion of the full 50-day exposure 

period. Similarly, all four rabbits exposed under the same conditions had lobular pneumonia and 

leucocytic infiltration of the alveolar walls, sometimes with edema and thickening of the walls, when 

necropsied 7–8 months after the last exposure. No clinical signs of toxicity were reported in rabbits and 

weight gain was generally similar to the controls. This study is limited by the small number of animals 

used and the incomplete reporting of the data. 

Hydrogen Fluoride and Fluoride Dusts. A study of an occupational cohort exposed to hydrogen 

fluoride and fluoride dusts in the pot rooms of an aluminum smelter reported a significantly lower forced 

expiratory volume and increased cough and sputum production in the highest exposure group, compared 

with controls who worked in the office or casting department and were reported to have no significant 

occupational exposure to air contaminants. Corrections were made for age, height, and smoking habits. 

The ambient air fluoride concentration in the high-exposure area was 0.2 mg fluoride/m3

 as vapor 

(presumably hydrogen fluoride) and 0.28 mg/m3

 "particulate fluoride." It is not clear whether the latter 

value represented the air concentration of fluoride in particulates or the concentration of the particulates 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 59 

3. HEALTH EFFECTS 

that contain fluoride. Actual exposure was unknown because the workers wore respirators. Although 

urinary fluoride levels increased over the course of one work shift in the high-exposure group and not in 

the control group, the decrease in respiratory volume in the same time period was about the same in both 

groups (Chan-Yeung et al. 1983a). This effect was attributed to the fact that the exposed workers wore 

respirators; historical use of respirators was not reported. Because actual exposure was not known, no 

quantitative relationship between clinical symptoms and environmental or urinary fluoride levels could be 

established. There also may have been concomitant exposure to other respiratory irritants. 

Fluoride Particulates. There is limited information on the respiratory toxicity of fluorides. Significant 

increases in relative lung weight were observed in mice exposed to 13.3 mg F/m3

 as sodium fluoride 

4 hours/day for 10, 20, or 30 days (Chen et al. 1999). The toxicological significance of this effect is not 

known because histopathology was not conducted. In another study of mice (Yamamoto et al. 2001), 

lung damage, as evidenced by significant decreases in total cells and alveolar macrophages and increases 

in polymorphocytic neutrophils and lymphocytes in the bronchoalveolar lavage fluid, was found in mice 

exposed to 10 mg F/m3

 as sodium fluoride 4 hours/day for 14 days. An increase in polymorphocytic 

neutrophils was also observed at 5 mg/m3

. 

Fluorine. Limited data are available regarding respiratory effects of fluorine on humans. Five volunteers 

(19–50 years of age; gender not specified) were exposed to fluorine through a face mask that covered the 

eyes and nose but not the mouth (Keplinger and Suissa 1968). A concentration of 10 ppm was not 

irritating to the respiratory tract for at least 15 minutes. Slight nasal irritation was reported following a 

3-minute exposure to 50 ppm, and exposure to 100 ppm for 0.5 or 1 minute was very irritating to the 

nose. Intermittent inhalation (3–5-minute exposure every 15 minutes for 2–3 hours) of 23 ppm did not 

cause respiratory difficulty. 

An occupational cohort study comparing the incidence of respiratory complaints by 61 exposed workers 

with over 2,000 "unexposed" workers found no increase in the exposed group (Lyon 1962). The average 

fluorine level was 0.9 ppm, and the maximum measured value was 24 ppm. The study author concluded 

that the workers became "hardened" to the irritating effects of fluorine. The study is limited in that both 

groups were also exposed to uranium hexafluoride and hydrogen fluoride. The method of measuring 

respiratory complaints (visits to the plant medical department) was also not very sensitive. However, the 

observation of tolerance caused by repeated low level exposures is supported by the results from animal 

studies discussed in Section 3.2.1.1 and later in this section (Keplinger 1969). 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 60 

3. HEALTH EFFECTS 

Diffuse lung congestion has been reported in rats, mice, guinea pigs, dogs, and rabbits exposed to fluorine 

for 5–60 minutes (Keplinger and Suissa 1968). The severity was concentrated-related. The adverse 

effect levels for each exposure duration did not appear to vary across species. The ranges of adverse 

effect levels for each exposure duration were 174–175 ppm for 5 minutes, 87–100 ppm for 15 minutes, 

67–71 ppm for 30 minutes, and 47–135 ppm for 60 minutes. Other respiratory effects that were observed 

in these animals included dyspnea, irritation, and alveolar necrosis. 

In 5-week exposure studies conducted by Stokinger (1949), pulmonary hemorrhage, edema, and bronchial 

inflammation were reported. These studies found species differences in sensitivity to fluorine-induced 

respiratory effects. Exposure to 2 ppm, 6 hours/day, 6 days/week for 5 weeks resulted in no effects in 

rats, pulmonary hemorrhage and edema in dogs, and mild bronchial inflammation in rabbits; respiratory 

effects (severe pulmonary irritation) were observed in rats exposed to 18 ppm. 

Swiss-Webster mice that were preexposed once to 30 ppm fluorine for 60 minutes and then exposed to 

118–410 ppm fluorine for 15 minutes after an interval of 4–96 hours showed markedly less lung 

pathology than animals that were not pretreated (Keplinger 1969). At the highest level (410 ppm), 

exposure 4 hours prior to the challenge reduced the lung pathology from the most severe rating to a rating 

of normal–mild. Preexposure also reduced the increased lung weight otherwise seen following fluorine 

exposure. However, a similar preexposure regimen only resulted in slight increases in the LC50, as 

discussed in Section 3.2.1.1. 

Cardiovascular Effects. 

Hydrogen Fluoride. Cardiac arrhythmias have been seen in humans following hydrofluoric acid splashes 

in the face region, where both dermal and inhalation exposures were involved (Chan et al. 1987; 

Tepperman 1980). It is not known whether inhalation exposure alone would cause these effects. 

However, myocardial necrosis and congestion were observed in three rabbits following inhalation 

exposure of 26 ppm fluoride as anhydrous hydrogen fluoride for an unspecified period (Machle et al. 

1934). The study was limited by the small sample size and undetermined exposure period. 

Gastrointestinal Effects. 

Hydrogen Fluoride. A population exposed to airborne hydrogen fluoride near a smelter reported nausea 

(22.6%) and diarrhea (21.7%). The corresponding levels reported by a control population were 6.9 and 

12.1%, respectively. The total levels of gastrointestinal complaints were 70.5 and 36.2% in the subject 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 61 

3. HEALTH EFFECTS 

and control populations, respectively. The subject population appears to have been derived by selfselection and random house-to-house sampling, while the control population lived in a nonindustrial area. 

Although atmospheric concentrations were not presented, concentrations of fluoride in animals and plants 

in the area surrounding the smelter were substantially above normal. The smelter was also reported to 

emit metallic oxide fumes (Waldbott 1979). 

Similar gastrointestinal effects (diarrhea, nausea, and vomiting) were reported by Texas residents exposed 

to an accidental 2-hour release of hydrogen fluoride (Dayal et al. 1992). During the first month after the 

accident, 38.5% of the highly exposed residents reported severe gastrointestinal effects; 15.5% of the 

residents still reported severe gastrointestinal effects 2 years after the accident. The occurrence of severe 

gastrointestinal effects among nonexposed residents was 4.5 and 2.7%, respectively, for these time 

periods. 

Hematological Effects. 

Hydrogen Fluoride. Hemograms of 20 variables (not specified) determined in the rat (30/group), rabbit 

(10/group), and dog (4/group) following exposure to 18 ppm fluoride for 6 hours/day, 6 days/week, for 

5 weeks showed no clear changes (Stokinger 1949). 

Five rabbits and two Rhesus monkeys were exposed to 18 ppm fluoride as hydrogen fluoride via 

inhalation 6–7 hours/day, for 50 days (Machle and Kitzmiller 1935). Blood counts were done beginning 

1 week prior to exposure and ending 3 months after the final exposure. There was a small but significant 

decrease in erythrocyte levels in both species, but the study authors considered that the result may have 

been due to biological variation. Significant increases in hemoglobin levels were seen in monkeys. There 

was no effect on hemoglobin levels in rabbits or on leukocyte levels in either species. These experiments 

used only a few animals from each species, and the exposure measurement technology was not very 

precise. 

Hydrogen Fluoride and Fluoride Dusts. No signs of hematological effects, as measured by routine 

blood counts, were seen in a large cohort of aluminum workers exposed to total fluoride levels below 

2.5 mg/m3

 for durations of at least 10 years (Chan-Yeung et al. 1983b). Similarly, no increase in 

abnormal findings was seen in 74 workers exposed at a phosphate fertilizer plant (Derryberry et al. 1963). 

The average urinary fluoride level in the exposed group was 4.6 mg/L. Significantly reduced levels of 

hemoglobin were reported in Slovak children aged 6–14 years living near an aluminum smelter (Macuch 

et al. 1963), but no information was provided on any statistical tests used. No information was provided 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 62 

3. HEALTH EFFECTS 

on air fluoride concentrations, but urinary fluoride levels were about 0.8 mg/L for 6–11-year-old children 

and about 0.4 mg/L for 12–14-year-old children. In an outdated study of 78 workers exposed to cryolite, 

anemia was present in 11/30 subjects with pathological bone changes (Moller and Gudjonsson 1932). 

Blood parameters were not analyzed for the workers without bone changes. 

Fluorine. No studies were located on hematological effects of inhalation exposure of humans to fluorine. 

No effect on complete blood count parameters was observed in Osborne-Mendel rats exposed to 142 ppm 

for 60 minutes or 329 ppm for 15 minutes or in dogs exposed to 109 ppm for 60 minutes or 93 ppm for 

15 minutes (Keplinger and Suissa 1968). These concentrations were higher than the corresponding 

LC50 values. Blood counts were monitored for 21 days postexposure. Similarly, Stokinger (1949) saw no 

effect on hematological parameters in dogs, rabbits, or rats following repeated exposures at 

concentrations up to lethal levels (31 ppm). This study did not specify which parameters were measured. 

Musculoskeletal Effects. 

Fluoride. There are several case reports of radiological alterations (primarily thickening of the bone) in 

workers exposed to sodium fluoride (McGarvey and Ernstene 1947), rock phosphate dust containing 

3.88% fluoride (Wolff and Kerr 1938), or cryolite (Roholm 1937). In the two cryolite workers, the 

fluorine content of the costa bone was 10-fold higher than in non-exposed individuals. Roholm (1937) 

also examined 68 cryolite workers exposed to high levels (35 mg/m3

) of cryolite dust. Approximately 

35% of the workers complained of “rheumatic attacks, pains, or feeling of stiffness” and reduced mobility 

was found in approximately 21% of the workers. Radiological examinations revealed diffuse 

osteosclerosis in approximately 84% of the workers. 

No studies were located regarding musculoskeletal effects in animals after inhalation exposure to fluoride. 

Hydrogen Fluoride. Human data on the musculoskeletal effects of hydrogen fluoride (in the absence of 

concomitant exposure to fluoride dusts) are limited to a case report of a worker employed at an alkylation 

unit of an oil company (Waldbott and Lee 1978). The worker complained of back pains, leg pains, and 

loss of memory and was diagnosed with advanced osteoarthritis of the spine. The data presented in this 

report are inadequate to assess whether the back and leg pains were related to hydrogen fluoride exposure, 

the osteoarthritis, or a petroleum product. 

Duration- and concentration-related increases in tooth and bone fluoride levels were reported in the rat 

following exposure to 8.2 or 31 ppm fluoride as hydrogen fluoride for 6 hours/day, 6 days/week for 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 63 

3. HEALTH EFFECTS 

5 weeks (Stokinger 1949). The study author did not report whether there were any visible or radiological 

signs of dental or skeletal fluorosis. 

Hydrogen Fluoride and Fluoride Dusts. Marked evidence of skeletal fluorosis was reported in workers 

exposed to gaseous fluoride (largely hydrogen fluoride) and fluoride dust in the pot rooms of the 

aluminum industry (Kaltreider et al. 1972). Individual exposure concentrations and durations were not 

presented. However, the estimated time-weighted average (TWA) 8-hour exposure to total fluorides for 

one plant ranged from 2.4 to 6.0 mg/m3

. Average post-shift urinary fluoride levels were about 9 mg/L. 

Exposure at a second plant was lower as a result of industrial hygiene measures; no TWA was available, 

but post-shift urinary fluoride levels ranged from 1.4 to 4.6 mg/L. No skeletal changes were observed at 

the second plant, and detailed physical examinations of the workers at both plants revealed no general 

health impairment. No data were presented that correlated urinary fluoride levels to the presence or 

absence of fluorosis. 

In a follow-up study of 59 of the potroom workers at the second plant, the average preshift (after 48 hours 

away from work) urinary fluoride level was 2.24 mg/L (range, 1.4–3.1). The average level after 3– 

5 working days (postshift) was 5.68 mg/L (range, 2.7–10.4). In spite of this evidence of fluoride 

exposure, there was no radiological evidence of any fluoride-related bone abnormalities (Dinman et al. 

1976c). Total occupational exposure ranged from 10 to 43 years. This study may provide urinary 

fluoride levels that are not associated with any bone effects in healthy adults. However, because only 

workers who remained at the high-exposure tasks for the duration of the study were examined, any 

sensitive population that may have found work elsewhere because of adverse health effects might have 

been missed. 

Clinical and radiological investigations were performed for 2,258 aluminum workers exposed to fluoride 

for an average of 17.6 years (Czerwinski et al. 1988). The form of fluoride was not reported, but it was 

probably hydrogen fluoride and fluoride dust. Possible fluorosis (multiple joint pains, limited motion in 

at least two joints or in the spine, and initial ossifications visible on x-ray films) was found in 14% of the 

workers. Indications of early skeletal fluorosis (advanced painful symptoms, advanced limitation of 

motion in at least two joints or spine, marked ossifications on two or more x-rays, initial osteosclerosis, 

slight periosteal reaction, and thickening of long bone cortices ) were found in 5.12% of the workers and 

definite fluorosis (stage I) was found in 1.0% of the workers. The study authors reported finding a close 

positive correlation between the occurrence of fluorosis and the time and level of fluoride exposure. 

Another health study of 2,066 workers in an aluminum smelter reported early signs of skeletal fluorosis 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 64 

3. HEALTH EFFECTS 

(mild increase in bone density, periosteal changes, calcifications of ligaments) in a few pot room workers 

employed for >10 years. The study authors noted that there was poor agreement on early signs of 

fluorosis among the two radiologists reading the x-ray films. No effects were seen in workers exposed for 

<10 years. Actual airborne fluoride levels measured at the time of the health assessment were 0.2 mg/m3 

hydrogen fluoride and 0.28 mg/m3

 fluoride dusts. Historical fluoride levels were not reported; although 

the study authors implied that exposure levels had been below 2.5 mg/m3

 for some period (Chan-Yeung et 

al. 1983b). 

Skeletal fluorosis was also observed in workers involved in study the crushing and refining of cryolite 

(Moller and Gudjonsson 1932). Thirty-nine of the 78 examined workers showed evidence of skeletal 

fluorosis in the form of dense calcification in the long bones, cartilage, and in extreme cases, of the skull 

as well. Although an average exposure period was not presented, no workers with <2 years of exposure 

were included; some workers had been exposed for as long as 40 years. 

While the above studies generally found radiologically-apparent skeletal fluorosis appearing prior to or 

concurrent with musculoskeletal symptoms, Carnow and Conibear (1981) found musculoskeletal 

symptoms in aluminum workers in the absence of radiological findings. Questionnaire answers suggested 

a significant increase in incidence and severity of musculoskeletal disease and fracture frequency with 

fluoride exposure. By contrast, there was no exposure-related increase in evidence of skeletal fluorosis 

on chest and spinal x-ray films. Neither radiologic data nor actual exposure levels or durations were 

reported. As the authors recognized, the exposure group was heterogeneous and was exposed to other 

chemicals, and some of the musculoskeletal symptoms may have actually been due to heavy physical 

labor. 

Fluorine. No data were located regarding musculoskeletal effects of fluorine inhalation on humans. 

Fluoride levels in the teeth of rats exposed to 18 ppm fluorine for approximately 6 hours/day, 6 days/week 

for 5 weeks were about 14 times the levels in controls; fluoride levels in the femur were about 6 times that 

of the controls (Stokinger 1949). The appearance of the teeth was characterized as corresponding to that 

of very mild to mild dental fluorosis. The fluoride levels in the teeth and bone at lower concentrations 

decreased in a concentration-related manner. Pigment changes were reported as just perceptible in 

animals exposed to 2 ppm fluorine. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 65 

3. HEALTH EFFECTS 

Hepatic Effects. 

Hydrogen Fluoride. Ten animals (five rabbits, three guinea pigs, and two Rhesus monkeys) were 

exposed via inhalation to 18 ppm fluoride as hydrogen fluoride 6–7 hours/day for 50 days (Machle and 

Kitzmiller 1935). Fatty degeneration of the liver parenchyma, scattered focal necroses, and fibroblastic 

encroachment of periportal spaces were observed in the guinea pigs. Two of the three guinea pigs began 

losing weight after about 145 hours of exposure, were withdrawn from the exposure regimen, and died 

about 2 weeks later. Generalized fatty changes were also seen in two of four rabbits sacrificed 7 months 

after exposure termination. These experiments used only a few animals from each species, and the 

exposure measurement technology was not very precise. 

Hydrogen Fluoride and Fluoride Dusts. The occupational health study by Chan-Yeung et al. (1983b) 

discussed above revealed no adverse effects on liver function, as measured by levels of total bilirubin, 

serum glutamic oxaloacetic transaminase (SGOT), and alkaline phosphatase. 

Fluorine. No studies were located regarding hepatic effects of fluorine inhalation in humans. Mice 

exposed to fluorine exhibited coagulation necrosis of the liver, periportal hemorrhages, and diffuse cloudy 

swelling (Keplinger and Suissa 1968). These effects were generally observed after exposure to 

concentrations of 195, 144, 116, or 80 ppm fluoride for 5, 15, 30, or 60 minutes, respectively. Damage 

became apparent 7–14 days after exposure. Liver congestion was reported in dogs, but not in other 

species subjected to repeated exposures to a lethal concentration of fluorine (18 ppm 6 hours/day, 

6 days/week for 5 weeks) (Stokinger 1949). 

Renal Effects. 

Hydrogen Fluoride. Pathologically elevated serum creatinine and urea levels were seen 24 hours after 

accidental dermal and inhalation exposure to a mixture of 70–80% sulfuric acid and 10% hydrofluoric 

acid at 150 °C (Braun et al. 1984). Neither the effect of the sulfuric acid nor the exposure levels were 

known. 

Degeneration and necrosis of the renal cortex was reported in 27/30 rats exposed to 31 ppm fluoride as 

hydrogen fluoride for 6 hours/day, 6 days/week for 5 weeks, but not in rats exposed to 8.2 ppm fluoride 

(Stokinger 1949). Pathological examination of rabbits and guinea pigs (n=3/species/exposure level) 

exposed to hydrogen fluoride revealed tubular necrosis, congestion, and edema (Machle et al. 1934). A 

variety of different exposure levels and durations were tested, but the levels at which exposure-related 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 66 

3. HEALTH EFFECTS 

effects were seen were not reported. Rabbits (n=4) exposed via inhalation to 18 ppm fluoride as 

hydrogen fluoride 6–7 hours/day for 50 days developed degeneration and necrosis of convoluted tubules, 

accompanied by fibrous tissue replacement of cortical tissues (Machle and Kitzmiller 1935). 

Degenerative and inflammatory changes were also seen in the single exposed monkey at necropsy. The 

experiments described in both of these papers used a small number of animals and no control data were 

presented. 

Hydrogen Fluoride and Fluoride Dusts. Increased incidence of albuminuria (p<0.1) was observed in 

phosphate fertilizer plant workers with an average urinary fluoride level of 4.6 mg/L (Derryberry et al. 

1963). However, the testing method used in this study is considered to be hypersensitive (Dinman et al. 

1976a), and several other studies have found no effects. No signs of renal effects, as measured by 

standard renal function tests, were seen in a large cohort of aluminum workers exposed to total fluoride 

levels estimated to be below 2.5 mg/m3

 (Chan-Yeung et al. 1983b). Two other studies of aluminum 

workers failed to find an increase in the incidence of albuminuria (Dinman et al. 1976c; Kaltreider et al. 

1972). Average postshift urinary fluoride levels were ≤5.68 mg/L (Dinman et al. 1976c) and ≤9.6 mg/L 

(Kaltreider et al. 1972). The exposed population included workers exposed to estimated air fluoride 

levels of 4–6 mg/m3

 (time-weighted average), of which 50% was gaseous fluoride (presumably hydrogen 

fluoride) (Kaltreider et al. 1972). 

The weight-of-evidence indicates that typical inhalation occupational exposure to hydrogen fluoride and 

fluoride dust is not nephrotoxic. The overall animal data indicate that inhalation exposure to sufficiently 

high levels of hydrogen fluoride or fluorine can cause kidney damage, but the relevance to human health 

and the potential nephrotoxic level cannot be determined because of generally incomplete human and 

animal data. In addition, only one animal experiment was located that conducted a histopathic exam 

following fluorine exposure. 

Fluorine. No studies were located regarding renal effects of fluorine inhalation in humans. Mice 

exposed to fluorine exhibited focal areas of coagulation necrosis in the renal cortex and focal areas of 

lymphocyte infiltration in the cortex and medulla following exposure to 114 ppm for 5 minutes, 82 ppm 

for 15 or 30 minutes, or 55 ppm for 60 minutes (Keplinger and Suissa 1968). Damage became apparent 

7–14 days postexposure. 

Endocrine Effects. No studies were located regarding endocrine effects in humans or animals after 

inhalation exposure to fluoride, hydrogen fluoride, or fluorine. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 67 

3. HEALTH EFFECTS 

Dermal Effects. 

Hydrogen Fluoride/Hydrofluoric Acid. Dermal exposure to hydrogen fluoride can cause irritation of the 

skin and mucous membranes. Residents exposed to hydrogen fluoride following an accidental release 

reported a number of skin effects including itching, burning, and rash; 43.8% of the highly exposed 

residents reported severe skin problems, as compared to 5.3% of nonexposed residents (Dayal et al. 

1992). Two years after the accident, severe skin problems were reported by 21.9% of the high-exposure 

group compared to 2.7% of the control group. “Smarting" of exposed skin occurred in humans within 

1 minute of exposure to hydrogen fluoride at about 122 ppm fluoride (Machle et al. 1934). This was the 

highest concentration that two male volunteers could tolerate for >1 minute. Repeated exposures did not 

reveal any habituation. 

Exposure to hydrogen fluoride levels approaching the LC50 can cause lesions of the face in rats (Haskell 

Laboratory 1988). Rats exposed to hydrogen fluoride (whole body) at a concentration of approximately 

1,395 ppm fluoride for 60 minutes were observed to have erythema of an unspecified severity of the 

exposed skin (Wohlslagel et al. 1976). Subcutaneous hemorrhages around the eyes and on the feet 

developed in rats exposed to 8.2 or 31 ppm fluoride as hydrogen fluoride for 6 hours/day, 6 days/week for 

5 weeks (Stokinger 1949). The effect was more severe at the higher exposure level. Dogs exposed to 

31 ppm fluoride for the same time periods developed inflammation of the scrotal epithelium. 

Fluorine. When the shaved backs of New Zealand rabbits were exposed to fluorine gas under 40 pounds 

of pressure for 0.2–0.6 seconds at distances of 0.5–1.5 inches, the resulting burn appeared to be thermal, 

rather than chemical in nature (Stokinger 1949). Exposure for 0.2 seconds produced an ischemic area 

about 1⁄4 inch in diameter, surrounded by an erythematous area. This became a superficial eschar that 

sloughed off within 4 days, revealing normal epidermis. The longer exposures produced a flash of flame 

that resulted in combustion of hair, singeing, and erythema over an area several times the area of the 

primary burn. Coagulation necrosis and charring of the epidermis was also reported. The wound healed 

within 13 days. The burns resembled those produced by an oxyacetylene flame, rather than those made 

by hydrofluoric acid, and so were characterized as thermal, rather than chemical. However, it is not clear 

if the difference from the hydrofluoric acid burn is due to the shorter exposure to fluorine. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 68 

3. HEALTH EFFECTS 

Ocular Effects. 

Hydrogen Fluoride. Marked conjunctival irritation was noted in humans within 1 minute of exposure to 

hydrogen fluoride at about 122 ppm fluoride (Machle et al. 1934). This was the highest concentration 

that two male volunteers could tolerate for >1 minute. At 61 ppm fluoride, conjunctival and nasal 

irritations were still marked, and tickling and discomfort of the nasal passages were reported. A 

concentration of 32 ppm fluoride produced mild irritation of the nose and eyes and irritation of the larger 

air passages. This concentration could be tolerated for "several" minutes (at least 3 minutes). The 

authors of this study reported some difficulties with their measurements of exposure. Repeated exposures 

did not reveal any habituation. 

Severe symptoms of eye problems were reported by 63.2% of Texas residents exposed to high levels of 

hydrogen fluoride following an accidental release (Dayal et al. 1992). The most commonly reported eye 

effects were redness, itching, and burning or irritation. Two years after the accident, 11.5% of the 

population still reported severe eye problems. In nonexposed residents, the prevalence of severe 

symptoms within the first month of the accident was 7.4; 2 years later, the prevalence was 4.9. 

Mild eye irritation was observed in five volunteers exposed 6 hours/day for 15–50 days, to hydrogen 

fluoride at concentrations averaging from approximately 0.85 to 7.7 ppm fluoride; the mean of the 

average concentrations was 2.98 ppm (Largent 1960). This study is limited by the inadequacy of both the 

experimental details and the description of effects observed. 

Hydrogen fluoride levels approaching the LC50 can cause corneal opacity in rats (Haskell Laboratory 

1988), while slight ocular irritation was observed in rats exposed to levels as low as 6% of the LC50 

(Rosenholtz et al. 1963). Eye irritation, evidenced by pawing of eyes, was observed in rats exposed to 

140 or 175 ppm fluorine for 30 or 5 minutes, respectively, and in dogs exposed to 68 or 93 ppm fluorine 

for 60 or 15 minutes, respectively. In experiments with exposure for durations of 15–60 minutes, eye and 

nose irritation was reported only at ~50% of the LC50. Similar results were obtained with Swiss-Webster 

mice, New England guinea pigs, and New Zealand rabbits (Keplinger and Suissa 1968). 

Fluorine. Volunteers (19–50 years of age) were exposed to 10 ppm fluorine for 15 minutes without 

discomfort or irritation of the eyes or nose (Keplinger and Suissa 1968). However, repeated exposures to 

10 or 23 ppm fluorine for 3–5 minutes every 15 minutes over a 2–3-hour period caused slight eye 

irritation. Exposure was through a face mask that covered the eyes and nose but not the mouth. Eye 

irritation was also reported following exposure to 50 ppm for 3 minutes and 67 and 78 ppm for 1 minute. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 69 

3. HEALTH EFFECTS 

Exposure to 100 ppm was very irritating and became uncomfortable after a few seconds. At this 

concentration, the subjects reported that the eyes burned and felt as though they were covered by a film. 

Body Weight Effects. 

Hydrogen Fluoride. Pronounced weight loss shortly before death was observed in rats exposed to a 

lethal level of hydrogen fluoride (31 ppm fluoride for 6 hours/day, 6 days/week for 5 weeks). Guinea 

pigs exposed under the same conditions lost weight following the third exposure week, even though there 

were no deaths (Stokinger 1949). While a decrease compared to the low-exposure level group is clear, no 

control animals were used and the lowest exposure level that would result in a significant change was not 

established. Animals surviving a lethal exposure exhibited a body weight loss of 10–15% for up to a 

week after exposure (Rosenholtz et al. 1963; Stavert et al. 1991). 

Fluorine. Decreased weight gain was observed in rats, guinea pigs, and rabbits exposed to 18 ppm 

fluorine for about 6 hours/day, 6 days/week for 5 weeks (Stokinger 1949). While a decreased weight gain 

in the high-exposure group compared to the low-exposure groups is clear, no control animals were used 

and the lowest exposure level that would result in a significant change was not established. 

3.2.1.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans or animals after inhalation exposure 

to hydrogen fluoride or fluorine. 

Fluoride Particulates. A significant decrease in pulmonary bactericidal activity was observed in mice 

challenged for 30 minutes with aerosol inhalation of Staphylococcus aureus following a 14-day exposure 

(4 hours/day) to 5 or 10 mg F/m3

 as sodium fluoride (Yamamoto et al. 2001). Bactericidal activity was 

not significantly altered in mice exposed to 2 mg/m3

. The highest NOAEL values and all reliable LOAEL 

values for immunologic effects in each species and duration category of inhalation exposure to fluoride 

are recorded in Table 3-3 and plotted in Figure 3-3. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 70 

3. HEALTH EFFECTS 

3.2.1.4 Neurological Effects 

Hydrogen Fluoride. The threshold of the light adaptive reflex was measured as a marker for neurological 

effects in three subjects following exposure to hydrogen fluoride at concentrations of 0.02, 0.03, or 

0.06 ppm fluoride (Sadilova et al. 1965). While the threshold level was determined to be 0.03 ppm, it is 

not clear whether this response is due to irritation of mucous membranes or is the result of an effect on 

cerebral cortical function. The toxicological significance of a change in light adaptive reflex is not 

known. 

Exposure to concentrations at about 50% of the LC50 values was reported to cause general weakness and 

decreased activity in Wistar rats (Rosenholtz et al. 1963). Albino rats given 24-hour exposures to either 

0.03 or 0.1 ppm fluoride as hydrogen fluoride for 5 months developed central nervous system 

dysfunctions, as evidenced by diminished conditioned responses and increased time before motor nerve 

response. Histological studies showed changes in the nerve cell synapses of only those animals exposed 

to 0.1 ppm. A concentration of 0.01 ppm was found to be without effect on conditioned responses, 

latency in motor nerve response, or neurohistological parameters. When additional stresses were added 

(alcohol, 24-hour starvation), the conditioned responses were extinguished more frequently (Sadilova et 

al. 1965). Some recovery in conditioned responses was seen following a 1-month recovery period in the 

animals exposed to 0.1 ppm. Animals exposed to 0.03 ppm recovered completely. 

All reliable LOAEL values for neurological effects of exposure to hydrogen fluoride in each species and 

duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

Fluorine. No studies were located regarding neurological effects in humans of fluorine following 

inhalation exposure. Dogs exposed to 5 or 18 ppm for 6 hours/day, 6 days/week for up to 35 days had 

seizures prior to death (Stokinger 1949). Because no further details were available, the neurotoxic 

potential of fluorine cannot be evaluated. 

3.2.1.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after inhalation exposure to fluoride, 

hydrogen fluoride, or fluorine, and no studies were located regarding reproductive effects in animals after 

inhalation exposure to fluoride. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 71 

3. HEALTH EFFECTS 

Hydrogen Fluoride. All four dogs exposed to 18 ppm fluoride as hydrogen fluoride for 6 hours/day, 

6 days/week for 5 weeks developed degenerative testicular changes and ulceration of the scrotum 

(Stokinger 1949). This effect was not seen at 8.2 ppm, or in rabbits or rats at either exposure level. No 

further details were available. Furthermore, it is not clear whether this is a systemic effect or a result of 

irritation from dermal contact with the gas. 

Fluorine. Rats exposed to 18 ppm fluorine, 6 hours/day, 6 days/week for 5 weeks showed testicular 

degeneration (Stokinger 1949). No further details were available. It is not clear whether this effect was 

seen both in animals that died and in those that survived. 

3.2.1.6 Developmental Effects 

No studies were located regarding developmental effects in humans or animals after inhalation exposure 

to fluoride, hydrogen fluoride, or fluorine. 

3.2.1.7 Cancer 

Hydrogen Fluoride and Fluoride Dusts. Most occupational exposure to fluoride occurs as a result of 

inhalation of hydrofluoric acid fumes or dust from cryolite or fluorspar. A cohort of cryolite workers in 

Denmark was reported to have an increase in mortality and morbidity from respiratory cancer compared 

with the national average (standardized mortality ratio [SMR] of 2.52, 95% confidence interval of 1.40– 

4.12, Standardized Incidence Ratio of 2.5 , 95% confidence interval of 1.6–3.5) (Grandjean et al. 1985). 

The study authors stated that the increase can be explained by the fact that the respiratory cancer death 

rate for the Copenhagen area is about twice the national average for the birth cohorts from 1890 to 1929, 

so that comparison with national rates may not be appropriate. Respiratory cancer rates for the workers 

were slightly higher than those of the general population of Copenhagen (standardized incidence ratio of 

1.5, 95% confidence interval of 1.0–2.1). No apparent relationship between incidence of all cancers and 

the length of employment or latency period was found. Significant increases in cancer mortality, 

particularly respiratory cancer, were also found in a follow-up study of this cohort (Grandjean et al. 

1992). The SMR for all cancer was 1.34 (95% confidence interval of 1.2–1.50) compared to Danish 

national rates and the standardized incidence ratio for lung cancer was 1.40 (95% confidence interval 

of 1.01–1.90) compared with rates for Copenhagen. Additionally, a significant increase in bladder cancer 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 72 

3. HEALTH EFFECTS 

incidence was seen (standardized incidence ratio of 1.84, 95% confidence interval of 1.08–2.96). The 

investigators noted that smoking habits may have accounted for some of the lung cancer risk. 

Increased lung cancer rates have been reported in several studies of aluminum industry workers 

(Andersen et al. 1982; Gibbs and Horowitz 1979; Milham 1979), but no correction was made for smoking 

or concurrent exposure to tars and polycyclic aromatic hydrocarbons. Similarly, fluorspar miners had 

increased lung cancer rates, but they were also exposed to elevated radon levels (deVilliers and Windish 

1964). A cohort study of 21,829 workers in aluminum reduction plants for ≥5 years did not find an 

increase in lung cancer, but did report an increase in mortality due to pancreatic cancer, lymphohematopoietic cancers, genitourinary cancer, and nonmalignant respiratory disease (Rockette and Arena 1983). 

Only the effect on pancreatic cancer rates was statistically significant. Increases in incidence of 

hematopoietic cancers and respiratory disease were also reported by Milham (1979). Because of the 

confounding factors mentioned above, and because no breakdown was done by fluoride exposure, these 

studies are of questionable relevance to the issue of possible carcinogenicity of inhalation exposure to 

hydrogen fluoride and/or fluorides. 

A study was published describing a positive relationship between increased lung cancer occurrence and 

exposure to fluoride among individuals residing near, or working in, the steel industry (Cecilioni 1972). 

Possible occupational exposures to other carcinogenic substances from steel and other industries were not 

considered. Carcinogenicity via inhalation of fluoride is not considered to be likely by most investigators 

reporting in the existing literature. 

No studies were located regarding cancer in animals after inhalation exposure to fluoride, hydrogen 

fluoride, or fluorine. 

3.2.2 Oral Exposure 

Because hydrogen fluoride and fluorine are gases, oral exposure to these substances occurs only 

concomitant with inhalation exposure. Oral exposure to hydrofluoric acid has been reported very rarely. 

Except where otherwise indicated, the following sections on oral exposure refer to oral exposure to 

fluoride. 

The oral toxicity of fluoride has been investigated in humans and animals. The human database mostly 

consists of epidemiology studies designed to assess whether consumption of fluoridated water is 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 73 

3. HEALTH EFFECTS 

associated with adverse health effects, particularly skeletal effects and cancer. Most of these studies are 

community-based and do not provide data on individual exposure levels or the particular fluoride 

compound. Fluorosilicic acid and sodium hexafluorosilicate are the primary fluoride compounds used in 

water fluoridation programs, although exposure to other fluoride compounds, such as 

monofluorophosphate, used in dental products also contribute to total fluoride exposure. Additional 

information on the toxicity of fluoride in humans comes from studies of communities with naturally high 

levels of fluoride in the drinking water and experimental studies typically involving exposure to sodium 

fluoride. Animal studies have primarily involved exposure to sodium fluoride in drinking water or the 

diet. A few animal studies also examined the toxicity of fluoride following exposure to calcium fluoride, 

cryolite, and fluoride from rock phosphate. For all forms of fluoride discussed, doses are reported as 

amount of the fluoride ion. 

Conflicting results have been obtained from animal experiments addressing whether fluorine is an 

essential element. Much of this conflict appears to result from the great difficulty in preparing an animal 

diet that has negligible amounts of fluoride, but otherwise allows normal animal growth and development. 

As discussed in Section 3.2.2.6, there have been suggestions that fluoride can aid fertility by improving 

intestinal absorption of iron and other trace elements (Messer et al. 1973; Tao and Suttie 1976). In a 

study where fluoride was rigorously removed from dietary components, a total of 110 Wistar rats were 

observed over the course of four generations (Maurer and Day 1957). There were no adverse effects 

compared to controls that received the same diet and 0.28 mg fluoride/kg/day in drinking water. Animals 

fed the low-fluoride diet were healthy, had sleek coats and healthy teeth, and had similar weight gains to 

those of the controls. Low success in bringing pups to weaning (50%) was reported for both the lowfluoride and control groups. No fluoride was detectable in the diet (detection limit not reported), and 

fluoride levels in femurs were ≤8.8 ppm fluoride in bone ash. In a more recent study, dose-dependent 

increases in daily weight gain of F344 rats were observed when a low-fluoride diet was supplemented 

with fluoride (Schwarz and Milne 1972). The fluoride provided by the basal diet varied, but was 

sometimes 0.023 mg/kg/day and occasionally dropped below 0.002 mg/kg/day. However, the results are 

likely to be due to other nutritional deficiencies that were partially compensated by fluoride. Rats in both 

the control and low-fluoride groups had shaggy fur, loss of hair, and seborrhea. Fluoride was only 

partially effective in correcting the bleached incisors found in the low-fluoride group. Bleached incisors 

have been related to deficiencies of calcium, phosphorus, magnesium, iron, and vitamins E, D, and A. 

None of these studies provide strong evidence that fluoride is an essential element. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 74 

3. HEALTH EFFECTS 

Several organizations consider fluoride to be an important dietary element for humans. The Institute of 

Medicine (IOM 1997) has derived adequate intake values ranging from 0.01 to 4 mg/day to reduce the 

occurrence of dental caries. Adequate intake values broken down by age group are 0–6 months, 

0.01 mg/day; 7–12 months, 0.5 mg/day; 1–3 years, 0.7 mg/day; 4–8 years, 1 mg/day; 9–13, 2 mg/day; 

14–18 years, 3 mg/day; 19 years and older, 4 mg/day (males) and 3 mg/day (females); pregnancy, 

3 mg/day; and lactation, 3 mg/day. Using body weight data reported by IOM (2000), these dietary intakes 

are equivalent to doses of approximately 0.05 mg/kg/day for ages 6 months to >18 years; the dose in 

infants 0–6 months is 0.0014 mg/kg/day. The World Health Organization (WHO) considers fluoride to 

be “essential” because it considered “resistance to dental caries to be a physiologically important 

function” (WHO 2002). 

3.2.2.1 Death 

Fluoride. Fatal ingestion of sodium fluoride has been reported as early as 1899 (Sharkey and Simpson 

1933). A summary of early fatalities indicates that the primary symptoms were the sudden onset of 

nausea and vomiting, accompanied by burning, cramp-like abdominal pains and diarrhea. Clonic 

convulsions and pulmonary edema were reported in some cases; the pulmonary edema may have been 

due to aspiration of vomitus. While a few of these deaths were suicides, most of them resulted from 

accidental exposure to sodium fluoride when containers of insecticide were mistaken for baking powder 

or epsom salts. Based on numerous incidents of fatal fluoride poisoning, Hodge and Smith (1965) 

estimated the certainly lethal dose to be 5–10 g sodium fluoride (32–64 mg fluoride/kg) in adults. 

More recent information includes the case report of a 3-year-old boy who swallowed 200 sodium fluoride 

tablets (1 mg fluoride each) for a dose of 16 mg fluoride/kg body weight (Eichler et al. 1982). 

Immediately after ingestion, he vomited and appeared to recover, but he collapsed 4 hours later. The boy 

died 7 hours after fluoride ingestion. Upon autopsy, hemorrhagic edema of the lungs, hemorrhagic 

gastritis, and massive cerebral edema were observed. The hemorrhagic edema observed in the lungs was 

probably due to aspiration of the gastric contents. Cloudy swelling was observed in the cells of the liver, 

heart, and kidney. In another case, a 27-month-old child died 5 days after ingesting about 100 fluoride 

tablets, for a dose of about 8 mg fluoride/kg body weight (Whitford 1990). Based on this case and weight 

tables for 3-year-old boys, Whitford (1990) calculated a probable toxic dose of about 5 mg fluoride/kg 

body weight. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 75 

3. HEALTH EFFECTS 

Erickson (1978) examined the possible relationship between water fluoridation and increased death rate 

among residents of 24 cities with fluoridation and 22 cities without water fluoridation. Although there 

was a difference in crude death rates for all causes between the two study populations (1,109.9 and 

1,053.6/100,000 person-years for the fluoridation and non-fluoridation populations, respectively), similar 

death rates (1,123.9 and 1,137.1/100,000 person-years, respectively) were found after adjustment for 

differences in age, sex, race, and analysis of covariance (median education and city population density 

In rats, LD50 values for sodium fluoride administered by oral gavage range from 31 to 126.3 mg 

fluoride/kg (DeLopez et al. 1976; Lim et al. 1978; Skare et al. 1986; Whitford et al. 1990). Differences in 

rat strains, variations in weight (and presumably differences in ages), and gender differences may account 

for the reported differences in LD50 values. LD50 values were higher in younger female rats (52– 

54 mg/kg) than in older female rats (31 mg/kg) (DeLopez et al. 1976). LD50 values (84.3–146.3 mg 

fluoride/kg) were also estimated in rats administered monofluorophosphate (Whitford et al. 1990). These 

LD50 values were similar to the LD50 values for sodium fluoride (85.5-126.3 mg fluoride/kg) measured in 

the same study. An LD50 of 44.3 mg fluoride/kg was reported for mice (Lim et al. 1978). 

All reliable LD50 and LOAEL values for death in each species and duration category are recorded in 

Table 3-4 and plotted in Figure 3-4. 

Hydrofluoric Acid. Six deaths were reported to have occurred between 1 and 6 hours following 

accidental or intentional ingestion of a rust remover containing hydrofluoric acid (Menchel and Dunn 

1984). No dose levels of fluoride were reported. At autopsy, severe hemorrhagic gastritis was noted in 

all cases. In one case, hemorrhage and necrosis of the pancreas were also noted. A fatal case of 

hydrofluoric acid ingestion occurred when a 29-year-old man drank a mouthful, thinking it was water 

(Manoguerra and Neuman 1986). In spite of immediate vomiting, respirations were shallow within an 

hour, and the patient died within 2 hours of exposure. Serum calcium and SGOT levels were markedly 

depressed. Serum fluoride level was 35 ppm. Another study reported six deaths due to hydrofluoric acid 

ingestion (Menchel and Dunn 1984). The major symptoms reported were nausea, thirst, and ulcerations 

of the buccal mucosa, followed by the rapid onset of tetany and coma. 

3.2.2.2 Systemic Effects 

No studies were located regarding dermal or ocular effects in humans or animals after oral exposure to 

fluoride, hydrogen fluoride, or fluorine. 
Table 3-4 Levels of Significant Exposure to Fluoride - Oral 

a 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) Species (Strain) Key to figure 

ACUTE EXPOSURE Death 

1 

(C) 

1d 1x/d 

Human 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

(mg/kg/day) 

Serious 

16 (1 child) 

2 

(SpragueDawley) 

Rat 

(GW) 

1 d 1x/d 52 

54 31 

b

(LD50 for 150g rats) (LD50 for 80g rats) 

(LD50 for 250g rats) 

3 

(Rochester) 

Rat 

(GW) 

1 d 1x/d 51.6 (LD50) 

4 

(SpragueDawley) 

Rat 

(GW) 

1 d 1x/d 101.3 (LD50) 

5 

(SpragueDawley) 

Rat 

(GW) 

once 

126.3 M (LD50) 

6 

(SpragueDawley) 

Rat 

(GW) 

once 

85.5 M (LD50) 

7 

(SpragueDawley) 

Rat 

(GW) 

once 

146.3 M (LD50) 

8 

(SpragueDawley) 

Rat 

(GW) 

once 

84.3 M (LD50) 
Table 3-4 Levels of Significant Exposure to Fluoride - Oral (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

9 Mouse 1 d 

44.3 (LD50) 1x/d (Swiss) 

Systemic 

10 Rat 2wk 

Musc/skel 9.5 (decreased modulus of (W) elasticity) 

Reproductive 

11 Mouse 5d 

1x/d 32 

(G) 

Developmental 

12 Rat GD 6-19 

18 F (increased percentage of (Wistar) (GW) skeletal and visceral 

abnormalities) 

13 Rat Gd 6-15 

daily 13.21 (Sprague- 

Dawley) (W)

14 Rabbit Gd 6-19 

daily 13.72 (New 

Zealand) (W)

INTERMEDIATE EXPOSURE Death 

15 Mouse 6 mo 

67 (increased mortality) daily (B6C3F1) 

(W) 

16 Mouse 6mo c 

300 M (increased mortality) ad lib 

(W) 600 F (increased mortality) 
a 

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) 

NOAEL Less Serious

System (mg/kg/day) (mg/kg/day)

Table 3-4 Levels of Significant Exposure to Fluoride 

LOAEL 

- Oral 

(mg/kg/day) 

Serious 

(continued) 

17 

Systemic Rat 

(W) 

2 mo 7d/wk 24hr/d 

Endocr 0.5 (decreased thyroxine levels; 

increased T3- resin uptake ratio) 

18 

(CD) 

Rat 

(W) 

daily 16-19 weeks Musc/skel 8.25 F 10.7 (prominent growth lines on 

upper incisors) 

F 

19 

(SpragueDawley) 

Rat 

(W) 

7d/wk 24hr/d Musc/skel 10.5 (decr mineral content and incr 

proline in tooth enamel matrix) 

20 

(Wistar) 

Rat 

(W) 

5 wk 

Musc/skel 13 19 (histological fluorosis; decr 

bone growth) 

21 

(Fischer- 344) 

Rat 

(W) 

6 mo daily Gastro 

Hepatic Renal 

20 20 

7 (hyperplasia of glandular 

stomach) 

22 

(SpragueDawley) 

Rat 

(W) 

daily 16 or 48 weeks Musc/skel 0.15 M 0.5 (decreased vertebral strength 

and bone mineralization) 

M 

23 Rat 

(W) 

30d 

Musc/skel 14 (delayed healing of broken 

bones) 
Table 3-4 Levels of Significant Exposure to Fluoride - Oral (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

24 Mouse 280 d 

daily Hepatic 0.95 (pale, granular hepatocytes with fatty vacuoles) 

(W) 

25 Mouse 280d 

Renal 1.9 (nephron degeneration) (W) 

26 Mouse 4 wk 

7d/wk Musc/skel 0.8 (incr bone formation rate; slight 

daily decr bone calcium) 

(W) 

27 Mouse 6 mo 

Cardio 67 (multifocal mineralization and daily (B6C3F1) degeneration of the 

(W) myocardium) 

Musc/skel 5.6 M (increased osteoid in femur and 

tibia) 

Hepatic 67 (megaolocytosis and syncytial 

alteration) 

Renal 67 (multifocal nephrosis) Bd Wt 67 (20% decr bw gain) 

28 Mouse 35 d 

1x/d Hemato 5.2 (decr RBC and hemoglobin, incr 

WBC) 

(GW) 

Bd Wt 5.2 (decr body weight) 
Table 3-4 Levels of Significant Exposure to Fluoride - Oral (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

29 Mouse daily 

100-150 days Musc/skel 0.06 M 3.2 M (incisor fluorosis) (Kunmin) 

(W) 

Endocr 0.06 M 3.2 M (decreased radiolabelled iodine 

uptake) 

Bd Wt 3.2 M 

30 Rabbit 6 mo 

daily Resp 4.5 (congestion, edema fluid, (NS) desquamation of respiratory 

(F) epithelium in lungs) 

Neurological 

31 Rat 6 wk 

daily 6 F (altered spontaneous behavior) (Sprague- 

Dawley) (W)

32 Rat 6 wk 

daily 5.5 F 7.5 F (altered spontaneous behavior) (Sprague- 

Dawley) (W)

33 Rat 60 d 

daily 9 (decr spontaneous activity) (Wistar) 

(GW) 

Reproductive 

34 Rat daily 

10.21 F (decreased number of viable 30 days (Sprague- fetuses, increased resorptions) 

Dawley) (W) 

35 Rat 60 d 

2.3 (decr seminiferous tubule 4.5 (50% reduction in fertility, decr 7d/wk (CD) diameter) in percentage of seminiferous 

(F) tubules containing spermatozo

and decr testosterone levels) 
Table 3-4 Levels of Significant Exposure to Fluoride - Oral (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

36 Rat daily 

2.3 (decreased fertility and sperm (NS) 30 d counts) 

(GW)

37 Rat 30 or 50 days 

4.5 (decreased sperm motility and d (Charles count) 

Foster) (F)

38 Rat daily 

16-19 weeks 10.7 F (CD) 

(W) 

39 Rat daily 

6 wk 21 (Wistar) 

(W) 

40 Rat daily 

16 wk 7.5 (seminiferous tubule atrophy) (Wistar) 

(W) 

41 Rat 3 mo 

7d/wk 23 

(F) 

42 Rat daily 

50 d 4.5 (decr testosterone levels and Charles Leydig cell diameter) 

Foster (GW) 

43 Rat daily 

16

(Sprague- (W) 

Dawley)
Table 3-4 Levels of Significant Exposure to Fluoride - Oral (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

44 Rat daily 

16

(Sprague- (W) 

Dawley)

45 Mouse 30 d 

4.5 (decr sperm motility and count daily (Swiss) and infertility) 

(F) 

46 Mouse 25 wks 

9.5 19 (nearly complete infertility) (Swiss- (W) 

Webster)

47 Mouse 35 d 

1x/d 5.2 

(GW) 

48 Gn Pig 30 d 

4.5 (decr sperm motility and daily (NS) viability) 

(GW)

Developmental 

49 Rat Gd 1-20 

daily 11.2 11.4 (incr in average number of (CD) fetuses per litter with 3+ skeletal 

(W) variations) 

50 Rat daily 

16-19 weeks 12.2 F (CD) 

(W) 

51 Rat 28 wk 

7d/wk 21 (Sprague- 

24hr/d Dawley) 

(W) 
a 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) Species (Strain) Key to figure 

CHRONIC EXPOSURE Systemic 

52 

(W) 

Human daily

NOAEL Less Serious

System (mg/kg/day) (mg/kg/day)

Table 3-4 Levels of Significant Exposure to Fluoride 

Musc/skel 0.04

LOAEL 

- Oral 

(mg/kg/day) 

Serious 

(continued) 

53 Human 

(W) 

Daily Musc/skel 0.15 d 0.25 (Increased prevalence of bone 

fractures) 

54 Human 

(C) 

4 yr Musc/skel 0.56 (increased fracture rate) 

55 

(Fischer- 344) (W) 

Rat 103 wk

Resp 3.9 

Cardio 3.9 Gastro 3.9 Hemato 3.9 Musc/skel Hepatic Renal 

2.5 3.9 3.9 

4.3 (osteoscleosis) 

Bd Wt 3.9 
Table 3-4 Levels of Significant Exposure to Fluoride - Oral (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

56 Mouse 103 wk 

Resp 7.6 (B6C3F1) (W) 

Cardio 7.6 Gastro 7.6 Hemato 7.6 Musc/skel 4.3 M 7.6 M (dentine dysplasia) Hepatic 7.6 Renal 7.6 Bd Wt 7.6 

57 Rabbit 24 mo 

1x/d Gastro 5 (roughened duodena mucosa) 

(GW) 

58 Rabbit 7-12 mo 

1x/d Hemato 4.52 (decr leukocyte and hemoglobin 

levels) 

(G) 

59 Mink 382 d 

24hr/d Musc/skel 5 (mottled and brittle kit teeth) 9.1 (sagittal crests deformed, 3/6 

adults) 

(F) 

Immuno/ Lymphoret 

60 Rabbit 18 mo 

1x/d 4.5 (decr primary and secondary (albino) antibody titers) 

(G) 
Table 3-4 Levels of Significant Exposure to Fluoride - Oral (continued) 

a 

Key to 

figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Specific Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

(mg/kg/day) 

Serious 

61 

Reproductive 

(F) 

Mouse 3 gen 13 

62 

(NS) 

Rabbit 

(GW) 

daily 18 mo 4.5 (structural damage of the 

spermatid and epididymal spermatozoa) 

M 

63 

(NS) 

Rabbit 

(GW) 

daily 20 or 23 mo 4.5 (structural damage of the 

spermatid and epididymal spermatozoa) 

M 

64 

(NS) 

Rabbit 

(GW) 

daily 18 or 29 mo 4.5 (complete cessation of 

spermatogenesis) 

65 

(New Zealand) 

Rabbit 

(GW) 

daily 18 or 23 mo 4.5 (Leydig cell damage) 

66 Mink 

(F) 

382 d daily 9.1 
Table 3-4 Levels of Significant Exposure to Fluoride - Oral (continued) 

Exposure/ LOAEL

Duration/

a 

Key to Species Frequency NOAEL Less Serious Serious 

(Specific Route) figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 

Cancer 

67 Rat 103 wk 

2.4 M (osteosarcoma of bone) (Fischer- 344) (W) 

a The number corresponds to entries in Figure 3-4. b Only this dose level, for the most sensitive group, is plotted in Figure 3-4. c Differences in levels of health effects and cancer effects between males and females are not indicated in Figure 3-4. Where such differences exist, only the lmost sensitive gender are presented. d Used to derive a chronic-duration oral minimal risk level (MRL) of 0.05 mg fluoride/kg/day; the dose was divided by an uncertainty factor of 3 to account for had lib = ad libitum; Bd Wt = body weight; (C) = capsule); d = day(s); decr = decrease; Endocr = endocrine; (F) = feed; F = female(s); (G) = gavage; Gastro = gagestational day; gen = generation(s); (GW) = gavage in water; Hemato = hematological; hr = hour(s); incr = increase; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = males; mg/kg/day = milligram per kilogram per day; mo = month(s); Musc/skel = muscular/skeletal; NOAEL = no-oblevel; RBC = red blood cell(s); Resp = respiratory; T3 = triiodothyronine; (W) = water; WBC = white blood cell(s); wk = week(s); x = time 
1000 

Death Musculoskeletal Reproductive Developmental 

Figure 3-4. Levels of Significant Exposure to Fluoride - Oral 

Acute (≤14 days) 

Systemic 

mg/kg/day 

7r5r

100 4r

6r 8r 

2r 3r

9m2r 

11m 2r 

12r

1

13r 14h 

10 10r 

1 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat h-Rabbit e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 
1000 

Death Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal 

Figure 3-4. Levels of Significant Exposure to Fluoride - Oral (Continued) 

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

16m 16m 

100 

15m 27m 27m 27m 

20r 21r 21r

23r 20r

10 18r 19r 18r 21r 

28m 27m 30h 

29m 

25m 

1 24m 26m 

22r 22r 

0.1 

29m 

0.01 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat h-Rabbit e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 
Body Weight Neurological Reproductive Developmental 

Figure 3-4. Levels of Significant Exposure to Fluoride - Oral (Continued) 

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

1000 

100 

27m 

41r 39r 51r 46m 43r 44r 

49r 50r 38r 49r 10 46m 34r 33r 32r 40r 

31r 28m 32r 47m 48g 45m 35r 37r 42r 

29m 

35r 36r 

1 

0.1 

0.01 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat h-Rabbit e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 
100 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Body Weight Immuno/Lymphor Repro

Figure 3-4 Levels of Significant Exposure to Fluoride - Oral (Continued)

Chronic (≥365 days)

Systemic 

mg/kg/day 

61m

10 59n 66n 

56m 56m 56m 56m 56m 56m 56m 56m 

57h 59n 58h 56m 55r 60h 62h 63h 

55r 55r 55r 55r 55r 55r 55r 

55r 

1

54

53 53 

0.1 

52 

*Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer endpoint. 0.01 

c-Cat k-Monkey f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog m-Mouse j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat h-Rabbit e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig a-Sheep s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow g-Guinea Pig 
 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 91 

3. HEALTH EFFECTS 

The highest NOAEL values and all reliable LOAEL values for systemic effects in each species and 

duration category are recorded in Table 3-4 and plotted in Figure 3-4. 

Respiratory Effects. No studies were located regarding respiratory effects in humans after oral 

exposure to fluoride, hydrogen fluoride, or fluorine. 

Congestion, the presence of edema fluid, and desquamation of respiratory epithelium were observed in 

the lungs of rabbits exposed to 4.5 or 9 mg fluoride/kg/day as sodium fluoride in the diet for 6 months 

(Purohit et al. 1999). Inflammatory cell infiltrates, congestion, and desquamated epithelium were also 

observed in the large bronchi and trachea of rabbits fed 9 mg fluoride/kg/day. Necrosis of the lung 

parenchyma was also observed in two high-dose rabbits that died before the end of the study. 

Cardiovascular Effects. The cardiovascular effects of fluoride have been attributed to hypocalcemia 

and hyperkalemia caused by high fluoride levels. Fluoride can bind with serum calcium if the dose is 

sufficient and cause hypocalcemia. Calcium is necessary for the functional integrity of the voluntary and 

autonomic nervous systems. Hypocalcemia can cause tetany, decreased myocardial contractility, and 

possibly cardiovascular collapse (Bayless and Tinanoff 1985). Hyperkalemia has been suggested as the 

cause of the repeated episodes of ventricular fibrillation and eventual death that are often encountered in 

cases of fluoride poisoning (Baltazar et al. 1980). 

Approximately 2 hours after ingestion of 120 g of roach powder (97% sodium fluoride) in an 

unsuccessful suicide attempt, a 25-year-old male had severe toxic reactions that included tetany, multiple 

episodes of ventricular fibrillation, and esophageal stricture (Abukurah et al. 1972). Within 14 hours 

following exposure, the patient experienced 63 episodes of ventricular fibrillation. In a study of adults 

with skeletal fluorosis living in an area of China with high levels of fluoride in the drinking water (4.1– 

8.6 ppm) (Xu and Xu 1997), a higher percentage of electrocardiogram abnormalities was observed in 

individuals with skeletal fluorosis (50.73%), as compared to a control group (0.1–0.6 ppm fluoride in 

water) (20.0%). 

In two epidemiological studies, fluoride in the drinking water did not increase the mortality rates from 

cardiovascular effects. One of these studies was a report of 428,960 people in 18 areas of "high" natural 

fluoride (0.4–>3.5 ppm) in England and Wales and 368,580 people in control areas (<0.2 ppm fluoride). 

The water supply for 52% of the "high" fluoride population had average fluoride levels of ≥1 ppm 

(Heasman and Martin 1962). Results indicated that there were no significant differences between areas 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 92 

3. HEALTH EFFECTS 

with different fluoride levels in mortality due to coronary disease, angina, and other heart disease, as 

evidenced by standard mortality ratios (SMRs). The second study (Hagan et al. 1954) examined 32 pairs 

of cities in the United States that contained 892,625 people in the high fluoride areas and 

1,297,500 people in the control cities. A positive relationship between heart disease and water 

fluoridation was reported, but these authors did not adjust for a doubling of the members of this 

population over 75 years old during the period of fluoridation under study (Jansen and Thomson 1974). 

In addition, this study lacked statistical analysis and drew conclusions regarding trends that were not 

obvious from the data presented. The large variation in the presented data was not discussed. Doses of 

fluoride are difficult to estimate for large populations, however, because most people are potentially 

exposed to fluoride through a variety of sources, such as food, beverages, medicine, and dental products. 

Similarly, no significant alterations in the rate of cardiovascular system abnormalities were observed in a 

community with 8 ppm fluoride in the water supply, as compared to a community with 0.4 ppm (Leone et 

al. 1954). 

The results of other studies have suggested a role for fluoride in reducing cardiovascular disease. A study 

of 300 North Dakota residents who drank water containing 4–5.8 ppm and 715 people who drank water 

containing 0.15–0.3 ppm found a lower incidence of calcification of the aorta in the high-fluoride group 

(Bernstein et al. 1966). Significant differences were found in 45–54-year-old males (p<0.05), as well as 

in males aged 55–64 and 65+ years (p<0.01). This effect was not due solely to differences in age 

distribution, because the incidence in the 55–64-year-old, high-fluoride group was lower than the 

incidence in the 45–54-year-old, low-fluoride group. A crude analysis also found no association with 

milk and cheese consumption. In a study of four towns in Finland, Luoma (1980) found that incidence of 

cardiovascular disease correlated negatively with water fluoride concentration. Taves (1978) likewise 

found that standard mortality ratios decreased to a greater extent in fluoridated cities from 1950 to 

1970 as compared to non-fluoridated control cities. Both studies, however, relied on population-summary 

information for disease rates. A mechanism for this potential reduction in cardiovascular disease could be 

the ability of fluoride to inhibit the calcification of soft tissue such as the aorta, as demonstrated in in vitro 

studies (Taves and Neuman 1964; Zipkin et al. 1970). 

About half of the male and female B6C3F1 mice that died as a result of exposure to 67–71 mg 

fluoride/kg/day for 6 months as sodium fluoride in drinking water had mineralization of the myocardium 

(NTP 1990); some female mice also had myocardial degeneration. Electrocardiogram alterations and 
 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 93 

3. HEALTH EFFECTS 

histological alterations in the myocardium were observed in rabbits exposed to sodium fluoride (Okushi 

1971). 

Gastrointestinal Effects. The primary gastrointestinal effects following both acute and chronic oral 

exposure to fluoride consist of nausea, vomiting, and gastric pain. The irritation of the gastric mucosa is 

attributed to fluoride (as sodium fluoride) forming hydrofluoric acid in the acidic environment of the 

stomach (Hoffman et al. 1980; Waldbott 1981). The uncharged hydrogen fluoride molecule can then 

penetrate cell membranes and enter the neutral environment of the cytoplasm where it dissociates to 

release both fluoride and hydrogen ions. 

Thirty-four students (kindergarten through third grade) exhibited acute gastrointestinal effects after 

drinking water from school water fountains that provided a fluoride supplement designed to raise the 

water level to a range of 1–5 ppm (Hoffman et al. 1980). An accident with the delivery system resulted in 

the water levels reaching 375 ppm; specific doses could not be calculated, but were estimated to range 

from 1.4 to 90 mg per child. In two other cases, individuals vomited and had abdominal pain 

immediately after accidentally consuming 1 tablespoon of sodium fluoride (used as a dusting powder for 

poultry) (Rao et al. 1969) or sodium fluorosilicate (Dadej et al. 1987). 

Of the 150 cases involving fluoride intake reported to a poison control center from 1978 to 1979, most of 

the cases involved ingestion of <1 mg/kg fluoride, although exact doses could not be determined (Spoerke 

et al. 1980). Effects included nausea (13.9%), vomiting (77.8%), and diarrhea (8.3%). These effects 

usually subsided within 24 hours. Symptoms of a more serious nature were not reported. 

Endoscopies were performed and biopsy samples were taken from healthy volunteers either after no 

treatment (control), or 2 hours after drinking 20 mL of a solution containing 20 mg fluoride (1,000 ppm) 

as sodium fluoride (Spak et al. 1989), or application of 0.42% fluoride dental gel (5.1 mg fluoride 

ingested) (Spak et al. 1990). Fluoride treatment resulted in petechiae (minute hemorrhages) or erosions in 

most of the subjects. Histological examination of biopsied stomach tissue revealed signs of irritation. 

Nausea was present in one-third of the subjects drinking the sodium fluoride solution, suggesting that 

nausea may not be the first sign of fluoride irritation of the gastric mucosa. 

While high levels of fluoride clearly can cause gastrointestinal irritation, it is unclear whether there are 

any gastrointestinal effects of chronic exposure to fluoride in drinking water. Gastrointestinal tract 

disorders were not evaluated in the Bartlett-Cameron study of the effect of water containing 8 ppm 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 94 

3. HEALTH EFFECTS 

fluoride (Leone et al. 1954). The sole evidence of an effect comes from a study of 20 non-ulcer dyspepsia 

patients at an outpatient clinic in India and 10 volunteers without gastrointestinal problems from the 

surgical clinic (Susheela et al. 1992). While none of the drinking water supplies of the controls had 

fluoride levels >1 ppm, the water supplies of 55% of the dyspepsia patients were at this level. In addition, 

all of the dyspepsia patients and 30% of the controls had serum fluoride levels >0.02 ppm (mean of the 

dyspepsia group, 0.1 ppm); all of the dyspepsia patients and none of the controls had urine fluoride levels 

>0.1 ppm (mean, 1.34 ppm). The study was compromised by small treatment size, undetermined total 

fluoride doses, undetermined nutritional status of the subjects, and lack of statistical comparisons. In 

addition, the appropriateness of the control population was not clear. 

Seventy-eight workers engaged in the crushing and refining of cryolite, a mineral compound composed of 

sodium, aluminum, and fluoride, were examined (Moller and Gudjonsson 1932). Although an average 

exposure period was not presented, no workers with <2 years of exposure were included; 18 workers had 

been exposed for >10 years. Forty-two workers reported evidence of gastrointestinal effects. The 

primary effect was nausea, followed by loss of appetite and vomiting. Chronic indigestion was also 

reported in these workers. The study authors stated that the effects were due only to cryolite dust being 

swallowed (either due to dust being deposited in the mouth during mouth-breathing, or due to deposition 

on the bronchial tree followed by mucociliary action bringing the material to the epiglottis) and absorbed 

through the gastrointestinal tract. They based this conclusion on the fact that 21 enamel-, glass-, and 

sulphuric acid-industry workers exposed by inhalation to fluorine gas (some for up to 40 years) revealed 

no evidence of any effect on the stomach. In light of what is now known about the absorption of fluorides 

through the lung, the cryolite workers probably were exposed by both the oral and inhalation routes. 

Decreased appetite, congestion of the duodenum, and mild diarrhea were reported in sheep given a single 

intragastric dose of 28.5 mg fluoride/kg in the form of sodium fluoride via nasoesophageal catheter 

(Kessabi et al. 1985). It is difficult to extrapolate possible human effects from this study because the 

gastrointestinal system of ruminants (sheep, cows, goats) is quite different from that of humans. 

Thickening of the mucosa of the glandular stomach and punctate hemorrhages were seen in F344/N rats 

given 20 mg fluoride/kg/day as sodium fluoride in drinking water for 26 weeks (NTP 1990). Similar, but 

less severe, alterations were seen in some rats that received 7 mg fluoride/kg/day. Stomach ulcers were 

also seen in some high-dose males and females. Histologically identified stomach lesions included 

necrosis and hyperplasia. No gastrointestinal effects were reported in B6C3F1 mice in this study at doses 

up to 67–71 mg fluoride/kg/day. No gastrointestinal effects were reported in the chronic portion of this 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 95 

3. HEALTH EFFECTS 

study at doses up to 9.1 mg/kg/day (mice) or 4.5 mg/kg/day (rats). Roughened duodenal mucosa and a 

"cracked-clay" appearance of the absorptive cells were observed following daily dosage of nine rabbits 

with 5 mg/kg fluoride via oral gavage for 24 months (Susheela and Das 1988). The rabbit gastrointestinal 

system also differs from that of humans, and the study is limited by the small number of rabbits per group 

and the use of only one dose. 

Hematological Effects. The incidence of abnormal white blood cell counts was significantly higher 

in a community with high levels of naturally occurring fluoride (8 ppm) as compared to a community 

with low levels of fluoride (0.4 ppm fluoride). However, the study authors did not consider this finding 

as necessarily an effect of fluoride (Leone et al. 1954). No other significant hematological effects were 

observed. No significant alterations in hemoglobin, erythrocyte, and total leukocyte levels were found in 

children living in a community with fluoridated water (1.2 ppm), as compared to children living in a 

community with nonfluoridated water (Schlesinger et al. 1956). 

As part of the 2-year National Toxicology Program (NTP) study of fluoride (NTP 1990), hematological 

analyses were conducted at 27 and 66 weeks. No treatment-related effects were observed at doses up to 

4.5 and 9.1 mg/kg/day in F344/N rats and B6C3F1 mice, respectively. 

Lactating Holstein cows were fed a mineral supplement containing soft rock phosphate (6,000 ppm 

fluoride) and a protein supplement containing 1,088 ppm fluoride (Hillman et al. 1979). Because 

consumption of minerals fed ad libitum could not be determined accurately under farm conditions, no 

dose estimates could be made. After 9 months, red blood cells per unit volume, blood hemoglobin, 

hematocrit, and mean corpuscular volume were significantly lower (p<0.05) in herds exhibiting evidence 

of high fluoride exposure. The number of eosinophils increased with increasing urinary fluoride. Rabbits 

administered 4.52 mg fluoride/kg/day by gavage for 6–12 months had significantly decreased numbers of 

blood cells (e.g., erythrocytes, leukocytes, thrombocytes, monocytes, neutrophils) and hemoglobin 

(Susheela and Jain 1983). Similar, although not identical, results were seen in mice fed 5.2 mg 

fluoride/kg body weight (Pillai et al. 1988). These animals showed a significant decrease in red blood 

cell count, but a significant increase in white cells. Although a dose-effect relationship cannot be 

determined from single-dose studies, these studies suggest that the hematopoietic system may be affected 

by oral exposure to high levels of fluoride. 

Musculoskeletal Effects. The skeletal system is the primary site of fluoride deposition in the body 

resulting in both beneficial and adverse effects. Oral exposure to fluoride has been shown to decrease the 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 96 

3. HEALTH EFFECTS 

prevalence of dental caries in children (the relationship between fluoride and dental caries is discussed in 

greater detail in Appendix D); however, at higher doses, fluoride can also result in non-beneficial effects 

on the teeth, dental fluorosis. Dental or enamel fluorosis occurs when excess amounts of fluoride are 

ingested during tooth development (1–8 years of age). It is characterized by increased porosity (or 

hypomineralization) of the subsurface enamel and well mineralized surface layer of enamel. Mildly 

fluorosed enamel is full functional (denBesten and Thariani 1992), but may be cosmetically 

objectionable. As the severity of dental fluorosis increases, the depth of the enamel involvement and the 

degree of porosity increases (Fejerskov et al. 1990). More severely fluorosed enamel is more porous, 

pitted, and discolored and is prone to fracture and wear because the well mineralized zone is very fragile 

to mechanical stress (denBesten and Thariani 1992; Fejerskov et al. 1990). Not all teeth are similarly 

affected by elevated fluoride levels. Teeth that develop earlier in life appear to be less affected than those 

that develop later (Fejerskov et al. 1990). Several methods have been developed for quantifying dental 

fluorosis. The most commonly used method is Dean's index (Dean 1934), which classifies fluorosis as a 

scale of from 0 to 4 as follows: class 0, no fluorosis; class 1, very mild fluorosis (opaque white areas 

irregularly covering ≤25% of the tooth surface); class 2, mild fluorosis (white areas covering 25–50% of 

the tooth surface); class 3, moderate fluorosis (all surfaces affected, with some brown spots and marked 

wear on surfaces subject to attrition); and class 4, severe fluorosis (widespread brown stains and pitting). 

The average score of the two most severely affected teeth is used to derive the classification. Other 

commonly used methods to rate dental fluorosis include the Thylstrup-Fejerskov (TF) index (Thylstrup 

and Fejerskov 1978) and the tooth surface index of fluorosis (TSIF) (Horowitz et al. 1984). Unlike the 

Dean’s index, the TF and TSIF indexes use all tooth surfaces to develop the final index score. 

The development and severity of dental fluorosis is dependent on the amount of fluoride ingested, the 

duration of exposure, and the stage of amelogenesis at the time of exposure. The relationship between 

fluoride exposure levels and the prevalence and severity of dental fluorosis was first established in the 

1930s and 1940s. There is an extensive amount of literature on the relationship between the prevalence of 

dental fluorosis and the concentration of fluoride in municipal water (e.g., Alarcón-Herrera et al. 2001; 

DHHS 1991; Eklund et al. 1987; Heifetz et al. 1988; Jackson et al. 1995; Selwitz et al. 1995; Teotia and 

Teotia 1994) and the use of fluoridated dentifrices (as reviewed by Warren and Levy 1999). Studies 

examining children living in communities with different fluoride levels found that the severity of dental 

fluorosis is directly related to fluoride exposure levels. Higher fluorosis severity scores were found in 

children living in communities with 4 ppm fluoride in drinking water compared to children living in 

communities with 1 ppm fluoride in drinking water (Heifetz et al. 1988; Jackson et al. 1995; Selwitz et al. 

1995). No signs of dental fluorosis (using the TSIF scoring method) were found in 81.8, 54.7, and 7.9% 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 97 

3. HEALTH EFFECTS 

of the children aged 7–14 years living in communities with 0.2, 1, or 4 ppm, fluoride in drinking water, 

respectively (Jackson et al. 1995). Moderate dental fluorosis (TSIF score of 3) was observed in 0, 0.9, 

and 25.7%, respectively, of the children. The maximum TSIF score was 2 (3.2% of the children received 

this score) in the 0.2 ppm community, 4 (0.9% of children) in the 1 ppm community, and 7 (6.9% of 

children) in the 4 ppm community. Studies in adults have not always found a direct relationship between 

severity of dental fluorosis and prevalence of dental caries (Eklund et al. 1987). A recent meta-analysis 

of 88 studies on dental fluorosis (McDonagh et al. 2000) found a dose-related response relationship 

between the levels of fluoride in drinking water and the prevalence of dental fluorosis. At a water 

fluoride concentration of 1 ppm, the estimated prevalence of dental fluorosis is 48% (95% confidence 

interval of 40–57%) and the prevalence of fluorosis of aesthetic concern would be 12.5% (95% 

confidence interval of 7.0–21.5%). Another meta-analysis found a significant association between dental 

fluorosis and use of fluoride supplements (Ismail and Bandekar 1999). 

There is also evidence that the prevalence of dental fluorosis has increased over time due to the multiple, 

widespread sources of fluoride in food processed with fluoridated water and dentifrices containing 

fluoride, which has resulted in higher fluoride exposure levels. The DHHS (1991) compared the 

prevalence of dental fluorosis in three cities (Kingston, New York, Kewanee, Illinois, and Newburgh, 

New York) measured in 1939 or 1955 with prevalence in those cities in 1980 or 1985. In Kingston, 

which had a municipal fluoride level of 0 ppm, the prevalence of dental fluorosis (using the Dean’s index) 

increased from 0.0 to 7.3%, primarily in the very mild (4.4% received this score) category. In the other 

two cities (0.9 or 1.0 ppm fluoride in water), there was only a slight change in the overall prevalence 

(12.2 versus 14.6% for Kewanee and 7.3 versus 7.7% in Newburgh) of dental fluorosis. However, there 

was a shift toward higher severity scores. For example in Kewanee, the prevalence in the very mild, mild, 

moderate, and severe categories was 10.6, 1.6, 0.0, and 0.0%, respectively, in 1939 and 7.4, 4.8, 1.8, and 

0.6%, respectively, in 1980. In another comparison conducted by DHHS (1991), the prevalence and 

severity of dental fluorosis measured in children living in 21 cities in the 1940s were compared with the 

prevalence and severity of dental fluorosis measured in 28 cities in the 1980s. During the 40-year period, 

the prevalence of fluorosis in areas with <0.4 ppm fluoride increased from <1% to about 6%; nearly all of 

the increase was in the very mild and mild categories. Both the prevalence and severity of fluorosis 

increased in communities with 0.7–1.2 ppm fluoride, with prevalence increasing from about 13% to about 

22%. Most of the increase was in the very mild and mild categories, which increased from 12.3% to 

17.7% and from 1.4% to 4.4% of the population, respectively. The combined prevalence of the severe 

and moderate categories increased from 0.0% to 0.9%. While there were some differences between the 

studies in the 1940s and those in the 1980s, such as the subject population and examination conditions, 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 98 

3. HEALTH EFFECTS 

they do not affect the overall trends. Although total fluoride intake was not measured, these studies 

indicate that intake by children at risk has increased since the 1940s, because fluorosis levels increased 

for all water fluoride levels. Another series of studies compared the prevalence and severity of dental 

fluorosis in 8–10 and 13–15-year-old children living in communities with 1, 2, 3, or 4 ppm fluoride in 

drinking water in 1980 to the prevalence in 1985 (Heifetz et al. 1988) and 1990 (Selwitz et al. 1995). 

While there were no marked changes in fluorosis levels in 8–10-year-old children, both the prevalence 

and severity increased in the 13–15-year-old children (this group of children also participated in the 1980 

study). Increases in the 1-ppm communities were mostly in the category of barely visible white spots. 

However, the percentage of labial surfaces of incisors and canines from children in the 2-ppm group that 

had brown mottling increased from 0 to 7.6%. Less marked increases in mottled and pitted teeth were 

seen in the higher exposure groups. The increased levels of fluorosis were attributed to increased fluoride 

exposure from multiple sources. However, the apparent increase in fluorosis did not continue from 1985 

to 1990 (Selwitz et al. 1995); in many cases, the severity of the fluorosis declined in the period of 1985– 

1990 compared to the 1985 levels. 

There is some evidence to suggest that exposure to very high levels of fluoride can increase the 

susceptibility to dental caries. Studies in children and adolescents aged 8–16 years (Driscoll et al. 1986; 

Mann et al. 1987) found higher incidences of dental caries in individuals with severe dental fluorosis than 

in individuals with less severe dental fluorosis. However, for children with very mild, mild, or moderate 

fluorosis, no significant associations were found. Driscoll et al. (1986) reported a mean decayed, missing, 

and filled surface (DMFS) score of 2.96 for children with severe fluorosis (TSIF score of 4) compared to 

1.40 for children with very mild dental fluorosis (TSIF score of 0.5) or 1.58 for children with mild to 

moderate fluorosis (TSIF score of 1–3). It is possible that the higher prevalence of filled teeth was due to 

the increased rate of fracture and wear in severely fluorosed teeth rather than a higher risk of tooth decay. 

As with the dental effects, fluoride has both beneficial and adverse effects on bone. Because fluoride 

stimulates bone formation, and increases bone mass, especially in cancellous bone, and inhibit bone 

resorption, fluoride has been used as a treatment for osteoporosis. However, the effect of fluoride on the 

bone varies in different parts of the body. It increases bone formation earlier and to a larger extent in 

trabecular bone than in cortical bone (Gruber and Baylink 1991). There is an excellent response in the 

spine, slight response in the hip, and poor response in the wrist as a result of fluoride treatment. Studies 

examining the efficiency of fluoride treatment for osteoporosis have found an increased risk of hip 

fractures; the prevailing view is that the beneficial increase in spinal bone mass is at the expense of an 

increasing risk of hip fractures. There is some evidence that exposure to low doses of slow released 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 99 

3. HEALTH EFFECTS 

sodium fluoride can significantly reduce the occurrence of spinal fractures in individuals with 

osteoporosis (Pak et al. 1995). A large number of studies have examined the adverse skeletal effects of 

fluoride; the human studies primarily consist of clinical trials of elderly subjects administered fluoride for 

the treatment of osteoporosis and community-based studies of populations exposed to fluoride in drinking 

water. The observed effects include increases in bone density, increased risk of bone non-vertebral 

fractures, and skeletal fluorosis. 

Skeletal fluorosis is a condition associated with an accumulation of fluoride in the bone resulting in brittle 

bones and decreased tensile strength. In severe cases (crippling skeletal fluorosis), complete rigidity of 

the spine, often accompanied by kyphosis (humpbacked) or lordosis (arched back), is observed. Skeletal 

fluorosis is associated with long-term exposure to very high oral doses of fluoride or occupational 

exposure to cryolite (AlF6Na2) dust (which would involve inhalation and oral exposure to fluoride). 

Cases of skeletal fluorosis are predominantly found in developing countries, particularly India and China, 

and are associated with high fluoride intakes coupled with malnutrition (WHO 2002). High tea 

consumption and increased consumption of water with high levels of naturally occurring fluoride are the 

primary contributors to the elevated fluoride intake; in China, the indoor burning of fluoride-rich coal also 

contributes to the overall fluoride intake. Most reports of skeletal fluorosis are inadequate for establishing 

dose-response relationships. Choubisa et al. (1997) examined the prevalence of skeletal fluorosis in 

residents of 15 villages in India. At 1.4 ppm fluoride in drinking water, the prevalence of skeletal 

fluorosis was 4.4%; at 6.0 ppm fluoride, the prevalence was 63.0%. Another investigator found that 

skeletal fluorosis occurred 10 years after the initiation of increased fluoride consumption; the average 

water concentration was 9.2 ppm fluoride and daily water consumption was 4.6 L/day (42 mg 

fluoride/day) (Saralakumari and Ramakrishna Rao 1993); after 20 years of exposure, the prevalence of 

skeletal fluorosis was 100%. A limited number of cases of skeletal fluorosis have been reported in the 

United States (Bruns and Tytle 1988; Fisher et al. 1981; Goldman et al. 1971; Sauerbrunn et al. 1965); 

where doses are known, they are generally 15–20 mg fluoride/day for over 20 years. In a study of 

116 people who had lived in an area with an average of 8 ppm fluoride in the drinking water for at least 

15 years, a 10–15% incidence of fluoride-related bone changes was observed (Leone et al. 1955). 

Coarsened trabeculation and thickened bone were observed, but no exostoses were evident, and the 

subjects were asymptomatic. The severity of the skeletal fluorosis appears to be related to bone fluoride 

levels. Among persons whose drinking water contains about 1 ppm fluoride, bone ash fluoride 

concentrations trypically range from 500 to 1,500 ppm. The higher values are generally found among 

older persons since the concentrations tend to increase gradually throughout life. Bone from people with 

preclinical skeletal fluorosis, which is generally asymptomatic and characterized by slight radiologically 
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3. HEALTH EFFECTS 

detectable increases in bone mass, contains 3,500–5,500 ppm fluoride. Sporadic pain, joint stiffness, and 

osteosclerosis of the pelvis are observed at 6,000–7,000 ppm, while chronic joint pain, increased 

osteosclerosis, and slight calcification of ligaments occur at 7,500–9,000 ppm. Crippling fluorosis is 

observed at fluoride bone concentrations >10,000 ppm (Franke et al. 1975). 

Studies of individuals undergoing fluoride treatment for osteoporosis, epidemiology studies of 

communities with high levels of fluoride in drinking water, and community-based studies of populations 

with different fluoride levels in the water have examined the possible relationship between exposure to 

fluoride and alterations in bone mineral density and/or the risk of bone fractures. The effect of fluoride 

on bone fracture rate and mineralization has alos been investigated in children. 

A prospective, randomized of 135 women with postmenopausal osteoporosis ascertained the effect of 

administering 34 mg fluoride/day as sodium fluoride (0.56 mg fluoride/kg/day) for 4 years (Riggs et al. 

1990). The fluoride treated and the placebo control groups received 1,500 mg calcium/day. Although 

bone mineral density in the lumbar spine, femoral neck, and femoral trochanter increased markedly in the 

treatment group, bone mineral density in the shaft of the radius decreased 4%. There was no significant 

difference in the number of new vertebral fractures between the treatment and control groups, although 

the number of vertebral fractures in the fluoride group was slightly elevated in the first year. In contrast, 

the level of nonvertebral fractures in the fluoride group was 3.2 times that of the control group, with 

significant increases in both the frequency and rate of fractures. Most of the increase was due to 

increased incidences of incomplete ("stress") fractures, which occurred 16.8 times more often in the 

treatment group. In a follow-up to this study, Riggs et al. (1994) examined 50 of the women in the 

fluoride treatment group after an additional 2 years of treatment with 34 mg fluoride/day as sodium 

fluoride. The lumbar spine, femoral neck, and femoral trochanter bone mineral density continued to 

increase and the bone mineral density of the radius continued to decrease during years 4–6 of treatment. 

The vertebral fracture rate decreased during years 4–6 as compared to years 0–4. The nonvertebral 

fracture rate also decreased during the last 2 years, but the rate for the full 6-year period was still 3 times 

higher than the rate in the placebo control group. In addition to extending the study for an additional 

2 years, Riggs et al. (1994) also re-examined the data from the previous study. Vertebral fracture rate was 

influenced by several factors. Vertebral fracture rate decreased with increasing lumbar spine bone 

mineral density except in the cases where the higher bone mineral density was associated with a rapid rate 

of increase in the lumbar spine bone mineral density or a large increase from baseline serum fluoride 

level. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 101 

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In a similar study by Kleerekoper et al. (1991), the anti-fracture efficacy of 34 mg fluoride/day as sodium 

fluoride was examined in 46 postmenopausal women (mean age of 66.2 years) with spinal osteoporosis. 

A daily dose of 1,500 mg calcium was also administered to this group as well as a placebo control group 

of 38 postmenopausal women with spinal osteoporosis (mean age of 67.9 years). No significant 

differences in bone mineral density of the forearm, vertebral fractures, or peripheral fractures were found. 

A significant increase in painful lower extremity syndrome was observed in the fluoride group. It should 

be noted that Riggs et al. (1990, 1994) considered the lower extremity syndrome to be incomplete 

fractures and the incidence of incomplete fractures was added to the complete fracture incidence to 

calculate nonvertebral fracture incidence. 

Haguenauer et al. (2000) performed a meta-analysis to examine the effects of fluoride on the treatment 

and prevention of postmenopausal osteoporosis using the data from the Riggs et al. (1990, 1994), 

Kleerekoper et al. (1991), and 10 other studies. The meta-analysis showed a significant increase in bone 

mineral density in the lumbar spine and hip and a decrease in bone mineral density in the forearm after 

2 or 4 years of fluoride treatment. When the data from all studies were used, fluoride treatment for 2– 

4 years did not affect the relative risk of vertebral fractures. However, in studies in which the subjects 

were exposed to low levels of fluoride or a slow-release formulation for 4 years, a significant decrease in 

vertebral fracture relative risk was seen. An increase in the relative risk of nonvertebral fracture was 

observed when data from all studies were used; no effect was seen in studies using low levels of fluoride 

(<30 mg/day) or slow-release fluoride. 

Conflicting findings on whether fluoride exposure in drinking water results in increased bone mineral 

density have been reported, with studies finding increases in spine and femur bone mineral density 

(Kröger et al. 1994; Phipps et al. 1998, 2000), decreases in radius mineral density (Phipps et al. 1998), or 

no effect on bone mineral density (Cauley et al. 1995; Lehmann et al. 1998; Sowers et al. 1991). Lumbar 

spine, proximal femur, and forearm bone mineral densities were measured in men and women 60 years 

and older living in one of three cities with different levels of naturally occurring fluoride in drinking 

water (Phipps et al. 1998). After adjusting for a number of non-fluoride related risk factors, significant 

elevations in bone mineral density of the lumbar spine (men and women) and proximal femur (women 

only) were observed in residents with the highest levels of fluoride (2.5 mg/L), as compared to densities 

in residents with the lowest fluoride concentration (0.03 mg/L); no significant differences in bone mineral 

density were found between residents with the mid-level fluoride concentration (0.7 mg/L) and the lowest 

concentration. In contrast to this finding, a negative correlation between bone mineral density of the 

forearm and an individual’s fluoride intake from drinking water and toothpaste was found. Significant 
 

 

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increases in bone mineral density were also reported in another study by this group (Phipps et al. 2000). 

Adjusted (age, weight, education, knee/grip strength, surgical menopause, calcium intake, alcohol 

consumption, estrogen use, thiazide use, diabetes, thyroid hormone levels, exercise, and smoking) mineral 

densities were higher in the lumbar spine and femur and lower in the radius in women aged 65 years and 

older exposed to fluoridated drinking water, as compared to women with no reported exposure to 

fluoridated water. Kröger et al. (1994) also found significant increases in bone mineral density (adjusted 

for confounding factors such as age, weight, menopausal status, calcium intake, physical activity) of the 

femoral neck and lumbar spine among women aged 47–56 years exposed to fluoridated drinking water 

(1.2 mg/L) for >10 years (mean exposure duration was 25.9 years), as compared to women exposed to 

fluoridated drinking water for <10 years. 

In a study of women aged 65 years and older, no significant alterations in bone mineral density of the 

radius, calcaneus, hip, or lumbar spine were found between women with no exposure to fluoridated water 

(n=1,248), 1–10 years of exposure (n=438), 11–20 years of exposure (n=198), or greater than 20 years of 

exposure (n=192) (Cauley et al. 1995). Total calcium intake was significantly higher in the >20-year 

group and lower in the 11–20-year group. Lehmann et al. (1998) also found no difference in age- and 

weight-adjusted bone mineral density of the spine and femur of women aged 20–69 years living in an area 

with fluoridated water (1 mg/L). In the men living in the fluoridated water a community, there was a 

significant increase in age- and weight-adjusted bone mineral density of the Ward’s triangle portion of the 

femur, but no effect on neck or trochanter portions of the femur or the spine. The lack of adjustment for 

other risk factors limits the interpretation of this study; significantly higher alcohol consumption and 

lower calcium intakes were found in the fluoride-exposed group. Sowers et al. (1991) also found no 

significant alterations in bone mass in women aged 20–80 years living in a community with naturally 

high fluoride levels (4 mg/L) as compared to women living in a community with fluoridated water 

(1 mg/L). However, radius bone mass was significantly lower in the high fluoride group. 

As with bone mineral density, conflicting results have been found on the effect of low levels of fluoride 

on the risk of fractures, particularly hip fractures. These studies have found conflicting results, with 

studies finding a lower or higher incidence of hip fractures or no differences in hip fracture between 

humans exposed to fluoride in drinking water. 

Several studies have found decreases in hip fracture incidences in communities with fluoride in the 

drinking water, suggesting that there may be a beneficial effect. Simonen and Laittinen (1985) examined 

male and female residents older than 50 years living in two cities in Finland with either trace amounts of 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 103 

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fluoride in the water or with 1 ppm fluoride in the water. The occurrence of femoral neck fractures was 

lower in the men 50–80 years old and women >70 years old living in the area with fluoridated water, as 

compared to the low fluoride community. No difference in femoral neck fracture was observed in women 

50–69 years of age. In a prospective study of older women, Phipps et al. (2000) examined the possible 

relationship between living in an area with fluoridated water and the risk of fractures among women 

≥65 years old. Fewer spine, hip, and humerus fractures were observed in this group. However, a 

nonsignificant trend toward higher incidences of wrist fractures was observed in the continuous exposure 

group. Lehmann et al. (1998) also found a significant decrease in the occurrence of hip fractures 

(adjusted for age) in men and women living in an area with fluoridated water (approximately 1 ppm), as 

compared to residents living in a city with low levels of fluoride in the water. 

In contrast to the results of these studies, other studies have found an increase in the incidence of hip 

fractures in communities with fluoride in the drinking water. Sowers et al. (1986) found a higher 

incidence of hip fractures among women aged 55–80 years living in a community with high levels of 

naturally occurring fluoride (4 ppm) in the water, as compared to women living in an area with 

fluoridated water (1 ppm). The lower calcium intake in the high fluoride group may have influenced 

these results. A geographical correlational study of 541,985 white women hospitalized for hip fractures 

found a weak association (regression coefficient=0.001, p=0.1) between hip fracture incidence and 

fluoridation of water (Jacobsen et al. 1990). The association was strengthened (regression 

coefficient=0.003, p=0.0009) after correcting by county for other factors found to correlate with hip 

fracture incidence (latitude, hours of sunlight, water hardness, income level, and percentage of land in 

farms). Another study by this group (Jacobsen et al. 1992) also found a significantly elevated risk of hip 

fractures in residents living in counties with fluoridated water. The relative risks were 

1.17 (95% CI=1.13–1.22) and 1.08 (95% CI=1.06–1.10) for men and women aged 65 years and older. 

The highest prevalence of hip fractures was found in counties that began a fluoridation program within 

the last 5 years. Madans et al. (1983) examined the association between fluoride in drinking water and 

risk of hip fractures using hip fracture data from the National Health Interview Surveys of 1973–1977 and 

Centers for Disease Control and Prevention (CDC) data on the percent of a population in each U.S. 

county served with water having a natural or adjusted fluoride content of at least 0.7 ppm in 1973. 

Female residents over 45 years of age living in areas with lower fluoride levels in the drinking water had 

9% more hip fractures than women living in high fluoride areas; however, the difference was not 

statistically significant. An increase in the risk of hip fractures (age, sex, and quatelet index-adjusted 

odds ratio of 1.86, 95% CI=1.02–3.36) was also observed in adults aged 65 years and older living in areas 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 104 

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with drinking water fluoride levels ranging from 0.11 to 1.83 ppm (Jacqmin-Gadda et al. 1995); these 

data were reported as a letter to the editor and limited study details were provided. 

A study in England and Wales also found increased rates of hip fractures in men and women over 

age 45 as water fluoride levels increased up to 0.93 ppm (Cooper et al. 1991). Hip fracture rates in 

39 counties (standardized by age and sex) were compared with water fluoride levels in those counties. In 

the original analysis (Cooper et al. 1990), no significant correlation was found. However, when the 

authors reanalyzed the data using a weighted least-squares technique (weighting by the size of the 

population aged ≥45 years) to account for differences in the precision of the county-specific rates, a 

significant positive correlation between water fluoride levels and hip fracture rates was found (r=0.41, 

p=0.009). The correlation existed for both women (r=0.39, p=0.014) and men (r=0.42, p=0.007) (Cooper 

et al. 1991). Kurttio et al. (1999) studied over 144,000 residents living in rural areas of Finland from 

1967 to –1980. When all age groups were considered together, no relationship between fluoride levels in 

drinking water and the risk of hip fractures was found. However, among women aged 50–64 years with 

higher fluoride levels, an increase in the risk of hip fractures was found. No consistent relationships were 

found in men or in older women. The study authors suggested that other risk factors for hip fracture may 

be more important than fluoride exposure in determining risk of hip fractures in older women. An 

ecologic cohort study compared the hip fracture rate for men and women in a Utah community that had 

water fluoridated to 1 ppm with the rate in two communities with water containing <0.3 ppm fluoride 

(Danielson et al. 1992). The age-adjusted rate was significantly elevated in both women (relative risk 

1.27, 95% CI=1.08–1.46) and men (relative risk 1.41, 95% CI=1.00–1.81). In men, the rates in the 

fluoridated and nonfluoridated communities were similar until age 70. After age 75, the difference 

between the rates in the fluoridated and nonfluoridated areas increased with age. The difference between 

the hip fracture rates in the fluoridated and nonfluoridated areas increased for women in the 70- and 

75-year age groups. However, the fracture rates in women at ages ≥80 years old were similar in the 

fluoridated and nonfluoridated towns. The study authors attributed this to the fact that women older than 

80 years would have already gone through menopause by the beginning of fluoridation, and so would 

have had less bone remodeling and less incorporation of fluoride into the bone. The study authors also 

suggested that the reason that they found an effect when other investigators have not was the low levels of 

exposure to risk factors for osteoporosis (smoking and alcohol) in the Utah populations. This was a wellconducted study that suggests that communities with fluoridated water have an elevated risk of hip 

fracture. However, several possible confounding factors were not examined. Calcium levels in the water, 

total calcium and vitamin D intake, and individual fluoride intake were not determined. Estrogen use was 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 105 

3. HEALTH EFFECTS 

not evaluated, but was assumed to be similar since the communities were similar distances from larger 

medical centers. In addition, estrogen levels would not cause the effect in men. 

A study by Li et al. (2001) found a U-shaped pattern for the prevalence of overall bone fractures and the 

level of fluoride in the drinking water of six communities in rural China. The prevalence of bone 

fractures (adjusted for age and gender) was significantly elevated in the communities with 0.25–0.34 ppm 

fluoride (7.41%) or 4.32–7.97 ppm fluoride (7.40%), as compared to the prevalence (5.11%) in the 

community with 1.00–1.06 ppm fluoride in the water. When only hip fractures since age 20 years were 

examined, the age- and body mass index (BMI)-adjusted prevalence was only significantly higher in the 

4.32–7.97 ppm group; prevalence of 1.20% compared to 0.37% in the 1.00–1.06 ppm group. A similar 

pattern was found for overall fractures since age of 50 years; the age-adjusted prevalences were 4.80 and 

3.28% in the 4.32–7.97 and 1.00–1.06 ppm groups, respectively. 

Other studies have not found a relationship between fluoride in drinking water and hip fracture 

prevalence. No significant differences in the incidence or type of upper femoral fracture were observed 

when groups of subjects living in communities with low fluoride (<0.3 ppm), fluoridated (1.0–1.2 ppm), 

or high fluoride (>1.5 ppm) drinking water (Arnala et al. 1986). Kröger et al. (1994) found no effect on 

self-reported fractures among a group of older Finnish residents (mean age of approximately 53 years) 

living in an area with fluoridated water (1.0–1.2 mg/L), as compared to residents living in an area with 

low fluoride levels in the drinking water (<0.3 ppm). Similarly, Avorn and Niessen (1986) found no 

statistically significant alteration in the occurrence of long bone fractures among women aged 65 years 

and older living in counties with fluoridated water (fluoride concentrations were not reported) as 

compared to residents living in counties without fluoridated water. No alteration in the occurrence of hip 

or ankle fractures were observed in men and women aged 65 years or older residents living in 

communities with fluoridated water, as compared to residents living in communities without a water 

fluoridation program (Karagas et al. 1996). In men, the risk of proximal humerus fracture (relative risk 

1.23, 95% CI=1.06–1.43) and distal forearm fractures (relative risk of 1.16, 95% CI=1.02–1.33) were 

higher in the fluoridated water areas; the relative risks of these fractures in women living in fluoridated 

areas were not significantly altered. Cauley et al. (1995) found no effect on the risk of vertebral or 

nonvertebral fractures among women aged 65 years and older exposed to fluoridated water for 13 years 

(mean exposure duration). 

Jacobsen et al. (1993) compared hip fractures rates in the 10-year period prior to fluoridation to the rates 

in the 10-year period after fluoridation of a city’s water source (fluoride concentration of 1.1 ppm). No 
 

 

 

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significant differences in the risk of hip fractures were found in men or women aged 50 years and older; 

the relative risks, after adjusting for other risk factors, were 0.78 (95% CI=0.37–1.66) and 0.60 (95% 

CI=0.42–0.85) for men and women, respectively. No significant alterations in the risk of hip fracture 

were found among male and female residents aged 45 and older living in a city with fluoridated water 

(Suarez-Almazor et al. 1993). However, when male residents were considered separately, the relative risk 

of hip fracture was statistically significant in the 65 years and older age bracket (risk ratio of 1.13, 95% 

CI=1.00–1.24) and all men combined (risk ratio of 1.12, 95% CI=1.01–1.24). 

With the exception of studies examining skeletal fluorosis, most of the studies on the skeletal effects of 

fluoride involved older adult populations. There is also some limited evidence that fluoride may affect 

bone mineralization in children. Increased trabecular height and area were observed in the distal radial 

metaphysis of boys (11–12 years of age) with dental fluorosis living in an area with 2.7 ppm fluoride in 

water (Chlebna-Sokol and Czerwinski 1993). No alterations were observed in similarly aged girls or 

older (13.5–15 years) boys and girls. The trabecular changes were correlated with lower serum calcium 

levels and higher alkaline phosphatase activity levels. Alarcón-Herrera et al. (2001) found a significant 

correlation between bone fracture incidence and Dean’s index of dental fluorosis among children aged 6– 

12 years and adults aged 13–60 years. 

Evidence from animal experiments supports the association of high levels of fluoride and adverse effects 

on bone. The femurs of weanling male rats of a Wistar-derived strain that were given ≥9.5 mg 

fluoride/kg/day as sodium fluoride for 2 weeks exhibited a marked decrease in the modulus of elasticity. 

It is not clear if the change was analyzed statistically. No lower doses were tested (Guggenheim et al. 

1976). Musculoskeletal effects in albino rats (strain not identified) following oral exposure of 

intermediate duration have been investigated. After 30 days of exposure to 100 ppm of fluoride in water 

(14 mg fluoride/kg/day), tibia bones were broken and allowed to heal (Uslu 1983). Collagen synthesis 

was determined to be defective, and fracture healing was delayed, when compared to the controls. 

Decreased bone growth and signs of fluorosis were observed in rats given 19 mg fluoride/kg/day as 

sodium fluoride in their drinking water and adequate calcium for 5 weeks; with elevated calcium levels, 

fluorosis was not observed until the fluoride level reached 35 mg fluoride/kg/day (Harrison et al. 1984). 

Male mice administered 0.80 mg fluoride/kg/day for 4 weeks exhibited a statistically significant increase 

in the bone formation rate and a slight but statistically significant decrease in bone calcium levels (Marie 

and Hott 1986). The authors concluded that 0.80 mg fluoride/kg increased the population of osteoblasts 

under the conditions of this experiment. Turner et al. (1992) found a biphasic relationship between bone 

strength and bone fluoride content in rats. At lower fluoride intakes, increased bone strength was 
 

 

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observed; the maximum bone strength was achieved at 1,000–1,500 ppm fluoride in the bone. At fluoride 

concentrations >1,000 ppm bone strength started to decrease. The sagittal crests were enlarged and/or 

deformed in three of six adult female mink fed 9.1 mg fluoride/kg/day as sodium fluoride for 382 days 

(Aulerich et al. 1987). The authors attributed the abnormalities of the sagittal crests to increased 

osteoblastic activity. An increase in the diameter of the femur bone and decreased breaking strength was 

observed in pigs administered sodium fluoride or rock phosphate in the diet (Kick et al. 1933). 

Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to 

fluoride, hydrogen fluoride, or fluorine. 

Pale, granular hepatocytes, compatible with parenchymal degeneration, were observed in mice 

administered 0.95 mg fluoride/kg/day in drinking water for 7–280 days (Greenberg 1982a). Fatty 

granules were observed after 3 weeks. Liver congestion was observed in sheep given a single intragastric 

dose of fluoride as low as 9.5 mg fluoride/kg. Mild serum increases of liver enzymes (glutamate 

dehydrogenase [GDH] and gamma-glutamyl transferase [GGT]) also occurred in sheep administered 

38 mg fluoride/kg (Kessabi et al. 1985). It is difficult to use this result to predict to possible human 

effects because ruminants (sheep, cows, goats) have gastrointestinal systems quite different from that of 

humans. 

Enlarged liver cells with multiple foci were seen in about half of the male B6C3F1 mice that died after 

receiving 33–36 or 67–71 mg fluoride/kg/day for up to 6 months as sodium fluoride in drinking water 

(NTP 1990). This change was seen in all of the female mice that died at the 71 mg/kg/day dose level. No 

liver effects were seen in a parallel experiment with F344/N rats at doses up to 20 mg/kg/day. Similarly, 

no liver histopathology was seen in the chronic portion of this study (NTP 1990), in which rats received 

total fluoride doses (amount added to water plus endogenous fluoride in food) of about 4.5 mg/kg/day 

(rats) or up to 9.1 mg/kg/day (mice). Alkaline phosphatase levels were significantly increased in male 

and female mice at the 66-week interim sacrifice of the chronic study. 

Renal Effects. One study was located in which ingestion of fluoride appeared to be linked with renal 

insufficiency (Lantz et al. 1987). A 32-year-old man ingested 2–4 L of Vichy water (a highly gaseous 

mineral water containing sodium bicarbonate and approximately 8.5 mg/L of fluoride) every day for 

about 21 years. This exposure ended 4 years before his hospital admission. The patient also had 

osteosclerosis and a moderate increase in blood and urinary levels of fluoride. No teeth mottling was 

observed. The authors could not find factors, other than fluoride, related to his interstitial nephritis. No 
 

 

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3. HEALTH EFFECTS 

effect on the incidence of urinary tract calculi or the incidence of albuminuria was found in the BartlettCameron study of people drinking water containing 8 ppm fluoride (Leone et al. 1954). 

Congestion of the kidney was observed in sheep given a single intragastric dose of fluoride as low as 

9.5 mg fluoride/kg (Kessabi et al. 1985). An intermediate exposure study tested the effect of 

administering up to 67–71 mg fluoride/kg/day to B6C3F1 mice (8–9/group) as sodium fluoride in drinking 

water for 26 weeks (NTP 1990). Acute nephrosis characterized by extensive multifocal degeneration and 

necrosis of the tubular epithelium was believed to be the main cause of death in two of the four males 

exposed to 67 mg/kg/day that died, the single male that died after exposure to 33 mg/kg/day, and two of 

the four females in the high dose group that died. No kidney histopathology was observed in surviving 

mice or in rats exposed to 20 mg fluoride/kg/day and higher (NTP 1990). Significant increases in water 

consumption and apparent (based on qualitative descriptions) increases in acid phosphatase activity in the 

glomeruli were observed in monkeys exposed to 0.46 mg fluoride/kg/day as hydrofluosilicic acid for 

180 days (Manocha et al. 1975). The toxicological significance of these changes is not known. 

Changes in kidney histology were seen in mature Swiss mice given a dose of sodium fluoride in drinking 

water for up to 280 days that was described as the maximum dose that could be chronically tolerated, i.e., 

1.9 mg/kg/day (Greenberg 1986). Using a sensitive staining technique, increased collagen levels were 

seen after about 45 days. Thickening of the Bowman's capsule, edematous swelling of the tubules, and 

infiltrations of mononuclear cells were also noticed. No kidney pathology was seen in a 2-year study in 

B6C3F1 mice at doses up to 8.1 mg/kg/day (males) or 9.1 mg/kg/day (females), or in F344/N rats at doses 

up to 4.1 mg/kg/day (males) or 4.5 mg/kg/day (females) (NTP 1990). 

Endocrine Effects. Significant increases in serum thyroxine levels were observed in residents of 

North Gujarat, India with high levels of fluoride in the drinking water (range of 1.0–6.53 mg/L; mean of 

2.70 mg/L) (Michael et al. 1996). No significant changes in serum triiodothyronine or thyroid stimulating 

hormone levels were found. Increases in serum epinephrine and norepinephrine levels were also 

observed. In another study conducted in India, a positive dose-response relationship between parathyroid 

hormone and fluoride intake from drinking water was observed in children aged 6–12 years (Gupta et al. 

2001). It is unclear if nutritional deficiencies played a contributing role to the observed endocrine effects. 

Jooste et al. (1999) found a higher goiter prevalence among children (6–15 years of age) living in two 

towns in South Africa with high levels of fluoride in the water (1.7 or 2.6 ppm), as compared to children 

living in towns with low (0.3 or 0.5 ppm) or optimal (0.9 or 1.1 ppm) fluoride levels in the water. The 

prevalence of goiter was also elevated in three of the other four towns, although the prevalence was lower 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 109 

3. HEALTH EFFECTS 

than in the high fluoride towns; suggesting that the children were exposed to other goitrogens. Iodine 

deficiency was not the likely etiological agent because the median urinary iodine levels were higher than 

iodine sufficiency standards. These data are inadequate to assess the relationship between elevated 

fluoride intake and goiter formation. 

Fluoride has been shown to affect the endocrine system in rats given 0.5 mg fluoride/kg/day as sodium 

fluoride in drinking water every day for 2 months (Bobek et al. 1976). These animals showed decreased 

thyroxine levels and an increased T3-resin uptake ratio. In contrast, Zhao et al. (1998) did not find any 

alterations in serum T3 or T4 levels in mice exposed to 3.2 mg fluoride/kg/day as sodium fluoride in 

drinking water for 100 or 150 days. However, a decrease in thyroid radiolabelled iodine uptake was 

observed at 3.2 mg fluoride/kg/day, but not at 0.06 mg fluoride/kg/day. 

No significant alterations in parathyroid hormone levels or morphological alterations in the parathyroid 

gland were observed in rats exposed to 3.3 mg fluoride/kg in drinking water for 46 weeks (Rosenquist et 

al. 1983). 

Body Weight Effects. Final body weight was reduced by >40% relative to the controls in female 

F344/N rats administered 25 mg fluoride/kg/day as sodium fluoride in drinking water for 14 days; body 

weight in males was reduced by >10% at doses ≥6.3 mg/kg/day (NTP 1990). A clear and consistent 

effect on body weight of B6C3F1 mice was seen only at the high dose (69 mg/kg/day), which was lethal 

to males (3/5), but not to females. In the intermediate-duration (6 months) phase of the study, the body 

weight of mice administered 17 mg fluoride/kg/day was reduced by 20%; it was reduced by 10% at 

19 mg/kg/day in male and female rats. 

F344/N rats and B6C3F1 mice given large doses of sodium fluoride in drinking water for 14 days had 

reduced water intake (NTP 1990). Male and female rats given 25 mg fluoride/kg/day drank about 30% 

less water than the controls. Water consumption by male rats given 51 mg fluoride/kg/day was 50% of 

controls, while it was 25% of controls for females. Similarly, mice given 69 mg fluoride/kg/day drank 

≤60% the volume of water consumed by the controls. This means that actual fluoride doses are lower 

than the estimates given here, since these values were calculated assuming normal water intake. 

However, the reduced water intake may have been due to the disagreeable taste of fluoride at high 

concentrations in the water. 
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3. HEALTH EFFECTS 

3.2.2.3 Immunological and Lymphoreticular Effects 

A request to the American Academy of Allergy was made by the U.S. Public Health Service for an 

evaluation of suspected allergic reactions to fluoride as used in the fluoridation of community water 

supplies (Austen et al. 1971). The response to this request included a review of clinical reports and an 

opinion as to whether these reports constituted valid evidence of a hypersensitivity reaction to fluoride 

exposure of types I, II, III, or IV (Austen et al. 1971), which are, respectively, anaphylactic or reaginic, 

cytotoxic, toxic complex, and delayed-type reactivity. The Academy reviewed the wide variety of 

symptoms presented (vomiting, abdominal pain, headaches, scotomata [blind, or partially blind areas in 

the visual field], personality change, muscular weakness, painful numbness in extremities, joint pain, 

migraine headaches, dryness in the mouth, oral ulcers, convulsions, mental deterioration, colitis, pelvic 

hemorrhages, urticaria, nasal congestion, skin rashes, epigastric distress, and hematemesis) and concluded 

that none of these symptoms were likely to be immunologically mediated reactions of types I–IV. No 

studies were located that investigated alterations in immune response following fluoride exposure in 

humans. 

In a study with rabbits administered 4.5 mg fluoride/kg/day as sodium fluoride for 18 months, decreased 

antibody titers were observed (Jain and Susheela 1987). These results were observed after 6 months of 

treatment; the authors hypothesized that a threshold level is reached at which time the immune system is 

impaired. However, as only one dose level (4.5 mg fluoride/kg/day) was tested, no dose-effect 

relationships can be established. An increase in the cellularity of Peyer’s patches and mesenteric lymph 

nodes was observed in rats administered sodium fluoride (Butler et al. 1990). 

3.2.2.4 Neurological Effects 

There are limited data on the neurological toxicity of fluoride in humans. Exposure to very high doses of 

fluoride can result in neuromuscular symptoms (e.g., tetany, paresthesia, paresis, convulsions). These 

effects are probably due to hypocalcemia caused by fluoride binding of calcium causes these symptoms 

(Eichler et al. 1982). As discussed in the Developmental Effects section, decreases in intelligence were 

reported in children living in areas of China with high levels of fluoride in the drinking water, as 

compared to matched groups of children living in areas with low levels of fluoride in the drinking water 

(Li et al. 1995a; Lu et al. 2000), but these studies are weak inasmuch as they do not address important 

confounding factors. Using dental fluorosis as a surrogate for high fluoride intake, Morgan et al. (1998) 
 

 

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examined the possible correlation between dental fluorosis and behavioral problems in children aged 7– 

11 years. No significant correlations were found. 

There are limited animal data on the neurotoxicity of fluoride. Significant decreases in spontaneous 

motor activity were observed in rats exposed via gavage to 9 mg fluoride/kg/day as sodium fluoride in 

saline for 60 days (Paul et al. 1998). No alterations in motor coordination, as assessed with the rotarod 

test, were found. A decrease in blood cholinesterase activity was also observed in these rats. Another 

study (Mullenix et al. 1995a) found alterations in spontaneous behavior in female rats exposed to 7.5 mg 

fluoride/kg/day as sodium fluoride in drinking water for 6 weeks beginning at 3 weeks of age and in 

female rats exposed to 6.0 mg fluoride/kg/day as sodium fluoride in drinking water for 6 weeks beginning 

at 13 weeks of age. The study authors noted that the observed effects were consistent with hyperactivity 

and cognitive deficits. In a recent study only available as an abstract (Whitford et al. 2003), no significant 

alterations in performance on operant behavior tests were observed in female rats exposed to 2.9–11.5 mg 

fluoride/kg/day in drinking water for 7 months. Varner et al. (1998) found increases in the frequency of 

neuronal abnormalities in the neocortex and a bilateral accumulation of β-amyloid in the thalamus of rats 

exposed to 0.11 mg fluoride/kg/day as sodium fluoride in drinking water. This study did not assess 

neurofunction; thus, it is difficult to assess the toxicological significance of these effects. 

3.2.2.5 Reproductive Effects 

There are limited data on the potential of fluoride to induce reproductive effects in humans following oral 

exposure. A meta-analysis found a statistically significant association between decreasing total fertility 

rate and increasing fluoride levels in municipal drinking water (Freni 1994). Annual county birth data 

(obtained from the National Center for Health Statistics) for over 525,000 women aged 10–49 years living 

in areas with high fluoride levels in community drinking water were compared to a control population 

approximately 985,000 women) living in adjacent counties with low fluoride drinking water levels. The 

fluoride-exposed population lived in counties reporting a fluoride level of 3 ppm or higher in at least one 

system. The weighted mean fluoride concentration (county mean fluoride level weighted by the 1980 size 

of the population served by the water system) was 1.51 ppm (approximately 0.04 mg fluoride/kg/day 

calculated using a reference water intake of 2 L/day and body weight of 70 kg), and 10.40% of the 

population was served by water systems with at least 3 ppm fluoride. The mean weighted mean fluoride 

concentration in the control population was 1.08 ppm (approximately 0.03 mg fluoride/kg/day). 

However, this meta-analysis relied on a comparison of two quite disparate data sets, inasmuch as the 

fluoridation population often did not correlate well with the population for whom health statistics was 
 

 

 

 

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3. HEALTH EFFECTS 

available. The ecologic nature of this study design does not allow an evaluation of the nature of the total 

fertility rate and fluoride association. Another study found significantly decreased serum testosterone 

levels in 30 men diagnosed with skeletal fluorosis and in 16 men related to men with fluorosis and living 

in the same house as the patient (Susheela and Jethanandani 1996). The mean drinking water fluoride 

levels were 3.9 ppm (approximately 0.11 mg fluoride/kg/day), 4.5 ppm (0.13 mg fluoride/kg/day), and 

0.5 ppm (0.014 mg fluoride/kg/day) in the patients with skeletal fluorosis, related men, and a control 

group of 26 men living in areas with low endemic fluoride levels. No correlations between serum 

testosterone and urinary fluoride levels or serum testosterone and serum fluoride levels were found. One 

limitation of this study is that the control men were younger (28.7 years) than the men with skeletal 

fluorosis (39.6 years) and the related men (38.7 years). In addition, the groups are small and potentially 

confounding factors are not well addressed. 

Animal studies have examined the effect of fluoride on reproductive hormone levels, histology of the 

testes, spermatogenesis, and fertility. No alterations in mean serum levels of testosterone, luteinizing 

hormone, or follicle stimulating hormone were found in male rats exposed to 16 mg fluoride/kg/day as 

sodium fluoride in drinking water for 14 weeks or in their male offspring exposed during gestation, 

lactation, and for 14 weeks after weaning (Sprando et al. 1997). In contrast, significant decreases in 

serum testosterone levels were observed in rats receiving daily gavage doses of 4.5 mg fluoride/kg/day as 

sodium fluoride for 50 days (Narayana and Chinoy 1994) and in rats exposed for 60 days to 4.5 mg 

fluoride/kg/day as sodium fluoride in the diet (Araibi et al. 1989). 

No alterations in Sertoli cells or in the seminiferous tubules were observed in the male offspring of rats 

exposed during gestation, lactation, and for 14 weeks post weaning to 16 mg fluoride/kg/day as sodium 

fluoride in drinking water (Sprando et al. 1998). However, other studies have reported testicular damage, 

which appears to be directly related to the length of exposure. No histological alterations were observed 

in the testes of rats exposed to 21 mg fluoride/kg/day as sodium fluoride for 6 weeks (Krasowska and 

Wlostowski 1992). However, after 16 weeks of exposure, seminiferous tubule atrophy was observed at 

7.5 mg fluoride/kg/day and higher (Krasowska and Wlostowski 1992). A decrease in the mean diameter 

of the seminiferous tubules was observed in rats exposed to 2.3 or 4.5 mg fluoride/kg/day as sodium 

fluoride in the diet for 60 days (Araibi et al. 1989); thickening of the peritubular membrane of the 

seminiferous tubules was also observed at 4.5 mg fluoride/kg/day. Consistent with the decreases in serum 

testosterone levels, significant decreases in Leydig cell diameter were observed in rats (Narayana and 

Chinoy 1994) and rabbits (Susheela and Kumar 1991) receiving 4.5 mg fluoride/kg/day via gavage as 

sodium fluoride in water for 50 days or 18–23 months, respectively. 
 

 

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Although some studies have not found significant alterations in spermatogenesis or sperm morphology, a 

number of studies have reported adverse effects. No alterations in sperm head abnormalities (Li et al. 

1987a) or sperm morphology (Dunipace et al. 1989) were observed in B6C3F1 mice administered sodium 

fluoride by gavage at doses up to 32 mg fluoride/kg/day for 5 days and killed 30 days later or in 

B6C3F1 mice administered 23 mg fluoride/kg/day as sodium fluoride in water. In CD rats administered 

4.5 mg fluoride/kg/day as sodium fluoride in the diet for 60 days, a significant decrease in the percentage 

of seminiferous tubules containing spermatozoa was observed (Araibi et al. 1989). Damage to the 

spermatid and epididymal spermatozoa were observed in rabbits administered by gavage 4.5 mg 

fluoride/kg/day as sodium fluoride in water for at least 18 months (Kumar and Susheela 1994, 1995), and 

complete cessation of spermatogenesis was observed after 29 months of exposure (Susheela and Kumar 

1991). A number of studies have found significant alterations in cauda epididymal and vas deferens 

sperm. Decreased sperm counts, sperm motility, and sperm viability (the ratio of live to dead sperm) have 

been observed in rats exposed to 2.3 mg fluoride/kg/day and higher (Chinoy et al. 1992, 1995) and mice 

(Chinoy and Sequeira 1992) and guinea pigs (Chinoy et al. 1997) exposed to 4.5 mg fluoride/kg/day and 

higher. When exposed male rats were mated with unexposed females, decreased fertility was observed at 

2.3 mg fluoride/kg/day as sodium fluoride and higher (Chinoy and Sequeira 1992; Chinoy et al. 1992). 

The alterations in sperm and the infertility were reversible 30–60 days after termination of a 30-day 

exposure period (Chinoy and Sequeira 1992). 

Adverse reproductive effects have also been observed in females. Nearly complete infertility was 

observed in female Swiss-Webster mice exposed to 19 mg fluoride/kg/day as sodium fluoride in the 

drinking water for 25 weeks (Messer et al. 1973). However, this effect was not repeated in another study 

of Webster mice exposed to 13 mg fluoride/kg/day as sodium fluoride in the diet for three generations 

(Tao and Suttie 1976). The study authors attributed the difference between this study and the Messer et 

al. (1973) study to the higher iron levels in the Tao and Suttie (1976) study, as anemia was reported by 

Messer et al. (1973), but not by Tao and Suttie (1976). Significant decreases in the number of viable 

fetuses and increases in the resorption rate were observed in female Sprague-Dawley rats exposed to 

10.21 mg fluoride/kg/day as sodium fluoride in drinking water for 30 days prior to mating with 

unexposed males (Al-Hiyasat et al. 2000); it is not known if these effects were directly related to fluoride 

exposure or were secondary to the severe decreases in body weight (31% lower than controls) and water 

consumption. In contrast, a two-generation study by Collins et al. (2001a) did not find any significant 

alterations in reproductive performance in CD rats exposed to 10.7 mg fluoride/kg/day as sodium fluoride 

in drinking water for 10 weeks prior to mating with similarly exposed males. This study only found a 
 

 

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3. HEALTH EFFECTS 

small decrease in body weight gain (approximately 6%) in the rats exposed to a similar sodium fluoride 

concentration as used by Al-Hiyasat et al. (2000). Decreased estrus rate and increased incidence of 

missed pregnancies was observed in Sheltie dogs fed dog food supplemented with rock phosphate at a 

level of 11.5 mg fluoride/kg/day (Shellenberg et al. 1990). However, these changes were also observed in 

groups provided with distilled water rather than well water. No adverse effects on reproduction were 

observed in a two-generation rat study in which male and female rats were fed diets containing 23 mg 

fluoride/kg/day (Marks et al. 1984). Additional evidence that fluoride adversely affects female 

reproduction includes decreased lactation in rats exposed to 21 mg fluoride/kg/day in drinking water for 

88 days (Yuan et al. 1994) and decreased calving rate (Van Rensburg and de Vos 1966) and decreased 

milk production (Maylin and Krook 1982) in cows ingesting large amounts of fluoride. 

The highest NOAEL values and all reliable LOAEL values for reproductive effects for each species and 

duration category are recorded in Table 3-4 and plotted in Figure 3-4. 

3.2.2.6 Developmental Effects 

Fluoride readily crosses the placenta and is found in fetal and placental tissue (Armstrong et al. 1970; 

Gupta et al. 1993; Malhotra et al. 1993; Shen and Taves 1974). A number of human and animal studies 

have examined the potential of fluoride to induce developmental effects. 

Analysis of birth certificates and hospital records for over 200,000 babies born in an area with fluoridated 

water and over 1,000,000 babies born in a low fluoride area found no difference in the incidence of birth 

defects attributable to fluoride (Erickson et al. 1976). Exposure to high levels of fluoride has been 

described together with an increased incidence of spina bifida (Gupta et al. 1995). The occurrence of 

spina bifida was examined in a group of 50 children aged 5–12 years living in an area of India with high 

levels of fluoride in the drinking water (4.5–8.5 ppm) and manifesting either clinical (bone and joint pain, 

stiffness, and rigidity), dental, or skeletal fluorosis. An age- and weight-matched group of children living 

in areas with lower fluoride levels (≤1.5 ppm) served as a control group. Spina bifida was found in 

22 (44%) of the children in the high fluoride area and in 6 (12%) of the children in the control group. 

This study did not examine the possible role of potentially important nutrients such as folic acid, 

however, and had other study design flaws. 

Three studies (Li et al. 1995a; Lu et al. 2000; Zhao et al. 1996) conducted in China have found significant 

decreases in intelligence score in children living in areas with high endemic levels of fluoride in the 
 

 

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3. HEALTH EFFECTS 

water. As noted below, these studies have a number of design limitations, which restrict the interpretation 

of the results. A fourth study did not find significant alterations in IQ scores in Mexican children 

(Calderon et al. 2000). The study by Li et al. (1995a) examined intelligence in children living in areas 

with high fluoride levels due to soot from coal burning. A group of 907 children aged 8–13 years were 

divided into four groups depending on the existence and severity of dental fluorosis; 20–24 children in 

each age group for each area were examined for intelligence. A significant decrease in IQ was measured 

in children living in the medium- (mean IQ of 79.7) and severe- (mean of 80.3) fluorosis areas, as 

compared to the children living in the non- (mean of 89.9) or slight- (mean of 89.7) fluorosis areas. More 

children with IQs of <70 and 70–79 and fewer children with IQs of 90–109 and 110–119 were found in 

the medium- and severe-fluorosis areas than in the non- or slight-fluorosis areas. No information on 

exposure levels were provided; the mean urinary fluoride levels were 1.02, 1.81, 2.01, and 2.69 mg/L in 

the non-, slight-, medium-, and severe-fluorosis areas, respectively. Numerous potentially confounding 

variables were not mentioned in this study, however, which raises questions regarding the validity of the 

study’s findings. A study by Lu et al. (2000) also examined exposure to high fluoride levels and 

decreased intelligence. Sixty children aged 10–12 years living in an area with high fluoride levels in the 

drinking water (3.15 mg/L) were examined for intelligence. The test results were compared to a group of 

58 children with similar social, education, and economic backgrounds who lived in an area with low 

fluoride levels in water (0.37 mg/L). A significant decrease in IQ was observed in the high fluoride area 

(mean IQ of 92.27) as compared to the control group (103.05). Additionally, there was a significantly 

higher number of children from the high exposure area with IQ scores of <70 (retarded) and 70– 

79 (borderline retarded) than in the control group. A significant inverse relationship between urinary 

fluoride levels and IQ was also found. Nevertheless, because this study relied on small groups and 

presented scant discussion of numerous potential confounders, the strength of its conclusions are 

questionable. Zhao et al. (1996) found significantly lower IQ scores in children living in a village with 

high levels of fluoride in drinking water (4.12 ppm) as compared to children living in a village with 

0.91 ppm fluoride in water. The study authors noted that IQ levels in children were correlated with the 

educational levels of the parents; however, the educational level of parents in the village with low fluoride 

levels was higher than those in the high fluoride village. 

No significant alterations in IQ scores were found in Mexican children (6–8 years of age) exposed to 1.2– 

3 ppm fluoride in drinking water (Calderon et al. 2000; only available as an abstract). However, increases 

in reaction time and decreases in visuospatial organization were found; the scores on these tests were 

correlated with urinary fluoride levels. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 116 

3. HEALTH EFFECTS 

Rapaport (1956) reported an increased prevalence of Down’s syndrome in areas with fluoridated water. 

However, this finding has not been replicated by several other investigations (Berry 1958; Erickson et al. 

1976; Needleman et al. 1974). No correlation was found between fluoridation and Down's syndrome 

incidence (corrected for maternal age) in a study of over 234,000 children in fluoridated areas and over 

1,000,000 children in low-fluoride areas (Erickson et al. 1976). Ascertainment was based on birth 

certificates and hospital records, but was probably incomplete. Takahashi (1998) criticized the methods 

used by Erickson et al. (1976) to analyze the data. Using the same dataset and combining Down’s 

syndrome prevalence for the three youngest maternal ages, Takahashi (1998) found a significant 

association between water fluoridation and Down’s syndrome. Similar to Erickson et al. (1976), 

Needleman et al. (1974) found no maternal age-specific increases in Down’s syndrome; ascertainment 

was nearly complete in this study of over 80,000 children in fluoride areas and over 1,700,000 children in 

low-fluoride areas. Similarly, a study of the incidence of Down's syndrome in England did not find an 

association with the level of fluoride in water, but age-specific rates were not determined and tea was not 

taken into account as a source of fluoride (Berry 1958). 

No alterations in the number of live births, sex ratio, fetal body weights, or the occurrence of external, 

visceral, or skeletal malformations were observed in the offspring of rats and rabbits exposed to doses as 

high as 13.21 or 13.72 mg fluoride/kg/day, respectively, as sodium fluoride in drinking water consumed 

on gestational days 6–15 or 6–19, respectively (Heindel et al. 1996) or in the offspring of F0 or F1 rats 

exposed to 12.2 mg fluoride/kg/day as sodium fluoride in drinking water for 10 weeks prior to mating and 

during gestation (Collins et al. 2001b). Similarly, no developmental effects were observed in offspring of 

rats drinking water containing at least 11.2 mg fluoride/kg/day as sodium fluoride on gestational days 1– 

20 (Collins et al. 1995). An increase in the average number of fetuses per litter with at least three skeletal 

variations was seen at the highest dose tested (11.4 mg fluoride/kg/day); however, this was associated 

with decreased maternal water and food consumption and decreased body weight gain. Significant 

increases in the percentage of fetuses with skeletal or visceral abnormalities were also observed in the 

fetuses of rats receiving gavage doses of 18 mg fluoride/kg/day as sodium fluoride on gestational days 6– 

19 (Guna Sherlin and Verma 2001). As with the Collins et al. (1995) study, significant decreases in 

maternal body weight and food consumption were also observed in the dams. 

Bone morphology of weanling Sprague-Dawley rats from dams that received 21 mg fluoride/kg day for 

10 weeks prior to breeding and during gestation was examined with both light and electron microscopy. 

No pathological changes were seen, suggesting that although fluoride is transported across the placenta, 

the amount transported was not sufficient to affect fetal bone development (Ream et al. 1983). There 
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3. HEALTH EFFECTS 

were no developmental effects of fluoride in the first litter of an extended two-litter reproduction study in 

rats that were fed diets containing 23 or 2.8 mg fluoride/kg/day (two litters from each dam) (Marks et al. 

1984). However, the second litters born to mothers in the high-fluoride group had a higher number of 

abnormal newborns and affected litters than were found in the low-fluoride group. The significance of 

this finding is unclear because the effect was not analyzed statistically. 

Wild and domestic animals may be more sensitive than laboratory animals to developmental effects of 

fluoride. Stunted growth (Krook and Maylin 1979) and lameness (Maylin and Krook 1982) have been 

reported in calves that foraged on land downwind of an aluminum plant. Severe dental fluorosis 

confirmed high levels of fluoride ingestion. Mink kits that were born to mothers fed 9.1 mg 

fluoride/kg/day and fed the same feed after weaning exhibited a marked decrease in survivability (14% at 

3 weeks, compared with 86% for the control) (Aulerich et al. 1987). There was no effect at the next 

lower dose. No further clinical details were provided for these pups. However, survival of the females 

exposed to that level was also decreased (17% at the end of the trial [382 days], compared with 100% for 

the control), so it is not clear if the kit effects were secondary to maternal toxicity. The only clinical signs 

in the adult mink were general unhealthiness, hyperexcitability, and lethargy a few days before they died. 

No lameness was observed. 

3.2.2.7 Cancer 

Numerous epidemiological studies have examined the issue of a connection between fluoridated water 

and cancer. Most studies have not found significant increases in cancer mortality (Erickson 1978; Hoover 

et al. 1976; Rogot et al. 1978; Taves 1977) or site-specific cancer incidence (Freni and Gaylor 1992; 

Gelberg et al. 1995; Hoover et al. 1976; Mahoney et al. 1991; McGuire et al. 1991). However, a couple 

of studies have reported significant fluoridation-related increases in cancer mortality (Yiamouyiannis and 

Burk 1977) or incidence (Takahashi et al. 2001). The lack of control for potential confounding variables 

(i.e., age, race) limits the interpretation of these study results. Most of the investigations were 

community-based studies, and the sensitivity limit of even the most sensitive analysis in these studies 

appears to be a 10–20% increase. 

Yiamouyiannis and Burk (1977) were the first investigators to suggest a relationship between water 

fluoridation and increased cancer risk. In their study, cancer death rates for 1940–1950 were compared to 

rates for 1953–1969 for residents of the 10 largest cities in the United States with fluoridated water. 

Similar comparisons were made in 10 cities without fluoridated water. The investigators noted that prior 
 

 

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3. HEALTH EFFECTS 

to fluoridation (1940–1950) the crude cancer deaths were similar in the two groups of cities. After 

fluoridation (1953–1969), a sharp increase in cancer deaths was observed in the cities with fluoridated 

water. The increases in cancer deaths among residents aged 45–64 years and ≥65 years living in cities 

with fluoridated water were significantly higher than in residents of cities with nonfluoridated water. 

Yiamouyiannis and Burk (1977) noted that there was a greater increase in nonwhites in the fluoridated 

cities than in the nonfluoridated cities. Because they found no correlation between the increase in ageadjusted cancer death rate and the increase in the number of nonwhites living in each city, they concluded 

that the change in racial composition did not contribute to the fluoridation-related increase in cancer death 

rates. 

A number of investigators have criticized the methods used by Yiamouyiannis and Burk and have reanalyzed the data (Chilvers 1982, 1983; Doll and Kinlen 1977; Hoover et al. 1976; Kinlen and Doll 1981; 

Oldham and Newell 1977; Smith 1980; Taves 1977). The study was primarily criticized for the 

dissimilarity of the age, sex, and race distribution between the fluoridated and nonfluoridated cities and 

the rather short cancer latency period. Chilvers (1983) and Smith (1980) noted that the divergence in 

crude cancer deaths began almost immediately after fluoridation was initiated. The latency period (the 

period of time between first exposure and the discovery of cancer) is usually >5 years and the period 

between first exposure and death from cancer is typically >15 years. Thus, Chilvers (1983) and Smith 

(1980) suggested that exposure to fluoridated water was not the likely cause of the divergence in cancer 

mortality between the two groups of cities that began shortly after initiation of a water fluoridation 

program. Smith (1980) noted that using age bands of 20 years is problematic for cancer studies because 

cancer mortality dramatically increases with age so that small differences in the age distribution between 

two populations can result in apparently significant differences in cancer mortality. 

Smith (1980) also criticized Yiamouyiannis and Burk’s dismissal of the potential confounding variable of 

race based on the lack of significant correlation relationships. Additionally, he noted that the appropriate 

analytical method should account for race, age, and sex differences at the same time. Between 1950 and 

1970, the proportion of nonwhites and individuals over the age of 65 years increased more rapidly in the 

fluoridated cities than in the nonfluoridated cities (Doll and Kinlen 1977). This change in demographics 

would have likely resulted in increased cancer deaths independent of fluoridation. Oldham and Newell 

(1977) noted that although the crude cancer rates in the two groups of cities were similar, the 1950 excess 

cancer rate (which accounts for race, sex, and age differences) in the fluoridated cities was 10.3 per 

100,000 higher than in the nonfluoridated cities. The higher excess cancer rate in the fluoridated cities 

was attributed to the smaller number of white elderly women and greater number of elderly white males. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 119 

3. HEALTH EFFECTS 

Oldham and Newell (1977) estimated that in 1970, the excess cancer rate increased by 1% in the 

fluoridated cities and 4% in the nonfluoridated cities; the increases in absolute deaths were 8.8 per 

100,000 and 7.7 per 100,000 in the fluoridated and nonfluoridated cities, respectively. In re-examining 

the data used by Yiamouyiannis and Burk (1977), Hoover et al. (1976) noted that when fluoride was the 

only variable used in the regression analysis, it was a significant predictor of cancer mortality rate. 

However, when other demographic variables (population density, education level, race, employment in 

manufacturing, and geographic section of the country) were also entered into the equation, fluoride only 

statistically predicted stomach cancer mortality rate. Re-analysis of stomach cancer data with adjustment 

for high-risk ethnic groups resulted in a nonsignificant association for females and a significant 

association for males. 

Yiamouyiannis and Burk’s selection of nonfluoridated cities has also been criticized because they did not 

select the 10 largest cities (the criteria used for selecting fluoridated cities), rather they selected the 

10 largest cities with a crude cancer death rate exceeding 155 per 100,000 (the average in fluoridated 

cities). Comparison of the SMRs for 1950, 1960, and 1970 and the change from 1950 to 1970 using 

cancer mortality analysis of data from the original 10 largest fluoridated cities and the 10 largest 

nonfluoridated cities did not result in any relevant changes in cancer mortality (Kinlen and Doll 1981). 

Similarly, Taves (1977) calculated SMRs for three 2-year periods (1949–1951, 1959–1961, and 1969– 

1971) for all cancers in the fluoridated and nonfluoridated cities examined by Yiamouyiannis and Burk 

and for the next 10 largest fluoridated cities and 5 nonfluoridated cities. The SMRs for the 20 fluoridated 

cities, as well as the SMRs for the 15 nonfluoridated cities, were relatively constant for the three time 

periods, suggesting that water fluoridation did not increase the cancer risk. 

A number of other population studies have examined the possible association between water fluoridation 

and increased risk of all cancers or site-specific cancers. Hoover et al. (1976) examined cancer mortality 

data for counties in Texas with varying levels of naturally occurring fluoride. For white males and 

females, no significant increases in SMRs for all cancers combined or site-specific cancers were found in 

the three groups of counties with high levels of fluoride (0.7–1.2 ppm, 1.3–1.9 ppm, and ≥2.0 ppm) as 

compared to counties with very low fluoride levels in the drinking water. Hoover et al. (1976) also 

examined the effect of artificial fluoridation on cancer mortality. SMRs were calculated for residents of 

counties in the United States that were 67% urban. No significant differences in the SMRs for all cancer 

combined between the fluoridated and nonfluoridated counties were seen prior to fluoridation or 5, 10, or 

15 years after fluoridation. Similarly, no significant differences in SMRs were seen for individual cancer 

sites. A third study conducted by Hoover et al. (1976) examined cancer incidence data from Birmingham, 
 

 

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Alabama (nonfluoridated) and Denver, Colorado (fluoridated after 1947–1948). No fluoridation-related 

increases in age-adjusted, site-specific cancer incidence rates were found prior to fluoridation (1947– 

1948) or after fluoridation (1969–1971). 

Using mortality data from 22 nonfluoridated and 24 fluoridated cities with populations greater than 

250,000, Erickson (1978) calculated crude and adjusted death rates for all malignant neoplasms and 

several site-specific cancers (digestive, respiratory, breast, genital, urinary, leukemia). Slightly higher 

crude mortality rates were seen in the fluoridated cities (206.6 versus 183.0); however, when the mortality 

rates were adjusted for age, sex, and race, and demographic, social, and economic variables, no 

significant differences were found. Rogot et al. (1978) also found no association between fluoridation 

and cancer mortality among cities with populations of 25,000 or more in 1950. Mortality rates for 1950, 

1960, and 1970 and the change from 1950 to 1970 were compared for fluoridated and nonfluoridated 

cities. In a study of cancer mortality rates in three counties in Kansas with fluoridated water, and one 

county with nonfluoridated water, no consistent fluoridation-related increases in age-adjusted mortality 

from all cancers were found (Neuberger 1982). In one fluoridated county, there was a significant increase 

in mortality; however, in another county, cancer mortality was significantly lower than in the 

nonfluoridated county and in the third county, there were no significant differences. Examination of 

cancer mortality data for individual tumor sites revealed slightly higher rates of rectum cancer in females, 

higher rates of pancreatic cancer in females living in the county with the longest history of fluoridation, 

and bone cancer in males with the longest history of fluoridation exposure; the statistical significance of 

these findings was not reported. Using data from the NCI Surveillance, Epidemiology and End Result 

(SEER) program, Hoover et al. (1991a) evaluated cancer mortality data for 36 years and incidence data 

for 15 years. No consistent evidence of a relationship between site-specific cancer mortality or incidence 

and the pattern of fluoridation was found. A suggestive relationship between renal cancer incidence and 

duration of fluoridation was found. However, when the incidence data were divided into two time periods 

(1973–1980, 1981–1987), no relationship between renal cancer incidence and duration of fluoridation was 

found. 

A more recent study has also examined cancer incidence in populations with fluoridated water. Using 

data from three states (Connecticut, Iowa, and Utah) and six cities (Atlanta, Detroit, New Orleans, Seattle, 

San Francisco, and Los Angeles), Takahashi et al. (2001) conducted regression analysis of site-specific 

cancers. Statistically significant positive associations between fluoridation index (percentage of 

population with naturally or artificially fluoridated water) and cancer at a number of sites including the 

oral cavity, esophagus, colon, liver, pancreas, bronchus, lungs, kidney, urinary bladder, and bone were 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 121 

3. HEALTH EFFECTS 

found. However, interpretation of these data is limited by the lack of control for potential confounding 

variables (particularly age and race) between the fluoridated and nonfluoridated communities. 

In the early 1990s, two population-based studies found increases in the incidence of bone and joint cancer 

or osteosarcoma among males under the age of 20 living in areas with fluoridated water (Cohn 1992; 

Hoover et al. 1991b). Based on the NCI SEER program data, Hoover et al. (1991b) found 47 and 79% 

increases in the incidences of bone and joint cancer and osteosarcoma, respectively, among males and 

females living in areas with fluoridated water. In contrast, 34 and 4% declines in bone and joint cancer 

and osteosarcoma, respectively, were found in the nonfluoridated areas. The investigators questioned the 

biological significance of this finding because no relationship between the increased incidence and the 

initiation of fluoridation was found (Hoover et al. 1991b). In the Cohn (1992) study of the New Jersey 

cancer registry data, significant increases in the osteosarcoma incidence risk ratios were found among 

males under the age of 20 years living in areas with fluoridated water. The investigator cautioned that 

these results were based on a small number of cases. Other population-based studies (Freni and Gaylor 

1992; Mahoney et al. 1991) did not find significant associations between fluoridation and bone cancer. 

Freni and Gaylor (1992) reported significant increases in the cumulative risk of bone cancer among young 

men aged 10–29 years in 40 cancer registry areas in the United States, Canada, and Europe for the period 

of 1958–1987. However, when registry data for areas with known fluoridation status were examined, no 

consistent pattern was observed; both increases and decreases in cumulative risk were found in areas with 

fluoridated water. Similarly, Mahoney et al. (1991) reported a significant trend for increasing incidence 

of bone cancer among young men (<30 years of age) living in New York State, exclusive of New York 

City. A significant trend was not observed in young females or for osteosarcomas. Comparisons between 

bone cancer and osteosarcoma incidence rates among residents of counties with fluoridated water and 

residents of counties with nonfluoridated water did not reveal any statistically significant associations. A 

case-control study of New York residents, excluding New York City, also failed to show an association 

between fluoridated water and increased risk of osteosarcoma (Gelberg et al. 1995). A significant 

protective trend (odds ratio decreased with increased fluoride intake) was observed for males, although 

the authors noted that this may be due to good health practices rather than fluoride because a significant 

trend was not observed when only fluoridated water was considered. A small-scale case-control study 

(22 cases examined) also failed to find a significant association between fluoridated water and 

osteosarcoma occurrence (McGuire et al. 1991). 

The NTP conducted two chronic oral bioassays of fluoride administered as sodium fluoride (0, 25, 100, or 

175 ppm) in drinking water for 103 weeks, using F344/N rats and B6C3F1 mice (Bucher et al. 1991; NTP 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 122 

3. HEALTH EFFECTS 

1990). The first study was considered compromised for reasons that will be discussed below. However, 

pathology data from the first study were used in determining the doses for the second study. The 

specially formulated diet used in the second study contained 8.6 ppm fluoride; daily fluoride amounts 

administered in the food for control and experimental groups were 0.43 mg/kg/day in rats and 

1.1 mg/kg/day in mice. Based on the total amount of fluoride ingested and the amount in the feces, and 

apparently assuming that none of the fluoride found in the feces was absorbed, Bucher et al. (1991) 

calculated that the average bioavailability of fluoride in the food over the course of the experiment was 

60%. Assuming complete absorption of fluoride in the water, they estimated total fluoride intake 

(including fluoride in both water and diet) of control, low-, medium-, and high-dose male rats as 0.2, 0.8, 

2.5, and 4.1 mg/kg/day, respectively. Similarly, the high doses for female rats, male mice, and female 

mice were 4.5, 8.1, and 9.1 mg/kg/day, respectively. 

The study found osteosarcomas in the bone of 1/50 male rats in the mid-dose group and 3/80 of the highdose male rats. An additional high-dose male had an extraskeletal osteosarcoma in subcutaneous tissue. 

Examination of radiographs did not reveal a primary site in bone for the extraskeletal tumor, suggesting 

that it was a soft-tissue tumor that later ossified. No osteosarcomas were found in the low-dose or control 

rats. One of the osteosarcomas in the high-dose group was missed on radiographic examination and in the 

necropsy, and found only on microscopic examination. Three of the tumors were in the vertebra and only 

one was in a long bone. This is unusual, as Bucher et al. (1991) stated that chemically-induced 

osteosarcomas usually appear in the long bones, rather than in the vertebrae. Statistical analysis found a 

significant dose-response trend in the four osteosarcomas of the bone (p=0.027), but no significant 

difference (p=0.099) in a pairwise comparison of the controls with the high-dose group. The probability 

value for the trend test was decreased (p=0.010) when the extraskeletal osteosarcoma was included, but 

the pairwise test was still not significant (p=0.057). Osteosarcomas are rarely observed in control male 

rats in NTP studies; the historical incidence is 0.6% (range 0–6%). The rate in the high-dose group in this 

study was 3.75 or 5%, depending on whether or not the extraskeletal tumor is included. Tumor rates 

could not be compared with the historical controls because the diet generally used for NTP studies 

contains >20 ppm fluoride. Assuming the same bioavailability of 60%, the study report states that this 

would place the historical controls between the low- and mid-dose groups in the fluoride study. 

Conversely, the more extensive bone examinations used in the fluoride study, both at the macroscopic 

level and histologically, could have led to higher bone tumor levels being observed than in historical 

controls. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 123 

3. HEALTH EFFECTS 

The average fluoride level in the bones of male rats in the high-dose group was 5,260 ppm. While similar 

bone fluoride levels were found in the bones of female rats and male and female mice, there was no 

evidence of treatment-related osteosarcomas in these groups. Osteosclerosis was observed in high-dose 

female rats, suggesting a stimulatory or mitogenic effect on osteoblasts (Marie and Hott 1986). 

Osteosclerosis was not observed in mice, despite the higher dose. Osteosarcomas were observed in one 

low-dose male mouse, one low-dose female mouse, and one control female mouse. There was also one 

osteoma in a control female mouse. No osteosarcomas were observed at mid- or high-dose levels in 

female rats or male or female mice. The study authors stated that the absence of treatment-related 

osteosarcomas in female rats and male and female mice may have limited relevance to the findings in 

male rats. Results in the literature are mixed as to whether there is a sex-linked response in bone tumor 

formation (Litvinov and Sikivuev 1973; NCI 1978). 

Increased tumor incidence in rats or mice was noted in a few other tissues, but was not considered 

biologically significant. For example, the combined incidence of squamous cell papillomas and 

carcinomas in the oral mucosa was marginally increased in the high-dose male and female rats and 

thyroid follicular cell neoplasms were marginally increased in the high-dose male rats. Neither increase 

was statistically significant, and both types of neoplasms lacked a supporting pattern of increased 

preneoplastic lesions. Similarly, increased levels of keratoacanthomas were observed in high-dose female 

rats, but were not considered biologically significant because other benign neoplasms arising from 

stratified squamous epithelium was found in the controls. Malignant lymphoma and histiocytic sarcoma 

incidence in female high-dose mice was marginally increased (combined rate 30%), but the increase was 

not considered biologically significant. The incidence was well within the range of historical controls at 

the study laboratory (18–48%) and at all NTP laboratories (10–74%). The incidence of hepatocellular 

neoplasms in male and female mice of the treatment and control groups was higher than in historical 

controls. The study authors noted similar increases in other NTP studies that were conducted 

contemporaneously, and suggested that they may be associated with increased animal weight. Hepatocholangiocarcinomas, which are rare liver neoplasms, were identified in the original pathology 

examination in five treated male mice, four treated female mice, and one control female mouse. The 

Pathology Working Group reclassified all of the neoplasms (except one in a high-dose female mouse and 

one in a control female mouse) as hepatoblastomas, because they contained well-defined populations of 

cells that resembled embryonal liver cells more closely than they did biliary cells. The dose levels at 

which the reclassified hepatocholangiocarcinomas were found were not reported. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 124 

3. HEALTH EFFECTS 

Interpretation of this study is further complicated because higher doses might have been tolerated in both 

the rat and the mouse studies (NTP 1990). Fluoride-related tooth abnormalities found in the study 

included dental attrition in males of both species that was dose-related in rats but not in mice, dentine 

dysplasia in both genders of both species, and tooth deformities in male rats. No other treatment-related 

toxic effects were found in any group, and there was no evidence of decreased body weight gain in any 

group. Higher fluoride levels may have affected the teeth of the male rats so severely as to interfere with 

the animals' ability to eat. However, it appears that the mice and possibly the female rats could have 

tolerated a higher dose. 

Based on the finding of a rare tumor in a tissue known to accumulate fluoride, but not at the usual site for 

chemically-associated osteosarcomas, a weakly significant dose-related trend, and the lack of supporting 

data in female rats and mice of either gender, the NTP concluded that there was "equivocal evidence of 

carcinogenic activity of sodium fluoride in male F344/N rats." NTP defined equivocal evidence of 

carcinogenic activity to be a situation where the results show "a marginal increase in neoplasms that may 

be chemically related." NTP further concluded that there was no evidence that fluoride was carcinogenic 

at doses up to 4.73 mg/kg/day in female F344/N rats, or at doses up to 17.8 and 19.9 mg/kg/day in male 

and female B6C3F1 mice, respectively. 

The first chronic study in this series conducted by NTP was a 2-year cancer study in B6C3F1 mice and 

F344/N rats using a semisynthetic diet containing 2.1 ppm fluoride and fluoride provided in drinking 

water as sodium fluoride at 0, 10, 30, or 100 ppm. Several nontreatment-related clinical signs developed 

in rats, including corneal lesions and head tilt. Analysis of the diet revealed marginal to marked 

deficiencies in manganese, chromium, choline, and vitamins B12 and D. Based on these findings, the 

study was considered compromised, but the results were used to aid in dose selection for the second 

study. Only the following unverified pathology findings were reported: (1) one osteosarcoma in the 

occipital bone of one low-dose male rat; (2) one osteoma in the vertebra of a male control mouse; (3) one 

subcutaneous osteosarcoma in one female high-dose mouse; and (4) no osteosarcomas in female rats 

(male mice were not mentioned). 

A study sponsored by Procter and Gamble examined the carcinogenic potential of sodium fluoride 

administered in feed to Sprague-Dawley rats (Maurer et al. 1990). One group of controls was fed 

laboratory chow, and another control group was fed a semisynthetic low-fluoride diet. The control group 

fed the low-fluoride diet received 0.14 (males) or 0.18 (females) mg fluoride/kg/day as sodium fluoride. 

The fluoride level in the laboratory chow was not determined. Treatment groups ingested 1.8, 4.5, or 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 125 

3. HEALTH EFFECTS 

11.3 mg fluoride/kg/day in the diet as sodium fluoride. Fluoride bioavailability was not determined and 

water fluoride levels were not reported. Fluoride-related toxicity included dose-related hyperostoses in 

males and females, tooth abnormalities, and stomach inflammation. Fluoride levels in the bone ash of the 

high-dose males and females were 16,761 and 14,438 ppm, respectively. Primary tumors in target tissues 

as reported by the study authors were one fibroblastic sarcoma with areas of osteoid formation in a highdose male, one osteosarcoma in a low-dose female, one chordoma in a mid-dose male, one chondroma 

each in a mid-dose male and a low-dose female, one odontoma in a laboratory-chow control, and one 

stomach papilloma in a low-fluoride control. Re-examination of tissue slides as part of a review of the 

study by the Carcinogenicity Assessment Committee, Center for Drug Evaluation and Research, Food and 

Drug Administration (CAC/CDER/FDA) revealed an additional osteosarcoma in a low-dose female and 

one osteosarcoma in a high-dose male. Statistical analysis of the incidence of bone tumors found no 

dose-response relationship (CDER 1991). 

Several limitations of the study were not apparent in the study report, but were noted in the CAC review 

(CDER 1991). The low-fluoride diet may not have allowed normal growth and development, since pale 

livers and gastric hairballs were observed in all study animals except those fed laboratory chow. The diet 

and water were often above specifications for minerals, ions, and vitamins. A virus was found during the 

pretest period and its continued presence during the study was suspected; this may have compromised the 

health of the animals. The finding of bone tumors missed by the contract laboratory raised questions 

about the adequacy of the examination at gross necropsy. Finally, bone sections from only 50–80% of the 

mid- and low-dose animals were analyzed microscopically. The CAC review concluded that there are 

"flaws and uncertainties in the studies that keep them from providing strongly reassuring data." However, 

the committee concluded that the study results reaffirm the negative finding of the NTP study in female 

rats, and do not reinforce the equivocal finding in male rats. 

3.2.3 Dermal Exposure 

Several human and animal studies investigating the health effects following accidental dermal exposure to 

hydrofluoric acid were located. In addition, many of the human and animal studies investigating the 

health effects of inhalation exposure to hydrogen fluoride or fluorine found dermal/ocular effects due to 

the irritating effects of these chemicals. (In this section, hydrogen fluoride refers to the gas while 

hydrofluoric acid refers to the liquid.) One study regarding dermal exposure to sodium fluoride was 

located. Fluorine causes severe irritation of the eyes and skin and can severely burn the skin at high 

concentrations. Hydrofluoric acid is a caustic acid and can produce severe tissue damage either as the 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 126 

3. HEALTH EFFECTS 

water solution, or in the anhydrous form (hydrogen fluoride). Hydrofluoric acid can also rapidly 

penetrate the skin and cause systemic effects, especially cardiac arrhythmias. If left untreated, death can 

result. 

3.2.3.1 Death 

Hydrofluoric Acid. Fatalities from dermal fluoride exposure occur most frequently from accidental 

exposure to hydrofluoric acid in an occupational setting. The actual systemic doses are seldom known. 

However, the extent and severity of the burns, and occasionally, clinical chemistry values are reported. 

Death following hydrofluoric acid burns to the extremities, in the absence of inhalation exposure, is due 

to cardiac arrhythmias, with pronounced hypocalcemia, hyperkalemia, and hypomagnesemia. Ion pump 

disruption is thought to be the mechanism of systemic toxicity. Hydrofluoric acid exposure of the face 

has also resulted in death due to respiratory insufficiency, but the respiratory effects are likely to be due to 

concurrent inhalation exposure. Depending on the extent of the body surface exposed and the 

effectiveness of medical treatment, death usually occurs within a few hours (Chan et al. 1987; Chela et al. 

1989; Kleinfeld 1965). 

A patient with hydrofluoric acid burns on his leg involving 8% of his body surface area died from 

intractable cardiac arrhythmia, presumably secondary to the depletion of ionized calcium by the fluoride 

ion (Mullett et al. 1987). Serum fluoride level 4 hours after the burn injury was reported to be 

9.42 μg/mL, about 400 times the value reported as normal for that age and sex. A 23-year-old man who 

sustained second and third degree burns of his thighs, covering 9–10% of his body surface area died of 

cardiac arrhythmia 17 hours after exposure (Mayer and Gross 1985); serum fluoride was 4.17 μg/mL. 

The death of a chemist who sustained first- and second-degree burns of the face, hands, and arms when a 

vat containing hydrofluoric acid accidentally broke has been reported (Kleinfeld 1965). This 29-year-old 

male died 10 hours after admission to the hospital. Postmortem examination showed severe 

tracheobronchitis and hemorrhagic pulmonary edema. A petroleum refinery worker was splashed in the 

face with 100% anhydrous hydrofluoric acid (Tepperman 1980). The burn produced acute systemic 

fluoride poisoning with profound hypocalcemia and hypomagnesemia. The patient died <24 hours after 

exposure. A young woman splashed in the face with hydrofluoric acid died a few hours after exposure 

occurred (Chela et al. 1989). The autopsy revealed severe burns of the skin and lungs, with pulmonary 

hemorrhagic edema produced by hydrofluoric acid and its vapor. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 127 

3. HEALTH EFFECTS 

No studies were located regarding lethality in humans after dermal exposure to fluorine or fluoride, and 

no studies were located regarding lethality in animals after dermal exposure to fluoride, hydrofluoric acid, 

or fluorine. 

3.2.3.2 Systemic Effects 

No studies were located regarding gastrointestinal, hematological, musculoskeletal, endocrine, or body 

weight effects in humans or animals after dermal exposure to fluoride, hydrofluoric acid, or fluorine. 

The highest NOAEL values and all reliable LOAEL values for systemic effects in each species and 

duration category of exposure to hydrofluoric acid are recorded in Table 3-5. All reliable LOAEL values 

for systemic effects in each species and duration category for fluoride are recorded in Table 3-6. 

Respiratory Effects. 

Hydrofluoric Acid. Respiratory effects including pulmonary edema, tracheobronchitis, and pulmonary 

hemorrhagic edema have been reported in humans following acute dermal exposure of the face to 

hydrofluoric acid (Chela et al. 1989; Kleinfeld 1965). However, the pulmonary effects are likely to be 

due to concomitant inhalation of the acid vapor. As two of these cases were occupational accidents and 

the third was a homicide, no doses could be estimated from the information provided. 

No studies were located regarding respiratory effects in humans after dermal exposure to fluoride or 

fluorine, and no studies were located regarding respiratory effects in animals after dermal exposure to 

fluoride, hydrofluoric acid, or fluorine. 

Cardiovascular Effects. Cardiac arrhythmias are found following acute dermal exposure to 

hydrofluoric acid in humans (Mayer and Gross 1985; Mullett et al. 1987). A man who received a 

hydrofluoric acid burn on the arm covering 5% of the body experienced repeated ventricular fibrillation 

episodes, but survived following administration of intravenous calcium chloride, subcutaneous calcium 

gluconate, and excision of the burn area (Buckingham 1988). These cardiovascular effects are believed to 

result from the strong binding of fluoride to calcium, which produces hypocalcemia. Serum calcium is 

critical for proper ion transport in neuromuscular synapses; hypocalcemia can cause the ventricles not to 

contract properly. 
Table 3-5 Levels of Significant Exposure to Hydrogen Fluoride - Dermal 

Exposure/ 

Species 

(Strain) 

Duration/ 

Frequency 

(Specific Route) System NOAEL Less Serious 

LOAEL 

Serious 

ACUTE EXPOSURE 

Systemic 

Rabbit 1 d 

1-4hr/d 

Dermal 2 

Percent (%) 

2 

Percent (%) (necrotic lesions) 

Dehy

INTERMEDIATE EXPOSURE 

Systemic 

(NS) Rat 5 wks 

6d/wk 6hr/d 

Dermal 8.2 

ppm (subcutaneous hemorrhage around the 

eyes and on the feet) 

Sthy

Reproductive 

(NS) Dog 5 wks 

6d/wk 6hr/d 

8.2 

ppm 

31 

ppm (ulceration of the scrotum) St

hy

d = day(s); hr = hour(s); LOAEL = lowest-observed-adverse-effect level; min = minute(s); NOAEL = no-observed-adverse-effect level; wk = week(s); ppm = pa
Table 3-6 Levels of Significant Exposure to Fluoride - Dermal 

Exposure/

Duration/ LOAEL 

Species Frequency 

(Strain) (Specific Route) System NOAEL Less Serious Serious 

ACUTE EXPOSURE 

Systemic 

Rat 1 d Dermal 0.5 1 Es

24hr/d (superficial necrosis, (extensive necrosis, (Sprague- Dawley) Percent (%) Percent (%) moderate edema, PMN marked edema, so

infiltration) degenerating mast cells) 

d = day(s); hr = hour(s); LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; PMN = polymorphnuclear leukocyte 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 130 

3. HEALTH EFFECTS 

No studies were located regarding cardiovascular effects in humans after dermal exposure to fluoride or 

fluorine, and no studies were located regarding cardiovascular effects in animals after dermal exposure to 

fluoride, hydrofluoric acid, or fluorine. 

Hepatic Effects. 

Hydrofluoric Acid. Elevated SGOT, serum glutamic pyruvic transaminase (SGPT), and lactate dehydrogenase levels were found in a man who was splashed in the face and on the neck with a mixture of 10% 

hydrofluoric acid and sulfuric acid (Braun et al. 1984). The elevated SGOT and SGPT levels were 

attributed to either muscle necrosis or temporary liver damage caused by toxic metabolic products from 

necrotic tissue. 

Renal Effects. 

Hydrofluoric Acid. A 49-year-old man who was splashed in the face and on the neck with a mixture of 

hydrofluoric acid and sulfuric acid became oliguric for a brief period on the day after the accident, and 

then became anuric (Braun et al. 1984). Concomitant inhalation exposure is likely, and the effect of the 

sulfuric acid is unknown. 

Dermal Effects. Skin irritation and damage has been observed in humans and/or animals exposed to 

fluoride, hydrogen fluoride, hydrofluoric acid, or fluorine. Dermal effects related to exposure to 

hydrogen fluoride or fluorine are discussed under Inhalation Exposure (Section 3.2.1.2). 

Fluoride. Sodium fluoride applied topically to the abraded skin of Sprague-Dawley rats (0.5 or 1.0%) for 

24 hours produced both morphological and biochemical changes (Essman et al. 1981). At 0.5%, the 

abraded surface showed focal superficial necrosis of the epidermis. At 1.0%, the abraded surface showed 

edema and vacuolization. There was marked edema of the dermis with inflammation. Skin histamine 

concentrations were also increased following application of 0.5 or 1% sodium fluoride to shaved-only or 

epidermally abraded skin, although the variance of these measurements was quite high. 

Hydrofluoric Acid. Dermal exposure to hydrofluoric acid results in extensive skin burns (Chela et al. 

1989). Hydrofluoric acid quickly penetrates into soft tissues and causes necrosis. As a result of cell 

membrane destruction, the fluoride ion has easy access to lymph and the venules, can be distributed 

rapidly, and can cause significant adverse effects such as inhibition of glycolytic enzymes, hypocalcemia, 

and hypomagnesia. Untreated burns of the fingers can result in loss of fingers. There are many reports of 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 131 

3. HEALTH EFFECTS 

hydrofluoric acid skin burns in humans. In one case, a 23-year-old man received fatal second- and thirddegree burns over 9–10% of his body from a 70% hydrofluoric acid spill (Mayer and Gross 1985). The 

patient died 17 hours after exposure due to cardiac arrhythmias. Two case studies of accidental dermal 

exposure of the hands to hydrofluoric acid (5–7%) reported serious dermal injury following exposures 

from 45 minutes to 6 hours (Roberts and Merigian 1989). Topical treatment with calcium gluconate 

prevented loss of nails. Other case reports are discussed in Section 3.2.3.1. 

The concentration of hydrofluoric acid and the length of exposure affect the severity of dermal lesions 

(Derelanko et al. 1985). Rabbits exposed to a hydrofluoric acid solution of 0.01% for 5 minutes had 

visible skin lesions, whereas exposure to 2% hydrofluoric acid for 1 minute did not produce lesions. A 

longer exposure of 1–4 hours to 2% hydrofluoric acid solution produced necrotic lesions on the backs of 

rabbits (Derelanko et al. 1985). The application of 0.2 mL of a 47% hydrofluoric acid solution to the 

shaved backs of New Zealand rabbits over a surface of 11⁄4 inches produced no immediate reaction 

(Stokinger 1949). The material was held in place by lanolin and allowed to dry for 24 hours. Within a 

few days of exposure, erythema and dark spots of liquefaction necrosis appeared. Multiple eschars were 

formed in the necrotic areas. These wounds healed more slowly than those produced by fluorine gas. 

Healing did not near completion until 27 days after exposure. 

Ocular Effects. Ocular irritation and damage has been observed in humans and animals exposed to 

hydrogen fluoride, hydrofluoric acid, and fluorine. The ocular effects resulting from exposure to 

hydrogen fluoride or fluorine are discussed under inhalation exposure (Section 3.2.1.2). 

Some evidence of delayed ocular damage due to persistence of the fluoride ion was observed 4 days after 

a 3-year-old girl accidentally sprayed a hydrofluoric-acid-containing product in her eyes (Hatai et al. 

1986). Opacification of the corneal epithelium and thrombosis of the conjunctival vessels were seen. 

These changes were not permanent; after 30 days, the eyes returned to normal, and vision was 20/20. 

However, it is difficult to generalize from this report as the product contained both hydrofluoric acid and 

phosphoric acid at unspecified concentrations. 

McCulley et al. (1983) concluded that the greater severity of hydrofluoric acid eye injuries compared to 

injuries from other inorganic acids at comparable strengths probably results from the destruction of the 

corneal epithelium allowing substantial penetration of the fluoride ion into the corneal stroma and 

underlying structures. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 132 

3. HEALTH EFFECTS 

No studies were located regarding the following effects in humans and animals after dermal exposure to 

fluoride, hydrofluoric acid, or fluorine: 

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 

In general, positive genotoxicity findings occurred at doses that are highly toxic to cells and whole 

animals. Lower doses were generally negative for genotoxicity. Tables 3-7 and 3-8 present the results of 

more recent assays. 

The in vivo genotoxicity of fluoride has been tested in humans and animals following inhalation, oral, or 

parenteral exposure. No alterations in the occurrence of sister chromatid exchange were observed in a 

population living in areas with high levels of fluoride (4.8 ppm) in the drinking water (Li et al. 1995b). 

Mixed results have been reported in animal studies examining the clastogenic potential of hydrogen 

fluoride and sodium fluoride. Increases in the occurrence of chromosome aberrations were found in the 

bone marrow cells of rats exposed by inhalation to 1.0 mg/m3

 hydrogen fluoride 6 hours/day, 6 days/week 

for 1 month (Voroshilin et al. 1975) and in mouse bone marrow cells following oral, intraperitoneal, or 

subcutaneous exposure to sodium fluoride (Pati and Bunya 1987). However, other studies did not find 

significant alterations in the occurrence of chromosome aberrations in mouse bone marrow cells 

following oral exposure (Kram et al. 1978; Martin et al. 1979). Additionally, no alterations in sister 

chromatid exchange occurrence were observed in mouse or Chinese hamster bone marrow cells following 

oral exposure (Kram et al. 1978; Li et al. 1987b). Intraperitoneal injection of sodium fluoride resulted in 

an increase in micronuclei in mouse bone marrow cells (Pati and Bhunya 1987); no alterations were 

observed in rat bone marrow cells following oral exposure (Albanese 1987). Hydrogen fluoride was 
 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 133 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Fluoride In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference Form 

Prokaryotic organisms: 

Salmonella typhimurium Gene mutation – – Martin et al. 1979; NTP NaF 

1990; Tong et al. 1988 

Eukaryotic organisms: 

 Human lymphocytes Chromosomal No data + Albanese 1987 NaF 

aberrations 

 Human lymphocytes Chromosomal No data – Thomson et al. 1985 NaF, KF

aberrations 

 Human fibroblasts Chromosome No data + Tsutsui et al. 1984c NaF 

aberrations 

 Human fibroblasts Chromosomal No data – Tsutsui et al. 1995 NaF 

aberrations 

Human diploid IMR-90 Chromosomal No data + Oguro et al. 1995 NaF 

cells aberrations 

Human lymphocytes Sister chromatid No data – Thomson et al. 1985; NaF 

exchange Tong et al. 1988 

Human lymphocytes Sister chromatid No data – Thomson et al. 1985 KF 

exchange 

Human lymphoblasts Gene mutation + + Caspary et al. 1988 NaF 

 Human fibroblasts Unscheduled No data + Tsutsui et al. 1984c NaF 

DNA synthesis 

Syrian hamster embryo Chromosomal No data + Tsutsui et al. 1984b NaF 

cell aberrations 

Syrian hamster embryo Sister chromatid No data + Tsutsui et al. 1984b NaF 

cell exchange 

Syrian hamster embryo Unscheduled No data + Tsutsui et al. 1984b NaF 

cell DNA synthesis 

Chinese hamster ovary Sister chromatid No data – Li et al. 1987b NaF 

cells exchange 

Chinese hamster ovary Sister chromatid No data – Tong et al. 1988 NaF 

cells exchange 

Chinese hamster ovary Sister chromatid + + NTP 1990 NaF 

cells exchange 

Chinese hamster ovary Chromosomal + + Aardema et al. 1989 NaF 

cells aberrations 

Chinese hamster ovary Chromosomal – + NTP 1990 NaF 

cells aberrations 

 Chinese hamster Gene mutation No data – Slameńová et al. 1992 NaF 

V79 cells 

Mouse lymphoma cells Gene mutation No data (+) Cole et al. 1986 NaF 

Mouse lymphoma cells Gene mutation + + Caspary et al. 1987, NaF 

1988; NTP 1990 
 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 134 

3. HEALTH EFFECTS 

Table 3-7. Genotoxicity of Fluoride In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference Form 

Mouse lymphoma cells Gene mutation + + Caspary et al. 1987 KF 

Rat hepatocytes DNA repair No data – Tong et al. 1988 NaF 

Rat liver epithelium cells Gene mutation No data – Tong et al. 1988 NaF 

 Rat vertebral body Chromosome No data + Mihashi and Tsutsui NaF 

derived cells aberrations 1996 

Rat bone marrow cells Chromosome No data (+) Khalil 1995 NaF, KF 

aberrations 

Rat bone marrow cells Sister chromatid No data – Khalil and Da’dara 1994 NaF, KF 

exchange 

– = negative result; + = positive result; (+) = weakly positive result; DNA = deoxyribonucleic acid; KF = potassium 

fluoride; NaF = sodium fluoride 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 135 

3. HEALTH EFFECTS 

Table 3-8. Genotoxicity of Fluoride In Vivo 

Species (test system) End point Results Reference Form 

Human lymphocytes (oral exposure) Sister chromatid exchange – Li et al. 1995b NR 

Rat bone marrow cells (oral Micronuclei – Albanese 1987 NaF 

exposure)
 

Rat bone marrow Chromosome aberrations + Voroshilin et al. 1975 HF 

Rat testis cells (oral exposure) DNA strand breaks – Skare et al. 1986 NaF 

Mouse (C57B1) Dominant lethal – Voroshilin et al. 1975 HF 

Mouse (Harlan Sprague-Dawley) Sperm head abnormality – Li et al. 1987a NaF 

Mouse bone marrow and testis cells Chromosome aberrations – Martin et al. 1979 NaF 

(oral exposure) 

Mouse bone marrow cells (oral, Chromosome aberrations + Pati and Bhunya 1987 NaF 

intraperitoneal, or subcutaneous 

exposure)
 

Mouse bone marrow cells Micronuclei + Pati and Bhunya 1987 NaF 

(intraperitoneal exposure)
 

Mouse bone marrow cells (oral Chromosome aberrations – Kram et al. 1978 NaF 

exposure)
 

Mouse bone marrow cells (oral Sister chromatid exchange – Kram et al. 1978 NaF 

exposure)
 

Chinese hamster bone marrow cells Sister chromatid exchange – Li et al. 1987b NaF 

(oral exposure) 

– = negative result; + = positive result; DNA = deoxyribonucleic acid; HF = hydrogen fluoride; NaF = sodium fluoride; 

NR = not reported 
 

 

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3. HEALTH EFFECTS 

negative for dominant lethal mutations following inhalation exposure to hydrogen fluoride in C57B1 mice 

(Voroshilin et al. 1975). In a study in Drosophila melanogaster in which reproductive parameters were 

measured as an indicator of genotoxicity, significant reductions in the number of eggs per female and 

male fertility were observed following inhalation exposure to hydrogen fluoride (Gerdes et al. 1971b). 

The maximum lethality to adults of one of the two tested strains was 60%; under most of the test 

conditions, the lethality was ≤40%. 

3.4 TOXICOKINETICS 

The majority of data on the toxicokinetics of fluoride focus on sodium fluoride and hydrofluoric acid. 

Data regarding the toxicokinetics of calcium fluoride and other fluorides in human or animals are limited. 

While radioactive isotopes are useful in toxicokinetic studies, this use is limited in studies of fluoride 

because the fluorine isotope 18F has a short half-life (Wallace-Durbin 1954). 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Data providing information on absorption exist on the inhalation exposure of humans to hydrogen 

fluoride or mixtures of hydrogen fluoride and fluoride dusts, and inhalation exposure of animals to 

hydrogen fluoride. Animal data also exist showing that fluorine is absorbed. 

Hydrogen Fluoride. Increases in plasma fluoride levels were observed in humans inhaling 0.8–2.8 or 

2.9–6.0 ppm fluoride as hydrogen fluoride of 60 minutes (Lund et al. 1997); maximum plasma 

concentrations were observed 60–90 minutes after exposure initiation. A study in rats suggests that 

hydrogen fluoride is absorbed primarily by the upper respiratory tract, and that removal of hydrogen 

fluoride from inhaled air by the upper respiratory tract approaches 100% for exposures that range from 

30 to 176 mg fluoride/m3

 (Morris and Smith 1982). Furthermore, it is apparent that distribution to the 

blood is rapid. Immediately following 40 minutes of intermittent exposure, plasma fluoride 

concentrations correlated closely (correlation coefficient=0.98; p<0.01) with the concentration of 

hydrogen fluoride in the air passed through the surgically isolated upper respiratory tract. Plasma levels 

were not measured at time points <40 minutes. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 137 

3. HEALTH EFFECTS 

Hydrogen Fluoride and Fluoride Dusts. The absorption in humans of inhaled hydrogen fluoride and 

fluoride dusts has been demonstrated in several studies. In a study by Collings et al. (1952), two workers 

were exposed to approximately 5 mg fluoride/m3

 for 6 hours with 15-minute breaks every 2 hours. 

Absorption of fluoride was evaluated by monitoring urinary excretion of fluoride during and after 

exposure. Analysis of 2-hour serial urine samples showed a peak fluoride level 2–4 hours after cessation 

of exposure, which decreased to base levels within 12–16 hours after exposure. Similar results were 

obtained using the same protocol to measure urinary fluoride following exposure to air containing 5.0 mg 

fluoride/m3

 as rock phosphate dust (Collings et al. 1951). Another study reported clinical observations of 

employees in the production of phosphate rock and triple superphosphate (Rye 1961). Three employees 

were exposed to airborne fluoride (2–4 ppm) composed of approximately 60% dust and 40% hydrogen 

fluoride gas. Within 2–3 hours after exposure began, urinary fluoride levels increased from 0.5 to 

4.0 mg/L and peaked 10 hours (7–8 mg/L) following cessation of exposure. None of the subjects had 

prior occupational exposure to fluoride. Two studies of aluminum potroom workers found elevated 

plasma fluoride levels (Ehrnebo and Ekstrand 1986; Søyseth et al. 1994). In workers exposed to 

0.910 mg fluoride/m3

 total fluoride (34% of which was gasous fluoride) during an 8-hour workshift, 

elevated plasma fluoride concentrations and urinary fluoride levels were observed (Ehrnebo and Ekstrand 

1986). Although these studies demonstrate absorption of fluoride, none measure the extent of fluoride 

absorption. 

Fluorine. No data were located regarding the absorption of fluorine in humans. Hepatic and renal effects 

were observed in mice following exposure to fluorine for periods up to 60 minutes (Keplinger and Suissa 

1968). This indicates that the fluoride ion was systemically available following the exposure. Fluoride, 

rather than fluorine, is the agent that is toxicologically active systemically, since fluorine is too reactive to 

be absorbed unchanged. Similarly, the finding of elevated fluoride levels in bones, teeth, and urine during 

intermediate-duration exposure to fluorine indicates that fluoride is absorbed under these conditions 

(Stokinger 1949). No information on absorption rate or extent is available. 

Furthermore, although the data presented concern only acute exposures, it is expected that virtually 

complete absorption would also be observed during long-term exposure to low levels of fluoride in the 

air. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 138 

3. HEALTH EFFECTS 

3.4.1.2 Oral Exposure 

Fluoride. In humans and animals, fluoride is rapidly and efficiently absorbed from the gastrointestinal 

tract. Elevated plasma fluoride levels are seen shortly after exposure to sodium fluoride; peak plasma 

levels are typically seen within 30–60 minutes of ingestion (Carlson et al. 1960a; Ekstrand et al. 1977, 

1978). Fluoride is absorbed from both the stomach and small intestine via passive diffusion. Nopakun et 

al. (1989) estimated that in rats, approximately 20% of total absorbed fluoride was absorbed from the 

stomach. Absorption of fluoride from the stomach is inversely proportional to pH (Messer and Ophaug 

1993; Whitford and Pashley 1984), suggesting that fluoride is absorbed from the stomach as the 

undissociated hydrogen fluoride rather than the fluoride ion (Whitford and Pashley 1984). After gastric 

emptying, fluoride was rapidly absorbed from the small intestine (Messer and Ophaug 1993). An in vitro 

study suggests that in the small intestine, fluoride is primarily absorbed as the fluoride ion (Nopakun and 

Messer 1990). The absorption of fluoride does not appear to be homeostatically regulated. A linear 

correlation between fluoride (as sodium fluoride) intake and the area under the plasma fluoride 

concentration curve was found in humans ingesting 2–10 mg doses of sodium fluoride (Trautner and 

Seibert 1986). 

A number of dietary factors can influence the absorption of fluoride. Delayed gastric emptying slows the 

rate of fluoride absorption, but does not appear to affect the total amount of fluoride absorbed (Messer 

and Ophaug 1993). Ingestion of sodium fluoride with food delayed the peak plasma level but did not 

significantly alter the total amount of fluoride absorbed, as compared to values when the subjects ingested 

sodium fluoride after an 8-hour fast (Shulman and Vallejo 1990; Trautner and Einwag 1987). In contrast, 

ingestion of calcium fluoride with a meal dramatically increased (33.5 versus 2.8%) the absorption of 

fluoride, as compared to absorption after an 8-hour fast; similar results were found for the fluoride in bone 

meal tablets (Trautner and Einwag 1987). It is likely that the increased residence time in the upper 

gastrointestinal tract increased absorption. Ingestion of sodium fluoride with milk decreased fluoride 

absorption by 13–50% (Ekstrand and Ehrnebo 1979; Shulman and Vallejo 1990; Trautner and Seibert 

1986). Other studies have also shown that co-exposure to calcium carbonate or a diet high in calcium 

decreases fluoride absorption (Jowsey and Riggs 1978; Whitford 1994). Increased exposure to 

magnesium (Stookey et al. 1964; Weddle and Muhler 1954) or aluminum (Stookey et al. 1964; Weddle 

and Muhler 1954) also resulted in decreases in fluoride absorption. 

Soluble fluoride compounds, such as sodium fluoride, hydrogen fluoride, and fluorosilic acid, are readily 

absorbed from the gastrointestinal tract. Studies in humans and animals have found that >80% of an oral 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 139 

3. HEALTH EFFECTS 

dose of soluble fluoride compound is absorbed (Ericsson 1958; McClure et al. 1950, 1945; Zipkin and 

Likins 1957); several studies have reported 99–100% absorption efficiencies (Ekstrand et al. 1978; 

Trautner and Einwag 1987). Poorly soluble fluoride compounds, such as calcium fluoride, magnesium 

fluoride, and aluminum fluoride, do not appear to be well absorbed. Very little (<10%) fluoride was 

absorbed in fasting subjects ingesting calcium fluoride (Afseth et al. 1987; Trautner and Einwag 1987). 

Compared to sodium fluoride, the fluoride from bone meal (McClure et al. 1945; Trautner and Einwag 

1987) and cryolite (McClure et al. 1945) was poorly absorbed. 

The absorption of fluoride in infants, children, and adults appears to be similar. A study of four infants 

(mean age 8 months) reported mean absorption rates of 88.9–96.0% when a sodium fluoride solution was 

administered along with infant formula (Ekstrand et al. 1994b). As discussed previously, the absorption 

efficiency in adults usually exceeds 90% (Ekstrand et al. 1978; Trautner and Einwag 1987). As with 

adults, peak plasma levels usually occurred in 30–60 minutes (mean of 39 minutes) in infants (Ekstrand et 

al. 1994a) and young children aged 3–4 years (Ekstrand et al. 1983). One observed difference between 

fluoride absorption in infants and adults is that administration of fluoride with a high calcium diet did not 

result in a significant decrease in fluoride absorption (88.9 versus 96.0%) in infants (Ekstrand et al. 

1994b); a decrease in absorption has been reported in adults (Ekstrand and Ehrnebo 1979; Shulman and 

Vallejo 1990; Trautner and Einwag 1987). 

3.4.1.3 Dermal Exposure 

Data exist on dermal absorption of hydrofluoric acid in humans and animals, and limited quantitative rate 

data are available in animals. 

Hydrofluoric Acid. Dermal application of hydrofluoric acid results in rapid penetration of the fluoride 

ion into the skin. Sufficiently large amounts cause necrosis of the soft tissue and decalcification and 

corrosion of bone in humans (Browne 1974; Dale 1951; Dibbell et al. 1970; Jones 1939; Klauder et al. 

1955). Systemic fluoride poisoning has been reported following accidental dermal exposure to anhydrous 

hydrogen fluoride (Buckingham 1988; Burke et al. 1973). Although the extent of the contribution of 

inhalation exposure in these cases is not known, the reports suggest that hydrogen fluoride is quickly 

absorbed into the body following dermal exposure. However, these studies did not provide useful 

information concerning the extent of fluoride absorption, or information on absorption of smaller doses. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 140 

3. HEALTH EFFECTS 

Dermal absorption of hydrofluoric acid in albino mice of the d.d. strain was inferred in a study by 

Watanabe et al. (1975). Mice were painted with 0.02 mL of 50% hydrofluoric acid, and the residual acid 

was wiped off after 5 minutes. The mice were then injected intraperitoneally with [14C]glucose and 

analyzed by whole body radiography. Radioactivity levels in the liver, renal cortex, lungs, and blood 

were elevated 30 minutes after injection. This suggests that fluoride was absorbed through the skin and 

interfered with the tissue distribution of glucose. No data were located on the extent of absorption of 

fluoride in animals exposed dermally to hydrofluoric acid. 

These studies indicate that fluoride as hydrofluoric acid is absorbed through the skin in humans and 

animals. However, the degree of absorption is not known, nor is it known whether other forms of fluoride 

would be absorbed, and to what extent. Furthermore, it is expected that the relationship between duration 

or concentration and degree of absorption would be affected by the corrosive action of hydrofluoric acid. 

Therefore, prediction of the extent of absorption following exposure to a low concentration of 

hydrofluoric acid cannot be made based on the existing data. 

Fluorine. Systemic effects have been observed following whole-body exposure to fluorine (Keplinger 

and Suissa 1968; Stokinger 1949). However, these effects are likely to be due to inhalation exposure, 

rather than dermal exposure. 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

Hydrogen Fluoride. No data were located regarding the distribution of fluoride in humans following 

exposure to only hydrogen fluoride. Evidence from studies in animals supports the inference from 

occupational studies of exposure to hydrogen fluoride and fluoride dust that fluoride is distributed to the 

rest of the body when inhaled. Duration- and concentration-related increases in tooth and bone fluoride 

levels were reported in the rat following exposure to 7 or 24 mg/m3

 for 6 hours/day, 6 days/week for up to 

30 days (Stokinger 1949). Fluoride levels in new bone were up to twice the levels in old bone. The 

distribution of the fluoride ion was studied in the tissues of rabbits, a guinea pig, and a monkey exposed 

to hydrogen fluoride at various concentrations (1.5–1,050 mg/m3

) and exposure times (Machle and Scott 

1935). The observation period ranged from 9 to 14 months. As might be expected, based on the 

following discussion of human occupational exposure to fluoride compounds, the fluoride ion 

accumulated chiefly in the skeleton of all three species. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 141 

3. HEALTH EFFECTS 

Several studies in animals have demonstrated that fluoride is widely available through the blood, although 

actual concentrations in tissues other than blood have, for the most part, not been reported. For example, 

whole body exposure of male rats to levels ranging from 11 to 116 mg fluoride/m3

 as hydrogen fluoride 

for 6 hours resulted in a dose-dependent increase in lung and plasma fluoride concentrations (Morris and 

Smith 1983). In another study, rats exposed to 84 mg fluoride/m3 as hydrogen fluoride by whole body 

exposure had significantly elevated levels of fluoride in plasma and lungs 6 hours postexposure (Morris 

and Smith 1983). 

Hydrogen Fluoride and Fluoride Dusts. Limited information was located on the distribution of inhaled 

fluoride in humans. However, reports of skeletal fluorosis (Chan-Yeung et al. 1983b; Czerwinski et al. 

1988; Kaltreider et al. 1972) and elevated bone fluoride levels (Baud et al. 1978; Boivin et al. 1988) after 

occupational exposure to hydrogen fluoride and fluoride dusts indicate that fluoride is distributed to bone 

and accumulates there. 

Fluoride deposition in bone occurs mainly in regions undergoing active ossification or calcification. If 

the source of fluoride exposure has been removed, fluoride levels in bone decrease as the bone undergoes 

remodeling. Areas of fluoride deposition during high-level exposure are distinguished by highly elevated 

fluoride levels even after the average fluoride level of the bone has returned to normal (Baud et al. 1978). 

Fluorine. No data were located regarding the distribution of fluoride following the inhalation exposure 

of humans to fluorine. In rats exposed to 25 mg/m3

 fluorine for about 5 hours/day, 6 days/week for 

21 days, markedly elevated fluoride levels were observed in teeth and bone, the only tissues that were 

analyzed (Stokinger 1949). Tooth fluoride levels were about 14 times the levels in controls, and fluoride 

levels in the femur were about 6 times those in the controls. Similar concentration-related increases in 

bone and tooth fluoride levels were observed at the lower concentrations (3 and 0.8 mg/m3

). 

3.4.2.2 Oral Exposure 

Fluoride. Once absorbed, fluoride is rapidly distributed throughout the body via the blood. Fluoride is 

distributed between the plasma and blood cells, with plasma levels being twice as high as blood cell levels 

(Whitford 1990). After ingestion of sodium fluoride, the plasma fluoride does not appear to be bound to 

proteins (Ekstrand et al. 1977a; Rigalli et al. 1996). However, there is evidence that following ingestion 

of sodium monofluorophosphate, the plasma contains diffusible fluoride and protein-bound fluoride 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 142 

3. HEALTH EFFECTS 

(Rigalli et al. 1996). The elimination of fluoride from plasma following short-term exposure to sodium 

fluoride has been fit to a two-compartment model (Ekstrand et al. 1977a). The half-life of the terminal 

phase ranged from 2 to 9 hours. The rapid phase of fluoride distribution represents distribution in soft 

tissues, with fluoride being more rapidly distributed to well-perfused tissues. In pigs, the plasma 

clearance half-time of fluoride was 0.88 hours (Richards et al. 1982). Fluoride does not accumulate in 

most soft tissue; the ratio between tissue fluoride levels and plasma fluoride levels is typically between 

0.4 and 0.9 (Whitford et al. 1979a). It is likely that fluoride enters the intracellular fluid of soft tissues as 

hydrogen fluoride (Whitford et al. 1979a). Studies in rats and ewes suggest that the blood brain barrier is 

effective in preventing fluoride migration into the central nervous system (Spak et al. 1986; Whitford et 

al. 1979a); brain fluoride concentrations typically do not exceed 10% of plasma concentrations (Whitford 

et al. 1979a). Higher fluoride concentrations are found in the renal tubules, the concentration often 

exceeding plasma concentrations. 

The largest concentration of fluoride in the body is found in calcified tissues. Approximately 99% of the 

fluoride in the body is found in bones and teeth (Hamilton 1990; Kaminsky et al. 1990). The pineal gland 

which contains hydroxyapatite also accumulates fluoride (Luke 2001). Fluoride is incorporated into bone 

by replacing the hydroxyl ion in hydroxyapatite to form hydroxyfluroapatite (McCann and Bullock 1957; 

Neuman et al. 1950). Fluoride is not irreversibly bound to bone and is mobilized from bone through the 

continuous process of bone remodeling and to a lesser extent from ionic flux between interstitial fluoride 

and the crystalline bone surface (Turner et al. 1993; Whitford 1990). The biological half-life of fluoride 

was estimated to be 58.5 days in pigs orally exposed 2 mg fluoride/kg/day as sodium fluoride for 

6 months (Richards et al. 1985). A comparison between the retention of sodium fluoride, fluorosilicic 

acid, and sodium fluorosilicate did not find significant differences in the percentage of intake retained in 

the body of female rats exposed to 24 ppm fluoride in the diet for 5 months; fluoride retentions were 66.2, 

68.1, and 64.8, respectively (Whitford and Johnson 2003; only available as an abstract). 

Tissue fluoride levels are not homeostatically regulated. In adults, plasma fluoride levels appear to be 

directly related to fluoride intake. At higher fluoride intakes, a wide fluctuation of plasma fluoride levels 

were found in two adults and three children consuming 9.6 ppm fluoride in water (Ekstrand 1978); the 

fluctuation in plasma fluoride levels was smaller in the children, as compared to the adults. Mean plasma 

levels in individuals living in areas with a water fluoride concentration of <0.1 ppm was 0.4 μmol/L, 

compared to a mean plasma fluoride level of 1 μmol/L in individuals with a water fluoride content of 0.9– 

1.0 ppm (Guy et al. 1976). The level of fluoride in bone is influenced by several factors including age, 

past and present fluoride intake, and the rate of bone turnover. In adults (mean age, 47–60 years), 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 143 

3. HEALTH EFFECTS 

fluoride levels in the iliac crest ranged from 0.06 to 0.10% of bone ash (Boivin et al. 1988). In contrast, 

in subjects undergoing sodium fluoride treatment for osteoporosis for 5–6 years, the fluoride content of 

the iliac crest was 0.67% bone ash. Termination of high fluoride exposure can result in a decrease in 

bone fluoride levels. In aluminum workers diagnosed with skeletal fluorosis, there was a significant and 

progressive decrease in bone fluoride levels (Boivin et al. 1988). 

Age strongly influences the distribution of fluoride. The amount of fluoride taken up by bone is inversely 

related to age (Lawrenz et al. 1940; Miller and Phillips 1956; Suttie and Phillips 1959; Zipkin and 

McClure 1952; Zipkin et al. 1956). In a study of dogs (Ekstrand and Whitford 1984; Whitford 1990), the 

fractional uptake of fluoride by bone steadily declined during the first year of life. At weaning, 90% of an 

administered dose was taken up by bone compared to 50% at 1 year of age. Similar findings have been 

reported in human studies. In infants aged 37–410 days exposed to 0.25 mg fluoride supplement, the 

mean retention (bone uptake) of fluoride ranged from 68.1 to 83.4% (Ekstrand et al. 1994a, 1994b). In 

contrast, retention in adults receiving a fluoride supplement was 55.3% (Ekstrand et al. 1979). 

Human and animal studies have shown that fluoride is readily transferred across the placenta. There 

appears to be a direct relationship between maternal blood fluoride levels and cord blood fluoride levels 

(Armstrong et al. 1970; Gupta et al. 1993; Malhotra et al. 1993; Shen and Taves 1974). At relatively low 

maternal blood levels, the cord blood levels were at least 60% of that of maternal blood (Brambilla et al. 

1994; Gupta et al. 1993). Although cord fluoride levels were typically lower than maternal levels, one 

study found no statistical difference between maternal and newborn (1 day old) serum fluoride levels 

(Shimonovitz et al. 1995). However, a partial placental barrier may exist at high maternal fluoride levels. 

At higher maternal blood levels, the cord to maternal fluoride ratio is lower than at lower maternal 

fluoride levels (Gupta et al. 1993). Another study found that the use of fluoride supplements markedly 

increased placental fluoride levels, while fluoride levels in fetal blood remained relatively constant, 

suggesting that the placenta can regulate the transfer of fluoride from maternal blood to fetal blood 

(Gedalia 1970). Animal studies also demonstrate that maternal fluoride exposure also results in increased 

levels of fluoride in fetal teeth and bones (Bawden et al. 1992b; Nedeljković and Matović 1991; Theuer et 

al. 1971). 

In humans, fluoride is poorly transferred from plasma to milk (Ekstrand et al. 1981c, 1984b; Esala et al. 

1982; Spak et al. 1983). A single dose of 1.5 mg sodium fluoride did not result in a significant rise in 

fluoride breast milk concentrations within 3 hours of the exposure (Ekstrand et al. 1981c). Although no 

linear correlation between fluoride levels in tap water and fluoride levels in breast milk has been found, 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 144 

3. HEALTH EFFECTS 

significantly higher breast milk fluoride concentrations were found in women living in an area with high 

levels of naturally occurring fluoride (1–7 ppm) as compared to women in areas with low fluoride levels 

in tap water (0.2 ppm) (Esala et al. 1982). Fluoride levels in human milk of 5–10 μg/L have been 

measured (Fomon and Ekstrand 1999). 

3.4.2.3 Dermal Exposure 

No information was located in humans or animals regarding the distribution of fluoride, hydrogen 

fluoride, or fluorine following dermal absorption. 

3.4.2.4 Other Routes of Exposure 

Based on the results of a five-compartment computer model, Charkes et al. (1978) calculated that about 

60% of intravenously administered radiolabelled fluoride (18F) is taken up by bone; the half-time for this 

uptake is about 13 minutes. 

Perkinson et al. (1955) found initial rates of removal of fluoride from sheep and cow blood to be 41 and 

32%/minute of the intravenously administered dose, respectively. These data suggest a rapid distribution 

of fluoride and corroborate findings reported by other routes of administration. 

Fluoride distribution in rats was examined during and after continuous intravenous infusion of 

radiolabeled sodium fluoride at varying chemical dose rates for 3 hours (Knaus et al. 1976). Blood, 

kidneys, and lungs contained the highest fluoride concentrations at doses up to 3.6 mg fluoride/kg/hour, 

but at 6 mg/kg/hour, the fluoride content of the liver, spleen, and hollow organs increased sharply, 

indicating that the dose exceeded the amount readily processed by the excretory mechanisms of the body. 

In rat pups injected intraperitoneally with 0.1 μg fluoride/g body weight as sodium fluoride solution, 

significant increases in the fluoride content occurred in the developing enamel and bone (Bawden et 

al. 1987). Thus, regardless of the route of administration, some fluoride is deposited in teeth, bone, and 

soft tissues of animals, and some is excreted in the urine, sweat, and saliva. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 145 

3. HEALTH EFFECTS 

3.4.3 Metabolism 

Fluoride is believed to replace the hydroxyl ion (OH-) and possibly the bicarbonate ion (HCO3

-

) 

associated with hydroxyapatite—a mineral phase during formation of bone (McCann and Bullock 1957; 

Neuman et al. 1950). The resultant material is hydroxyfluorapatite. Once absorbed, a portion of the 

fluoride is deposited in the skeleton, and most of the remainder is excreted in the urine, with smaller 

amounts in feces, and sweat, and saliva within 24 hours (Dinman et al. 1976a, 1976b; McClure et al. 

1945). Urinary excretion is markedly decreased in the presence of decreased renal function (Kono et al. 

1984; Spak et al. 1985). 

A portion of the circulating inorganic fluoride acts as an enzyme inhibitor because it forms metalfluoride-phosphate complexes that interfere with the activity of those enzymes requiring a metal ion 

cofactor. In addition, fluoride may interact directly with the enzyme or the substrate. It is a general 

inhibitor of the energy production system of the cell (i.e., glycolytic processes and oxidative 

phosphorylation enzymes responsible for forming ATP) (Guminska and Sterkowicz 1975; Najjar 1948; 

Peters et al. 1964; Slater and Bonner 1952). Although much is known about enzyme inhibition by 

fluoride, the human health significance remains to be determined. The studies on enzymatic inhibition by 

fluoride were in vitro studies and used fluoride concentrations that were significantly (100–1,000 times) 

higher than concentrations that would be normally found in human tissues. 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

Hydrogen Fluoride. Overnight urinary fluoride excretion in dogs and rabbits exposed to 7 mg/m3 

hydrogen fluoride for 6 hours/day, 6 days/week for 30 days was about 1.5 times that of controls 

(Stokinger 1949). No further details were reported. 

Hydrogen Fluoride and Fluoride Dusts. Studies in humans indicate that fluoride absorbed from inhaled 

hydrogen fluoride and fluoride dusts over an 8-hour work shift is excreted even during exposure, with 

urinary excretion peaking approximately 2–4 hours after cessation of exposure (about 10 hours following 

beginning of exposure) (Collings et al. 1951; Rye 1961). A significant correlation between urinary 

fluoride excretion and the area under the plasma concentration-time curve was found in aluminum 
 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 146 

3. HEALTH EFFECTS 

workers (Ehrnebo and Ekstrand 1986). A significant correlation between urinary fluoride excretion and 

exposure levels of gaseous fluoride, but not particulate fluoride, was also found. 

Fluorine. No data were located regarding excretion of fluoride following human inhalation exposure to 

fluorine. Urinary fluoride levels were increased in dogs and rabbits exposed to levels as low as 0.8 mg/m3 

for 5–6 hours/day, 6 days/week for 35 days (Stokinger 1949). No quantitative data were reported at this 

level, but urinary fluoride levels in rabbits exposed to 3 mg/m3

 were 1.5 times normal. No further details 

were reported. 

3.4.4.2 Oral Exposure 

Fluoride. The primary pathway for fluoride excretion is via the kidneys and urine; to a lesser extent, 

fluoride is also excreted in the feces, sweat, and saliva. A study in rats suggests that the source of the 

small amount fecal fluoride may be fluoride that has re-entered the more distal portion of the intestine and 

became associated with unabsorbed cations (Whitford 1994). It has been estimated that approximately 

1% or less of an ingested dose is excreted in saliva (Carlson et al. 1960a; Oliveby et al. 1989), because 

saliva is swallowed, this amount does not enter mass balance calculations. The concentration of fluoride 

in the saliva appears to mirror plasma fluoride levels (Ekstrand 1977; Oliveby et al. 1989, 1990) and the 

ratio of saliva fluoride to plasma fluoride is about 0.5–0.64 (Ekstrand 1977; Oliveby et al. 1989). There 

are limited data on fluoride excretion via sweat. An older study (McClure et al. 1945) estimated that 19% 

of an ingested fluoride dose (3.7 mg) was excreted in sweat under comfortable conditions. Excretion of 

fluoride increased to 42% under hot-moist conditions. However, this study appears to have grossly 

overestimated fluoride excretion in sweat. A more recent study (Henschler et al. 1975), reported low 

levels of fluoride in sweat, approximately 20% of plasma levels, 2 hours after administration of sodium 

fluoride. 

Renal excretion is the major route of fluoride removal from the body; it typically equals 35–70% of intake 

in adults (Ekstrand et al. 1978; Machle and Largent 1943;). The fluoride ion is filtered from the plasma 

as it passes through the glomerular capillaries followed by a varying degree (10–70%) of tubular 

reabsorption; there is no evidence of tubular secretion of fluoride (Schiffl and Binswanger 1982; Whitford 

1990). Renal clearance rates in humans can range from 12.4 to 71.4 mL/minute with average values of 

36.4–41.8 mL/minute (Schiffl and Binswanger 1982; Waterhouse et al. 1980). A number of factors, 

including urinary pH, urinary flow, and glomerular filtration rate, can influence urinary fluoride 

excretion. Urinary pH appears to be the major determining factor for fluoride reabsorption from the renal 
 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 147 

3. HEALTH EFFECTS 

tubules (Ekstrand et al. 1980a, 1982; Järnberg et al. 1980, 1981, 1983; Whitford et al. 1976). At lower 

pH levels, more fluoride exists in the undissociated form (hydrogen fluoride) than in the ion form; the 

uncharged hydrogen fluoride more readily diffuses through the tubular epithelium to the interstitial fluid 

than the free charged fluoride ion. In the neutral interstitial fluid, the hydrogen fluoride would rapidly 

dissociate and the fluoride ions would be returned to the systemic circulation (Whitford et al. 1976). 

Thus, renal clearance of fluoride is directly related to urinary pH. A significant correlation between 

urinary flow and urinary fluoride excretion has been reported in humans (Ekstrand et al. 1978, 1982). 

Ekstrand et al. (1982) noted that a high flow rate in the renal tubules would likely increase the renal 

clearance of a substance that is reabsorbed at a slow rate. Similarly, a decrease in glomerular filtration 

rate would result in a decrease in urinary fluoride excretion (Jeandel et al. 1992). 

Most of the data on renal clearance of fluoride in humans come from studies of health adults; however, 

several studies have examined renal clearance of fluoride at different age levels (Ekstrand et al. 1994a; 

Jeandel et al. 1992; Spak et al. 1985; Villa et al. 2000). Whitford (1999) compared the results of many of 

these studies in infants and children with those in adults and concluded that there are no apparent agerelated differences in renal clearance rates (adjusted for body weight or surface area) between children 

and adults. However, in older adults (>65 years), a significant decline in renal clearance of fluoride has 

been reported (Jeandel et al. 1992). This is consistent with the decline in glomerular filtration rate and 

renal clearance of many substances that are also observed in the elderly (Whitford 1999). 

3.4.4.3 Dermal Exposure 

No studies were located regarding excretion of fluoride, hydrogen fluoride, or fluorine in humans or 

animals following dermal exposure. However, in the absence of evidence to the contrary, it is expected 

that dermally absorbed fluoride would be sequestered in bone and excreted in urine in a manner similar to 

that observed following oral or inhalation exposure. 

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 
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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 et al. 

1987; Andersen and Krishnan 1994). 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 

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 parametrization, (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) is 

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). 
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3. HEALTH EFFECTS 

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 3-5 shows a conceptualized representation of a PBPK model. 

Only one published PBPK model has been identified (Rao et al. 1995); it differs from published 

compartmental models for fluoride kinetics (Charkes et al. 1978, 1979; Ekstrand et al. 1977a; Hall et al. 

1977; Richards et al. 1982, 1985) in that the earlier models were data-based and useful only to simulate 

short-term fluoride kinetics. Because the fluoride ion is characterized by its long residence time in the 

body, health effects based on long-term fluoride exposure are of concern. In contrast to the earlier 

models, the Rao et al. (1995) PBPK model is amenable to extrapolation across species, routes, and doses, 

thereby offering an advantage in quantitative risk assessment for fluoride exposure. 

In order to assess the complex relationship between extended fluoride exposure, target tissue (bone) dose, 

and tissue response, a sex-specific PBPK model has been developed to describe the absorption, 

distribution, and elimination of fluorides in rats and humans (Rao et al. 1995). The PBPK model 

incorporates age and body weight dependence of the physiological processes that control the uptake of 

fluoride by bone and the elimination of fluoride by the kidneys. Six compartments (lung, liver, kidney, 

bone, and slowly- and rapidly-perfused compartments) make up the model. The bone compartment 

includes two subcompartments: a small, flow-limited, rapidly exchangeable surface bone compartment, 

and a bulk, virtually nonexchangeable inner bone compartment. The inner bone compartment contains 

nearly all of the whole body content of fluoride, which, in the longer time frame, may be mobilized 

through the process of bone modeling and remodeling. This model has been validated by comparing 

predictions with experimental data gathered in rats and humans after drinking water and dietary ingestion 

of fluoride. 

The PBPK model permits the analysis of the combined effect of ingesting and inhaling fluorides on the 

target organ, bone. It takes into account the effects of age and growth; in the human model, for instance, 

the bone and renal clearance rates accounted for 90 and 10%, respectively, during the growth period, 

compared to about 50% each in adulthood. Estimates of fluoride concentrations in bone are calculated 

and related to chronic fluoride toxicity. The model incorporates nonlinear binding rates of fluoride to 

bone, which has been described at high plasma concentrations. The model is thus useful for predicting 

some of the long-term metabolic features and tissue concentrations of fluoride that may be of value in 

understanding positive or negative effects of fluoride on human health. In addition, the PBPK model 
 

 

 

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Figure 3-5. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance 

Source: adapted from Krishnan et al. 1994 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical 

chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, 

metabolized in the liver, and excreted in the urine or by exhalation. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 151 

3. HEALTH EFFECTS 

provides a basis for cross-species extrapolation of the effective fluoride dose at the target tissue (bone) in 

the assessment of risk from different exposure conditions. 

3.5 MECHANISMS OF ACTION 

Skeletal Effects. A number of mechanisms are involved in the toxicity of fluoride to bone. Fluoride ions 

are incorporated into bone by substituting for hydroxyl groups in the carbonate-apatite structure to 

produce hydroxyfluorapatite, thus altering the mineral structure of the bone (Chachra et al. 1999). Unlike 

hydroxyl ions, fluoride ions reside in the plane of the calcium ions, resulting in a structure that is 

electrostatically more stable and structurally more compact (Grynpas 1990). Following administration of 

fluoride, there is a shift in the mineralization profile towards higher densities and increased hardness 

(Chachra et al. 1999). However, the structure of the bone (cortical thickness and the trabecular 

architecture of the femoral head) was largely unchanged in rabbits by fluoride administration. Chachra et 

al. (1999) suggest that the shift in mineralization could be due to either hypermineralization of older 

(denser) fractions or to a greater packing density of the hydroxyapatite crystals. Although high-dose 

fluoride administration is associated with an increase in bone mass, in vivo and in vitro animal studies 

have found a negative association between fluoride-induced new bone mass and bone strength, suggesting 

that the quality of the new bone was impaired by the fluoride (Silva and Ulrich 2000; Turner et al. 1997). 

Because bone strength is thought to derive mainly from the interface between the collagen and the 

mineral (Catanese and Keavney 1996), alteration in mineralization probably affects strength. The wider 

crystals, which are formed after fluoride exposure, are presumably not as well associated with collagen 

fibrils and thus, do not contribute to mechanical strength. Turner et al. (1997) found that the crystal width 

was inversely correlated with bending strength of the femur. Thus, although there is an increase in 

hardness and bone mass and unaltered structure, the mechanical strength of bone is decreased with longterm, high-dose administration of fluoride (Chachra et al. 1999). 

In addition to the physicochemical effect of fluoride on the bone, at high doses, fluoride can be mitogenic 

to osteoblasts (Farley et al. 1990; Gruber and Baylink 1991) and inhibitory to osteoclasts. The osteoblasts 

are still active, although there are fewer plump, cuboidal, highly secretory osteoblasts; whereas fluoride is 

mitogenic to osteoblastic precursors (Bonjour et al. 1993), it is toxic to individual osteoblasts at the same 

concentration (Chachra et al. 1999). The effect of fluoride on osteoclasts is not well understood; it 

appears that fluoride decreases the amount of bone resorbed by osteoclasts (Chachra et al. 1999). 
 

 

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Studies in humans and animals suggest that the effect of fluoride on bone strength is biphasic. In rats 

administered 1–128 ppm fluoride as sodium fluoride in drinking water for 16 weeks, both increases and 

decreases in bone strength were found; the maximum femoral bone strength occurred at 16 ppm (Turner 

et al. 1992). A biphasic relationship between femoral bone strength and bone fluoride content was found. 

Bone strength increased 18% as the bone fluoride content increased from 100 to 1,216 ppm, and 

decreased by 31% as the bone fluoride levels increased from 1,216 to 10,000 ppm. It should be noted that 

the bone fluoride levels in this study, as well as other studies discussed in this section, resulted from high 

doses of fluoride. Arnala et al. (1986) measured fluoride levels in iliac crest biopsies taken from 18– 

25 subjects with hip fractures living in areas with low fluoride (<0.3 ppm), high fluoride (>1.5 ppm), or 

with fluoridated (1.0–1.2 ppm) water. The average fluoride levels in the bone were 450, 3,720, and 

1,590 ppm, respectively. 

The biphasic nature of bone effects is supported by data from clinical trials in women with 

postmenopausal osteoporosis (Haguenauer et al. 2000). The meta-analyses of 12 studies found a 

significant increase in the relative risk of nonvertebral fractures in subjects ingesting high doses of 

fluoride (>30 mg/day); in subjects administered low fluoride doses or slow-release formulations, there 

was no effect on nonvertebral fractures. Further,, there was no effect on vertebral fracture risk in high 

fluoride dose subjects, but a decrease in this risk in subjects administered low fluoride doses or slowrelease formulations was found. 

Dental Fluorosis. Numerous human and animal studies have demonstrated that exposure to elevated 

fluoride levels during tooth development can result in dental fluorosis. As described previously, 

fluorosed enamel is composed of hypomineralized subsurface enamel covered by well-mineralized 

enamel. The exact mechanisms of dental fluorosis development have not been fully elucidated. Although 

there are a number of proposed mechanisms, most of the recent research has focused on the theory that 

dental fluorosis results from a fluoride-induced delay in the hydrolysis and removal of amelogenin matrix 

proteins during enamel maturation and subsequent effects on crystal growth (as reviewed by Aoba 1997; 

Bawden et al. 1995; DenBesten and Thariani 1992; Whitford 1997). Amelogenins, proteins secreted by 

ameloblasts, comprise >90% of the enamel matrix proteins and are involved in the regulation of the form 

and size of hydroxapatite crystallites; large molecular weight amelogenins inhibit the growth of enamel 

crystallites. In the early maturation phase of tooth development, the amelogenins are removed from the 

enamel matrix by amelogeninases, and crystallite growth dramatically increases. This phase of enamel 

maturation appears to be the most sensitive to elevated fluoride levels. The current evidence strongly 

suggests that fluoride inhibits amelogeninase activity. In one proposed mechanism, fluoride indirectly 
 

 

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inhibits amelogeninase, a calcium-dependent metalloenzyme, by binding to calcium in the mineralizing 

milieu and thereby decreasing the calcium concentration (or its activities) and the activation of 

amelogeninases (Aoba 1997; DenBesten and Thariani 1992; Whitford 1997). Another proposed 

mechanism is that amelogeninases are activated by a metalloproteinase and that calcium is required for 

this activation (Bawden et al. 1995; DenBesten and Thariani 1992); fluoride thus interferes with the 

proteolytic cascade necessary for hydrolysis of amelogenins. The fluoride-calcium interaction is 

supported by the findings that the enzymatic cleavage of amelogenins occurs at a slow rate during the 

secretory phase when calcium transport is low and dramatically increase during the early maturation 

phase (in the absence of excess fluoride) when calcium transport is high (Aoba 1997). 

An alternative theory on the mechanism of dental fluorosis is related to the effects of fluoride on 

maturation-stage ameloblasts (Bawden et al. 1995; DenBesten and Thariani 1992). Elevated fluoride 

exposure results in a decrease in the number of ameloblast modulations, which in turn could reduce the 

number of zone refinement cycles. As defined by Bawden et al. (1995), zone refinement is the process by 

which impurities (such as magnesium) that have been incorporated into forming crystals are reduced, 

resulting in an improvement of the structural characteristics of the crystal. Thus, a reduction in zone 

refinement cycles could result in inferior apatite crystalline structure. This theory is not incompatible 

with the theory that fluoride interferes with the hydrolysis of amelogenins. The fluoride-induced 

inhibition of amelogeninases results in an enamel matrix with a higher organic content, which could 

influence ameloblast modulation rate. 

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 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Colborn and Clement (1992), was also used in 1996 when Congress mandated the 

Environmental Protection Agency (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), which in 1998 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 
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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 1998c). 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). 

Although there is no evidence that fluoride is an endocrine disruptor, there are some data to suggest that 

fluoride does adversely affect some endocrine glands. An increase in serum thyronine levels, in the 

absence of changes in triiodothyronine and thyroid stimulating hormone levels, was observed in 

individuals living in areas of India with high fluoride levels in the drinking water (Michael et al. 1996). 

In contrast, a decrease in thyroxine levels was observed in rats exposed to fluoride in drinking water for 

2 months (Bobek et al. 1976). Significant decreases in serum testosterone have been observed in rats 

exposed to sodium fluoride for 50–60 days (Araibi et al. 1989; Narayana and Chinoy 1994). 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 
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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 

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 
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alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

A number of studies have examined the effects of fluoride in children. Due to its cariostatic properties, 

several agencies (for example, IOM 1997; WHO 1973) advocate the use of fluoride supplementation in 

children. However, there is a delicate balance between prevention of dental caries and the occurrence of 

dental fluorosis. Dental fluorosis, which is an increased porosity or hypomineralization of the tooth 

enamel, results from excess exposure to fluoride during tooth development (ages 1–8 years). The 

development and severity of dental fluorosis are dependent on the amount of fluoride ingested, the 

duration of exposure, and the stage of enamel development at the time of exposure. In the more severe 

cases, the tooth enamel is discolored, pitted, and prone to fracture and wear. Severe dental fluorosis is not 

commonly found in the United States; one study found prevalences of 0.9 and 6.9% in children living in 

communities with 1 or 4 ppm fluoride in drinking water, respectively (Jackson et al. 1995). In milder 

forms of dental fluorosis, opaque striations can run horizontally across the surface of the teeth, sometimes 

becoming confluent giving rise to white opaque patches. In mild dental fluorosis, the tooth enamel is 

fully functional; the opaque spots are considered a cosmetic effect. A recent meta-analysis (McDonagh et 

al. 2000) estimated the prevalence of dental fluorosis in children consuming 1 ppm fluoride in water to be 

48%; in 12.5% of the children, the fluorosis would be of aesthetic concern. Most of the community-based 

studies used for the meta-analysis did not consider other sources of fluoride, such as dental products, 

manufactured beverages, or food. 

Approximately 99% of the body’s fluoride is found in calcified tissues. Chronic exposure to high levels 

of fluoride results in bone thickening and exostoses (skeletal fluorosis). Because of the dynamic nature of 

growing bone, it is likely that children will deposit more fluoride in bone than adults consuming an equal 

amount of fluoride. However, it is not known if children would be more susceptible to skeletal fluorosis 

than adults. 

Developmental effects have been observed in humans and animals exposed to fluoride. In humans, an 

increased occurrence of spina bifida was found in children living in areas of India with high levels of 

fluoride in the drinking water (Gupta et al. 1995). However, this study had several deficiencies. For 

example, it did not address the nutritional status of the mothers. This is important because folic acid 

deficiency has been implicated in the etiology of spina bifida (Hernandez-Diaz et al. 2001; Honein et al. 

2000). In addition, the paper did not provide the fluoride levels in the blood of the mothers, nor 

radiographic evidence of spina bifida. Studies by Li et al. (1995a) and Lu et al. (2000) concluded that 
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there were decreases in IQ scores in children living in areas of China with high fluoride levels due to soot 

from coal burning, but it is not known if other contaminants in the soot also contributed to this effect, and 

the adequacy of the design of these studies is highly questionable. In the Gupta et al. (1995) and Li et al. 

(1995a) studies, the observed effects occurred in children with dental and/or skeletal fluorosis. In general, 

developmental effects have not been observed in rat or rabbit oral exposure studies (Collins et al. 1995; 

Heindel et al. 1996). However, the animal studies did not assess potential neurodevelopmental effects. 

The available human and animal data suggest that the developing fetus is not a sensitive target of fluoride 

toxicity. 

Fluoride retention appears to be higher in children than adults; although on a body weight basis, clearance 

is about the same in children and adults. Approximately 80% of an absorbed dose of fluoride is retained 

in young children compared to 50% in adults (Ekstrand et al. 1994a, 1994b). This is supported by the 

finding that renal fluoride excretion rate is lower in children than adults (Gdalia 1958; Spak et al. 1985). 

This difference in fluoride retention is due to high fluoride uptake in developing bones. Data on other 

potential age-related differences in the toxicokinetic properties of fluoride were not located. Fluoride is 

poorly transferred from maternal blood to breast milk (Ekstrand et al. 1981c; 1984b; Escala et al. 1982; 

Spak et al. 1983). 

Most of the available information on biomarkers, interactions, and methods for reducing toxic effects is 

from adults and mature animals; no child-specific information was identified, with the exception of 

biomarker data. It is likely that the available information in adults will also be applicable to children. 

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 or substance-specific metabolites in 

readily obtainable body fluid(s), or excreta. However, several factors can confound the use and 
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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 fluorides, hydrogen fluoride, and fluorine are 

discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by fluorides, hydrogen fluoride, and fluorine 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 Fluorides, Hydrogen 

Fluoride, and Fluorine 

There is extensive literature regarding fluoride levels in biological tissues such as urine, teeth, bone, and 

fingernails as indices of exposure. Since it does not produce any metabolites, the fluoride ion itself is the 

measured indicator. The most commonly used medium for identifying fluoride exposure is urinary levels 

(Ekstrand and Ehrnebo 1983). Several investigators have used this parameter to detect exposure to 

sodium fluoride through drinking water (Zipkin et al. 1956) or by ingestion (i.e., toothpaste or diet) 

(Ekstrand et al. 1983). Villa et al. (2000) found that measurement of fractional urinary fluoride excretion 
 

 

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in children is a good predictor of total daily fluoride intake. Occupational exposure to hydrogen fluoride 

is also evaluated from urine fluoride levels (Yoshida et al. 1978). 

Urinary fluoride levels are generally ≤1 mg/L when the water supply contains ≤1 ppm fluoride 

(Schamschula et al. 1985; Venkateswarlu et al. 1971; Zipkin et al. 1956). Only one report was located of 

urinary fluoride levels following acute poisoning. Following dermal exposure to about 5 g hydrofluoric 

acid over 2.5% of the body surface (along with concomitant inhalation exposure), the urinary fluoride 

level in the first sample obtained 3.5 hours after the accident was 87.0 mg/L (Burke et al. 1973). It is 

difficult to determine urine levels that are associated with chronic effects such as skeletal fluorosis, 

because no studies that report urinary fluoride levels, accurate exposure levels, duration of exposure, and 

health effects were located. Probably the most complete study reports average urinary fluoride levels of 

9 mg/L following inhalation exposure to 2.4–6.0 mg/m3

 for an unspecified period of time (Kaltreider et 

al. 1972). Marked evidence of fluorosis was seen in these workers. In another study (Dinman et al. 

1976c), the average postshift urinary fluoride level after 3–5 working days was 5.7 mg/L (range, 2.7– 

10.4). No exposure levels were available, but they were reported to be lower than in the plant where 

urinary fluoride levels were 9 mg/L. In spite of 10–43 years of occupational exposure, no signs of 

skeletal fluorosis were seen. This study may provide urinary fluoride levels that are not associated with 

skeletal fluorosis, but any sensitive workers may have left such work and not been included in the study. 

These studies are described in more detail in Section 3.2.1.2. 

Urinary fluoride levels up to 13.5 mg/L have been reported in areas of India where skeletal fluorosis due 

to high water fluoride levels (up to 16.2 ppm) is prevalent (Singh et al. 1963). 

Other media that have been used to measure fluoride exposure include plasma (Ekstrand et al. 1983), 

ductal saliva (Oliveby et al. 1990; Whitford et al. 1999b), nails (Whitford et al. 1999a), and tooth enamel 

(McClure and Likins 1951). When using plasma or saliva as a biomarker, the samples should be obtained 

under fasting conditions when measuring body burden (long-term intake) of fluoride (Whitford et al. 

1999b). Care must be taken when using plasma fluoride as an indicator of exposure; dosage, time, and 

duration must be taken into account (Whitford and Williams 1986). A wide range of plasma fluoride 

levels have been reported for the general population; the daily intake of fluoride appears to be one of the 

major contributors to plasma fluoride levels (Ikenishi et al. 1988; NAS 1971a). One study (Guy et al. 

1976) found a mean plasma fluoride concentration of 0.4 μmol/L (7.5 μg/L) in individuals consuming 

drinking water containing <0.1 ppm fluoride and an average plasma fluoride level of 1 μmol/L (19 μg/L) 

in individuals consuming 0.9–1.0 ppm fluoride in drinking water. Much higher plasma fluoride levels 
 

 

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have been reported in poisoning cases. For example, a plasma fluoride level of 2,000 μg/L was reported 

in a case of severe oral poisoning with 53 g fluoride as sodium fluoride (Abukurah et al. 1972). Chronic 

exposure to high levels of fluoride can result in wide fluctuations in plasma fluoride levels during the day 

(Ekstrand 1978). 

Urine, plasma, or saliva can be used as biomarkers of acute exposure to fluoride. Concentrations can 

peak within 1 hour after exposure since fluoride is rapidly absorbed from all routes of exposure. Fluoride 

salts possess a peculiar "soapy-salty" taste that enables some individuals to recognize that they are 

consuming large quantities of fluoride. With chronic exposures, such as from drinking water containing 

fluoride, urinary fluoride levels initially increase, and then reach a constant level. In workers, postshift 

urinary levels differ from preshift levels since fluoride exposure during the work day is absorbed rapidly 

into the body. However, these measurements may not always be useful for quantifying chronic exposure 

because fluoride can accumulate in bones. It may be retained in the skeletal tissues for a long period after 

the end of exposure, and later re-enter circulating blood to be taken up by bone again or excreted in urine. 

Furthermore, background tissue/fluid levels may affect these measurements since fluoride is prevalent in 

the environment from dietary sources. An important factor in biological fluid fluoride concentration is 

urinary pH (Whitford 1990). When urine is alkaline, fluoride urine excretion increases and is followed by 

a decline in plasma fluoride. 

Bone fluoride levels can be used to quantitate long-term fluoride exposure (Baud et al. 1978; Boivin et al. 

1988). However, this requires a bone biopsy, so bone fluoride levels are most frequently measured after 

clinical signs appear. As described in Section 3.2.2.2, the fluoride level found in bone varies between 

bones and increases with age. That section also describes fluoride levels in normal bone and levels 

associated with various effects. 

Studies of Hungarian (Schamschula et al. 1985) or Brazilian (Whitford et al. 1999a) children have 

demonstrated a direct relationship between fluoride concentrations in drinking water and fluoride levels in 

fingernail clippings, suggesting that fluoride in fingernails may be a reliable biomarker of exposure. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Fluorides, Hydrogen 

Fluoride, and Fluorine 

Because soft tissues do not accumulate significant levels of fluoride over long periods of time, effects of 

chronic exposure to fluoride first appear in the teeth or skeletal system. Chronic oral fluoride exposure 
 

 

 

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3. HEALTH EFFECTS 

can produce dental fluorosis (denBesten and Thariani 1992; DHHS 1991; Eklund et al. 1987; Fejerskov et 

al. 1990; Heifetz et al. 1988; Ismail and Bandekar 1999; Jackson et al. 1995; McDonagh et al. 2000; 

Selwitz et al. 1995; Teotia and Teotia 1994; Warren and Levy 1999), and higher levels of oral or 

inhalation exposure can lead to skeletal effects (Kaltreider et al. 1972; Leone et al. 1955). Evidence of 

moderate or severe dental fluorosis (pitting, staining, and/or excessive wear) are possible markers of 

effect for fluoride exposure (Walton 1988). However, dental fluorosis is reflective of fluoride exposure 

during tooth development (typically during ages 1–8 years), rather than current fluoride exposure. 

Alteration in bone density or derangement of trabecular structure can be detected by radiographs, and can 

indicate fluoride-induced changes. However, these are nonspecific changes and can be associated with 

other exposures. Other elements can sequester in the skeleton and produce similar changes observed in 

radiographs. Exostoses, apposition of new bone, ossification of ligaments and tendon insertions, and 

metastatic aberrant growth of new bone appear to be much more specific and constant findings in severe 

cases of skeletal fluorosis (Vischer et al. 1970). Skeletal fluorosis has been reported following inhalation 

exposure to 2.4–6.0 mg/m3

 for an unspecified duration (Kaltreider et al. 1972). As discussed in 

Section 3.2.2.2, nutritional status plays a large role in determining the oral fluoride exposure levels that 

lead to this effect. In the few cases of skeletal fluorosis in the United States for which doses are known, 

they are generally 15–20 mg/day for over 20 years (Bruns and Tytle 1988; Sauerbrunn et al. 1965). 

No well-documented information was located regarding biomarkers of effect for fluoride, although there 

are studies in which cellular changes occurred after fluoride exposure. Increases in glucose or lipid 

metabolism have been reported in tissues after exposure to fluorides (Dousset et al. 1984; Shearer 1974; 

Watanabe et al. 1975). Changes in erythrocyte enzyme activities including enolase, pyruvate kinase, and 

ATPase were found in chronically exposed workers in conjunction with slightly increased fluoride levels 

in the body (Guminska and Sterkowicz 1975). These alterations may explain the decreased red blood cell 

counts observed in other studies (Hillman et al. 1979; Susheela and Jain 1983). However, none of these 

enzyme alterations are specific to fluoride exposure. No information is available regarding how long 

these effects last after the last exposure. The enzymatic effects were measured within a few hours of a 

single fluoride treatment, while the red blood cell effects were seen as a result of chronic exposure. 

There is evidence that in patients with skeletal diseases, the proportion of dialyzable and nondialyzable 

hydroxyproline peptides serves as an index of bone collagen turnover. A decreased proportion of 

nondialyzable hydroxyproline peptides in the urine of fluorosis patients indicates either a decreased rate 

of synthesis of new collagen or an increased utilization of newly formed collagen for matrix formation. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 162 

3. HEALTH EFFECTS 

This marker offers potential for an early, although nonspecific, indication of altered bone metabolism 

after long-term fluoride exposure (Anasuya and Narasinga Rao 1974). No information is available 

regarding how long this lasts after chronic exposure. Sudden hyperkalemia and hypocalcemia are effects 

seen with fluoride intoxication due to the marked potassium efflux from intact cells caused by fluoride 

(McIvor et al. 1985). These ionic shifts are the only serologic markers of effect that have been identified, 

and these changes are not unique to fluoride. They last for a few hours after exposure. Polydypsia and 

polyuria are also nonspecific markers of effect. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

The absorption of fluoride from the gastrointestinal tract of humans and/or animals is affected by the 

presence of several minerals including calcium, magnesium, phosphorus, and aluminum (Rao 1984). 

These effects are discussed in Section 3.11. No reliable data on interactions that exacerbate negative 

effects of fluoride were located. 

Teotia and Teotia (1994) found that deficient calcium intake and elevated fluoride intake (1.1–4.0 ppm) 

resulted in a significant increase in the occurrence of dental fluorosis (100%) and dental caries (74%), as 

compared to children with normal calcium intakes and excess fluoride intakes (prevalences of dental 

fluorosis and caries were 14.2 and 31.4%, respectively). 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to fluorides, hydrogen fluoride, and 

fluorine than will most persons exposed to the same level of fluorides, hydrogen fluoride, and fluorine 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 fluorides, hydrogen fluoride, and fluorine, or compromised function of organs affected by 

fluorides, hydrogen fluoride, and fluorine. Populations who are at greater risk due to their unusually high 

exposure to fluorides, hydrogen fluoride, and fluorine are discussed in Section 6.7, Populations With 

Potentially High Exposures. 

Some existing data indicate that subsets of the population may be unusually susceptible to the toxic 

effects of fluoride and its compounds. These populations include the elderly, people with osteoporosis, 

people with deficiencies of calcium, magnesium, vitamin C, and/or protein (Murray and Wilson 1948; 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 163 

3. HEALTH EFFECTS 

Pandit et al. 1940; Parker et al. 1979), and people with kidney problems (Kono et al. 1984, 1985; Schiffl 

and Binswanger 1980; Spak et al. 1985). For most of these populations, there are very limited data to 

support or refute increased susceptibility to fluoride. Additionally, there are no data to suggest that 

exposure to typical fluoride drinking water levels would result in adverse effects in these potentially 

susceptible populations. 

The major route of fluoride excretion is via the kidney and the urine; fluoride excretion is influenced by a 

number of factors, including glomerular filtration rate, urinary flow, and urinary pH (Ekstrand et al. 1978, 

1980a, 1982; Järnberg et al. 1980, 1981, 1983; Whitford et al. 1976). In chronic renal failure, there is a 

decrease in glomerular filtration rate, which would result in a decrease in urinary fluoride excretion 

(Jeandel et al. 1992; Schiffl and Binswanger 1980). Decreases in fluoride excretion have been seen in 

adults (Kono et al. 1984; Schiffl and Binswanger 1980) and children (Spak et al. 1985) with impaired 

renal function. In children with low glomerular filtration rates (<92 mL/minute), renal fluoride clearance 

was 31.4 mL/minute compared to 45.0 mL/minute in children with normal glomerular filtration rates 

(Spak et al. 1985). In older adults (>65 years of age), there is a decline in renal function, which results in 

a decrease in renal clearance of fluoride (Jeandel et al. 1992; Kono et al. 1985). 

Poor nutrition increases the incidence and severity of dental fluorosis (Murray and Wilson 1948; Pandit et 

al. 1940) and skeletal fluorosis (Pandit et al. 1940). Comparison of dietary adequacy, water fluoride 

levels, and the incidence of skeletal fluorosis in several villages in India suggested that vitamin C 

deficiency played a major role in the disease (Pandit et al. 1940). Calcium intake met minimum 

standards, although the source was grains and vegetables, rather than milk, and bioavailability was not 

determined. Because of the role of calcium in bone formation, calcium deficiency would be expected to 

increase susceptibility to effects of fluoride. Calcium deficiency was found to increase bone fluoride 

levels in a 2-week study in rats (Guggenheim et al. 1976), but not in a 10-day study in monkeys (Reddy 

and Srikantia 1971). Guinea pigs administered fluoride and a low-protein diet had larger increases in 

bone fluoride than those given fluoride and a control diet (Parker et al. 1979). Bone changes in monkeys 

following fluoride treatment appear to be more marked if the diet is deficient in protein or vitamin C, but 

the conclusions are not definitive because of incomplete controls and small sample size (Reddy and 

Srikantia 1971). Inadequate dietary levels of magnesium may affect the toxic effects of fluoride. 

Fluoride administered to magnesium-deficient dogs prevented soft-tissue calcification, but not muscle 

weakness and convulsions (Chiemchaisri and Philips 1963). In rats, fluoride aggravated the 

hypomagnesemia condition, which produced convulsive seizures. The symptoms of magnesium 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 164 

3. HEALTH EFFECTS 

deficiency are similar to those produced by fluoride toxicity. This may be because of a fluoride-induced 

increase in the uptake of magnesium from plasma into bone. 

Although the possible relationship between fluoride in drinking water and the risk of fractures has been 

extensively investigated, the data are inconclusive with studies finding beneficial (Madans et al. 1983; 

Phipps et al. 2000; Simonen and Laittenen 1985) and deleterious (Cooper et al. 1990, 1991; Danielson et 

al. 1992; Jacobsen et al. 1990; Kurttio et al. 1999; Sowers et al. 1986) effects or no effects (Arnala et al. 

1984; Cauley et al. 1995; Kröger et al. 1994). Clinical trials of postmenopausal women with osteoporosis 

have found an increased risk of nonvertebral fractures following exposure to high doses of fluoride 

(34 mg/day) (Haguenauer et al. 2000; Riggs et al. 1990, 1994); no effect on vertebral fracture risk was 

found. However, administration of low doses of slow release sodium fluoride medications has been 

effective in treating spinal osteoporosis (Pak et al. 1995). 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to fluorides, hydrogen fluoride, and fluorine. 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 fluorides, hydrogen fluoride, and fluorine. When specific exposures have occurred, poison 

control centers and medical toxicologists should be consulted for medical advice. The following texts 

provide specific information about treatment following exposures to fluorides, hydrogen fluoride, and 

fluorine: 

Bronstein AC, Currance PL. 1988. Emergency care for hazardous materials exposure. St. Louis, MO: 

The C.V. Mosby Company, 113-114, 165-166. 

Ellenhorn MJ, Barceloux DG. 1988. Medical toxicology: Diagnosis and treatment of human poisoning. 

New York, NY: Elsevier Science Publishing Company, Inc. 76, 83, 531-536, 873-874, 924-929. 

Goldfrank LR, Flomenvaum NE, Lewin NA, et al., eds. 1990. Goldfrank’s toxicologic emergencies. 

Norwalk, CT: Appleton & Lange, 220-221, 745, 769-779. 

In all cases of acute high-level exposure to fluoride, hydrogen fluoride/hydrofluoric acid, or fluorine, the 

focus of mitigation is to limit further absorption and to complex or remove the free fluoride ions from the 

blood while maintaining the proper electrolyte balances. The majority of relevant acute high-level 

exposure situations for which mitigation information is available involve dermal and/or inhalation 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 165 

3. HEALTH EFFECTS 

exposure to hydrofluoric acid or gaseous hydrogen fluoride. Some information is also available regarding 

mitigation of chronic oral exposure to fluoride. 

3.11.1 Reducing Peak Absorption Following Exposure 

Fluoride. Ingested fluoride is rapidly absorbed from the gastrointestinal tract. However, fluoride 

absorption is affected by the presence of several minerals including calcium, magnesium, and aluminum 

which bind to the fluoride to form less soluble complexes (Ekstrand and Ehrnebo 1979; Kuhr et al. 1987; 

Machle and Largent 1943; McClure et al. 1945; Spencer and Lender 1979; Spencer et al. 1980a, 1981; 

Whitford 1994). Gastric lavage with solutions of calcium gluconate, calcium carbonate, calcium lactate, 

calcium chloride, calcium hydroxide, calcium- or magnesium-based antacid, or aluminum hydroxide gel 

have been used in the treatment of fluoride poisoning (Ellenhorn and Barceloux 1988; Goldfrank et al. 

1990; Haddad and Winchester 1990; Morgan 1989). Two treatments that are not recommended are 

attempting to neutralize the acid with orally administered sodium bicarbonate due to the resulting 

exothermic reaction (Bronstein and Currance 1988) and emesis due to the formation of hydrofluoric acid 

in the stomach (Bronstein and Currance 1988; Haddad and Winchester 1990). 

Hydrogen Fluoride/Hydrofluoric Acid. In cases of dermal and inhalation exposure, the exposed persons 

are first removed from the source of exposure, and any particles or excess liquids are removed by 

brushing or blotting (Bronstein and Currance 1988). Thorough irrigation with cold water or saline is then 

done to further limit absorption through exposed skin and eyes. Irrigation is followed by washing the 

affected skin with an alkaline soap and water (Bronstein and Currance 1988; Dibbell et al. 1970). 

Persistent pain is an indication that large amounts of free fluoride ions remain. In such cases, magnesium 

oxide paste is applied or the exposed skin is soaked in cold solutions of magnesium sulfate, calcium salts, 

or quaternary ammonium compounds (benzalkonium chloride, benzethonium) (Browne 1974; Goldfrank 

et al. 1990; Haddad and Winchester 1990). However, the evolving standard of treatment for mild to 

moderate burns involves massaging the affected area with a penetrating calcium gluconate gel, to avoid 

problems with magnesium oxide precipitation (Borak et al. 1991; Browne 1974; Goldfrank et al. 1990). 

Fluorine. Inhalation exposure to fluorine is treated very similarly to inhalation exposure to hydrogen 

fluoride. The source of exposure is removed and water used to decontaminate the patient. The eyes are 

washed with saline if necessary, and magnesium oxide paste can be applied (Bronstein and Currance 

1988; Stutz and Janusz 1988). 
 

 

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3. HEALTH EFFECTS 

3.11.2 Reducing Body Burden 

Fluoride. There is limited information on reducing the body burden of fluoride. Whitford (1994) 

demonstrated that a diet high in calcium resulted in a negative fluoride balance in rats due to a significant 

increase in fecal excretion of fluoride. Although no significant alterations in plasma fluoride levels were 

found, the high calcium diet did result in a significant decrease in fluoride levels in the femur epiphysis. 

In a study of 10 individuals with clinical manifestations of fluorosis (Susheela and Bhatnagar 2002), a 

diet with adequate levels of calcium, vitamins C and E, and other antioxidants and access to drinking 

water with low levels of fluoride (1 ppm or lower) resulted in a decrease in urinary and blood fluoride 

levels and a decrease in clinical signs were observed. One year after intervention, there was complete 

recovery of gastrointestinal complaints, muscular weakness, polyuria, polydypsea, and pain and rigidity in 

the joints. A study by Khandare et al. (2000) provides suggestive evidence that co-administration of 

fluoride and tamarind results in increased urinary excretion of fluoride and decreased bone fluoride levels 

in dogs. 

Hydrogen Fluoride/Hydrofluoric Acid. Hydrogen fluoride burns are characterized by intense pain and 

progressive tissue destruction. The damage associated with this burn occurs in two stages. The first stage 

is immediate tissue damage caused by a high concentration of hydrogen ions and the second is 

liquefaction necrosis that is caused by free fluoride ions (Seyb et al. 1995). There are a number of 

recommended forms of therapy; these therapies have the common goal of binding the fluoride ion and/or 

altering its reactivity with tissues (Dunn et al. 1992). Recommended forms of therapy include topical 

treatments with calcium gluconate paste, magnesium oxide paste, and iced solutions of quaternary 

ammonium compounds, alcohol, or magnesium sulfate and intradermal injections of either magnesium 

sulfate or calcium gluconate, or intraarterial injection of calcium gluconate (Dunn et al. 1992; Seyb et al. 

1995). Intra-arterial infusions of calcium gluconate are often preferred to intradermal injections due to 

the ability of the infusions to deliver more calcium to the burn site, better distribution of calcium in the 

tissues, and the need for only a single injection, as opposed to an injection for every square centimeter of 

affected dermal tissue (Haddad and Winchester 1990). Additionally, in burns involving the hands, 

multiple intradermal injections pose the risk of elevating tissue pressures and forcing the removal of the 

nails (Ellenhorn and Barceloux 1988; Goldfrank et al. 1990). One source reports that calcium gluconate 

injection was successfully used in at least 96 cases without causing damage (Browne 1974). 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 167 

3. HEALTH EFFECTS 

Several studies have compared different therapies in an attempt to identify the most effective treatment. 

The therapeutic effects of calcium gluconate, magnesium acetate, and magnesium sulfate on hydrofluoric 

acid burns of shaved Sprague-Dawley rats were compared using intradermal and subcutaneous injection 

(Harris et al. 1981). Although this study found that injection of calcium gluconate, but not the 

magnesium compounds, was irritating in the absence of a burn, and the duration, depth, and area of 

lesions were reduced with the magnesium compounds compared with calcium gluconate, no reports were 

located of using intradermal injection of magnesium compounds in humans. Seyb et al. (1995) found that 

subcutaneous injections of 10% calcium gluconate and magnesium sulfate solution and topically applied 

calcium gluconate mixed with dimethyl sulfoxide significantly reduced the damage caused by hydrogen 

fluoride exposure in rats exposed to 70% hydrogen fluoride for 60 seconds followed by continuously 

rinsing with tap water for 5 minutes. Treatment with topically applied dimethyl sulfoxide only or calcium 

gluconate only did not affect the degree of tissue damage. In contrast, Dunn et al. (1992) found that 

injection of 10% calcium gluconate was the least effective therapy in pigs following topical application of 

38% hydrogen fluoride. The most effective treatments were soaking in calcium acetate or iced Zephiran 

(benzalkonium chloride), or injection of 5% calcium gluconate. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Fluoride. The major treatment strategies for long-term, low-level exposure to fluorides are removal of 

the source of exposure and administration of compounds that reduce intestinal absorption. Skeletal 

fluorosis has been reported to be partially reversed 8–15 years after the elevated exposure ended 

(Grandjean and Thomsen 1983). Sclerosis of the trabecular bone in ribs, vertebral bodies, and pelvis 

faded, but calcification of muscle insertions and ligaments was not altered. Techniques that increase bone 

turnover or bone resorption might be effective in reversing skeletal fluorosis. However, no information 

on such techniques was located. 

Chinoy and associates have examined the effectiveness of calcium, ascorbic acid, vitamin E, and 

vitamin D in reversing the reproductive effects associated with oral exposure to sodium fluoride. 

Administration of ascorbic acid and/or calcium and cessation of sodium fluoride exposure enhanced the 

recovery of sperm function and morphology and testicular damage, as compared to no treatment, in rats 

(Chinoy et al. 1993), mice (Chinoy and Sharma 2000), and rabbits (Chinoy et al. 1991). The combined 

administration of ascorbic acid and calcium was the most effective treatment. Postexposure 

administration of vitamins E and/or D was also effective in the recovery of sodium-fluoride induced 

testicular effects in mice (Chinoy and Sharma 1998). Likewise, posttreatment administration of ascorbic 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 168 

3. HEALTH EFFECTS 

acid and/or calcium and vitamins E and/or D also aided in the recovery of ovarian effects in mice (Chinoy 

and Patel 1998; Chinoy et al. 1994). It is believed that the antioxidant properties of ascorbic acid and 

vitamin E aid in the recovery of fluoride damage. Vitamin D promotes the intestinal absorption of 

calcium and phosphorus, thus maintaining the optimal blood concentration of these elements (Chinoy and 

Patel 1998). The calcium may act by forming insoluble complexes with fluoride (Chinoy and Patel 1998; 

Chinoy et al. 1994). Similarly, Guna Sherlin and Verma (2001) found that co-administration of 

vitamin D reduced the maternal toxicity (decreased body weight gain and feed intake) and fetal toxicity 

(increased percentage of fetuses with skeletal or visceral abnormalities) as compared to rats only 

receiving sodium fluoride. 

Hydrogen Fluoride/Hydrofluoric Acid. The primary focus of research on reducing the toxic effects 

following dermal exposure to hydrogen fluoride or hydrofluoric acid is on methods for reducing 

absorption and decreasing the amount of fluoride ions. The tissue damage associated with hydrogen 

fluoride exposure is believed to be caused by the binding of fluoride ions with tissue calcium and 

magnesium cations to form insoluble salts, which are believed to interfere with cellular metabolism, 

inducing cellular death and necrosis. Thus, the most effective method for interfering with the mechanism 

of action is removal of the fluoride ions; these methods are discussed in Section 3.11.2. 

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 fluorides, hydrogen fluoride, and fluorine 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 fluorides, 

hydrogen fluoride, and fluorine. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 169 

3. HEALTH EFFECTS 

3.12.1 Existing Information on Health Effects of Fluorides, Hydrogen Fluoride, and 

Fluorine 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

fluorides, hydrogen fluoride, and fluorine are summarized in Figures 3-6, 3-7, and 3-8. The purpose of 

these figures is to illustrate the existing information concerning the health effects of fluorides, hydrogen 

fluoride, and fluorine. 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. 

There are many case reports and epidemiological studies investigating the health effects of hydrogen 

fluoride in humans by the inhalation and dermal routes, and the health effects of fluoride compounds by 

the inhalation and oral routes. There are also limited data from experimental human exposure to fluorine. 

Most human studies of the health effects of oral exposure to fluoride are community-based studies of 

populations ingesting drinking water with various levels of fluoride and case reports of acute and chronic 

oral exposure to sodium fluoride. There are also some case reports of acute dermal exposure to 

hydrofluoric acid. 

Human fatalities have resulted from both oral exposure to sodium fluoride and dermal exposure to 

hydrofluoric acid. Dermal exposure to hydrofluoric acid is often accompanied by inhalation of 

hydrofluoric acid fumes. Human studies and case reports have investigated the effects of nonlethal oral 

doses of sodium fluoride, although only after acute exposure. These exposures have resulted in mostly 

gastrointestinal effects and consequences of hypocalcemia (e.g., nervous system and cardiovascular 

effects). Exposure to fluorine gas causes respiratory, ocular, and dermal irritation in humans after acute 

exposure. One study on chronic exposure to fluorine was located. Chronic human studies have generally 

examined health effects in workers exposed to hydrogen fluoride or fluoride-containing dusts by 

inhalation, and populations exposed to ionic fluoride through drinking water. These studies have 

investigated the relationship between fluoride and neurological and reproductive effects and cancer. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 170 

3. HEALTH EFFECTS 

Figure 3-6. Existing Information on Health Effects of Fluoride 
 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 171 

3. HEALTH EFFECTS 

Figure 3-7. Existing Information on Health Effects of

Hydrogen Fluoride/Hydrofluoric Acid
 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 172 

3. HEALTH EFFECTS 

Figure 3-8. Existing Information on Health Effects of Fluorine 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 173 

3. HEALTH EFFECTS 

Studies conducted on animals have been fairly extensive, and have focused on the health effects following 

inhalation of hydrogen fluoride and oral exposure to fluoride. A few studies on inhalation exposure to 

fluorine also exist. Dermal studies in animals are limited to those investigating dermal and ocular effects 

from exposure to fluorine, hydrofluoric acid, and sodium fluoride. A number of studies on the 

genotoxicity of fluoride were located. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. 

Fluoride. Information on the acute toxicity of inhaled fluoride dust is limited to two animal studies that 

found respiratory tract damage and impaired immune response in mice exposed to sodium fluoride for 

4 hours/day for 10–14 days (Chen et al. 1999; Yamamoto et al. 2001). These data were not considered 

adequate for derivation of an acute-duration inhalation MRL because the upper respiratory tract, a 

potentially sensitive target of toxicity, was not examined in either study. Studies examining a wide range 

of end points, including the upper respiratory tract, and using a number of exposure concentrations would 

be useful for establishing concentration-response relationships and deriving an acute-duration inhalation 

MRL for fluorides. The acute toxicity of ingested fluorides has been investigated in human and animal 

studies. Most of the available human (Eichler et al. 1982; Hodge and Smith 1965; Sharkey and Simpson 

1933) and animal (DeLopez et al. 1976; Lim et al. 1978; Skare et al. 1986; Whitford et al. 1990) acute 

studies reported lethal doses and effects resulting from exposure to a lethal dose of sodium fluoride. The 

gastrointestinal tract (Hoffman et al. 1980; Kessabi et al. 1985; Spak et al. 1989, 1990; Spoerke et al. 

1980) and bone (Guggenheim et al. 1976) have been identified as targets of toxicity following a nonlethal 

exposure to fluorides in human and rat studies, respectively. The potential of sodium fluoride to induce 

reproductive (Li et al. 1987a) and developmental (Guna Sherlin and Verma 2001; Heindel et al. 1996) 

effects has also been investigated in laboratory animals. An acute-duration oral MRL was not derived for 

fluoride; the available data suggest that gastric irritation is the most sensitive end point of acute fluoride 

toxicity; however, additional studies are needed to establish a concentration-response curve and to assess 

whether the gastric mucosa would adapt to repeated exposure to fluoride. These studies should also 

examine other potentially sensitive targets. Data on the dermal toxicity of fluoride is limited to a study 

that found epidermal necrosis and marked edema of the dermis following application of sodium fluoride 

to the abraded skin of rats (Essman et al. 1981). Additional dermal exposure studies would be useful for 

establishing concentration-response relationships for fluoride. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 174 

3. HEALTH EFFECTS 

Hydrogen Fluoride/Hydrofluoric Acid. A number of studies have examined the acute toxicity of 

hydrogen fluoride in humans under accidental exposure conditions (Dayal et al. 1992; Wing et al. 1991) 

or experimental conditions (Lund et al. 1997, 1999, 2002; Machle et al. 1934) and in laboratory animals 

(Dalbey et al. 1998a, 1998b; Rosenholtz et al. 1963; Stavert et al. 1991). These studies demonstrate that 

the respiratory tract is the most sensitive target of toxicity; at slightly higher concentrations, skin and eye 

irritation are also observed. Hematological (increased red blood cell and hemoglobin levels) and liver 

(increased aspartate aminotransferase activity) alterations have also been observed in laboratory animals 

exposed to much higher concentrations (Dalbey et al. 1998a, 1998b). An acute duration inhalation MRL 

based on lower respiratory tract irritation in humans (Lund et al. 1997) was derived for hydrogen fluoride. 

Data on the oral toxicity of hydrofluoric acid are limited to a report of six deaths following accidental 

consumption of a rust remover containing hydrofluoric acid (Menchel and Dunn 1986). These data were 

not considered adequate for derivation of an acute-duration oral MRL for hydrofluoric acid. It is likely 

that the most sensitive target following acute oral exposure to hydrofluoric acid would be the 

gastrointestinal tract; studies are needed to confirm this hypothesis and establish a concentration-response 

curve. Dermal exposure studies demonstrate that hydrofluoric acid is very caustic, and severe tissue 

damage can result from direct contact (Chela et al. 1989; Derelanko et al. 1985; Mayer and Gross 1985; 

Roberts and Merigan 1989). Exposure to a high concentration or prolonged exposure can result in 

systemic effects that are similar to fluoride (Braun et al. 1984; Mayer and Gross 1985; Mullett et al. 

1987). There are limited concentration-response data and additional dermal exposure studies would be 

useful. 

Fluorine. A series of studies conducted by Keplinger and Suissa (1968) have investigated the acute 

toxicity of fluorine in humans, rats, mice, rabbits, guinea pigs, and dogs. In all species tested, fluorine 

was irritating to the respiratory tract, skin, and eyes. In addition to these direct contact effects, exposure 

to fluorine also resulted in liver (necrosis and cloudy swelling) and kidney (necrosis) effects in the 

laboratory animal species. An acute-duration MRL for fluorine was derived from the Keplinger and 

Suissa (1968) human study, which identified a NOAEL and LOAEL for nasal irritation. Additional 

studies are needed to evaluate the concentration-response relationship for skin effects as well as other end 

points following dermal-only exposure. 

Intermediate-Duration Exposure. 

Fluoride. The toxicity of inhaled fluoride is limited to an animal study that found lung effects in mice 

exposed to sodium fluoride for 4 hours/day for 20–30 days (Chen et al. 1999). With the exception of 

direct contact effects, it is likely that the toxicity of inhaled fluoride would be similar to ingested fluoride. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 175 

3. HEALTH EFFECTS 

Additional inhalation studies would be useful for establishing a concentration-response relationship and 

deriving an intermediate-duration inhalation MRL for fluorides. A number of animal studies have 

investigated the toxicity of fluoride following intermediate oral exposure; no intermediate-duration 

human studies were located. These animal studies have reported a number of systemic effects, including 

alterations in bone and tooth mineralization (Collins et al. 2001a; DenBesten and Crenshaw 1984; 

Harrison et al. 1984; Marie and Hott 1986; Turner et al. 2001; Uslu 1983; Zhao et al. 1998), hyperplasia 

of the glandular stomach (NTP 1990), alterations in thyroid function (Bobek et al. 1976; Zhao et al. 

1998), and kidney damage (Greenberg 1986; NTP 1990). Additionally, neurological (Mullenix et al. 

1995; Paul et al. 1998; Purohit et al. 1999), reproductive (Al-Hiyasat et al. 2000; Araibi et al. 1989; 

Chinoy and Sequeira 1992; Chinoy et al. 1992, 1997; Krasowska and Wlostowski 1992; Messer et al. 

1973; Narayana and Chinoy 1994), and developmental effects in the presence of maternal toxicity 

(Collins et al. 1995) have been observed. The available studies identify the bones and possibly the 

thyroid as the most sensitive targets of fluoride toxicity in rodents following intermediate-duration 

exposure to fluoride. Chronic-duration studies in humans strongly support the identification of bone as a 

sensitive target of fluoride toxicity. However, bone growth in rats differs from humans, and it is not 

known whether it is appropriate to extrapolate an adverse effect level from rats to humans. The potential 

of fluoride to induce thyroid effects in humans has not been adequately assessed; additional studies are 

needed to determine whether this end point is relevant for humans. The intermediate-duration database 

was considered inadequate for derivation of an MRL due to the uncertainties associated with the use of 

rodent data, and derivation of an MRL using the Bobek et al. (1976) or Turner et al. (2001) animal studies 

that identified the lowest LOAEL values would result in an MRL that is lower than the human-based 

chronic-duration MRL. No intermediate-duration dermal toxicity studies were identified for fluorides; 

based on the results of an acute-duration rat study (Essman et al. 1981), it is likely that fluoride exposure 

would result in damage to the skin. Studies are needed to confirm that this would also be the most 

sensitive target of toxicity following longer-duration exposure and to assess whether there are other 

sensitive targets. 

Hydrogen Fluoride/Hydrofluoric Acid. Nasal irritation was reported in the only human intermediateduration study identified for hydrogen fluoride (Largent 1960). A small number of animal studies are 

available. These inhalation studies found respiratory tract irritation (Machle and Kitzmiller 1935; 

Stokinger 1949), skin and eye irritation (Stokinger 1949), kidney damage (Machle and Kitzmiller 1935), 

and neurobehavioral alterations (Sadilova et al. 1965) in laboratory animals. An intermediate-duration 

inhalation MRL was not derived for hydrogen fluoride because an MRL based on the Largent (1960) 

study is higher than the acute-duration inhalation MRL derived from the Lund et al. (1997, 1999) study. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 176 

3. HEALTH EFFECTS 

Additional studies are needed to identify a NOAEL for respiratory tract effects. No intermediate-duration 

oral or dermal exposure studies were identified; the gastrointestinal tract and skin, respectively, are the 

likely targets of toxicity. Studies are needed for establishing concentration-response curves for these 

exposure routes and identifying other possible targets of toxicity. 

Fluorine. The database on the intermediate-duration toxicity of fluorine is limited to a multispecies study 

that found eye, nose, and mouth irritation in rats and dogs and lung damage in rats, rabbits, and dogs 

(Stokinger 1949). Because the measurements of exposure concentrations were questionable, this study 

was not selected as the basis of an intermediate-duration inhalation MRL for fluorine. Additional studies 

using multiple exposure concentrations are needed to establish the concentration-response relationship for 

fluorine and derive an MRL. Studies involving dermal-only exposure to fluorine gas would be useful for 

assessing the dermal toxicity of this element in humans wearing respirators without adequate protective 

clothing. 

Chronic-Duration Exposure and Cancer. 

Fluoride. No studies have examined the chronic toxicity of inhaled fluorides; however, several 

occupational exposure studies have examined workers exposed to hydrogen fluoride and fluoride dusts, 

and these are discussed under hydrogen fluoride. Thus, a chronic-duration inhalation MRL was not 

derived for fluorides. Shorter-term inhalation studies and chronic-duration oral studies suggest that the 

respiratory tract, teeth, and bones are likely to be the principal targets of fluoride. Studies are needed to 

confirm this hypothesis and to establish concentration-response data. A large number of human and 

animal studies have investigated the chronic toxicity of ingested fluoride. Most of the human studies are 

ecological studies examining communities with fluoridated water or naturally high levels of fluoride in 

water. For the most part, these studies have focused on the occurrence of dental fluorosis (DHHS 1991; 

Eklund et al. 1987; Heifetz et al. 1988; Ismail and Bandekar 1999; Jackson et al. 1995; McDonagh et al. 

2000; Selwitz et al. 1995; Teotia and Teotia 1994; Warren and Levy 1999) and alterations in bone density 

or increased bone fracture rates (Arnala et al. 1986; Cauley et al. 1995; Cooper et al. 1990, 1991; 

Danielson et al. 1992; Goggin et al. 1965; Jacobsen et al. 1990, 1992, 1993; Haguenauer et al. 2000; 

Hillier et al. 2000; Karagas et al. 1996; Kleerekoper et al. 1991; Kröger et al 1994; Kurttio et al. 1999; 

Lehmann et al. 1998; Li et al. 2001; Phipps et al. 2000; Riggs et al. 1990, 1994; Simonen and Laittinen 

1985; Suarez-Almazor et al. 1993). At typical fluoridation levels (0.9–1.0 ppm), increases, decreases, or 

no effect on bone fracture rates have been found. At higher doses, fluoride has consistently increased 

bone fracture rates. Other potential targets of toxicity that have been examined in humans include the 

cardiovascular system (Hagan et al. 1954; Heasman and Martin 1962), gastrointestinal tract (Susheela et 
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3. HEALTH EFFECTS 

al. 1992), kidneys (Lantz et al. 1987), intelligence and behavior (Li et al. 1995a; Lu et al. 2000; Morgan et 

al. 1998), reproductive system (Freni 1994; Susheela and Jethanandani 1996), and developing organism 

(Berry 1958; Erickson et al. 1976; Li et al. 1995a; Lu et al. 2000; Needleman et al. 1974; Rapaport 1956; 

Takahashi 1998). These studies did not find positive and/or consistent results. Several animal studies 

have examined the chronic toxicity; the observed effects included bone alterations in rats (NTP 1990), 

mice (NTP 1990), and mink (Aulerich et al. 1987), intestinal damage in rabbits (Susheela and Das 1988), 

hematological effects in rabbits (Susheela and Jain 1983), immunological effects in rabbits (Jain and 

Susheela 1987), and male reproductive effects in rabbits (Kumar and Susheela 1994, 1995; Susheela and 

Kumar 1991, 1997). One limitation of the animal studies is that the doses used were much higher 

(>10 times higher) than doses that result in increased fracture rates in humans. Additional animal studies 

that used lower doses would be useful in determining if there are additional sensitive targets of toxicity 

following chronic-duration oral exposure to fluoride. A large community-based study by Li et al. (2001) 

was used to derive a chronic-duration oral MRL for fluoride. No chronic-duration dermal studies were 

identified. The toxicity of fluoride is not likely to be route-specific, with the exception of direct contact 

effects. An acute toxicity study (Essman et al. 1981) found skin damage in animals exposed to sodium 

fluoride; studies are needed to identify the threshold of toxicity of dermal irritation and other potentially 

sensitive targets such as teeth and bone. 

The carcinogenicity of fluoride has been assessed in a number of human studies of communities with 

fluoridated water or naturally high levels of fluoride in the drinking water (Cohn 1992; Erickson 1978; 

Freni and Gaylor 1992; Gelberg et al. 1995; Hoover et al. 1976, 1991a, 1991b; Kinlen and Doll 1981; 

Mahoney et al. 1991; McGuire et al. 1991; Neuberger 1982; Oldham and Newell 1977; Rogot et al. 1978; 

Takahashi et al. 2001; Taves 1977; Yiamouyiannis and Burk 1977) and chronic-duration oral exposure 

studies of rats (Maurer et al. 1990; NTP 1990) and mice (NTP 1990). Although some human studies have 

found positive results, particularly for bone cancer (Cohn 1992; Hoover et al. 1991b; Takahashi et al. 

2001; Yiamouyiannis and Burk 1977), the majority of the studies have not found significant increases in 

cancer risk. The NTP (1990) bioassay found a weak, equivocal fluoride-related increase in the 

occurrence of osteosarcomas in male rats, and no evidence of carcinogenicity in female rats or male or 

female mice. Significant increases in cancer risk were found in the Maurer et al. (1990) study. 

Additional studies are needed to further evaluate the potential of fluoride to induce bone cancers 

following chronic oral exposure. 

Hydrogen Fluoride/Hydrofluoric Acid. The available data on the chronic toxicity are limited to several 

occupational exposure studies of workers (Carnow and Conibear 1981; Chan-Yeung et al. 1983a, 1983b; 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 178 

3. HEALTH EFFECTS 

Czerwinski et al. 1988; Derryberry et al. 1963; Dinman et al. 1967c; Kaltreider et al. 1972; Macuch et al. 

1963; Moller and Gudjonsson 1932) exposed to hydrogen fluoride and fluoride dusts and an inhalation 

study in guinea pigs (Rioufol et al. 1982). The occupational exposure studies primarily focused on 

respiratory tract and skeletal effects and the guinea pig study examined the kidneys. Although the 

occupational exposure studies examined the primary targets of hydrogen fluoride and fluoride toxicity, 

they are limited by co-exposure to a number of other chemicals and limited, if any, exposure data. 

Additional chronic-duration studies are needed to derive a chronic-duration inhalation MRL for hydrogen 

fluoride. No chronic-duration dermal exposure studies were located for hydrogen fluoride. At high 

concentrations, the skin is the most sensitive target of toxicity; however, long-term exposure to lower 

concentrations is likely to result in different targets of toxicity, possibly the same as chronic fluoride 

toxicity. Additional chronic-duration studies are needed to establish the concentration-response 

relationships for direct contact effects and other possible targets of toxicity. 

Several studies have examined the carcinogenicity of hydrogen fluoride and fluoride dust exposures in 

cryolite workers (Grandjean et al. 1985, 1992), aluminum industry workers (Andersen et al. 1982; Gibbs 

and Horowitz 1979; Milham 1979; Rockette and Arena 1983), fluorspar miners (deVilliers and Windish 

1964), and individuals residing near or working in the steel industry (Cecilioni 1972). Several studies 

reported increases in respiratory tract cancer rates (Andersen et al. 1982; deVilliers and Windish 1964; 

Gibbs and Horowitz 1979; Grandjean et al. 1985, 1992; Milham 1979); however, no adjustments for 

occupational exposure to other carcinogenic compounds and smoking were made in most of these studies. 

Well-controlled studies are needed to assess the carcinogenic potential of hydrogen fluoride and fluoride 

dust exposure. 

Fluorine. Data on the chronic toxicity of fluorine is limited to an occupational exposure study in which a 

relatively insensitive measure of respiratory tract effects (visits to the medical department with respiratory 

complaints and absences from work) was used and in which the controls and exposed workers were 

exposed to uranium hexafluoride and hydrogen fluoride (Lyon 1962). This study was considered 

inadequate for derivation of a chronic-duration inhalation MRL. Additional studies are needed to define 

the concentration-response relationships following exposure to inhaled fluorine gas and following dermalonly exposure to fluorine. There are no data on the carcinogenicity of fluorine; the carcinogenicity of 

absorbed fluorine is expected to be similar to fluoride. However, additional studies are needed to assess 

whether long-term exposure to fluorine would result in portal-of-entry cancers. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 179 

3. HEALTH EFFECTS 

Genotoxicity. There is a significant database on the genotoxicity of fluoride compounds in several 

species and several cell types. However, the results from well-characterized systems are much more 

limited, and additional well-designed experiments would be useful in resolving contradictory data. The 

results have been inconsistent in many instances, but a consensus is developing that at toxic levels 

(>10 μg/mL, and usually seen at >40 μg/mL), there may be a general inhibition of enzymes, including the 

DNA polymerases (Caspary et al. 1987, 1988). 

Reproductive Toxicity. Hydrogen fluoride and fluorine animal inhalation exposure studies and 

human and animal fluoride oral exposure studies have assessed reproductive toxicity. No data are 

available on the reproductive toxicity following dermal exposure in humans or animals. Degenerative 

testicular changes were observed in rats exposed to high concentrations of hydrogen fluoride (Stokinger 

1949) or fluorine (Stokinger 1949); it is possible that these effects were due to direct contact with the gas 

rather than a systemic effect. Several studies have investigated the reproductive toxicity of fluoride in 

humans. One study found a significant association between decreasing total fertility rates and increasing 

fluoride levels in drinking water (Freni 1994) and another study found decreases in serum testosterone 

levels in men with skeletal fluorosis (Susheela and Jethanandani 1996). Both studies have several 

limitations that preclude drawing firm conclusions from them about the potential of fluoride to induce 

reproductive toxicity. Alterations in the male reproductive system have also been observed in rats and 

rabbits orally exposed to sodium fluoride. The observed effects included alterations in serum testosterone 

levels (Araibi et al. 1989; Narayana and Chinoy 1994), histological alterations in the testes (Krasowska 

and Wlostowski 1992; Narayana and Chinoy 1994; Susheela and Kumar 1991), alterations in sperm 

morphology or spermatogenesis (Chinoy et al. 1992, 1995, 1997; Kumar and Susheela 1994, 1995; 

Susheela and Kumar 1991), and impaired fertility (Chinoy and Sequeira 1992; Chinoy et al. 1992). 

However, other studies have not found any effects on male reproduction (Dunipace et al. 1989; Li et al. 

1987a; Sprando et al. 1997, 1998). Additional studies are needed to address the conflicting results. As 

with the male reproductive effects, conflicting results have been found for fluoride-induced female 

reproductive effects. Infertility was observed in one study (Messer et al. 1973), but not in three others 

(Collins et al. 2001a; Marks et al. 1984; Tao and Suttie 1973). A decrease in fetus viability and an 

increase in resorption rate have also been reported at maternally toxic doses (Al-Hiyasat et al. 2000). 

Developmental Toxicity. The potential of fluoride, hydrogen fluoride, or fluorine to induce 

developmental effects following inhalation or dermal exposure has not been investigated in humans or 

animals. Several community-based studies have examined the possible association between fluoridated 

water consumption and developmental effects (Berry 1958; Erickson et al. 1976; Needleman et al. 1974; 
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3. HEALTH EFFECTS 

Rapaport 1956; Takahashi 1998); the overall weight of evidence suggests that low levels of fluoride are 

not associated with developmental effects. However, higher exposure levels (levels associated with 

dental or skeletal fluorosis) have been associated with developmental effects in humans (Gupta et al. 

1995; Li et al. 1995a; Lu et al. 2000); additional studies are needed to confirm the results of these studies, 

which do not appear to adjust for potential confounders such as poor nutrition and exposure to other 

chemicals. Studies in laboratory animals have not found adverse developmental effects in the offspring of 

rats or rabbits exposed to sodium fluoride in drinking water (Collins et al. 1995, 2001b; Heindel et al. 

1996); however, fetal mortality and abnormalities were observed at maternally toxic doses (Collins et al. 

1995; Guna Sherlin and Verma 2001). Studies in wild or domestic animals (cattle and mink) (Aulerich et 

al. 1987; Krook and Maylin 1979; Maylin and Krook 1982) have reported developmental effects; the 

relevance to humans is not known. 

Immunotoxicity. Information of the potential of fluoride, hydrogen fluoride, or fluorine to induce 

immune effects is limited to an inhalation study in mice that found a decrease in bactericidal activity 

following exposure to sodium fluoride (Yamamoto et al. 2001) and an oral exposure study in rabbits that 

found a decrease in antibody titers following an 18-month exposure via gavage to sodium fluoride and 

immunization with transferrin (Jain and Susheela 1987). These studies provide some suggestive evidence 

that the immune system is a target of fluoride toxicity. A study utilizing an immune battery of tests 

would be useful in assessing the immunotoxic potential of fluoride. 

Neurotoxicity. Alterations in the light adaptive reflex were found in humans exposed to very low 

concentrations of hydrogen fluoride (Sadilova et al. 1965). The investigators of this study also found 

alterations in conditioned responses in rats exposed to relatively low concentrations. This finding has not 

been supported by other human or animal studies. A decrease in IQ scores has also been observed in 

children living in areas with high fluoride levels in the water (Li et al. 1995a; Lu et al. 2000; Zhao et al. 

1996); however, the lack of control of potential confounding variables limits the interpretation of these 

studies. Epidemiology studies examining this end point and controlling for potentially confounding 

variables, such as poor nutrition and exposure to other chemicals, would provide confirming or refuting 

data. Alterations in spontaneous behavior were found in rats orally exposed to sodium fluoride (Mullenix 

et al. 1995a; Paul et al. 1998); however, another study did not find this effect (Whitford et al. 2003). 

Studies utilizing a neurobehavioral test battery would provide valuable information on the neurotoxic 

potential of fluoride, hydrogen fluoride, and fluorine. 
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3. HEALTH EFFECTS 

Epidemiological and Human Dosimetry Studies. Available data on the toxicity of inhaled 

hydrogen fluoride and fluorine come from case reports involving exposure to hydrogen fluoride (Bennion 

and Franzblau 1997; Braun et al. 1984; Chan et al. 1987; Chela et al. 1989; Dieffenbacher and Thompson 

1962; Kleinfeld 1965; Machle et al. 1934; Tepperman 1980; Waldbott and Lee 1978), accidental exposure 

of a community to hydrogen fluoride (Dayal et al. 1992; Wing et al. 1991), experimental studies of 

exposure to hydrogen fluoride (Largent 1960; Lund et al. 1997, 1999, 2002; Machle et al. 1934) and 

fluorine (Keplinger and Suissa 1968), and occupational exposure to hydrogen fluoride and fluoride dusts 

(Carnow and Conibear 1981; Chan-Yeung et al. 1983a; Czerwinski et al. 1988; Derryberry et al. 1963; 

Dinman et al. 1976c; Kaltreider et al. 1972; Moller and Gudjonsson 1932), fluorides (McGarvey and 

Ernstene 1947; Roholm 1937; Wolff and Kerr 1938), or fluorine (Lyon 1962). These studies identify the 

respiratory tract as the most sensitive target of toxicity, and data are sufficient to derive acute-duration 

inhalation MRLs for hydrogen fluoride and fluorine using these human data. However, the long-term 

toxicity of fluorides, hydrogen fluoride, and fluorine has not been adequately investigated. The only 

consistently reported effect is skeletal fluorosis (Czerwinski et al. 1988; Dinman et al. 1976c; Kaltreider 

et al. 1972; Moller and Gudjonsson 1932); poor exposure characterization and difficulty assessing the 

skeletal fluorosis limit these studies. 

Many studies have examined the possible association between the long-term exposure to fluoridated 

water and adverse health effects, particularly effects on bone and teeth. Most of the studies are 

community-based studies examining the prevalence of dental fluorosis (DHHS 1991; Eklund et al. 1987; 

Heifetz et al. 1988; Jackson et al. 1995; McDonagh et al. 2000; Selwitz et al. 1995; Teotia and Teotia 

1994; Warren and Levy 1999) and bone fracture rates (Arnala et al. 1986; Cauley et al. 1995; Cooper et 

al. 1990, 1991; Danielson et al. 1992; Goggin et al. 1965; Jacobsen et al. 1990, 1992, 1993; Karagas et al. 

1996; Kröger et al 1994; Kurttio et al. 1999; Lehmann et al. 1998; Phipps et al. 2000; Simonen and 

Laittinen 1985; Suarez-Almazor et al. 1993) in residents living in communities with fluoridated water or 

water with naturally high levels of fluoride. Overall, the data on dental fluorosis provide strong evidence 

of increased prevalence and severity of dental fluorosis with increasing fluoride exposure levels. 

However, a dose-response relationship is difficult to establish because other sources of fluoride (e.g., 

dentrifices, bottled water) were typically not taken into consideration. The findings on the possible 

association between exposure to approximately 1 ppm fluoride in water (typical level of fluoride in 

communities with fluoridated water) and increases in hip fracture rates in the elderly are inconsistent, 

with studies finding increases, decreases, or no effect. A common limitation of these community-based 

studies is the lack of individual exposure data; fluoride levels in drinking water were used to estimate 

intake and other sources of fluoride or water consumption levels were not taken into consideration. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 182 

3. HEALTH EFFECTS 

Experimental studies (Haguenauer et al. 2000; Riggs et al. 1990, 1994) and a community study (Li et al. 

2001) involving exposure to higher levels of fluoride have consistently found increases in bone fracture 

rates. Human case reports (Hoffman et al. 1980; Rao et al. 1969; Spoerke et al. 1980) and experimental 

studies (Spak et al. 1989, 1990) have also identified the gastrointestinal tract as a sensitive target 

following bolus administration of fluoride; additional studies are needed to establish the dose-response 

relationship for this end point. 

In addition to these effects, human studies have examined reproductive (Freni et al. 1994), neurodevelopmental (Li et al. 1995a; Lu et al. 2000 Zhao et al. 1996), and developmental (Erickson et al. 1976; Gupta 

et al. 1995) end points; inadequate exposure characterization and adjustments for potentially confounding 

variables limit the interpretation of these studies. A number of studies have examined the carcinogenicity 

of fluoride in communities with fluoridated water (or high levels of naturally occurring fluoride) (Cohn 

1992; Erickson 1978; Freni and Gaylor 1992; Gelberg et al. 1995; Hoover et al. 1976, 1991a, 1991b; 

Kinlen and Doll 1981; Mahoney et al. 1991; McGuire et al. 1991; Neuberger 1982; Oldham and Newell 

1977; Rogot et al. 1978; Takahashi et al. 2001; Taves 1977; Yiamouyiannis and Burk 1977). Most of 

these studies have not found a significant association, although some studies have found increased risks 

(Takahashi et al. 2001; Yiamouyiannis and Burk 1977), particularly for bone cancer in young men (Cohn 

1992; Hoover et al. 1991b). Additional studies that control for potentially confounding variables are 

needed to adequately assess whether there is an increased risk of bone cancer in young males living in 

communities with fluoridated water. 

Biomarkers of Exposure and Effect. 

Exposure. Fluoride can be readily detected in biological tissues such as urine (Ekstrand and Ehrnebo 

1983; Ekstrand et al. 1983; Zipkin et al. 1956), plasma (Ekstrand et al. 1983), nails (Whitford et al. 

1999a), saliva (Oliveby et al. 1990; Whitford et al. 1999b), and tooth enamel (McClure and Likins 1951). 

Urinary fluoride is most commonly used to assess fluoride exposure and has been shown to be a good 

predictor of total daily fluoride intake (Villa et al. 2000). Urine, plasma, and saliva can be used as 

biomarkers for acute exposures; however, measurements should be taken shortly after exposure due to the 

rapid elimination of fluoride. Bone (Baud et al. 1978; Boivin et al. 1988) and nail (Schamschula et al. 

1985; Whitford et al. 1999a) fluoride levels can be used to quantitate long-term fluoride exposure. 

Additional studies are needed to relate levels of fluoride in these biological tissues to exposure dose. 

Effect. Fluoride accumulates in bone, with levels increasing with age. This accumulation of fluoride in 

bone can lead to adverse effects such as alterations in bone density, which can be detected by radiographs. 
 

 

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3. HEALTH EFFECTS 

However, these are nonspecific changes and other elements can sequester in the skeleton and produce 

similar changes observed in radiographs. Exposure to elevated levels of fluoride can also result in dental 

fluorosis in children (Den Besten and Thariani 1992; DHHS 1991; Eklund et al. 1987; Fejerskov et al. 

1990; Heifetz et al. 1988; Ismail and Bandekar 1999; Jackson et al. 1995; McDonagh et al. 2000; Selwitz 

et al. 1995; Teotia and Teotia 1994; Warren and Levy 1999). There is some evidence that dental fluorosis 

can be used as a reliable biomarker in children younger than 7 years of age (Den Besten 1994). However, 

additional studies are needed to quantify the effect of several variables including dose, duration of 

exposure, and timing of exposure. 

Absorption, Distribution, Metabolism, and Excretion. The absorption, distribution, 

metabolism, and excretion of fluoride, hydrogen fluoride, and fluorine have been investigated in humans 

and animals. Evidence for absorption of fluorine, hydrogen fluoride, and fluoride after exposure via the 

inhalation and dermal routes is provided by the observation of elevated urine and plasma levels in 

workers exposed to hydrogen fluoride and fluoride dusts (Collings et al. 1951; Ehrnebo and Ekstrand 

1986; Rye 1961; Søyseth et al. 1994), in people accidentally exposured to hydrofluoric acid (Buckingham 

1988; Burke et al. 1973), and in subjects experimental exposed to hydrogen fluoride (Lund et al. 1997). 

A number of human experimental studies provide strong evidence that fluoride is rapidly and completely 

absorbed following oral exposure to soluble fluoride compounds (Carlson et al. 1960a; Ekstrand et al. 

1977, 1978; Shulman and Vallejo 1990; Trautner and Einwag 1987) and insoluble fluoride compounds 

are poorly absorbed (Afseth et al. 1987; Trautner and Einwag 1987). The results of animal inhalation 

(Keplinger and Suissa 1968; Morris and Smith 1982; Stokinger 1949), oral (McClure et al. 1945, 1950; 

Zipkin and Likins 1957), and dermal (Keplinger and Suissa 1968; Watanabe et al. 1975) exposure studies 

confirm the results of the human studies. Additional studies would be useful in characterizing the 

absorption of fluoride, hydrogen fluoride, and fluorine following inhalation and dermal exposure. 

The distribution of fluoride following oral exposure has been characterized in human (Ekstrand et al. 

1977a, 1978, 1979, 1994a, 1994b; Guy et al. 1976; Rigalli et al. 1996) and animal (Ekstrand and Whitford 

1984; Richards et al. 1982; Spak et al. 1986; Whitford and Johnson 2003; Whitford et al. 1979a, 1990) 

studies. The limited available information on the distribution of inhaled fluoride (Baud et al. 1978; 

Boivin et al. 1988; Chan-Yeung et al. 1983b; Czerwinski et al. 1988; Kaltreider et al. 1972), hydrogen 

fluoride (Machle and Scott 1935; Morris and Smith 1983; Stokinger 1949), and fluorine (Stokinger 1949) 

suggested that the long-term distribution is similar to fluoride following oral exposure. No information is 

available on the distribution of fluoride following dermal exposure; it is likely that the distribution would 

be similar to the oral route. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 184 

3. HEALTH EFFECTS 

Occupational exposure studies provide some information on the excretion of hydrogen fluoride and 

fluoride dusts (Collings et al. 1951; Ehrnebo and Ekstrand 1986; Rye 1961) and animal inhalation studies 

provide excretion data for hydrogen fluoride (Stokinger 1949) and fluorine (Stokinger 1949). The 

excretion of fluoride following ingestion has been extensively investigated in humans (Carlson et al. 

1960a; Ekstrand 1977; Ekstrand et al. 1978, 1980a, 1982; Järnberg et al. 1980, 1981, 1983; Jeandel et al. 

1992; Oliveby et al. 1989, 1990; Machle and Largent 1943; Schiffl and Binswanger 1982; Spak et al. 

1985; Villa et al. 2000; Waterhouse et al. 1980; Whitford et al. 1976). No excretion data are available for 

the dermal route of exposure. Because the excretion of fluoride, hydrogen fluoride, and fluorine 

following inhalation or dermal exposure would be similar to that following ingestion of fluoride, no 

additional excretion studies are needed at this time. 

Comparative Toxicokinetics. A study by Whitford et al. (1991) provides evidence for differences 

in the toxicokinetic properties of fluoride in dogs, cats, rabbits, rats, and hamsters. Plasma, renal, and 

extrarenal clearance in the dog was most similar to humans. Although there are adequate data to assess 

the toxicokinetics of fluoride in humans and the current MRLs are based on human data, additional 

studies are needed to evaluate the relevance of other animal species to humans to allow for the assessment 

of other potentially relevant end points of toxicity, such as reproductive toxicity and carcinogenicity. 

Methods for Reducing Toxic Effects. Fluoride, hydrogen fluoride, and fluorine are rapidly 

absorbed following inhalation, oral, or dermal exposure. For fluoride, gastric lavage administration of 

calcium, magnesium, or aluminum compounds can decrease absorption by forming less soluble 

complexes with the fluoride (Ellenhorn and Barceloux 1988; Goldfrank et al. 1990; Haddad and 

Winchester 1990; Morgan 1989). For hydrogen fluoride and fluorine, the recommended methods for 

decreasing absorption involve removal from the area, irrigation of skin and eyes (Bronstein and Curranc 

1988; Dibbell et al. 1970), and application of magnesium, calcium, or quaternary ammonium compounds 

to limit further dermal absorption (Browne 1974; Goldfrank et al. 1990; Haddad and Winchester 1990; 

Stutz and Janusz 1988). There is some evidence that a diet high in calcium will reduce the fluoride body 

burden (Susheela and Bhatnagar 2002; Whitford 1994); additional studies are needed to determine if this 

is an effective method for reducing bone fluoride levels. 

Children’s Susceptibility. The available human studies that examined the toxicity of fluoride in 

children primarily focused on effects on teeth, particularly dental fluorosis. It should be noted that there 

is also an extensive database on the beneficial effects of fluoride in preventing dental caries, which will 
 

 

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3. HEALTH EFFECTS 

not be discussed in this section dealing with fluoride toxicity. Excess fluoride exposure has been shown 

to cause dental fluorosis in young children; the severity is dependent on the amount of fluoride ingested, 

the duration of exposure, and the stage of enamel development at the time of exposure (DHHS 1991; 

Eklund et al. 1987; Heifetz et al. 1988; Jackson et al. 1995; Selwitz et al. 1995; Teotia and Teotia 1994; 

Warren and Levy 1999). Although the severity of fluorosis is known to increase with dose, the exact 

dose-response relationship is not known because very few studies measured individual fluoride intake; 

additional studies are needed to better assess this relationship. Because more fluoride is deposited in 

children’s bones than adults, there is a need for additional studies to assess whether children are more 

susceptible to skeletal effects. Human studies have suggested that high doses of fluoride may result in 

spina bifida (Gupta et al. 1995) or decreased intelligence (Li et al. 1995a; Lu et al. 2000; Zhao et al. 1996) 

but, as noted previously, the Gupta et al. (1995), Li et al. (1995a), Lu et al. (2000), and Zhao et al. (1996) 

studies appear to have major study design deficiencies. In general, animal studies have not found 

developmental effects following oral exposure; however, these studies did not examine neurodevelopmental end points. Additional animal studies are needed to assess neurodevelopmental potential of 

fluoride. 

A number of studies have examined potential differences in the toxicokinetic properties of fluoride 

between adults and children. These studies suggest that absorption (Ekstrand et al. 1978, 1983, 1994a, 

1994b) and excretion (Whitford 1999) of ingested fluoride do not appear to be strongly influenced by age. 

However, the uptake of fluoride into bone is strongly influenced by age; with a higher percentage of 

ingested fluoride being sequestered in bone in very young children compared to adults (Ekstrand and 

Whitford 1984; Ekstrand et al. 1979, 1994a, 1994b; Lawrenz et al. 1940; Miller and Phillips 1956; Suttie 

and Phillips 1959; Whitford 1990; Zipkin and McClure 1952; Zipkin et al. 1956). 

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 

Ongoing studies pertaining to fluoride, hydrogen fluoride, or fluorine have been identified and are shown 

in Table 3-9. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 186 

3. HEALTH EFFECTS 

Table 3-9. Ongoing Studies on the Health Effects of Fluoride, 

Hydrogen Fluoride, or Fluorine
 

Investigator Affiliation Research description 

Ziegler, EE University of Iowa Toxicokinetic properties in infants 

Levy, SM University of Iowa Bone development in children 

Boskey, AL Hospital for Special Therapies Osteoporosis therapy 

Source: FEDRIP 2002 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 187 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

The common synonyms and other information for fluorine, hydrogen fluoride, sodium fluoride, 

fluorosilicic acid, and sodium fluorosilicate are listed in Table 4-1. The terms “fluorine” and “fluoride” 

are often used interchangeably in the literature as generic terms. In this document, we will use “fluoride” 

as a general term to refer to all combined forms of fluorine unless the particular compound or form is 

known and there is a reason for referring to it. The term “fluorine gas” will sometimes be used to 

emphasize the fact that we are referring to the elemental form of fluorine rather than a combined form. In 

general, the differentiation between different ionic and molecular or gaseous and particulate forms of 

fluorine-containing substances is uncertain and may also be unnecessary. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Fluorine is the lightest member of Group 17 (VIIA) of the periodic table. This group, the halogens, also 

includes chloride, bromine, and iodine. As with the other halogens, fluorine occurs as a diatomic 

molecule, F2, in its elemental form. It has only one stable isotope and its valence in all compounds is -1. 

Fluorine is the most reactive of all the elements, which may be attributed to its large electronegativity 

(estimated standard potential +2.85 V). It reacts at room temperature or elevated temperatures with all 

elements other than nitrogen, oxygen, and the lighter noble gases. Fluorine is also notable for its small 

size; large numbers of fluorine atoms fit around atoms of another element. This, along with its 

electronegativity, allows the formation of many simple and complex fluorides in which the other element 

is in its highest oxidation date. Important physical and chemical properties of fluorine, hydrogen fluoride, 

sodium fluoride, fluorosilicic acid, and sodium fluorosilicate are presented in Table 4-2. It should be 

noted that fluorosilicic acid only exists in aqueous solution, and not in the anhydrous state. Its properties 

will depend on its concentration and temperature (Aigueperse et al. 1988). 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 188 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Fluorine, Hydrogen Fluoride, Sodium Fluoride, 

Fluosilicic Acid, and Sodium Silicofluoridea
 

Characteristic Fluorine Hydrogen fluoride Sodium fluoride 

Synonym(s) Fluorine-19 Hydrofluoric acid; hydrofluoride Monosodium 

flurorideb 

Registered trade name(s) No data No data Alcoa sodium 

fluorideb 

Chemical formula F2 FH FNa 

Chemical structure F-F H-F Na-F 

Identification numbers: 

 CAS registry 7782-41-4 7664-39-3 7681-49-4 

 NIOSH RTECS NIOSH/LM64750000 NIOSH/MW7890000 NIOSH/WB0350000 

EPA hazardous waste P056 U134 No data 

 OHM/TADS No data 7216750 7216897 

 DOT/UN/NA/IMO UN1045; fluorine UN1790; hydrofluoric acid UN1690; sodium 

shipping solution fluoride 

UN1052; anhydrous hydrogen 

fluoride 

HSDB 541 546 1766 

EINECS 231-954-8 231-634-8 231-667-8 

NCI No data No data C55221 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 189 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Fluorine, Hydrogen Fluoride, Sodium Fluoride, 

Fluosilicic Acid, and Sodium Silicofluoridea
 

Characteristic Fluorosilicic acid Sodium fluorosilicate 

Synonym(s)c Dihydrogen hexafluorosilicate; 

hexafluorosilicic acid; fluosilicic 

Disodium hexafluorosilicate; disodium 

silicofluoride; silicon sodium fluoride; 

acid; hexafluosilicic acid; hydrofluorosilicic acid; hydrogen hexafluorosilicate; hydrosilicofluoric 

sodium silicofluoride; sodium fluosilicate; 

sodium hexafluorosilicate; sodium 

hexafluosilicate; sodium silicon fluoride 

acid; silicofluoric acid; silicon hexafluoride dihydride 

Registered trade name(s)c

 FKS Prodan; Salufer 

Chemical formula H2SiF6 Na2SiF6 

Chemical structure F 

F 

Si 

F 

F 

2HF F 

F 

F 

Si 

F 

F 2 Na+ 

2­

F 

Identification numbers: 

 CAS registry 16961-83-4 16893-85-9 

 NIOSH RTECS NIOSH/VV8410000 NIOSH/VV8225000 

EPA hazardous waste No data No data 

OHM/TADS No data No data 

 DOT/UN/NA/IMO 

shipping 

UN 2674; sodium silicofluoride UN 1778; fluosilicic acid 

HSDB 770 2018 

EINECS 241-034-8 240-934-8 

NCI No data No data 

a

All information obtained from HSDB 2003 and ChemID 2001 except where noted. b

Sodium fluoride is an ingredient in many dental care products and rodenticides. Since it is not the only component 

in these products, they cannot properly be considered trade names or synonyms. Some of these products are: 

Floridine, Antibulit, Cavi-trol, Chemifluor, Credo, Duraphat, F1-tabs, Florocid, Flozenges, Fluoral, Fluorident, 

Fluorigard, Fluorineed, Fluorinse, Fluoritab, Fluorocid, Fluor-o-kote, Fluorol, Fluoros, Flura, Flura drops, Flura-gel, 

Flura-Loz, Flurcare, Flursol, Fungol B, Gel II, Gelution, Gleem, Iradicav, Karidium, Karigel, Kari-rinse, Lea-Cov, 

Lemoflur, Luride, Luride Lozi-tabs, Luride-SF, Nafeen, Nafpak, Na Frinse, Nufluor, Ossalin, Ossin, Osteofluor, 

Pediaflor, Pedident, Pennwhite, Pergantene, Phos-flur, Point Two, Predent, Rafluor, Rescue Squad, Roach salt, 

So-flo, Stay-flo, Studafluor, Super-dent, T-fluoride, Thera-flur, Thera-Flur-N, Villiaumite, and Zymafluor. Another 

compound of sodium and fluorine is sodium bifluoride (also called sodium hydrofluoride and sodium hydrofluoride), 

NaF-HF or NaHF2, which is not discussed here. c

IARC 1982 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 

America/International Maritime Organization Code; EINECS = European INventory of Existing Chemical Substances; 

EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank; NCI = National Cancer 

Institute; NIOSH = National Institute for Occupational Safety and Health; OHM/TADS = Oil and Hazardous 

Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances
 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 190 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Fluorine, Hydrogen Fluoride, 

Sodium Fluoride, Fluosilicic Acid, and Sodium Silicofluoridea
 

Property	 Fluorine Hydrogen fluoride Sodium fluoride 

Molecular weight 37.997 20.006 42.00 

Color Pale yellow Colorless Colorless 

Physical state Gas Gas Cubic or tetragonal 

crystals 

Molecular formula F2 FH FNa 

Melting point, °C -219.61 -83.36 993 

Boiling point, °C -188.13 19.51b 1,704 

Density, g/cm3 1.5127 at -188.13 °C 0.991 at 19.54 °C 2.78 

Odor Pungent, irritating odor Strong, irritating odor Odorless 

Odor threshold: 

Water Not relevant No data No data 

Air 0.035 ppm 0.5–3 ppm No data 

Solubility: 

Water 1.69 mg/L Miscible 43 g/L at 25 °C 

Organic solvents No data Benzene (2.54); toluene (1.80); Very slightly soluble 

ethanol (very soluble); m-xylene in ethanol 

(1.28); tetraline (0.27)b 

Partition coefficients: 

 Log Kow Not relevant No data No data 

 Log Koc Not relevant Not relevant No data 

Vapor pressure 0.4 kPa (3 mmHg) at 400 mmHg at 2.5 °C 1 mmHg at 1,077 °C 

55 °Kc

; 12.3 kPa (92.3 

mmHg) at 70 °K 

Henry’s Law constant at No data 0.104 at m-L/molee

 No data 

20 °C 

Autoignition temperature No data No data No data 

Flashpoint Not flammable Not flammable Not flammable 

Flammability limits No data No data No data 

Conversion factors 1 mg/m3

 = 1.554 ppmd 1 mg/m3 = 1.223 ppmd Not applicable 

1 ppm = 0.64 mg/m3 1 ppm = 0.82 mg/m3 

Explosive limits No data No data No data 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 191 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Fluorine, Hydrogen Fluoride, 

Sodium Fluoride, Fluosilicic Acid, and Sodium Silicofluoridea
 

Property Fluorosilicic Acid Sodium Fluorosilicate 

Molecular weight 144.1 188.1 

Color Colorless, fuming liquid white 

Physical state liquid granular powder 

Molecular formula H2SiF6 Na2SiF6 

Melting point, °C 60-70% solution solidifies at about decomposes at red heatb 

19 °C, forming a crystalline dihydrate 

Boiling point, °C decomposes decomposes at red heatb 

Density, g/cm3 1.4634 (60.97% solution) at 25 °C: 2.679f 

17.5/17.5 1.2742 (30% solution)f 

Odor Sour, pungent odorb

 No data 

Odor threshold: 

 Water No data No data

 Air No data No data 

Solubility: 

Water No data 0.76 g/100 g water at 25 °Cg 

Organic solvents No data No data 

Partition coefficients: 

 Log Kow No data No data

 Log Koc No data No data 

Vapor pressure No data No data 

Henry’s Law constant at No data No data 

20 °C 

Autoignition temperature No data No data 

Flashpoint No data No data 

Flammability limits No data No data 

Conversion factors Not applicable Not applicable 

Explosive limits No data No data a

All information obtained from HSDB 2003 except where noted 

b

Budavari 2001 

c

Lide 1992 

d

NAS 1971a 

e

Betterton 1992; apparent Henry’s law constant (ratio of the gas phase concentration to that of the total dissolved 

solute)

f

IARC 1982 

g

Aigueperse et al. 1988 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 193 

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

5.1 PRODUCTION 

The most important natural starting material for the production of fluorine chemicals, including fluorine, 

hydrogen fluoride, and sodium fluoride, is the mineral fluorite (calcium fluoride [CaF2]), commonly 

called fluorspar. Other important fluorine minerals are fluorapatite (Ca5(PO4)3F) and cryolite (Na3AlF6). 

There has been no fluorspar mine production in the United States since 1996; supplies were imported or 

purchased from the National Defense Stockpile. In addition, some byproduct calcium fluoride was 

recovered from industrial waste streams. An estimated 8,000–10,000 metric tons of fluorspar are 

recovered each year from uranium enrichment, stainless steel pickling, and petroleum alkylation. To 

supplement fluorspar supplies, fluorosilicic acid is recovered from phosphoric acid plants processing 

phosphate rock. In 2001, the main fluorspar-producing countries, in order of importance, were China, 

Mexico, South Africa, Russia, Spain, and France (USGS 2002b). The apparent consumption of fluorspar 

(excluding fluorspar equivalents of fluorosilicic acid, hydrofluoric acid, and cryolite) in the United States 

was 601,000 metric tons in 2000 and was estimated to be 636,000 metric tons in 2001 (USGS 2002a). 

Approximately 60–65% of the fluorspar consumed goes into the production of hydrogen fluoride. Large 

amounts are also used as a flux in steel production. 

In 2001, 65,200 tons of byproduct fluorosilicic acid (equivalent to 104,000 tons of fluorspar) were 

produced by 10 plants owned by 6 companies. Fluorosilicic acid was used primarily in water 

fluoridation, either directly or after processing into sodium silicofluoride. Fluorosilicic acid is also used 

to make aluminum fluoride for the aluminum industry. About 41,200, 4,700, and 13,200 tons of 

byproduct fluorosilicic acid were sold for water fluoridation, AlF3 production for the aluminum industry, 

and for other uses, such as sodium silicofluoride production, respectively. Domestic production data for 

fluorosilicic acid for 2001 were developed by the U.S. Geological Survey from voluntary surveys of U.S. 

operations. Of the 11 fluorosilicic acid operations surveyed, 10 respondents reported production and 

1 respondent reported zero production (USGS 2002b). 

Anhydrous hydrogen fluoride is manufactured by the action of sulfuric on calcium fluoride. Powdered 

acid-grade fluorspar (≥97% CaF2) is distilled with concentrated sulfuric acid; the gaseous hydrogen 

fluoride that leaves the reactor is condensed and purified by distillation (Smith 1994). The U.S. capacity 

for hydrogen fluoride production was 208,000 metric tons in 2001 (SRI 2002). The demand for 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 194 

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

hydrofluoric acid, which was 350,000 metric tons in 2001, is expected to increase to 364,000 metric tons 

in 2005 (CMR 2002). 

Sodium fluoride is manufactured by the reaction of hydrofluoric acid with sodium carbonate or sodium 

hydroxide. The salt is centrifuged and dried (Mueller 1994). Information concerning the amount of 

sodium fluoride produced is not available. Fluorosilicic acid is a byproduct of the action of sulfuric acid 

on phosphate rock containing fluorides and silica or silicates. Hydrogen fluoride acts on silica to produce 

silicon tetrafluoride, which reacts with water to form fluorosilicic acid (Lewis 1997). 

Fluorine is produced commercially by electrolyzing anhydrous hydrogen fluoride containing dissolved 

potassium fluoride to achieve adequate conductivity (Jaccaud and Faron 1988; Shia 1994). Potassium 

fluoride and hydrogen fluoride form potassium bifluoride (KHF2 or KF·HF). Fluoride is oxidized at the 

anode, producing fluorine, and the hydrogen ion is reduced at the cathode, producing hydrogen gas. 

Information concerning the amount of fluorine produced is not available. The commercial fluorine 

production capacity of the United States and Canada is over 5,000 tons/year (Shia 1994). 

Current U.S. manufacturers of fluorine, hydrogen fluoride, sodium fluoride, fluorosilicic acid, and sodium 

silicofluoride are given in Table 5-1. Tables 5-2 and 5-3 list the number of facilities in each state that 

manufacture, process, or use hydrogen fluoride and fluorine, respectively, their intended uses, and the 

range of maximum amounts of these substances that are stored on-site. In 2000, there were, respectively, 

1,031 and 15 reporting facilities that produced, processed, or used hydrogen fluoride or fluorine in the 

United States. The data listed in Tables 5-2 and 5-3 are derived from the Toxics Release Inventory 

(TRI01 2003). Only certain types of facilities were required to report. Therefore, this is not an 

exhaustive list. Sodium fluoride or other fluoride salts are not listed on TRI. 

5.2 IMPORT/EXPORT 

In 2000, the United States imported 484,000 metric tons of acid grade (>97%) fluorspar and 

39,000 metric tons of metallurgical-grade (<97%) fluorspar (USGS 2002a). This importation was 

supplemented by the fluorspar equivalent of 208,000 metric tons from hydrofluoric acid plus cryolite. 

The estimated imports of fluorspar for 2001 were 530,000 metric tons of acid-grade, 33,000 of 

metallurgical-grade, and 181,000 tons from hydrofluoric acid plus cryolite. Between 1997 and 2000, 63% 

of fluorspar imports came from China, 26% from South Africa, and 11% from Mexico. Exports of 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 195 

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

Table 5-1. U.S. Manufacturers of Hydrogen Fluoride, Fluorine, Sodium Fluoride, 

Fluosilicic Acid, and Sodium Silicofluoridea
 

Company Location 

Hydrogen Fluorideb,c 

Dupont La Porte, Texas 

 Honeywelld

 Geismar, Louisiana 

Fluorine 

 Honeywelld

 Metropolis, Illinois 

Sodium fluoride 

 Mallinckrodt Baker, Inc. Phillipsburg, New Jersey 

Ozark Fluorine Specialties, Inc. Tulsa, Oklahoma 

Solvay Fluorides, Inc. Alorton, Illinois 

Sodium silicofluoride 

IMC Phosphates Company, IMC-Agrico Phosphates Faustina, Louisiana 

Kaiser Aluminum and Chemical Corporation Mulberry, Florida 

Solvay Fluorides, Inc. Alorton, Illinois 

Fluosilicic acid 

Cargill Fertilizer, Inc. Riverview, Florida 

Farmland Hydro, L.P. Bartow, Florida 

IMC Phosphates Company, IMC-Agrico Phosphates Faustina, Louisiana; Nichols, Florida; South 

Pierce, Florida; Uncle Sam, Louisiana 

PCS Phosphate Co. Inc. Aurora, North Carolina 

Royster-Clark Inc. Americus, Georgia; Chesapeake, Virginia; 

Florence, Alabama; Hartsville, South Carolina 

Solvay Fluorides, Inc. Alorton, Illinois 

U.S. Agri-Chemicals Corporation Fort Meade, Florida 

a

Derived from SRI 2002 

b

Plant capacity was available only for hydrogen fluoride, and was reported as 80,000 and 120,000 metric tons for 

DuPont and Honeywell, respectively. 

c

Merchant producers. Alcoa produces hydrogen fluoride as a nonisolatable product. d

Formally General Electric 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 196 

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

Table 5-2. Facilities that Produce, Process, or Use Hydrogen Fluoride 

Number of Minimum amount on Maximum amount on 

Statea facilities site in poundsb site in poundsb Activities and usesc 

AK 2 0 99,999 1, 5, 13 

AL 28 0 9,999,999 1, 5, 6, 11, 12, 13 

AR 13 0 9,999,999 1, 5, 6, 7, 8, 11, 12, 13 

AZ 23 0 999,999 1, 4, 5, 6, 7, 9, 10, 11, 12, 13 

CA 34 0 49,999,999 1, 3, 4, 5, 6, 7, 9, 10, 11, 12, 14 

CO 16 0 999,999 1, 5, 7, 9, 11, 12 

CT 5 100 99,999 1, 5, 10, 11, 12 

DE 3 0 999,999 1, 5, 6 

FL 24 0 999,999 1, 2, 3, 5, 6, 7, 9, 10, 11, 12, 13, 14 

GA 26 0 999,999 1, 5, 7, 11, 12, 13 

IA 15 0 99,999 1, 5, 7, 12 

ID 5 100 99,999 1, 5, 10, 11, 12, 13, 14 

IL 41 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13 

IN 36 0 999,999 1, 5, 7, 10, 11, 12, 13, 14 

KS 14 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 13 

KY 29 0 9,999,999 1, 2, 3, 5, 6, 9, 10, 11, 12 

LA 19 0 9,999,999 1, 3, 4, 5, 6, 10, 12 

MA 11 0 99,999 1, 5, 10, 11, 12 

MD 12 0 9,999 1, 5, 11, 13 

ME 3 0 9,999 1, 11, 13 

MI 25 0 99,999 1, 2, 3, 5, 6, 7, 10, 11, 12, 13 

MN 14 0 99,999 1, 5, 6, 10, 11, 12, 13 

MO 27 0 99,999 1, 5, 7, 11, 12 

MS 9 0 999,999 1, 5, 8, 11, 13 

MT 6 0 999,999 1, 5, 10 

NC 37 0 999,999 1, 5, 11, 12, 13 

ND 8 0 999,999 1, 5, 10, 12, 13 

NE 8 0 999,999 1, 3, 5, 9, 13 

NH 4 0 99,999 1, 5, 12 

NJ 15 0 9,999,999 1, 5, 6, 10, 12 

NM 7 0 999,999 1, 5, 10, 11, 13 

NV 2 0 999,999 1, 5 

NY 29 0 99,999 1, 5, 6, 10, 11, 12 

OH 62 0 999,999 1, 5, 6, 7, 8, 9, 10, 11, 12, 13 

OK 17 0 999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13 

OR 20 0 999,999 1, 3, 4, 5, 7, 9, 10, 11, 12 

PA 67 0 9,999,999 1, 2, 3, 5, 6, 7, 9, 10, 11, 12, 13 

PR 1 100,000 999,999 6 

RI 3 100 99,999 6, 10, 11 

SC 30 0 999,999 1, 3, 5, 6, 10, 11, 12, 14 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 197 

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

Table 5-2. Facilities that Produce, Process, or Use Hydrogen Fluoride 

Number of Minimum amount on Maximum amount on 

Statea facilities site in poundsb site in poundsb Activities and usesc 

SD 1 0 99 1, 13 

TN 19 0 999,999 1, 2, 5, 6, 10, 11, 13 

TX 82 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

UT 14 0 999,999 1, 5, 6, 10, 11, 12, 13 

VA 23 0 99,999 1, 5, 10, 11, 12 

VT 2 1,000 99,999 11 

WA 18 0 999,999 1, 5, 10, 11, 12 

WI 24 0 99,999 1, 5, 7, 10, 11, 12, 13 

WV 20 0 999,999 1, 5, 10, 11, 12 

WY 9 0 99,999 1, 2, 3, 5, 10, 13 

Source: TRI01 2003 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 198 

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

Table 5-3. Facilities that Produce, Process, or Use Fluorine 

Number of Minimum amount Maximum amount on 

Statea facilities on site in poundsb site in poundsb Activities and usesc 

AL 1 0 99 1, 13 

IL 1 10,000 99,999 1, 3, 6, 7 

KS 1 0 99 1, 5, 12 

LA 1 1,000 9,999 1, 3, 6, 12 

OK 1 1,000 9,999 8 

PA 2 1,000 999,999 1, 3, 4, 6, 9, 10 

PR 1 1,000 9,999 10 

TX 1 1,000 9,999 12 

Source: TRI01 2003 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 199 

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

fluorspar for 2000 were 40,000 metric tons and are estimated to be 21,000 in 2001 (USGS 2002a). 

Exports consist of imported material that was reexported or material obtained from the National Defense 

Stockpile. In 2001, no disposal of metalurgical-grade fluorspar from the stockpile was reported. In 2001, 

most of the exports were to Canada and Taiwan (USGS 2002a, 2002b). 

U.S. imports for consumption are available for three other fluorides: hydrofluoric acid, cryolite, and 

aluminum fluoride. For 2001, these were 112,000, 6,750, and 17,400 metric tons, respectively. For 

hydrofluoric acid, 74% of imports came from Mexico and 23% from Canada (USGS 2002b). 

5.3 USE 

Hydrogen fluoride is the most important compound of fluorine. Anhydrous hydrogen fluoride is used in 

the production of most fluorine-containing chemicals. It is used in the production of refrigerants, 

herbicides, pharmaceuticals, high-octane gasoline, aluminum, plastics, electrical components, and 

fluorescent light bulbs. Aqueous hydrofluoric acid is used in stainless steel pickling, glass etching, metal 

coatings, exotic metal extraction, and quartz purification (Hance et al. 1997). The most important use of 

hydrogen fluoride is in the production of fluorocarbon chemicals, including hydrofluorocarbons, hydrofluorochlorocarbons, and fluoropolymers; 60% of production is used for this purpose. Demand for 

hydrogen fluoride for fluorocarbons, broadly used as refrigerants, is increasing as a nonchlorinated 

alternative to ozone-depleting chlorofluorocarbons. (Production of fluorocarbons uses more hydrogen 

fluoride than production of chlorofluorocarbons.) The next most important uses of hydrogen fluoride are: 

chemical derivatives, 18%; aluminum manufacturing, 6%; stainless steel pickling, 5%; petroleum 

alkylation catalysts, 4%; and uranium chemicals production, 3%. Miscellaneous other uses include glass 

etching, herbicides, and rare metals (CMR 2002). Generally, the aluminum industry consumes 10–40 kg 

of fluoride per metric ton of aluminum produced. The AlF3 used in aluminum reduction cells may be 

produced directly from acid-grade fluorspar or byproduct fluorosilicic acid, rather than from hydrogen 

fluoride. Anhydrous hydrogen fluoride is used as a catalyst in the petroleum alkylation, a process that 

increases the octane rating of petroleum. In uranium chemicals production, hydrogen fluoride is used to 

convert uranium oxide (yellow cake, U3O8) to UF4 before further fluorination to UF6. 

Fluorine gas is used captively for the production of various inorganic fluorides. The preparation of 

fluorides of an element in its highest oxidation state makes use of fluorine’s oxidizing and fluorinating 

ability. The most important product is uranium hexafluoride (UF6), which is used in the gaseous diffusion 

process for producing enriched uranium-235 for the nuclear industry. This use consumes 70–80% of 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 200 

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

fluorine production. The second most important product is sulfur hexafluoride (SF6), which is used as a 

gaseous dielectric for electrical and electronic equipment and a tracer gas for determining ventilation rates 

and air movements in buildings. Other uses of fluorine include: the treatment of polyolefin containers to 

reduce their permeability to organic liquids; the treatment of a polymer surface for the application of an 

adhesive or coating; and the production of some fluorinated organic compounds (Guo et al. 2001; Shia 

1994). 

The chemicals most commonly used by American waterworks for water fluoridation are fluorosilicic acid, 

sodium silicofluoride, and sodium fluoride (Urbansky 2002). Generally, 1.5–2.2 mg of sodium fluoride is 

added per liter of water (0.7–1.0 mg/L as fluoride) (Mueller 1994). Data from the Centers for Disease 

Control’s (CDC) 1992 Fluoridation Census indicate that 25% of utilities reported using sodium fluoride; 

however, this corresponds to 9.2% of the U.S. population drinking fluoride-supplemented tap water 

(Urbansky 2002). Sodium fluoride may also be applied topically to teeth as a 2% solution to prevent 

tooth decay. It is also used as a flux for deoxidizing rimmed steel, as a component of laundry sours 

(removal of iron stains), and in the re-smelting of aluminum, manufacture of vitreous enamels, pickling of 

stainless steel, wood preservative compounds, casein glues, manufacture of coated papers, and heattreating salts (Mueller 1994). Fluorosilicic acid, as a 1–2% solution, is used widely for sterilizing 

equipment in brewing and bottling. Other concentrations of fluorosilicic acid solutions are used in 

electrolytic refining of lead, in electroplating, for hardening cement, for crumbling lime or brick work, for 

removal of lime from hides during the tanning process, for removals of molds, and as a preservative for 

timber. Sodium fluorosilicate is also used in enamels for china and porcelain, in the manufacturing of 

opal glass, as an insecticide, as a rodentcide, and for mothproofing of wool. It is also an intermediate in 

the production of synthetic cryolite (Budavari 2001). 

5.4 DISPOSAL 

According to the TRI, in 2001, an estimated 2.5 million pounds of hydrogen fluoride were transferred offsite, including to publicly owned-treatment works (POTWs), by 991 reporting facilities presumably for 

disposal (TRI01 2003). In 2001, 240,196 pounds of fluorine were transferred off-site by 9 reporting 

facilities. According to the TRI, in 2001, 77% of hydrogen fluoride that was recycled or treated was 

performed on-site (TRI01 2003). Of the hydrogen fluoride recycled in 2001, 23.8 million pounds were 

recycled on-site and 251,203 pounds were recycled off-site. Of the hydrogen fluoride that was treated, 

234 million pounds were treated on-site and 2 million pounds were treated off-site (TRI01 2003). No 

information was found concerning how hydrogen fluoride is generally treated for disposal. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 201 

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

Fluorine gas can be disposed of by conversion to perfluorocarbons or fluoride salts. Because of the long 

atmospheric lifetimes of perfluorocarbons, conversion to fluoride salts is preferable. Industrially, the 

waste stream is scrubbed with a caustic solution, KOH or NaOH, and for dilute streams, allowed to react 

with limestone (Shia 1994). Adequate contact and residence time is essential in the scrubber to ensure 

complete neutralization of the intermediate oxygen difluoride to prevent it from leaving the scrub tower. 

According to the TRI, in 2001, 18,973 pounds of fluorine were treated on-site and 240,196 pounds were 

treated off-site (TRI01 2003). 

No information was found regarding the disposal of sodium fluoride. It would appear from its use that 

most of it is disposed of in municipal landfills or POTWs. 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 203 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Fluorides, hydrogen fluoride, and fluorine have been identified in at least 188 of the 1,636 hazardous 

waste sites that have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 

2003). However, the number of sites evaluated for fluorides, hydrogen fluoride, and fluorine is not 

known. The frequency of these sites can be seen in Figure 6-1. Of these sites, all are located within the 

United States. 

Fluorides are naturally-occurring components of rocks and soil and are also found in air, water, plants, 

and animals. They enter the atmosphere through volcanic emissions and the resuspension of soil by wind. 

Volcanoes also emit hydrogen fluoride and some fluorine gas. Fluorine is a highly reactive element and 

readily hydrolyzes to form hydrogen fluoride and oxygen. Hydrogen fluoride reacts with many materials 

both in the vapor phase and in aerosols. The resultant fluorides are typically nonvolatile, stable 

compounds. Marine aerosols also release small amounts of gaseous hydrogen fluoride and fluoride salts 

into the air (Friend 1989). Anthropogenic fluoride emissions include the combustion of fluorinecontaining materials, which releases hydrogen fluoride, as well as particulate fluorides, into the air. Coal 

contains small amounts of fluorine, and coal-fired power plants constitute the largest source of 

anthropogenic hydrogen fluoride emissions. According to the Toxic Chemical Release Inventory (TRI), 

in 2001, the largest contributing industrial sectors were electrical utilities (TRI01 2003). Total air 

emissions of hydrogen fluoride by electrical utilities in 1998, 1999, 2000, and 2001 were reported as 64.1, 

58.3, 58.3, and 55.8 million tons, respectively. Major sources of industrial fluoride emissions are 

aluminum production plants and phosphate fertilizer plants; both emit hydrogen fluoride and particulate 

fluorides (EPA 1998b). Other industries releasing hydrogen fluoride are: chemical production; steel; 

magnesium; and brick and structural clay products. Hydrogen fluoride would also be released by 

municipal incinerators as a consequence of the presence of fluoride-containing material in the waste 

stream. Hydrogen fluoride is one of the 189 chemicals listed as a hazardous air pollutant (HAP) in 

Title III, Section 112 of the Clean Air Act Amendments of 1990. Maximum achievable control 

technology (MACT) emission standards are being developed by the EPA for each HAP. The goal of 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 204 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Fluoride, Hydrogen Fluoride, and 

Fluorine Contamination 

1-2 

3-4 

5-6 

7-8 

9-11 

14-19 

Frequency of

NPL S ites 

D erived from HazDat 2003 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 205 

6. POTENTIAL FOR HUMAN EXPOSURE 

HAP emissions control is to reduce human health risks (Kelly et al. 1994). In addition to industrial 

effluent and natural releases (e.g., weathering of rocks and runoff from soil), fluorides are released into 

surface water in municipal waste water as a result of water fluoridation. 

In the atmosphere, gaseous hydrogen fluoride will be absorbed by atmospheric water (rain, clouds, fog, 

snow) forming an aerosol or fog of aqueous hydrofluoric acid. It will be removed from the atmosphere 

primarily by wet deposition. Particulate fluorides are similarly removed from the atmosphere and 

deposited on land or surface water by wet and dry deposition. Atmospheric precipitation weathers crustal 

rocks and soil, but dissolves out very little fluoride; most of the fluoride mobilized during weathering is 

bound to solids such as clays. Upon reaching bodies of water, fluorides gravitate to the sediment 

(Carpenter 1969). Fluorides have been shown to accumulate in some marine aquatic organisms (Hemens 

and Warwick 1972). When deposited on land, fluoride is strongly retained by soil, forming complexes 

with soil components. Fluorides in soils are transported to surface waters through leaching or runoff of 

particulate-bound fluorides. Leaching removes only a small amount of fluorides from soils. Fluorides 

may be taken up from soil and accumulate in plants. The amount of fluorides accumulated depends on 

the type of plant and soil and the concentration and form of fluoride in the soil. Fluorides may also be 

deposited on above-ground surfaces of the plant. Tea plants are particularly known to accumulate 

fluoride, 97% of which is accumulated in the leaves (Fung et al. 1999). Fluoride accumulates primarily in 

the skeletal tissues of terrestrial animals that consume fluoride-containing foliage. However, milk and 

edible tissue from animals fed high levels of fluorides do not appear to contain elevated fluoride 

concentrations (NAS 1971a). 

In natural water, fluoride forms strong complexes with aluminum in water, and fluorine chemistry in 

water is largely regulated by aluminum concentration and pH (Skjelkvale 1994). Below pH 5, fluoride is 

almost entirely complexed with aluminum and consequently, the concentration of free F- is low. As the 

pH increases, Al-OH complexes dominate over Al-F complexes and the free F-

 levels increase. Fluoride 

forms stable complexes with calcium and magnesium, which are present in sea water. Calcium carbonate 

precipitation dominates the removal of dissolved fluoride from sea water (Carpenter 1969). Fluorine is 

incorporated into the calcium salt structure and removed from solution when the latter precipitates. 

Fluoride occurs in soil in a variety of minerals and complexes with aluminum, iron, and calcium. 

Fluorides occur predominantly as aluminum fluorosilicate complexes in acidic soils and calcium fluoride 

in alkaline soils. The availability of these soluble complexes increases with decreasing pH (Fung et al. 

1999; Shacklette et al. 1974). This explains why acidic soils have both higher water-soluble fluoride and 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 206 

6. POTENTIAL FOR HUMAN EXPOSURE 

higher extractable aluminum levels. The retention of fluoride in alkaline soils depends largely upon the 

aluminum content of the soil. 

The general population is exposed to fluoride through consumption of drinking water, foods, and 

dentifrices. Fluorides used in dentifrices are sodium fluoride, sodium monofluorophosphate, and 

stannous fluoride (Pader 1993). Populations living in areas with naturally high fluoride levels in water 

and soil may be exposed to high levels of fluoride in water. This is especially true if drinking water is 

derived from wells. 

Fluoride intake in infants depends on whether or not the child is nursed. Fluoride intake by an infant who 

is exclusively breast fed is generally <2 μg/kg-day(Fomon and Ekstrand 1999). Levy et al. (2001) found 

that for most children, water fluoride intake was the predominant source of fluoride, especially through 

age 12 months. This was due in large part to children receiving fluoridated water mixed with infant 

formula concentrate (Levy et al. 1995b, 2001). Fluoride exposure was calculated to be 102, 105, and 

167 μg/kg-day for infants consuming concentrated liquid milk-based formula, concentrated liquid isolated 

soy protein-based formula, and powdered milk-based formula, respectively, which were diluted with 

water that is 1 ppm in fluoride. Infants may be exposed to higher fluoride concentrations now than in the 

past. In the 1960s, nearly 80% of infants were fed cow's milk by 6 months of age. In 1991, 80% of 

6-month-old infants were fed formula (Fomon and Ekstrand 1999). 

Some plants, most notably tea, accumulate fluorides, and people who drink large quantities of tea may be 

exposed to high levels of fluoride in their diets. Populations living near industrial sources of fluoride may 

be exposed to higher levels of fluorides in the air they breathe. Vegetables and fruits grown near such 

sources may contain higher levels of fluorides particularly from fluoride-containing dust settling on the 

plant. Populations exposed to relatively high concentrations of fluoride include workers in fluorideprocessing industries and individuals residing near such industries. Similarly, populations living near 

hazardous waste sites may also be exposed to high levels of fluoride by analogous routes. 

6.2 RELEASES TO THE ENVIRONMENT 

According to the TRI, in 2001, total releases of hydrogen fluoride to the environment (including air, 

water, soil, and underground injection) from 991 reporting facilities that produced, processed, or used 

hydrogen fluoride were 72.1 million pounds (TRI01 2003). Table 6-1 lists amounts released from these 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 207 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or 

Use Hydrogen Fluoride 

Reported amounts released in pounds per yeara 

Under- Total off- Total on and 

Stateb 

Number of 

facilities Airc

 Water 

ground 

injection Land 

Total on-site 

released 

site 

releasee off-site release 

AK 2 73,027 No data 0 0 73,027 0 73,027 

AL 28 3,304,387 0 0 12,000 3,316,387 18,596 3,334,983 

AR 13 942,385 0 0 0 942,385 8 942,393 

AZ 23 694,190 No data 0 3,405 697,595 1,062 698,657 

CA 35 9,211 5 0 0 9,216 2,886 12,102 

CO 17 795,831 No data 0 0 795,831 0 795,831 

CT 5 107,388 0 0 0 107,388 10,732 118,120 

DE 3 201,815 No data 0 0 201,815 0 201,815 

FL 24 2,358,937 5 0 7,965 2,366,907 0 2,366,907 

GA 28 3,286,300 0 0 0 3,286,300 2,944 3,289,244 

IA 16 1,300,253 No data 0 0 1,300,253 0 1,300,253 

ID 5 208,065 0 0 0 208,065 255 208,320 

IL 41 2,255,380 1 0 5 2,255,386 1,510 2,256,896 

IN 36 3,888,416 250 0 0 3,888,666 0 3,888,666 

KS 16 775,771 0 0 0 775,771 930 776,701 

KY 29 2,090,877 0 0 0 2,090,877 1,301 2,092,178 

LA 19 613,860 250 0 11 614,121 0 614,121 

MA 11 197,829 No data 0 0 197,829 237 198,066 

MD 14 1,376,506 No data 0 0 1,376,506 15 1,376,521 

ME 3 1,286 0 0 0 1,286 0 1,286 

MI 27 2,139,731 0 0 0 2,139,731 39,376 2,179,107 

MN 15 217,532 0 0 0 217,532 0 217,532 

MO 29 2,464,416 0 0 158,300 2,622,716 0 2,622,716 

MS 9 461,108 197 0 2,287 463,592 0 463,592 

MT 7 167,298 0 0 0 167,298 0 167,298 

NC 38 5,160,908 5 0 0 5,160,913 0 5,160,913 

ND 8 490,133 0 0 0 490,133 260 490,393 

NE 8 1,279,219 No data 0 0 1,279,219 0 1,279,219 

NH 4 208,550 No data 0 0 208,550 391 208,941 

NJ 15 249,406 0 0 0 249,406 2 249,408 

NM 7 209,568 No data 0 0 209,568 420 209,988 

NV 2 439,874 No data 0 0 439,874 0 439,874 

NY 31 1,137,383 0 0 0 1,137,383 750 1,138,133 

OH 64 6,147,565 1,601 4,400,000 0 10,549,166 34,884 10,584,050 

OK 18 892,504 100 0 0 892,604 250 892,854 

OR 21 67,943 0 0 18,398 86,341 0 86,341 

PA 70 5,056,848 35 0 5 5,056,888 17,156 5,074,044 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 208 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or 

Use Hydrogen Fluoride 

Reported amounts released in pounds per yeara 

Under- Total off- Total on and 

Stateb 

Number of 

facilities Airc

 Water 

ground 

injection Land 

Total on-site 

released 

site 

releasee off-site release 

PR 1 500 No data 0 0 500 0 500 

RI 3 3,683 No data 0 0 3,683 0 3,683 

SC 30 2,153,397 0 0 0 2,153,397 0 2,153,397 

SD 2 89,000 No data 0 0 89,000 0 89,000 

TN 19 2,069,004 0 0 0 2,069,004 0 2,069,004 

TX 83 3,828,730 10 0 21 3,828,761 1,100 3,829,861 

UT 14 467,778 0 0 24,930 492,708 0 492,708 

VA 23 1,745,413 0 0 0 1,745,413 0 1,745,413 

VT 2 4,141 0 0 0 4,141 0 4,141 

WA 19 323,942 0 0 0 323,942 1,405 325,347 

WI 24 1,231,556 0 0 0 1,231,556 0 1,231,556 

WV 21 3,722,619 19,090 0 0 3,741,709 0 3,741,709 

WY 9 337,011 No data 0 52,248 389,259 0 389,259 

Total 991 67,248,474 21,549 4,400,000 279,575 71,949,598 136,470 72,086,068 

Source: TRI01 2003 

a

Data in TRI are maximum amounts released by each facility.

b

Post office state abbreviations are used. 

c

The sum of fugitive and stack releases are included in releases to air by a given facility.

d

The sum of all releases of the chemical to air, land, water, and underground injection wells. 

e

Total amount of chemical transferred off-site, including to publicly owned treatment works (POTW). 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 209 

6. POTENTIAL FOR HUMAN EXPOSURE 

facilities grouped by state. In addition, 136,470 pounds of hydrogen fluoride were transferred off-site by 

these facilities (TRI01 2003). Starting in 1998, metal mining, coal mining, electric utilities and Resource 

Conservation and Recovery Act (RCRA)/solvent recovery industries were required to report to the TRI, 

industries with potentially large releases of hydrogen fluoride. The industrial sector producing, 

processing, or using hydrogen fluoride that contributed the greatest environmental releases was electrical 

utilities, which contributed 78% of the total environmental releases. 

According to the TRI, in 2001, total releases of fluorine to the environment (including air, water, soil, and 

underground injection) from 9 reporting facilities that produced, processed, or used fluorine were 

165,938 pounds (TRI01 2003). Table 6-2 lists amounts of fluorine released from these facilities grouped 

by state. The two largest contributing industrial sectors were electrical utilities and primary metals, which 

respectively contributed 65 and 19% of the total environmental releases. Neither sodium fluoride nor any 

other fluorides are listed on TRI. The TRI data should be used with caution because only certain types of 

facilities are required to report. This is not an exhaustive list. 

Hydrogen fluoride is one of the 189 chemicals listed as a HAP in Title III, Section 112 of the Clean Air 

Act Amendments of 1990. MACT emission standards are being developed by the EPA for each HAP. 

The goal of HAP emissions control is to reduce human health risks (Kelly et al. 1994). The Final Air 

Toxic MACT Rule for fluoride emissions from primary aluminum reduction plants, published in 1997, 

was projected to reduce fluoride emissions by 3,700 tons per year. The Final Air Toxic MACT Rule for 

fluoride emissions from phosphoric acid manufacturing and phosphate fertilizer production, published in 

1999, was projected to reduce fluoride emissions by 260 tons per year (EPA 2000). 

Fluorides have been identified in a variety of environmental media (air, surface water, leachate, 

groundwater, soil, and sediment) collected at 188 of 1,636 current or former NPL hazardous waste sites 

(HazDat 2003). 

6.2.1 Air 

The major natural source of hydrogen fluoride emissions to the atmosphere is volcanoes. These 

emissions are estimated to range from 0.6 to 6 million metric tons per year. On average, <10% of these 

emissions are a result of large eruptions that are efficiently injected into the stratosphere (Symonds et al. 

1988). Passive degassing of volcanoes is a major source of tropospheric hydrogen fluoride. In addition 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 210 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Releases to the Environment from Facilities that Produce, Process, or 

Use Fluorine 

Reported amounts released in pounds per yeara 

Under- Total on and 

Stateb 

Number of 

facilities Airc

 Water 

ground 

injection Land 

Total on-site 

released 

Total off-site 

releasee 

off-site 

release 

AL 1 0 31,328 0 0 31,328 0 31,328 

IL 1 4,979 No data 0 0 4,979 0 4,979 

KS 1 429 No data 0 107,282 107,711 0 107,711 

LA 1 2,280 No data 0 0 2,280 0 2,280 

OK 1 263 No data 0 0 263 0 263 

PA 2 1,001 No data 0 0 1,001 0 1,001 

PR 1 0 18,376 0 0 18,376 0 18,376 

TX 1 0 No data 0 0 0 0 0 

Total 9 8,952 49,704 0 107,282 165,938 0 165,938 

Source: TRI01 2003 

a

Data in TRI are maximum amounts released by each facility.

b

Post office state abbreviations are used. 

c

The sum of fugitive and stack releases are included in releases to air by a given facility.

d

The sum of all releases of the chemical to air, land, water, and underground injection wells. 

e

Total amount of chemical transferred off-site, including to publicly owned treatment works (POTW). 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 211 

6. POTENTIAL FOR HUMAN EXPOSURE 

to hydrogen fluoride, volcanic gases also contain other fluorine compounds, namely SiF4, H2SiF6, and F2. 

Soil naturally contains fluoride, and resuspension of soil by wind also contributes to the atmospheric 

burden of fluorides in the form of soil minerals (NAS 1971a). Another source is sea salt aerosol, which 

releases small amounts of gaseous hydrogen fluoride and fluoride salts into the air. The marine aerosol is 

potentially a major source of tropospheric hydrogen fluoride (Friend 1989). However, these releases 

would be confined to the air over the oceans. 

The largest anthropogenic source of hydrogen fluoride emissions to air in the United States is electrical 

utilities. Coal naturally contains fluorides as impurities and this will be released primarily in the form of 

hydrogen fluoride during combustion. Some of the fluoride in the coal may be absorbed onto fly ash or 

bottom ash. A typical 650 megawatt coal-burning power plant running at 67% capacity (the average for 

U.S. coal plants) would release 180,000 pounds of hydrogen fluoride per year (Rubin 1999). EPA 

(1998a) reports an emission factor of 0.15 pounds/ton (0.075 kg/Mg) for coal combustion under a variety 

of firing conditions. The Canadian Environmental Protection Act (CEPA) (1996) reports hydrogen 

fluoride emission factors for bituminous and lignite coals of 0.12 and 0.01 kg/Mg coal, respectively. 

Hydrogen fluoride is water soluble and emissions are readily controlled by acid gas scrubbers. Other 

gaseous fluorides that may occur in the flue gas are SiF4 and H2SiF6. Emissions of fluorides from 

aluminum reduction processes are primarily gaseous hydrogen fluoride and particulate fluorides, 

principally aluminum fluoride and calcium fluoride. Emission factors for aluminum production are 

0.03 pounds of total fluorides and 0.02 pounds of hydrogen fluoride per ton of aluminum produced (EPA 

1998b). Fluorine-containing compounds are contained in the raw materials used to produce brick and 

structural clay products and, therefore, hydrogen fluoride and other fluoride compounds are emitted from 

kilns used to manufacture these products. In addition, coal may be used to fire the kilns and contribute to 

the fluoride emissions. In the production of phosphate fertilizers, gaseous fluorides (hydrogen fluoride 

and silicon tetrafluoride), as well as particulate fluorides, may be released. EPA’s Office of Air Quality 

Planning and Standards has developed emission factors for hydrogen fluoride for these and other 

hydrogen fluoride emitting industries. Hydrogen fluoride would be released by municipal incinerators as 

a consequence of the presence of fluoride-containing material in the waste stream. The amount of 

hydrogen fluoride released in flue gas would depend on the fluorine content of the waste stream and the 

efficiency of pollution control devises used in the stack. 

Anthropogenic hydrogen fluoride emissions to the atmosphere in Canada were estimated to be 

5,400 metric tons per year, of which 75% was contributed by primary aluminum producers. Other 

industries releasing hydrogen fluoride in Canada and their relative contributions were: coal-burning 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 212 

6. POTENTIAL FOR HUMAN EXPOSURE 

utilities, 10%; chemical production, 6%; steel production, 4%; phosphate fertilizer production, 2%; and 

magnesium production, 1% (CEPA 1996). 

On a global scale, emissions of fluorides from coal combustion and other anthropogenic sources are 

minor and of local concern compared with natural emissions, estimated as 2.5x1010 kg/year (Carpenter 

1969). Anthropogenic releases of total fluorides into the atmosphere were 155,300 tons/year from the 

major fluoride-processing industries measured between 1964 and 1970 (EPA 1980a). The major 

contributors were steel, brick, tile, and aluminum manufacturing, combustion of coal, and production of 

phosphorus and phosphate fertilizer (EPA 1980a; NAS 1971a). In 1977 and 1978, monthly atmospheric 

emission factors for fluorides from the Kitimat aluminum plant in British Columbia, Canada ranged from 

4.0 to 6.8 kg fluoride per ton of aluminum produced; production capacity was 300,000 tons of aluminum 

per year (Sauriol and Gauthier 1984). Subsequently, regulations were established that set emissions 

standards for aluminum manufacturing (EPA 1980b) and phosphate fertilizer plants (EPA 1975). 

Fluorides can also enter the atmosphere in dusts and aerosols from the manufacture and use of pesticides 

such as sodium fluoride, sodium fluorosilicate, barium fluorosilicate, and cryolite (NAS 1971a). In the 

United States, fluoride emissions from coal-burning electric utilities are estimated to be around 

37x106

 kg/year (Bauer and Andren 1985). 

There is evidence that emissions of fluorides have been declining. Fluoride in precipitation has declined 

since 1967 (Ares 1990). A recent study from a forested area near Cologne, Germany registered a sharp 

decline in the fluoride content of Roe deer antlers from peak levels in the 1950s and 1960s (Kierdorf and 

Kierdorf 2000). In the 1990s, levels were almost an order of magnitude lower than the peak levels, which 

are attributed to reduced emissions from stationary sources. Fluoride is a skeletally-deposited 

contaminant, and it can be assumed that fluoride is mobilized during the annual antler growth period and 

transported to the mineralizing antlers. Therefore, the fluorine content of antlers is a good indicator of 

fluoride release. 

According to the TRI, in 2001, releases of 67.2 million pounds of hydrogen fluoride to air from 

991 reporting facilities accounted for 93% of the total environmental releases of hydrogen fluoride 

(TRI01 2003). Table 6-1 lists amounts of hydrogen fluoride released to air from these facilities grouped 

by state. The industrial sector contributing the largest release of hydrogen fluoride to air was electrical 

utilities, which contributed 83% of releases to air. 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 213 

6. POTENTIAL FOR HUMAN EXPOSURE 

According to the TRI, in 2001, releases of 8,952 pounds of fluorine to air from 9 reporting facilities 

accounted for 5% of the total environmental releases of fluorine (TRI01 2003). Table 6-2 lists amounts of 

fluorine released to air from these facilities grouped by state. The TRI data should be used with caution, 

however, since only certain types of facilities are required to report. This is not an exhaustive list. 

According to the TRI, total air emissions for hydrogen fluoride ranged from 15.9 million pounds in 1998 

to 8.9 million pounds in 1994, during the period from 1988 to 2001. Total air emissions of fluorine have 

decreased from 18,319 pounds in 1995 to 8,523 pounds in 2001 (TRI01 2003). This trend information 

only includes emission data from the original industry subtotal, those industries with Standard Industrial 

Classification (SIC) Codes 20–39. Starting in 1998, metal mining, coal mining, electric utilities, 

Resource Conservation and Recovery Act (RCRA)/solvent recovery industries, and chemical wholesalers 

were also required to report. Of these industries, electrical utilities contribute significantly to emissions 

of hydrogen fluoride to air. Total air emissions of hydrogen fluoride by electrical utilities in 1998, 1999, 

2000, and 2001 were reported as 64.1, 58.3, 58.3, and 55.8 million tons, respectively. 

Fluorides were detected in the air at 8 of the 188 current or former NPL hazardous waste sites, where they 

were detected in some environmental media (HazDat 2003). 

6.2.2 Water 

Natural sources of fluoride released to waters are primarily a result of runoff from the weathering of 

fluoride-containing rocks and soils and the leaching of fluorides from the soil into groundwater. In the 

western regions of the United States, rocks and soils have greater than average concentrations of fluoride; 

as a result, greater amounts of fluorides leach into the groundwater. Leaching from alkaline igneous 

rocks, dolomite, phosphorite, and volcanic glasses may result in water with high-fluoride levels (EPA 

1980a; NAS 1971a). 

Anthropogenic sources contributing to fluoride levels in water include atmospheric deposition of 

emissions from coal-fired power plants and other industrial sources that are deposited directly into water 

or that are first deposited on land and enter waterways in runoff. Most of this deposition is in the form of 

precipitation. Waste water may enter surface water directly or as effluent of water treatment plants. 

Since much of the nation’s water supplies are fluoridated to a level of 0.7–1.2 ppm to decrease the 

incidence of tooth decay (DHHS 1991), this will contribute to fluoride in effluents from treatment plants. 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 214 

6. POTENTIAL FOR HUMAN EXPOSURE 

According to the TRI, in 2001, releases of 21,549 pounds of hydrogen fluoride to water from 

991 reporting facilities accounted for 0.030% of the total environmental releases of these substances 

(TRI01 2003). Table 6-1 lists amounts of hydrogen fluoride released to water from these facilities 

grouped by state. According to the TRI, in 2001, releases of 49,704 pounds of fluorine to water from 

9 reporting facilities accounted for 30% of the total environmental releases of this substance (TRI01 

2003). Table 6-2 lists amounts of fluorine released to water from these facilities grouped by state. As of 

1998, TRI no longer separately collects data on substances released indirectly to POTWs, part of which 

may ultimately be released to surface waters. The TRI data should be used with caution, however, since 

only certain types of facilities are required to report. This is not an exhaustive list. 

Fluorides were detected in groundwater and surface water at 135 and 53 sites, respectively, of the 

188 NPL hazardous waste sites where they were detected in some environmental media (HazDat 2003). 

6.2.3 Soil 

Fluoride comprises about 0.09% of the earth’s crust, ranking 13th in order of abundance (Lindahl and 

Mahmood 1994). Fluoride-containing minerals include biotite, muscovite, hornblende, apatite, and 

fluorspar (NAS 1971a). Fluorides are released to soils from the weathering of crustal rock and minerals, 

deposition of fluorides released to air from natural and anthropogenic sources, and plant and animal 

residues. Man-made sources applied directly to soil include phosphate fertilizers, mine tailings, and 

landfilled industrial and municipal waste (EPA 1980a; NAS 1971a). In a study by Oelschläger (1971), 

fertilization with superphosphates added 8–20 kg fluoride/hectare to the soil. Soil contamination by 

atmospheric fluorides near an industrial source reflected the gradient of fluoride deposition. In one study, 

the total fluoride concentration was found to decrease over a distance of 8.8 km from 2,700 to 616 μg/g 

fluoride and the water extractable fraction decreased from 292 to 10 μg fluoride/g (Polomski et al. 1982). 

According to the TRI, in 2001, releases of 279,575 pounds and 4.4 million pounds of hydrogen fluoride 

respectively to land and underground injection from 991 reporting facilities accounted for respectively 

0.38 and 6.1% of total environmental releases of these substances (TRI01 2003). Table 6-1 lists amounts 

of hydrogen fluoride released to land and underground injection from these facilities grouped by state. 

According to the TRI, in 2001, 107,282 pounds of fluorine were released to land from 9 reporting 

facilities accounted for 65% of the total environmental releases of this substance (TRI01 2003). 

However, it is not clear how a gaseous substance can be released to land, and this figure is likely an error. 

Table 6-2 lists amounts of fluorine released to air from these facilities grouped by state. The TRI data 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 215 

6. POTENTIAL FOR HUMAN EXPOSURE 

should be used with caution, however, since only certain types of facilities are required to report. This is 

not an exhaustive list. 

Fluorides were detected in soil and sediment collected at 32 and 22 sites, respectively, of the 178 NPL 

hazardous waste sites, where they were detected in some environmental media (HazDat 2003). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

In the atmosphere, gaseous hydrogen fluoride will be absorbed by atmospheric water (rain, clouds, fog, 

snow) forming an aerosol or fog of aqueous hydrofluoric acid. It will be removed from the atmosphere 

primarily by wet deposition (including rainout or in-cloud scavenging and washout or below-cloud 

scavenging). Particulate fluorides are similarly removed from the atmosphere and deposited on land or 

surface water by wet and dry deposition. Atmospheric precipitation weathers crustal rocks and soil, but 

dissolves out very little fluoride; most of the fluoride mobilized during weathering is bound to solids such 

as clays. Upon reaching bodies of water, fluorides gravitate to the sediment (Carpenter 1969). 

Most of the fluorides in the oceans are received from rivers; a lesser amount comes from atmospheric 

deposition. Losses occur in aerosols to the atmosphere and incorporation into the tissue of aquatic 

organisms. Fluorides have been shown to accumulate in some marine aquatic organisms. In a study by 

Hemens and Warwick (1972), toxic effects due to fluorosis were observed in species of mussel, mullet, 

crab, and shrimp in an estuary where waste from an aluminum plant was released. 

Fluoride is strongly retained by soil, forming complexes with soil components. Fluorides in soils are 

transported to surface waters through leaching or runoff of particulate-bound fluorides. Leaching 

removes only a small amount of fluorides from soils. Oelschläger (1971) reported that about 0.5–6.0% of 

the yearly increment of fluoride added to forest and agricultural areas through the application of 

phosphate fertilizer was lost in the leaching process. In this study, superphosphates added 8–20 kg 

fluoride/hectare to the soil, while seepage water contained between 52 and 208 μg fluoride/L, depending 

upon soil levels of clay, lime, and fluoride. 

Fluorides may be taken up from soil and accumulate in plants. They may also be deposited on aboveground surfaces of the plant. Tea plants are known to accumulate fluoride, 97% of which is accumulated 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 216 

6. POTENTIAL FOR HUMAN EXPOSURE 

in the leaves and 3% in the other parts of the plant. Fung et al. (1999) observed that the fluoride contents 

of tea leaves were 1,000 times the soluble fluoride content of the soil and 2–7 times the total fluoride 

content. The amount of fluoride taken up by plants is more a function of the soil type, its pH, and calcium 

and phosphorous content than of the total fluoride content of the soil (Brewer 1966). The addition of 

soluble fluoride to unlimed soil will result in increased fluoride uptake. In studies of plants grown on 

heavily polluted soil near aluminum smelters, uptake was via the roots and the stomata. Fluoride 

concentrations were much lower in the leaves than in the roots of plants, and most of the fluoride 

adsorbed by the roots was desorbed in water. Others have found that fluoride uptake is increased by the 

presence of aluminum, probably due to the uptake of aluminum–fluoride complexes. The fluoride uptake 

in ryegrass and clover from contaminated soil was strongly correlated with water and calcium chlorideextractable fluoride in the soil (Arnesen 1997). In this study, the fluoride content of pasture ryegrass 

exceeded the recommended fluoride limit only in grass grown in the most polluted soil, while that in 

clover exceeded this limit even in moderately polluted soil. 

Fluoride accumulates primarily in the skeletal tissues of terrestrial animals that consume fluoridecontaining foliage. However, milk and edible tissue from animals fed high levels of fluorides do not 

appear to contain elevated fluoride concentrations (NAS 1971a). Fluoride is taken up by hens and 

concentrated in the shell of their eggs. Hens living in the vicinity of two major coal-fired power plants 

had fluoride levels in egg shells of 1.75 mg/kg compared with reference means of 0.07 mg/kg, indicating 

significant uptake of anthropogenic fluoride (de Moraes Flores and Martins 1997). 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Hydrogen fluoride is the most abundant gaseous fluoride released into the atmosphere. It reacts with 

many materials both in vapor and in aerosols. For example, hydrogen fluoride reacts with silica, forming 

silicon tetrafluoride. However, no information was found on the reactions of hydrogen fluoride with 

common atmospheric species or estimates of its overall atmospheric half-life. The predominant mode of 

degradation of inorganic fluorides in the air is hydrolysis. Silicon tetrafluoride, a major industrial 

pollutant, reacts with water vapor in air to form hydrated silica and fluorosilicic acid. Sulfur 

hexafluoride, a gaseous dielectric for electrical and electronic equipment, reacts with water at elevated 

temperatures (>850 °C) to form sulfuric acid and hydrogen fluoride (Guo et al. 2001). Molecular fluorine 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 217 

6. POTENTIAL FOR HUMAN EXPOSURE 

hydrolyzes to form hydrogen fluoride and oxygen. Hydrolysis of uranium hexafluoride, which is used in 

nuclear power applications, also produces hydrogen fluoride as well as nonvolatile uranyl fluoride. These 

compounds are then removed from the atmosphere by condensation or nucleation processes (NAS 1971a). 

Fluorides emitted by industries in particulate matter are stable compounds that do not readily hydrolyze. 

6.3.2.2 Water 

Contrary to traditional thought, hydrogen fluoride, a very weak acid in dilute solution, is dissociated in 

solution, but forms tight ion pairs F-

...H+–OH2, unique to F-, which reduce the thermodynamic activity 

coefficient of H3O+

 (Cotton et al. 1999). In natural water, fluoride ions form strong complexes with 

aluminum, and fluorine chemistry in water is largely regulated by aluminum concentration and pH. 

Below pH 5, fluorine is almost entirely complexed with aluminum and consequently, the concentration of 

free F- is low. As the pH increases, Al-OH complexes dominate over Al-F complexes and the free Flevel increases. The dominant Al-F complex at pH <5 is AlF2+ (Skjelkvale 1994). In the absence of 

aluminum, dissolved fluorides are usually present as free F-

 at neutral pH (Bell et al. 1970). As the pH 

decreases, the proportion of F-

 decreases, while HF2

-

 and undissociated hydrogen fluoride increase. 

Levels of undissociated hydrogen fluoride also increase in concentrated solutions. Fluorine can form 

stable complexes with calcium and magnesium, which are present in sea water. Using the stability 

constants valid for sea water, 51.0% of fluorine will be present as free F-

, 47.0% as MgF+, and 2.0% as 

CaF+

 (Stumm and Morgan 1981). Calcium carbonate precipitation dominates the removal of dissolved 

fluoride from sea water. Fluoride is incorporated into the calcium salt structure and is removed from 

solution when the latter precipitates. The next most important removal mechanism is incorporation into 

calcium phosphates (Carpenter 1969). The residence time of dissolved fluoride in the oceans, as 

calculated from its sedimentation rate, is 2–3 million years (Carpenter 1969). 

In a recent review article, different models of the equilibria of the hexafluorosilicate anion in water 

solution were compared. It was concluded that concentrations of any fluorosilicate species are extremely 

small at drinking water pH (Urbansky 2002). The analysis presented reaffirms the conclusions made 

earlier by Feldman et al. (1957), that in drinking water with a pH of ≥5, fluoridated with sodium 

silicofluoride to a concentration of ≤16 ppm of fluoride ion or less, silicofluoride is completely 

hydrolyzed to silicic acid, fluoride ion, and hydrogen fluoride. While the kinetics of dissociation and 

hydrolysis of the hexafluorosilicate anion are not well understood from a mechanistic or fundamental 

perspective, the rate data suggest that equilibrium should be achieved by the time drinking water reaches 

the consumer (Urbansky 2002). 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 218 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.2.3 Sediment and Soil 

Fluoride occurs in soil as a variety of minerals and complexes with aluminum, iron, and calcium. At low 

pH, aluminum complexes, AlF3, AlF2

+

, and AlF2+, are the dominant dissolved species, and the availability 

of these soluble complexes increases with decreasing pH (Fung et al. 1999; Shacklette et al. 1974). This 

explains why more acidic soils have both higher water-soluble fluoride and higher extractable aluminum 

levels. While aluminum may complex with organic ligands, this does not appear to alter aluminumfluoride complexation significantly (Ares 1990). In certain soils in which calcium is present mostly as 

calcium fluoride and in which there is sufficient alumina, fluoride is fixed by the formation of relatively 

insoluble aluminum fluorosilicate, Al2(SiF6)3 (Brewer 1966). 

6.3.2.4 Other Media 

Several species of plants have the capacity to convert fluoride obtained from soil or water into carbonfluorine compounds such as monofluoroacetic acid, ω-fluoro-oleic acid, ω-fluoropalmitic acid, and 

ω-fluoromyristic acid (Marais 1944; NRC Canada 1971; Ward et al. 1964). These compounds have a 

higher mammalian toxicity than inorganic fluoride salts. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

6.4.1 Air 

The concentration of fluoride in ambient air depends on the presence of industrial sources of fluoride in 

the area, the distance from the sources, meteorological conditions, and topography (Davis 1972). 

Ambient concentrations of hydrogen fluoride measured in the United States (ca. 1985) ranged from 1.0 to 

7.5 μg/m3

 (Kelly et al. 1993). In a study by Thompson et al. (1971) of 9,175 urban air samples in the 

United States in 1966, 1967, and 1968, 87% of all measurements at urban stations and 97% of all 

measurements at non-urban stations showed fluoride concentrations below 0.05 μg/m3

, the threshold of 

detectability. Only 18 measurements (0.2%) exceeded 1.00 μg/m3

; the maximum concentration was 

1.89 μg/m3

 at urban locations and 0.16 μg/m3 at non-urban locations (Yunghans and McMullen 1970). 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 219 

6. POTENTIAL FOR HUMAN EXPOSURE 

The ambient air concentration of gaseous fluoride varies from 0.01 to 1.65 μg/m3 in Canada and the 

United States, approximately 75% of which exists as hydrogen fluoride (CEPA 1996). 

Atmospheric hydrogen fluoride concentrations were measured at nine sites in Southern California during 

the last 8 months of 1986. Samples were collected every 6th day for a 24-hour sampling period. Average 

hydrogen fluoride concentrations ranged between 0.13 μg/m3

 (0.15 ppb) and 0.22 μg/m3 (0.25 ppb) 

(Hance et al. 1997). The lowest concentration was at a remote off-shore location (San Nicolas Island). 

The maximum hydrogen fluoride levels at the eight on-shore sites varied from 0.34 μg/m3

 (0.38 ppb) to 

1.91 μg/m3

 (2.14 ppb). Ambient hydrogen fluoride levels were fairly constant throughout the year. 

However, there were occasional isolated peaks in the hydrogen fluoride levels. These are thought to be 

the result of accidental releases. Although there are major refineries and chemical plants in the area that 

use hydrogen fluoride, it was not possible to correlate the spike in hydrogen fluoride levels with any 

reported accidental releases. 

Atmospheric fluoride levels are often elevated near fluorine-related industrial operations. A 1976 study 

reported fluoride levels 1.5 km from an aluminum plant that emitted 34 kg fluoride/hour (Krook and 

Maylin 1979). The average particulate fluoride level was 0.31 μg/m3

 (5.53 μg/m3, 12-hour maximum), 

and the average gaseous fluoride level was 0.36 μg/m3

 (6.41 μg/m3, 12-hour maximum). An indicator of 

atmospheric fluoride levels is the amount of fluoride dust deposited on foliage. After an aluminum plant 

began operating in 1958 in Oregon, the average fluoride content of foliage in cherry and peach trees 

jumped from 13 to 65 and 76 ppm, respectively. The highest average values occurred 2 years later, 

measuring 196 and 186 ppm, respectively (NAS 1971a). Since then, the fluoride levels in foliage 

dropped appreciably. 

6.4.2 Water 

Surface Water. Fluoride levels in water vary according to local geology and proximity to emission 

sources. In rivers, fluoride concentrations range from <1 to 6,500 μg/L; the average fluoride 

concentration is around 200 μg/L (Fleischer et al. 1974). Fluoride levels may be higher in lakes, 

especially in saline lakes and lakes in closed basins in areas of high evaporation. The Great Salt Lake in 

Utah has a fluoride content of 14,000 μg/L (Fleischer et al. 1974). Lakes in East Africa where fluoride 

leaches from the alkalic rocks in the region contain 1,000–1,600 mg/L of fluoride. Fluoride levels in the 

Norwegian ‘1,000 lake survey’ ranged from <5 to 560 μg/L with one outlier at 4,120 μg/L and a median 

of 37 μg/L (Skjelkvale 1994). The highest levels were found in lakes in Southern Norway that receive the 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 220 

6. POTENTIAL FOR HUMAN EXPOSURE 

greatest amounts of acid rain. Fluoride concentrations at these lakes are correlated with sulfate 

concentrations, an indicator of acid rain. In studies of natural water in the Rift Valley of Kenya and 

Tanzania, high fluoride levels in water and a high incidence of fluorosis were correlated with low levels 

of calcium and magnesium in the water (Gaciri and Davies 1993). Calcium carbonate entraps fluorides 

and removes it from solution. These results are consistent with researchers who maintain that waters low 

in hardness and high in alkalinity present the highest risk of fluorosis. Other reasons for high fluoride 

levels in some Kenyan waters are evaporative concentration resulting in much higher fluoride levels in 

surface water than groundwater, fluoride-rich volcanic rocks in the region, and contamination by waste 

water from fluorspar mining. Seawater contains more fluoride than fresh water, approximately 1,200– 

1,500 μg/L (Bowen 1966; Carpenter 1969; Fleischer et al. 1974; Goldschmidt 1954). 

Fluoride content of waters for Yellowstone National Park ranged from 0.5 mg/L in Yellowstone River to 

24.0 mg/L in the Midway Geyser Basin. Fluoride concentrations in some selected thermal waters in 

Idaho ranged from 9 to 30 mg/L. Data from more than 300 geothermal waters in the Western United 

States indicate that at least 68% of these waters contain fluoride, with concentrations ranging from 2.1 to 

30 mg/L. Fluoride concentrations from a regular well and a geothermal well from a ranch in Idaho were 

0.8 and 14.2 mg/L, respectively. Use of geothermal well water for irrigation induces high fluoride levels 

in alfalfa and pasture grasses consumed by cattle (Miller et al. 1999). 

Groundwater. The fluoride content of groundwater generally ranges from 20 to 1,500 μg/L (EPA 1980a; 

Fleischer 1962). Fleischer et al. (1974) contains a map of the fluoride content in groundwater in the 

conterminous United States by county. Highest fluoride levels in groundwater are generally found in the 

southwest, and maximum groundwater levels in Nevada, southern California, Utah, New Mexico, and 

western Texas exceed 1,500 μg/L. In a survey of fluoride levels in Texas groundwater in which water 

from nearly 7,000 wells in 237 counties were analyzed, Hudak (1999) identified four regions with high 

fluoride levels. In one region in northwest Texas, at least 50% of the wells sampled in each of five 

counties had fluoride levels exceeding the primary drinking water standard of 4,000 μg/L. Countymedian fluoride concentrations ranged from 90 to 5,110 μg/L. Twenty-five counties had median fluoride 

levels above the secondary standard of 2,000 μg/L and 84 counties had median concentrations higher than 

1,000 μg/L, the target fluoride concentration for many water fluoridation programs. Factors responsible 

for the elevated fluoride levels were the mineral constitution of the aquifers, seepage from nearby saline 

formations, and low recharge and dilution rates in the aquifers. The results of this study suggest that 

geology has an important influence on the distribution of fluoride in Texas groundwater. Groundwater 

constitutes approximately 60% of the water consumed in Texas. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 221 

6. POTENTIAL FOR HUMAN EXPOSURE 

Fluoride levels in groundwater are higher than in surface water because they are more influenced by the 

rocks in which they occur (EPA 1980a; Fleischer et al. 1974; NAS 1971a; WHO 1984). Groundwater 

from granitic rock, basaltic rock, limestones and dolomites, and shales and clays average 1,200, 100, 300, 

and 400 μg fluoride/L, respectively, while groundwater from alkalic rocks average 8,700 μg fluoride/L 

(Fleischer et al. 1974). An example of the influence of geology on the concentration of fluorides in 

groundwater is illustrated by a region in the Pampa in Argentina where groundwater is alkaline and 

moderately saline (Nicolli et al. 1989). Forty-two percent of groundwater samples from this area had 

fluoride levels exceeding 1,400 μg/L and the maximum level was 6,300 μg/L. The highest levels of 

fluoride were found in waters with the highest sodium and potassium contents. 

Drinking Water. The concentration of fluoride in 384 Norwegian waterworks sampled during the winter 

of 1983 ranged from 13 to 1,210 μg/L with a mean and median of 87 and 58 μg/L, respectively (Flaten 

1991). Fluoride is a naturally-occurring constituent of groundwater and the fluoride in the water was 

mostly a consequence of local soil or rock formations. In addition, there was evidence that the fluoride 

levels were influenced by local sources and long-range transport. In a random survey of farmstead wells 

by the Kansas Department of Health and Environment, 2 of the 103 wells sampled contained fluoride 

levels above EPA’s maximum contaminant level (MCL) that was reported at the time as 1,800 μg/L for 

public water supplies (Steichen et al. 1988). The highest fluoride level found in this study was 

2,300 μg/L. 

Rain Water. Rain water sampling was conducted in eight arctic catchments in Northern Europe from 

May to September in 1994 (Reimann et al. 1997). Some of the world’s largest industrial sources are in 

this region. The median concentrations of fluoride in all of the 30-day composite rain water samples from 

the eight catchments were <0.05 mg/L. In five of the catchments, all samples contained <0.05 mg/L of 

fluoride. The maximum concentration of fluoride was 1.53 mg/L. Concentrations of fluoride in 

precipitation in Norway ranged from 0 to 253 μg/L with volume-weighted averages from 13 to 25 μg/L 

(Skjelkvale 1994). Correlations of fluoride content with other ions indicated that the fluoride is not of 

marine origin and is mostly correlated with industrial sources of sulfur oxides. Higher fluoride levels in 

some rain samples were due to nearby aluminum smelters. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 222 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.3 Sediment and Soil 

Fluorides are widely distributed in the earth's crust. The concentration of fluoride in soils and other 

surficial materials in the conterminous United States ranges from <10 to 3,700 ppm with a mean of 

430 ppm (Shacklette and Boerngen 1984). Other values for the mean fluoride content of mineral soils 

ranges from 200 to 300 ppm (Bowen 1966; NAS 1971a; Worl et al. 1973). The fluoride content of 

organic soils is usually lower. The chief fluorine-containing minerals are fluorspar, cryolite, and 

fluorapatite. In soils with high concentrations of these minerals, the soil fluoride content is much higher 

and may range from 7 to 38 g/kg (Smith and Hodge 1979). In most soils, fluorine is associated with 

micas and other clay minerals. Robinson and Edgington (1946) reported the fluorine content of 137 soil 

samples in 30 soil profiles as ranging from trace to 7.07% fluorine, with an average of 0.029%. While the 

highest fluoride concentration was found in a Tennessee soil high in rock phosphate (apatite), the main 

source of fluoride in the soil were micaceous clays. In general, silt and clay loam soils had higher 

fluoride content than sandy soils. Average fluoride soil concentrations differ between the eastern and 

western United States. The average concentrations are 340 ppm in the east and 410 ppm in the west 

(EPA 1980a). Fluoride concentrations also tend to increase with soil depth. Of 30 domestic soil samples, 

the mean fluoride concentration at a depth of 0–3 inches was 190 ppm, whereas the mean concentration at 

a depth of 3–12 inches averaged 292 ppm (NAS 1971a). 

The fluoride content of soil may be increased by the addition of fluoride-containing phosphate fertilizers 

(WHO 1984). Soils near industrialized sources show elevated concentrations that decrease with distance 

from the source and depth below the surface. Concentrations of fluoride in the top 0.5 inches of soil 

located near a phosphorus extraction facility near Silver Bow, Montana, were reported to range from 

265 to 1,840 ppm (Van Hook 1974). Humus near an elementary phosphorus plant in Newfoundland, 

Canada, where 80–95% of balsam fir trees were dead because of the pollution, contained average fluoride 

levels of 58 ppm dry weight in 1973 and 24.2 ppm in 1974 (Sauriol and Gautier 1984). In 1975, when the 

plant was not in operation during the growing season, the humus fluoride content was 8.1 ppm. Humus 

fluoride levels in an uncontaminated zone were 2.0 ppm. 

The fluoride concentrations in recent oceanic sediments appear to vary between 450 and 1,100 ppm 

(Carpenter 1969). Similar levels have been reported for fresh water lakes. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 223 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.4 Other Environmental Media 

Several factors influence the level of fluorides in food. These include the locality in which the food is 

grown and whether there were sources of fluoride emissions in the area, the amount of fertilizer and 

pesticides applied, the type of processing the food receives, and whether fluoridated water is used in food 

preparation (McClure 1949; Myers 1978; Waldbott 1963b). Foods characteristically high in fluoride 

content are certain types of fish and seafood (1.9–28.5 mg/kg), especially those types in which the bones 

are consumed, bone products such as bone meal and gelatin, and tea, which contains approximately 

0.52 mg fluoride/cup (Cook 1969; Kumpulainen and Koivistoinen 1977). 

During a comprehensive total diet study, foods were collected in Winnipeg, Canada in 1987 and were 

processed into 148 composite food samples (Dabeka and McKenzie 1995). The mean, median, and range 

of fluoride in all samples were 325, 99, and <11–4,970 ng/g, respectively. Food categories with the 

highest mean fluoride levels were fish (2,118 ng/g), beverages (1,148 ng/g), and soups (606 ng/g). 

Individual samples with the highest fluoride levels were tea (4,970 ng/g), canned fish (4,570 ng/g), 

shellfish (3,360 ng/g), cooked veal (1,230 ng/g), and cooked wheat cereal (1,020 ng/g). The drinking 

water used to prepare the food came from a single source containing the optimal fluoride concentration of 

1 mg/L. This fluoride would contribute substantially to the fluoride levels in the food. The fluoride level 

in 68 samples of cows’ milk purchased in retail stores throughout Canada ranged from 7 to 86 ng/g, with 

a mean and median concentration of 41 and 40 ng/g, respectively (Dabeka and McKenzie 1987). 

Provincial mean levels varied from 25 to 74 ng/g. Other studies of fluoride levels in cows from 

uncontaminated areas reported similar fluoride levels in milk (Dabeka and McKenzie 1987). A study 

compared fluoride content in foods and beverages from a negligibly fluoridated community 

(Connersville, Indiana) and an optimally fluoridated community (Richmond, Indiana). The fluoride 

concentrations in Connersville and Richmond are 0.16±0.01 and 0.90±0.05 μg F/g. It was found that 

fluoride content in non-cooked and non-reconstituted foods and beverages ranged from 0.12 to 

0.55 μg F/g and that there was no significant difference between the two communities. The difference in 

fluoride content of foods prepared and/or cooked with water from the two study sites were statistically 

different, except in the case of cooked vegetables (Jackson et al. 2002). 

Beverages may contain fluoride from the fluoride content of the water used in their production, as well as 

the base ingredients (e.g., fruit, flavoring) in the product. In a North Carolina study, beverages purchased 

from six regions of the state showed considerable differences in the fluoride content of the product. This 

was especially true for carbonated beverages. The ranges (means) of fluoride concentrations in various 

beverage types were: sodas, 0.07–1.37 ppm (0.28 ppm); juices, 0.01–1.70 ppm (0.36 ppm); punches, 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 224 

6. POTENTIAL FOR HUMAN EXPOSURE 

0.00–1.44 ppm (0.33 ppm); tea, 0.61–6.68 ppm (2.56 ppm); and Gatorade, 0.02–1.04 ppm (0.85 ppm) 

(Pang et al. 1992). Fluoride concentrations were measured in 332 carbonated soft drinks, manufactured 

by 10 companies, which are available in Iowa grocery stores. Fluoride concentrations were found to 

range from 0.02 to 1.28 ppm, with a mean of 0.72 ppm. For 71% of the drinks analyzed, fluoride 

concentrations exceeded 0.60 ppm. Concentrations were found to vary substantially by production site, 

even within the same company and for the same product (Heilman et al. 1999). 

The fluoride content of most plant foliage growing in areas removed from sources of fluoride pollution 

ranges from 2 to 20 ppm dry weight (Brewer 1966). A notable exception is tea plants. The highest 

fluoride concentration reported in vegetation was over 8,000 ppm in tea leaves. Tea plants take up 

fluoride from soil and accumulate it in the leaves. A large percentage of the total fluoride, 25–84%, is 

released during infusion, and tea is considered to be a major source of fluoride. The older tea leaves 

contain more fluoride and brick tea, which is prepared from older leaves, may be very high in fluoride 

content, 4.73–7.34 mg/L, compared with quality green and black tea, which is prepared from younger 

leaves and may contain 1.2–1.7 and 0.9–1.9 mg/L, respectively (Fung et al. 1999). 

Fruits and vegetables grown in industrial areas where fluoride emissions are high contain elevated 

fluoride levels compared with those grown in control areas. The highest levels are found in the leafy 

parts of the plants rather than the roots. In a Polish study, vegetables grown 1.5 and 5 km from a steel 

plant contained average fluoride levels of 0.54–8.82 and 0.39–4.95 mg/kg, respectively, compared with 

0.02–0.41 mg/kg for controls (Krelowska-Kulas 1994). Fruits grown 1.5 and 5 km from the steel plant 

contained average fluoride levels of 1.42–5.44 and 1.24–2.75 mg/kg, respectively, compared with 0.40– 

1.05 mg/kg for controls. Vegetables from the Saint-Régis Mohawk Indian reservation contained an 

average of 1.54–45.17 ppm fluoride dry weight compared with 0.63–11.3 ppm fluoride for vegetables 

from an uncontaminated site (Sauriol and Gauthier 1984). The reservation is located along the 

St. Lawrence River, straddling territory in New York State, Québec, and Ontario, where there are three 

potential sources of industrial fluoride emissions, namely two aluminum plants and a phosphate fertilizer 

plant. 

Fluoride concentrations in vegetation form Yellowstone National Park varies over a wide range from 3 to 

430 ppm. Studies where plants were watered by spray treatments containing 4 ppm fluoride showed that 

plants accumulated up to 36 ppm fluoride (dry weight), but a significant amount of this could be removed 

by washing the leaves in distilled water. In another experiment using 6 ppm fluoride solution, leaf 

analysis contained up to 55 ppm fluoride in the unwashed leaves and 35 ppm in washed leaves. Fluoride 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 225 

6. POTENTIAL FOR HUMAN EXPOSURE 

content in vegetation around a phosphate plant was found to range from 4 to 718 ppm. Fluoride was 

present in the air in the form of particulate fluorides and hydrogen fluoride gas (Miller et al. 1999). 

Fluoride levels in various marine crustaceans were found to range from not detected to 2,500 (wholebody), not detected to 5,977 (exoskeleton), and not detected to 257 (muscle) μg/g, dry weight. Fluoride 

levels in saltwater fish were found to range from 45 to 1,207 (skeletal bone) and from 1.3 to 26 (muscle) 

mg/kg, wet weight (Camargo 2003). 

The fluoride concentration in most dental products available in the United States ranges from 230 ppm 

(0.05% NaF mouth rinse) to 12,300 ppm (1.23% acidulated phosphate fluoride gel) (NRC 1993). The 

most commonly used dental products, toothpastes, contain 900–1,100 ppm fluoride (ca. 0.10%), most 

often as sodium fluoride, but also as disodium monofluorophosphate. 

The fluoride concentration of a bituminous coal used in power generation is around 65.0 ppm dry weight 

and may contain up to 200 mg fluoride/kg (Rubin 1999; Skjelkvale 1994). The fluoride in the coal occurs 

predominantly as fluorapatite and fluorspar. Hydrogen fluoride and other fluorides are released from the 

coal during combustion. Bauer and Andren (1985) studied fluoride emissions from an electricitygenerating plant in Portage, Wisconsin that consisted of two nearly-identical 527-MW pulverized-coal 

units, differing only in the type of coal burned and the operating conditions. In one unit, emissions 

contained a median of 1.9 mg fluoride/scm (86% of available fluoride in coal) and the other contained a 

median of 0.22 mg fluoride/scm (4.2% of available fluoride in coal). The first unit burned a bituminous 

coal from Colstrip, Montana containing 9% ash and 46 ppm fluoride and the second unit burned a 

bituminous coal from Gillette, Wyoming containing 5% ash and 45 ppm fluoride. It was thought that the 

greater mineral matter in the coal feeding the first unit may have played a role in the greater release of 

fluoride in the vapor phase from this unit. The concentration of hydrogen fluoride reported in emissions 

from a modern municipal waste incinerator in Germany was 0.2–0.3 mg/m3

 (Greim 1990). Fluoride 

concentrations in waste water from a coal-fired power plant in Utah ranged from 2.4 to 3.8 ppm (Miller et 

al. 1999). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

The major sources of fluoride intake by the general population are water, beverages, food, and fluoridecontaining dental products. Since levels in ambient air are, in most cases, below detectable limits, the 

levels inhaled are generally very low except for in areas immediately surrounding industries that emit 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 226 

6. POTENTIAL FOR HUMAN EXPOSURE 

fluorides into the air. Hodge and Smith (1977) estimated air intake of fluoride of about 0.01 mg/day. In 

occupational settings where airborne concentrations are frequently at the exposure limit of 2.5 mg/m3 

(OSHA 1985), fluoride intake via inhalation can be 16.8 mg/day, assuming an 8-hour shift and that a 

person inhales 20 m3

 air/day. The daily intake of fluoride from drinking water fluoridated at the optimal 

levels (0.7–1.2 mg/L) would be 1.4–2.4 mg. 

The chemicals most commonly used by American waterworks are fluorosilicic acid, sodium 

silicofluoride, and sodium fluoride. Data from the CDC's 1992 Fluoridation Census indicate that 25% of 

utilities reported using sodium fluoride; however, this corresponds to 9.2% of the U.S. population 

drinking fluoride-supplemented tap water (Urbansky 2002). Concerns over the purity of water 

fluoridation agents have been raised as well as possible links between fluoridation agents and lead levels 

in the bloodstream (Masters et al. 2000). Analyses of available grades of fluorosilicic acid, sodium 

fluoride, and sodium fluorosilicate show the presence of arsenic and lead, but at levels far below that 

which would necessitate recommended maximum impurity content (RMIC) values based on the 

maximum dosage of 1.2 mg of fluoride ion per liter (NRC 1982). 

Based on a comprehensive total diet study conducted in Winnipeg, Canada in 1987, the estimated daily 

dietary intake of fluoride by the average Canadian was 1,763 μg and varied from 353 μg for the 1–4-yearold-age group to 3,032 μg for 40–64-year-old males (Dabeka and McKenzie 1995). The results for all 

age groups are shown in Table 6-3. The drinking water used to prepare the food came from a single 

source containing the optimal fluoride concentration of 1 μg/mL (1 mg/L). This fluoride would 

contribute substantially to the fluoride intake in the food. In an earlier study in which the dietary intake of 

24 adult Canadians was assessed, Dabeka et al. (1987) compared the intake of half of the participants who 

lived in communities with 1 μg/g (1 mg/L) fluoride in their drinking water with those who lived in 

communities with <0.2 μg/g (<0.2 mg/L) of fluoride in water. The respective median intakes of fluoride 

were 2,090 or 30.3 μg/kg/day and 414 or 7.0 μg/kg/day. For the cities with fluoridated water, the 

majority of fluoride was contributed by beverages (68%) and water (13%); for the nonfluoridated cites, 

beverages contributed 58% of the fluoride intake. These results can be compared with earlier estimates of 

fluoride intake by U.S. adults. San Filippo and Battistone (1971) estimated the average daily adult 

fluoride intake from food ranged from 0.8 to 0.9 mg, while the daily intake from food and water was 2.1– 

2.4 mg. Spencer et al. (1970) estimated the fluoride intakes as 1.2–2.7 mg/day from food and 2.82– 

5.9 mg/day from food and water. Kumpulainen and Koivistoinen (1977) reported the average total 

dietary intake in 12 fluoridated U.S. cities as 2.7 mg/day. In areas where fluoride is not added to water, 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 227 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Mean Daily Dietary Intake of Fluoride for Selected Canadian 

Population Groupsa
 

Population Mean daily intake (μg/day) 

1–4 years, males and females 353 

5–11 years, males and females 530 

12–19 years, males and females 1,025 

12–19 years, females 905 

20–39 years, males 2,544 

20–39 years, females 2,172 

40–65 years, males 3,032 

40–65 years, females 2,615 

65+ years, males 2,588 

65+ years, females 2,405 

All ages male and female 1,763 

a

Dabeka and McKenzie 1995 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 228 

6. POTENTIAL FOR HUMAN EXPOSURE 

the total intake from food and water does not usually exceed 1.0 mg/day (WHO 1984). However, there 

are exceptions, such as an area in China where the fluoride content of the water is low, but the intake from 

food and tea is high enough that the rate of dental fluorosis exceeds 80% (Han et al. 1995). In England, 

where much more tea is consumed, a study found daily average intakes of fluoride from tea to be 

1.26 mg/day in children and 2.55 mg/day in adults (Cook 1969). In areas near sources of fluoride 

emissions, oral intake may also be increased from dust contamination of food (WHO 1984). Fluoridated 

dentifrices and mouth rinses are additional sources of fluoride (Barnhart et al. 1974; Ericsson and 

Forsman 1969). Fluorides approved by the FDA for use in dentifrices are sodium fluoride (0.22%), 

sodium monofluorophosphate (0.76%), and stannous fluoride (0.41%) (Pader 1993). The concentration 

of fluoride in each of these formulations is 0.1% (equivalent to 1,000 mg/kg or 1,000 ppm). Fluoride 

tablets or drops are ingested in some areas where water fluoride levels are low, providing 0.25, 0.50, or 

1.00 mg/day depending on the age of the child and the drinking water fluoride concentration. In his 

analysis of systemic fluoride intake, Burt (1992) found that there is no evidence from dietary surveys to 

show that fluoride intake in adults has increased since the 1970s. 

In considering dietary intake, it is important to take bioavailability into account, and not simply the 

fluoride content of the consumed substance. As discussed in Sections 2.3.1.2 and 2.8, absorption is 

affected by factors such as whether the material was eaten with a meal, the chemical and physical form of 

the fluoride, and the current health status of the individual (Rao 1984). The bioavailability of fluoride as 

sodium fluoride is high. In contrast, absorption of calcium fluoride is rather inefficient, but is enhanced 

when administered with food. Thus, the actual absorbed dose could be smaller than the intake levels 

reported above. NRC (1993) reports that approximately 75–90% of ingested fluoride is absorbed from 

the alimentary tract. 

The fluoride content of urine and plasma are useful as short-term indicators of fluoride exposure; hair, 

fingernails, and tooth enamel are indicators of longer-term response. The mean and median serum 

fluoride levels of 168 representative Danish adults were 470±270 and 400 nmol/L (0.00893±0.00513 and 

0.00760 mg/L), respectively (Poulsen et al. 1994). Levels were significantly higher in urban inhabitants 

than rural inhabitants and increased significantly with age. Shida et al. (1986) measured fluoride 

concentrations in five different layers of enamel of incisors that had been extracted due to periodontal 

disease. Half of the teeth were treated with 0.9% acidified fluorophosphate for 4 minutes. In the 

fluoride-treated group, the outer layer of enamel contained 1,660–5,910 ppm fluoride compared with 

147–698 ppm in the untreated group. A similar method was employed by Schamschula et al. (1982) on 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 229 

6. POTENTIAL FOR HUMAN EXPOSURE 

enamel of children. They found that the fluoride content of enamel did reflect environmental fluoride 

exposure of the group, but variations occurred among individuals. 

The NIOSH National Occupational Exposure Survey (NOES) conducted in 1981–1983 estimated that 

about 182,589 workers were potentially exposed to hydrogen fluoride (NIOSH 1989). The NOES was 

based on field surveys of 4,490 facilities that included virtually all workplace environments, except 

mining and agriculture, where eight or more persons are employed. The principal exposure pathway 

would be inhalation. 

Workers in the electronics industry in Japan who used hydrogen fluoride for glass etching (e.g., TV 

picture tubes) and as a silicon cleaner (e.g., semiconductors) are exposed daily to mean air hydrogen 

fluoride concentrations of up to 5 ppm (Kono et al. 1987). The mean urinary fluoride levels were linearly 

related to the hydrogen fluoride concentration in the air and there were also significant differences in preand postshift urinary fluoride level of the workers. The workers in this study were only exposed to 

gaseous hydrogen fluoride. The wide variation of fluoride levels in serum and urine in the workers and 

controls has been ascribed to dietary differences, particularly the consumption of tea and seafood (water 

fluoridation is not practiced in Japan). In a follow-up study Kono et al. (1993) found a linear correlation 

between urine fluoride levels and hair fluoride levels. 

A study evaluated the use of urinary fluoride as an exposure index for a prospective study of asthma in an 

aluminum smelter. In the first part of the study, 32 subjects wore personal air sampling pumps. The 

12-hour time weighted average results show that overall mean levels were 15.7, 4.07, and 0.74 mg/m3

 for 

particulate mass, total fluoride, and hydrogen fluoride, respectively. Urinary fluoride concentrations were 

considered reasonably low, 1.3 and 3.0 mg/g creatinine in pre- and post-shift collections. Carbon 

smelters had the highest exposure levels as compared to workers working as potmen and trappers (Seixas 

et al. 2000). An average total fluoride exposure of 0.91 mg/m3

, of which 34% was gaseous fluoride, was 

measured for 41 workers in an aluminum plant in Sweden. Mean fluoride plasma concentrations were 

determined to be 23 and 48 ng/mL pre- and post-shift, respectively. Use of a safety mask during the shift 

led to a reduction in exposure of inhaled fluoride. Workers wearing a safety-mask throughout the whole 

shift reduced inhalation of fluoride to 30–40% of those workers not wearing masks (Ehrnebo and 

Ekstrand 1986). 

Certain populations, such as patients with kidney disease, may be especially sensitive to fluoride 

exposure. In 1993, 20 patients became ill due to acute fluoride intoxication after receiving hemodialysis 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 230 

6. POTENTIAL FOR HUMAN EXPOSURE 

treatment for end-stage renal failure. This outbreak was found to be caused by errors in the maintenance 

of the deionization system used to treat the water used for dialysis. In this case, the deionization units 

continued to be used after the ion exchange resins were exhausted, resulting in the release of the resinbound fluoride into the treated water (Arnow et al. 1994). 

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 exposed to fluorides primarily through their diets and dental products. Normal dietary 

sources of fluorides are augmented by fluoridation of water supplies. Based on data obtained from a 1987 

total diet study in Winnipeg, Canada, the average 1–4 and 5–11 year olds consume 353 and 530 μg 

fluoride/day, respectively, compared with 1,763 μg/day for all age groups combined (Dabeka and 

McKenzie 1995). The mean daily dietary intakes of fluoride by 6-month-old infants and 2-year-old 

children in four regions of the United States were 0.21–0.54 and 0.32–0.61 mg/day, respectively (NRC 

1993; Ophaug et al. 1985). The mean intake of 2-year-old children, but not 6-month-old infants, was 

directly related to the fluoride concentration in the drinking water. Dietary intake may increase in areas 

where there are industrial emissions containing fluorides. Increased incidences of mottled teeth were 

observed in children living within 3 km of a superphosphate fertilizer plant in Port Maitland, Ontario 

(Sauriol and Gauthier 1984). The most plausible reason for the increased fluoride intake is higher 

fluoride levels in vegetables and fruits from dust deposited on the plants. 

It has been assumed that children in communities without fluoridated water consume a negligible amount 

of fluoride other than from food. Because of the marked increase in dental fluorosis in nonfluoridated 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 231 

6. POTENTIAL FOR HUMAN EXPOSURE 

populations and the increased consumption of beverages that may have been prepared with fluoridated 

water, a study was conducted to estimate the average daily amount of fluoride ingested by a sample of 

North Carolinian children aged 2–10 from these beverages (Pang et al. 1992). The study found that 

children of ages 2–3, 4–6, and 7–10 consumed daily means of 0.36, 0.54, and 0.6 mg fluoride, 

respectively, from beverages. This is a significant source of fluoride intake. Beverages contributed about 

60% of the children’s total liquid consumption. While fluoride consumption increased with age, little 

difference was found between males and females. Children in a high fluoride area of Kenya consume 

high levels of fluoride from the water (9 ppm) and from the practice of giving tea to young children. In 

this area, children aged 0–1 and 1–4 years old had mean daily fluoride intakes of 0.62 and 1.23 mg/kg 

body weight, respectively. Tea accounted for nearly half of the fluoride intake of 1–2-year-old children. 

The daily fluoride consumption from breast milk supplements and substitutes averaged 7.6 mg, 

>250 times the amount of fluoride provided by 800 mL of breast milk (Opinya et al. 1991a). 

Fluoride intake in infants depends on whether the child is nursed or not. Human breast milk contains very 

little fluoride (about 0.5 μmol/L or 0.01 mg/L) and provides <0.01 mg fluoride/day (NRC 1993). 

Fluoride intake by an infant who is exclusively breast fed and consuming 170 mL/kg-day is generally 

<2 μg/kg-day (Fomon and Ekstrand 1999). Levy et al. (2001) found that for most children, water fluoride 

intake was the predominant source of fluoride, especially through age 12 months. This was due in large 

part to children receiving fluoridated water mixed with infant formula concentrate (Levy et al. 1995b, 

2001). 

The results of a survey of fluoride levels in 68 samples of cows’ milk and 115 samples of infant formulas 

and oral electrolytes are shown in Table 6-4. Mean fluoride levels in cows’ milk, evaporated milk, and 

ready-to-use formula were 0.041, 0.23, and 0.79 μg/g, respectively. Mean levels in concentrated liquid 

and powder formula were 0.60 and 1.13 μg/g, respectively (Dabeka and McKenzie 1987). A major 

source of fluoride in the infant formulas appears to be the processing water used in its manufacture. In 

the United States where manufacturers remove fluoride from the processing water, mean levels of 

fluoride were much lower than in the Canadian products. All U.S. products were well within the upper 

guideline of 0.40 μg/g for ready-to-use formula proposed by the Committee on Nutrition of the American 

Academy of Pediatrics. Fluoride exposure was calculated to be 102, 105, and 167 μg/kg-day for infants 

consuming 170 mL/kg-day of concentrated liquid milk-based formula, concentrated liquid isolated soy 

protein-based formula, and powdered milk-based formula, respectively, which were diluted with water 

that is 1 ppm in fluoride. Infants may be exposed to higher fluoride concentrations now than in the past. 
 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 232 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Comparison of Fluoride Levels (μg/g) in Cow Milk and Infant 

Formulasa

 Number Mean Median Rangea 

Cow milk 64 0.041 0.040 0.007–0.086 

Evaporated milk 9 0.23 0.12 0.06–0.55 

Ready-to-use formula, all 

 Canadian 34 0.90 0.86 0.35–2.31 

U.S. 7 0.23 0.26 0.15–0.28 

Ready-to-use formula, glassb

 Canadian 20 0.82 0.83 0.46–1.13 

U.S. 3 0.28 0.28 0.28–0.28 

Ready-to-use formula, canned 

 Canadian 14 1.02 0.95 0.35–2.31 

U.S. 4 0.19 0.17 0.15–0.26 

Concentrated liquid formula, canned 33 0.60 0.60 0.15–1.47 

Formula, powdered concentrate 18 1.13 0.80 0.14–5.53 

Electrolytes (water), glassb

 12 0.066 0.04 0.01–0.15 

a

Dabeka and McKenzie 1995 

b

Product not available on retail market, obtained from hospitals. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 233 

6. POTENTIAL FOR HUMAN EXPOSURE 

In the 1960s, nearly 80% of infants were fed cow's milk by 6 months of age. In 1991, 80% of 6-monthold infants were fed formula (Fomon and Ekstrand 1999). Fluorinated organic chemicals are widely used 

and may accumulate in breast milk due to their high fat solubility and slow rate of metabolism and 

excretion. The breast milk fluoride concentration from a German study was 25 ppb (Broomhall and 

Kovar 1986). Fluoride may be an important mineral for babies born prematurely, since prematurity is 

associated with an increased incidence of dental caries; however, recommendations for fluoride intake are 

only available for full-term infants (Zlotkin et al. 1995). 

Fluoridated dentifrices and mouth rinses are additional sources of fluoride, particularly in small children 

who do not have complete control of the swallowing reflex. Dentifrice ingestion was inversely correlated 

with age; average ingested levels per brushing for children aged 2–4, 5–7, and 11–13 were 0.30, 0.13, and 

0.07 g (Barnhart et al. 1974). Average fluoride intake from these sources in children younger than 7 years 

old ranged from 0.3 to 0.4 mg/use for mouth rinses, depending on the child's age, and was about 

0.1 mg/brushing for fluoridated toothpaste use (Ericsson and Forsman 1969). Other studies indicated that 

an average of 25% (range, 10–100%) of the toothpaste introduced into the mouth was swallowed. The 

average amount of fluoride in toothpaste used in one brushing is about 1.0 mg. From these studies, it has 

been estimated that the amount of fluoride ingested in toothpaste by children who live in communities 

with fluoridated water, who have good control of swallowing, and brush their teeth twice a day is 

approximately equal to dietary fluoride intakes. For younger children who have poor control of 

swallowing, intakes from dental products could exceed dietary intakes. 

Although Burt (1992) concludes that data on fluoride intake by children from food and beverages, infant 

foods included, are not strong enough to conclude that an increase in fluoride ingestion has occurred since 

the 1970s, he warns that the suggested upper limit of fluoride intake is substantially being reached by 

many children by ingestion of fluoride from food and drink (0.2–0.3 mg/day) and from fluoride 

toothpaste (0.2–0.3 mg/day). Levy (1994) also found substantial variation in ingestion among 

individuals; 10–20% of individuals received up to several times as much exposure as the mean. Some 

children appeared to ingest enough fluoride from one source to exceed the total recommended fluoride 

intake, and are therefore at increased risk of dental fluorosis. Levy et al. (1995a) made the following 

recommendations concerning use of fluoride by children: 

“(1) the fluoride content of foods and beverages, particularly infant formulas and water used in their 

reconstitution, should continue to be monitored closely in an effort to limit excessive fluoride intake; 

(2) ingestion of fluoride from dentifrice by young children should be controlled, and the use of only small 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 234 

6. POTENTIAL FOR HUMAN EXPOSURE 

quantities of dentifrice by young children should be emphasized; and (3) dietary fluoride supplements 

should be considered a targeted preventive regimen only for those children at higher risk for dental caries 

and with low levels of ingested fluoride from other sources (Levy et al. 1995a).” 

Schamschula et al. (1985) analyzed various body fluids and tissue from a group of Hungarian children 

exposed to low, intermediate, and high levels of fluoride in their drinking water. These tissue levels, 

included in Table 6-5, are indicators of exposure over the short and long term. Fluoride dentifrices were 

not in general use in the villages from which the sample populations were drawn. Mean fluoride 

concentrations of 1.85, 5.28, and 7.52 mg/kg were found in fingernails of Brazilian children, 6–7 years 

old, living in communities where fluoride concentrations were 0.1, 1.6, and 2.3 ppm, respectively. 

Analysis of these data indicated a direct relationship between fluoride concentrations in drinking water 

and fingernails. The 95% confidence intervals for the 0.1 and 1.6–2.3 ppm areas showed no overlap; a 

small overlap was noted for the 1.6 and 2.3 ppm areas (Whitford et al. 1999a). 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Populations living in areas with high fluoride levels in groundwater may be exposed to higher levels of 

fluorides in their drinking water or in beverages prepared with the water. Among these populations, 

outdoor laborers, people living in hot climates, and people with polydipsia will generally have the greatest 

daily intake of fluorides because they consume greater amounts of water. Groundwater fluoride levels are 

especially high in the southwest; maximum groundwater levels in Nevada, southern California, Utah, 

New Mexico, and western Texas exceed 1,500 μg/L. In one region of northwest Texas, the median level 

in well water exceeded 4,000 μg/L. People who drink large amounts of tea or consume large quantities of 

seafood may also have high intakes of fluoride. 

Populations living downwind of facilities emitting high levels of fluorides (e.g., phosphate fertilizer 

plants, aluminum plants, or coal-fired power plants) may be exposed to higher fluoride levels in the air 

(Ernst et al. 1986). Emissions from these plants may contaminate vegetables and fruit with fluorides from 

industrial emissions, exposing people eating local produce to potentially high levels of fluorides in their 

diets. Workers in industries where fluoride-containing substances are used, most notably the aluminum 

and phosphate fertilizer plants, may be occupationally exposed to high levels of both gaseous and 

particulate fluorides. Workers using sulfur hexafluoride as a tracer gas for determining ventilation rates 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 235 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Levels of Fluoride in Human Tissue and Urine—Selected Studies 

Site Population Sample Concentration Type Units Reference 

Human plasma from blood banks in five U.S. cites with different fluoride levels in Guy et al. 1976 

drinking water 

Albany, NY (n=30) Blood plasma 0.38 (0.14-1.1) Mean μmol/L 

<0.1 ppm fluoride (Range) 

Rochester, NY (n=30) 0.89 (0.35-4.2) 

1 ppm fluoride 

Corpus Christi, TX (n=12) 1.0 (0.60-1.7) 

0.9 ppm fluoride 

Hillsboro, TX (n=4) 2.1 ppm 1.9 (0.60-2.6) 

fluoride 

Andrews, TX (n=30) 4.3 (1.4-8.7) 

5.6 ppm fluoride 

Poland (1980) Miszke et al. 1984 

Employee of electrolysis Urine, random 1.87 mg/dm3 

shop of aluminum plant 

HF workers in the electronics industry, Japan Kono et al. 1987 

Unexposed controls (n=82) Urine, random 0.58 (0.23) Geometric ppm 

mean 

(GSD) 

All workers (n=142) 2.34 (1.40)
 

Hydrogen fluoride exposure 

level 

0.3 ppm (n=16) 0.91 (0.26) 

0.5 ppm (n=20) 1.04 (0.34) 

0.6 ppm (n=12) 1.07 (0.41) 

1.2 ppm (n=14) 2.02 (0.57) 

1.6 ppm (n=17) 2.40 (0.68) 

2.8 ppm (n=21) 3.94 (1.07) 

4.2 ppm (n=32) 5.05 (1.30) 

5.0 ppm (n=10) 6.50 (1.98) 

HF workers in the electronics industry, Japan Kono et al. 1993 

All hydrogen fluoride Hair 61.1 (101.6) Geometric μg/g 

workers (n=142) mean 

(GSD) 

 Controls (n=237) 13.4 (6.4) 

HF workers, Japan Kono et al. 1984 

 Hydrogen fluoride workers Serum 40.10 (23.72) Mean (SD) μg/L 

(n=120) 

 Controls (n=320) 24.50 (12.10) 

 Hydrogen fluoride workers Urine, 24 hour 0.98 (0.75) Mean (SD) mg/L 

(n=120) 

 Controls (n=320) 0.54 (0.30)
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 236 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Levels of Fluoride in Human Tissue and Urine—Selected Studies 

Site Population Sample Concentration Type Units Reference 

Danish adults Poulsen et al. 1994 

 Representative population Serum 470 (270) Mean (SD) nmol/L 

(n=168) 

Brazilian children (6-7 years old) exposed to different water fluoride concentrations Whitford et al. 1999a 

Fluoride concentration in 

drinking water: 

0.1 ppm (n=19) fingernail 1.85 (0.75-3.53) Mean 

(range) 

mg/kg 

1.6 ppm (n=12) 5.28 (2.28-7.53) 

2.3 ppm (n=15) 7.52 (4.00-13.18) 

Hungarian children exposed to three levels of fluoride in drinking water Schamschula et al. 

1985 

 Low exposurea

 (n=45) Urine 0.15 (0.07) Mean (SD) ppm 

 Medium exposureb

 (n=53) 0.62 (0.26)

 High exposurec

 (n=41) 1.24 (0.52)

 Low exposurea

 (n=45) Nails 0.79 (0.26) Mean (SD) ppm 

 Medium exposureb

 (n=53) 1.31 (0.49)

 High exposurec

 (n=41) 2.31 (1.14)

 Low exposurea

 (n=45) Hair 0.18 (0.07) Mean (SD) ppm 

 Medium exposureb

 (n=53) 0.23 (0.11)

 High exposurec

 (n=41) 0.40 (0.25)

 Low exposurea

 (n=45) Saliva 6.25 (2.44) Mean (SD) ppb 

 Medium exposureb

 (n=53) 11.23 (4.29) 

 High exposurec

 (n=41) 15.87 (6.01) 

 Low exposurea

 (n=45) Enamel (0.44– 1,549 (728) Mean (SD) ppm 

0.48 μm 

depth) 

 Medium exposureb

 (n=53) 2,511 (1,044) 

 High exposurec

 (n=41) 3,792 (1,362) 

 Low exposurea

 (n=45) Enamel (2.44– 641 (336) Mean (SD) ppm 

2.55 μm 

depth) 

 Medium exposureb

 (n=53) 1,435 (502) 

 High exposurec

 (n=41) 2,107 (741) 

a

Low exposure: concentration of fluoride in water 0.06–0.11 ppm, 0.09 ppm, mean. b

Medium exposure: concentration of fluoride in water 0.5–1.1 ppm, 0.82 ppm, mean. c

High exposure: concentration of fluoride in water 1.6–3.1 ppm, 1.91 ppm, mean. 

GSD = geometric standard deviation; SD = standard deviation 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 237 

6. POTENTIAL FOR HUMAN EXPOSURE 

and air flow in buildings may be exposed to hydrogen fluoride when unvented combustion sources are 

present in the building because SF6 reacts with water vapor at high temperatures, forming hydrogen 

fluoride (Guo et al. 2001). 

Populations living in the vicinity of hazardous waste sites may be exposed to fluorides through contact 

with contaminated air, water, and soil. Food grown near the source may also be contaminated. Data on 

the concentrations of fluorides in waste site media are quite limited, and no information was located 

regarding daily intake of fluorides from these sources. 

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 fluorine, hydrogen fluoride, and fluorides 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 fluorine, 

hydrogen fluoride, and fluorides. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical/chemical properties of fluorine, hydrogen 

fluoride, and sodium fluoride are sufficiently well characterized to enable assessment of the 

environmental fate of these compounds. 

Production, Import/Export, Use, Release, and Disposal. Information on the production and 

importation of fluorspar and hydrogen fluoride are available (CMR 2002; USGS 2001). Information on 

exports is only available for fluorspar. No data are available on the production, import, or export of 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 238 

6. POTENTIAL FOR HUMAN EXPOSURE 

fluorine, sodium fluoride, and other fluorides. Information is readily available on the uses of fluorine, 

hydrogen fluoride, and other fluorides (Mueller 1994). Because of its high reactivity, fluorine is disposed 

of by conversion to fluoride salts in a scrubber (Shia 1994). The TRI contains information on the 

amounts of hydrogen fluoride transferred off-site, presumably for disposal, and the amount recycled. No 

information was found regarding the disposal of sodium fluoride. Additional quantitative information on 

production, import, and export of fluorides, as well as common disposal practices, would be useful in 

assessing the release of, and potential exposure to, these compounds. 

According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. 

Section 11023, industries are required to submit chemical release and off-site transfer information to 

EPA. The TRI, which contains this information for 2001, is currently available. This database will be 

updated yearly and should provide a list of industrial production facilities and emissions. 

Environmental Fate. Upon release to the atmosphere, fluorine gas will readily react to form 

hydrogen fluoride. Both hydrogen fluoride and particulate fluorides will be transported in the atmosphere 

and deposited on land or water by wet and dry deposition. Fluorides undergo transformations in soil and 

water, forming complexes and binding strongly to soil and sediment (NAS 1971a; WHO 1984). 

Information on the environmental fate of fluorides is sufficient to permit a general understanding of the 

widespread transport and transformation of fluorides in the environment. 

A recent review (Urbansky 2002) looked at the fate of fluorosilicate drinking water additives. Various 

fluorosilicates and aquo/hydroxo/oxo/fluorosilicates may exist in fluoridated water systems and these 

species may occur, regardless of the fluoridating agent used, since water may contain natural silica. The 

author states that it would be desirable to be able to identify and measure or calculate concentrations of 

those species that do exist and rule out those that do not exist (Urbansky 2002). 

Bioavailability from Environmental Media. Fluorides are absorbed by humans following 

inhalation of workplace and ambient air that has been contaminated (Chan-Yeung et al. 1983a; Waldbott 

1979), ingestion of drinking water and foods (Carlson et al. 1960a; Spencer et al. 1970), and dermal 

contact (Browne 1974; Buckingham 1988). Information is available on factors that influence 

bioavailability of ingested fluoride (Rao 1984). However, this information is rarely coupled with the 

available information on total ingested fluoride to determine actual bioavailable dose. Additional 

information on absorption following ingestion of contaminated soils (i.e., by children) would be useful in 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 239 

6. POTENTIAL FOR HUMAN EXPOSURE 

determining the bioavailability of fluorides from these routes of exposure, which may be of particular 

importance for populations living in the vicinity of hazardous waste sites. 

Food Chain Bioaccumulation. Fluorides have been shown to accumulate in animals that consume 

fluoride-containing foliage (Hemens and Warwick 1972). However, accumulation is primarily in skeletal 

tissue and therefore, it is unlikely that fluoride will biomagnify up the food chain. 

Exposure Levels in Environmental Media. Fluorides have been detected in ambient air, surface 

water, groundwater, drinking water, and foods (Barnhart et al. 1974; Davis 1972; EPA 1980a; Hudak 

1999; Waldbott 1963b). However, the existing monitoring data are not current. Air concentrations are 

expected to be different today in view of changes in industries and the wider use of pollution control 

devises. Recent serial measurements of fluorides in air are needed. Groundwater contains higher fluoride 

levels than surface water. Although Fleischer (1962) mapped the levels of fluoride in groundwater in the 

United States and these levels would not be expected to change, it would be useful to survey the 

concentration of fluoride in groundwater used for drinking. This is particularly important in areas where 

groundwater has high fluoride content, as in northwest Texas where 50% of the well water in some 

counties exceed 4 μg/L (Hudak 1999). The fluoride level in food depends on the locality in which the 

food is grown, including the geology, potential sources of fluorine emissions in the area, the amount of 

fertilizer and pesticides applied, the type of processing the food receives, and whether fluoridated water is 

used in food preparation (McClure 1949; Myers 1978; Waldbott 1963b). Foods characteristically high in 

fluoride content include tea, seafood, and bone products such as bone meal and gelatin (Cook 1969; 

Kumpulainen and Koivistoinen 1977). Old estimates of intake via ingestion have been made for members 

of the general population (Kumpulainen and Koivistoinen 1977; NAS 1971a; Spencer et al. 1970; WHO 

1984). Recent data are available on the concentration of fluoride in different foods in Canada and the 

daily dietary intakes for different Canadian age groups (Dabeka and McKenzie 1995). However, recent 

analogous information is not available for the United States. Up-to-date data on concentrations of 

fluoride in food items and the dietary intake of fluorides in the United States is important in view of the 

changes in fluoride emissions and the effect that the use of fluoridated water or water with a high natural 

fluoride content may have on the fluoride levels in processed food and beverages (Pang et al. 1992). 

Fluorides have also been detected in a limited number of surface water, groundwater, and soil samples 

taken at hazardous waste sites (HazDat 2003; Van Hook 1974). Additional information is needed on 

concentrations in ambient air, surface water, groundwater, and soils at these waste sites. This information 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 240 

6. POTENTIAL FOR HUMAN EXPOSURE 

will be helpful in estimating exposures of populations living near these sites through contact with 

contaminated media. 

Exposure Levels in Humans. Fluorides can be measured in urine, plasma, saliva, tooth enamel, 

nails, bone, and other tissues. Detection of fluoride in biological tissues, particularly urine, has been used 

as an indicator of human exposure to fluorides in the workplace and through consumption of fluoridated 

drinking water (Chan-Yeung et al. 1983a; Kaltreider et al. 1972; Spencer et al. 1970). Additional data on 

fluoride levels in urine and other fluids and tissues are needed for populations living near hazardous waste 

sites. This information will be helpful in establishing exposure profiles for waste site populations that 

may be exposed to higher than background levels of fluorides through contact with contaminated media. 

The total human intake is of interest, since multiple sources, all of which are generally considered safe by 

themselves, could, under some circumstances, provide total intake that is considered to be above the 

"safe" level. 

Exposures of Children. Children are exposed to fluorides primarily through their diets and the use 

of dental products, particularly toothpaste. Normal dietary sources of fluorides are augmented by 

fluoridation of water supplies. Human breast milk contains very little fluoride (NRC 1993). Information 

is available on the levels of fluoride in infant formula in Canada and results show that major source of 

fluoride appears to be the processing water used in its manufacture (Dabeka and McKenzie 1987). In the 

United States, manufacturers remove fluoride from the processing water and thus, fluoride levels in infant 

formulas are much lower. The mean dietary intake of fluoride by infants and children is available for 

Winnipeg, Canada and four regions of the United States (Dabeka and McKenzie 1995; Fomon and 

Ekstrand 1999; NRC 1993). The mean daily dietary intakes of fluoride by 6-month-old infants and 

2-year-old children in four regions of the United States were 0.21–0.54 and 0.32–0.61 mg/day, 

respectively. The mean intakes of 2 year olds, but not 6 month olds, were directly related to the fluoride 

concentration in the drinking water. Pang et al. (1992) noted that children obtain a sizeable amount of 

fluoride from beverages. Infants may be exposed to higher fluoride concentrations now than in the past. 

While nearly 80% of infants were fed cow's milk by 6 months of age in the 1960s, in 1991, 80% of 

6-month-old infants were fed formula, which contains higher fluoride concentrations than either human or 

cow's milk (Fomon and Ekstrand 1999). Since beverages may not be prepared with water from the local 

community and beverages constitute 60% of children’s total liquid consumption, more information on the 

fluoride content of beverages would be useful in estimating children’s dietary intake of fluoride. Intake 

of fluoride by children from fluoridated dentifrices and mouth rinses have been estimated (Barnhart et al. 

1974; Ericsson and Forsman 1969). For younger children who have poor control of swallowing, intakes 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 241 

6. POTENTIAL FOR HUMAN EXPOSURE 

from dental products could exceed dietary intakes. Fluoride may be an important mineral for babies born 

prematurely, since prematurity is associated with an increased incidence of dental caries; however, 

recommendations for fluoride intake are only available for full-term infants (Zlotkin et al 1995). 

Fluoride exposure in communities near mining and other industrial facilities where fluoride-containing 

rock or minerals are processed are a public health concern, especially for infants and children. The same 

is true for hazardous waste sites containing fluoride waste. Since fluoride remains in the surface soil 

indefinitely and long past land uses may be forgotten, people may not realize that they are living in areas 

where high levels of fluoride may occur in soil. Contaminated soils pose a particular hazard to children 

because of both hand-to-mouth behavior and intentional ingestion of soil (pica) that contains fluorides and 

other contaminants. In these communities, fluorides may have been tracked in from outdoors and 

contaminate carpeting. Fluoride-containing dust may be brought home in the clothing of parents working 

in industries where they are exposed to fluoride. Children may be exposed to this fluoride while crawling 

around or playing on contaminated carpeting. Exposure may also result from dermal contact with soil, or 

by inhaling dust and then swallowing it after mucociliary transport up out of the lungs. Because much of 

the fluoride in soil is embedded in or strongly adsorbed to soil particles or insoluble, it may not be in a 

form accessible for uptake by the body. 

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 fluorides were located. This compound is not 

currently one of the compounds for which a subregistry has been established in the National Exposure 

Registry. The compound will be considered in the future when chemical selection is made for 

subregistries to be established. The information that is amassed in the National Exposure Registry 

facilitates the epidemiological research needed to assess adverse health outcomes that may be related to 

the exposure to this compound. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2002) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 242 

6. POTENTIAL FOR HUMAN EXPOSURE 

Remedial investigations and feasibility studies conducted at the 188 NPL sites known to be contaminated 

with fluorine, hydrogen fluoride, or fluorides may add to the existing database on exposure levels in 

environmental media at hazardous waste sites, exposure levels in humans, and exposure registries. 

J.G. Schumacher of USGS, Water Resources Division, Weldon Spring, Missouri, is doing research 

sponsored by USGS to determine the geochemical controls on contaminant migration from the raffinate 

pits, Weldon Spring chemical plant, St. Charles County, Missouri. The former U.S. army facility 

processed uranium ore-concentrates and scrap into uranium trioxide, uranium tetrafluoride, and uranium 

metal. Waste from these operations (referred to as raffinate) was pumped into four large pits that contain 

various quantities of uranium, thorium, nitrate, sulfate, fluoride, magnesium, and other elements. The 

raffinate pits have been determined to be leaking and Li, U, NO3, and SO4, and various trace elements 

have been found in groundwater and surface water both on and off site. 

No other ongoing studies pertaining to the environmental fate of fluorine, hydrogen fluoride, or fluorides 

were identified. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 243 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring fluorides, hydrogen fluoride, and fluorine, its metabolites, and other 

biomarkers of exposure and effect to fluorides, hydrogen fluoride, and fluorine. 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. 

Fluorine gas is too reactive to exist in biological or environmental samples. Indeed, fluorine is too 

reactive to be analyzed directly by conventional methods, but rather is quantitatively converted to 

chlorine gas and the latter is analyzed (Shia 1994). The methods discussed below are for the analysis of 

the fluoride ion, or in the case of gaseous acid fluorides, hydrogen fluoride. The particular fluorine 

molecule is rarely identified. 

7.1 BIOLOGICAL MATERIALS 

Trace levels of fluoride in biological media are determined primarily by potentiometric (ion selective 

electrode [ISE]) and gas chromatographic (GC) methods. Colorimetric methods are available, but are 

more time consuming and lack the sensitivity of the other methods (Kakabadse et al. 1971; 

Venkateswarlu et al. 1971). Other methods that have been used include fluorometric, enzymatic, and 

proton activation analysis (Rudolph et al. 1973). The latter technique is sensitive to trace amounts of 

sample and requires minimal sample preparation. Urine and blood and other bodily fluids can be 

analyzed with a minimum of sample preparation. Tissue will require ashing, digestion with acid, or even 

fusion with alkali to free the fluoride from its matrix. The most accurate method of sample preparation is 

microdiffusion techniques, such as the acid-hexamethyldisiloxane (HMDS) diffusion method by Taves 

(1968). These methods allows for the liberation of fluoride from organic or inorganic matrices (WHO 

2002). During sample preparation, the analyst must be careful to avoid sample contamination, incomplete 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 244 

7. ANALYTICAL METHODS 

release from matrices, and losses due to volatilization (NRC Canada 1971). Vogel et al. (1990) reported 

methodologies for sample manipulation and fluoride analysis on very small sample volumes. Techniques 

included micropipette procedures for transferring samples, preparation of micro fluoride-selective 

electrodes, and methods for adapting standard electrodes for micro- and semi-micro volumes (0.005– 

5 μL). These techniques have been used for fluoride analysis of various biological samples, such as 

salvia, plaque, and tooth enamel (Vogel et al. 1990, 1992a, 1992b). Table 7-1 describes some analytical 

methods for determining fluorides in biological materials. 

There is extensive literature on the ISE methodology because it is the most frequently used method for 

fluoride measurement in biological media. The fluoride ion selective membrane utilizes a membrane 

consisting of a slice of a single crystal of lanthanum fluoride that has been doped with europium (II) 

fluoride to improve its conductivity (Skoog et al. 1990). It has a theoretical response to changes in 

fluoride ion activity in the range of 100

–10-6 M. It is selective to fluoride over other common anions by 

several orders of magnitude; only hydroxide ion causes serious interference. The pH of the solution 

analyzed is adjusted to approximately 5 to eliminate interference. ISE is the methodology recommended 

by NIOSH in Method 8308 for the determination of fluoride in urine (NIOSH 1994). Fluoride analyses 

using the ion selective electrode are simple, sensitive, and rapid. Recoveries are usually >90%, but this is 

dependent on the type of sample and the sample preparation required. Sample for ISE analysis must be 

prepared to solubilize the fluoride in the sample. For some samples, ashing or NaOH fusion is required. 

A total-ionic strength adjustment buffer (TISAB) is used to adjust samples and standards to the same 

ionic strength and pH; this allows the concentration, rather than the activity, to be measured directly and 

often read directly off a meter. The pH of the buffer is about 5, a level at which F-

 is the predominant 

fluorine-containing species. The buffer contains cyclo-hexylene-dinitrilotetraacetic acid, which forms 

stable complexes with Fe(III) and Al(III), thus removing interferences by freeing fluoride ions from 

complexes with these ions (NIOSH 1994; Schamschula et al. 1985; Tusl 1970). Bone fluoride levels can 

be measured using the ISE technique after ashing of the sample (Boivin et al. 1988). Fingernail fluoride 

levels can be measured using the ISE technique after nail clippings were prepared by HMDS-facilitated 

diffusion overnight. This sample preparation was found to quantitatively remove fluoride from the nail 

material (Whitford et al. 1999a). Whitford et al. (1999a) also reported that soaking the fingernail samples 

in deionized water for 6 hours or in a solution of 1.0 ppm fluoride for 2 hours did not change the 

concentration of fluoride found in the nail. 

Recent studies have employed GC to measure fluoride concentrations in human urine and plasma (Chiba 

et al. 1982; Ikenishi and Kitagawa 1988; Ikenishi et al. 1988). In this method, derivatization and 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 245 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Fluoride in Biological Materials 

Sample 

Analytical detection Percent 

Sample matrix Preparation method method limit recovery Reference 

Urine Extract with TMCS; inject organic GC 

phase (microwave induced plasma 

emission detector) 

Add equal volume TISAB solution ISE, 

NIOSH 

8308 

Add TMCS toluene solution; GC 

centrifuge; inject toluene layer 

Biological fluids Absorb with calcium phosphate; ISE 

and tissue ex- centrifuge; analyze 

tracts (ionic and 

ionizable 

fluoride) 

Saliva Resuspend in TISAB buffer; analyze ISE 

Biological fluids Add TMCS toluene solution; centri- GC 

fuge; inject toluene layer and 

analyze by measuring TMFS peak 

height 

Biological Extraction from acidified sample as ISE with 

tissues and fluorosilane; reverse extraction as hanging 

fluids fluoride ion into alkaline solution drop 

assembly 

Biological Sample pulverized to fine powder; PAA 

tissues irradiate with energetic beam of 

protons; detect gamma rays emitted 

Decomposition of sample at 700– Colori1,000 °C (pyrohydrolytic technique) metry 

Tooth enamel	 Soak teeth; decalcify in HClO4; add ISE 

TISAB; analyze 

Plaque Dried; microdiffusion; analyze ISE 

Bone Ash sample; dissolve in perchloric ISE 

acid; add 1,2-cyclohexylenedinitrotetraacetic acid 

Hair/fingernail Wash in diethylether; dry; de- ISE 

compose in NaOH 

Fingernail HMDS-facilitated diffusion overnight ISE 

4 μg/L 935 Chiba et al. 1982 

0.1 mg/L 95% NIOSH 1994 

>5 ng/mL No data Ikenishi et al. 1988 

10 μg/L 92–102% Venkateswarlu et 

al. 1971 

No data 99.8% Petersson et al. 

1987; Schamschula 

et al. 1985 

5 ng/L 88.1– Ikenishi et al. 1988 

97.2% 

>0.04 ng/ No data Venkateswarlu 

sample 1974 

<10 ng/ No data Rudolph et al. 1973 

sample 

1 μg/sam No data Kakabadse et al. 

ple 1971 

No data No data Schamschula et al. 

1982; Shida et al. 

1986 

No data 97% Schamschula et al. 

1985 

No data No data Boivin et al. 1988 

No data 94–96% Schamschula et al. 

1985 

No data No data Whitford et al. 

1999a 

GC = gas chromatography; HClO4 = perchloric acid; HMDS = hexamethyldisiloxane; ISE = ion selective electrode; 

NaOH = sodium hydroxide; NIOSH = National Institute for Occupational Safety and Health; PAA = proton activation 

analysis; TISAB = total ionic strength activity buffer; TMCS = trimethylchlorosilane; TMFS = trimethylfluorosilane 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 246 

7. ANALYTICAL METHODS 

extraction is achieved using trimethylchlorosilane (TMCS) in toluene to produce trimethylfluorosilane 

(TMFS). The organic layer is injected into the GC system and the TMFS peak height is compared with 

those of standard solutions. The GC method has the advantage of high sensitivity—nanogram quantities 

of fluoride are detectable in a milliliter of urine or plasma. This method is also useful for assessing the 

fluoride released from fluorine-containing drugs in biological fluids. The detection of bound fluorine 

provides an advantage over the ISE technique, which is not suitable for bound or organic fluoride 

measurements. It should also be noted that the aluminum ion may cause interference under the operating 

conditions of the GC, as it does with the ISE method. 

7.2 ENVIRONMENTAL SAMPLES 

The ISE method is the most widely used method for determining fluoride levels in the environmental 

media. Table 7-2 describes this and other methods for determining fluoride in environmental samples. 

Table 7-3 describes methods for determining hydrogen fluoride in air. ISE methods are simple to perform 

and have good precision and sensitivity. Fluoride-specific electrodes are commercially available. The 

method detects only free fluoride ions in solution. Because of the inherent restriction of this technique, 

several approaches have been recommended to prepare the sample for analysis. Lopez and Navia (1988) 

assayed total fluoride (bound and free) in food and beverages by initially acid hydrolyzing samples at 

100 °C in borosilicate vials. This closed-system approach decreases contamination, eliminates dry 

ashing, and yields high recoveries. Dabeka and McKenzie (1981) employed microdiffusion with 40% 

perchloric acid to food samples in Petri dishes at 60 °C for 24–48 hours. Difficulties arose in controlling 

contamination and fluoride loss in the Petri dishes, and low recoveries were reported. Preparation of total 

fluoride in dry plant material (i.e., hay, barley, straw, corn, grass) was described by Eyde (1982); samples 

were fused in nickel crucibles with sodium hydroxide at 350–475 °C. The ash was diluted and filtered for 

analysis. This method is more tedious than the others, and fluoride loss is expected from the high fusion 

temperatures. All of these preparatory techniques can liberate bound fluoride from the sample matrices. 

It is important to prevent interference of other ions and to avoid fluoride loss at high decomposition 

temperatures before potentiometric analyses. Kakabadse et al. (1971) described a pyrohydrolytic 

technique for tea, coca, or tobacco samples that could be employed prior to colorimetric or ISE analysis. 

Decomposition of the sample at 700–1,000 °C is mediated by a current of air or pure oxygen to evolve 

hydrogen fluoride. An advantage of this approach is that fluoride is collected from inorganic and organic 

fluorides in one operation. Ashing, which may produce loss of organic fluorine, is eliminated. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 247 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Fluoride in Environmental 

Samples 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Air Ambient air collected using teflon ISE 0.1 μg/L No data Danchik et 

tubing; detect with continuous al. 1980 

flow analyzer 

Sample at 1–2 L/minute using IC/conductivity 3 μg/sample No data NIOSH 1994 

cellulose ester membrane filter detector; (gas); 

and alkaline-impregnated backup NIOSH 7906 120 μg/sample 

pad to collect particulate and (particulate) 

gaseous fluorides. Extract 

hydrogen fluoride and soluble 

fluorides with water; insoluble 

fluorides require NaOH fusion 

Sample at 1–2 L/minute using ISE, 3 μg/sample No data NIOSH 1994 

cellulose ester membrane filter NIOSH 7902 

and alkaline-impregnated backup 

pad to collect particulate and 

gaseous fluorides; extract 

hydrogen fluoride and soluble 

fluorides with 50 mL 1:1 TISAB: 

water; insoluble fluorides require 

NaOH fusion 

Syringe-sampling; dilute with 50% Colorimetry 0.3 ppm No data Bethea 1974 

(v/v) 1,2-dioxane containing 

Amadec-F 

Water Dilute sample; add barium Colorimetry 2,000 μg/L No data Macejunas 

chloride; complex with zirconium­ 1969 

xylenol orange for color 

development 

Sample added to sulfuric acid Colorimetry; 0.10 mg/L No data EPA 1998c 

and distilled to remove inter- EMSLC 

ferences; distilled sample treated Method 340.1 

with SPADNS reagent; color loss 

resulting from reaction of reagent 

with fluoride is determined at 

570 nm and concentration read 

off standard curve 

Mix sample and standard 1:1 with ISE, OSW 0.500 mg/L No data EPA 1996 

TISAB (for soluble fluorides) Method 9214 

No sample treatment required ISE, EMSLC 0.100 mg/L No data EPA 1998c 

Method 340.2 

 Bellack distillationa

, after which Colorimetry, 0.050 mg/L No data EPA 1998c 

fluoride ion reacts with the red EMSLC 

cerous chelate of alizarin Method 340.3 

complexone in an autoanalyzer 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 248 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Fluoride in Environmental 

Samples 

Sample Analytical Sample Percent 

matrix Preparation method method detection limit recovery Reference 

Extract with TMCS; analyze GC 4 μg/L 93–100% Chiba et al. 

organic phase (microwave 1982 

induced plasma emission 

detector) 

Waste Centrifuge sample to settle solids; Anion exclusion 200 μg/L No data Hannah 1986 

water filter and dilute chromatography 

Water, rain Dilute sample with TISAB buffer; ISE 2 μg/L No data Fucsko et al. 

analyze in flow injection system 1987 

Food, Homogenize sample; acid ISE 0.1 μg/g 97% Lopez and 

beverage hydrolysis in a closed system Navia 1988 

Sample pulverized to powder PAA 1 μg/g dry No data Shroy et al. 

weight 1982 

Tea, Decomposition at 700–1,000 °C Colorimetry >1 μg No data Kakabadse 

cocoa, in moist current of oxygen or air; et al. 1971 

tobacco collect hydrogen fluoride; react to 

form Ce(III)alizarin-complexan 

Milk, peas, Sample is dried and ground to ISE 0.2–5 μg/g 54–109% Dabeka and 

pears powder; microdiffusion in Petri McKenzie 

dish; analyze 1981 

Vegetation Fluorine-19 sample activation INAA 14 μg/sample No data Knight et al. 

1988 

Extraction of sample ISE >0.05 μg/g >95% Jacobson 

and Heller 

1971 

Fusion with NaOH; dissolve in ISE 10 μg/g No data Sager 1987 

tiron buffer 

Feed Sample is dried and acidified ISE 15 μg/g 90–108% Melton et al. 

1974 

Household Dilute sample, add buffer; ISE No data 98–104% Schick 1973 

products addition procedure 

Plants Sample dried and fused in nickel ISE >0.3 μg/g 87–102% Eyde 1982 

crucibles; filter 

a

Bellack distillation uses HClO4/AgClO4 to remove chloride. 

Ce III = cesium ion (+3 oxidation state); EMSLC = EPA Environmental Monitoring Systems Laboratory in Cincinnati; 

GC = gas chromatography; HPLC = high pressure liquid chromatography; IC = ion chromatography; 

INAA = instrumental neutron activation analysis; ISE = ion selective electrode; NaOH = sodium hydroxide;
 

NIOSH = National Institute for Occupational Safety and Health; OSW = Office of Soild Waste; PAA = proton 

activation analysis; SPADNS = sodium 2-(parasulfophenylazo)-1,8-dihydroxy-3,6-naphthalene disulfonate; 

TISAB = total ionic strength activity buffer; TMCS = trimethylchlorosilane; (v/v) = volume/volume 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 249 

7. ANALYTICAL METHODS 

Table 7-3. Analytical Methods for Determining Hydrogen Fluoride in 

Environmental Samplesa 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Percent 

recovery Reference 

Air Personal air sampled at 1– 

2 L/minute for total sample of 12– 

800 L onto treated pad; soak pad 

in 25 mL water and 25 mL TISAB; 

ISE, 

NIOSH 7902 

0.7 μg fluoride/ 

sample 

No data NIOSH 1994 

collect using teflon tubing and 

analyze with continuous flow 

analyzer. 

Personal air sampled at 0.2– 

0.3 L/min for total sample size of 

3–100 L using silica gel sample 

tube; boil sorbent from sample tube 

in bicarbonate/carbonate buffer for 

10 minutes. 

IC/conductivity 

detector, 

NIOSH 7903 

0.7 μg/sample No data NIOSH 1994 

Personal air sampled at 1– 

2 L/minute using cellulose ester 

membrane filter and alkalineimpregnated backup pad to collect 

particulate and gaseous fluorides; 

extract hydrogen fluoride and 

soluble fluorides with water; 

IC/conductivity 

detector, 

NIOSH 7906 

3 μg/sample 

(gas); 120 μg/ 

sample 

(particulate) 

No data NIOSH 1994 

insoluble fluorides requires NaOH 

fusion. 

Hydrogen fluoride vapor collected 

with dosimeter containing polypropylene element. 

ISE 100 μg/L No data Young and 

Monat 1982 

Dual cellulose filter to separate 

particulate and gaseous fluoride; 

heat filters at 75 °C; extract; dilute 

ISE 1.2 μg/filter No data Einfeld and 

Horstman 

1979 

with TISAB buffer. 

a

Some methods measure both gaseous (HF) and particulate fluorides. 

IC = ion chromatography; ISE = ion selective electrode; NIOSH = National Institute for Occupational Safety and 

Health; TISAB = total ionic strength activity buffer, v/v = volume/volume 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 250 

7. ANALYTICAL METHODS 

Fluoride ions form stable, colorless complexes with certain multivalent ions, such as (AlF6)

3-, (FeF6)3-, 

and (ZrF6)

3-. Most colorimetric methods for the determination of fluoride are based on the bleaching of 

colored complexes of these metals with organic dyes when fluoride is added (WHO 1984). The degree of 

bleaching is determined with a spectrophotometer, and the concentration of fluoride ions is assessed by 

comparison with standard solutions. In EPA Method 340.1, the sodium 2-(parasulfophenylazo)-1,8-dihydroxy-3,6-naphthalenedisulfonate (SPADNS) reagent is used, and the color loss is measured at 570 nm 

(EPA 1998c). In EPA Method 340.3, the red cerium complex with alizarin complex one turns blue on the 

addition of fluoride (EPA 1998c). 

Ion chromatography (IC) utilizes anion exchange resins as a stationary phase to separate fluoride ions 

from other species. In most cases, conductivity detectors are used to detect the ions in the eluent. Both 

the stationary phase and the eluent must be chosen to separate fluoride from overlapping ions. Hannah 

(1986) used a variant of ion exchange chromatography, namely anion exclusion chromatography, to 

analyze fluoride in waste water. This method is generally applied to the separation of weak organic acids 

and its use for fluoride determinations is based on the fact that fluoride is an anion of a weak acid, 

hydrogen fluoride, with a pKa of 3.19, similar to that of weak organic acids. The acids elute in order of 

increasing pKa. At low pH, anions of strong acids remain disassociated and are excluded from the resin 

and are rapidly eluted. Hydrogen fluoride exists primarily in the molecular form, and interacts with the 

resin, delaying its elution. In this way, fluoride is sufficiently separated from ionic interferences to be 

reliably quantified. Interfering anions, such as chloride, emerge as one peak before the fluoride elutes. 

Resolution can be controlled by adjusting the pH. 

Fluorides in air may be present in the gas phase (generally hydrogen fluoride) or in the particulate phase. 

Sampling may involve trapping the particulate phase on a membrane filter and the hydrogen fluoride on 

an alkaline impregnated backup pad as in NIOSH Method 7906 (NIOSH 1994). Several modifications 

have been suggested for the air sample collection. Einfeld and Horstman (1979) found that gaseous 

fluoride, to some extent, may get trapped in the filter for particulate fluoride. They suggest that 

postsampling heat treatment promotes desorption of the gaseous fluoride from the particulate phase. The 

use of Teflon® tubing and materials in the analyzer is indicated for controlling loss of sample ions 

(Candreva and Dams 1981; Danchik et al. 1980). 

For the analysis of pollutants in the environment, EPA has approved the ISE (Method 340.2) and 

colorimetric methods (Methods 340.1 and 340.3) for determining inorganic fluoride in water (EPA 1998). 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 251 

7. ANALYTICAL METHODS 

NIOSH recommends the use of ISE (Method 7902) and IC methods (Methods 7903 and 7906) for the 

determination of fluoride and hydrogen fluoride in air (NIOSH 1994). 

Fluoride gas or vapors in ambient air are measured primarily with the ISE method. NIOSH Method 7902 

uses this technique for the determination of hydrogen fluoride and particulate fluorides in air (NIOSH 

1994). The hydrogen fluoride gas and particulate fluorides are collected on separate filters before 

determination. Several modifications have been suggested for the air sample collection. Einfeld and 

Horstman (1979) found that gaseous fluoride may get trapped in the filter for particulate fluoride to some 

extent. They utilized postsampling heat treatment to desorb hydrogen fluoride from particulates. The use 

of Teflon® tubing and materials in the analyzer is indicated for controlling fluoride loss (Candreva and 

Dams 1981; Danchik et al. 1980). 

Young and Monat (1982) developed a dosimeter to be worn on the lapel in the workplace for monitoring 

airborne fluoride vapor. A replaceable collection element adsorbs the fluoride vapors. Samples are 

desorbed with TISAB solution and analyzed on the ISE. The study authors noted its convenience, 

stability, retentivity, and insensitivity to moisture at 5–88% humidity and competing sulfur dioxide 

vapors. Interference may occur from reactive volatile fluorine compounds. Wind, temperature, and 

atmospheric pressure can affect results. The dosimeter yields a sample detection range of 0.1–387 ppm 

fluoride in air. 

Two analytical methods for fluorine determination have been developed based on neutron or proton 

activation of fluorine-9 (Knight et al. 1988; Shroy et al. 1982). Instruments measure the emitted gamma 

rays or x-rays using lithium-drifted germanium detectors. This approach has wide application, since it 

does not depend on a specific sample matrix or chemical form. However, the need for a special facility 

with a source of neutrons or protons limits its use. 

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 fluorides, hydrogen fluoride, and fluorine 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 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 252 

7. ANALYTICAL METHODS 

health effects (and techniques for developing methods to determine such health effects) of fluorides, 

hydrogen fluoride, and fluorine. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Sensitive, reproducible analytical methods are available for detecting fluorides in biological 

materials following short-term exposure (such as plasma and urine) and long-term exposure (i.e., bone). 

The most common technique is the ISE method because it is reliable, simple, and sensitive, and has good 

recoveries (NIOSH 1994; Venkateswarlu et al. 1971). GC is also useful for detection of trace levels of 

fluoride in plasma and urine (Chiba et al. 1982; Ikenishi and Kitagawa 1988; Ikenishi et al. 1988). Both 

methods can measure samples at concentrations at which health effects may occur. 

Urinary fluoride is a widely accepted biomarker of recent fluoride exposure and has frequently been used 

as an indicator of fluoride exposure in occupational studies (Chan-Yeung et al. 1983a; Kaltreider et al. 

1972) and to determine exposure from drinking water (Spak et al. 1985). A minimum fluoride level of 

4 mg/L in the urine using the ISE technique has been recommended as an indicator of recent fluoride 

exposure in workers (Derryberry et al. 1963). Other possible biomarkers of fluoride exposure include 

fluoride concentrations in tooth enamel (Shida et al. 1986), hair (Schamschula et al. 1982), nails 

(Schamschula et al. 1982; Whitford et al. 1999a), saliva (Petersson et al. 1987), blood (Jackson and 

Hammersley 1981), and bone (Baud et al. 1978; Bruns and Tytle 1988; Fisher 1981; Sauerbrunn et al. 

1965) for which analytical methods are available. 

Effect. For biomarkers of effect following chronic exposure, investigators have looked for skeletal 

fluorosis using radiographs. Bone density is a common index used for evaluation (Kaltreider et al. 1972). 

Guminska and Sterkowicz (1975) found an increase in erythrocyte enzyme activity (i.e., enolase, pyruvate 

kinase, ATPase) that may reflect altered glucose metabolism during prolonged fluoride exposure. These 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 253 

7. ANALYTICAL METHODS 

biochemical alterations are suggested for possible diagnostic purposes, but they represent a response that 

may be induced in the body by a physiological change or other chemical agents. Therefore, more specific 

analytical methods are needed for measuring biomarkers of effect. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods are available for determining fluoride levels in environmental samples. Methods 

determine the fluoride concentration and not the particular fluorine-containing compound. Therefore, 

analytical methods do not distinguish between parent compound and degradation product. The ISE 

method is the most common method for measuring fluoride in environmental samples. It is a convenient, 

sensitive, and reliable method, but fluoride ions must first be released from any matrix and rendered free 

in solution. Methods are available for preparing various types of environmental samples for analysis 

(Dabeka and McKenzie 1981; EPA 1998c; Eyde 1982; Kakabadse et al. 1971; Lopez and Navia 1988; 

NIOSH 1994; NRC Canada 1971; WHO 1984). 

7.3.2 Ongoing Studies 

One ongoing study regarding techniques for measuring and determining fluoride in biological and 

environmental samples was located. Noah Seixas of the University of Washington proposes to adapt realtime instruments for monitoring HF and SO2 and a nonspecific particulate, integrating currently available, 

electrochemical sensor, and light scattering technology and, using these instruments, to monitor exposure 

in four aluminum smelting operations (FEDRIP 2002). 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 255 

8. REGULATIONS AND ADVISORIES 

No international regulations pertaining to fluorides were found. The national and state regulations and 

guidelines regarding fluorides, hydrogen fluoride, and fluorine in air, water, and other media are 

summarized in Table 8-1. 

A chronic-duration oral MRL of 0.05 mg fluoride/kg/day has been derived for fluoride. This MRL is 

based on a NOAEL of 0.15 mg fluoride/kg/day and a LOAEL of 0.25 mg fluoride/kg/day for skeletal 

effects (increased fracture rate) (Li et al. 2001). The MRL was derived by dividing the NOAEL by an 

uncertainty factor of 3 to account for human variability. 

An acute-duration inhalation MRL of 0.02 ppm fluoride has been derived for hydrogen fluoride. This 

MRL is based on a minimal LOAEL of 0.5 ppm for upper respiratory tract inflammation in humans 

exposed to hydrogen fluoride for 1 hour (Lund et al. 1997, 1999). The MRL was derived by dividing the 

unadjusted LOAEL by an uncertainty factor of 30 (3 for a use of a minimal LOAEL and 10 to account for 

human variability). 

An acute-duration inhalation MRL of 0.01 ppm has been derived for fluorine. This MRL is based on a 

NOAEL of 10 ppm for respiratory irritation in humans exposed to fluorine for 15 minutes (Keplinger and 

Suissa 1968). The MRL was derived by dividing the 24-hour adjusted NOAEL of 0.1 ppm by an 

uncertainty factor of 10 to account for human variability. 

EPA (IRIS 2003) derived an oral reference dose (RfD) of 0.06 mg/kg/day for fluorine (soluble fluoride). 

The RfD was based on a NOAEL of 0.06 mg/kg/day and a LOAEL of 0.12 mg/kg/day for the cosmetic 

effect of dental fluorosis in children (Hodge 1950). The NOAEL was divided by an uncertainty factor 

of 1 to derive the RfD. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 256 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Fluoride, Sodium Fluoride, 

Hydrogen Fluoride, and Fluorine 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

 IARC Carcinogenicity classification 

Fluoride and sodium fluoride 

WHO Drinking water guideline 

 Fluoride 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV-TWA 

 Fluoride 

 Fluorine 

STEL (ceiling) 

 Fluorine 

 Hydrogen fluoride 

EPA Accidental release prevention 

 Threshold quantity 

Fluorine 

Hydrogen fluoride 

Accidental release prevention 

Toxic end point 

Fluorine 

Hydrogen fluoride 

OSHA PEL (8-hour TWA) 

 General industry 

Fluoride 

Fluorine 

Hydrogen fluoride 

PEL (8-hour TWA) 

 Construction industry 

Fluoride 

Fluorine 

Hydrogen fluoride 

PEL (8-hour TWA) 

Shipyards 

Fluoride 

Fluorine 

Hydrogen fluoride 

Highly hazardous chemicals 

 Threshold quantity 

Fluorine 

Highly hazardous chemicals 

 Threshold quantity 

Hydrogen fluoride 

IARC 1987 

Group 3a 

WHO 2001 

1.5 mg/L 

ACGIH 2000 

2.5 mg/m3 

1.0 ppm 

2.0 ppm 

3.0 ppm 

EPA 2001b 

40CFR68.130 

1,000 pounds Table 1 

1,000 pounds 

EPA 2001a 

40CFR68 

0.0039 mg/L Appendix A 

0.0160 mg/L 

OSHA 2001c 

29CFR1910.1000 

2.5 mg/m3 

0.2 mg/m3 

2.0 mg/m3 

Table Z-1 

OSHA 2001f 

29CFR1926.55 

2.5 mg/m3 

0.2 mg/m3 

2.0 mg/m3 

Appendix A 

OSHA 2001a 

29CFR1915.1000 

2.5 mg/m3 

0.2 mg/m3 

2.0 mg/m3 

Table Z 

OSHA 2001d 

29CFR1910.119 

1,000 pounds Appendix A 

OSHA 2001e 

29CFR1926.64 

1,000 pounds Appendix A 
 

 

 

 

 

 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 257 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Fluoride, Sodium Fluoride, 

Hydrogen Fluoride, and Fluorine 

Agency Description Information Reference 

NATIONAL (cont.) 

OSHA Brazing and gas welding fluxes 

shall have a cautionary wording 

to indicate that they contain 

fluorine compounds 

NIOSH REL (TWA) 

 Fluorine 

 Hydrogen fluoride 

 Sodium fluoride 

IDLH 

 Fluorine 

 Hydrogen fluoride 

 Sodium fluoride 

USC HAP 

b. Water 

EPA BPT effluent limitationCfluoride 

Maximum for 1 day 

Average of daily values for 

30 consecutive days 

Effluent limitationCfluoride 

Maximum for 1 day 

Average of daily values for 

30 consecutive days 

Groundwater protection 

standards at inactive uranium 

processing sitesClisted 

constituents include fluorine and 

hydrogen fluoride 

MCLGCfluoride 

MCLCfluoride 

Secondary MCLCfluoride 

Water pollutionChazardous 

substance designation 

c. Food 

EPA PesticidesCfluorine compounds; 

residue tolerances 

Apricots, beets, blackberries, 

blueberries, boysenberries, 

broccoli, brussels sprouts, 

cabbage, cauliflower, citrus 

fruits, collards, cranberries 

0.2 mg/m3 

2.5 mg/m3 

2.5 mg/m3 

25 ppm 

30 ppm 

250 ppm 

6.1 kg/kkg 

2.9 kg/kkg 

75 mg/L 

25 mg/L 

4.0 mg/L 

4.0 mg/L 

2.0 mg/L 

Hydrogen fluoride 

Sodium fluoride 

7 ppm 

 OSHA 2001b 

29CFR1910.252(c)(1) 

NIOSH 2001a 

NIOSH 2001b 

NIOSH 2001c 

NIOSH 2001a 

NIOSH 2001b 

NIOSH 2001c 

USC 2001 

42USC7412 

EPA 2001c 

40CFR415.82 

EPA 2001e 

40CFR422.42 

 EPA 2001f 

40CFR192 

Appendix I 

EPA 2001j 

40CFR141.51(b) 

EPA 2001k 

40CFR141.62(b) 

EPA 2001l 

40CFR143.3 

EPA 2001r 

40CFR116.4 

EPA 2001n 

40CFR180.145 
 

 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 258 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Fluoride, Sodium Fluoride, 

Hydrogen Fluoride, and Fluorine 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA PesticidesCfluorine compounds; 

residue tolerances

 Cucumbers, dewberries, 

eggplant, grapes, kale, 

kohlrabi, lettuce, loganberries, 

melons, nectarines, peaches, 

peppers, plums, pumpkins, 

radish, raspberries, rutabaga, 

 squash, strawberries, 

 tomatoes, turnip, 

 youngberries 

Potatoes 

Potatoes, processing waste 

Kiwifruit 

FDA Adhesive component, indirect 

food additiveCfor use only as 

bonding agent for aluminum foil, 

stabilizer, or preservative

 Hydrogen fluoride 

 Sodium fluoride 

Bottled waterCno fluoride added 

Bottled waterCfluoride added 

Over-the-counter drug products

 LabelingCfluoride, fluorine, 

and sodium fluoride 

Over-the-counter drug products

 TestingCfluoride 

Over-the-counter drug products

 Active ingredientCfluorine, 

hydrogen fluoride, and sodium 

fluoride 

7 ppm 

2 ppm 

22 ppm 

15 ppm 

Total fluoride from all 

sources not to exceed 

1% by weight of the 

finished adhesive 

Temperatureb mg/L 

53.7Bbelow 2.4 

53.8B58.3 2.2 

58.4B63.8 2.0 

63.9B70.6 1.8 

70.7B79.2 1.6 

79.3B90.5 1.4 

Temperatureb

 mg/L 

53.7Bbelow 1.7 

53.8B58.3 1.5 

58.4B63.8 1.3 

63.9B70.6 1.2 

70.7B79.2 1.0 

79.3B90.5 0.8 

EPA 2001n 

40CFR180.145 

FDA 2000e 

21CFR175.105(c)(5) 

FDA 2000g 

21CFR165.110 

 FDA 2000b 

21CFR355.50 

FDA 2000c 

21CFR355.60 

 FDA 2000d 

21CFR355.70 

 FDA 2000a 

21CFR355.10 

FDA 2000f 

21CFR310.545(a)(2) 
 

 

 

 

 

 

 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 259 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Fluoride, Sodium Fluoride, 

Hydrogen Fluoride, and Fluorine 

Agency Description Information Reference 

NATIONAL (cont.) 

FDA Surface component, food 

contactCsodium fluoride for use 

 FDA 2000h 

21CFR177.2800 

as preservative only (d)(5) 

d. Other 

 ACGIH Carcinogenicity classification 

 Fluoride A4c 

ACGIH 2000 

BEI 

Fluorides in urine 

Prior to shift 

End of shift 

3 mg/g creatinine 

10 mg/g creatinine 

CPSC Requirements for child-resistant 

packaging for household 

products containing elemental 

fluoride 

More than 50 mg and 

more than 0.5% 

CPSC 2001 

16CFR1700 

DOT Hazardous materials DOT 2001 

 Reportable quantity 

Fluorine 

Hydrogen fluoride 

Sodium fluoride 

10 pounds 

100 pounds 

1,000 pounds 

40CFR172.101 

Appendix A 

EPA RfDCfluorine 6x10-2 mg/kg/day IRIS 2003 

Toxic chemical release reporting; 

Community Right-toKnowCeffective date 

EPA 2001q 

40CFR372.65 

 Fluorine 

 Hydrogen fluoride 

01/01/95 

01/01/87 

Contaminated soilCfluoride Concentrations greater 

than 10 times UTS 

EPA 2001d 

40CFR268.49(f) 

Hazardous wasteChealth based 

limits for exclusion of wasteEPA 2001g 

40CFR266 

derived-residue 

Fluorine residue concentration 

limit 

4.0 mg/kg 

Appendix VII 

Hazardous wasteCidentification EPA 2001h 

and listing 

 Fluorine P056 

40CFR261.33(e) 

EPA 2001i 

 Hydrogen fluoride U134 40CFR261.33(f) 

PesticidesCresidue tolerances Not more than 25% of EPA 2001m 

 Sodium fluoride pesticide formulation 40CFR180.1001(d) 

SuperfundCreportable quantity 

 Fluorine 

 Hydrogen fluoride 

 Sodium fluoride 

1 pound 

5,000 pounds 

5,000 pounds 

EPA 2001o 

40CFR302.4 

Appendix A 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 260 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Fluoride, Sodium Fluoride, 

Hydrogen Fluoride, and Fluorine 

Agency Description Information 

NATIONAL (cont.) 

Reference 

EPA SuperfundCextremely hazardous EPA 2001p 

 Reportable quantity 40CFR355 

Fluorine 10 pounds Appendix A 

Hydrogen fluoride 100 pounds 

Threshold planning quantity 

Fluorine 500 pounds 

Hydrogen fluoride 

STATE 

100 pounds 

a. Air 

 Connecticut HAPCfluoride, fluorine, and BNA 2001 

hydrogen fluoride 

 Hawaii Air contaminantChydrogen 

fluoride 

 BNA 2001 

Idaho Toxic air pollutants BNA 2001 

 Fluoride 

OEL 2.5 mg/m3 

EL 

AAC 

 Fluorine 

0.167 pounds/hour 

0.125 mg/m3 

OEL 2.0 mg/m3 

EL 

AAC 

0.133 pounds/hour 

0.1 mg/m3 

 Michigan PEL (TWA) BNA 2001 

 Fluoride 

 Fluorine 

2.5 mg/m3 

0.2 mg/m3 

 Hydrogen fluoride 3.0 ppm 

Montana Air contaminant (TWA) BNA 2001 

 Fluoride 

 Fluorine 

 Hydrogen fluoride 

2.5 mg/m3 

0.2 mg/m3 

2.0 mg/m3 

New Mexico Toxic air pollutant BNA 2001 

 Fluorides 

OEL 2.5 mg/m3 

Emissions 

 Fluorine 

0.167 pounds/hour 

OEL 2.0 mg/m3 

Emissions 0.133 pounds/hour 

New York Air contaminant (TLV) BNA 2001 

 Fluoride 

 Fluorine 

 Hydrogen fluoride 

2.5 mg/m3 

0.2 mg/m3 

2.0 mg/m3 
 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 261 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Fluoride, Sodium Fluoride, 

Hydrogen Fluoride, and Fluorine 

Agency Description Information Reference 

STATE (cont.)

 Washington Toxic air pollutantCASIL 

 Fluoride 

 Fluorine 

 Hydrogen fluoride 

8.3 μg/m3 

5.3 μg/m3 

8.7 μg/m3 

BNA 2001 

PEL BNA 2001 

 Fluoride 

 Fluorine 

2.5 mg/m3 

0.2 mg/m3 

 Hydrogen fluoride (STEL) 3.0 ppm 

Wisconsin Emission rate (pounds/hour) <25 feet >25 feet BNA 2001 

 Fluoride 0.2088 0.8640 

 Fluorine 0.1656 0.6720 

 Hydrogen fluoride 0.1272 0.4800 

b. Water 

 Alaska MCLCfluoride 4.0 mg/L BNA 2001 

Secondary MCLCfluoride 2.0 mg/L 

 Arizona Drinking water guidelineCfluoride 4.0 mg/L HSDB 2003 

Reporting limitCfluoride 2.0 mg/L BNA 2001 

California Drinking water standardsC 2.0 mg/L HSDB 2003 

fluoride 

 Connecticut MCLCfluoride 4.0 mg/L BNA 2001 

 Delaware Drinking water standardsC 1.8 mg/L HSDB 2003 

fluoride 

Georgia MCLCfluoride 4.0 mg/L BNA 2001 

 Hawaii Drinking water standardsC 1.4B2.4 mg/L HSDB 2003 

fluoride 

Idaho Groundwater quality standardsC 4.0 mg/L BNA 2001 

fluoride 

 Kansas AgricultureCfluoride BNA 2001 

 Livestock 2.0 mg/L 

 Irrigation 1.0 mg/L 

Public health foodCfluoride

 Domestic water supply 2.0 mg/L 

Maine Drinking water guidelineCfluoride 2.4 mg/L HSDB 2003 

Maximum exposure guideline 2.4 mg/L BNA 2001 

Action level 1.2 mg/L 

 Mississippi Groundwater standardsCfluoride 4.0 ppm BNA 2001 

 Nebraska MCLCfluoride 4.0 mg/L BNA 2001 
 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 262 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Fluoride, Sodium Fluoride, 

Hydrogen Fluoride, and Fluorine 

Agency Description Information Reference 

STATE (cont.)

 New Jersey Groundwater quality criteriaC

fluoride 

PQLCfluoride 

 New York Groundwater effluent limitationsC

fluoride 

MCLCfluoride 

 North Carolina Drinking water standardsC

fluoride 

 North Dakota MCLCfluoride 

 Oklahoma MCLCfluoride 

 Pennsylvania Drinking water standardsC

fluoride 

 Rhode Island MCLGCfluoride 

MCLCfluoride 

 South Dakota Groundwater quality standardsC

fluoride 

 Tennessee MCLCfluoride 

Texas MCLCfluoride 

Utah Groundwater standards 

MCLCfluoride 

Vermont Groundwater quality standardsC

fluoride 

 Enforcement standard 

Preventive action level 

MCLCfluoride 

 Washington MCLCfluoride 

West Virginia Groundwater standards 

 Wisconsin MCLGCfluoride 

MCLCfluoride 

Groundwater standardsCfluoride 

Enforcement standard 

Preventive action limit 

c. Food 

d. Other 

Connecticut Use of pesticides; control of 

registrations and usesCsodium 

fluoride 

2.0 mg/L BNA 2001 

0.5 mg/L 

3.0 mg/L BNA 2001 

2.2 mg/L BNA 2001 

4.0 mg/L HSDB 2003 

4.0 mg/L BNA 2001 

4.0 mg/L BNA 2001 

2.0 mg/L HSDB 2003 

4.0 ppm BNA 2001 

4.0 ppm 

2.4 mg/L BNA 2001 

4.0 ppm BNA 2001 

4.0 mg/L BNA 2001 

4.0 mg/L BNA 2001 

4.0 mg/L BNA 2001 

BNA 2001 

4.0 mg/L 

2.0 mg/L 

4.0 mg/L BNA 2001 

4.0 mg/L BNA 2001 

Not to exceed 4.0 mg/L BNA 2001 

4.0 mg/L BNA 2001 

4.0 mg/L 

BNA 2001 

4.0 mg/L 

0.8 mg/L 

No data 

For use as a wood BNA 2001 

preservative 
 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 263 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Fluoride, Sodium Fluoride, 

Hydrogen Fluoride, and Fluorine 

Agency Description Information Reference 

STATE (cont.)

 Minnesota Hazardous substanceCfluoride BNA 2001 

(as F, as dust), fluorides 

(inorganic), fluorine, and 

hydrogen fluorine 

 New Jersey Hazardous substanceCfluorine BNA 2001 

and hydrogen fluoride 

a

Group 3: not classifiable as to its carcinogenicity to humans

b

Temperature: annual average of maximum daily air temperatures (EF) c

A4: not classifiable as a human carcinogen 

AAC = acceptable ambient concentrations; ACGIH = American Conference of Governmental Industrial Hygienists; 

ASIL = acceptable source impact levels; BEI = biological exposure indices; BNA = Bureau of National Affairs; 

BPT = best practicable control technology; CFR = Code of Federal Regulations; CPSC = Consumer Product Safety
 

Commission; DOT = Department of Transportation; EL = emissions levels; EPA = Environmental Protection Agency; 

FDA = Food and Drug Administration; HAP = hazardous air pollutant; HSDB = Hazardous Substances Data Bank; 

IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life and health; 

IRIS = Integrated Risk Information System; MCL = maximum contaminant level; MCLG = maximum contaminant 

level goal; NIOSH = National Institute for Occupational Safety and Health; OEL = occupational exposure limit; 

OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit; PQL = practical 

quantitation level; REL = recommended exposure limit; RfD = reference dose; STEL = short term exposure limit; 

TLV = threshold limit values; TWA = time-weighted average; USC = United States Code; UTS = universal treatment 

standards; WHO = World Health Organization
 

 

 

 

_______________________ 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 265 

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*Whitford GM, Pashley DH, Reynolds KE. 1979a. Fluoride tissue distribution: Short-term kinetics. 

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parenteral administration in the rat. J Dent Res 56:858-861. 

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FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 351 

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. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 352 

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. 

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. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 353 

10. GLOSSARY 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

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. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 354 

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) which represents the best estimate of relative risk (risk as a ratio of the 

incidence among subjects exposed to a particular risk factor divided by the incidence among subjects who 

were not exposed to the risk factor). An odds ratio 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 science of quantitatively predicting the fate (disposition) of an exogenous 

substance in an organism. Utilizing computational techniques, it provides the means of studying the 

absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 355 

10. GLOSSARY 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical information 

such as air/blood partition coefficients, and metabolic parameters. PBPK models are also called 

biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3

 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentrations for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL-from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 356 

10. GLOSSARY 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed. 

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 study of 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. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVEL 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 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 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 a hundredfold 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, expert panel peer reviews, and agencywide 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, Agency for Toxic Substances and Disease 

Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333. 
 

 

 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Fluoride 

CAS Number: NA 

Date: December 1, 2003 

Profile Status: Final 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Key to Figure: 53 

Species: Humans 

Minimal Risk Level: 0.05 [X] mg/kg/day [ ] mg/m3 

Reference: Li Y, Liang C, Slemenda CW, et al. 2001. Effect of long-term exposure to fluoride in 

drinking water on risks of bone fractures. J Bone Miner Res 16:932-939. 

Experimental design (human study details or strain, number of animals per exposure/control groups, sex, 

dose administration details): Six communities in rural China with different levels of naturally occurring 

fluoride in the water were examined. The subjects were 50 years and older; the mean ages ranged from 

62.6 to 64.0 years. The majority of the subjects had been living in the same community since birth. 

There was a higher percentage of males in the highest fluoride group (52.4%) than in the other groups 

(41.8–47.0%). The water fluoride concentrations were 0.25–0.34, 0.58–0.73, 1.00–1.06, 1.45–2.19, 2.62– 

3.56, and 4.32–7.97 ppm. Three-day dietary surveys were collected for 10% of randomly selected 

subjects; estimated nutrition levels were adequate for all six populations. None of the subjects used 

fluoride-containing toothpaste or mouthwashes and there was a minimal use of packaged beverages and 

canned foods; fluoride levels in brewed tea samples were largely determined by the levels of fluoride in 

the water. The authors calculated total daily fluoride intakes of 0.7, 2, 3, 7, 8, and 14 mg/day. The 

subjects self-reported bone fractures. If the fracture received medical attention, then original x-rays were 

obtained; for other fractures, x-rays were taken to verify self-reported fractures. The reliability of the 

reported fracture was 99.1%. 

Effects noted in study and corresponding concentrations: Age, gender, alcohol consumption, and level of 

physical activity were significant factors for the risk of overall bone fractures since age 20 years; cigarette 

smoking and BMI did not significantly alter bone fracture prevalence. The trend for overall bone fracture 

prevalence (adjusted for age and gender) had a U-shaped pattern. As compared to the 1.00–1.06 ppm 

group, significantly higher prevalences of bone fracture were found in the lowest (0.25–0.34 ppm 

fluoride) and highest (4.32–7.97 ppm) groups. The prevalences were 7.41, 6.40, 5.11, 6.04, 6.09, and 

7.40%, respectively. When only hip fractures since age 20 were examined, significantly higher 

prevalences (adjusted for age and BMI) were found in the highest fluoride group, as compared to the 

1.00–1.06 ppm group. The prevalences of hip fractures were 0.37, 0.43, 0.37, 0.89, 0.76, and 1.20%, 

respectively. A similar pattern was observed when overall fractures since age 50 were examined; the 

prevalences were 4.33, 3.20, 3.28, 3.30, 3.62, and 4.80 (p=0.02), respectively. Only a small number of 

subjects reported spine fractures (49); none of the fluoride groups significantly differed from the 1.00– 

1.06 ppm group. 
 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE A-4 

APPENDIX A 

Concentration and end point used for MRL derivation: 

The MRL is based on a NOAEL of 0.15 mg fluoride/kg/day for increased fracture rate. 

[X] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL in a sensitive subpopulation 

[ ] 10 for extrapolation from animals to humans 

[X] 3 for human variability; a value less than 10 was used because the most sensitive 

population, elderly men and women, were examined. 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Yes. Doses were 

calculated using the reported daily fluoride intakes of 0.7, 2, 3, 7, 8, and 14 mg/day and a reference body 

weight of 55 kg. 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: NA 

Was a conversion used from intermittent to continuous exposure? NA 

Other additional studies or pertinent information that lend support to this MRL: A number of studies 

have examined the possible association between exposure to fluoridated water and the risk of increased 

bone fractures, in particular, hip fractures. In general, the studies involved comparing the incidence of hip 

fractures among residents aged 55 years and older living in a community with fluoridated water (around 

1 ppm) with the incidence in a comparable community with low levels of fluoride in the water. 

Inconsistent results have been found, with studies finding decreases (Lehmann et al. 1998; Phipps et al. 

2000; Simonen and Laittinen 1985), increases (Cooper et al. 1990, 1991; Danielson et al. 1992; Jacobsen 

et al. 1990, 1992; Kurttio et al. 1999), or no effect (Arnala et al. 1986; Cauley et al. 1995; Goggin et al. 

1965; Jacobsen et al. 1993; Karagas et al. 1996; Kröger et al 1994; Suarez-Almazor et al. 1993) on hip 

fracture risk. Studies by Li et al. (2001) and Sowers et al. (1986) have examined communities with 

higher levels of naturally occurring fluoride in the water. Both studies found increases in the incidence of 

hip fractures in residents exposed to 4 ppm fluoride and higher (Li et al. 2001; Sowers et al. 1986, 1991); 

the hip fracture incidence in the highly exposed community was compared to the rates in communities 

with approximately 1 ppm fluoride in the water. Significant increases in the occurrence of nonvertebral 

fractures were also observed in postmenopausal women ingesting sodium fluoride (34 mg 

fluoride/kg/day) for the treatment of osteoporosis (Riggs et al. 1990, 1994). This result was not found in 

another study of postmenopausal women with spinal osteoporosis treated with 34 mg fluoride/kg/day as 

sodium fluoride (Kleerekoper et al. 1991). A meta-analysis of these data, as well as other clinical studies, 

found a significant correlation between exposure to high levels of fluoride and an increased relative risk 

of nonvertebral fractures (Haguenauer et al. 2000). 

Agency Contact (Chemical Manager): Carolyn A. Tylenda, D.M.D., Ph.D., Dennis Jones, D.V.M.. 
 

 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE A-5 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Hydrogen Fluoride 

CAS Number: 7664-39-3 

Date: December 1, 2003 

Profile Status: Final 

Route: [X] Inhalation [ ] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Key to Figure: 6 

Species: Humans 

Minimal Risk Level: 0.02 [ ] mg/kg/day [X] ppm 

Reference: Lund K, Ekstrand J, Poe J, et al. 1997. Exposure to hydrogen fluoride: an experimental study 

in humans of concentrations of fluoride in plasma, symptoms, and lung function. Occup Environ Med 

54:32-37. 

Lund K, Refsnes M, Sandstrøm T, et al. 1999. Increased CD3 positive cells in bronchoalveolar lavage 

fluid after hydrogen fluoride inhalation. Scand J Work Environ Health 25:326-334. 

Experimental design (human study details or strain, number of animals per exposure/control groups, sex, 

dose administration details): Groups of 7-9 healthy, nonsmoking males (21–44 years of age) were 

exposed to 0.2-0.6, 0.7–2.4, or 2.5–5.2 mg/m3 hydrogen fluoride for 1 hour. For the last 15 minutes of the 

exposure, the subjects performed an ergometric test at a fixed work load of 75W. Bronchoalveolar lavage 

(BAL) was performed 3 weeks prior to exposure and 24 hours after exposure. Lung function tests were 

performed immediately before exposure, every 15 minutes during exposure, at exposure termination, 30 

minutes after exposure, and 1, 2, 3, and 4 hours after exposure. Symptom surveys were completed before 

exposure initiation, after 30 minutes of exposure, at exposure termination, and 4 and 24 hours after 

exposure. Eye, upper airway (nose and throat), and lower airway symptoms were scored based on a 5 

point scale with 5 being the most severe. 

The midpoint of the range of concentrations was used to calculate ppm levels: 0.4 mg hydrogen 

fluoride/m3 x 24.45/20 x 19/20 = 0.5 ppm fluoride; 1.7 mg/m3 = 1.9 ppm, 3.9 mg/m3 = 4.5 ppm 

Effects noted in study and corresponding concentrations: No significant exposure-related alterations in 

lung function (FEV1 or FVC) were observed and no significant correlations between plasma fluoride 

concentrations and FVC or FEV1 were found. Increases (as compared to scores prior to exposure) in 

upper airway symptom scores were observed in the low (p=0.06) and high (p=0.02) concentration groups 

and for all concentrations combined (p<0.001); similarly, total symptom scores were significantly 

(p<0.04) increased in the low and high concentration groups and all groups combined. The severity of the 

upper airway score was low (scores of 1–3) in the low exposure group. All subjects reported a change in 

the upper airway symptom score in the high concentration group; four subjects scored the symptoms as 

low and three scored them as high. A significant increase in eye symptom score was also observed in all 

groups combined, but not for individual exposure level groups. The effect of hydrogen fluoride exposure 

was assessed by comparing the before and after exposure BAL fluid. Significant increases in the 

percentage of CD3-positive cells were found in the bronchial portion of the mid- and high-dose group and 

in the bronchoalveolar portion of the high-dose group. A significant increase in the percentage of 

lymphocytes in the bronchial and bronchoalveolar portions in the mid-concentration group was observed. 

A significant correlation between the individual changes in the percentage of CD3-positive cells and the 
 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE A-6 

APPENDIX A 

changes in the percentage of lymphocytes from the bronchoalveolar portion was also observed. 

Significant increases in myeloperoxidase and interkeukin-6 levels were found in the high dose group. 

Concentration and end point used for MRL derivation: The MRL is based on a minimal LOAEL of 

0.5 ppm fluoride as hydrogen fluoride for upper respiratory tract irritation. 

[ ] NOAEL [X] LOAEL 

Uncertainty Factors used in MRL derivation: 

[X] 3 for use of a minimal LOAEL 

[ ] 3 for extrapolation from animals to humans with dosimetric adjustments 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: 

Was a conversion used from intermittent to continuous exposure? No. Data on nasal irritation from the 

Largent (1960) report, the Lund et al. (2002) study, and the intermediate-duration study by Largent (1960) 

provide suggestive evidence that the severity of nasal irritation does not increase with increasing exposure 

duration. These three studies identified similar LOAEL values for different exposure durations: 

3.22 ppm 6 hours/day for 10 days (Largent 1960), 3.8 ppm 1 hour/day for 1 day (Lund et al. 2002), and 

2.98 ppm 6 hours/day, 6 days/week for 15–50 days. Thus, time scaling was not used to derive the acute 

MRL. 

Other additional studies or pertinent information that lend support to this MRL: The respiratory tract 

appears to be the primary target of hydrogen fluoride toxicity. Upper respiratory tract irritation and 

inflammation and lower respiratory tract inflammation have been observed in several human studies. 

Nasal irritation was reported by one subject exposed to 3.22 ppm fluoride as hydrogen fluoride 

6 hours/day for 10 days (Largent 1960). Very mild to moderate upper respiratory symptoms were 

reported by healthy men exposed to 0.5 ppm fluoride as hydrogen fluoride for 1 hour (Lund et al. 1997). 

At higher concentrations, 4.2–4.5 ppm fluoride as hydrogen fluoride for 1 hour, more severe symptoms of 

upper respiratory irritation were noted (Lund et al. 1997, 2002). In subjects exposed to 4.2 ppm for 

1 hour, analysis of nasal lavage fluid provided suggestive evidence that hydrogen fluoride induces an 

inflammatory response in the nasal cavity (Lund et al. 2002). Similarly, bronchoalveolar lavage fluid 

analysis revealed suggestive evidence of bronchial inflammation in another study of subjects exposed to 

1.9 ppm fluoride as hydrogen fluoride for 1 hour (Lund et al. 1999); no alterations were observed at 

0.5 ppm. Respiratory effects have also been reported in rats acutely exposed to hydrogen fluoride. Mild 

nasal irritation was observed during 60-minute exposure to 120 ppm fluoride (Rosenholtz et al. 1963), 

and respiratory distress was observed at 2,310, 1,339, 1,308, and 465 ppm fluoride for 5, 15, 30, or 

60 minutes, respectively (Rosenholtz et al. 1963). Midtracheal necrosis was reported in rats exposed to 

902 or 1,509 ppm fluoride as hydrogen fluoride for 2 or 10 minutes using a mouth breathing model with a 

tracheal cannula (Dalbey et al. 1998a, 1998b). These effects were not observed when the tracheal cannula 

was not used. 

The Lund et al. (1997, 1999) study was selected as the basis of the acute-duration inhalation MRL for 

hydrogen fluoride. As reported in the 1997 publication, a trend (p=0.06) toward increased upper 

respiratory tract symptom score, as compared to pre-exposure symptom scores, was observed at the 

lowest concentration tested (0.5 ppm). A significant increase in the total symptom score was also 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE A-7 

APPENDIX A 

observed at this concentration. No significant alterations in symptom scores were observed at the mid 

concentration (1.9 ppm), and increases in upper respiratory and total symptom scores were observed at 

the high concentration (4.5 ppm). Suggestive evidence of bronchial inflammation was also observed at 

≥1.9 ppm fluoride (Lund et al. 1999), although no alterations in lower respiratory tract symptoms (Lund 

et al. 1997) or lung function (Lund et al. 1997) were observed at any of the tested concentrations. 

Agency Contact (Chemical Manager): Carolyn A. Tylenda, D.M.D., Ph.D., Dennis Jones, D.V.M. 
 

 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE A-8 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Fluorine 

CAS Number: 7782-41-4 

Date: December 1, 2003 

Profile Status: Final 

Route: [X] Inhalation [ ] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Key to Figure: 6 

Species: Humans 

Minimal Risk Level: 0.01 [ ] mg/kg/day [X] ppm 

Reference: Keplinger ML, Suissa LW. 1968. Toxicity of fluorine short-term inhalation. Am Ind Hyg 

Assoc J 29(1):10-18. 

Experimental design (human study details or strain, number of animals per exposure/control groups, sex, 

dose administration details): Five volunteers (aged 19–50 years; gender not specified) were exposed to 

various concentrations of fluorine: 10 ppm for 3, 5, or 15 minutes; 23 ppm for 5 minutes, 50 ppm for 

3 minutes, 67 ppm for 1 minute, 78 ppm for 1 minute, and 100 ppm for 0.5 or 1 minute. The fluorine was 

administered via a mask that covered the eyes and nose; the subjects could remove the mask from their 

face and could breathe fresh air via their mouth. No information was provided on the amount of time 

between exposures or whether all subjects were exposed to all concentrations. 

Effects noted in study and corresponding concentrations: No nasal or eye irritation was noted by subjects 

exposed to 10 ppm for 3, 5, or 15 minutes; it was also noted that the 15-minute exposure did not result in 

respiratory tract irritation. Eye irritation was observed at ≥23 ppm; nose irritation at ≥50 ppm, and skin 

irritation at ≥78 ppm. The severity of the irritation was concentration related. Exposure to 100 ppm was 

considered very irritating and the subjects did not inhale during the exposure period. No incidence data 

were reported. 

Concentration and end point used for MRL derivation: The MRL is based on a NOAEL of 10 ppm and 

LOAEL of 23 ppm fluorine for irritation in humans. 

[X] NOAEL [] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[ ] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: NA 
 

 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE A-9 

APPENDIX A 

Was a conversion used from intermittent to continuous exposure? Yes. The 15-minute exposure duration 

was adjusted for a continuous 24-hour exposure using the following equation: 

10 ppm x 0.25 hours/24 hours = 0.1 ppm 

The study authors noted that exposure to 10 ppm for 3–5 minutes every 15 minutes over a 2- or 3-day 

period resulted slight irritation to the eyes and skin, but no other subjective effects (no additional details 

on this study were provided). These data are suggestive that the toxicity of fluorine may be dependent on 

concentration and duration of exposure. Thus, it is appropriate to adjust for continuous exposure. 

Other additional studies or pertinent information that lend support to this MRL: Respiratory effects have 

also been observed in, rats, mice, guinea pigs, rabbits, and dogs exposed to fluorine for 1–60 minutes 

(Keplinger and Suissa 1968). The observed effects include diffuse lung congestion, dyspnea, irritation, 

and alveolar necrosis and hemorrhage. The severity of the lung congestion was concentration-related and 

no species differences were found. 

Agency Contact (Chemical Manager): Carolyn A. Tylenda, D.M.D., Ph.D., Dennis Jones, D.V.M. 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE A-10 

APPENDIX A 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 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. 
 

 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE B-2 

APPENDIX B 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) Tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 

LEGEND 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE B-3 

APPENDIX B 

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 exists, 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 Table 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 

regimen 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 1,1,2,2-tetrachloroethane via 

inhalation for 6 hours/day, 5 days/week, for 3 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"). 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 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 intermediate and chronic 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 38r 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. 

(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*). 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE B-5 

APPENDIX B 

(19) Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
1 3 4 

SAMPLE 

→ TABLE 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

LOAEL (effect) Exposure Less serious Serious (ppm) frequency/ NOAEL (ppm) Key to figurea Species duration System (ppm) Re

2 → INTERMEDIATE EXPOSURE 

5 6 7 8 9 10 

→ Systemic ↓ ↓ ↓ ↓ ↓ 

→

18 Rat 13 wk 

5 d/wk 6 hr/d 

Resp 3b 10 (hyperplasia) 

N

CHRONIC EXPOSURE Cancer 11 

↓

38 Rat 18 mo 

5 d/wk 7 hr/d 

20 (CEL, multiple 

organs) 

W

39 Rat 89-104 

5 d/wk 6 hr/d 

wk 10 (CEL, lung tumors, 

nasal tumors) 

NT

40 Mouse 79-103 

5 d/wk 

wk 10 (CEL, lung tumors, 

hemangiosarcomas) 

NT

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 e

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 


FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 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 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE C-2 

APPENDIX C 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/International Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

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 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE 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 

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 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE C-4 

APPENDIX C 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE C-5 

APPENDIX C 

> ≥

= 

< ≤

% αβγδ

μm

μg q1

* 

– 

+ 

(+) 

(–) 

greater than 

greater than or equal to 

equal to 

less than 

less than or equal to 

percent 

alpha 

beta 

 gamma 

delta 

 micrometer 

microgram 

cancer slope factor 

negative 

positive 

weakly positive result 

weakly negative result 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE D-1 

APPENDIX D. FLUORIDE AND DENTAL CARIES 

Dental caries or tooth decay is a progressively destructive disease of the tooth caused by cariogenic 

bacteria. These bacteria, which reside in dental plaque, colonize on tooth surfaces and produce 

polysaccharides that enhance adherence of the plaque to the tooth enamel. Once plaque is formed, the 

bacteria on the teeth produce an enzyme that promotes erosion of the enamel by converting sugars and 

other fermentable carbohydrates into acids. The acids dissolve the minerals (calcium and phosphorus) in 

the tooth enamel in a process known as demineralization (DHHS 2001b). 

Several studies conducted by Dean and associates in the 1930s and 1940s demonstrated a relationship 

between the levels of naturally-occurring fluoride in drinking water and the prevalence of dental caries 

(Dean 1938; Dean et al. 1939, 1941, 1942). Children living in communities with high levels of fluoride 

in the drinking water had lower occurrences of dental caries. This relationship between fluoride and 

dental caries prompted the city of Grand Rapids, Michigan to implement a water fluoridation program in 

1945. Studies conducted in some of the earliest cities to adopt a fluoridation program reported dramatic 

decreases in the occurrence of dental caries (Ast et al. 1951; Dean et al. 1950; Hill et al. 1951; Hutton et 

al. 1951). The prevalence of dental caries in children living in communities with fluoridated water was 

50–70% lower than in children living in areas without fluoridated water. Surveys conducted after the late 

1980s found smaller differences; the occurrence of dental caries was 9–25% lower in communities with 

fluoridated water as compared to communities without fluoridated water (Brunelle and Carlos 1990; 

DeLiefde 1998; Eklund et al. 1987; Englander and DePaola 1979; Jackson et al. 1995; Selwitz et al. 

1995). In one study, no significant differences in the occurrence of dental caries was found in schoolaged children 5–17 years old (Yiamouyiannis 1990); however, when just 5 year olds were examined, the 

incidence of dental caries was 42% lower in children with lifetime exposure to fluoridated water and 24% 

lower in children exposed to fluoridated water for only a portion of their lifetime. Several studies have 

also examined the impact of termination of a water fluoridation program on the incidence of dental caries. 

Conflicting results have been reported. Some studies found increases in dental caries occurrence 

(Attwood and Blinkhorn 1991; Stephen et al. 1987; Thomas et al. 1995), some found no change in the 

occurrence of dental caries (Burt et al. 2000; Kalsbeek et al. 1993; Künzel and Fischer 1997; Seppä et al. 

2000; Stephen et al. 1987), and other studies found decreases in dental caries occurrence (Künzel and 

Fischer 2000; Künzel et al. 2000; Maupomé et al. 2001). A meta-analysis of 26 studies examined the 

relationship between water fluoridation and prevalence of dental caries or the change in decayed, missing, 

and filled teeth (DMFT) (McDonagh et al. 2000). In 19 of the 30 analyses conducted, a significant 

increase in the prevalence of children without dental caries was found in the fluoridated areas compared 
FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE D-2 

APPENDIX D 

to non-fluoridated areas. Additionally, 15 of the 16 analyses found a significant increase in the mean 

change in DMFT in fluoridated water areas (levels of DMFT declined in response to fluoridation). 

The decline or stabilization of the occurrence of dental caries in the absence of water fluoridation has 

been attributed to a number of factors (Horowitz 1996), including diffusion of effects of fluoridated 

drinking water, dilution effects from other sources of fluoride on the measurement of effectiveness of 

community water fluoridation, and improved dental care. The diffusion effect occurs when residents of 

communities without fluoridated water consume products manufactured or bottled in areas with 

fluoridated water (thus fluoride enters the foodstuff) or attend schools in areas with fluoridated water. An 

often cited example of the diffusion effect is the 1986–1987 NIDR survey of dental health status of U.S. 

school children (Brunelle and Carlos 1990). In the Pacific region, which has a low percentage of 

communities with fluoridated water (19%), children living in area with nonfluoridated water have 61% 

higher dental caries score as compared to children living in areas with fluoridated water. In contrast, in 

the Midwest region with a high percentage of communities with fluoridated water (74%), there is no 

difference in dental caries scores between fluoridated and nonfluoridated areas. The dilution effect is due 

to the development and use of other fluoride agents, including fluoride supplements, fluoride solutions, 

gels, and varnishes used by dental professionals, fluoridated toothpaste, and fluoride mouthwash. The use 

of the fluoride products that provide protection from dental decay diminishes the difference in the levels 

of dental decay between fluoridated and nonfluoridated communities (Ripa 1993). 

The primary mechanism by which fluoride prevents the occurrence of dental caries is through its 

influence on the demineralization and remineralization process (Featherstone 1999; Koulourides 1990; 

Ten Cate 1999). The acid produced from the metabolism of sugars and fermentable carbohydrates by 

cariogenic bacteria in plaque begins to dissolve or demineralize the enamel crystal surface of the tooth 

resulting in the loss of calcium, phosphate, and carbonate from the tooth enamel. The increased acid 

production results in a decrease in plaque pH and the release of fluoride from the dental plaque. This 

fluoride, along with calcium and phosphate, is incorporated into the apatite molecule to form 

fluor(hydroxyl)apatite. In the presence of fluoride, cycles of partial demineralization and then 

remineralization will create apatite, which has less carbonate, more fluoride, and is less soluble. 

Fluor(hydroxyl)apatite, which has high levels of fluoride and low levels of carbonate, is more acid 

resistant (Chow 1990; Ericsson 1977; Featherstone 1999; Kidd et al. 1980; Ten Cate 1999; Thylstrup 

1990; Thylstrup et al. 1979). When the beneficial effects of fluoride on caries prevention was first 

discovered, it was believed that the incorporation of the fluoride into developing enamel resulted in 

improved enamel and dental caries prevention (Dean et al. 1935; McClure and Likins 1951). However, 
 

 

FLUORIDES, HYDROGEN FLUORIDE, AND FLUORINE D-3 

APPENDIX D 

more recent data suggest that fluoride works primarily after teeth have erupted (Clarkson et al. 1996). In 

a fluoride-rich environment, demineralization and remineralization cycling, which occurs throughout the 

lifetime of the tooth, will result in teeth that are more resistant to cariogenic bacterial damage. Another 

mechanism in which fluoride prevents dental caries is via a direct effect on cariogenic bacterial 

metabolism. There are in vitro data that demonstrate that fluoride can inhibit bacterial metabolism of 

carbohydrates, which results in a decreased production of acids (Bowden 1990; Bowden et al. 1982; 

Marquis 1990; Rosen et al. 1978). However, it is likely that this would occur at fluoride levels that far 

exceed those present in the mouth (Geddes and Bowen 1990). 

Based on this relationship between fluoride and dental caries prevention, the Institute of Medicine (IOM 

1997) and the World Health Organization (WHO 2002) consider fluoride to be an essential dietary 

element. The Institute of Medicine has derived adequate intake levels (AIs) ranging from 0.01 to 

4 mg/day (IOM 1997). The AIs for each age group are presented below: 

Age Range Adequate Intake Level (mg/day) 

0–6 months 0.01 

6–12 months 0.5 

1–3 years 0.7 

4–8 years 1 

9–13 years (males and females) 2 

14–18 years (males and females) 3 

>18 years (males) 4 

>18 years (females) 3 

Expert panels convened by the U.S. Department of Health and Human Services (DHHS 1991, 2000, 

2001b) and the World Health Organization (WHO 1994) support optimal fluoridation of drinking water. 

A work group assembled by the Centers for Disease Control and Prevention (DHHS 2001b) made the 

following recommendation: 

“Because frequent exposure to small amounts of fluoride each day will best reduce the risk for 

dental caries in all age groups, the work group recommends that all persons drink water with an 

optimal fluoride concentration and brush their teeth twice daily with fluoride toothpaste. For 

persons at high risk of dental caries, additional fluoride measures might be needed. Measured use 

of fluoride modalities is particularly appropriate during the time of anterior tooth enamel 

development (i.e., age <6 years).”